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Hypertension and Hypertensive Vascular Disease
Updated: 08/26/2004


Dietary calcium and blood pressure: a meta-analysis of randomized clinical trials.

Allender PS, Cutler JA, Follmann D, et al.

Ann Intern Med. 1996 May 1; 124(9):825-31.

PURPOSE: To assess the effect of dietary calcium supplementation on blood pressure. DATA SOURCES: Published reports of trials studying the effect of dietary calcium supplementation on blood pressure were identified by a search of previous reviews, a MEDLINE search, a manual review of journal articles, and a review of abstracts from scientific meetings. STUDY SELECTION: Randomized clinical trials in which dietary calcium intake varied by intervention group were selected. Multifactorial trials were not included. DATA SYNTHESIS: Data from 28 active treatment arms or strata from 22 randomized clinical trials were pooled using a weighted average method, with weights proportional to the inverse of the variance of the treatment effect. The total sample comprised 1231 persons. Because trials of both normotensive and hypertensive persons were included, subgroup analyses could be done. Pooled estimates of the effect of calcium supplementation on blood pressure were -0.18 mm Hg for diastolic blood pressure (95% CI, -0.75 to 0.40 mm Hg) and -0.89 mm Hg for systolic blood pressure (CI, -1.74 to -0.05 mm Hg). Pooled estimates for systolic blood pressure were -0.53 mm Hg (CI, -1.56 to 0.49 mm Hg) for trials of normotensive persons and -1.68 mm Hg (CI, -3.18 to -0.18 mm Hg) for trials of hypertensive persons. Diastolic blood pressure was not significantly affected in either subgroup. CONCLUSION: The pooled estimate shows a statistically significant decrease of systolic blood pressure with calcium supplementation, both for hypertensive persons and for the overall sample. However, the effect is too small to support the use of calcium supplementation for preventing or treating hypertension

A clinical trial of the effects of dietary patterns on blood pressure.

Appel LF, DASH Collaborative Research Group.

N Engl J Med. 1997;(336):1117.


Diet supplementation with fish oils and blood pressure reduction: a metabolism-analysis.


Ann Intern Med. 1994;120-9.

Does supplementation of diet with 'fish oil' reduce blood pressure? A meta-analysis of controlled clinical trials.

Appel LJ, Miller ER, III, Seidler AJ, et al.

Arch Intern Med. 1993 Jun 28; 153(12):1429-38.

BACKGROUND: Several lines of evidence suggest that supplementation of diet with omega-3 polyunsaturated fatty acids (omega-3 PUFA), commonly referred to as fish oils, may reduce blood pressure (BP). However, most clinical trials of omega-3 PUFA supplementation have been of insufficient size to detect relevant BP changes. METHODS: We conducted a meta-analysis of 17 controlled clinical trials of omega-3 PUFA supplementation. To estimate an overall effect of omega-3 PUFA supplementation on BP, we calculated the net BP change in each trial (BP delta in omega-3 PUFA group minus BP delta in control group), which was then weighted according to the inverse of the variance. RESULTS: In the 11 trials that enrolled normotensive individuals (n = 728), omega-3 PUFA supplementation led to significant reductions of systolic BP (SBP) and diastolic BP (DBP) in two and one trials, respectively. In the six studies that enrolled untreated hypertensives (n = 291), significant reductions of SBP and DBP were present in two and four trials, respectively. Weighted, pooled estimates of SBP and DBP change (mm Hg) with 95% confidence intervals were -1.0 (-2.0 to 0.0) and -0.5 (-1.2 to +0.2) in the trials of normotensives, and -5.5 (-8.1 to -2.9) and -3.5 (-5.0 to -2.1) in the trials of untreated hypertensives. In 13 of 17 studies, trial duration was less than 3 months. Doses of omega-3 PUFA tended to be high (average dose > 3 g/d in 11 trials). The magnitude of BP reduction was greatest at high BP but was not significantly associated with dose of omega-3 PUFA. Side effects, most commonly eructation and a fishy taste, occurred more frequently in omega-3 PUFA participants than in control participants (28% vs 13%, P < .001). CONCLUSIONS: Our analyses indicate that diet supplementation with a relatively high dose of omega-3 PUFA, generally more than 3 g/d, can lead to clinically relevant BP reductions in individuals with untreated hypertension. However, use of omega-3 PUFA as antihypertensive therapy will require demonstration of long-term efficacy and patient acceptability of lower doses

Gamma-linolenic acid dietary supplementation can reverse the aging influence on rat liver microsome delta 6-desaturase activity.

Biagi PL, Bordoni A, Hrelia S, et al.

Biochim Biophys Acta. 1991 May 8; 1083(2):187-92.

We have recently demonstrated that in rats the process of delta 6-desaturation of linoleic and alpha-linolenic acids slows with aging. One method of counteracting the effect of slowed desaturation of linoleic acid would be to provide the 6-desaturated metabolite, gamma-linolenic acid (18:3(n-6) GLA) directly. We have here investigated the 6-desaturation of both linoleic and alpha-linolenic acids in liver microsomes of young and old rats given GLA in the form of evening primrose oil (EPO) (B diet) in comparison to animals given soy bean oil alone (A diet), monitoring also the fatty acid composition of liver microsomes and relating this to the microviscosity of the membranes. In young rats the different experimental diets did not produce any difference in delta 6-desaturase (D6D) activity on either substrate suggesting that, when D6D activity is at or near its peak, the variations in diet tested are unable to influence it. In the old animals the rate of 6-desaturation of linoleic and particularly of alpha-linolenic acid was significantly greater in the B diet fed animals than in the A diet fed. The effects of the diets on the fatty acid composition of liver microsomes were consistent with the findings with regard to 6-desaturation. Administration of GLA partially corrected the abnormalities of n-6 essential fatty acid (EFA) metabolism by raising the concentration of 20:4(n-6) and other 6-desaturated EFAs. Furthermore, the GLA rich diet also increased the levels of dihomo-gamma-linolenic acid and of 6-desaturated n-3 EFAs in the liver microsomes. The microviscosity of microsomal membranes as indicated by DPH polarization was correlated with the unsaturation index of the same membranes. There was a very strong correlation between the two. In both young and old rats the B diet reduced the microviscosity and increased the unsaturation index. However, the effect was much greater in the old animals

Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia or hypercholesterolemia.

Boger RH, Bode-Boger SM, Sydow K, et al.

Arterioscler Thromb Vasc Biol. 2000 Jun; 20(6):1557-64.

Hyperhomocyst(e)inemia is associated with endothelial dysfunction. Mechanisms responsible for endothelial dysfunction in hyperhomocyst(e)inemia may involve impaired bioavailability of endothelium-dependent nitric oxide. We tested the hypothesis that hyperhomocyst(e)inemia is associated with an elevated plasma concentration of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. One group of adult cynomolgus monkeys was fed either a control or hyperhomocyst(e)inemic diet for 4 weeks in a randomized crossover design. The second group was fed an atherogenic diet that produces both hyperhomocyst(e)inemia and hypercholesterolemia for 17 months, followed by an atherogenic diet supplemented with B vitamins for 6 months to decrease plasma homocyst(e)ine concentration. Human endothelial cells were used to study the effects of methionine and homocysteine in the presence or absence of B vitamins or the methylation inhibitor S-adenosylhomocysteine on the formation of ADMA and its inactive stereoisomer, symmetric dimethylarginine. The hyperhomocyst(e)inemic diet produced 2- to 3-fold increases in plasma levels of homocyst(e)ine and ADMA (both P<0.05). The atherogenic diet also produced elevated plasma levels of homocyst(e)ine and ADMA (both P<0. 05). Supplementation of the atherogenic diet with B vitamins decreased the plasma levels of homocyst(e)ine but did not affect the plasma levels of ADMA or endothelial function. There was a strong correlation between plasma ADMA and homocyst(e)ine and a strong inverse correlation between ADMA and carotid artery relaxation to acetylcholine. ADMA release by cultured endothelial cells was significantly increased in the presence of methionine or homocysteine. This effect was blocked by S-adenosylhomocysteine but not by B vitamins. We conclude that plasma levels of ADMA are elevated in hyperhomocyst(e)inemia. Because ADMA acts as a competitive inhibitor of endothelial nitric oxide synthase, these findings suggest a novel mechanism for impaired endothelial function in hyperhomocyst(e)inemia

Evidence for age-related differences in the fatty acid composition of human adipose tissue, independent of diet.

Bolton-Smith C, Woodward M, Tavendale R.

Eur J Clin Nutr. 1997 Sep; 51(9):619-24.

OBJECTIVE: To test the null-hypothesis that no age difference in adipose tissue fatty acid composition exists independent of dietary fat intake. DESIGN: A cross-sectional survey of coronary heart disease risk factors, the Scottish Heart Health Study, provided needle biopsy adipose tissue fatty acid data and food frequency-derived dietary data. SETTING: Twenty-two Scottish Districts between 1984 and 1986. SUBJECTS: A total of 10,359 men and women aged 40-59 y were randomly recruited in sex and five-year age bands from GP lists. A sub-set of 2308 men and 2049 women (42%) provided satisfactory adipose tissue and dietary data. MAIN OUTCOME AND MEASURES: Multiple regression analysis (adjusting for dietary fats, body mass index and smoking, with and without menopause status for women) of the relationship between individual fatty acids in adipose tissue and age, and between age and the ratio of linoleic acid (C18:2, n-6) to gamma-linolenic acid (C18:3, n-6) as an indicator of delta-6 desaturase activity. RESULTS: Sex-consistent changes with age occurred for linoleate (adjusted regression slope +/- s.e. for men -0.299 +/- 0.1339 and for women -0.504 +/- 0.1731) and gamma-linolenate (adjusted regression slope +/- s.e. for men -0.141 +/- 0.0341 and for women -0.154 +/- 0.0469) both P < 0.0001. These changes gave rise to a significant increase (P < or = "0.005)" in the C18:2, n-6 to C18:3, n-6 ratio with age). Dihomo-gamma-linolenic acid (C20:3, n-6) and docosahexa- plus docosapentaenoic acids (C22:5 + C22:6, n-3) also increased significantly with age (P < or = "0.01)." For the latter, the adjusted regression slopes were far greater for women (0.596 +/- 0.0575) than men (0.131 +/- 0.0417). CONCLUSIONS: The results show that ageing does influence adipose tissue fatty acid composition independent of diet. The sex differences may partially be due to inadequate adjustment for changes in sex hormone status in males with ageing. Using the current indicator, a decline in the rate limiting step of beta-6 desaturation appeared to occur with age, and was greater in women than in men. These results may indicate that an increase in dietary gamma-linolenic acid (C18:3, n-6) is necessary with age to offset the relative imbalance between PUFA levels which appears to occur. However, any direct health benefit regarding the common diseases of ageing from such a strategy still remain to be clarified

The relation between insulin sensitivity and the fatty-acid composition of skeletal-muscle phospholipids.

Borkman M, Storlien LH, Pan DA, et al.

N Engl J Med. 1993 Jan 28; 328(4):238-44.

BACKGROUND. Insulin resistance and hyperinsulinemia are features of obesity, non-insulin-dependent diabetes mellitus, and other disorders. Skeletal muscle is a major site of insulin action, and insulin sensitivity may be related to the fatty-acid composition of the phospholipids within the muscle membranes involved in the action of insulin. METHODS. We determined the relation between the fatty-acid composition of skeletal-muscle phospholipids and insulin sensitivity in two groups of subjects. In one study, we obtained samples of the rectus abdominis muscle from 27 patients undergoing coronary artery surgery; fasting serum insulin levels provided an index of insulin sensitivity. In the second study, a biopsy of the vastus lateralis muscle was performed in 13 normal men, and insulin sensitivity was assessed by euglycemic-clamp studies. RESULTS. In the patients undergoing surgery, the fasting serum insulin concentration (a measure of insulin resistance) was negatively correlated with the percentage of individual long-chain polyunsaturated fatty acids in the phospholipid fraction of muscle, particularly arachidonic acid (r = -0.63, P < 0.001); the total percentage of C20-22 polyunsaturated fatty acids (r = "-0.68," P < 0.001); the average degree of fatty-acid unsaturation (r = "-0.61," P < 0.001); and the ratio of the percentage of C20:4 n-6 fatty acids to the percentage of C20:3 n-6 fatty acids (r = "-0.55," P < 0.01), an index of fatty-acid desaturase activity. In the normal men, insulin sensitivity was positively correlated with the percentage of arachidonic acid in muscle (r = "0.76," P < 0.01), the total percentage of C20-22 polyunsaturated fatty acids (r = "0.76," P < 0.01), the average degree of fatty-acid unsaturation (r = "0.62," P < 0.05), and the ratio of C20:4 n-6 to C20:3 n-6 (rho = "0.76," P = "0.007)." CONCLUSIONS. Decreased insulin sensitivity is associated with decreased concentrations of polyunsaturated fatty acids in skeletal-muscle phospholipids, raising the possibility that changes in the fatty-acid composition of muscles modulate the action of insulin

Hyperhomocysteinemia in stroke-prevalence cause, and relationship to type of stroke and stroke risk factors.

Brattstrom L.

Eur J Clin Invest. 1992;(22):214-21.

The Healing Nutrients Within 1987.

Braverman EPC.



Dietary modulation of endothelial function: implications for cardiovascular disease.

Brown AA, Hu FB.

Am J Clin Nutr. 2001 Apr; 73(4):673-86.

The vascular endothelium is the primary site of dysfunction in many diseases, particularly cardiovascular disease. A variety of risk factors, including smoking, hypercholesterolemia, hyperhomocysteinemia, hypertension, and diabetes mellitus, adversely affect endothelial function. Emerging evidence suggests an important role of dietary factors in modulating endothelial function. In particular, n-3 fatty acids, antioxidant vitamins (especially vitamins E and C), folic acid, and L-arginine appear to have beneficial effects on vascular endothelial function, either by decreasing endothelial activation or by improving endothelium-dependent vasodilation in patients at high risk of cardiovascular disease as well as in healthy subjects. These effects may serve as one potential mechanism through which these nutrients reduce the risk of cardiovascular disease, as observed in epidemiologic studies and several clinical trials. This article reviews clinical and experimental evidence regarding the role of these nutrients in modulating endothelial function and their potential to prevent cardiovascular disease

Activation of L-arginine transport in peripheral blood mononuclear cells in chronic renal failure.

Brunini TM, Roberts NB, Yaqoob MM, et al.

Pflugers Arch. 2002 Oct; 445(1):147-51.

Transport of LL-arginine, the precursor for nitric oxide (NO) synthesis, has been investigated in human peripheral blood mononuclear cells (PBMCs) obtained from healthy volunteers and chronic renal failure patients. Chronic renal failure patients were either on treatment by haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Saturable influx of L-arginine in PBMCs was mediated by the cationic amino acid transport systems y(+) and y(+)L. Initial rates of L-arginine transport (2 microM) via system y(+) were significantly increased in chronic renal failure patients, whereas transport via system y(+)L was unaffected. The increase in L-arginine transport via system y(+) was: 1.7-fold in uraemic patients on CAPD, 4.3-fold in uraemic patients pre-haemodialysis and 2.6-fold post-haemodialysis. When the intracellular PBMCs amino acid profile was analysed in chronic renal failure patients and control subjects, L-lysine and L-arginine concentrations were significantly increased in pre-haemodialysis uraemic patients and restored to normal values by haemodialysis and CAPD. The present study provides the first evidence that system y(+) mediates the increased transport of L-arginine in PBMCs from patients with chronic renal failure. The increased activity of system y(+) may provide the necessary supply of L-arginine to sustain NO synthesis in PBMCs exposed to increased levels of circulating cytokines in chronic renal failure

N-3 polyunsaturated fatty acids in coronary heart disease: a meta-analysis of randomized controlled trials.

Bucher HC, Hengstler P, Schindler C, et al.

Am J Med. 2002 Mar; 112(4):298-304.

PURPOSE: Observational studies have shown an inconsistent association between n-3 polyunsaturated fatty acids and the risk of coronary heart disease. We investigated the effects of dietary and non-dietary (supplemental) intake of n-3 polyunsaturated fatty acids on coronary heart disease. SUBJECTS AND METHODS: We searched the literature to identify randomized controlled trials that compared dietary or non-dietary intake of n-3 polyunsaturated fatty acids with a control diet or placebo in patients with coronary heart disease. Studies had to have at least 6 months of follow-up data, and to have reported clinical endpoint data. We identified 11 trials, published between 1966 and 1999, which included 7951 patients in the intervention and 7855 patients in the control groups. RESULTS: The risk ratio of nonfatal myocardial infarction in patients who were on n-3 polyunsaturated fatty acid-enriched diets compared with control diets or placebo was 0.8 (95% confidence interval [CI]: 0.5 to 1.2, P = 0.16; Breslow-Day test for heterogeneity, P = 0.01), and the risk ratio of fatal myocardial infarction was 0.7 (95% CI: 0.6 to 0.8, P 0.20). In 5 trials, sudden death was associated with a risk ratio of 0.7 (95% CI: 0.6 to 0.9, P 0.20), whereas the risk ratio of overall mortality was 0.8 (95% CI: 0.7 to 0.9, P 0.20). There was no difference in summary estimates between dietary and non-dietary interventions of n-3 polyunsaturated fatty acids for all endpoints. CONCLUSION: This meta-analysis suggests that dietary and non-dietary intake of n-3 polyunsaturated fatty acids reduces overall mortality, mortality due to myocardial infarction, and sudden death in patients with coronary heart disease

Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension.

Burke BE, Neuenschwander R, Olson RD.

South Med J. 2001 Nov; 94(11):1112-7.

BACKGROUND: Increasing numbers of the adult population are using alternative or complementary health resources in the treatment of chronic medical conditions. Systemic hypertension affects more than 50 million adults and is one of the most common risk factors for cardiovascular morbidity and mortality. This study evaluates the antihypertensive effectiveness of oral coenzyme Q10 (CoQ), an over-the-counter nutritional supplement, in a cohort of 46 men and 37 women with isolated systolic hypertension. METHODS: We conducted a 12-week randomized, double-blind, placebo-controlled trial with twice daily administration of 60 mg of oral CoQ and determination of plasma CoQ levels before and after the 12 weeks of treatment. RESULTS: The mean reduction in systolic blood pressure of the CoQ-treated group was 17.8 +/- 7.3 mm Hg (mean +/- SEM). None of the patients exhibited orthostatic blood pressure changes. CONCLUSIONS: Our results suggest CoQ may be safely offered to hypertensive patients as an alternative treatment option


Calvert J.

Clinics in Family Practice. 2001;(3):733-56.


Effect of L-arginine on systemic and renal haemodynamics in salt-sensitive patients with essential hypertension.

Campese VM, Amar M, Anjali C, et al.

J Hum Hypertens. 1997 Aug; 11(8):527-32.

In response to a high sodium (Na+) intake, salt-sensitive patients with hypertension retain more Na+ and manifest a greater rise in arterial pressure than salt-resistant patients. Because there is limited information regarding the role of nitric oxide (NO) in salt-sensitivity we examined the effects of L-arginine (500 mg/kg, i.v. for 30 min) on mean arterial pressure and renal haemodynamics in 21 hypertensive and five normotensive African-Americans. At the end of L-arginine infusion mean arterial pressure fell more in salt-sensitive (-11.5 +/- 2.5) than in salt-resistant (-3.7 +/- 1.5 mm Hg) and control subjects (-3.2 +/- 3.8 mm Hg). At the end of L-arginine infusion effective renal plasma flow (ERPF) increased more (P < 0.05) in controls (+108 +/- 13.9 ml/min/1.73 m2) than in salt-resistant (+55 +/- 16.0 ml/min/1.73 m2) and salt-sensitive patients (+22 +/- 21.5 ml/min/1.73 m2). This study has shown that salt-sensitive African-Americans manifest different systemic and renal haemodynamic responses to L-arginine than salt-resistant patients and controls. The fall in mean blood pressure following L-arginine was greater in salt-sensitive than in salt-resistant patients and controls, whereas the increase in ERPF was reduced in salt-sensitive compared to salt-resistant and normal subjects. The data are in keeping with the notion that a defect in NO production may participate to the genesis of blood pressure sensitivity to salt

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report.

Chobanian AV, Bakris GL, Black HR, et al.

JAMA. 2003 May 21; 289(19):2560-72.

"The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" provides a new guideline for hypertension prevention and management. The following are the key messages(1) In persons older than 50 years, systolic blood pressure (BP) of more than 140 mm Hg is a much more important cardiovascular disease (CVD) risk factor than diastolic BP; (2) The risk of CVD, beginning at 115/75 mm Hg, doubles with each increment of 20/10 mm Hg; individuals who are normotensive at 55 years of age have a 90% lifetime risk for developing hypertension; (3) Individuals with a systolic BP of 120 to 139 mm Hg or a diastolic BP of 80 to 89 mm Hg should be considered as prehypertensive and require health-promoting lifestyle modifications to prevent CVD; (4) Thiazide-type diuretics should be used in drug treatment for most patients with uncomplicated hypertension, either alone or combined with drugs from other classes. Certain high-risk conditions are compelling indications for the initial use of other antihypertensive drug classes (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, beta-blockers, calcium channel blockers); (5) Most patients with hypertension will require 2 or more antihypertensive medications to achieve goal BP (<140/90 mm Hg, or <130/80 mm Hg for patients with diabetes or chronic kidney disease); (6) If BP is more than 20/10 mm Hg above goal BP, consideration should be given to initiating therapy with 2 agents, 1 of which usually should be a thiazide-type diuretic; and (7) The most effective therapy prescribed by the most careful clinician will control hypertension only if patients are motivated. Motivation improves when patients have positive experiences with and trust in the clinician. Empathy builds trust and is a potent motivator. Finally, in presenting these guidelines, the committee recognizes that the responsible physician's judgment remains paramount

Resting venous plasma adrenalin in 70-year-old men correlated positively to survival in a population study: the significance of the physical working capacity.

Christensen NJ, Schultz-Larsen K.

J Intern Med. 1994 Mar; 235(3):229-32.

OBJECTIVE. The aim of the study was to evaluate plasma noradrenaline (NA) and plasma adrenalin (A) as predictors of mortality in a population study. SUBJECTS. All subjects were 70 years of age in 1984. They were selected from the National Person Register. Altogether, 804 subjects participated in a comprehensive medical examination. INTERVENTIONS. Plasma NA and A were measured in blood samples collected after the subjects had rested in the supine position for 15 min. The subjects have now been followed for 7 years. MAIN OUTCOME MEASURES. Seven years later, 115 men and 63 women had died. RESULTS. Cox regression analysis showed that the mortality in the male group was positively correlated to plasma NA (P < 0.002) and inversely correlated to forced vital capacity (P < 0.0000) and plasma A (P < 0.02). A positive correlation was obtained between physical working capacity and plasma A. When an index of physical working capacity was included in the Cox regression analysis, both plasma NA and plasma A became insignificant, whereas a strong positive correlation appeared between physical working capacity and survival (P < 0.0000). Those who had low plasma A values in 1984 tended to die from cardiovascular diseases in the follow-up period, whereas in those who died from cancer, plasma A values were similar to those of the general population. CONCLUSIONS. Subjects with high plasma A values had the best survival rate during the 7 year follow-up period, probably because they also had the best physical working capacity. High plasma NA values, as expected, were associated with a reduced survival rate. Measurements of physical working capacity may be an inexpensive measure of probable survival in 70-year-old subjects

Hyperhomocysteinemia: an independent risk factor for vascular disease.

Clarke R, Daly L, Robinson K, et al.

N Engl J Med. 1991 Apr 25; 324(17):1149-55.

BACKGROUND. Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency. METHODS. We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age. RESULTS. Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia. CONCLUSIONS. Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency

The endothelium: a new target for therapy.

Cooke JP.

Vasc Med. 2000; 5(1):49-53.

At one time considered merely a monolayer of cells lining the vascular conduit, the endothelium has emerged recently as an organ with functions as complex as any in the body. A highly active regulatory organ, the endothelium senses and assesses the hemodynamic, humoral, and inflammatory signals to which it is constantly exposed by the blood and responds by secreting factors that affect vessel tone and structure. These interactions are not merely of academic interest. It has been increasingly recognized that endothelial dysfunction plays a pivotal role in the development and progression of atherosclerosis and coronary artery disease

Prevention and Treatment of Hypertension Study (PATHS): effects of an alcohol treatment program on blood pressure.

Cushman WC, Cutler JA, Hanna E, et al.

Arch Intern Med. 1998 Jun 8; 158(11):1197-207.

OBJECTIVE: To determine whether blood pressure is reduced for at least 6 months with an intervention to lower alcohol intake in moderate to heavy drinkers with above optimal to slightly elevated diastolic blood pressure, and whether reduction of alcohol intake can be maintained for 2 years. DESIGN: A randomized controlled trial. METHODS: Six hundred forty-one outpatient veterans with an average intake of 3 or more alcoholic drinks per day in the 6 months before entry into the study and with diastolic blood pressure 80 to 99 mm Hg were randomly assigned to a cognitive-behavioral alcohol reduction intervention program or a control observation group for 15 to 24 months. The goal of the intervention was the lower of 2 or fewer drinks daily or a 50% reduction in intake. A subgroup with hypertension was defined as having a diastolic blood pressure of 90 to 99 mm Hg, or 80 to 99 mm Hg if recently taking medication for hypertension. RESULTS: Reduction in average weekly self-reported alcohol intake was significantly greater (P<.001) at every assessment from 3 to 24 months in the intervention group vs the control group: levels declined from 432 g/wk at baseline by 202 g/wk in the intervention group and from 445 g/wk by 78 g/wk in the control group in the first 6 months, with similar reductions after 24 months. The intervention group had a 1.2/0.7-mm Hg greater reduction in blood pressure than the control group (for each, P = ".17" and P = ".18)" for the 6-month primary end point; for the hypertensive stratum the difference was 0.9/0.7 mm Hg (for each, P = ".58" and P = ".44)." CONCLUSIONS: The 1.3 drinks per day average difference between changes in self-reported alcohol intake observed in this trial produced only small nonsignificant effects on blood pressure. The results from the Prevention and Treatment of Hypertension Study (PATHS) do not provide strong support for reducing alcohol consumption in nondependent moderate drinkers as a sole method for the prevention or treatment of hypertension

Docosahexaenoic acid, a ligand for the retinoid X receptor in mouse brain.

de Urquiza AM, Liu S, Sjoberg M, et al.

Science. 2000 Dec 15; 290(5499):2140-4.

The retinoid X receptor (RXR) is a nuclear receptor that functions as a ligand-activated transcription factor. Little is known about the ligands that activate RXR in vivo. Here, we identified a factor in brain tissue from adult mice that activates RXR in cell-based assays. Purification and analysis of the factor by mass spectrometry revealed that it is docosahexaenoic acid (DHA), a long-chain polyunsaturated fatty acid that is highly enriched in the adult mammalian brain. Previous work has shown that DHA is essential for brain maturation, and deficiency of DHA in both rodents and humans leads to impaired spatial learning and other abnormalities. These data suggest that DHA may influence neural function through activation of an RXR signaling pathway

Mechanism of action of coenzyme Q10 in essential hypertension.

Digiesi V.

Curr Ther Res. 1992;(51):668-72.


Effect of coenzyme Q10 on essential arterial hypertension.

Digiesi V CFBB.

Curr Ther Res. 1990;(47):841-5.


Treatment of hypertension with ascorbic acid.

Duffy SJ, Gokce N, Holbrook M, et al.

Lancet. 1999 Dec 11; 354(9195):2048-9.

In a randomised, double-blind, placebo-controlled study we showed that treatment of hypertensive patients with ascorbic acid lowers blood pressure. Further studies of ascorbic acid to treat hypertension, with clinical endpoints, are warranted

Dietary gamma-linolenic acid lowers blood pressure and alters aortic reactivity and cholesterol metabolism in hypertension.

Engler MM, Engler MB, Erickson SK, et al.

J Hypertens. 1992 Oct; 10(10):1197-204.

OBJECTIVE: To determine the effects of dietary gamma-linolenic acid upon blood pressure, aortic reactivity and cholesterol metabolism in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. DESIGN: Randomized parallel-group study. METHODS: SHR and WKY rats were fed a purified diet containing either sesame or borage oil rich in gamma-linolenic acid for 7 weeks. Blood pressure measured by the tail-cuff method and weight were monitored weekly. At the end of the study, intra-arterial pressor responses to norepinephrine and angiotensin II, and reactivity of isolated aortic rings to norepinephrine, angiotensin II, KCl and acetylcholine were determined. Serum cholesterol and triglycerides were measured. Hepatic and intestinal enzymes and receptors of cholesterol metabolism were also measured. RESULTS: Dietary borage oil significantly decreased blood pressure in SHR and WKY rats compared with sesame oil-fed rats. Pressor responses to norepinephrine and angiotensin II, and aortic reactivity to norepinephrine, angiotensin II, KCl and acetylcholine were not significantly different. The borage oil diet increased serum cholesterol levels in WKY rats and hepatic B-hydroxy-3-methylglutaryl coenzyme A reductase in SHR. CONCLUSION: These data indicate that dietary borage oil has a blood pressure lowering effect in hypertensive and normotensive rats. However, the effect cannot be explained by altered sensitivity to humoral and neural vasoconstrictors or changes in cholesterol metabolism. Other mechanisms should be investigated

Comparative study of diets enriched with evening primrose, black currant, borage or fungal oils on blood pressure and pressor responses in spontaneously hypertensive rats.

Engler MM.

Prostaglandins Leukot Essent Fatty Acids. 1993 Oct; 49(4):809-14.

The effects of oils enriched with gamma-linolenic acid (GLA) on blood pressure and pressor responses were examined in spontaneously hypertensive rats (SHR). Rats were fed purified diets containing evening primrose (EPO), black currant (BCO), borage (BOR) or fungal (FGO) oils for 7 weeks. Significant reductions in blood pressure were obtained in SHR rats maintained on diets enriched with GLA oils. The antihypertensive effect was not associated with enhanced pressor responsiveness to norepinephrine or angiotensin II. Moreover, no differences were found in blood pressure responses to the calcium channel blocker, verapamil. The results suggest that GLA-enriched oils inhibit the development of hypertension in the SHR rat. The blood pressure lowering effect is not mediated by altered pressor responses to vasoconstrictor hormones or intracellular calcium mechanisms

Effects of dietary gamma-linolenic acid on blood pressure and adrenal angiotensin receptors in hypertensive rats.

Engler MM, Schambelan M, Engler MB, et al.

Proc Soc Exp Biol Med. 1998 Jul; 218(3):234-7.

In a previous study, we showed that dietary gamma-linolenic acid (GLA), an omega-6 polyunsaturated fatty acid found in borage oil (BOR), attenuates the development of hypertension in young spontaneously hypertensive rats (SHR). The purpose of this study was to determine the effects of dietary GLA on established hypertension in adult rats, as well as its effects on components of the renin-angiotensin-aldosterone axis. For 5 weeks, male SHR (14-15 weeks old) were fed a basal fat-free diet to which 11% by weight of sesame oil (SES) or BOR was added. Systolic blood pressure (SBP), determined by the tail cuff method, and weight were measured weekly. Plasma renin activity (PRA), aldosterone (PA), and corticosterone (PC) levels were measured at the end of the dietary treatments. The adrenal glands were homogenized, and angiotensin II (ANG II) binding was measured and plotted according to Scatchard. Systolic blood pressure was 12 mmHg lower at Week 5 in SHR fed the BOR diet compared to SES-fed rats (P < 0.005). Weight gains were similar in both dietary groups. Plasma aldosterone was lower, PRA was higher, and the PA/PRA ratio was significantly lower (P < 0.05) in BOR-fed rats. Levels of PC were the same in both groups. The BOR-enriched diet reduced adrenal ANG II receptor density and affinity compared to the SES diet. Results suggest that BOR inhibits adrenal responsiveness to ANG II by an action on adrenal receptors. Our findings demonstrated that dietary GLA lowers SBP in adult SHR. This effect may be mediated, at least in part, by interference with the renin-angiotensin-aldosterone system at the level of adrenal ANG II receptors

Docosahexaenoic acid is an antihypertensive nutrient that affects aldosterone production in SHR.

Engler MM, Engler MB, Goodfriend TL, et al.

Proc Soc Exp Biol Med. 1999 May; 221(1):32-8.

The effects of dietary docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, on blood pressure and some pressure-regulating systems were measured in young spontaneously hypertensive rats (SHR). Plasma aldosterone and corticosterone levels, adrenal aldosterone production in vitro, and characteristics of adrenal angiotensin receptors were measured after 6 weeks of diet. Renal cytochrome P450 (CYP) 4A gene expression and arachidonic acid metabolism by renal microsomes were also investigated. Plasma cholesterol, triglycerides, and high-density lipoprotein cholesterol were measured. Diets contained either corn/soybean oil alone (CSO), or oil enriched with DHA. After 6 weeks, rats fed DHA had systolic blood pressures averaging 34 mmHg less than controls (P < 0.001). Plasma aldosterone levels were 33% lower in the DHA-fed animals than in controls (22 +/- 3 vs. 33 +/- 3.7 ng/dl, P < 0.05). Plasma levels of corticosterone were 18% lower in animals fed DHA than in controls, but this difference was not statistically significant. Adrenal glomerulosa cells from DHA-fed rats produced less aldosterone in vitro in response to angiotensin II, ACTH, or potassium. The difference was less marked when aldosterone production was stimulated by supplying exogenous corticosterone, suggesting an effect of DHA on postreceptor steps in signal transduction or the early pathway of aldosteronogenesis. We found no significant differences in angiotensin receptor subtype, number, or affinity. Production of arachidonic epoxides by renal microsomes was 17% lower in DHA-fed animals than in controls (P < 0.05). Renal cortical mRNA levels of CYP4A genes and formation of 19- and 20-hydroxyeicosatetraenoic acid (HETE) did not differ between dietary groups. Plasma total cholesterol and high-density-lipoprotein (HDL) levels were significantly reduced in SHR fed the DHA supplement, but triglyceride levels were not significantly different. The effects of DHA on steroid and eicosanoid metabolism may be part of the mechanism by which this fatty acid prevents some of the hypertension in growing SHR

Vitamin C intake and mortality among a sample of the United States population.

Enstrom JE, Kanim LE, Klein MA.

Epidemiology. 1992 May; 3(3):194-202.

We examined the relation between vitamin C intake and mortality in the First National Health and Nutrition Examination Survey (NHANES I) Epidemiologic Follow-up Study cohort. This cohort is based on a representative sample of 11,348 noninstitutionalized U.S. adults age 25-74 years who were nutritionally examined during 1971-1974 and followed up for mortality (1,809 deaths) through 1984, a median of 10 years. An index of vitamin C intake has been formed from detailed dietary measurements and use of vitamin supplements. The relation of the standardized mortality ratio (SMR) for all causes of death to increasing vitamin C intake is strongly inverse for males and weakly inverse for females. Among those with the highest vitamin C intake, males have an SMR (95% confidence interval) of 0.65 (0.52-0.80) for all causes, 0.78 (0.50-1.17) for all cancers, and 0.58 (0.41-0.78) for all cardiovascular diseases; females have an SMR of 0.90 (0.74-1.09) for all causes, 0.86 (0.55-1.27) for all cancers, and 0.75 (0.55-0.99) for all cardiovascular diseases. Comparisons are made relative to all U.S. whites, for whom the SMR is defined to be 1.00. There is no clear relation for individual cancer sites, except possibly an inverse relation for esophagus and stomach cancer among males. The relation with all causes of death among males remains after adjustment for age, sex, and 10 potentially confounding variables (including cigarette smoking, education, race, and disease history)

Predictors and mediators of successful long-term withdrawal from antihypertensive medications. TONE Cooperative Research Group. Trial of Nonpharmacologic Interventions in the Elderly.

Espeland MA, Whelton PK, Kostis JB, et al.

Arch Fam Med. 1999 May; 8(3):228-36.

BACKGROUND: National guidelines recommend consideration of step down or withdrawal of medication in patients with well-controlled hypertension, but knowledge of factors that predict or mediate success in achieving this goal is limited. OBJECTIVE: To identify patient characteristics associated with success in controlling blood pressure (BP) after withdrawal of antihypertensive medication. DESIGN: The Trial of Nonpharmacologic Interventions in the Elderly tested whether lifestyle interventions designed to promote weight loss or a reduced intake of sodium, alone or in combination, provided satisfactory BP control among elderly patients (aged 60-80 years) with hypertension after withdrawal from antihypertensive drug therapy. Participants were observed for 15 to 36 months after attempted drug withdrawal. MAIN OUTCOME MEASURES: Trial end points were defined by (1) a sustained BP of 150/90 mm Hg or higher, (2) a clinical cardiovascular event, or (3) a decision by participants or their personal physicians to resume BP medication. RESULTS: Proportional hazards regression analyses indicated that the hazard (+/- SE) of experiencing an end point among persons assigned to active interventions was 75% +/- 9% (weight loss), 68% +/- 7% (sodium reduction), and 55% +/- 7% (combined weight loss/sodium reduction) that of the hazard for those assigned to usual care. Lower baseline systolic BP (P < .001), fewer years since diagnosis of hypertension (P < .001), fewer years of antihypertensive treatment (P < .001), and no history of cardiovascular disease (P = ".01)" were important predictors of maintaining successful nonpharmacological BP control throughout follow-up, based on logistic regression analysis. Age, ethnicity, baseline level of physical activity baseline weight, medication class, smoking status, and alcohol intake were not statistically significant predictors. During follow-up, the extent of weight loss (P = ".001)" and urinary sodium excretion (P = ".04)" were associated with a reduction in the risk of trial end points in a graded fashion. CONCLUSIONS: Withdrawal from antihypertensive medication is most likely to be successful in patients with well-controlled hypertension who have been recently (within 5 years) diagnosed or treated, and who adhere to life-style interventions involving weight loss and sodium reduction. More than 80% of these patients may have success in medication withdrawal for longer than 1 year

Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology.

Fardella CE, Mosso L, Gomez-Sanchez C, et al.

J Clin Endocrinol Metab. 2000 May; 85(5):1863-7.

There is evidence that primary aldosteronism (PA) may be common in patients with essential hypertension (EH) when determinations of serum aldosterone (SA), plasma renin activity (PRA), and the SA/PRA ratio are used as screening. An inherited form of primary hyperaldosteronism is the glucocorticoid-remediable aldosteronism (GRA) caused by an unequal crossing over between the CYP11B1 and CYP11B2 genes that results in a chimeric gene, which has aldosterone synthase activity regulated by ACTH. The aim of this study was to evaluate the prevalence of PA and the GRA in 305 EH patients and 205 normotensive controls. We measured SA (1-16 ng/dL) and PRA (1-2.5 ng/mL x h) and calculated the SA/PRA ratio in all patients. A SA/PRA ratio level greater than 25 was defined as being elevated. PA was diagnosed in the presence of high SA levels (>16 ng/dL), low PRA levels (50). Probable PA was diagnosed when the SA/PRA ratio was more than 25 but the other criteria were not present. A Fludrocortisone test was done to confirm the diagnosis. GRA was differentiated from other forms of PA by: the aldosterone suppression test with dexamethasone, the high levels of 18-hydroxycortisol, and the genetic detection of the chimeric gene. In EH patients, 29 of 305 (9.5%) had PA, 13 of 29 met all the criteria for PA, and 16 of 29 were initially diagnosed as having a probable PA and confirmed by the fludrocortisone test. Plasma potassium was normal in all patients. The dexamethasone suppression test was positive for GRA in 10 of 29 and 18-hydroxycortisol levels were high in 2 of 29 patients who had also a chimeric gene. In normotensive subjects, 3 of 205 (1.46%) had PA, and 1 of 205 had a GRA. In summary, we found a high frequency of normokalemic PA in EH patients. A high proportion of PA suppressed SA with dexamethasone, but only a few had a chimeric gene or high levels of 18-hydroxycortisol. These results emphasize the need to further investigate EH patients

Plasma testosterone in isolated systolic hypertension.

Fogari R MEPP.



Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta.

Forman BM, Chen J, Evans RM.

Proc Natl Acad Sci U S A. 1997 Apr 29; 94(9):4312-7.

Fatty acids (FAs) and their derivatives are essential cellular metabolites whose concentrations must be closely regulated. This implies that regulatory circuits exist which can sense changes in FA levels. Indeed, the peroxisome proliferator-activated receptor alpha (PPARalpha) regulates lipid homeostasis and is transcriptionally activated by a variety of lipid-like compounds. It remains unclear as to how these structurally diverse compounds can activate a single receptor. We have developed a novel conformation-based assay that screens activators for their ability to bind to PPARalpha/delta and induce DNA binding. We show here that specific FAs, eicosanoids, and hypolipidemic drugs are ligands for PPARalpha or PPARdelta. Because altered FA levels are associated with obesity, atherosclerosis, hypertension, and diabetes, PPARs may serve as molecular sensors that are central to the development and treatment of these metabolic disorders

Aspirin use and all-cause mortality among patients being evaluated for known or suspected coronary artery disease: A propensity analysis.

Gum PA, Thamilarasan M, Watanabe J, et al.

JAMA. 2001 Sep 12; 286(10):1187-94.

CONTEXT: Although aspirin has been shown to reduce cardiovascular morbidity and short-term mortality following acute myocardial infarction, the association between its use and long-term all-cause mortality has not been well defined. OBJECTIVES: To determine whether aspirin is associated with a mortality benefit in stable patients with known or suspected coronary disease and to identify patient characteristics that predict the maximum absolute mortality benefit from aspirin. DESIGN AND SETTING: Prospective, nonrandomized, observational cohort study conducted between 1990 and 1998 at an academic medical institution, with a median follow-up of 3.1 years. PATIENTS: Of 6174 consecutive adults undergoing stress echocardiography for evaluation of known or suspected coronary disease, 2310 (37%) were taking aspirin. Patients with significant valvular disease or documented contraindication to aspirin use, including peptic ulcer disease, renal insufficiency, and use of nonsteroidal anti-inflammatory drugs, were excluded. MAIN OUTCOME MEASURE: All-cause mortality according to aspirin use. RESULTS: During 3.1 years of follow-up, 276 patients (4.5%) died. In a simple univariable analysis, there was no association between aspirin use and mortality (4.5% vs 4.5%). However, after adjustment for age, sex, standard cardiovascular risk factors, use of other medications, coronary disease history, ejection fraction, exercise capacity, heart rate recovery, and echocardiographic ischemia, aspirin use was associated with reduced mortality (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.51-0.87; P =.002). In further analysis using matching by propensity score, 1351 patients who were taking aspirin were at lower risk for death than 1351 patients not using aspirin (4% vs 8%, respectively; HR, 0.53; 95% CI, 0.38-0.74; P =.002). After adjusting for the propensity for using aspirin, as well as other possible confounders and interactions, aspirin use remained associated with a lower risk for death (adjusted HR, 0.56; 95% CI, 0.40-0.78; P<.001). The patient characteristics associated with the most aspirin-related reductions in mortality were older age, known coronary artery disease, and impaired exercise capacity. CONCLUSION: Aspirin use among patients undergoing stress echocardiography was independently associated with reduced long-term all-cause mortality, particularly among older patients, those with known coronary artery disease, and those with impaired exercise capacity

Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study.

Hak AE, Witteman JC, de Jong FH, et al.

J Clin Endocrinol Metab. 2002 Aug; 87(8):3632-9.

In both men and women, circulating androgen levels decline with advancing age. Until now, results of several small studies on the relationship between endogenous androgen levels and atherosclerosis have been inconsistent. In the population-based Rotterdam Study, we investigated the association of levels of dehydroepiandrosterone sulfate (DHEAS) and total and bioavailable testosterone with aortic atherosclerosis among 1,032 nonsmoking men and women aged 55 yr and over. Aortic atherosclerosis was assessed by radiographic detection of calcified deposits in the abdominal aorta, which have been shown to reflect intimal atherosclerosis. Relative to men with levels of total and bioavailable testosterone in the lowest tertile, men with levels of these hormones in the highest tertile had age-adjusted relative risks of 0.4 [95% confidence interval (CI), 0.2-0.9] and 0.2 (CI, 0.1-0.7), respectively, for the presence of severe aortic atherosclerosis. The corresponding relative risks for women were 3.7 (CI, 1.2-11.6) and 2.3 (CI, 0.7-7.8). Additional adjustment for cardiovascular disease risk factors did not materially affect the results in men, whereas in women the associations diluted. Men with levels of total and bioavailable testosterone in subsequent tertiles were also protected against progression of aortic atherosclerosis measured after 6.5 yr (SD +/- 0.5 yr) of follow-up (P for trend = 0.02). No clear association between levels of DHEAS and presence of severe aortic atherosclerosis was found, either in men or in women. In men, a protective effect of higher levels of DHEAS against progression of aortic atherosclerosis was suggested, but the corresponding test for trend did not reach statistical significance. In conclusion, we found an independent inverse association between levels of testosterone and aortic atherosclerosis in men. In women, positive associations between levels of testosterone and aortic atherosclerosis were largely due to adverse cardiovascular disease risk factors

The effect of docosahexaenoic acid on aggression in young adults. A placebo-controlled double-blind study.

Hamazaki T, Sawazaki S, Itomura M, et al.

J Clin Invest. 1996 Feb 15; 97(4):1129-33.

41 students took either docosahexaenoic acid (DHA)-rich oil capsules containing 1.5-1.8 grams DHA/day (17 females and 5 males) or control oil capsules containing 97% soybean oil plus 3% fish oil (12 females and 7 males) for 3 mo in a double-blind fashion. They took a psychological test (P-F Study) and Stroop and dementia-detecting tests at the start and end of the study. The present study started at the end of summer vacation and ended in the middle of mental stress such as final exams. In the control group extraggression (aggression against others) in P-F Study was significantly increased at the end of the study as compared with that measured at the start (delta = +8.9%, P = 0.0022), whereas it was not significantly changed in the DHA group (delta = -1.0%). The 95% CI of differences between the DHA and control groups were -16.8 to -3.0%. DHA supplementation did not affect the Stroop and dementia-detecting tests. Thus, DHA intake prevented extraggression from increasing at times of mental stress. This finding might help understand how fish oils prevent disease like coronary heart disease

Correction of endothelial dysfunction in chronic heart failure: additional effects of exercise training and oral L-arginine supplementation.

Hambrecht R, Hilbrich L, Erbs S, et al.

J Am Coll Cardiol. 2000 Mar 1; 35(3):706-13.

OBJECTIVES: The aim of this study was to analyze whether L-arginine (L-arg.) has comparable or additive effects to physical exercise regarding endothelium-dependent vasodilation in patients with chronic heart failure (CHF). BACKGROUND: Endothelial dysfunction in patients with CHF can be corrected by both dietary supplementation with L-arg. and regular physical exercise. METHODS: Forty patients with severe CHF (left ventricular ejection fraction 19 +/- 9%) were randomized to an L-arg. group (8 g/day), a training group (T) with daily handgrip training, L-arg. and T (L-arg. + T) or an inactive control group (C). The mean internal radial artery diameter was determined at the beginning and after four weeks in response to brachial arterial administration of acetylcholine (ACh) (7.5, 15, 30 microg/min) and nitroglycerin (0.2 mg/min) with a transcutaneous high-resolution 10 MHz A-mode echo tracking system coupled with a Doppler device. The power of the study to detect clinically significant differences in endothelium-dependent vasodilation was 96.6%. RESULTS: At the beginning, the mean endothelium-dependent vasodilation in response to ACh, 30 microg/min was 2.54 +/- 0.09% (p = NS between groups). After four weeks, internal radial artery diameter increased by 8.8 +/- 0.9% after ACh 30 microg/min in L-arg. (p < 0.001 vs. C), by 8.6 +/- 0.9% in T (p < 0.001 vs. C) and by 12.0 +/- 0.3% in L-arg. +/- T (p < 0.005 vs. C, L-arg. and T). Endothelium-independent vasodilation as assessed by infusion of nitroglycerin was similar in all groups at the beginning and at the end of the study. CONCLUSIONS: Dietary supplementation of L-arg. as well as regular physical exercise improved agonist-mediated, endothelium-dependent vasodilation to a similar extent. Both interventions together seem to produce additive effects with respect to endothelium-dependent vasodilation

An overview of the 4 randomized trials of aspirin therapy in the primary prevention of vascular disease.

Hebert PR, Hennekens CH.

Arch Intern Med. 2000 Nov 13; 160(20):3123-7.

BACKGROUND: In the primary prevention of cardiovascular disease, in contrast to the recommendations of the American College of Chest Physicians and the American Heart Association, the US Food and Drug Administration recently stated that there was insufficient evidence to judge whether aspirin therapy decreases the risk of a first myocardial infarction. OBJECTIVE: To perform an overview of the 4 primary prevention trials of aspirin therapy to obtain the most reliable estimates of the effects of aspirin therapy on various vascular disease end points. METHODS AND RESULTS: These 4 trials included more than 51,000 subjects and 2284 important vascular events. Those assigned to aspirin therapy experienced significant reductions of 32% (95% confidence interval [CI], 21%-41%) for nonfatal myocardial infarction and 13% (95% CI, 5%-19%) for any important vascular event. There were possible small but nonsignificant increases in risks of vascular disease-related death (1%; 95% CI, -12% to 16%) and nonfatal stroke (8%; 95% CI, -12% to 33%). When strokes were subdivided by type, there was no significant effect of aspirin therapy on the risk of ischemic stroke, but, while based on small numbers, there was a 1.7-fold apparent increase (95% CI, 6%-269%) in the risk of hemorrhagic stroke, which did achieve statistical significance. CONCLUSIONS: For the primary prevention of vascular disease, aspirin therapy confers significant beneficial effects on first myocardial infarction and, as a result, on any important vascular event; these effects are clinically important. Whether there is any reduction in vascular disease-related death or stroke associated with treatment remains unclear because of inadequate numbers of events in the primary prevention trials completed to date. More data on hemorrhagic stroke are also needed. In addition, randomized trial data, especially in women but also in men, are needed to help to formulate a rational public health policy for individuals at usual risk. Meanwhile, these data provide evidence for a significant benefit of aspirin therapy in the primary prevention of myocardial infarction

Loss of delta-6-desaturase activity as a key factor in aging.

Horrobin DF.

Med Hypotheses. 1981 Sep; 7(9):1211-20.

Aging is characterized by a wide variety of defects, particularly in the cardiovascular and immune systems. Cyclic AMP levels fall, especially in lymphocytes. Delta-6-desaturase (D6D) levels have been found to fall rapidly in the testes and more slowly in the liver in aging rats. D6D is an enzyme which converts cis-linoleic acid to gamma-linolenic acid (GLA). Other factors which inhibit D6D activity are diabetes, alcohol and radiation, all of which may be associated with accelerated aging. In meat eaters or omnivores which can acquire arachidonic acid from food, the main consequences of D6D loss will be deficiencies of GLA, dihomogamma-linolenic acid (DGLA) and prostaglandin (PG) E1. PGE1 activates T lymphocytes, inhibits smooth muscle proliferation and thrombosis, is important in gonadal function and raises cyclic AMP levels in many tissues. It is a good candidate for a key factor lost in aging. Moderate food restriction, the only manoeuvre which consistently slows aging in homoiotherms, raises D6D activity by 300%. Other factors important in regulating D6D and the conversion of GLA to PGE1 are zinc, pyridoxine, ascorbic acid, the pineal hormone, melatonin, and possibly vitamin B3. GLA administration to humans has been found to lower blood pressure and cholesterol, and to cause clinical improvement in patients with Sjogren's syndrome, scleroderma and alcoholism. These diseases are associated with some features of accelerated aging. The proposition that D6D loss is not only a marker of aging but a cause of some of its major manifestations is amenable to experimental test even in humans. The blocked enzyme can be by-passed by giving GLA directly

The regulation of prostaglandin biosynthesis by the manipulation of essential fatty acid metabolism.

Horrobin DF.

Rev Pure Appl Pharmacol Sci. 1983 Oct; 4(4):339-83.

Two of the most widely used groups of drugs in medical practice are the non-steroidal anti-inflammatory agents and the steroids. Both act by modulating the conversion of essential fatty acids to prostaglandins, leukotrienes and related substances. The actions of these drugs are therefore likely to be modified by variations in the levels of substrates, notably arachidonic acid and dihomogammalinolenic acid, available for metabolism by lipoxygenase and cyclo-oxygenase enzymes. Yet most doctors who use the drugs and many scientists who carry out research on them seem unaware of the factors which determine the concentrations of the substrate essential fatty acids. This paper reviews in detail the metabolism of essential fatty acids and the interactions between nutrient intake and subsequent metabolism which determine the concentrations of the individual fatty acids. It is concluded that the efficacy of drug therapy as far as the steroids and the non-steroidal anti-inflammatory drugs are concerned could be substantially enhanced by greater knowledge of the factors which determine the availability of substrates to the key enzymes

Docosahexaenoic acid-enriched foods: production and effects on blood lipids.

Horrocks LA, Yeo YK.

Lipids. 1999; 34 Suppl:S313.

Health benefits of docosahexaenoic acid (DHA).

Horrocks LA, Yeo YK.

Pharmacol Res. 1999 Sep; 40(3):211-25.

Docosahexaenoic acid (DHA) is essential for the growth and functional development of the brain in infants. DHA is also required for maintenance of normal brain function in adults. The inclusion of plentiful DHA in the diet improves learning ability, whereas deficiencies of DHA are associated with deficits in learning. DHA is taken up by the brain in preference to other fatty acids. The turnover of DHA in the brain is very fast, more so than is generally realized. The visual acuity of healthy, full-term, formula-fed infants is increased when their formula includes DHA. During the last 50 years, many infants have been fed formula diets lacking DHA and other omega-3 fatty acids. DHA deficiencies are associated with foetal alcohol syndrome, attention deficit hyperactivity disorder, cystic fibrosis, phenylketonuria, unipolar depression, aggressive hostility, and adrenoleukodystrophy. Decreases in DHA in the brain are associated with cognitive decline during aging and with onset of sporadic Alzheimer disease. The leading cause of death in western nations is cardiovascular disease. Epidemiological studies have shown a strong correlation between fish consumption and reduction in sudden death from myocardial infarction. The reduction is approximately 50% with 200 mg day(-1)of DHA from fish. DHA is the active component in fish. Not only does fish oil reduce triglycerides in the blood and decrease thrombosis, but it also prevents cardiac arrhythmias. The association of DHA deficiency with depression is the reason for the robust positive correlation between depression and myocardial infarction. Patients with cardiovascular disease or Type II diabetes are often advised to adopt a low-fat diet with a high proportion of carbohydrate. A study with women shows that this type of diet increases plasma triglycerides and the severity of Type II diabetes and coronary heart disease. DHA is present in fatty fish (salmon, tuna, mackerel) and mother's milk. DHA is present at low levels in meat and eggs, but is not usually present in infant formulas. EPA, another long-chain n-3 fatty acid, is also present in fatty fish. The shorter chain n-3 fatty acid, alpha-linolenic acid, is not converted very well to DHA in man. These longchain n-3 fatty acids (also known as omega-3 fatty acids) are now becoming available in some foods, especially infant formula and eggs in Europe and Japan. Fish oil decreases the proliferation of tumour cells, whereas arachidonic acid, a longchain n-6 fatty acid, increases their proliferation. These opposite effects are also seen with inflammation, particularly with rheumatoid arthritis, and with asthma. DHA has a positive effect on diseases such as hypertension, arthritis, atherosclerosis, depression, adult-onset diabetes mellitus, myocardial infarction, thrombosis, and some cancers

Fish and omega-3 fatty acid intake and risk of coronary heart disease in women.

Hu FB, Bronner L, Willett WC, et al.

JAMA. 2002 Apr 10; 287(14):1815-21.

CONTEXT: Higher consumption of fish and omega-3 fatty acids has been associated with a lower risk of coronary heart disease (CHD) in men, but limited data are available regarding women. OBJECTIVE: To examine the association between fish and long-chain omega-3 fatty acid consumption and risk of CHD in women. DESIGN, SETTING, AND PARTICIPANTS: Dietary consumption and follow-up data from 84 688 female nurses enrolled in the Nurses' Health Study, aged 34 to 59 years and free from cardiovascular disease and cancer at baseline in 1980, were compared from validated questionnaires completed in 1980, 1984, 1986, 1990, and 1994. MAIN OUTCOME MEASURES: Incident nonfatal myocardial infarction and CHD deaths. RESULTS: During 16 years of follow-up, there were 1513 incident cases of CHD (484 CHD deaths and 1029 nonfatal myocardial infarctions). Compared with women who rarely ate fish (<1 per month), those with a higher intake of fish had a lower risk of CHD. After adjustment for age, smoking, and other cardiovascular risk factors, the multivariable relative risks (RRs) of CHD were 0.79 (95% confidence interval [CI], 0.64-0.97) for fish consumption 1 to 3 times per month, 0.71 (95% CI, 0.58-0.87) for once per week, 0.69 (95% CI, 0.55-0.88) for 2 to 4 times per week, and 0.66 (95% CI, 0.50-0.89) for 5 or more times per week (P for trend =".001)." Similarly, women with a higher intake of omega-3 fatty acids had a lower risk of CHD, with multivariable RRs of 1.0, 0.93, 0.78, 0.68, and 0.67 (P<.001 for trend) across quintiles of intake. For fish intake and omega-3 fatty acids, the inverse association appeared to be stronger for CHD deaths (multivariate RR for fish consumption 5 times per week, 0.55 [95% CI, 0.33-0.90] for CHD deaths vs 0.73 [0.51-1.04]) than for nonfatal myocardial infarction. CONCLUSION: Among women, higher consumption of fish and omega-3 fatty acids is associated with a lower risk of CHD, particularly CHD deaths

Dietary n-3 fatty acids influence the lipid composition and physical properties of liver microsomal membranes in diabetic rats.

Igal A, Gomez Dumm NT.

Prostaglandins Leukot Essent Fatty Acids. 1997 Mar; 56(3):245-52.

We examined the effect of n-3 fatty acid consumption on the lipid composition and physical properties of liver microsomal membranes in normal and experimental diabetic rats. Lipid analysis showed a significant increase in the cholesterol:phospholipid ratio in membranes of normal animals fed n-3 fatty acids as well as in both groups of diabetic rats. These changes would be in part responsible for the higher fluorescent polarization of DPH (1,6-diphenyl-1,3,5 hexatriene) observed in the diabetic groups compared with the normal ones. These alterations were partially compensated by an increase in the amount of phosphatidylcholine in the diabetic rats fed on n-3 fatty acids. However, proteins also play a role in determining the physical properties of the liver microsomes because in the liposomes derived from them, the fluorescent polarization of DPH decreased in the diabetics fed n-3 fatty acids. Measurements of fluorescence anisotropy of n-AS (2-, 7 and 12 (9 anthroyloxy) stearic acid) probes revealed a restricted rotational mobility in the middle zone of the bilayer. Consistently with this finding there was an elevation in the calculated unsaturation density of the fatty acids at the carbon 8 position. These experiments confirm the lipid abnormalities that take place in experimental diabetes and they show further that n-3 fatty-acid administration causes certain compensatory, and thus beneficial, changes in these abnormalities

Doxazosin and the ALLHAT Study .

IHP, Information for Health Professionals.


Prospective study of fat and protein intake and risk of intraparenchymal hemorrhage in women.

Iso H, Stampfer MJ, Manson JE, et al.

Circulation. 2001 Feb 13; 103(6):856-63.

BACKGROUND:-Dietary animal fat and protein have been inversely associated with a risk of intraparenchymal hemorrhage in ecological studies. METHODS AND RESULTS: In 1980, 85 764 women in the Nurses' Health Study cohort, who were 34 to 59 years old and free of diagnosed cardiovascular disease and cancer, completed dietary questionnaires. From these questionnaires, we calculated fat and protein intake. By 1994, after 1.16 million person-years of follow-up, 690 incident strokes, including 74 intraparenchymal hemorrhages, had been documented. Multivariate-adjusted risk of intraparenchymal hemorrhage was higher among women in the lowest quintile of energy-adjusted saturated fat intake than at all higher levels of intake (relative risk [RR], 2.36; 95% CI, 1.10 to 5.09; P:=0.03). For trans unsaturated fat, the corresponding RR was 2.50 (95% CI, 1.35 to 4.65; P:=0.004). Animal protein intake was inversely associated with risk (RR in the highest versus lowest quintiles, 0.32; 95% CI, 0.10 to 1.00; P:=0.04). The excess risk associated with low saturated fat intake was observed primarily among women with a history of hypertension (RR, 3.66; 95% CI, 1.09 to 12.3; P=0.04), but such an interaction was not seen for trans unsaturated fat or animal protein. These nutrients were not related to risk of other stroke subtypes. Dietary cholesterol and monounsaturated and polyunsaturated fat were not related to risk of any stroke subtype. CONCLUSIONS: Low intake of saturated fat and animal protein was associated with an increased risk of intraparenchymal hemorrhage, which may help to explain the high rate of this stroke subtype in Asian countries. The increased risk with low intake of saturated fat and trans unsaturated fat is compatible with the reported association between low serum total cholesterol and risk

Effects of strength training on muscle power and serum hormones in middle-aged and older men.

Izquierdo M, Hakkinen K, Ibanez J, et al.

J Appl Physiol. 2001 Apr; 90(4):1497-507.

Effects of 16-wk strength training on maximal strength and power performance of the arm and leg muscles and serum concentrations [testosterone (T), free testosterone (FT), and cortisol] were examined in 11 middle-aged (M46; 46 +/- 2 yr) and 11 older men (M64; 64 +/- 2 yr). During the 16-wk training, the relative increases in maximal strength and muscle power output of the arm and leg muscles were significant in both groups (P < 0.05-0.001), with no significant differences between the two groups. The absolute increases were higher (P < 0.01-0.05) in M46 than in M64 mainly during the last 8 wk of training. No significant changes were observed for serum T and FT concentrations. Analysis of covariance showed that, during the 16-wk training period, serum FT concentrations tended to decrease in M64 and increase in M46 (P < 0.05). However, significant correlations between the mean level of individual serum T and FT concentrations and the individual changes in maximal strength were observed in a combined group during the 16-wk training (r = "0.49" and 0.5, respectively; P < 0.05). These data indicate that a prolonged total strength-training program would lead to large gains in maximal strength and power load characteristics of the upper and lower extremity muscles, but the pattern of maximal and power development seemed to differ between the upper and lower extremities in both groups, possibly limited in magnitude because of neuromuscular and/or age-related endocrine impairments

Clinical Advisory Statement. Importance of systolic blood pressure in older Americans.

Izzo JL, Jr., Levy D, Black HR.

Hypertension. 2000 May; 35(5):1021-4.

Is the relation of systolic blood pressure to risk of cardiovascular disease continuous and graded, or are there critical values?

Kannel WB, Vasan RS, Levy D.

Hypertension. 2003 Oct; 42(4):453-6.

Biochem Pharmacol Science.

Kellis JT Jr NSVL.

Biochem Pharmacol Science. 1984;(225):1032-4.

EFA & Eicosanoids. Omega-6 and omega-3 polyunsaturated fatty acids in experimental atherosclerosis regression.

Khalilov EM.



Dietary docosahexaenoic acid (22: 6n-3) prevents the development of hypertension in SHRSP.

Kimura S, Minami M, Saito H, et al.

Clin Exp Pharmacol Physiol Suppl. 1995 Dec; 22(1):S308-S309.

1. We previously reported that hypertension in stroke-prone spontaneously hypertensive rats (SHRSP) caused renal membrane phospholipid degradation. Renal phospholipase A2 activity increased and membranous phospholipids decreased along with age in SHRSP. Membranous abnormalities induced by membrane fluidity and calcium permeability changes may contribute to the elevation of blood pressure in SHRSP. DHA, a major component of fish oil, constitutes a part of membrane phospholipid acylchains. 2. The purpose of this study was to clarify the effect of DHA on the relationship between the renal function and the development of hypertension in SHRSP. 3. Six week old male SHRSP were fed a semi-purified diet supplemented with DHA (0, 1 and 5%) for 14 weeks. 4. The systolic blood pressure of control SHRSP (DHA 0%) significantly increased from 120.2 mmHg to 202.9 mmHg. This increase in systolic blood pressure was significantly inhibited in a dose-dependent manner by 1 and 5% DHA diet to 167.8 to 149.8 mmHg, respectively. 5. Serum creatinine concentration and blood urea nitrogen (BUN) were significantly lower in DHA (5%)-treated SHRSP than in the control SHRSP. 6. These results indicate that DHA prevents the development of hypertension in SHRSP, which is associated with changes in renal function

Modern Nutrition in Health and Disease.

Kotchen TA KJ.

1999; 9:1217-27.


Effects of heavy-resistance training on hormonal response patterns in younger vs. older men.

Kraemer WJ, Hakkinen K, Newton RU, et al.

J Appl Physiol. 1999 Sep; 87(3):982-92.

To examine the adaptations of the endocrine system to heavy-resistance training in younger vs. older men, two groups of men (30 and 62 yr old) participated in a 10-wk periodized strength-power training program. Blood was obtained before, immediately after, and 5, 15, and 30 min after exercise at rest before and after training and at rest at -3, 0, 6, and 10 wk for analysis of total testosterone, free testosterone, cortisol, growth hormone, lactate, and ACTH analysis. Resting values for insulin-like growth factor (IGF)-I and IGF-binding protein-3 were determined before and after training. A heavy-resistance exercise test was used to evaluate the exercise-induced responses (4 sets of 10-repetition maximum squats with 90 s of rest between sets). Squat strength and thigh muscle cross-sectional area increased for both groups. The younger group demonstrated higher total and free testosterone and IGF-I than the older men, training-induced increases in free testosterone at rest and with exercise, and increases in resting IGF-binding protein-3. With training the older group demonstrated a significant increase in total testosterone in response to exercise stress along with significant decreases in resting cortisol. These data indicate that older men do respond with an enhanced hormonal profile in the early phase of a resistance training program, but the response is different from that of younger men

Influence of conjugated linoleic acid (CLA) on establishment and progression of atherosclerosis in rabbits.

Kritchevsky D, Tepper SA, Wright S, et al.

J Am Coll Nutr. 2000 Aug; 19(4):472S-7S.

OBJECTIVE: To determine effects of conjugated linoleic acid (CLA) on establishment and progression of experimentally-induced atherosclerosis in rabbits. METHODS: For establishment of atherosclerosis, New Zealand White rabbits were fed a semipurified diet containing 0.1% to 0.2% cholesterol for 90 days. Some groups were fed diet and CLA. For effects on progression of atherosclerosis, rabbits with established atherosclerosis were fed a semipurified diet +/- CLA for 90 days. RESULTS: At dietary levels as low as 0.1%, CLA inhibited atherogenesis. At dietary levels of 1%, CLA caused substantial (30%) regression of established atherosclerosis. This is the first example of substantial regression of atherosclerosis being caused by diet alone. CONCLUSION: Dietary CLA is an effective inhibitor of atherogenesis and also causes regression of established atherosclerosis

Are free radicals involved in the pathobiology of human essential hypertension?

Kumar KV, Das UN.

Free Radic Res Commun. 1993; 19(1):59-66.

Possible involvement of reactive oxygen species and nitric oxide in the pathogenesis of human essential hypertension was investigated. It was observed that both superoxide anion and hydrogen peroxide production by polymorphonuclear leukocytes and the plasma levels of lipid peroxides are higher in uncontrolled essential hypertension compared with normal controls. Nitric oxide levels measured as its stable metabolite nitrite, as an index of nitric oxide synthesis, revealed its levels to be low in hypertensive patients. Superoxide anion, hydrogen peroxide, lipid peroxides and nitric oxide levels reverted to normal values after the control of hypertension by drugs. The concentrations of anti-oxidants such as vitamin E and superoxide dismutase were found to be decreased in patients with uncontrolled hypertension. Several anti-hypertensive drugs inhibited lipid peroxidation in vitro. Angiotensin-II, a potent vasoconstrictor, stimulated free radical generation in normal leukocytes which could be blocked by calmodulin antagonists. These results suggest that an increase in free radical generation and a simultaneous decrease in the production of nitric oxide and anti-oxidants such as SOD and vitamin E occurs in essential hypertension. This increase in free radical generation can inactivate prostacyclin and nitric oxide and decrease their half life which can lead to an increase in peripheral vascular resistance and hypertension

Usefulness of coenzyme Q10 in clinical cardiology: a long-term study.

Langsjoen H, Langsjoen P, Langsjoen P, et al.

Mol Aspects Med. 1994; 15 Suppl:s165-s175.

Over an eight year period (1985-1993), we treated 424 patients with various forms of cardiovascular disease by adding coenzyme Q10 (CoQ10) to their medical regimens. Doses of CoQ10 ranged from 75 to 600 mg/day by mouth (average 242 mg). Treatment was primarily guided by the patient's clinical response. In many instances, CoQ10 levels were employed with the aim of producing a whole blood level greater than or equal to 2.10 micrograms/ml (average 2.92 micrograms/ml, n = 297). Patients were followed for an average of 17.8 months, with a total accumulation of 632 patient years. Eleven patients were omitted from this study: 10 due to non-compliance and one who experienced nausea. Eighteen deaths occurred during the study period with 10 attributable to cardiac causes. Patients were divided into six diagnostic categories: ischemic cardiomyopathy (ICM), dilated cardiomyopathy (DCM), primary diastolic dysfunction (PDD), hypertension (HTN), mitral valve prolapse (MVP) and valvular heart disease (VHD). For the entire group and for each diagnostic category, we evaluated clinical response according to the New York Heart Association (NYHA) functional scale, and found significant improvement. Of 424 patients, 58 per cent improved by one NYHA class, 28% by two classes and 1.2% by three classes. A statistically significant improvement in myocardial function was documented using the following echocardiographic parameters: left ventricular wall thickness, mitral valve inflow slope and fractional shortening. Before treatment with CoQ10, most patients were taking from one to five cardiac medications. During this study, overall medication requirements dropped considerably: 43% stopped between one and three drugs. Only 6% of the patients required the addition of one drug. No apparent side effects from CoQ10 treatment were noted other than a single case of transient nausea. In conclusion, CoQ10 is a safe and effective adjunctive treatment for a broad range of cardiovascular diseases, producing gratifying clinical responses while easing the medical and financial burden of multidrug therapy

Treatment of essential hypertension with coenzyme Q10.

Langsjoen P, Langsjoen P, Willis R, et al.

Mol Aspects Med. 1994; 15 Suppl:S265-S272.

A total of 109 patients with symptomatic essential hypertension presenting to a private cardiology practice were observed after the addition of CoQ10 (average dose, 225 mg/day by mouth) to their existing antihypertensive drug regimen. In 80 per cent of patients, the diagnosis of essential hypertension was established for a year or more prior to starting CoQ10 (average 9.2 years). Only one patient was dropped from analysis due to noncompliance. The dosage of CoQ10 was not fixed and was adjusted according to clinical response and blood CoQ10 levels. Our aim was to attain blood levels greater than 2.0 micrograms/ml (average 3.02 micrograms/ml on CoQ10). Patients were followed closely with frequent clinic visits to record blood pressure and clinical status and make necessary adjustments in drug therapy. Echocardiograms were obtained at baseline in 88% of patients and both at baseline and during treatment in 39% of patients. A definite and gradual improvement in functional status was observed with the concomitant need to gradually decrease antihypertensive drug therapy within the first one to six months. Thereafter, clinical status and cardiovascular drug requirements stabilized with a significantly improved systolic and diastolic blood pressure. Overall New York Heart Association (NYHA) functional class improved from a mean of 2.40 to 1.36 (P < 0.001) and 51% of patients came completely off of between one and three antihypertensive drugs at an average of 4.4 months after starting CoQ10. Only 3% of patients required the addition of one antihypertensive drug. In the 9.4% of patients with echocardiograms both before and during treatment, we observed a highly significant improvement in left ventricular wall thickness and diastolic function.(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of hypertrophic cardiomyopathy with coenzyme Q10.

Langsjoen PH, Langsjoen A, Willis R, et al.

Mol Aspects Med. 1997; 18 Suppl:S145-S151.

Hypertrophic cardiomyopathy (HCM) is manifested by severe thickening of the left ventricle with significant diastolic dysfunction. Previous observations on the improvement in diastolic function and left ventricular wall thickness through the therapeutic administration of coenzyme Q10 (CoQ10) in patients with hypertensive heart disease prompted the investigation of its utility in HCM. Seven patients with HCM, six non-obstructive and one obstructive, were treated with an average of 200 mg/day of CoQ10 with mean treatment whole blood CoQ10 level of 2.9 micrograms/ml. Echocardiograms were obtained in all seven patients at baseline and again 3 or more months post-treatment. All patients noted improvement in symptoms of fatigue and dyspnea with no side effects noted. The mean interventricular septal thickness improved significantly from 1.51 +/- 0.17 cm to 1.14 +/- 0.13 cm, a 24% reduction (P < 0.002). The mean posterior wall thickness improved significantly from 1.37 +/- 0.13 cm to 1.01 +/- 0.15 cm, a 26% reduction (P < 0.005). Mitral valve inflow slope by pulsed wave Doppler (EF slope) showed a non-significant trend towards improvement, 1.55 +/- 0.49 m/sec2 to 2.58 +/- 1.18 m/sec2 (P < 0.08). The one patient with subaortic obstruction showed an improvement in resting pressure gradient after CoQ10 treatment (70 mmHg to 30 mmHg)

Conjugated linoleic acid reduces arachidonic acid content and PGE2 synthesis in murine keratinocytes.

Liu KL, Belury MA.

Cancer Lett. 1998 May 15; 127(1-2):15-22.

Dietary conjugated linoleic acid (CLA) is associated with decreased 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced tumor promotion in mouse skin. In addition, CLA decreases TPA-induced prostaglandin E synthesis and ornithine decarboxylase activity in cultured keratinocytes compared with linoleic acid (LA) and arachidonic acid (AA). When LA or CLA was added to keratinocyte cell cultures, the amounts of each of these cellular fatty acids increased significantly in a dose-dependent manner. Furthermore, LA treatment was associated with increased cellular AA while the AA content of keratinocytes was reduced when cultures were treated with CLA. Moreover, CLA (16 microg/ml) was more potent than LA at decreasing the level of 14C-AA incorporated into cellular phosphatidylcholine. In order to determine the effect of CLA on arachidonate-derived PGE2, the release of 14C-AA and 14C-PGE2 synthesis was measured in cultures pre-treated with LA/14C-AA or CLA/14C-AA for 12 h. The amount of 14C-AA release induced by TPA in CLA/14C-AA pre-treated cultures was significantly lower than cultures pre-treated with LA/14C-AA. Furthermore, TPA-induced 14C-PGE2 was significantly lower in cultures pre-treated with CLA/14C-AA compared with cultures pre-treated with LA/14C-AA. The effects of LA and CLA on AA composition of phospholipids and subsequent arachidonate-derived PGE2 synthesis will provide insight into the anti-promoter mechanisms of CLA

Diet and sex hormone-binding globulin.

Longcope C, Feldman HA, McKinlay JB, et al.

J Clin Endocrinol Metab. 2000 Jan; 85(1):293-6.

The serum concentration of sex hormone-binding globulin (SHBG) is inversely related to weight and in animal studies is inversely related to protein intake. As SHBG can affect the biological activity of testosterone and estradiol, we wished to determine the role of protein intake on SHBG levels in men. Using data from the Massachusetts Male Aging Study we examined cross-sectional relationships between dietary components and SHBG levels in 1552 men (aged 40-70 yr) for whom these factors were known. Analyzed by multiple regression, controlling for testosterone and estradiol levels, age (P<0.001) and fiber intake (P = "0.02)" were positively correlated to SHBG concentration, whereas body mass index (P<0.001) and protein intake (P<0.03) were negatively correlated to SHBG concentration. The intakes of calories, fat (animal or vegetable), and carbohydrate were not related to SHBG concentration. We conclude that age and body mass index are major determinants of SHBG concentrations in older men, and fiber and protein intake are also significant contributors to SHBG levels, but total caloric intake and the intake of carbohydrate or fat are not significant. Thus, diets low in protein in elderly men may lead to elevated SHBG levels and decreased testosterone bioactivity. The decrease in bioavailable testosterone can then result in declines in sexual function and muscle and red cell mass, and contribute to the loss of bone density

Putative mechanism of blood pressure reduction induced by increases in dietary calcium intake.

Luft FC.

Am J Hypertens. 1990 Aug; 3(8 Pt 2):156S-60S.

An increase in dietary calcium intake lowers blood pressure in spontaneously hypertensive rats and in some patients with arterial hypertension. The mechanisms by which this decrease come about are not clear. A membrane-stabilizing effect wrought by an increase in extracellular calcium would appear unlikely, since the increases in extracellular calcium concentration with increased dietary intake are minimal. Calcium regulatory hormones may be the mediators, and a cybernetic framework has been suggested. Striking defects have been reported in the calcium handling and hormonal household of the spontaneously hypertensive rat. However, a clear cut relationship in terms of a hormonal "template" has not yet been identified in prospective experiments. Data have been presented to show that increased calcium intake has a direct effect on regulatory areas in the brain. However, the mechanisms by which such a response would be mediated are entirely unknown. Increased calcium intake may induce natriuresis. It has been suggested that increased calcium intake helps the "salt sensitive"; however, prospective studies to this effect have not been presented. Increased calcium intake may induce phosphaturia. However, the evidence that blood pressure lowering effects are mediated by phosphate depletion are unconvincing. Some evidence suggests that increased calcium intake may influence local regulatory processes which in turn influences cell integrity and growth. At this point, a unifying hypothesis is not available. However, the clues to various possibilities are intriguing

C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease.

Madsen T, Skou HA, Hansen VE, et al.

Am J Cardiol. 2001 Nov 15; 88(10):1139-42.

The acute-phase reactant C-reactive protein (CRP) has emerged as an independent risk factor for coronary artery disease. Experimental and clinical studies provide evidence of anti-inflammatory effects of n-3 polyunsaturated fatty acids (PUFA) derived from fish. We have studied the effect of marine n-3 PUFA on CRP levels in 269 patients referred for coronary angiography because of clinical suspicion of coronary artery disease. All patients filled out a food questionnaire regarding fish intake. The n-3 PUFA content of granulocyte membranes was determined and the concentration of CRP in serum was measured using a highly sensitive assay. The results were related to angiographic findings. CRP was significantly higher in patients with significant coronary stenoses than in those with no significant angiographic changes (p <0.001), but the CRP levels were not associated with the number of diseased vessels. Subjects with CRP levels in the lower quartile had a significantly higher content of docosahexaenoic acid (DHA) in granulocytes than subjects with CRP levels in the upper quartile (p = "0.02)," and in a multivariate linear regression analysis, DHA was independently correlated to CRP (R(2) = "0.179;" p = "0.003)." The inverse correlation between CRP and DHA may reflect an anti-inflammatory effect of DHA in patients with stable coronary artery disease and suggest a novel mechanism by which fish consumption may decrease the risk of coronary artery disease

In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress.

Maes M, Christophe A, Bosmans E, et al.

Biol Psychiatry. 2000 May 15; 47(10):910-20.

BACKGROUND: Psychologic stress in humans induces the production of proinflammatory cytokines, such as interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL-6), and that of the negative immunoregulatory cytokine, IL-10. An imbalance of omega6 to omega3 polyunsaturated fatty acids (PUFAs) in the peripheral blood causes an overproduction of proinflammatory cytokines. The omega3 PUFAs reduce the production of proinflammatory cytokines. METHODS: This study examines whether an imbalance in omega6 to omega3 PUFAs in human blood predicts a greater production of proinflammatory cytokines in response to psychologic stress. Twenty-seven university students had serum sampled a few weeks before and after as well as 1 day before a difficult oral examination. We determined the omega6 and omega3 fractions in serum phospholipids as well as the ex vivo production of IFN-gamma, TNF-alpha, IL-6, IL-10, and IL-5 by diluted whole blood stimulated with polyclonal activators. RESULTS: Academic examination stress significantly increased the ex vivo, stimulated production of IFN-gamma, TNF-alpha and IL-10, and the IFN-gamma/IL-5 production ratio. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had significantly greater stress-induced TNF-alpha and IFN-gamma responses than subjects with higher serum omega3 PUFAs and a lower omega6/omega3 ratio, respectively. Subjects with lower serum omega3 PUFA levels or with a higher omega6/omega3 ratio had a significantly higher stress-induced increase in the IFN-gamma/IL-5 ratio than the remaining subjects. CONCLUSIONS: Psychologic stress induces a Th-1-like or proinflammatory response in some subjects. An imbalance in the omega6 to omega3 PUFA ratio appears to predispose humans toward an exaggerated Th-1-like response and an increased production of monocytic cytokines, such as TNF-alpha, in response to psychologic stress. The results suggest that increased omega3 PUFA levels may attenuate the proinflammatory response to psychologic stress

[Homocysteine as a nonlipid factor in the pathogenesis of atherosclerosis].

Magott M.

Postepy Hig Med Dosw. 1998; 52(3):259-67.

Genetic abnormalities in two metabolic steps in homocysteine degradation: transsulfuration and remetylation can cause raised plasma homocysteine concentration. Homocysteine appeared to be an independent arteriosclerotic risk factor in the coronary, cerebral and peripheral circulation and elevated homocysteine levels have been found in chronic renal failure patients undergoing hemodialysis treatment and in transplant patients as well. Homocysteine has a direct toxic effect on endothelial cells, reduces normal activation of protein C by endothelial cells, increases the binding of Lp(a) to plasmin-modified fibrin, induces tissue factor procoagulant activity and inhibits the cofactor activity of thrombomodulin. Treatment with folic acid and piridoxine can lower the high level of homocysteine and should be associated with a clinical benefit

Integrative approaches to hypertension.

Maizes V.

Clinics Fam Practice. 2002;(4):895-905.

Dietary calcium and blood pressure: modifying factors in specific populations.

McCarron DA, Morris CD, Young E, et al.

Am J Clin Nutr. 1991 Jul; 54(1 Suppl):215S-9S.

Epidemiologic findings continue to add to the body of evidence supporting a relationship between calcium intake and blood pressure. These findings also indicate that there is a threshold of the potential protective effect of adequate calcium intake, below which the risk of hypertension increases at a greater rate. The set point of this threshold, estimated at 700-800 mg/d, may be modified by a variety of factors including dietary patterns and components, lifestyle, and genetics. This may explain, at least in part, the heterogeneous response observed in dietary-intervention studies. In animal models of hypertension it was shown that greater amounts of calcium must be given to cause a blood pressure change comparable with that in normal animals, suggesting that in high-risk human populations in which calcium metabolism may be disordered, calcium intake may have to be increased to amounts greater than 700-800 mg/d to demonstrate the blood-pressure-lowering effect. Calcium intake at or above the currently recommended daily allowance of 800 mg could be of potential benefit to certain racial groups, individuals ingesting excessive alcohol, and pregnant women, all of whom generally consume low amounts of calcium and who are at higher risk of developing hypertension

Role of adequate dietary calcium intake in the prevention and management of salt-sensitive hypertension.

McCarron DA.

Am J Clin Nutr. 1997 Feb; 65(2 Suppl):712S-6S.

During the past decade, a credible body of evidence has emerged supporting the concept that maintaining an adequate dietary mineral intake, specifically of calcium, magnesium, and potassium, protects against high blood pressure in humans. Observational and interventional studies in humans and extensive use of laboratory models showed that a significant portion of blood pressure variability in response to sodium chloride can be linked to the adequacy of the mineral content of the diet. This review summarizes the observational data from several large databases showing that when adults meet or exceed the recommended dietary allowances of calcium, potassium, and magnesium, the simultaneous ingestion of a diet high in sodium chloride is not associated with elevated arterial pressure. In fact, a higher sodium chloride intake in these adults is most likely associated with the lowest blood pressure in the society. This interaction between adequacy of mineral intake and protection against salt sensitivity in humans provides an important opportunity for further improving blood pressure control in our society. Educating individuals to maintain, on a daily basis, adequate intakes of calcium, potassium, and magnesium rather than limit their sodium chloride is a viable health recommendation that individuals can implement to reduce their risk of sodium chloride-induced hypertension

Importance of dietary calcium in hypertension.

McCarron DA.

J Am Coll Nutr. 1998 Feb; 17(1):97-9.

Homocysteine and vascular disease.

McCully KS.

Nat Med. 1996 Apr; 2(4):386-9.

Homocysteine and endothelial dysfunction: a link with cardiovascular disease.

McDowell IF, Lang D.

J Nutr. 2000 Feb; 130(2S Suppl):369S-72S.

The nature of the link between homocysteine and cardiovascular disease has not yet been clearly established. Impaired endothelium-independent vasodilatation is an early feature of vascular disease. In human studies, methionine loading, which acutely elevates plasma homocysteine, induces endothelial dysfunction. Folate therapy, which lowers homocysteine, enhances endothelial function. This is consistent with, but not proof of, homocysteine toxicity to endothelium in vivo. Homocysteine, in high concentration, can induce endothelial dysfunction in vitro. This is accompanied by increased superoxide production, which when inhibited, restores normal endothelial function. These observations suggest that homocysteine may induce vascular endothelial dysfunction by a mechanism involving reactive oxygen species

The inconsistent effects of calcium supplements upon blood pressure in primary hypertension.

Meese RB, Gonzales DG, Casparian JM, et al.

Am J Med Sci. 1987 Oct; 294(4):219-24.

The effects of 800 mg of elemental calcium per day (calcium carbonate or calcium citrate) on blood pressure were compared with a placebo in a controlled randomized, crossover, double-blinded trial involving 26 patients with uncomplicated primary hypertension. Each patient took two of the three forms of therapy orally for 8-week intervals with a 2-week washout period in between. Standing mean blood pressure rose an average of 5.7 mm Hg on placebo, rose an average of 0.5 mm Hg on calcium carbonate, and fell an average of 2.2 mm Hg on calcium citrate. Changes in sitting mean pressures averaged +1.9 mm Hg on placebo, -0.4 mm Hg on calcium carbonate, and -0.4 mm Hg on calcium citrate. Some patients had a fall, others had a rise in blood pressure on each form of calcium. Similarly, inconsistent responses were noted among the nine patients who took both forms of calcium. Neither initial nor post-treatment biochemical measures nor patient characteristics were predictive of the blood pressure response. Combinations of various measures and characteristics analyzed by the multiple regression technique explained only 30% of the overall variability in blood pressure. Therefore, until ways can be found to predict the response, calcium supplements should not be routinely prescribed for the treatment of hypertension and, if given for any indication, blood pressure should be monitored

Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects.

Mensink RP, Katan MB.

N Engl J Med. 1990 Aug 16; 323(7):439-45.

BACKGROUND. Fatty acids that contain a trans double bond are consumed in large amounts as hydrogenated oils, but their effects on serum lipoprotein levels are unknown. METHODS. We placed 34 women (mean age, 26 years) and 25 men (mean age, 25 years) on three mixed natural diets of identical nutrient composition, except that 10 percent of the daily energy intake was provided as oleic acid (which contains one cis double bond), trans isomers of oleic acid, or saturated fatty acids. The three diets were consumed for three weeks each, in random order. RESULTS. On the oleic acid diet, the mean (+/- SD) serum values for the entire group for total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were 4.46 +/- 0.66. 2.67 +/- 0.54, and 1.42 +/- 0.32 mmol per liter (172 +/- 26, 103 +/- 21, and 55 +/- 12 mg per deciliter), respectively. On the trans-fatty-acid diet, the subjects' mean HDL cholesterol level was 0.17 mmol per liter (7 mg per deciliter) lower than the mean value on the diet high in oleic acid (P less than 0.0001; 95 percent confidence interval, 0.13 to 0.20 mmol per liter). The HDL cholesterol level on the saturated-fat diet was the same as on the oleic acid diet. The LDL cholesterol level was 0.37 mmol per liter (14 mg per deciliter) higher on the trans-fatty-acid diet than on the oleic acid diet (P less than 0.0001; 95 percent confidence interval, 0.28 to 0.45 mmol per liter) and 0.47 mmol per liter (18 mg per deciliter) higher on the saturated-fat diet (P less than 0.001; 95 percent confidence interval, 0.39 to 0.55 mmol per liter) than on the oleic acid diet. The effects on lipoprotein levels did not differ between women and men. CONCLUSIONS. The effect of trans fatty acids on the serum lipoprotein profile is at least as unfavorable as that of the cholesterol-raising saturated fatty acids, because they not only raise LDL cholesterol levels but also lower HDL cholesterol levels

Effect of dietary cis and trans fatty acids on serum lipoprotein[a] levels in humans.

Mensink RP, Zock PL, Katan MB, et al.

J Lipid Res. 1992 Oct; 33(10):1493-501.

Serum lipoprotein[a] (Lp[a]) is a strong risk factor for coronary heart disease. We therefore examined the effect of dietary fatty acid composition on serum Lp[a] levels in three strictly controlled experiments with healthy normocholesterolemic men and women. In Expt. I, 58 subjects consumed a control diet high in saturated fatty acids for 17 days. For the next 36 days, 6.5% of total energy intake from saturated fatty acids was replaced by monounsaturates plus polyunsaturates (monounsaturated fatty acid diet; n = 29) or by polyunsaturates alone (polyunsaturated fatty acid diet; n = 29). Both diets caused a slight, nonsignificant, increase in median Lp[a] levels, with no difference between diets. In Expt. II, 10% of energy from the cholesterol-raising saturated fatty acids (lauric, myristic, and palmitic acid) was replaced by oleic acid or by trans-monounsaturated fatty acids. Each of the 59 participants received each diet for 3 weeks in random order. The median level of Lp[a] was 26 mg/l on the saturated fatty acid diet; it increased to 32 mg/l (P less than 0.020) on the oleic acid diet and to 45 mg/l (P less than 0.001) on the trans-fatty acid diet. The difference in Lp[a] between the trans-fatty acid and the oleic acid diets was also highly significant (P less than 0.001). Expt. III involved 56 subjects; all received 8% of energy from stearic acid, from linoleic acid, or from trans-monounsaturates, for 3 weeks each. All other nutrients were equal.(ABSTRACT TRUNCATED AT 250 WORDS)

Gamma linolenic acid attenuates cardiovascular responses to stress in borderline hypertensive rats.

Mills DE, Summers MR, Ward RP.

Lipids. 1985 Sep; 20(9):573-7.

The purpose of the present study was to investigate the effects of gamma linolenic acid (GLA) on cardiovascular responses to psychosocial stress (isolation) and to pressor hormones in the genetically borderline hypertensive rat (SHR X WKY). Adult male SHR X WKY were divided into two groups following five weeks of group housing. One group (GLA) received eight weeks constant flow osmotic pumps releasing 0.04 mg GLA in olive oil/kg-hr, while the second group received dummy pumps (DUM). One week following pump implantation, each group was divided into two subgroups and exposed to a four-week experimental period of either continued group housing (no stress) or isolation (stress). A two-week recovery period of group housing followed the experimental period. Blood pressure and heart rate were determined weekly by the tail cuff technique. At the end of the recovery period, animals in the no stress condition were anesthetized and received an arterial cannula for NOR and ANG infusion and direct BP recording. Then the responses to an ED50 of NOR and ANG were determined. All animals were then killed for determination of heart weight and adrenal weight. All groups had mean control period systolic BP values ranging from 143-146 mm Hg. In the no stress condition, neither GLA nor DUM altered BP over the course of the study. However, BP increased in the DUM group during all four weeks of the isolation period vs the control period (p less than 0.01), whereas BP increased only in week 1 in the GLA group (p less than 0.05). Heart rate increased during stress in the DUM group (p less than 0.05), but not in the GLA group. Vascular reactivity to NOR was unaffected by GLA administration.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of essential fatty acid administration on cardiovascular responses to stress in the rat.

Mills DE, Ward RP.

Lipids. 1986 Feb; 21(2):139-42.

This study examined the effects of 18:2(n-6), 18:3(n-6), 20:4(n-6) and 18:3(n-3) on cardiovascular responses to isolation stress in male rats. Group-acclimated rats were fasted for 2 days, then placed on a fat-free diet. Two wk later animals were divided into six groups (six animals per group) and given eight-wk intraperitoneal osmotic pumps releasing 1.47 X 10(-7) mol/hr of either olive oil (OL), or of 18:2(n-6), 18:3(n-6), 20:4(n-6) or 18:3(n-3) in OL. Another group received dummy pumps. Two wk after pump implantation, animals were isolated for four wk. Blood pressure (BP), heart rate and body weight were followed before and during stress. Following the stress period, animals were assessed for cardiovascular reactivity to norepinephrine (NOR) and angiotensin (ANG). Prior to isolation, 18:3(n-6) lowered BP vs OL (p less than 0.01). Stress increased BP within 24 hr in all groups except 18:3(n-6) and 20:4(n-6). Treatment with 20:4(n-6) vs OL prevented the BP rise (p less than 0.001) only for the first two wk of stress. Administration of 18:3(n-6) vs OL prevented any BP increase over the four-wk stress period (p less than 0.001). Stress increased heart rate in all groups except 20:4(n-6). Heart rate was lowered by 18:3(n-6) vs OL (p less than 0.01) before and during stress. Vascular reactivity to NOR was unaffected by treatment, but OL and 18:3(n-6) decreased responses to ANG infusion. These data suggest that 18:3(n-6) supplementation attenuates cardiovascular responses to chronic stress, and that delta 6- and delta 5-desaturase activity are inhibited during chronic psychological stress

Relationship of blood pressure to 25-year mortality due to coronary heart disease, cardiovascular diseases, and all causes in young adult men: the Chicago Heart Association Detection Project in Industry.

Miura K, Daviglus ML, Dyer AR, et al.

Arch Intern Med. 2001 Jun 25; 161(12):1501-8.

BACKGROUND: Data are limited on blood pressure (BP) in young adults and long-term mortality. Moreover, screening and hypertension treatment guidelines have been based mainly on findings for middle-aged and older populations. This study assesses relationships of BP measured in young adult men to long-term mortality due to coronary heart disease (CHD), cardiovascular diseases (CVD), and all causes. METHODS: This cohort from the Chicago Heart Association Detection Project in Industry included 10 874 men aged 18 to 39 years at baseline (1967-1973), not receiving antihypertensive drugs, and without CHD or diabetes. Relationship of baseline BP to 25-year CHD, CVD, and all-cause mortality was assessed. RESULTS: Age-adjusted association of systolic BP to CHD mortality was continuous and graded. Multivariate-adjusted CHD hazard ratios (HRs) for 1 SD higher systolic BP (15 mm Hg) and diastolic BP (10 mm Hg) were 1.26 (95% confidence interval [CI], 1.11-1.44) and 1.17 (95% CI, 1.01-1.35), respectively. Compared with the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure stratum with normal BP (and lowest mortality rates), the large strata with high-normal BP and stage 1 hypertension had 25-year absolute risks for death of 63 and 72 per 1000, respectively, and absolute excess risks of 10 and 20 per 1000, respectively; accounted for 59.8% of all excess CHD, CVD, and all-cause mortality; and were estimated to have life expectancy shortened by 2.2 and 4.1 years, respectively. CONCLUSIONS: In young adult men, BP above normal was significantly related to increased long-term mortality due to CHD, CVD, and all causes. Population-wide primary prevention, early detection, and control of higher BP are indicated from young adulthood on

Docosahexaenoic acid but not eicosapentaenoic acid lowers ambulatory blood pressure and heart rate in humans.

Mori TA, Bao DQ, Burke V, et al.

Hypertension. 1999 Aug; 34(2):253-60.

Animal studies suggest that the 2 major omega3 fatty acids found in fish, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), may have differential effects on blood pressure (BP) and heart rate (HR). The aim of this study was to determine whether there were significant differences in the effects of purified EPA or DHA on ambulatory BP and HR in humans. In a double-blind, placebo-controlled trial of parallel design, 59 overweight, mildly hyperlipidemic men were randomized to 4 g/d of purified EPA, DHA, or olive oil (placebo) capsules and continued their usual diets for 6 weeks. Fifty-six subjects completed the study. Only DHA reduced 24-hour and daytime (awake) ambulatory BP (P<0.05). Relative to the placebo group, 24-hour BP fell 5.8/3.3 (systolic/diastolic) mm Hg and daytime BP fell 3.5/2.0 mm Hg with DHA. DHA also significantly reduced 24-hour, daytime, and nighttime (asleep) ambulatory HRs (P="0." 001). Relative to the placebo group, DHA reduced 24-hour HR by 3. 5+/-0.8 bpm, daytime HR by 3.7+/-1.2 bpm, and nighttime HR by 2. 8+/-1.2. EPA had no significant effect on ambulatory BP or HR. Supplementation with EPA increased plasma phospholipid EPA from 1. 66+/-0.07% to 9.83+/-0.06% (P<0.0001) but did not change DHA levels. Purified DHA capsules increased plasma phospholipid DHA levels from 4.00+/-0.27% to 10.93+/-0.62% (P<0.0001) and led to a small, nonsignificant increase in EPA (1.52+/-0.12% to 2.26+/-0.16%). Purified DHA but not EPA reduced ambulatory BP and HR in mildly hyperlipidemic men. The results of this study suggest that DHA is the principal omega3 fatty acid in fish and fish oils that is responsible for their BP- and HR-lowering effects in humans. These results have important implications for human nutrition and the food industry

Aged garlic extract enhances production of nitric oxide.

Morihara N, Sumioka I, Moriguchi T, et al.

Life Sci. 2002 Jun 21; 71(5):509-17.

Nitric oxide (NO) controls several physiological functions of the cardiovascular system. Three kinds of NO synthases (NOSs), neuronal constitutive NOS (ncNOS), inducible NOS (iNOS) and endothelial constitutive NOS (ecNOS), were responsible for NO biosynthesis. This study investigated the effect of aged garlic extract (AGE) on NO production by measuring the NO metabolites nitrite and nitrate in the plasma of mice. AGE (2.86 g/kg, p.o.) temporarily increased NO production by 30-40% from 15 to 60 min after administration. The time course of the fluctuation in NO levels in the AGE-treated group was clearly different to that in a group of mice treated with lipopolysaccharides, a typical iNOS inducer. Arginine (63 mg/kg, p.o.) at the equivalent dose of AGE did not increase NO production. However diphenyleneiodonium chloride (1 mg/kg, i.p.), a selective cNOS inhibitor, administered prior to AGE, overcame the effect of AGE. These results indicate that AGE increased NO production by activating cNOS, but not iNOS. The arginine contained in AGE was not responsible for the effect. AGE may be a useful tool for the prevention of cardiovascular disease

Eicosapentaenoic acid protects endothelial cell function injured by hypoxia/reoxygenation.

Morita I, Zhang YW, Murota SI.

Ann N Y Acad Sci. 2001 Dec; 947:394-7.

Eicosapentaenoic acid (EPA) may protect against atherosclerosis by improving lipid metabolism and modulating vascular cell function. Ischemia/ reperfusion injury is one risk factor for atherosclerosis. We investigated if EPA could improve hypoxia/reoxygenation (H/R)-induced endothelial cell dysfunction of gap junctional intercellular communication (GJIC). GJIC in human umbilical vascular endothelial cells (HUVECs) was measured using a photobleaching technique. Results demonstrated that H (24h)/R 2h) induced a GJIC reduction in HUVECs; however, it was inhibited by EPA pretreatment. H/R produced reactive oxygen species, but it was not affected by EPA, and it contributed little to GJIC dysfunction. By contrast, tyrosine kinase activated by H/R was inhibited by EPA pretreatment, and tyrosine kinase inhibitors also abolished H/R-induced GJIC reduction. The protective effects of EPA on the H/R-induced GJIC reduction was also observed in cells treated with tyrosine phosphatase inhibitor. These data indicate the EPA improves H/R-induced endothelial dysfunction through inhibition of tyrosine kinase activation, and it could lead to prevention of progression and/or initiation of atherosclerosis

Fish oil to reduce blood pressure: a metabolism-analysis.

Morris MC SFRB.

Ann Intern Med. 1994;(120):10.


Potassium responsive hypertension. In: Hypertension: pathophysiology, diagnosis, and management. 2nd Ed.

Morris RC SA.



Endogenous sex hormones and cardiovascular disease in men.

Muller M, van der Schouw YT, Thijssen JH, et al.

J Clin Endocrinol Metab. 2003 Nov; 88(11):5076-86.

Unlike women, men do not experience an abrupt reduction in endogenous sex hormone production. It has, however, become clear that an age-associated decrease in the levels of (bioactive) sex hormones does occur. Whether endogenous sex hormones have an impact on cardiovascular disease has for many years remained largely unknown, but during the last decade more attention has been drawn to the importance of testosterone, estrogens, and adrenal androgens in etiology, prevention, and treatment of male cardiovascular disease. The purpose of this article is to summarize the evidence currently available on the association between endogenous sex hormones and cardiovascular disease in males. Published studies dealing with the relationship between circulating levels of sex hormones and cardiovascular disease in males were reviewed. The studies reviewed in this article suggest that circulating endogenous sex hormones and estrogens have a neutral or beneficial effect on cardiovascular disease in men

Endocrinol Metab .

Nadler JL RR.

Metab Clin N Am. 1995;(24):623-41.

Relationships between types of fat consumed and serum estrogen and androgen concentrations in Japanese men.

Nagata C, Takatsuka N, Kawakami N, et al.

Nutr Cancer. 2000; 38(2):163-7.

The relationships between types of fat consumed and serum concentrations of estrone, estradiol, total and free testosterone, dihydrotestosterone, and sex hormone-binding globulin were examined in 69 Japanese men aged 43-88 years. Diet was assessed by a semiquantitative food frequency questionnaire. Intake of saturated, monounsaturated, and polyunsaturated fats was inversely correlated with serum total testosterone after controlling for age, total energy, body mass index, alcohol intake, and smoking status, but the correlation was statistically significant only for polyunsaturated fat (r = -0.29, p = 0.02). Intakes of eicosapentanoic and docosahexaenoic acids, n-3 fatty acids from fish, were significantly inversely correlated with total testosterone (r = -0.25, p = 0.04 and r = -0.32, p = 0.01, respectively). Serum estrone, estradiol, and free testosterone were not significantly correlated with any type of fat studied. The correlations of total testosterone with n-3 fatty acids from fish remained significant after additional adjustment for the other categories of fat (r = -0.27, p = 0. 03 for eicosapentanoic acid and r = -0.32, p = 0.01 for docosahexaenoic acid), while the correlations with saturated and monounsaturated fats became nearly null after the adjustment

Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins.

Nappo F, De Rosa N, Marfella R, et al.

JAMA. 1999 Jun 9; 281(22):2113-8.

CONTEXT: Increased levels of homocysteine are associated with risk of cardiovascular disease. Homocysteine may cause this risk by impairing endothelial cell function. OBJECTIVE: To evaluate the effect of acute hyperhomocysteinemia with and without antioxidant vitamin pretreatment on cardiovascular risk factors and endothelial functions. DESIGN AND SETTING: Observer-blinded, randomized crossover study conducted at a university hospital in Italy. SUBJECTS: Twenty healthy hospital staff volunteers (10 men, 10 women) aged 25 to 45 years. INTERVENTIONS: Subjects were given each of 3 loads in random order at 1-week intervals: oral methionine, 100 mg/kg in fruit juice; the same methionine load immediately following ingestion of antioxidant vitamin E, 800 IU, and ascorbic acid, 1000 mg; and methionine-free fruit juice (placebo). Ten of the 20 subjects also ingested a placebo load with vitamins. MAIN OUTCOME MEASURES: Lipid, coagulation, glucose, and circulating adhesion molecule parameters, blood pressure, and endothelial functions as assessed by hemodynamic and rheologic responses to L-arginine, evaluated at baseline and 4 hours following ingestion of the loads. RESULTS: The oral methionine load increased mean (SD) plasma homocysteine level from 10.5 (3.8) micromol/L at baseline to 27.1 (6.7) micromol/L at 4 hours (P<.001). A similar increase was observed with the same load plus vitamins (10.0 [4.0] to 22.7 [7.8] micromol/L; P<.001) but no significant increase was observed with placebo (10.1 [3.7] to 10.4 [3.2] micromol/L; P=".75)." Coagulation and circulating adhesion molecule levels significantly increased after methionine ingestion alone (P<.05) but not after placebo or methionine ingestion with vitamins. While the mean (SD) blood pressure (-7.0% [2.7%]; P<.001), platelet aggregation response to adenosine diphosphate (-11.4% [4.5%]; P=".009)" and blood viscosity (-3.0% [1.2%]; P=".04)" declined in these parameters 10 minutes after an L-arginine load (3 g) following placebo, the increase after methionine alone (-2.3% [1.5%], 4.0% [3.0%], and 1.5% [1.0%], respectively; P<.05), did not occur following methionine load with vitamin pretreatment (-6.3% [2.5%], -7.9% [3.5%], and -1.5% [1.0%], respectively; P=".24)." CONCLUSION: Our data suggest that mild to moderate elevations of plasma homocysteine levels in healthy subjects activate coagulation, modify the adhesive properties of endothelium, and impair the vascular responses to L-arginine. Pretreatment with antioxidant vitamin E and ascorbic acid blocks the effects of hyperhomocysteinemia, suggesting an oxidative mechanism

Thiolation of low-density lipoprotein by homocysteine thiolactone causes increased aggregation and altered interaction with cultured macrophages.

Naruszewicz M MEOA.

Nutr Metab Cardiovasc Dis. 1994;(4):70-7.


Effect of zinc administration on plasma testosterone, dihydrotestosterone, and sperm count.

Netter A, Hartoma R, Nahoul K.

Arch Androl. 1981 Aug; 7(1):69-73.

The effects of zinc therapy on plasma testosterone (T), dihydrotestosterone (DHT), and sperm count were studied in 37 patients with idiopathic infertility of more than five years duration. In the first group (T less than 4.8 ng/ml; 22 patients), T and DHT rose significantly after oral administration of zinc, as did the sperm count. Nine wives became pregnant, six within 3 months and three within 2 months of a second trial. In the second group (T greater than or equal to 4.8 ng/ml; 15 patients), T and sperm count were unaffected by zinc, while DHT increased significantly. There was no conception observed. The rationale of this treatment and the significance of the results are discussed

Antihypertensive efficacy of olmesartan medoxomil, a new angiotensin II receptor antagonist, as assessed by ambulatory blood pressure measurements.

Neutel JM, Elliott WJ, Izzo JL, et al.

J Clin Hypertens (Greenwich ). 2002 Sep; 4(5):325-31.

Olmesartan medoxomil is a new angiotensin II receptor blocker. In this randomized, double-blind, placebo-controlled study, the efficacy and safety of olmesartan medoxomil was assessed in 334 patients with moderate to severe essential hypertension. Patients were randomized to receive placebo; 5, 20, or 80 mg olmesartan medoxomil q.d.; or 2.5, 10, or 40 mg olmesartan medoxomil b.i.d. Ambulatory and cuff blood pressure were measured prior to and after 8 weeks of treatment. Treatment with olmesartan medoxomil resulted in a significant placebo-adjusted reduction of mean 24-hour ambulatory diastolic blood pressure of 9.6 mm Hg, 12.2 mm Hg, and 10.6 mm Hg in the 5-, 20-, and 80-mg q.d. groups, respectively. Corresponding reductions in mean ambulatory systolic blood pressure were 14.5 mm Hg, 16.5 mm Hg, and 15.4 mm Hg. Similar reductions of diastolic and systolic blood pressure were seen with b.i.d. dosing. The diastolic trough-to-peak ratios of the q.d. doses of olmesartan medoxomil ranged from 57%-70%, indicating 24-hour effectiveness. The safety profile of olmesartan medoxomil was similar to that of placebo. Olmesartan medoxomil appears to be a safe and effective once-a-day treatment for hypertension

Effect of gamma tocotrienol on blood pressure, lipid peroxidation and total antioxidant status in spontaneously hypertensive rats (SHR).

Newez MA.

Clin Exp Hyperten. 1999;(21):1297-313.

Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery.

Newman MF, Kirchner JL, Phillips-Bute B, et al.

N Engl J Med. 2001 Feb 8; 344(6):395-402.

BACKGROUND: Cognitive decline complicates early recovery after coronary-artery bypass grafting (CABG) and may be evident in as many as three quarters of patients at the time of discharge from the hospital and a third of patients after six months. We sought to determine the course of cognitive change during the five years after CABG and the effect of perioperative decline on long-term cognitive function. METHODS: In 261 patients who underwent CABG, neurocognitive tests were performed preoperatively (at base line), before discharge, and six weeks, six months, and five years after CABG surgery. Decline in postoperative function was defined as a drop of 1 SD or more in the scores on tests of any one of four domains of cognitive function. (A reduction of 1 SD represents a decline in function of approximately 20 percent.) Overall neurocognitive status was assessed with a composite cognitive index score representing the sum of the scores for the individual domains. Factors predicting long-term cognitive decline were determined by multivariable logistic and linear regression. RESULTS: Among the patients studied, the incidence of cognitive decline was 53 percent at discharge, 36 percent at six weeks, 24 percent at six months, and 42 percent at five years. We investigated predictors of cognitive decline at five years and found that cognitive function at discharge was a significant predictor of long-term function (P<0.001). CONCLUSIONS: These results confirm the relatively high prevalence and persistence of cognitive decline after CABG and suggest a pattern of early improvement followed by a later decline that is predicted by the presence of early postoperative cognitive decline. Interventions to prevent or reduce short- and long-term cognitive decline after cardiac surgery are warranted

Beyond Aspirin .

Newmark TM SP.


Beyond Aspirin .

Newmark TM SP.


Antihypertensive agents and the drug therapy of hypertension. In: Goodman & Gilman's The Pharmacological Basis of Therapeutics.

Oates JA BN.

2001; 10:871-900.

Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells.

Outinen PA, Sood SK, Pfeifer SI, et al.

Blood. 1999 Aug 1; 94(3):959-67.

Alterations in the cellular redox potential by homocysteine promote endothelial cell (EC) dysfunction, an early event in the progression of atherothrombotic disease. In this study, we demonstrate that homocysteine causes endoplasmic reticulum (ER) stress and growth arrest in human umbilical vein endothelial cells (HUVEC). To determine if these effects reflect specific changes in gene expression, cDNA microarrays were screened using radiolabeled cDNA probes generated from mRNA derived from HUVEC, cultured in the absence or presence of homocysteine. Good correlation was observed between expression profiles determined by this method and by Northern blotting. Consistent with its adverse effects on the ER, homocysteine alters the expression of genes sensitive to ER stress (ie, GADD45, GADD153, ATF-4, YY1). Several other genes observed to be differentially expressed by homocysteine are known to mediate cell growth and differentiation (ie, GADD45, GADD153, Id-1, cyclin D1, FRA-2), a finding that supports the observation that homocysteine causes a dose-dependent decrease in DNA synthesis in HUVEC. Additional gene profiles also show that homocysteine decreases cellular antioxidant potential (glutathione peroxidase, NKEF-B PAG, superoxide dismutase, clusterin), which could potentially enhance the cytotoxic effects of agents or conditions known to cause oxidative damage. These results successfully demonstrate the use of cDNA microarrays in identifying homocysteine-respondent genes and indicate that homocysteine-induced ER stress and growth arrest reflect specific changes in gene expression in human vascular EC

Skeletal muscle membrane lipid composition is related to adiposity and insulin action.

Pan DA, Lillioja S, Milner MR, et al.

J Clin Invest. 1995 Dec; 96(6):2802-8.

The cellular basis of insulin resistance is still unknown; however, relationships have been demonstrated between insulin action in muscle and the fatty acid profile of the major membrane structural lipid (phospholipid). The present study aimed to further investigate the hypothesis that insulin action and adiposity are associated with changes in the structural lipid composition of the cell. In 52 adult male Pima Indians, insulin action (euglycemic clamp), percentage body fat (pFAT; underwater weighing), and muscle phospholipid fatty acid composition (percutaneous biopsy of vastus lateralis) were determined. Insulin action (high-dose clamp; MZ) correlated with composite measures of membrane unsaturation (% C20-22 polyunsaturated fatty acids [r= 0.463, P < 0.001], unsaturation index [r= "-0.369," P < 0.01]), a number of individual fatty acids and with delta5 desaturase activity (r= "0.451," P < 0.001). pFAT (range 14-53%) correlated with a number of individual fatty acids and delta5 desaturase activity (r= "-0.610," P < 0.0001). Indices of elongase activity (r= "-0.467," P < 0.001), and delta9 desaturase activity (r= "0.332," P < 0.05) were also related to pFAT but not insulin action. The results demonstrate that delta5 desaturase activity is independently related to both insulin resistance and obesity. While determining the mechanisms underlying this relationship is important for future investigations, strategies aimed at restoring "normal" enzyme activities, and membrane unsaturation, may have therapeutic importance in the "syndromes of insulin resistance."

Direct proinflammatory effect of C-reactive protein on human endothelial cells.

Pasceri V, Willerson JT, Yeh ET.

Circulation. 2000 Oct 31; 102(18):2165-8.

BACKGROUND: The acute-phase reactant C-reactive protein (CRP) is an important risk factor for coronary heart disease. However, the possible effects of CRP on vascular cells are not known. METHODS AND RESULTS: We tested the effects of CRP on expression of adhesion molecules in both human umbilical vein and coronary artery endothelial cells. Expression of vascular cell adhesion molecule (VCAM-1), intercellular adhesion molecule (ICAM-1), and E-selectin was assessed by flow cytometry. Incubation with recombinant human CRP (10 microg/mL) for 24 hours induced an approximately 10-fold increase in expression of ICAM-1 and a significant expression of VCAM-1, whereas a 6-hour incubation induced significant E-selectin expression. Adhesion molecule induction was similar to that observed in endothelial cells activated with interleukin-1beta. In coronary artery endothelial cells, induction of ICAM-1 and VCAM-1 was already present at 5 microg/mL and reached a maximum at 50 microg/mL, at which point a substantial increase in expression of E-selectin was also evident. The CRP effect was dependent on presence of human serum in the culture medium, because no effect was seen in cells cultured with serum-free medium. In contrast, interleukin-1beta was able to induce adhesion molecule expression in the absence of human serum. CONCLUSIONS: CRP induces adhesion molecule expression in human endothelial cells in the presence of serum. These findings support the hypothesis that CRP may play a direct role in promoting the inflammatory component of atherosclerosis and present a potential target for the treatment of atherosclerosis

Omega 3 fatty acid: a key nutrient in cancer care.

Pizzorno J.


Effect of medium-term supplementation with a moderate dose of n-3 polyunsaturated fatty acids on blood pressure in mild hypertensive patients.

Prisco D.


Syndrome X: Overcoming the Silent Killer That Can Give You a Heart Attack.

Reaven G STFB.


Randomized, double-blind, placebo-controlled study of supplemental oral L-arginine in patients with heart failure.

Rector TS, Bank AJ, Mullen KA, et al.

Circulation. 1996 Jun 15; 93(12):2135-41.

BACKGROUND. Patients with heart failure have reduced peripheral blood flow at rest, during exercise, and in response to endothelium-dependent vasodilators. Nitric oxide formed from L-arginine metabolism in endothelial cells contributes to regulation of blood flow under these conditions. A randomized, double-blind crossover study design was used to determine whether supplemental oral L-arginine can augment peripheral blood flow and improve functional status in patients with moderate to severe heart failure. METHODS AND RESULTS. Fifteen subjects were given 6 weeks of oral L-arginine hydrochloride (5.6 to 12.6 g/d) and 6 weeks of matched placebo capsules in random sequence. Compared with placebo, supplemental oral L-arginine significantly increased forearm blood flow during forearm exercise, on average from 5.1 +/- 2.8 to 6.6 +/- 3.4 mL. min-1. dL-1 (P < .05). Furthermore, functional status was significantly better on L-arginine compared with placebo, as indicated by increased distances during a 6-minute walk test (390 +/- 91 versus 422 +/- 86 m, P < .05) and lower scores on the Living With Heart Failure questionnaire (55 +/- 28 versus 42 +/- 26, P < .05). Oral L-arginine also improved arterial compliance from 1.99 +/- 0.38 to 2.36 +/- 0.30 mL/mm Hg (P < .001) and reduced circulating levels of endothelin from 1.9 +/- 1.1 to 1.5 +/- 1.1 pmol/L (P < .05). CONCLUSIONS. Supplemental oral L-arginine had beneficial effects in patients with heart failure. Further studies are needed to confirm the therapeutic potential of supplemental oral L-arginine and to identify mechanisms of action in patients with heart failure

Cardioprotective actions of wild garlic (allium ursinum) in ischemia and reperfusion.

Rietz B, Isensee H, Strobach H, et al.

Mol Cell Biochem. 1993 Feb 17; 119(1-2):143-50.

The susceptibility to ventricular arrhythmias under the conditions of cardiac ischemia and reperfusion was investigated in the Langendorff heart preparation of rats fed for eight weeks a standard chow enriched with 2% of pulverized wild garlic leaves. The isolated hearts were perfused with a modified Krebs-Henseleit solution. The incidence of ventricular fibrillation (VF) during 20 min occlusion of the descending branch of the left coronary artery (LAD) was significantly reduced in the wild garlic group as compared to untreated controls (20% vs 88%). The same holds for the size of the ischemic zone (33.6% vs 40.9% of heart weight). In the reperfusion experiments (5 min after 10 min ischemia), ventricular tachycardia (VT) occurred in 70% of the wild garlic group vs 100% in untreated controls and VF in 50% vs 90%. The time until occurrence of extrasystoles, VT or VR was prolonged. No significant alterations in cardiac fatty acid composition could be observed. Although the prostacyclin production was slightly increased in hearts of the wild garlic group, inhibition of cyclooxygenase by acetylsalicylic acid (ASA; aspirin) could not completely prevent the cardioprotective effects suggesting that the prostaglandin system does not play a decisive role in the cardioprotective action of wild garlic. Furthermore, a moderate angiotensin converting enzyme (ACE) inhibiting action of wild garlic was found in vitro as well as in vivo that could contribute to the cardioprotective and blood pressure lowering action of wild garlic. Whether a free radical scavenging activity of wild garlic is involved in its cardioprotective effects remains to be established

Hyperhomocysteinemia and low pyridoxal phosphate. Common and independent reversible risk factors for coronary artery disease.

Robinson K, Mayer EL, Miller DP, et al.

Circulation. 1995 Nov 15; 92(10):2825-30.

BACKGROUND: High plasma homocysteine is associated with premature coronary artery disease in men, but the threshold concentration defining this risk and its importance in women and the elderly are unknown. Furthermore, although low B vitamin status increases homocysteine, the link between these vitamins and coronary disease is unclear. METHODS AND RESULTS: We compared 304 patients with coronary disease with 231 control subjects. Risk factors and concentrations of plasma homocysteine, folate, vitamin B12, and pyridoxal 5'-phosphate were documented. A homocysteine concentration of 14 mumol/L conferred an odds ratio of coronary disease of 4.8 (P < .001), and 5-mumol/L increments across the range of homocysteine conferred an odds ratio of 2.4 (P < .001). Odds ratios of 3.5 in women and of 2.9 in those 65 years or older were seen (P < .05). Homocysteine correlated negatively with all vitamins. Low pyridoxal 5'-phosphate (< 20 nmol/L) was seen in 10% of patients but in only 2% of control subjects (P < .01), yielding an odds ratio of coronary disease adjusted for all risk factors, including high homocysteine, of 4.3 (P < .05). CONCLUSIONS: Within the range currently considered to be normal, the risk for coronary disease rises with increasing plasma homocysteine regardless of age and sex, with no threshold effect. In addition to a link with homocysteine, low pyridoxal-5'-phosphate confers an independent risk for coronary artery disease

Blood pressure, dietary fats, and antioxidants.

Salonen JT, Salonen R, Ihanainen M, et al.

Am J Clin Nutr. 1988 Nov; 48(5):1226-32.

We investigated the association of dietary fatty acids and antioxidants with blood pressure in 722 eastern Finnish men aged 54 y, examined in the Kuopio Ischaemic Heart Disease Risk Factor Study in 1984-86. Men with self-reported hypertension or cerebrovascular disease or under antihypertensive medication were excluded. Allowing for the major anthropometric, dietary, medical, and psychological determinants of blood pressure in multivariate regression analyses, both plasma ascorbic acid (p = 0.0008) and serum selenium (p = 0.0017) concentrations had a moderate, independent inverse association, estimated dietary intake of saturated fatty acids had a positive association (p = 0.013), and estimated dietary intake of linolenic acid had an inverse (p = 0.048) association with the mean resting blood pressure. The marked elevation of blood pressure at the lowest levels of plasma ascorbic acid and serum Se concentrations supports the hypothesis that antioxidants play a role in the etiology of hypertension

Feature Story: Getting to the heart of homocysteine testing.

Sandrick K.

CAP Today. 2000.Nov

Introduction to Clinical Nutrition .

Sardesai VM.


The effect of docosahexaenoic acid on plasma catecholamine concentrations and glucose tolerance during long-lasting psychological stress: a double-blind placebo-controlled study.

Sawazaki S, Hamazaki T, Yazawa K, et al.

J Nutr Sci Vitaminol (Tokyo). 1999 Oct; 45(5):655-65.

We previously found that docosahexaenoic acid (DHA) intake prevented aggression from increasing at times of mental stress. In the present study, we investigated whether DHA intake modified the plasma catecholamines and cortisol of medical students during a 9-wk period of final exams. We also investigated the effects of DHA intake on a 75 g oral glucose tolerance test (oGTT). Fourteen medical students participated in the present study. They were randomly allocated to either control or DHA group in a double-blind manner. Subjects in the control group (4 males and 3 females) took 10 control capsules/d, each capsule containing 280 mg of mixed plant oil, and those in the DHA group (4 males and 3 females) took 10 DHA capsules/d containing 1.5 g DHA for 9 wk, during which subjects underwent more than 20 stressful final exams. At the start and end of the study, plasma catecholamines (epinephrine, norepinephrine (NE) and dopamine) and cortisol were measured; a 75 g oGTT was also performed. There were no intra- or intergroup differences in plasma glucose concentrations. However, NE concentrations were significantly reduced after DHA administration (-31%, p < 0.03). The other catecholamines and cortisol did not change significantly. The plasma ratio of epinephrine to NE increased in every DHA subject (+78%, p < 0.02), and intergroup differences were significant (p < 0.03). We conclude that these effects of DHA may be applied to people under long-lasting psychological stress to prevent stress-related diseases

Changes in blood lipids and fibrinogen with a note on safety in a long term study on the effects of n-3 fatty acids in subjects receiving fish oil supplements and followed for seven years.

Saynor R, Gillott T.

Lipids. 1992 Jul; 27(7):533-8.

The present study was designed to assess the effectiveness of the n-3 fatty acids in modifying serum total, low density lipoprotein and high density lipoprotein (HDL) cholesterol, as well as serum triglycerides, over a seven-year period. Changes in plasma fibrinogen were recorded and long term safety assessed. A total of 365 subjects with ischemic heart disease (IHD), hyperlipidemia or a strong family history of IHD had their diet supplemented with MaxEPA (Seven Seas Ltd., Hull, England) fish oil containing 18-19% eicosapentaenoic acid. Venous blood samples were taken at regular intervals for lipid and fibrinogen assays and routine clinical chemistry and hematological profiling. Current medication was recorded and no further dietary modification was attempted. Triglyceride and fibrinogen were significantly reduced, whereas a significant reduction in total cholesterol occurred only in the subjects with a pre-oil level greater than 6.5 mmol/L. HDL cholesterol significantly increased over the study period. Clinical chemistry and hematological profiles were not adversely affected, and platelet count did not change significantly. The type of lipid changes observed were those usually considered antiatherogenic. Reducing fibrinogen may result in beneficial changes in the pathological processes leading to thrombotic occlusion. The consumption of MaxEPA by our patients over a seven-year period did not indicate any adverse effects

Decreased rate of coronary restenosis after lowering of plasma homocysteine levels.

Schnyder G, Roffi M, Pin R, et al.

N Engl J Med. 2001 Nov 29; 345(22):1593-600.

BACKGROUND: We have previously demonstrated an association between elevated total plasma homocysteine levels and restenosis after percutaneous coronary angioplasty. We designed this study to evaluate the effect of lowering plasma homocysteine levels on restenosis after coronary angioplasty. METHODS: A combination of folic acid (1 mg), vitamin B12 (400 microg), and pyridoxine (10 mg)--referred to as folate treatment--or placebo was administered to 205 patients (mean [+/-SD] age, 61+/-11 years) for six months after successful coronary angioplasty in a prospective, double-blind, randomized trial. The primary end point was restenosis within six months as assessed by quantitative coronary angiography. The secondary end point was a composite of major adverse cardiac events. RESULTS: Base-tine characteristics and initial angiographic results after coronary angioplasty were similar in the two study groups. Folate treatment significantly lowered plasma homocysteine levels from 11.1+/-4.3 to 7.2+/-2.4 micromol per liter (P<0.001). At follow-up, the minimal luminal diameter was significantly larger in the group assigned to folate treatment (1.72+/-0.76 vs. 1.45+/-0.88 mm, P="0.02)," and the degree of stenosis was less severe (39.9+/-20.3 vs. 48.2+/-28.3 percent, P="0.01)." The rate of restenosis was significantly lower in patients assigned to folate treatment (19.6 vs. 37.6 percent, P="0.01)," as was the need for revascularization of the target lesion (10.8 vs. 22.3 percent, P="0.047)." CONCLUSIONS: Treatment with a combination of folic acid, vitamin B12, and pyridoxine significantly reduces homocysteine levels and decreases the rate of restenosis and the need for revascularization of the target lesion after coronary angioplasty. This inexpensive treatment, which has minimal side effects, should be considered as adjunctive therapy for patients undergoing coronary angioplasty

Primary endothelial dysfunction: atherosclerosis.

Shimokawa H.

J Mol Cell Cardiol. 1999 Jan; 31(1):23-37.

The endothelium synthesizes and releases several vasodilating factors, including nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. Under certain conditions, it also liberates vasocontracting factors. Thus, the endothelium plays an important role in regulating vascular homeostasis. Several intracellular mechanisms are involved in the synthesis of nitric oxide, including receptor-coupled G proteins, the availability of L-arginine, cofactors for endothelial nitric oxide synthase and the expression of the enzyme. Endothelial dysfunction by aging, menopause and hypercholesterolemia is involved in the development of atherosclerotic vascular lesions, and predisposes the blood vessel to several vascular disorders, such as vasospasm and thrombosis. Multiple mechanisms are apparently involved in the pathogenesis of the endothelial dysfunction in atherosclerosis. The reduced production of nitric oxide by the endothelium is caused by abnormalities in endothelial signal transduction, availability of L-arginine, cofactors for endothelial nitric oxide synthase and expression of the enzyme. Other mechanisms may also be involved in the impaired endothelium-dependent relaxations in atherosclerosis, including increased destruction of nitric oxide by superoxide anion, altered responsiveness of vascular smooth muscle, and concomitant release of vasocontracting factors. In addition to the treatment of the underlying risk factors, several pharmacological agents can improve endothelial dysfunction in atherosclerosis. Thus, the endothelium is a novel therapeutic target for the treatment of atherosclerotic cardiovascular disease

Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group.

Shulman NB, Ford CE, Hall WD, et al.

Hypertension. 1989 May; 13(5 Suppl):I80-I93.

The Hypertension Detection and Follow-up Program followed up 10,940 persons for 5 years in a community-based, randomized, controlled trial of treatment for hypertension. Participants were randomized to one of two treatment groups, stepped care and referred care. The primary end point of the study was all-cause mortality, with morbid events involving the heart, brain, and kidney as secondary end points. Loss of renal function, ascertained by a change in serum creatinine, was among these secondary events. Baseline serum creatinine concentration had a significant prognostic value for 8-year mortality. For persons with a serum creatinine concentration greater than or equal to 1.7 mg/dl, 8-year mortality was more than three times that of all other participants. The estimated 5-year incidence of substantial decline in renal function was 21.7/1,000 in the stepped-care group and 24.6/1,000 in the referred-care group. Among persons with a baseline serum creatinine level between 1.5 and 1.7 mg/dl, the 5-year incidence of decline was 113.3/1,000 (stepped care) and 226.6/1,000 (referred care) (p less than 0.01). The incidence of decline in renal function was greater in men, blacks, and older adults, as well as in those with higher entry diastolic blood pressure. Among persons with a baseline serum creatinine level greater than or equal to 1.7 mg/dl, serum creatinine concentration declined by 25% or more in 28.6% of stepped-care and 25.2% of referred-care participants. Although the incidence of clinically significant hypercreatininemia in a hypertensive population is low, an elevated serum creatinine concentration is a very potent independent risk factor for mortality. The slightly lower rate of development of hypercreatininemia and the higher rate of improvement in stepped-care compared with referred-care participants is consistent with the belief that aggressive treatment of hypertension may reduce renal damage and the associated increased risk of death

Blood pressure and metabolic changes during dietary L-arginine supplementation in humans.

Siani A, Pagano E, Iacone R, et al.

Am J Hypertens. 2000 May; 13(5 Pt 1):547-51.

Dietary L-arginine supplementation has been proposed to reverse endothelial dysfunction in such diverse pathophysiologic conditions as hypercholesterolemia, coronary heart disease, and some forms of animal hypertension. In particular, chronic oral administration of L-arginine prevented the blood pressure rise induced by sodium chloride loading in salt-sensitive rats. To investigate the effects of L-arginine-rich diets on blood pressure and metabolic and coagulation parameters we performed a single-blind, controlled, crossover dietary intervention in six healthy volunteers. The subjects (aged 39+/-4 years, body mass index [BMI] 26+/-1 kg/m2, mean +/- SEM) received, in random sequence, three different isocaloric diets, each for a period of 1 week (Diet 1: control; Diet 2: L-arginine enriched by natural foods; Diet 3: identical to Diet 1 plus oral L-arginine supplement). Sodium intake was set at a constant level (about 180 mmol/day) throughout the three study periods. A blood pressure decrease was observed with both L-arginine-rich diets (Diet 2 v 1, SBP: -6.2 mm Hg [95% CI: -0.5 to -11.8], DBP: -5.0 mm Hg [-2.8 to -7.2]; Diet 3 v 1, SBP: -6.2 mm Hg [-1.8 to -10.5], DBP: -6.8 mm Hg [-3.0 to -10.6]). A slight increase in creatinine clearance (P = .07) and a fall in fasting blood glucose (P = .008) occurred after Diet 3 and, to a lesser extent, after Diet 2. Serum total cholesterol (P = .06) and triglyceride (P = .009) decreased and HDL cholesterol increased (P = .04) after Diet 2, but not after Diet 3. These results indicate that a moderate increase in L-arginine significantly lowered blood pressure and affected renal function and carbohydrate metabolism in healthy volunteers

A meta-analysis of the effect of garlic on blood pressure.

Silagy CA NH.

1994; J Hyperten(12):463-8.


Garlic as a lipid-lowering agent-a meta-analysis of randomized controlled trials.

Silagy CA NH.

J R Coll Physicians London. 1994;(28):39-45.

A meta-analysis of the effect of garlic on blood pressure.

Silagy CA, Neil HA.

J Hypertens. 1994 Apr; 12(4):463-8.

OBJECTIVE: To undertake a systematic review, including meta-analysis, of published and unpublished randomized controlled trials of garlic preparations to determine the effect of garlic on blood pressure relative to placebo and other antihypertensive agents. DATA IDENTIFICATION: Studies were identified by a search of Medline and the Alternative Medicine electronic databases, from references listed in primary and review articles, and through direct contact with garlic manufacturers. STUDY SELECTION: Only randomized controlled trials of garlic preparations that were at least 4 weeks in duration were deemed eligible for inclusion in the review. DATA EXTRACTION: Data were extracted from the published reports by the two authors independently, with disagreements resolved by discussion. RESULTS: Eight trials were identified (all using the same dried garlic powder preparation (Kwai) with data from 415 subjects included in the analyses. Only three of the trials were specifically conducted in hypertensive subjects, and many had other methodological shortcomings. Of the seven trials that compared the effect of garlic with that of placebo, three showed a significant reduction in systolic blood pressure (SBP) and four in diastolic blood pressure (DBP). The overall pooled mean difference in the absolute change (from baseline to final measurement) of SBP was greater in the subjects who were treated with garlic then in those treated with placebo. For DBP the corresponding reduction in the garlic-treated subjects was slightly smaller. CONCLUSIONS: The results suggest that this garlic powder preparation may be of some clinical use in subjects with mild hypertension. However, there is still insufficient evidence to recommend it as a routine clinical therapy for the treatment of hypertensive subjects. More-rigorously designed and analysed trials are needed

Essential fatty acids in health and chronic disease.

Simopoulos AP.

Am J Clin Nutr. 1999 Sep; 70(3 Suppl):560S-9S.

Human beings evolved consuming a diet that contained about equal amounts of n-3 and n-6 essential fatty acids. Over the past 100-150 y there has been an enormous increase in the consumption of n-6 fatty acids due to the increased intake of vegetable oils from corn, sunflower seeds, safflower seeds, cottonseed, and soybeans. Today, in Western diets, the ratio of n-6 to n-3 fatty acids ranges from approximately 20-30:1 instead of the traditional range of 1-2:1. Studies indicate that a high intake of n-6 fatty acids shifts the physiologic state to one that is prothrombotic and proaggregatory, characterized by increases in blood viscosity, vasospasm, and vasoconstriction and decreases in bleeding time. n-3 Fatty acids, however, have antiinflammatory, antithrombotic, antiarrhythmic, hypolipidemic, and vasodilatory properties. These beneficial effects of n-3 fatty acids have been shown in the secondary prevention of coronary heart disease, hypertension, type 2 diabetes, and, in some patients with renal disease, rheumatoid arthritis, ulcerative colitis, Crohn disease, and chronic obstructive pulmonary disease. Most of the studies were carried out with fish oils [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)]. However, alpha-linolenic acid, found in green leafy vegetables, flaxseed, rapeseed, and walnuts, desaturates and elongates in the human body to EPA and DHA and by itself may have beneficial effects in health and in the control of chronic diseases

Nutritional supplements for the cardiac patient.

Sinatra ST.

Int J Integrative Med. 2001 Jan;31-43.

Effects of dietary oleic, linoleic and alpha-linolenic acids on blood pressure, serum lipids, lipoproteins and the formation of eicosanoid precursors in patients with mild essential hypertension.

Singer P, Jaeger W, Berger I, et al.

J Hum Hypertens. 1990 Jun; 4(3):227-33.

Forty-four male in-patients with mild essential hypertension were randomly allocated to three groups and put on diets supplemented with 60 ml/day of olive (n = 15), sunflowerseed (n = 15) or linseed oils (n = 14), respectively, for two weeks within a blind study. In the group receiving sunflowerseed oil an increase of linoleic acid in serum lipids could be observed, whereas arachidonic and eicosapentaenoic acids appeared unchanged in serum triglycerides and even significantly lower in cholesterol esters. The subjects ingesting the linseed oil-rich diet showed an increase of alpha-linolenic acid in serum lipids, whereas arachidonic and eicosapentaenoic acids remained unchanged in serum triglycerides. In cholesterol esters, however, arachidonic acid was significantly decreased and eicosapentaenoic acid appeared increased only to a low level of significance. In the group put on the olive oil-rich regimen only a significant fall of linoleic acid was obvious in serum triglycerides. The results might indicate a defective desaturation and elongation of linoleic and alpha-linolenic acids and, consequently, a slow formation of arachidonic and eicosapentaenoic acids in patients with mild essential hypertension, which should be considered in dietary studies. After the sunflowerseed oil-rich diet a significant decrease of total cholesterol, low density lipoprotein (LDL) cholesterol and the LDL/high density lipoprotein (HDL) cholesterol ratio was found. Systolic blood pressure during a psychophysiological stress test and urinary sodium excretion appeared significantly lower after the linoleic acid-rich diet. After the linseed oil-rich diet, in addition to total cholesterol, LDL cholesterol and the LDL/HDL cholesterol ratio, serum triglycerides and lecithin cholesterol acyl transferase (LCAT) activity were significantly depressed.(ABSTRACT TRUNCATED AT 250 WORDS)

Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction.

Singh RB, Wander GS, Rastogi A, et al.

Cardiovasc Drugs Ther. 1998 Sep; 12(4):347-53.

The effects of oral treatment with coenzyme Q10 (120 mg/d) were compared for 28 days in 73 (intervention group A) and 71 (placebo group B) patients with acute myocardial infarction (AMI). After treatment, angina pectoris (9.5 vs. 28.1), total arrhythmias (9.5% vs. 25.3%), and poor left ventricular function (8.2% vs. 22.5%) were significantly (P < 0.05) reduced in the coenzyme Q group than placebo group. Total cardiac events, including cardiac deaths and nonfatal infarction, were also significantly reduced in the coenzyme Q10 group compared with the placebo group (15.0% vs. 30.9%, P < 0.02). The extent of cardiac disease, elevation in cardiac enzymes, and oxidative stress at entry to the study were comparable between the two groups. Lipid peroxides, diene conjugates, and malondialdehyde, which are indicators of oxidative stress, showed a greater reduction in the treatment group than in the placebo group. The antioxidants vitamin A, E, and C and beta-carotene, which were lower initially after AMI, increased more in the coenzyme Q10 group than in the placebo group. These findings suggest that coenzyme Q10 can provide rapid protective effects in patients with AMI if administered within 3 days of the onset of symptoms. More studies in a larger number of patients and long-term follow-up are needed to confirm our results

Effect of hydrosoluble coenzyme Q10 on blood pressures and insulin resistance in hypertensive patients with coronary artery disease.

Singh RB, Niaz MA, Rastogi SS, et al.

J Hum Hypertens. 1999 Mar; 13(3):203-8.

In a randomised, double-blind trial among patients receiving antihypertensive medication, the effects of the oral treatment with coenzyme Q10 (60 mg twice daily) were compared for 8 weeks in 30 (coenzyme Q10: group A) and 29 (B vitamin complex: group B) patients known to have essential hypertension and presenting with coronary artery disease (CAD). After 8 weeks of follow-up, the following indices were reduced in the coenzyme Q10 group: systolic and diastolic blood pressure, fasting and 2-h plasma insulin, glucose, triglycerides, lipid peroxides, malondialdehyde and diene conjugates. The following indices were increased: HDL-cholesterol, vitamins A, C, E and beta-carotene (all changes P<0.05). The only changes in the group taking the B vitamin complex were increases in vitamin C and beta-carotene (P<0.05). These findings indicate that treatment with coenzyme Q10 decreases blood pressure possibly by decreasing oxidative stress and insulin response in patients with known hypertension receiving conventional antihypertensive drugs

Relationship of baseline major risk factors to coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago cohorts.

Stamler J, Dyer AR, Shekelle RB, et al.

Cardiology. 1993; 82(2-3):191-222.

The focus here is on relationships between major risk factors and long-term mortality from coronary heart disease (CHD) and all causes, and on longevity, in Chicago cohorts: 25-year follow-up for Peoples Gas (PG) men aged 25-39 (n = 1,119), 30-year follow-up for PG men aged 40-59 (n = 1,235), 24-year follow-up for Western Electric (WE) men aged 40-55 (n = 1,882); also 15-year follow-up for five cohorts of the Chicago Heart Association (CHA) Study: men aged 25-39 (n = 7,873), 40-59 (n = 8,515), 60-74 (n = 1,490), and women aged 40-59 (n = 7,082) and 60-74 (n = 1,243); also 12-year findings for very low risk men (n = 11,098) and other men (n = 350,564) screened for the Multiple Risk Factor Intervention Trial (MRFIT). With a high degree of consistency, multivariate analyses showed independent positive relationships of baseline serum cholesterol, blood pressure and cigarette use to risk of death from CHD and all causes. For the WE cohort, with baseline nutrient data, dietary cholesterol was also independently related to these mortality risks. Combined risk factor impact was strong for both men and women of all baseline ages. Thus, for WE men, favorable compared to observed levels of serum cholesterol, blood pressure, cigarette use and dietary cholesterol were estimated to result in 24-year risk of CHD death 69% lower, all-cause death 42% lower and longevity 9 years greater. For CHA middle-aged and older women, favorable baseline levels of serum cholesterol, blood pressure and cigarette use were estimated to yield 15-year-CHD risk lower by about 60% and longevity greater by about 5 years. For MRFIT, very low risk men (serum cholesterol < 182 mg/dl, systolic/diastolic blood pressure < 120/<80), nonsmokers, nondiabetic, no previous heart attack), compared to all others, observed 12-year death rates were lower by 89% for CHD, 79% for stroke, 86% for all cardiovascular diseases, 30% for cancers, 21% for other causes, 53% for all causes, and longevity was estimated to be more than 9 years longer. These findings indicate great potentials for prevention of the CHD epidemic and for increased longevity with health for men and women, through improved life-styles and consequent lower risk factor levels

Low risk-factor profile and long-term cardiovascular and noncardiovascular mortality and life expectancy: findings for 5 large cohorts of young adult and middle-aged men and women.

Stamler J, Stamler R, Neaton JD, et al.

JAMA. 1999 Dec 1; 282(21):2012-8.

CONTEXT: Three major coronary risk factors-serum cholesterol level, blood pressure, and smoking-increase incidence of coronary heart disease (CHD) and related end points. In previous investigations, risks for low-risk reference groups were estimated statistically because samples contained too few such people to measure risk. OBJECTIVE: To measure long-term mortality rates for individuals with favorable levels for all 3 major risk factors, compared with others. DESIGN: Two prospective studies, involving 5 cohorts based on age and sex, that enrolled persons with a range of risk factors. Low risk was defined as serum cholesterol level less than 5.17 mmol/L (<200 mg/dL), blood pressure less than orequal to 120/80 mm Hg, and no current cigarette smoking. All persons with a history of diabetes, myocardial infarction (MI), or, in 3 of 5 cohorts, electrocardiogram (ECG) abnormalities, were excluded. SETTING AND PARTICIPANTS: In 18 US cities, a total of 72144 men aged 35 through 39 years and 270671 men aged 40 through 57 years screened (1973-1975) for the Multiple Risk Factor Intervention Trial (MRFIT); in Chicago, a total of 10025 men aged 18 through 39 years, 7490 men aged 40 through 59 years, and 6229 women aged 40 through 59 years screened (1967-1973) for the Chicago Heart Association Detection Project in Industry (CHA) (N = "366559)." MAIN OUTCOME MEASURES: Cause-specific mortality during 16 (MRFIT) and 22 (CHA) years, relative risks (RRs) of death, and estimated greater life expectancy, comparing low-risk subcohorts vs others by age strata. RESULTS: Low-risk persons comprised only 4.8% to 9.9% of the cohorts. All 5 low-risk groups experienced significantly and markedly lower CHD and cardiovascular disease death rates than those who had elevated cholesterol level, or blood pressure, or smoked. For example, age-adjusted RRs of CHD mortality ranged from 0.08 for CHA men aged 18 to 39 years to 0.23 for CHA men aged 40 through 59 years. The age-adjusted relative risks (RRs) for all cardiovascular disease mortality ranged from 0.15 for MRFIT men aged 35 through 39 years to 0.28 for CHA men aged 40 through 59 years. The age-adjusted RR for all-cause mortality rate ranged from 0.42 for CHA men aged 40 through 59 years to 0.60 for CHA women aged 40 through 59 years. Estimated greater life expectancy for low-risk groups ranged from 5.8 years for CHA women aged 40 through 59 years to 9.5 years for CHA men aged 18 through 39 years. CONCLUSIONS: Based on these very large cohort studies, for individuals with favorable levels of cholesterol and blood pressure who do not smoke and do not have diabetes, MI, or ECG abnormalities, long-term mortality is much lower and longevity is much greater. A substantial increase in the proportion of the population at lifetime low risk could contribute decisively to ending the CHD epidemic

Endothelium-derived relaxing factor modulates the atherothrombogenic effects of homocysteine.

Stamler JS, Loscalzo J.

J Cardiovasc Pharmacol. 1992; 20 Suppl 12:S202-S204.

Hyperhomocysteinemia is a risk factor for atherosclerosis, and is found in the heterozygous form in approximately one-third of all individuals with coronary artery disease. The sulfhydryl group of homocysteine has been viewed as contributing to the atherogenic effects of this low-molecular-weight thiol, largely as a consequence of facilitating the generation of hydrogen peroxide from oxygen. Hydrogen peroxide, in turn, is presumed to induce dysfunction and damage to the endothelial cell, leading to attenuation of its antithrombotic and vasodilatory properties. As we have shown that endothelium-derived relaxing factor (EDRF) and other oxides of nitrogen can form adducts with thiols, we hypothesized that EDRF released from normal endothelium S-nitrosates homocysteine, rendering it nontoxic to the endothelium. We show that EDRF released from endothelial cells in the presence of homocysteine can lead to the formation of S-nitrosohomocysteine; that, like other S-nitrosothiols, S-nitrosohomocysteine induces vasorelaxation and platelet inhibition; and that, in contrast to homocysteine, S-nitrosohomocysteine does not support hydrogen peroxide generation and does not lead to endothelial dysfunction. These data suggest that normal endothelial cells modulate the adverse effects of homocysteine by facilitating the formation of the EDRF adduct, S-nitrosohomocysteine. The toxic effects of homocysteine may, then, result from an inability of the endothelium to sustain adequate production of EDRF in the face of elevated homocysteine concentration

Biological chemistry of thiols in the vasculature and in vascular-related disease.

Stamler JS, Slivka A.

Nutr Rev. 1996 Jan; 54(1 Pt 1):1-30.

For all their similarities in structure and common chemistry, the functions of the amino thiols in vascular biology are remarkably different. This review details the basic chemistry of sulfhydryls that dictates their functions in health and disease. In addition, the biochemistry and metabolism of each thiol are outlined, in an effort to highlight its specific contributions to the normal biology and physiology of blood vessels and to the pathogenesis of vascular-related disease

A double-blind crossover study in moderately hypercholesterolemic men that compared the effect of aged garlic extract and placebo administration on blood lipids.

Steiner M, Khan AH, Holbert D, et al.

Am J Clin Nutr. 1996 Dec; 64(6):866-70.

A double-blind crossover study comparing the effect of aged garlic extract with a placebo on blood lipids was performed in a group of 41 moderately hypercholesterolemic men [cholesterol concentrations 5.7-7.5 mmol/L (220-290 mg/dL)]. After a 4-wk baseline period, during which the subjects were advised to adhere to a National Cholesterol Education Program Step I diet, they were started on 7.2 g aged garlic extract per day or an equivalent amount of placebo as a dietary supplement for a period of 6 mo, then switched to the other supplement for an additional 4 mo. Blood lipids, blood counts, thyroid and liver function measures, body weight, and blood pressure were followed over the entire study period. The major findings were a maximal reduction in total serum cholesterol of 6.1% or 7.0% in comparison with the average concentration during the placebo administration or baseline evaluation period, respectively. Low-density-lipoprotein cholesterol was also decreased by aged garlic extract, 4% when compared with average baseline values and 4.6% in comparison with placebo period concentrations. In addition, there was a 5.5% decrease in systolic blood pressure and a modest reduction of diastolic blood pressure in response to aged garlic extract. We conclude that dietary supplementation with aged garlic extract has beneficial effects on the lipid profile and blood pressure of moderately hypercholesterolemic subjects

Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract.

Steiner M, Lin RS.

J Cardiovasc Pharmacol. 1998 Jun; 31(6):904-8.

Garlic and some of its organosulfur components have been found to be potent inhibitors of platelet aggregation in vitro. Demonstration of their efficacy in vivo, however, especially when administered over extended periods, is sparse. We recently performed a 10-month study comparing the effect of aged garlic extract (AGE) with placebo on the lipid profiles of moderately hypercholesterolemic men. In the course of the intervention trial, we examined platelet functions and susceptibility of lipoproteins to oxidation in a subgroup of this study population. Study subjects supplemented with 7.2 AGE per day showed a significant reduction of epinephrine- and, to a lesser degree, collagen-induced platelet aggregation but failed to demonstrate an inhibition of adenosine diphosphate (ADP)-induced aggregation. Platelet adhesion to fibrinogen, measured in a laminar flow chamber at moderately high shear rate, was reduced by approximately 30% in subjects taking AGE compared with placebo supplement. A trend toward decreased susceptibility of lipoproteins to oxidation also was noted during AGE administration compared with the placebo period. We conclude that the beneficial effect of garlic preparations on lipids and blood pressure extends also to platelet function, thus providing a wider potential protection of the cardiovascular system

Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats.

Storlien LH, James DE, Burleigh KM, et al.

Am J Physiol. 1986 Nov; 251(5 Pt 1):E576-E583.

High levels of dietary fat may contribute to both insulin resistance and obesity in humans but evidence is limited. The euglycemic clamp technique combined with tracer administration was used to study insulin action in vivo in liver and individual peripheral tissues after fat feeding. Basal and nutrient-stimulated metabolic rate was assessed by open-circuit respirometry. Adult male rats were pair-fed isocaloric diets high in either carbohydrate (69% of calories; HiCHO) or fat (59% of calories; HiFAT) for 24 +/- 1 days. Feeding of the HiFAT diet resulted in a greater than 50% reduction in net whole-body glucose utilization at midphysiological insulin levels (90-100 mU/l) due to both reduced glucose disposal and, to a lesser extent, failure to suppress liver glucose output. Major suppressive effects of the HiFAT diet on glucose uptake were found in oxidative skeletal muscles (29-61%) and in brown adipose tissue (BAT; 78-90%), the latter accounting for over 20% of the whole-body effect. There was no difference in basal metabolic rate but thermogenesis in response to glucose ingestion was higher in the HiCHO group. In contrast to their reduced BAT weight, the HiFAT group accumulated more white adipose tissue, consistent with reduced energy expenditure. HiFAT feeding also resulted in major decreases in basal and insulin-stimulated conversion of glucose to lipid in liver (26-60%) and brown adipose tissue (88-90%) with relatively less effect in white adipose (0-43%). We conclude that high-fat feeding results in insulin resistance due mainly to effects in oxidative skeletal muscle and BAT.(ABSTRACT TRUNCATED AT 250 WORDS)

Fish oil prevents insulin resistance induced by high-fat feeding in rats.

Storlien LH, Kraegen EW, Chisholm DJ, et al.

Science. 1987 Aug 21; 237(4817):885-8.

Non-insulin-dependent diabetes mellitus is an increasingly prevalent disease in Western and developing societies. A major metabolic abnormality of non-insulin-dependent diabetes is impaired insulin action (insulin resistance). Diets high in fat from vegetable and nonaquatic animal sources (rich in linoleic acid, an omega-6 fatty acid, and saturated fats) lead to insulin resistance. In rats fed high-fat diets, replacement of only 6 percent of the linoleic omega-6 fatty acids from safflower oil with long-chain polyunsaturated omega-3 fatty acids from fish oil prevented the development of insulin resistance. The effect was most pronounced in the liver and skeletal muscle, which have important roles in glucose supply and demand. The results may be important for therapy or prevention of non-insulin-dependent diabetes mellitus

Dietary fats and insulin action.

Storlien LH, Baur LA, Kriketos AD, et al.

Diabetologia. 1996 Jun; 39(6):621-31.

Vitamin C improves endothelium-dependent vasodilation by restoring nitric oxide activity in essential hypertension.

Taddei S, Virdis A, Ghiadoni L, et al.

Circulation. 1998 Jun 9; 97(22):2222-9.

BACKGROUND: Essential hypertension is associated with impaired endothelium-dependent vasodilation. Inactivation of endothelium-derived nitric oxide by oxygen free radicals participates in endothelial dysfunction in experimental hypertension. To test this hypothesis in humans, we evaluated the effect of antioxidant vitamin C on endothelium-dependent responses in essential hypertensive patients. METHODS AND RESULTS: In 14 healthy subjects (47.1+/-4.8 years; blood pressure, 120.6+/-4.5/80.9+/-3.5 mm Hg) and 14 essential hypertensive patients (47.3+/-5.1 years; blood pressure, 153.9+/-7.1/102.3+/-4.1 mm Hg), we studied forearm blood flow (strain-gauge plethysmography) modifications induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 microg x 100 mL(-1) x min(-1)) or sodium nitroprusside (1, 2, and 4 microg/100 mL forearm tissue per minute), an endothelium-dependent and -independent vasodilator, respectively, in basal conditions and during infusion of intrabrachial vitamin C (2.4 mg/100 mL forearm tissue per minute). In hypertensive patients but not in control subjects, vitamin C increased (P<0.01) the impaired vasodilation to acetylcholine, whereas the response to sodium nitroprusside was unaffected. Moreover, in another 14 hypertensive patients (47.1+/-5.2 years; blood pressure, 155.2+/-6.9/103.7+/-4.5 mm Hg), the facilitating effect of vitamin C on vasodilation to acetylcholine was reversed by N(G)-monomethyl-L-arginine (100 microg/100 mL forearm tissue per minute), a nitric oxide synthase inhibitor, suggesting that in essential hypertension superoxide anions impair endothelium-dependent vasodilation by nitric oxide breakdown. Finally, because in adjunctive 7 hypertensive patients (47.8+/-6.1 years; blood pressure, 155.3+/-6.8/103.5+/-4.3 mm Hg), indomethacin (50 microg/100 mL forearm tissue per minute), a cyclooxygenase inhibitor, prevented the potentiating effect of vitamin C on vasodilation to acetylcholine, it is possible that in essential hypertension a main source of superoxide anions could be the cyclooxygenase pathway. CONCLUSIONS: In essential hypertensive patients, impaired endothelial vasodilation can be improved by the antioxidant vitamin C, an effect that can be reversed by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. These findings support the hypothesis that nitric oxide inactivation by oxygen free radicals contributes to endothelial dysfunction in essential hypertension

Homocysteine impairs coronary microvascular dilator function in humans.

Tawakol A, Forgione MA, Stuehlinger M, et al.

J Am Coll Cardiol. 2002 Sep 18; 40(6):1051-8.

OBJECTIVES: We sought to use positron emission tomography (PET) to test the hypothesis that hyperhomocysteinemia adversely effects coronary microvascular dilator function. BACKGROUND: Hyperhomocysteinemia is associated with abnormal endothelium-dependent vasodilation in peripheral human arteries. However, its effect on the coronary circulation is not known. METHODS: Eighteen healthy humans, age 24 to 56 years, were enrolled in a double-blind, crossover trial. Basal and adenosine-stimulated myocardial blood flow (MBF) was determined by PET: after ingestion of placebo and after methionine-induced hyperhomocysteinemia. Further, brachial ultrasonography was used to assess flow-mediated vasodilation. Additionally, to assess the role of nitric oxide (NO) in adenosine-mediated vasodilation, the MBF response to adenosine was measured in the presence and absence of the NO synthase antagonist NG-monomethyl-l-arginine (l-NMMA) (0.3 mg/kg/min intravenously). RESULTS: Hyperhomocysteinemia resulted in a reduction in the MBF dose-response curve to adenosine (p < 0.05). This was most apparent with low dose adenosine, where MBF augmentation was significantly blunted during hyperhomocysteinemia (1.06 +/- 1.00 ml/min/g vs. 0.58 +/- 0.78 ml/min/g, placebo vs. methionine, p < 0.05). Similarly, flow-mediated brachial artery vasodilation was impaired during hyperhomocysteinemia (4.4 +/- 2.6% vs. 2.6 +/- 2.3%, placebo vs. methionine, p < 0.05). In a separate series of experiments, MBF during adenosine was reduced in the presence of l-NMMA (p < 0.05 analysis of variance). This was most apparent at the low dose of adenosine, where MBF response to adenosine was blunted in the presence of l-NMMA (2.08 +/- 1.34 ml/min/g vs. 1.48 +/- 1.32 ml/min/g, placebo vs. l-NMMA, p < 0.05). CONCLUSION: The data, therefore, support the hypothesis that acute hyperhomocysteinemia impairs microvascular dilation in the human coronary circulation as a result of reduced NO bioavailability

Effects of n-3 polyunsaturated fatty acids on glucose homeostasis and blood pressure in essential hypertension. A randomized, controlled trial.

Toft I, Bonaa KH, Ingebretsen OC, et al.

Ann Intern Med. 1995 Dec 15; 123(12):911-8.

OBJECTIVE: To determine whether dietary supplementation with fish oil adversely affects glycemic control in patients with hypertension. DESIGN: Randomized, double-blind, placebo-controlled study. PATIENTS: 78 persons with untreated hypertension recruited from a population survey. INTERVENTION: Participants were randomly assigned to receive eicosapentaenoic and docosahexaenoic acids, 4 g/d, or corn oil placebo, 4 g/d, for 16 weeks. MEASUREMENTS: An oral glucose tolerance test; assessments of insulin release, glucose disposal, and insulin sensitivity done using the hyperglycemic clamp technique to keep plasma glucose levels at 10 mmol/L for 180 minutes; assessment of insulin sensitivity done using a euglycemic hyperinsulinemic clamp technique (infusing insulin and glucose to keep plasma glucose levels at 5 mmol/L); assessments of lipid levels and blood pressure. Measurements were done before and after intervention. RESULTS: Changes in integrated glucose and insulin response after the oral glucose challenge did not differ between the fish oil and corn oil groups after intervention (-0.6 +/- 0.7 compared with -1.0 +/- 0.6 mmol/L [P > 0.3] for integrated glucose and 143 +/- 76 compared with 169 +/- 84 pmol/L [P > 0.3] for insulin response). Changes in first-phase insulin release (34 +/- 72 pmol/L in the fish oil group compared with 191 +/- 112 pmol/L in the corn oil group [P > 0.3]), second-phase insulin release (179 +/- 66 pmol/L compared with 257 +/- 122 pmol/L [P > 0.3]), and insulin sensitivity index (-0.03 +/- 0.01 compared with -0.01 +/- 0.01 [mumol/kg.min divided by pmol/L]; P > 0.3) were also similar in both groups after treatment. Fish oil lowered systolic blood pressure by 3.8 mm Hg more than control (P = 0.04) and lowered diastolic blood pressure by 2.0 mm Hg more than control (P = 0.10). After fish oil treatment, triglyceride levels decreased by 0.28 +/- 0.08 mmol/L more than control (P = 0.01), and very-low-density lipoprotein cholesterol levels decreased by 0.13 +/- 0.04 mmol/L more than control (P = 0.01). CONCLUSION: Fish oil, in doses that reduce blood pressure and lipid levels in hypertensive persons, does not adversely affect glucose metabolism

The influence of different ratios and dosages of an w6:w3 fatty acid supplement on the lipoprotein cholesterol and fatty acid profile in nonhuman primates on a Western atherogenic diet.

van Jaarsveld PJ.

Nutr Res. 1997;(17):1733-47.

Impact of high-normal blood pressure on the risk of cardiovascular disease.

Vasan RS, Larson MG, Leip EP, et al.

N Engl J Med. 2001 Nov 1; 345(18):1291-7.

BACKGROUND: Information is limited regarding the absolute and relative risk of cardiovascular disease in persons with high-normal blood pressure (systolic pressure of 130 to 139 mm Hg, diastolic pressure of 85 to 89 mm Hg, or both). METHODS: We investigated the association between blood-pressure category at base line and the incidence of cardiovascular disease on follow-up among 6859 participants in the Framingham Heart Study who were initially free of hypertension and cardiovascular disease. RESULTS: A stepwise increase in cardiovascular event rates was noted in persons with higher baseline blood-pressure categories. The 10-year cumulative incidence of cardiovascular disease in subjects 35 to 64 years of age who had high-normal blood pressure was 4 percent (95 percent confidence interval, 2 to 5 percent) for women and 8 percent (95 percent confidence interval, 6 to 10 percent) for men; in older subjects (those 65 to 90 years old), the incidence was 18 percent (95 percent confidence interval, 12 to 23 percent) for women and 25 percent (95 percent confidence interval, 17 to 34 percent) for men. As compared with optimal blood pressure, high-normal blood pressure was associated with a risk-factor-adjusted hazard ratio for cardiovascular disease of 2.5 (95 percent confidence interval, 1.6 to 4.1) in women and 1.6 (95 percent confidence interval, 1.1 to 2.2) in men. CONCLUSIONS: High-normal blood pressure is associated with an increased risk of cardiovascular disease. Our findings emphasize the need to determine whether lowering high-normal blood pressure can reduce the risk of cardiovascular disease

Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study.

Vasan RS, Beiser A, Seshadri S, et al.

JAMA. 2002 Feb 27; 287(8):1003-10.

CONTEXT: The long-term risk for developing hypertension is best described by the lifetime risk statistic. The lifetime risk for hypertension and trends in this risk over time are unknown. OBJECTIVES: To estimate the residual lifetime risk for hypertension in older US adults and to evaluate temporal trends in this risk. DESIGN, SETTING, AND PARTICIPANTS: Community-based prospective cohort study of 1298 participants from the Framingham Heart Study who were aged 55 to 65 years and free of hypertension at baseline (1976-1998). MAIN OUTCOME MEASURES: Residual lifetime risk (lifetime cumulative incidence not adjusted for competing causes of mortality) for hypertension, defined as blood pressure of 140/90 mm Hg or greater or use of antihypertensive medications. RESULTS: The residual lifetime risks for developing hypertension and stage 1 high blood pressure or higher (greater-than-or-equal to 140/90 mm Hg regardless of treatment) were 90% in both 55- and 65-year-old participants. The lifetime probability of receiving antihypertensive medication was 60%. The risk for hypertension remained unchanged for women, but it was approximately 60% higher for men in the contemporary 1976-1998 period compared with an earlier 1952-1975 period. In contrast, the residual lifetime risk for stage 2 high blood pressure or higher (greater-than-or-equal to 160/100 mm Hg regardless of treatment) was considerably lower in both sexes in the recent period (35%-57% in 1952-1975 vs 35%-44% in 1976-1998), likely due to a marked increase in treatment of individuals with substantially elevated blood pressure. CONCLUSION: The residual lifetime risk for hypertension for middle-aged and elderly individuals is 90%, indicating a huge public health burden. Although the decline in lifetime risk for stage 2 high blood pressure or higher represents a major achievement, efforts should be directed at the primary prevention of hypertension

Effects of essential fatty acids on mild to moderate essential hypertension.

Venter CP, Joubert PH, Booyens J.

Prostaglandins Leukot Essent Fatty Acids. 1988 Jul; 33(1):49-51.

A double-blind placebo-controlled study with a crossover design was conducted on 25 non-obese black patients with mild-moderate uncomplicated essential hypertension. They were randomly assigned into two groups. After having received placebo capsules for 4 weeks, they received dietary supplementation with either Efamol-marine (containing desaturated n-6 and n3 essential fatty acids), or sunflower seed and linseed oil capsules for 12 weeks. Thereafter a second 4 weeks placebo phase and a subsequent second 12-week active phase were entered into during which a crossover of the dietary supplementation of the groups was brought about. The mean systolic blood pressure of patients receiving Efamol-marine was significantly lowered after 8 and 12 weeks, while those receiving sunflower/linseed oil supplementation had no significant reduction of blood pressure. This observation may indicate that defective desaturation of the essential fatty acids by the enzyme delta-6-desaturase, could play an important role in the etiology of essential hypertension

Hyperhomocysteinemia and related factors in 600 hospitalized elderly subjects.

Ventura P, Panini R, Verlato C, et al.

Metabolism. 2001 Dec; 50(12):1466-71.

Hyperhomocysteinemia (HHcy) is a metabolic disorder frequently occurring in the elderly population. Recently several reports have suggested abnormalities in homocysteine (tHcy) metabolism implicating HHcy as a metabolic link in the multifactorial processes characterizing many geriatric illnesses-with special emphasis on atherosclerotic vascular diseases and cognitive impairment. The present study was undertaken in a large sample of elderly hospitalized subjects to determine (1) the prevalence of HHcy, (2) the association of HHcy with vascular and cognitive disorders, and (3) the factors independently predicting Hhcy. Six hundred elderly subjects (264 men and 336 women; mean age, 79 +/- 9 years) were randomly chosen from those admitted as inpatients over a period of 3 years. In all patients, body mass index (BMI), mid-upper arm muscle area (MUAMA), plasma cholesterol, triglycerides, total proteins, albumin, lymphocyte count, creatinine, homocysteine (fasting and 4 hours after methionine oral load), serum vitamin B(6), vitamin B(12), and folate concentrations were measured. The presence of disease or use of medications known to affect homocysteine plasma levels were also recorded. The mean fasting tHcy level was 16.8 +/- 12 micromol/L in the whole sample, 18.18 +/- 13.25 micromol/L in men, and 15.86 +/- 12.14 micromol/L in women (P =.005 men v women). The mean Hcy level 4 hours after methionine load was 37.95 +/- 20.9 in the whole sample. Prevalence of hyperhomocysteinemia (fasting Hcy > or = 15 micromol/L or 4 hours after methionine load > or = 35 micromol/L) was 61% (365/600) (67% in men and 56% in women, P <.05). HHcy was rarely (8%) an isolated disorder; in addition to diabetes (20%), renal failure (48.2%), and malnutrition (20.2%), it was often associated with heart failure (30%), malignancies (20.5%), and the use of diuretics (56%) and anticonvulsant drugs (13%). Plasma homocysteine progressively increases across subjects from those with no diabetes, malnutrition, renal failure, obesity, inflammatory bowel disease, heart failure to those with 1, 2, or more concurrent diseases. Multiple stepwise regression analysis showed that 72% of plasma total fasting tHcy variability was explained by age, serum folate, plasma albumin, use of diuretics, and renal function (measured as plasma creatinine clearance). In conclusion, the present study documents that hyperhomocysteinemia, in elderly hospitalized patients is (1) a common finding, (2) frequently associated with vascular and cognitive disorders, and (3) probably a secondary phenomenon in most cases. The major predictor of high plasma homocysteine levels were age, serum folate, plasma albumin, plasma creatinine clearance, and use of diuretic drugs. These variables explain a large proportion of plasma Hcy variability

Cigarette smoking, ambulatory blood pressure and cardiac hypertrophy in essential hypertension.

Verdecchia P, Schillaci G, Borgioni C, et al.

J Hypertens. 1995 Oct; 13(10):1209-15.

OBJECTIVE: To assess the role of blood pressure in the association between cigarette smoking and left ventricular mass in male and female subjects with essential hypertension. DESIGN: A case-control study with matching ratio of 1:4. PATIENTS AND METHODS: We studied 115 heavy smokers (> or = 20 cigarettes/day; 91 men) and 460 non-smokers (364 men) with essential hypertension. Subjects were matched by sex, age (within 5 years) and clinic systolic and diastolic blood pressures (within 5 mmHg). All the subjects underwent 24 h off-therapy non-invasive ambulatory blood pressure monitoring and echocardiography. RESULTS: By matching, clinic blood pressure was nearly identical in smokers and non-smokers (158/99 versus 158/98 mmHg). Daytime ambulatory blood pressure was significantly higher in the smokers than in the non-smokers (150/97 versus 143/93 mmHg), whereas night-time blood pressure did not differ between the two groups (129/79 versus 126/78 mmHg). Smokers had a higher 24 h but not clinic heart rate. Variability of systolic and diastolic blood pressure was slightly greater in smokers when expressed in terms of the standard deviation of the 24 h average (15.9/13.0 versus 14.6/12.2 mmHg), but not after correction for average blood pressure. Left ventricular mass was greater in the smokers than in the non-smokers (119 versus 110 g/m2), and this difference remained after adjustment for clinic blood pressure and other related covariates. However, when clinic blood pressure was replaced by daytime ambulatory blood pressure in the equation, adjusted values of left ventricular mass did not differ between the smokers and the non-smokers (113 versus 112 g/m2). CONCLUSION: In patients with essential hypertension, heavy cigarette smoking (> or = 20 cigarettes/day) is associated with a definite increase in left ventricular mass through a rise in whole-day blood pressure. A pressor mechanism of that type may not be detected by the standard measurement of blood pressure in the clinic, which would make ambulatory blood pressure monitoring a valuable diagnostic tool in this setting

Dyslipemia in diabetes mellitus.

Vergas BL.


Insulin sensitivity is related to the fatty acid composition of serum lipids and skeletal muscle phospholipids in 70-year-old men.

Vessby B, Tengblad S, Lithell H.

Diabetologia. 1994 Oct; 37(10):1044-50.

Recent data indicate that peripheral insulin sensitivity may be influenced by dietary fat quality and skeletal muscle phospholipid fatty acid composition. During a health survey of 70-year-old men insulin sensitivity was measured by the euglycaemic hyperinsulinaemic clamp technique and the fatty acid composition of the serum cholesterol esters was determined (n = 215) by gas liquid chromatography. In a subsample the fatty acids of the skeletal muscle phospholipids and triglycerides were determined after fine needle biopsy from m. vastus lateralis (n = 39). The peripheral insulin sensitivity was significantly and negatively correlated to the proportion of palmitic (r = -0.31, p < 0.001), palmitoleic (r = "-0.25," p < 0.001) and di-homo-gamma-linolenic (r = "-0.33," p < 0.001) acids and positively to the content of linoleic (r = "0.28," p < 0.001) acid in the serum cholesterol esters. There was an even stronger negative relationship to the proportion of palmitic acid in the skeletal muscle phospholipds (r = "-0.45," p < 0.004). The fatty acid composition was also significantly related to insulin sensitivity in a stepwise multiple regression analysis in the presence of other clinical variables, which were associated with insulin action in univariate analysis. Thus, more than 51% of the variation of the insulin sensitivity was explained by an equation containing body mass index, serum triglyceride concentration and the content of palmitic acid in the skeletal muscle phospholipids. It is concluded that the fatty acid composition in serum and of the phospholipids of skeletal muscle may influence insulin action in elderly men

Coronary risk factors, endothelial function, and atherosclerosis: a review.

Vogel RA.

Clin Cardiol. 1997 May; 20(5):426-32.

The traditional risk factors for coronary heart disease, which include hypercholesterolemia, hypertension, cigarette smoking, diabetes mellitus, and high-fat diet, have all been associated with impairments in endothelial function. Impaired endothelium function may promote the development of atherosclerosis through its effects on vasoregulation, platelet and monocyte adhesion, vascular smooth muscle cell growth, and coagulation. Increased oxidative stress may be another mechanism by which endothelial dysfunction contributes to atherosclerosis, although controversy exists on this issue. Risk factor modification, particularly lowering elevated concentrations of low-density lipoprotein cholesterol, improves endothelial function. At least seven clinical studies have demonstrated improved endothelial function with cholesterol reductions in patients with markedly elevated or even borderline elevations in cholesterol concentrations, whether or not coronary heart disease is present. Other interventions that improve endothelial function include blood pressure reduction, smoking cessation, and administration of estrogen to postmenopausal women

Fatty acids, eicosanoids, and hypolipidemic agents regulate gene expression through direct binding to peroxisome proliferator-activated receptors.

Wahli W, Devchand PR, IJpenberg A, et al.

Adv Exp Med Biol. 1999; 447:199-209.

Aldosterone and spironolactone in heart failure.

Weber KT.

N Engl J Med. 1999 Sep 2; 341(10):753-5.

Hypertensive vascular disease. In: Harrison's Principles of Internal Medicine.

Williams GH.

2001; 15:1414-30.

Hypertensive vascular disease. In: Harrison's Principles of Internal Medicine.

Williams GH BE.

1987; 11:1024-37.

A prospective study of nutritional factors and hypertension among US women.

Witteman JC, Willett WC, Stampfer MJ, et al.

Circulation. 1989 Nov; 80(5):1320-7.

The relation of various nutritional factors with hypertension was examined prospectively among 58,218 predominantly white US female registered nurses, aged 34-59 years. In 1980, all women completed an independently validated dietary questionnaire. During 4 years of follow-up, 3,275 women reported a diagnosis of hypertension; the validity of the self-report was shown in a subsample. Age, relative weight, and alcohol consumption were the strongest predictors for the development of hypertension. Dietary calcium and magnesium had independent and significant inverse associations with hypertension. For women with a calcium intake of at least 800 mg/day, the relative risk of hypertension was 0.78 (95% confidence interval, 0.69-0.88) when compared with an intake of less than 400 mg/day. The relative risk for magnesium intake of 300 mg/day or more compared with an intake of less than 200 mg/day was 0.77 (95% confidence interval, 0.67-0.88). For women with high intakes of both calcium and magnesium compared with those having low intakes of both, the relative risk of hypertension was 0.65 (95% confidence interval, 0.53-0.80). No independent associations with hypertension were observed for intakes of potassium, fiber, and saturated and polyunsaturated fatty acids. These prospective findings add to the growing evidence to support the need for randomized trials to determine whether there is a protective role of dietary calcium and magnesium in the regulation of blood pressure

Dietary trans-fatty acids and serum lipoproteins in humans.

Zock PL, Mensink RP.

Curr Opin Lipidol. 1996 Feb; 7(1):34-7.

Trans-fatty acids increase serum LDL-cholesterol and decrease HDL-cholesterol levels in humans when substituted for cis unsaturated fatty acids in the diet. Trans-fatty acids also increase lipoprotein (a) levels relative to other fatty acids. The effects on LDL and HDL may be mediated by the cholesteryl ester transfer protein