Sinatra ST
Manchester Hospital.
Conn Med (United States) Nov 1997, 61 (11) p707-11

Vitamin coenzyme Q10 is a critical adjuvant complementary therapy for patients with congestive heart failure, especially when traditional medical therapy is unsuccessful. The following case studies, with systolic and/or diastolic dysfunction, demonstrate the effectiveness of coenzyme Q10 in improving quality of life, as well as survival.

Sinatra ST
Manchester Hospital, CT, USA.
Mol Aspects Med (England) 1997, 18 Suppl pS299-305

Coenzyme Q10 (CoQ10) is a critical adjuvant therapy for patients with congestive heart failure (CHF), even when traditional medical therapy is successful. Adjunctive therapy with Q10 may allow for a reduction of other pharmacological therapies, improvement in quality of life, and a decrease in the incidence of cardiac complications in congestive heart failure. However, dosing, clinical application, bioavailability and dissolution of CoQ10 deserve careful scrutiny whenever employing the nutrient. The assessment of blood levels in 'therapeutic failures' appears warranted.

Soja AM; Mortensen SA
Department of Medicine, County Hospital Sct. Elisabeth, Copenhagen, Denmark.
Mol Aspects Med (England) 1997, 18 Suppl pS159-68

The purpose of this was to investigate the effect of coenzyme Q10 (CoQ10) in patients with congestive heart failure (CHF) by measuring the possible improvement of certain relevant hemodynamic heart parameters. A statistic aggregation method know as a meta-analysis was used to measure the changes in the cardiac parameters. To begin with we collected the total number of randomized controlled trials and from a total of 14 studies published in the period of 1984-1994, eight studies met our inclusion criteria. The rest were excluded because of a lack of data which made a meta-analysis impossible. The relevant effect parameters investigated were stroke volume (SV), cardiac output (CO), ejection fraction (EF), cardiac index (CI), end diastolic volume index (EDVI), systolic time intervals (PEP/LVET) and total work capacity (Wmax). Seven meta-analyses were performed, one for each of the parameters, and the calculated effect sizes were all positive. Statistical significance could be demonstrated for all of the parameters except the PEP/LVET and Wmax thereby indicating an improvement of greater or lesser magnitude in the CoQ10 group as opposed to the placebo group. Accordingly, the average patient in the CoQ10 group had a better score with regard to SV and CO than 76 and 73% respectively of the patients in the placebo group. In conclusion, supplemental treatment of CHF with CoQ10 is consistent with an improvement of SV, EF, CO, CI and EDVI. Homogeneity could be established for SV and CO. Additional clinical trials of the effect of CoQ10 on CHF are necessary, but, on the basis of the evidence currently available, the possibility remains that CoQ10 will receive a well-documented role as an adjunctive treatment of CHF.

Costello RB; Moser-Veillon PB; DiBianco R
Department of Cardiology, Washington Adventist Hospital, Takoma Park, Maryland 20912, USA.
J Am Coll Nutr (United States) Feb 1997, 16 (1) p22-31

OBJECTIVE: To evaluate several potential clinical indicators of magnesium status (diet, blood, urine, 24-hour load retention) in patients with congestive heart failure before, during, and after oral magnesium supplementation.

METHODS: Twelve patients with New York Heart Association class II-III heart failure and 12 age and sex matched healthy control subjects were supplemented with 10.4 mmol oral magnesium lactate for 3 months. For the determination of magnesium status, samples of whole blood, serum, plasma, red blood cells, and urine (24-hour) were collected. Four-day dietary intake records were reviewed. A 4-hour IV magnesium load retention study was performed before and 3 months after magnesium supplementation. A non-supplemented control group was similarly studied.

RESULTS: At baseline, magnesium intakes for all groups were below the RDA. No significant differences were seen in serum, plasma, ultrafiltrates of serum or plasma or red cell magnesium concentrations among groups over time. At baseline 5/27 subjects (19%) compared to 11/27 subjects (41%) after supplementation demonstrated normal magnesium retentions (< 25%). Magnesium excretions among groups were significantly different during supplementation. Percent magnesium retentions among groups were not different.

CONCLUSIONS: Supplementation with 10.4 mmol oral magnesium daily for 3 months did not significantly alter blood levels or magnesium retention; however, patients demonstrated lower retention of magnesium after supplementation. Differences in magnesium retention was not related to basal magnesium intake, blood levels or excretion. Unfortunately, even an intensive effort at characterizing magnesium status did not identify a clinical indicator of utility for differentiating patients with congestive heart failure before, during, and after 3 months of magnesium supplementation.

Feuerstein G.Z.; Shusterman N.H.; Ruffolo R.R.
R.R. Ruffolo, Pharmacological Sciences, SmithKline Beecham Pharmaceuticals, UW2523, 709 Swedeland Road, King of Prussia, PA 1904-0939 United States
Drugs of Today (Spain) 1997, 33/7 (453-473)

Summary On May 29, 1997, the United States Food and Drug Administration granted final approval for the use of carvedilol in the treatment of mild to moderate congestive heart failure. In this action, the United States joined 20 countries worldwide that have approved carvedilol (Coreg(R)/Kredex(R)) for treatment of hypertension and congestive heart failure. Carvedilol is also approved for the treatment of angina in several countries. Carvedilol (Fig. 1) is a chemically distinct and pharmacologically unique agent that possesses multiple pharmacological actions, including: l)nonselective beta-adrenoceptor blockade, 2) alphainf 1-adrenoceptor blockade, 3) potent antioxidant activity, and 4) regulation of genes involved in cardiovascular organ remodeling and apoptosis. Based on this pharmacological profile, carvedilol is uniquely positioned to inhibit several of the major pathological processes that drive the progression of congestive heart failure, including: 1) hemodynamics: reduction of preload, afterload and heart rate; 2) neurohormonal: inhibition of the sympathetic nervous system, renin-angiotensin system and endothelin; 3) oxidative stress: scavenging potentially toxic oxygen radicals and restoring endogenous antioxidants; 4) genomic reformatting: suppression of several genes associated with pathological organ remodeling. Thus, carvedilol, through its multiple actions, has the capacity to provide broad cardiovascular organ protection. As a result of these multiple actions, carvedilol, when used in conjunction with standard therapy for heart failure (i.e., diuretics, digoxin, and angiotensin-converting enzyme inhibitors), significantly reduced morbidity, mortality and hospitalization in patients with congestive heart failure of either ischemic or nonischemic (i.e., idiopathic dilated cardiomyopathy) origin, independent of disease severity (mild to moderate) or left ventricular function (ejection fraction). The highly favorable clinical outcomes from the large multicenter clinical trials conducted with carvedilol in the United States and Australia/New Zealand merits a detailed update of the unique mechanisms of action of carvedilol, and a thorough review of the clinical trial results. Accordingly, we will highlight in this update our previous experimental findings with carvedilol as well as more recent data that shed light on the mechanisms by which this drug produces its effects in congestive heart failure. In addition, an update of the results from the large multicenter clinical trials, which formed the basis for the approval of the drug for the treatment of heart failure, will be presented.

Chen B.P.; Chow M.S.S.
Formulary (United States) 1997, 32/8 (795-805)

Carvedilol (Coreg) is a nonselective beta-adrenoreceptor blocker with vasodilating activity. In addition to its earlier approval for the treatment of essential hypertension, the drug has recently become the first beta-blocking agent cleared in the United States for the treatment of congestive heart failure (CHF). Clinical trials have shown that adding carvedilol to standard CHF therapy significantly reduces the risk of death and hospitalization in patients with mild to moderate CHF. To achieve these results, it is imperative that the dosage of carvedilol be titrated carefully. Because of its documented ability to improve survival and morbidity outcomes, carvedilol is a welcome addition to the formulary.

Forgosh L.B.; Zolotor W.
Dr. L.B. Forgosh, Arizona Heart Institute/Foundation, 2632 N. 20th Street, Phoenix, AZ 85006 United States
Congestive Heart Failure (United States) 1997, 3/2 (21-24)

Magnesium has been shown to increase cardiac output and low serum magnesium concentrations are associated with frequent arrhythmias and higher mortality in patients with HF. We investigated the use of oral magnesium oxide in decreasing the morbidity and mortality in patients with mild-to- moderate HF. Oral magnesium oxide or placebo was given to 10 patients with NYHA Class II and III HF in a double-blind manner. In monthly follow-up visits, we measured magnesium levels, Euroquol quality of life values, mean arterial pressures, heart rates, and feet walked in 6 minutes. The mean arterial pressure increased an average of 5.3 mm Hg in the magnesium oxide group and decreased an average of 0.67 mm Hg in the placebo group (p = 0.0174). In addition, the heart rate decreased in the patients receiving magnesium oxide, and increased in the patients receiving placebo (p=0.0994). In each group, the NYHA Class decreased, while the Euroquol scale values and feet walked in 6 minutes increased. Due to the small number of patients enrolled, studies with greater numbers of patients that analyze additional oral formulations of magnesium would be beneficial. In addition enrolling HF patients in outpatient programs would be helpful.

Capaldo B; Lembo G; Rendina V; Vigorito C; Guida R; Cuocolo A; Fazio S; Sacca L
Department of Internal Medicine, IRCCS, NEUROMED, Pozzilli Isernia, Italy
Eur Heart J (England) Apr 1998, 19 (4) p623-7

AIMS: We examined the effects of growth hormone administration on the sympathetic nervous system in patients with idiopathic dilated cardiomyopathy .

BACKGROUND: Growth factor therapy is emerging as a new potential option in the treatment of heart failure. Although growth hormone provides functional benefit in the short term, it is unknown whether it affects the sympathetic nervous system, which plays a role in the progression of heart failure.

METHODS: Seven patients with idiopathic cardiomyopathy received 3 months treatment with recombinant human growth hormone (0.15-0.20 IU.kg-1.week-1). Standard medical therapy was unchanged. Myocardial norepinephrine release, both at rest and during submaximal physical exercise, plasma aldosterone, and plasma volume were measured before and after growth hormone treatment. Myocardial norepinephrine release was assessed from arterial and coronary venous plasma concentrations of unlabelled and tritiated norepinephrine and coronary plasma flow (thermodilution).

RESULTS: Growth hormone induced a significant fall in myocardial norepinephrine release in response to physical exercise (from 180 +/- 64 to 99 +/- 34 ng.min-1; P < 0.05). Basally, plasma aldosterone was 189 +/- 28 and 311 +/- 48 pg.ml-1 in the supine and upright position, respectively, and fell to 106 +/- 16 (P < 0.01) and 182 +/- 29 pg.ml-1 (P < 0.05) after growth hormone therapy. Growth hormone increased plasma volume from 3115 +/- 493 ml to 3876 +/- 336 ml (P < 0.05), whereas serum sodium and potassium concentrations were unaffected.

CONCLUSIONS: The data demonstrate that growth hormone administration to patients with idiopathic cardiomyopathy reduces myocardial sympathetic drive and circulating aldosterone levels. This neurohormonal deactivation may be relevant to the potential, long-term use of growth hormone in the treatment of patients with heart failure.

Kothari SS; Sharma M
Department of Cardiology, All India Institute of Medical Sciences, New Delhi.
Indian Heart J (India) Jan-Feb 1998, 50 (1) p59-61

L-carnitine has been used in dilated cardiomyopathy secondary to carnitine deficiency in children, with favourable results. There are no reports on the effects of L-carnitine in children with idiopathic dilated cardiomyopathy . We undertook a prospective study to evaluate the effects of L-carnitine in children with idiopathic dilated cardiomyopathy . Thirteen children, mean age 3.29 +/- 1.44 years, with idiopathic dilated cardiomyopathy underwent echocardiographic evaluation while on conventional treatment alone, and with additional L-carnitine (50 mg/kg/day). To obviate the effects of spontaneous improvement , eight patients (Group 1) were restudied three weeks after stopping the drug, and five (Group 2) were restudied three weeks after addition of carnitine. Conventional treatment was continued throughout. After repeat echocardiographic examination, the parameters were compared statistically. With addition of carnitine, besides symptomatic improvement , the mean left ventricular ejection fraction improved from 36.9 +/- 16.1 percent to 46.9 +/- 14.5 percent (p < 0.001) and the mean pre-ejection period/left ventricular ejection time ratio from 39.07 +/- 14.8 to 43.2 +/- 8.1 (p < 0.01) in the entire group. These changes were concordant in both the subgroups. It was concluded that L-carnitine therapy in children with idiopathic dilated cardiomyopathy led to modest improvement in left ventricular function.

Dunn JT; Semigran MJ; Delange F
Division of Endocrinology, Department of Medicine, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
Thyroid (United States) Jan 1998, 8 (1) p101-6

Review of available literature and experience supports a recommended daily iodine intake of 150 microg for adults, 200 microg during pregnancy, 50 microg for the first year of life, 90 microg for ages 1 to 6, and 120 microg for ages 7 to 12. The amount of iodine added to salt in fortification programs should be adjusted to achieve these intakes. Iodine-induced hyperthyroidism (IIH) is an occasional consequence of the correction of iodine deficiency, occurring most frequently in older subjects with multinodular goiter. This complication is usually mild and self-limited, but may be serious and occasionally lethal. The most important clinical manifestations are cardiovascular. Thyrotoxicosis can aggravate pre-existing cardiac disease and can also lead to atrial fibrillation, congestive heart failure , worsening of angina, thromboembolism, and rarely, death. In the absence of pre-existing cardiac disease, treatment of thyrotoxicosis usually returns cardiac function to normal. Heightened awareness on the part of the health sector will promote early detection and prompt treatment of IIH. Monitoring should be an important part of a successful program of iodization, and in addition it offers the best opportunity for recognizing and treating IIH. Further research to improve the characterization and prevention of IIH is strongly encouraged. The most important conclusion is that IIH, while an issue that needs serious address, is not a reason to stop iodine supplementation in deficient regions. The benefits to the community from correcting iodine deficiency and avoiding its associated disorders far outweigh the damage from IIH. (36 Refs.)

Gomberg-Maitland M; Frishman WH
Department of Medicine, New York Hospital-Cornell Medical Center, NY, USA.
Am Heart J (United States) Feb 1998, 135 (2 Pt 1) p187-96

Thyroid hormone directly affects the heart and peripheral vascular system. The hormone can increase myocardial inotropy and heart rate and dilate peripheral arteries to increase cardiac output. An excessive deficiency of thyroid hormone can cause cardiovascular disease and aggravate many preexisting conditions. In severe systemic illness and after major surgical procedures changes in thyroid function can occur, leading to the "euthyroid sick syndrome." Patients will have normal or decreased levels of T4, decreased free and total T3, and usually normal levels of thyroid stimulating hormone. This syndrome may be an adaptive response to systemic illness that usually will revert to normal without hormone supplementation as the illness subsides. Recently, however, many investigators have explored the benefits of thyroid hormone supplementation in those diseases associated with euthyroid sick syndrome. Thyroid hormone's effects on the cardiovascular system make it an attractive therapy for those patients with impaired hemodynamics and low T3. Thyroid hormone has also been considered a treatment for patients with congestive heart failure , for patients undergoing cardiopulmonary bypass and heart transplantation, and for patients with hyperlipidemia. At present there is no evidence suggesting a favorable treatment outcome using thyroid hormone supplementation for any systemic condition except in those patients with documented hypothyroidism. (112 Refs.)

Ito K; Akita H; Kanazawa K; Yamada S; Terashima M; Matsuda Y; Yokoyama M
The First Department of Internal Medicine, Kobe University School of Medicine, Japan.
Am J Cardiol (United States) Sep 15 1998, 82 (6) p762-7

Impaired endothelium-dependent vasodilation has been reported to play an important role in the pathogenesis of cardiovascular diseases such as coronary artery disease (CAD) and congestive heart failure (CHF). However, the precise mechanism of endothelial dysfunction has not been elucidated in these conditions. To evaluate the role of oxidative stress in endothelial dysfunction, the effect of antioxidant ascorbic acid on brachial flow-mediated, endothelium-dependent vasodilation during reactive hyperemia and nitroglycerin-induced endothelium-independent vasodilation was examined with high resolution ultrasound in 12 patients with CHF caused by idiopathic dilated cardiomyopathy without established coronary atherosclerosis and in 10 patients with CAD. Flow-mediated vasodilation in CHF (4.4+/-0.5%) and CAD (4.0 - 0.8%) was significantly (p <0.05) attenuated compared with that in 10 control subjects (9.6+/-0.9%). However, nitroglycerin-induced vasodilation was similar in 3 groups (13.7+/-1.3% in control, 13.9+/-1.1% in CHF, 12.7+/-1.4% in CAD). Ascorbic acid could significantly improve flow-mediated vasodilation only in patients with CAD (9.1+/-0.9%) but not with CHF (5.6+/-0.6%), and had no influence on nitroglycerin-induced vasodilation (13.6+/-1.1% in CHF, 14.0+/-1.3% in CAD). These results suggest that, in brachial circulation, augmented oxidative stress mainly leads to endothelial dysfunction in CAD but not in CHF caused by idiopathic dilated cardiomyopathy .

Ning Z.; Connor W.E.; Ott G.Y.
Z. Ning, Department of Cardiovascular Disease, Second Affiliated Hospital, Dalian Medical University, Dalian 116027 China
Chinese Journal of Cardiology (China), 1998, 26/1 (12-14)

Objective: To study the biochemical changes of the myocardium in dilated cardiomyopathy (DCM), the myocardial fatty acid composition was determined.

Methods: From samples of the left ventricular myocardium, removed either, from patients at the time of surgery for cardiac transplantation in OHSU. U.S.A. or from accidental death of normal person, the fatty acid compositions of 10 DCM hearts, 10 coronary disease hearts and 10 control hearts were analyzed. Myocardial phospholipid and triglyceride from the lipid extracts were subjected to thin layer chromatography. Then the fatty acids were analysed by gas-liquid chromatography.

Results: Phospholipids of the DCM had a lower content of essential fatty acid, linoleic acid (18: 2n-6), in comparing with the control hearts. Linoleic acid was lowered to 18.3plus or minus0.9% of the total phospholipid fatty acids in DCM versus 25.3plus or minus3.0% in control hearts (P<0.05). The content of linoleic acid in the myocardial phospholipid of coronary heart disease patients was also lower than that of controls (P<0.05) but higher than DCM. The myocardial triglyceride fatty acids were similar among the three groups.

Conclusion: Our data demonstrated that the phospholipid of the myocardium from patients with DCM had a lower content of linoleic acid. Arachidonic acid is synthesized from linoleic acid. Since arachidonic acid is the precursor of prostaglandin, a lower linoleic acid content might affect prostaglandin production and membrane composition and, in turn, affect myocardial function. Its correction by dietary linoleic acid supplementation may be beneficial to DCM patients.

Singh RB, Niaz MA
Centre of Nutrition, Medical Hospital and Research Centre, Moradabad, India.
Int J Cardiol 1999 Jan;68(1):23-9

OBJECTIVE: To examine the effect of coenzyme Q10 supplementation on serum lipoprotein(a) in patients with acute coronary disease.

STUDY DESIGN: Randomized double blind placebo controlled trial.

SUBJECTS AND METHODS: Subjects with clinical diagnosis of acute myocardial infarction, unstable angina, angina pectoris (based on WHO criteria) with moderately raised lipoprotein(a) were randomized to either coenzyme Q10 as Q-Gel (60 mg twice daily) (coenzyme Q10 group, n=25) or placebo (placebo group, n=22) for a period of 28 days.

RESULTS: Serum lipoprotein(a) showed significant reduction in the coenzyme Q10 group compared with the placebo group (31.0% vs 8.2% P<0.001) with a net reduction of 22.6% attributed to coenzyme Q10. HDL cholesterol showed a significant increase in the intervention group without affecting total cholesterol, LDL cholesterol, and blood glucose showed a significant reduction in the coenzyme Q10 group. Coenzyme Q10 supplementation was also associated with significant reductions in thiobarbituric acid reactive substances, malon/dialdehyde and diene conjugates, indicating an overall decrease in oxidative stress.

CONCLUSION: Supplementation with hydrosoluble coenzyme Q10 (Q-Gel) decreases lipoprotein(a) concentration in patients with acute coronary disease.

Matthews RT, Yang L, Browne S, Baik M, Beal MF
Neurochemistry Laboratory, Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Proc Natl Acad Sci U S A 1998 Jul 21;95(15):8892-7

Coenzyme Q10 is an essential cofactor of the electron transport chain as well as a potent free radical scavenger in lipid and mitochondrial membranes. Feeding with coenzyme Q10 increased cerebral cortex concentrations in 12- and 24-month-old rats. In 12-month-old rats administration of coenzyme Q10 resulted in significant increases in cerebral cortex mitochondrial concentrations of coenzyme Q10. Oral administration of coenzyme Q10 markedly attenuated striatal lesions produced by systemic administration of 3-nitropropionic acid and significantly increased life span in a transgenic mouse model of familial amyotrophic lateral sclerosis. These results show that oral administration of coenzyme Q10 increases both brain and brain mitochondrial concentrations. They provide further evidence that coenzyme Q10 can exert neuroprotective effects that might be useful in the treatment of neurodegenerative diseases.

Sacher H.L.; Sacher M.L.; Landau S.W.; Kersten R.; Dooley F.; Sacher A.; Sacher M.; Dietrick K.; Ichkhan K.
H.L. Sacher, 510 Hicksville Road, Massapequa, NY 11758 USA
American Journal of Therapeutics (USA), 1997, 4/2-3 (66-72)

Despite major advances in treatment congestive heart failure (CHF) is still one of the major causes of morbidity and mortality. Coenzyme Q10 is a naturally occurring substance that has antioxidant and membrane stabilizing properties. Administration of coenzyme Q10 in conjunction with standard medical therapy has been reported to augment myocardial kinetics, increase cardiac output, elevate the ischemic threshold, and enhance functional capacity in patients with congestive heart failure. The aim of this study was to investigate some of these claims. Seventeen patients (mean New York Heart Association functional class 3.0 plus or minus 0.4) were enrolled in an open-label study. After 4 months of coenzyme Q10 therapy, functional class improved 20% (3.0 plus or minus 0.4 to 2.4 plus or minus 0.6, p < 0.001) and there was a 27% improvement in mean CHF score (2.8 plus or minus 0.4 to 2.2 plus or minus 0.4, p < 0.001). Percent change in the resting variables included the following: left ventricular ejection fraction (LVEF), +34.8%; cardiac output, +15.7%; stroke volume index, +18.9%; end- diastolic volume area, -8.4%; systolic blood pressure (SBP), -4.4%; and E(max), (SBP + end-systolic volume index (ESVI)) +11.7%. MV(O2) decreased by 5.3% (31.9 plus or minus 2.6 to 30.2 plus or minus 2.4, p = NS). Therapy with coenzyme Q10 was associated with a mean 25.4% increase in exercise duration and a 14.3% increase in workload. Percent changes after therapy include the following: exercise LVEF, +24.6%; cardiac output, +19.1%; stroke volume index, +13.2%; heart rate, +6.5%; SBP, -4.3%; SBP + ESVI, +18.6%; end-diastolic volume (EDV) area, -6.0%; MV(O2), -7.0%; and ventricular compliance (%Delta SV + EDV) improved >100%. In summary, coenzyme Q10 therapy is associated with significant functional, clinical, and hemodynamic improvements within the context of an extremely favorable benefit-to-risk ratio. Coenzyme Q10 enhances cardiac output by exerting a positive inotropic effect upon the myocardium as well as mild vasodilatation.

McCarty M.F.
Nutrition 21, 1010 Turquoise Street, San Diego, CA 92109 USA
Medical Hypotheses (United Kingdom), 1996, 46/4 (400-406)

Published clinical research, as well as various theoretical considerations, suggest that supplemental intakes of the 'metavitamins' taurine, coenzyme Q10, and L-carnitine, as well as of the minerals magnesium, potassium, and chromium, may be of therapeutic benefit in congestive heart failure. High intakes of fish oil may likewise be beneficial in this syndrome. Fish oil may decrease cardiac afterload by an antivasopressor action and by reducing blood viscosity, may reduce arrhythmic risk despite supporting the heart's beta-adrenergic responsiveness, may decrease fibrotic cardiac remodeling by impeding the action of angiotensin II and, in patients with coronary disease, may reduce the risk of atherothrombotic ischemic complications. Since the measures recommended here are nutritional and carry little if any toxic risk, there is no reason why their joint application should not be studied as a comprehensive nutritional therapy for congestive heart failure.

Forgosh L.B.; Zolotor W.
Dr. L.B. Forgosh, Arizona Heart Institute/Foundation, 2632 N. 20th Street, Phoenix, AZ 85006 USA
Congestive Heart Failure (USA), 1997, 3/2 (21-24)

Magnesium has been shown to increase cardiac output and low serum magnesium concentrations are associated with frequent arrhythmias and higher mortality in patients with HF. We investigated the use of oral magnesium oxide in decreasing the morbidity and mortality in patients with mild-to- moderate HF. Oral magnesium oxide or placebo was given to 10 patients with NYHA Class II and III HF in a double-blind manner. In monthly follow-up visits, we measured magnesium levels, Euroquol quality of life values, mean arterial pressures, heart rates, and feet walked in 6 minutes. The mean arterial pressure increased an average of 5.3 mm Hg in the magnesium oxide group and decreased an average of 0.67 mm Hg in the placebo group (p = 0.0174). In addition, the heart rate decreased in the patients receiving magnesium oxide, and increased in the patients receiving placebo (p=0.0994). In each group, the NYHA Class decreased, while the Euroquol scale values and feet walked in 6 minutes increased. Due to the small number of patients enrolled, studies with greater numbers of patients that analyze additional oral formulations of magnesium would be beneficial. In addition enrolling HF patients in outpatient programs would be helpful.

Ogihara T.; Hiwada K.; Matsuoka H.; Matsumoto M.; Shimamoto K.; Ouchi Y.; Abe I.; Fujishima M.; Morimoto S.; Nakahashi T.; Mikami H.; Kohara K.; Takasaki M.; Takizawa S.; Kiyohara Y.; Ibayashi S.; Eto M.; Ishimitsu T.; Nakamura T.; Masusa A.; Takagawa Y.
Japanese Journal of Geriatrics (Japan), 1996, 33/12 (945-974)

We propose the following guidelines for treatment of hypertension in the elderly.

1. Indications for Treatment.

1) Age: Lifestyle modification is recommended for patients aged 85 years and older. Antihypertensive therapy should be limited to patients in whom the merit of the treatment is obvious. 2) Blood pressure: Systolic BP > 160 mmHg, diastolic BP>90similar100 mmHg. Systolic BP<age . 100 mmHg for those aged 70 years and older. Patients with mild hypertension (140 160/90 95 mmHg) associated with cardiovascular disease should be considered for antihypertensive drug therapy.

2. Goal of Therapy for BP: The goal BP in elderly patients is higher than that in younger patients (BP reduction of 10-20 mmHg for systolic BP and 5-10 mmHg for diastolic BP). In general, 140 160/<90 mmHg is recommended as the goal. However, lowering the BP below 150/85 should be done with caution.

3. Rate of Lowering BP: Start with half the usual dose, observe at the same dose for at least four weeks, and reach the target BP over two months. Increasing the dose of antihypertensive drugs should be done very slowly.

4. Lifestyle Modification:

1) Dietary modification:

(1) Reduction of sodium intake is highly effective in elderly patients due to their high salt-sensitivity. NaCl intake of less than 10 g/day is recommended. Serum Na+ should be occasionally measured. (2) Potassium supplementation is recommended, but with caution in patients with renal insufficiency, (3) Sufficient intake of calcium and magnesium is recommended. (4) Reduce saturated fatty acids. Intake of fish is recommended.

2) Regular physical activity: Recommended exercise for patients aged 60 years and older: peak heart rate 110/minute, for 30-40 minutes a day, 3-5 days a week. 3) Weight reduction. 4) Moderation of alcohol intake, smoking cessation.

5. Pharmacologic Treatment:

1) Initial drug therapy. First choice: Long-acting (once or twice a day) Ca antagonists or ACE inhibitors. Second choice: Thiazide diuretics (combined with potassium-sparing diuretic). 2) Combination therapy.

(1) For patients without complications, either of the following is recommended.

i) Ca antagonist + ACE inhibitor, ii) ACE inhibitor + Ca antagonist (or low-dose diuretic), iii) diuretic + Ca antagonist (or ACE inhibitor), iv) beta- blockers, alpha1-blockers, alpha + beta blockers can be used according to the pathophysiological state of the patient.

(2) For patients with complications. Drug(s) should be selected according to each complication.

3) Relatively contraindicated drugs. beta-Blockers and alpha1-blockers are relatively contraindicated in elderly patients with hypertension in Japan. Centrally acting agents such as reserpine, methyldopa and clonidine are also relatively contraindicated. beta-Blockers are contraindicated in patients with congestive heart failure, arteriosclerosis obliterans, chronic obstructive pulmonary disease, diabetes mellitus (or glucose intolerance), or bradycardia. These conditions are often present in elderly subjects. Elderly subjects are susceptible to alpha1-blocker-induced orthostatic hypotension, since their baroreceptor reflex is diminished. Orthostatic hypotension may cause falls and bone fractures in the elderly.

Predictors of sudden death and death from pump failure in congestive heart failure are different. Analysis of 24 h Holter monitoring, clinical variables, blood chemistry, exericise test and radionuclide angiography

Madsen B.K.; Rasmussen V.; Hansen J.F.
Denmark
International Journal of Cardiology (Ireland), 1997, 58/2 (151-162)

One hundred and ninety consecutive patients discharged with congestive heart failure were examined with clinical evaluation, blood chemistry, 24 h Holter monitoring, exercise test and radionuclide angiography. Median left ventricular ejection fraction was 0.30, 46% were in New York Heart Association class II and 44% in III. Total mortality after 1 year was 21%, after 2 years 32%. Of 60 deaths, 33% were sudden and 49% due to pump failure. Multivariate analyses identified totally different risk factors for sudden death: ventricular tachycardia, s-sodium less than or equal to 137 mmol/l, s-magnesium less than or equal to 0.80 mmol/l, s-creatinine > 121 micromol/l, and maximal change in heart rate during exercise less than or equal to 35 min-1, and for death from progressive pump failure: New York Heart Association class III + IV, Deltaheart rate over 24 h less than or equal to 50 min-1, low ejection fraction, high resting p-noradrenaline, s-urea > 7.6 mmol/l, s-potassium < 3,5 mmol/l, and maximal exercise duration less than or equal to 4 min. In conclusion, this study demonstrated different risk factors for sudden death and for death from progressive pump failure.

Costello R.B.; Moser-Veillon P.B.; DiBianco R.
USA
Journal of the American College of Nutrition (USA), 1997, 16/1 (22-31)

Objective: To evaluate several potential clinical indicators of magnesium status (diet, blood, urine, 24-hour load retention) in patients with congestive heart failure before, during, and after oral magnesium supplementation.

Methods: Twelve patients with New York Heart Association class II-III heart failure and 12 age and sex matched healthy control subjects were supplemented with 10.4 mmol oral magnesium lactate for 3 months. For the determination of magnesium status, samples of whole blood, serum, plasma, red blood cells, and urine (24-hour) were collected. Four-day dietary intake records were reviewed. A 4-hour IV magnesium load retention study was performed before and 3 months after magnesium supplementation. A non-supplemented control group was similarly studied.

Results: At baseline, magnesium intakes for all groups were below the RDA. No significant differences were seen in serum, plasma, ultrafiltrates of serum or plasma or red cell magnesium concentrations among groups over time. At baseline 5/27 subjects (19%) compared to 11/27 subjects (41%) after supplementation demonstrated normal magnesium retentions (<25%). Magnesium excretions among groups were significantly different during supplementation. Percent magnesium retentions among groups were not different.

Conclusions: Supplementation with 10.4 mmol oral magnesium daily for 3 months did not significantly alter blood levels or magnesium retention; however, patients demonstrated lower retention of magnesium after supplementation. Differences in magnesium retention was not related to basal magnesium intake, blood levels or excretion. Unfortunately, even an intensive effort at characterizing magnesium status did not identify a clinical indicator of utility for differentiating patients with congestive heart failure before, during, and after 3 months of magnesium supplementation.

Seelig M.; Altura B.M.
USA
Journal of the American College of Nutrition (USA), 1997, 16/1 (4-6)

No abstract.

Meinertz T.
Prof. Dr. T. Meinertz, Abteilung fur Kardiologie, Medizinische Klinik, Universitatskrankenhaus Eppendorf, Martinistr. 52, 20246 Hamburg Germany
Zeitschrift fur Kardiologie (Germany), 1996, 85/Suppl. 6 (147-151)

The therapeutic efficacy of magnesium has been studied during recent years in a number of cardiovascular diseases: supraventricular and ventricular arrhythmias (multifocal atrial tachycardia, Torsade de pointes-tachycardia, glycoside-associated arrhythmias, sustained ventricular tachycardia), acute myocardial infarction, heart failure and arterial hypertension. Although only a few of these arrhythmias were studied under controlled conditions, the therapeutic efficacy of intravenous magnesium given in a high dose in these arrhythmias seems to be established. By contrary, the efficacy of magnesium in acute myocardial infarction, congestive heart failure and arterial hypertension remains controversial up to now. Magnesium cannot be regarded as standard therapy for example for patients with acute myocardial infarction.

Azfal N.; Dhalla N.S.
Institute of Cardiovascular Sciences, St Boniface General Hosp. Res. Ctr., 351 Tache Avenue, Winnipeg, Man. R2H 2A6 Canada
Canadian Journal of Cardiology (Canada), 1996, 12/10 (1065-1073)

Objective: Earlier studies have shown a depression in the sarcoplasmic reticular (SR) Ca2+ uptake and gene expression in Ca2+ pump ATPase protein in congestive heart failure subsequent to myocardial infarction. It is the objective of this study to understand further the mechanisms of depressed SR Ca2+ pump activity in the failing heart.

Methods: Heart failure in rats was induced by occluding the left coronary artery for 16 weeks and the viable left ventricle was processed for the isolation of SR membranes. Sham-operated animals were used as control. The characteristics of SR Ca(2+) pump ATPase in the presence of different concentrations of K+, Ca2+ and ATP were examined and that the purity of these membranes was monitored by determining the marker enzyme activities. In addition to measuring changes in cyclic adenosine monophosphate (cAMP) protein kinase and C2+ calmodulin induced phosphorylation, alterations in SR phospholipid composition as well as sulfhydryl (SH) group content were investigated.

Results: Ca2+stimulated ATPase activity, unlike Mg2+-ATPase activity, was depressed in the left ventricular SR from failing hearts as compared to control. The decreased in Ca2+stimulated ATPase activity was seen at different concentrations of Ca2+, K+ and ATP but no change in the affinities of the enzyme for Ca2+ and ATP were evident. The SR Ca2+stimulated ATPase activities in the presence of both cAMP-dependent protein kinase and Ca2+-calmodulin were markedly decreased in the failing hearts when compared to control preparations. Furthermore, the 32P incorporation in the presence of cAMP-dependent protein kinase or Ca2+-calmodulin was also reduced in the experimental heart SR membranes. The phospholipid composition of the SR membranes from the failing heart was markedly altered. No changes in SH-group of the degree of cross contaminaton with other membranes were apparent in the failing heart SR.

Conclusions: The results suggest the abnormalities in membrane phospholipid composition and phosphorylation of the enzyme may partly explain the observed depression in SR Ca(2+) pump ATPase activity in heart following myocardial infarction.

Douban S.; Brodsky M.A.; Whang D.D.; Whang R.
Division of Cardiology, Irvine Medical Center, University of California, 101 The City Dr., Orange, CA 92668-3298 USA
American Heart Journal (USA), 1996, 132/3 (664-671)

Electrolyte balance has been regarded as a factor important to cardiovascular stability, particularly in congestive heart failure. Among the common electrolytes, the significance of magnesium has been debated because of difficulty in accurate measurement and other associated factors, including other electrolyte abnormalities. The serum magnesium level represents <1% of total body stores and does not reflect total-body magnesium concentration, a clinical situation very similar to that of serum potassium. Magnesium is important as a cofactor in several enzymatic reactions contributing to stable cardiovascular hemodynamics and electrophysiologic functioning. Its deficiency is common and can be associated with risk factors and complications of heart failure. Typical therapy for heart failure (digoxin, diuretic agents, and ACE inhibitors) are influenced by or associated with significant alteration in magnesium balance. Magnesium therapy, both for deficiency replacement and in higher pharmacologic doses, has been beneficial in improving hemodynamics and in treating arrhythmias. Magnesium toxicity rarely occurs except in patients with renal dysfunction. In conclusion, the intricate role of magnesium on a biochemical and cellular level in cardiac cells is crucial in maintaining stable cardiovascular hemodynamics and electrophysiologic function. In patients with congestive heart failure, the presence of adequate total-body magnesium stores serve as an important prognostic indicator because of an amelioration of arrhythmias, digitalis toxicity, and hemodynamic abnormalities.

Shechter M.; Hod H.; Kaplinsky E.; Rabinowitz B.
Prev./Rehabilitative Cardiac Center, Cedars-Sinai Medical Center, 444 South San Vicente Blvd., Los Angeles, CA 90048 USA
American Heart Journal (USA), 1996, 132/2 II (483-486)

Only one third of hospitalized patients with acute myocardial infarction receive thrombolytic therapy despite its proven benefits on outcomes. Elderly patients, for example, have a greater risk cf death after myocardial infarction, but studies demonstrate that thrombolytic therapy is less likely to be used in older patients. Intravenous magnesium supplementation, both theoretically and experimentally, has been demonstrated to decrease myocardial damage and reduce the mortality rate in subsets of patients, including the elderly and/or patients not suitable for thrombolysis, if it is administered before reperfusion occurs. The aim of this study is to review the rationale of magnesium supplementation as alternative therapy for patients with acute myocardial infarction without thrombolytic therapy.

Teo K.K.; Montague T.; Ackman M.; Barnes M.; Taylor C.; Mansell G.; Greenwood P.; Prosser A.; Tsuyuki R.; Nilsson C.; Kornder J.; Ashton T.; McLeod D.; Morris A.; Robinson K.; Johnstone D.; Barnhill S.; Chatterton P. ; Montague P.; et al.
Division of Cardiology, 2C2 Mackenzie Centre, University of Alberta Hospitals, Edmonton, Alta. T6G 2B7 Canada
Archives of Internal Medicine (USA), 1996, 156/15 (1669-1673)

Objective: To define contemporary patterns of risk and management among patients with congestive heart failure (CHF).

Methods: Cross-sectional records audit of 4606 hospitalized patients with CHF in 1992 and 1993.

Results: Overall medication use was diuretics, 82%; angiotensin-converting enzyme inhibitors, 53%; nitrates, 49%; digoxin, 46%; potassium, 40%; acetylsalicylic acid, 36%; calcium antagonists, 20%; warfarin, 17%; beta- blockers, 15%; and magnesium, 10%. Angiotensin-converting enzyme inhibitors were used less frequently in women and patients 70 years or older (P<.01). Total in-hospital mortality was 19%. The most common single cause of death was CHF progression, but noncardiac causes accounted for 30% of all deaths. Logistic regression analysis revealed age 70 years or older and the use of magnesium and nitrates to be associated with increased relative risk of in- hospital mortality; angiotensin-converting enzyme inhibitors, acetylsalicylic acid, calcium antagonists, beta-blockers, and warfarin were associated with decreased risk.

Conclusions: Hospitalized patients with CHF have high all-cause mortality risk and less than optimal use of proven efficacious therapy, particularly among women and the elderly. Increased use of proven CHF therapy would likely decrease the risk of cardiac events, but the competing noncardiac risks in this patient population are high and may not be affected by improved use of efficacious cardiac therapies.

Marusaki S.; Shimamoto K.
Second Dept. of Internal Medicine, Sapporo Medical Univ. School of Med., S.1, W.17, Chuo-ku, Sapporo 060 Japan
Sapporo Medical Journal (Japan), 1996, 65/1 (23-32)

It is now known that the serum magnesium level is low in patients with chronic congestive heart failure (CHF). In this study, to clarify the role of renal magnesium handling in CHF, the following parameters were examined in normal subjects (control: n = 28) and patients with CHF (n = 37): serum magnesium (s-Mg), plasma aldosterone concentration (PAC), endogenous creatinine clearance (C(Cr)), urinary excretions of magnesium (U(Mg)V) and sodium (U(Na)V), and fractional excretions of magnesium (FE(Mg)), sodium (FE(Na)) and potassium (FE(K)). The relationship between s-Mg and the severity of cardiac dysfunction (NYHA subclass in CHF) was also investigated in CHF. All subjects were admitted to our hospital and given a standard diet including 120 mEq of Na and 75 mEq of K/day, and all the parameters were measured in the early morning after an overnight fast. Compared with the controls, the patients with CHF showed lower levels of s-Mg, C(Cr), U(Na)V and FE(Na), and higher levels of FE(Mg) and PAC. On the other hand, there was no significant difference in U(Mg)V between the controls and CHF patients. In both groups, significant positive correlations were observed between U(Mg)V and FE(Mg), and between U(Mg)V and C(Cr). FE(Mg) correlated positively with FE(K) and PAC in patients with CHF, suggesting an important role of mineralocorticoids in magnesium handling in the distal renal tubules. In the severe CHF (NYHA II or III) subgroup, levels of s-Mg and FE(Mg) were quite similar to those in the mild CHF (NYHA I) subgroup, but the severe CHF subgroup used potassium-magnesium sparing drugs (spironolactone, triamterene and angiotensin converting enzyme inhibitor) more frequently. In CHF patients, combined use of loop diuretics and potassium-magnesium sparing drugs did not show any significant influence on the levels of s-Mg and FE(Mg). These results suggest that the low level of s-Mg in CHF patients is attributable to enhancement of renal magnesium excretion by secondary aldosteronism, and that use of potassium-magnesium sparing drugs may be beneficial for prevention of magnesium deficiency in CHF.

Forman D.E.; Rich M.W.
Division of Geriatrics, Miriam Hospital, Brown University, Providence, RI 02906 USA
Drugs and Aging (New Zealand), 1996, 8/5 (358-377)

The prevalence of myocardial infarction (MI) is high among the elderly population. Many of the physiological and morphological changes attributable to 'normal' aging predispose older adults to cardiovascular instability. The incidence of both MIs and their associated morbidity and mortality increase with aging. Older MI patients may therefore derive substantial benefit from appropriately selected therapeutic intervention. In fact, given the high morbidity and mortality associated with MI in the elderly, aggressive therapeutic strategies may be particularly warranted. There are a number of age-related cardiovascular changes that contribute to the increasing incidence of MI as adults age. However, age itself is not a contraindication to aggressive therapy. Common MI management options include invasive and pharmaceutical strategies. The relative advantages of angioplasty and thrombolytics must be considered. Other drugs used in the treatment of MI include beta-blockers, ACE inhibitors, nitrates, aspirin, anticoagulants, magnesium, antiarrhythmics and calcium antagonists. Significant peri-infarction complications, including heart failure, hypotension, arrhythmias, myocardial rupture and cardiogenic shock, often occur in older adults. Age-specific management strategies for these complications are reviewed.

Nally B.R.; Dunbar S.B.; Zellinger M.; Davis A.
PO Box 1253, Cartersville, GA 30120 USA
Heart and Lung: Journal of Acute and Critical Care (USA), 1996, 25/1 (31-36)

Objective: To explore the relationship between fluid and electrolyte variables and the development of supraventricular tachycardia (SVT) after coronary artery bypass grafting (CABG) surgery.

Design: Retrospective chart review. Random selection from a list obtained from the medical records department and with use of the International Classification of Diseases code to identify patients undergoing their initial CABG.

Setting: Medical records department of a southeastern 600-bed urban referral hospital with a large cardiovascular surgical program.

Patients: Forty patients experiencing SVT and 40 patients not experiencing SVT during their stay in an intensive care unit after CABG.

Outcome Measures: Fluid and electrolyte variables and the development of SVT in the intensive care unit after CABG. Variables: Data collected included preoperative demographic variables such as age and gender; previous history of SVT, congestive heart failure, cardiac arrest, previous surgery, diabetes, hypertension, valve disease, tobacco use, obesity; preoperative and postoperative medications; postoperative laboratory values of potassium, calcium, and magnesium; intravenous intake; hourly urine output; and chest tube drainage.

Results: Demographic variables revealed that patients with SVT were older (p = 0.001) and had a higher incidence of preoperative SVT (p = 0.04). Although groups did not differ by numbers of patients with high or low potassium, calcium, or magnesium, patients receiving additional intravenous potassium by bolus after surgery had a higher incidence of SVT (p = 0.02). Patients who lost blood via the chest tube at a rate greater than 100 ml per hour for at least 1 hour after surgery had a higher incidence of SVT (p = 0.02). Patients with a urine output greater than 300 ml per hour for longer than 9 hours had an increased incidence of SVT (p = 0.02). In the patients experiencing SVT, 62% had it occur 24 to 48 hours after surgery.

Conclusions: These data suggest that shifts in fluid and electrolytes may be important characteristics of patients in whom SVT will develop, which could lead to better identification and nursing management of SVT and improve hemodynamic status, patient recovery, and cost after CABG.

Dreifuss P.M.; Khardori R.; Taraben A.; Taylor G.J.; Falcone H.; Wilmshurst P.; Giustina A.; Volterrani M.; Desenzani P.
P.M. Dreifuss, Division of Cardiology, University Hospital of Basel, 4055 Basel Switzerland
Lancet (United Kingdom), 1997, 349/9068 (1841-1843)

No abstract.

Volterrani M.; Desenzani P.; Lorusso R.; D'Aloia A.; Manelli F.; Giustina A.
Italy
Lancet (United Kingdom), 1997, 349/9058 (1067-1068)

No abstract.

Bernocchi P.; Ceconi C.; Pedersini P.; Pasini E.; Curello S.; Ferrari R.
Fondazione Salvatore Maugeri, Clinica Lavoro delia Riabilitazione, Lab Ricerca Fisiopatol Cardiovascol, Via Pinidolo 23, 25064 Gussago (Brescia) Italy
Journal of Molecular and Cellular Cardiology (United Kingdom), 1996, 28/11 (2263-2273)

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorum longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus, ATP declined from 20.31 plus or minus 2.5 of control group to 9.55 plus or minus 0.61 micromol/g dry wt, while in the extensor digitorum longus ATP declined from 30.92 plus or minus 2.68 to 22.7 plus or minus 1.54 micromol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 plus or minus 3.34 to 6.95 plus or minus 0.97 and from 18.88 plus or minus 3.43 to 10.57 plus or minus 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Munzel T.; Kurz S.; Rajagopalan S.; Thoenes M.; Berrington W.R.; Thompson J.A.; Freeman B.A.; Harrison D.G.
Cardiology Division, Emory University School of Medicine, Atlanta, GA 30322 USA
Journal of Clinical Investigation (USA), 1996, 98/6 (1465-1470)

Hydralazine has been shown to reduce mortality in patients with congestive heart failure when given concomitantly with isosorbide dinitrate. Recently, we demonstrated that nitrate tolerance is in part due to enhanced vascular superoxide .O2/- production. We sought to determine mechanisms whereby hydralazine may prevent tolerance. Rabbits either received no treatment, nitroglycerin patches (1.5 microg/kg/min x 3 d), hydralazine alone (10 mg/kg/d in drinking water), or hydralazine and nitroglycerin. Aortic segments were studied in organ chambers and relative rates of vascular .O2 production were determined using lucigenin-enhanced chemiluminescence. Nitroglycerin treatment markedly inhibited relaxations to nitroglycerin (maximum relaxations in untreated: 92 plus or minus 1 vs. 64 plus or minus 3% in nitroglycerin- treated patients and increased vascular .O2 production by over twofold (P < 0.05). Treatment with hydralazine in rabbits not receiving nitroglycerin significantly decreased .O2 production in intact rabbit aorta and increased sensitivity to nitroglycerin. When given concomitantly with nitroglycerin, hydralazine completely prevented the development of nitrate tolerance and normalized endogenous rates of vascular .O2 production. Studies of vessel homogenates demonstrated that the major source of .O2 was an NADH-dependent membrane-associated oxidase displaying activities of 67 plus or minus 12 vs. 28 plus or minus 2 nmol .O2 .min-1.mg protein-1 in nitroglycerin-treated vs. untreated aortic homogenates. In additional studies, we found that acute addition of hydralazine (10 microM) to nitroglycerin-tolerant vessels immediately inhibited .O2 production and NADH oxidase activity in vascular homogenates. The chemiluminescence signal was inhibited by a recombinant heparin-binding superoxide dismutase (HB-SOD) demonstrating the specificity of this assay for .O2. These observations suggest that a specific membrane-associated oxidase is activated by chronic nitroglycerin treatment, and the activity of this oxidase is inhibited by hydralazine, providing a mechanism whereby hydralazine may prevent tolerance. The ability of hydralazine to inhibit vascular .O2 anion production represents a novel mechanism of action for this drug.

Morrison R.T.
Dr. R.T. Morrison, 386 North Detroit Street, Xenia, OH 45385 USA
Medical Clinics of North America (USA), 1997, 81/3 (689-704)

Diuretics have changed the approach to many diseases and have turned once fatal conditions into tolerable ones. Treatment of salt and water overload and edema can be quite satisfying for the clinician as long as the patient is closely watched for side effects. Thiazide diuretics have their greatest use in hypertension, loop diuretics in edema and congestive heart failure, CA inhibitors in glaucoma and altitude sickness, potassium-sparing diuretics in hypokalemia induced by other diuretics and ascites, and osmotic diuretics in acute renal failure and dialysis. They are among the most widely prescribed medications in the world today and rightly have a prominent place in the armamentarium against disease.

Koumi S.-I.; Martin R.L.; Sato R.
Japan
American Journal of Physiology - Heart and Circulatory Physiology (USA), 1997, 272/4 41-4 (H1656-H1665)

Little is known about the involvement of preexisting heart disease on characteristics of ATP-sensitive K channels (I(K(ATP))) in human heart. We have characterized I(K(ATP)) in isolated cardiac myocytes from patients with congestive heart failure (HF) and compared these channel characteristics with those from donor hearts (healthy control) using the patch-clamp technique. During metabolic inhibition induced by treatment with cyanide (1 mM) and 2- deoxyglucose (10 mM), action potential shortening occurred in atrial myocytes isolated from both HF and donors, but this response was significantly greater and sooner in HF than in donors. The action potential duration at 90% repolarization was 24.7 plus or minus 4.1% (n = 15) of control in HF, whereas it was 58.7 plus or minus 5.9% (n = 10, P < 0.001) of control in donors measured at 30-min metabolic inhibition. The shortening of the action potential was partially reversed by glibenclamide (0.5 microM) in both groups. Consistent with the action potential measurements, the whole cell membrane current response to metabolic inhibition, evaluated by the differential current measurement, was sooner and greater in HF than in donors. Single channel atrial I(K(ATP)) from both HF and donors, recorded in the excised inside-out patch configuration, exhibited bursting opening, conductance, and gating behaviors that did not differ between the two groups. However, the concentration of ATP at half- maximal inhibition of the channel in HF was greater (131.0 microM) than in donors (26.1 microM). We conclude that I(K(ATP)) in cardiac myocytes from patients with HF has channel characteristics substantially similar to those in donors, but that the channel is less sensitive to ATP inhibition in HF than in donors.

Mallie J.P.; Bichet D.G.; Halperin M.L.
Dr. J.P. Mallie, Explorations Fonctionnelles Renales, Centre Hospitalier, Universitaire de Nancy, 54511 Vandoeuvre Cedex France
Clinical and Investigative Medicine (Canada), 1997, 20/1 (16-24)

Objective: To demonstrate

(1) that hyponatremia is usually due to an inappropriately low rate of excretion of electrolyte-free water and

(2) that the measure 'effective water clearance' (EWC) provides better information about renal defence of the body tonicity than does the classic measure free-water clearance, and to provide the rationale for calculating a 'tonicity balance,' which involves using water and sodium plus potassium intakes and their renal excretion to reveal the basis for changes in body tonicity.

Design: Prospective study.

Participants: Four normal subjects with no conditions affecting excretion, 10 patients with advanced congestive heart failure (CHF) and 5 patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Intervention: Normals and patients were administered a standard water load (20 mL per kg of body weight) during 45 minutes, and blood and urine samples were taken before, during and after the load was given.

Main outcome measures: Urine and blood sodium and potassium concentrations, osmolar clearance, free-water clearance, electrolyte clearance and EWC.

Results: The water load was excreted rapidly by normals, more slowly by patients with CHF, and not at all by patients with SIADH. The EWC was positive in normals and those with CHF, but negative in those with SIADH. In patients with CHF, the EWC, but not the free-water clearance, helped explain why hyponatremia was corrected after the water load was given.

Conclusions: In subjects with abnormal water excretion, the EWC provides the physiologic explanation for the renal role in variations in natremia. The authors propose a bedside evaluation of renal water and electrolyte handling that takes into consideration the role of urinary potassium in body tonicity. Changes in body tonicity can be explained by a 'tonicity balance,' a calculation in which the source and the net balance of sodium, potassium and water are considered.

Hyman B.N.; Moser M.
7707 Fannin, Houston, TX 77054 USA
Survey of Ophthalmology (USA), 1996, 41/1 (79-89)

Hypertension affects approximately fifty million Americans. About 80% of hypertensive patients are aware that their blood pressure is elevated. While more than 50% are on medication, only about 20% of all hypertensive adults are controlled at normotensive levels. Ophthalmologists should be aware of the seriousness of' hypertension because it affects many of' their patients and is a risk factor for myocardial infarction, stroke, congestive heart failure, end-stage renal disease and peripheral vascular disease. As medically trained eye specialists, ophthalmologists should be knowledgeable about and take all interest in their patients medical problems, thus playing an integral role on the health care team. As a primary health care provider, ophthalmologists should perform in office blood pressure monitoring.

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Does aspirin cause acute or chronic renal failure in experimental animals and in humans?

D'Agati V.
Department of Pathology, College of Physicians and Surgeons, Columbia University, 630 W 168th St, New York, NY 10032 USA
American Journal of Kidney Diseases (USA), 1996, 28/1 Suppl. (S24-S29)

There are conflicting reports on the ability of aspirin as a single agent to cause acute or chronic renal failure in experimental animals. Chronic administration of aspirin alone over 18 to 68 weeks in doses of 120 to 500 mg/kg/d has been reported to cause renal papillary necrosis in rate. However, some investigators have been unable to produce renal papillary necrosis in other species or in rats given lower divided doses comparable to therapeutic doses used in humans. In a variety of rat strains, aspirin administered as a single high dose intravenously or by oral gavage produces acute tubular necrosis of proximal tubules, rarely accompanied by renal papillary necrosis in susceptible strains. Several human studies have addressed the chronic nephrotoxicity of aspirin alone or relative risk of end-stage renal disease in association with aspirin use after correction for other analgesics. With the exception of one case control study demonstrating a low, but statistically significant risk of end-stage renal disease in association with aspirin use, all other case control studies and several prospective studies have been unable to identify a significant risk of chronic renal failure in patients using aspirin alone in therapeutic doses. In healthy adults, short-term aspirin administration in therapeutic doses has no effect on creatinine clearance, urine volume, osmolar clearance, or sodium and potassium excretion. However, in predisposed individuals with glomerulonephritis, cirrhosis, and chronic renal insufficiency, and in children with congestive heart failure, short-term aspirin use in therapeutic doses may precipitate reversible acute renal failure. Acute aspirin intoxication (>300 mg/kg) frequently causes acute renal failure and doses of 500 mg/kg may be lethal. Chronic salicylate intoxication has been reported to cause reversible or irreversible acute renal failure in association with a pseudosepsis syndrome.

Elevated myocardial interstitial norepinephrine concentration contributes to the regulation of Na+,K+-ATPase in heart failure

Lai L.-P.; Fan T.-H.M.; Delehanty J.M.; Yatani A.; Liang C.-S.
Cardiology Unit, Department of Medicine, Univ. of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642 USA
European Journal of Pharmacology (Netherlands), 1996, 309/3 (235-241)

Myocardial Na+,K+-ATPase is reduced in congestive heart failure. To study the regulation of Na+,K+-ATPase in congestive heart failure, we performed Western and Northern blot analyses of ventricular myocardium of dogs with pacing-induced congestive heart failure and chronic norepinephrine infusion, using isoform-specific antibodies and cDNA probes. Congestive heart failure and norepinephrine infusion caused similar increases in myocardial interstitial norepinephrine concentration and reductions of myocardial Na+,K+-ATPase alpha3-subunit protein, but differed in their effects on myocardial Na+,K+-ATPase alpha3-subunit gene expression. Chronic norepinephrine infusion produced no changes in the steady-state mRNA level for the alpha3-subunit of Na+,K+-ATPase, suggesting that the changes in Na+,K+-ATPase protein were induced via a post-transcriptional mechanism. In contrast, down-regulation of the Na+,K+-ATPase alpha3-subunit in the failing heart was accompanied by a decreased alpha3-subunit mRNA level, indicating the presence of a transcriptional event. The alpha3-subunit protein content and mRNA level were not affected by either norepinephrine infusion or rapid ventricular pacing. We conclude that, while elevated myocardiaI interstitial norepinephrine levels may contribute substantially to the down-regulation of the Na+,K+-ATPase alpha3-subunit in the failing myocardium, additional regulatory factors are responsible for the decreased myocardial alpha3-subunit mRNA expression in congestive heart failure.

[Magnesium: current studies--critical evaluation--consequences]

Meinertz T
Abteilung fur Kardiologie, Universitatskrankenhaus Eppendorf, Hamburg.
Z Kardiol (Germany) 1996, 85 Suppl 6 p147-51

The therapeutic efficacy of magnesium has been studied during recent years in a number of cardiovascular diseases: supraventricular and ventricular arrhythmias (multifocal atrial tachycardia, Torsade de pointes-tachycardia, glycoside-associated arrhythmias, sustained ventricular tachycardia), acute myocardial infarction, heart failure and arterial hypertension. Although only a few of these arrhythmias were studied under controlled conditions, the therapeutic efficacy of intravenous magnesium given in a high dose in these arrhythmias seems to be established. By contrary, the efficacy of magnesium in acute myocardial infarction, congestive heart failure and arterial hypertension remains controversial up to now. Magnesium cannot be regarded as standard therapy for example for patients with acute myocardial infarction. (13 Refs.)

Nonsustained polymorphous ventricular tachycardia during amiodarone therapy for atrial fibrillation complicating cardiomyopathy. Management with intravenous magnesium sulfate.

Winters SL; Sachs RG; Curwin JH
Morristown Memorial Hospital, NJ 07962-1956, USA.
Chest (United States) May 1997, 111 (5) p1454-7

A case is presented in which amiodarone was administered to suppress paroxysmal atrial fibrillation in a patient with an idiopathic cardiomyopathy. Eleven days after initiation of therapy with amiodarone, the patient experienced syncope and was noted to have recurrent episodes of polymorphous ventricular tachycardia. The patient was hospitalized and treated with a bolus as well as continuous infusion of intravenous magnesium sulfate. When the infusion was transiently discontinued, recurrences of polymorphous ventricular tachycardia were noted. The probable proarrhythmic action of amiodarone, although rare, is reviewed along with a discussion of the novel use of intravenous magnesium sulfate therapy. (6 Refs.)

Magnesium deficiency-related changes in lipid peroxidation and collagen metabolism in vivo in rat heart

Kumar BP; Shivakumar K; Kartha CC
Division of Cellular and Molecular Cardiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, India.
Int J Biochem Cell Biol (England) Jan 1997, 29 (1) p129-34

Magnesium deficiency is known to produce a cardiomyopathy, characterised by myocardial necrosis and fibrosis. As part of the ongoing investigations in this laboratory to establish the biochemical correlates of these histological changes, the present study probed the extent of lipid peroxidation and alterations in collagen metabolism in the heart in rats fed a magnesium-deficient diet for 28, 60 or 80 days. While lipid peroxidation was measured by the thiobarbituric acid reaction, collagen turnover rates and fibroblast proliferation were assessed using [3H]-proline and [3H]-thymidine, respectively. Tissue levels of magnesium and calcium were determined by atomic absorption spectrophotometry. A 39% increase in the cardiac tissue level of thiobarbituric acid reactive substances was observed on day 60 of deficiency (p < 0.001). A marked drop in collagen deposition rate (59%, p < 0.001%) on day 28 but a significant rise in fractional synthesis rate (12%, p < 0.001) and collagen deposition rate (24%, p < 0.001) on day 60 were observed. A fibroproliferative response in the heart was evident on day 80 but not at earlier time-points. Thus, the present study provides evidence of increased lipid peroxidation and net deposition of collagen in the myocardium in response to dietary deficiency of magnesium. These changes were, however, not directly related to alterations in the tissue levels of Mg. It is suggested that the increase in cardiac collagen synthesis and fibroplasia associated with Mg deficiency may represent reparative fibrogenesis, upon oxidative damage to the cardiac muscle, and is mediated by a mechanism independent of changes in cardiac tissue levels of Mg.

[Value of magnesium in acute myocardial infarct]

Beuckelmann DJ
Klinik III fur Innere Medizin, Universitat zu Koln.
Z Kardiol (Germany) 1996, 85 Suppl 6 p129-34

Experiments in animal models of myocardial infarction have provided evidence that early magnesium infusion can limit the infarct size. One mechanism that has been postulated to be of importance is a protection of the cardiomyocyte against a calcium overload during or after ischemia. We had shown that in isolated human myocytes from patient with ischemic cardiomyopathy an increase of the extracellular magnesium concentration could block the L-type-calcium current in a dose dependent manner. Until recently only small, uncontrolled studies have indicated there may be a reduction of mortality due to myocardial infarction when intravenous magnesium infusion was added to standard therapy. However, two recently published randomized studies showed different results, although similar doses of magnesium were used (70-80 mmol magnesium over 24 h). The LIMIT-2-study was a double-blind, placebo controlled investigation of over 2300 patients with suspected myocardial infarction. Magnesium infusion was associated with a reduction of the 28 day mortality by 24%. The ISIS-4-study on over 50,000 patients with suspected myocardial infarction did not show any positive effect of magnesium on mortality. Major differences between both studies were differences in thrombolysis (LIMIT-2:1/3, ISIS-4: 70%). Furthermore, in LIMIT-2 magnesium infusion was started as early as possible, whereas in ISIS-4 magnesium was given after the end of thrombolytic therapy. In can be concluded that magnesium therapy in acute myocardial infarction after thrombolytic therapy is not useful. However, in patients where thrombolytic therapy is not feasable, early infusion of magnesium may be beneficial. As side effects are minor and costs are low, a therapeutic trial may be warranted, although a final decision on the effects of magnesium cannot be made. (15 Refs.)

NADH-coenzyme Q reductase (complex I) deficiency: heterogeneity in phenotype and biochemical findings.

Pitkanen S; Feigenbaum A; Laframboise R; Robinson BH
Department of Pediatrics, University of Toronto, Ontario, Canada.
J Inherit Metab Dis (Netherlands) 1996, 19 (5) p675-86

Twelve patient cell lines with biochemically proven complex I deficiency were compared for clinical presentation and outcome, together with their sensitivity to galactose and menadione toxicity. Each patient had elevated lactate to pyruvate ratios demonstrable in fibroblast cultures. Each patient also had decreased rotenone-sensitive NADH-cytochrome c reductase (complexes I and III) with normal succinate cytochrome c reductase (complexes II and III) and cytochrome oxidase (complex IV) activity in cultured skin fibroblasts, indicating a deficient NADH-coenzyme Q reductase (complex I) activity. The patients fell into five categories: severe neonatal lactic acidosis; Leigh disease; cardiomyopathy and cataracts; hepatopathy and tubulopathy; and mild symptoms with lactic acidaemia. Cell lines from 4 out of the 12 patients were susceptible to both galactose and menadione toxicity and 3 of these also displayed low levels of ATP synthesis in digitonin-permeabilized skin fibroblasts from a number of substrates. This study highlights the heterogeneity of complex I deficiency at the clinical and biochemical level.

Familial cardiomyopathy with cataracts and lactic acidosis: a defect in complex I (NADH-dehydrogenase) of the mitochondria respiratory chain.

Pitkanen S; Merante F; McLeod DR; Applegarth D; Tong T; Robinson BH
Department of Pediatrics, University of Toronto, Quebec, Canada.
Pediatr Res (United States) Mar 1996, 39 (3) p513-21

Four patients in one generation of a multiply consanguineous pedigree died with cardiomyopathy, cataracts, and lactic acidemia. Postmortem heart and skeletal muscle tissues from one patient were analyzed. A low (12% control) activity of NADH-CoQ reductase (complex I) in heart and normal activity in skeletal muscle mitochondria was found. Cultured skin fibroblasts obtained from two individuals in the pedigree showed elevated lactate to pyruvate ratios in the range of 2 to 3.5 times normal and decreased complex I + III activity (42 and 54% of control activities) in isolated mitochondria. Western blot analysis and enzymatic assay showed normal levels of CuZn-superoxide dismutase, but grossly elevated levels of the mitochondrial Mn-superoxide dismutase. Southern blot analysis in heart muscle cells from the patient tested revealed multiple mitochondrial DNA deletions which indicate free oxygen radical damage. We hypothesize that a nuclear-encoded defect in the respiratory chain is responsible for excessive free oxygen radical production in these infants which contributes to the prenatal onset of cardiomyopathy and cataracts.

Comparison of calcium-current in isolated atrial myocytes from failing and nonfailing human hearts.

Cheng TH; Lee FY; Wei J; Lin CI
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China.
Mol Cell Biochem (Netherlands) Apr 12-26 1996, 157 (1-2) p157-62

To identify possible alterations of the L-type calcium currents (I(Ca),L) in cardiomyopathy, I(Ca),L were recorded in atrial myocytes dissociated from the nonfailing heart (NF) of patients undergoing corrective open-heart surgery and explanted failing heart (FH) of patients with dilated cardiomyopathy undergoing heart transplantation. The patch-clamp technique was applied in the single-electrode whole-cell mode. The electrophysiological properties of I(Ca),L, including cell capacitance and current density, were similar in atrial myocytes from both groups of patients. Further to identify possible alterations of the myocardial beta-adrenergic pathway in cardiomyopathy, we examined the effects of isoproterenol,forskolin, 8-Br-cAMP and IBMX on I(Ca),L in both groups of atrial myocytes. Perfusion of isoproterenol (1 microM) significantly increased the peak I(Ca),L by 515 +/- 44% in 6 atrial myocytes from NF but increased only by 135 +/- 25% in 27 atrial myocytes from FH. However, forskolin (1 microM) or 8-Br-cAMP (0.1 mM) increased the peak I(Ca),L to a similar extent in atrial myocytes from NF and FH. IBMX (20 microM) also induced a comparable increase in the peak I(Ca),L by 213 +/- 31% (n = 5) and 207 +/- 59% (n = 4) in atrial myocytes from NF and FH, respectively. The above findings suggest that in atrial myocytes obtained from FH the beta-adrenoceptor numbers might be decreased but no impairment of the signal transduction cascade occurred beyond the GTP binding proteins level.

Mitochondrial complex I deficiency leads to increased production of superoxide radicals and induction of superoxide dismutase.

Pitkanen S; Robinson BH
Department of Pediatrics, University of Toronto, Ontario, Canada.
J Clin Invest (United States) Jul 15 1996, 98 (2) p345-51

Mitochondria were isolated from skin fibroblast cultures derived from healthy individuals (controls) and from a group patients with complex I (NADH-CoQ reductase) deficiency of the mitochondrial respiratory chain. The complex I deficient patients included those with fatal infantile lactic acidosis (FILA), cardiomyopathy with cataracts (CC), hepatopathy with tubulopathy (HT), Leigh's disease (LD), cataracts and developmental delay (CD), and lactic acidemia in the neonatal period followed by mild symptoms (MS). Production of superoxide radicals, on addition of NADH, were measured using the luminometric probe lucigenin with isolated fibroblast mitochondrial membranes. Superoxide production rates were highest with CD and decreased in the order CD >> MS > LD > control > HT > FILA = CC. The quantity of Mn-superoxide dismutase (MnSOD), as measured by ELISA techniques, however, was highest in CC and FILA and lowest in CD. Plots of MnSOD quantity versus superoxide production showed an inverse relationship for most conditions with complex I deficiency. We hypothesize that oxygen radical production is increased when complex I activity is compromised. However, the observed superoxide production rates are modulated by the variant induction of MnSOD which decreases the rates, sometimes below those seen in control fibroblast mitochondria. In turn, we show that the variant induction of MnSOD is most likely a function of the change in the redox state of the cell experienced rather than a result of the complex I defect per se.

A preliminary study of growth hormone in the treatment of dilated cardiomyopathy

Fazio S; Sabatini D; Capaldo B; Vigorito C; Giordano A; Guida R; Pardo F; Biondi B; Sacca L
Department of Internal Medicine, University Federico II, Naples, Italy.
N Engl J Med (United States) Mar 28 1996, 334 (13) p809-14
Comment in N Engl J Med 1996 Mar 28;334(13):856-7
Comment in: N Engl J Med 1996 Aug 29;335(9):672; discussion 673-4

BACKGROUND. Cardiac hypertrophy is a physiologic response that allows the heart to adapt to an excess hemodynamic load. We hypothesized that inducing cardiac hypertrophy with recombinant human growth hormone might be an effective approach to the treatment of idiopathic dilated cardiomyopathy, a condition in which compensatory cardiac hypertrophy is believed to be deficient.

METHODS. Seven patients with idiopathic dilated cardiomyopathy and moderate-to-severe heart failure were studied at base line, after three months of therapy with human growth hormone, and three months after the discontinuation of growth hormone. Standard therapy for heart failure was continued throughout the study. Cardiac function was evaluated with Doppler echocardiography, right-heart catheterization, and exercise testing.

RESULTS. When administered at a dose of 14 IU per week, growth hormone doubled the serum concentrations of insulin-like growth factor I. Growth hormone increased left-ventricular-wall thickness and reduced chamber size significantly. Consequently, end-systolic wall stress (a function of both wall thickness and chamber size) fell markedly (from a mean [+/-SE] of 144+/-11 to 85+/-8 dyn per square centimeter, P<0.001). Growth hormone improved cardiac output, particularly during exercise (from 7.4+/-0.7 to 9.7+/-0.9 liters per minute, P=0.003), and enhanced ventricular work, despite reductions in myocardial oxygen consumption (from 56+/-6 to 39+/-5 ml per minute, P=0.005) and energy production (from 1014+/-100 to 701+/-80 J per minute, P=0.002). Thus, ventricular mechanical efficiency rose from 9+/-2 to 21+/-5 percent (P=0.006). Growth hormone also improved clinical symptoms, exercise capacity, and the patients' quality of life. The changes in cardiac size and shape, systolic function, and exercise tolerance were partially reversed three months after growth hormone was discontinued.

CONCLUSIONS. Recombinant human growth hormone administered for three months to patients with idiopathic dilated cardiomyopathy increased myocardial mass and reduced the size of the left ventricular chamber, resulting in improvement in hemodynamics, myocardial energy metabolism, and clinical status.

Effect of protection and repair of injury of mitochondrial membrane-phospholipid on prognosis in patients with dilated cardiomyopathy

Ma A, Zhang W, Liu Z
Department of Cardiology, First Affiliated Hospital of Xi'an Medical University, China.
Blood Press Suppl. 1996;3:53-5

We have already proved that the mitochondrial membrane-phospholipid (MMP) injury changes of peripheral lymphocytes in patients with heart failure can be used as an injury indicator of myocardia, and are related to the long-term prognosis. In the present study, MMP localization of the peripheral lymphocytes was performed by modified Demer's tricomplex flocculation method, and we compared the changes, after classification, between the pre-treatment and the 12-week post-treatment, of coenzyme Q10 (Co.Q10) and captopril in 61 hospitalized patients with dilated cardiomyopathy (DCM). They were followed up for 16.1 +/- 7.8 months (mean). The results showed that compared with the placebo, Co.Q10 and captopril could significantly protect against and repair MMP injury and improve the heart function of patients with DCM after 12 weeks, and the 2-year survival rate rose significantly by 72.7% for Co.Q10, and 64.0% for captopril, vs 24.7% for placebo. As for Longrank test, X2 equals 4.660 and 6.318, respectively, with both p < 0.05. The aforementioned results indicate that MMP injury of peripheral lymphocytes can predict the prognosis of the patients with DCM, thus the protection and repairment of MMP injury can improve the life-quality and prolong the life-span of the patients.

[Therapeutic effects of coenzyme Q10 on dilated cardiomyopathy: assessment by 123I-BMIPP myocardial single photon emission computed tomography (SPECT): a multicenter trial in Osaka University Medical School Group]

Nishimura T; Hori M
Tracer Kinetics and Nuclear Medicine, Osaka University, Japan.
Kaku Igaku (Japan) Jan 1996, 33 (1) p27-32

To evaluate therapeutic effects of Cenzyme Q10 (CoQ10), 15 patients with dilated cardiomyopathy were investigated by 123I-BMIPP myocardial single photon emission computed tomography (SPECT). The BMIPP defect score was determined semiquantitatively by using representative short and long axial SPECT images. Mean BMIPP defect score with CoQ10 treatment was significantly low, 7.7 +/- 6.1 compared to 12.7 +/- 7.4 without CoQ10 treatment. On the other hand, in 8 patients of dilated cardiomyopathy, % fractional shortening using echocardiography was not different before and after CoQ10 treatment. In conclusion, 123I-BMIPP myocardial SPECT was proved to be sensitive to evaluate the therapeutic effects of CoQ10, which improve myocardial mitochondrial function, in the cases of dilated cardiomyopathy.

The effects of calcium channel blockers on blood fluidity.

Koenig W, Ernst E
Department of Medicine (Cardiology), Klinikum der Universitat, Ulm, F.R.G.
J Cardiovasc Pharmacol 1990;16 Suppl 6:S40-4

Although vasodilation, direct cardiac actions, or both represent the main properties of calcium channel blockers, there are further pharmacologic effects that may be therapeutically relevant. For example, hemorrheological effects, which have been demonstrated for a variety of calcium antagonists, have received relatively little attention to date. Hemorrheology describes the mechanics of blood and its components. It is of particular interest in the context of cardiovascular disease, as it has been shown that under certain conditions (reduced pump function, impaired vasomotor reserve), parameters of blood fluidity may be crucial for tissue perfusion. Whole-blood viscosity is the dominating factor in large arteries. For geometrical reasons, plasma viscosity and the rheological properties of blood cells may become of paramount importance at the microcirculatory level. In ischemic states, erythrocytes may be depleted of ATP, which they need for maintenance of normal shape and for transformation. This results in rigidification of the red blood cell and hindrance of its passage in the microcirculatory bed. Hence, blood flow deteriorates with the consequence of further unfavorable changes of the "milieu interieur," leading to the induction of a vicious cycle. Although effects on several hemorrheological parameters, for example, whole-blood viscosity, plasma viscosity, and red cell aggregation, can be demonstrated for various calcium channel blockers, the main rheological effects of these compounds are believed to consist in the improvement of erythrocyte deformability. When the ATP-dependent calcium pump is impaired in ischemia, calcium channel blockers may inhibit the slow inward transmembrane calcium flux and prevent the accumulation of intracellular calcium. (33 Refs.)

Increased whole blood and plasma viscosity in patients with angina pectoris and 'normal' coronary arteries

Larsson H, Gustavsson CG, Odeberg H, Persson S
Department of Internal Medicine, University Hospital, Lund, Sweden.
Acta Med Scand 1988;224(2):109-14

Blood and plasma viscosity was measured in eight patients with typical effort-induced angina pectoris who did not have coronary artery stenosis at angiography. The same variables were studied in 14 patients with angina pectoris and verified coronary artery desease that in most cases was extensive. Both groups of patients had significantly higher viscosity values in whole blood, at natural hematocrit as well as at standardized hematocrit (45%), than 25 healthy subjects serving as a reference group. Plasma viscosity was also significantly elevated in both patient groups. The patients without coronary artery stenosis had as high blood and plasma viscosity values as had the stenosis group. It is concluded that increased blood and plasma viscosity should be added to the list of pathological findings in patients with angina pectoris in the absence of organic coronary artery stenosis.

Can lifestyle changes reverse coronary heart disease?

Ornish D, Brown SE, Scherwitz LW, Billings JH, Armstrong WT, Ports TA, McLanahan SM, Kirkeeide RL, Brand RJ, Gould KL
Pacific Presbyterian Medical Center, Sausalito, California.
Lancet 1990 Jul 21;336(8708):129-33

In a prospective, randomised, controed trial to determine whether comprehensive lifestyle changes affect coronary atherosclerosis after 1 year, 28 patients were assigned to an experimental group (low-fat vegetarian diet, stopping smoking, stress management training, and moderate exercise) and 20 to a usual-care control groups. 195 coronary artery lesions were analysed by quantitative coronary angiography. The average percentage diameter stenosis regressed from 40.0 (SD 16.9)% to 37.8 (16.5)% in the experimental group yet progressed from 42.7 (15.5)% to 46.1 (18.5)% in the control group. When only lesions greater than 50% stenosed were analysed, the average percentage diameter stenosis regressed from 61.1 (8.8)% to 55.8 (11.0)% in the experimental group and progressed from 61.7 (9.5)% to 64.4 (16.3)% in the control group. Overall, 82% of experimental-group patients had an average change towards regression. Comprehensive lifestyle changes may be able to bring about regression of even severe coronary atherosclerosis after only 1 year, without use of lipid-lowering drugs.

The natural history of atherosclerosis: An ecologic perspective

Mozar HN, Bal DG, Farag SA
Chronic Diseases Control Branch, California State Department of Health Services, Sacramento 94234-7320.
Atherosclerosis 1990 May;82(1-2):157-64

Virologic findings reported in recent atherosclerosis literature may have profound implications. To assess them, we have viewed atherosclerosis in a broad biologic context and against a background of environmental, behavioral, and social change. Reasonable grounds exist, we believe, for regarding atherosclerosis as a chronic, low-grade infectious macroangiopathy which is aggravated by hypercholesterolemia and other recognized risk factors. There are probably multiple infective pathogens and transmission routes. The putative agents that initiate atherosclerosis might include ubiquitous viruses that produce clinically unapparent infections in many animal species. Pathways for their transmission to humans may include the food chain and contaminated water. Food-chain transmission may have been largely responsible for the parallel increases of meat consumption and mortality from coronary heart disease in the United States during the middle third of the century. It proring thermal intervention as a heretofore unrecognized factor that may actually best account for the surprising reversal of climbing heart disease mortality rates. Improved sanitation and food hygiene as well as improvements in diet, lifestyle, and medical care may have shaped the downward mortality curve. The virus hypothesis may reconcile apparent epidemiologic conflicts and elucidate the natural history of atherosclerosis.

Concordant dyslipidemia, hypertension and early coronary disease in Utah families

Williams RR, Hunt SC, Wu LL, Hopkins PN, Hasstedt SJ, Schumacher MC, Stults BM, Kuida H
Department of Medicine, University of Utah, Salt Lake City.
Klin Wochenschr 1990;68 Suppl 20:53-9

A detailed family history questionnaire collected from families of 35,000 sixteen year old high school students in Utah was used to identify population-based sibships with two or more living adults affected with hypertension under age 60 or coronary artery disease before age 55. Detailed clinical and biochemical evaluations performed during a four-hour visit to a research clinic provided data to test for concordant abnormalities in siblings with either early hypertension or early coronary heart disease. A new syndrome, familial dyslipidemic hypertension (FDH), was found in 48% of the hypertensive sibships. In these FDH subjects, 68% had HDL-cholesterol below the 10th percentile, 49% had triglyceride level above the 90th percentile, and 27% had LDL levels above the 90th percentile. When compared to normolipidemic hypertensive subjects, persons with FDH had significantly elevated fasting plasma insulin levels, increased subscapular skinfold thickness, increased knee width and wrist circumference, and increased levels of VLDL cholesterol and apolipoprotein B. In coronary sibships, concordant abnormalities for lipids were consistent with familial combined hyperlipidemia in 30-40% of sibships, FDH in 15-45% of sibships, and low HDL-C (with normal cholesterol) in 10%. Concordant normal lipids were found in only 15% of sibships. These data suggest that inherited metabolic abnormalities likely explain some co-aggregation of hyperinsulinemia, obesity, hypertension, and early coronary heart disease. Current knowledge also suggests these metabolic abnormalities could be treated or prevented with appropriate modification in lifestyle factors such as diet and exercise as well as through the use of prescription medications.

Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease.

de Lorgeril M, Renaud S, Mamelle N, Salen P, Martin JL, Monjaud I, Guidollet J, Touboul P, Delaye J
INSERM (Institut National de la Sante et de la Recherche Medicale), Units 63, Bron, France.
Lancet 1994 Jun 11;343(8911):1454-9
Published erratum appears in Lancet 1995 Mar 18;345(8951):738

In a prospective, randomised single-blinded secondary prevention trial we compared the effect of a Mediterranean alpha-linolenic acid-rich diet to the usual post-infarct prudent diet. After a first myocardial infarction, patients were randomly assigned to the experimental (n = 302) or control group (n = 303). Patients were seen again 8 weeks after randomisation, and each year for 5 years. The experimental group consumed significantly less lipids, saturated fat, cholesterol, and linoleic acid but more oleic and alpha-linolenic acids confirmed by measurements in plasma. Serum lipids, blood pressure, and body mass index remained similar in the 2 groups. In the experimental group, plasma levels of albumin, vitamin E, and vitamin C were increased, and granulocyte count decreased. After a mean follow up of 27 months, there were 16 cardiac deaths in the control and 3 in the experimental group; 17 non-fatal myocardial infarction in the control and 5 in the experimental groups: a risk ratio for these two main endpoints combined of 0.27 (95% CI 0.12-0.59, p = 0.001) after adjustment for prognostic variables. Overall mortality was 20 in the control, 8 in the experimental group, an adjusted risk ratio of 0.30 (95% CI 0.11-0.82, p = 0.02). An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.

Effect of antioxidant-rich foods on plasma ascorbic acid, cardiac enzyme, and lipid peroxide levels in patients hospitalized with acute myocardial infarction

Singh RB; Niaz MA; Agarwal P; Begom R; Rastogi SS
Heart Research Laboratory, Medical Hospital, Moradabad, UP, India.
J Am Diet Assoc 1995 Jul;95(7):775-80

Objective: To determine whether a fat- and energy-reduced diet rich in antioxidant vitamins C and E, beta carotene, and soluble dietary fiber reduces free-radical stress and cardiac enzyme level and increases plasma ascorbic acid level 1 week after acute myocardial infarction.

Design: Randomized, single blind, controlled study.

Setting: Primary- and secondary- care research center for patients with myocardial infarction.

Subjects: All subjects with suspected acute myocardial infarction (n=505) were considered for entry to the study. Subjects with definite or possible acute myocardial infarction and unstable angina (according to World Health Organization criteria) were assigned to either an intervention diet (n=204) or a control diet (n=202) within 48 hours of symptoms of infarction. Interventions: Intervention and control groups were advised to consume a fat-reduced, oil- substituted diet. The intervention group was also advised to cat more fruits, vegetable soup, pulses, and crushed almonds and walnuts mixed with skim milk.

Main outcome measures: Reduction in plasma lipid peroxide and lactate dehydrogenase cardiac enzyme levels, increase in plasma ascorbic acid level, and compliance with diet, especially with vitamin C intake as determined by chemical analysis.

Statistical analysis: A two-sample t test using one-way analysis of variance for comparison of data.

Results: Plasma lipid peroxide level decreased significantly in the intervention group compared with the control group (0.59 pmol/L in the intervention group and 0.10 pmol/L in the control group; 95% confidence interval of difference=0.19 to 0.83). Lactate dehydrogenase level increased less in the intervention group than in the control group (427.7 vs 561.2 U/L; confidence interval of difference=82.9 to 184.7). Plasma ascorbic acid level increased more in the intervention group than in the control group (23.38 vs 7.95 micromol/L; confidence interval of difference= 12.85 to 26.13). Applications/conclusions: Consumption of an antioxidant-rich diet may reduce the plasma levels of lipid peroxide and cardiac enzymeioxidant- rich foods may reduce myocardial necrosis and reperfusion injury induced by oxygen free radicals.

Dietary supplementation with orange and carrot juice in cigarette smokers lowers oxidation products in copper-oxidized low-density lipoproteins

Abbey M, Noakes M, Nestel PJ
Division of Human Nutrition, Commonwealth Scientific and Industrial Research Organization, Adelaide, Australia.
J Am Diet Assoc 1995 Jun;95(6):671-5

Objective: Our objective was to evaluate the effect of daily supplementation with foods high in vitamin C and beta carotene on plasma vitamin levels and oxidation of low-density lipoprotein (LDL) in cigarette smokers.

Subjects: Fifteen normolipidemic male cigarette smokers who did not usually take vitamin supplements were recruited into the study. Interventions: Throughout the study, subjects consumed a diet rich in polyunsaturated fatty acids, which provided 36% of energy as fat: 18% from meat, dairy products, vegetable oils, and fat spreads and 18% from walnuts (68 g/day). Subjects consumed a vitamin-free drink daily for 3 weeks; then for 3 weeks they consumed daily supplements of orange juice (145 mg vitamin C) and carrot juice (16 mg beta carotene).

Results: Vitamin-rich food supplements raised plasma levels of ascorbic acid (1.6-fold; P<.01) and beta carotene (2.6-fold; P<.01). Malondialdehyde, one end product of oxidation, was lower in copper-oxidized LDL after vitamin supplementation (meanplus or minusstandard error=65.7plus or minus2.0 and 57.5plus or minus2.9 micromol/g LDL protein before and after supplementation, respectively; P<.01). Rate of LDL oxidation and lag time before the onset of LDL oxidation were not affected by antioxidant supplementation.

Conclusions: In habitual cigarette smokers, antioxidant vitamins, which can be feasibly provided from food, partly protected LDL from oxidation despite a diet rich in polyunsaturated fatty acids.

Women, hormones and blood pressure

Khaw KT
Clinical Gerontology Unit, University of Cambridge School of Medicine, Addenbrooke's Hospital, UK.
Can J Cardiol 1996 Jun;12 Suppl D:9D-12D

Raised blood pressure is an important risk factor for both coronary artery disease and stroke in women. In terms of exogenous sex hormones, use of premenopausal oral contraceptives has been consistently associated with higher blood pressure levels; both estrogenic and progestogenic components have been implicated. In contrast, a randomized trial has shown no effect of postmenopausal hormone use on blood pressure. Observational studies indicate a protective effect of postmenopausal estrogen use on coronary artery disease. This is probably largely mediated through effects on lipoproteins and not blood pressure; data on post menopausal estrogen use and stroke risk are less consistent. Treatment trials have demonstrated beneficial effects of lowering blood pressure on cardiovascular disease, particularly regarding stroke in women. The women most likely to benefit from individually based clinical preventive interventions for cardiovascular disease, such as hypertension treatment or estrogen replacement therapy, are women who have high absolute risk of cardiovascular disease, ie, older women with high risk factor levels with a family or existing history of cardiovascular disease. Nevertheless, the large international variation in rates of cardiovascular disease indicate the large potential for prevention and suggest that most women are likely to benefit from lifestyles conducive to cardiovascular health, that is, increasing physical activity, not smoking and following diets low in sodium and saturated fat and high in fruits and vegetables.

Protective effect of fruits and vegetables on development of stroke in men

Gillman MW, Cupples LA, Gagnon D, Posner BM, Ellison RC, Castelli WP, Wolf PA
Department of Ambulatory Care and Prevention, Harvard Medical School, Boston, MA 02215, USA.
JAMA 1995 Apr 12;273(14):1113-7

Objective. - To examine the effect of fruit and vegetable intake on risk of stroke among middle-aged men over 20 years of follow-up.

Design. - Cohort.

Setting. - The Framingham Study, a population-based longitudinal study.

Participants. - All 832 men, aged 45 through 65 years, who were free of cardiovascular disease at baseline (1966 through 1969).

Measurements and Data Analysis. - The diet of each subject was assessed at baseline by a single 24- hour recall. The estimated total number of servings per day of fruits and vegetables was the exposure variable for this analysis. Using Kaplan-Meier survival analysis, we examined age-adjusted cumulative incidence of stroke by quintile of servings per day. To adjust for multiple covariates, we used proportional hazards regression to calculate the relative risk (RR) of stroke for each increment of throe servings per day.

Main Outcome Measure. - Incidence of completed strokes and transient ischemic attacks.

Results. - At baseline, the mean (plus or minusSD) number of fruit and vegetable servings per day was 5.1 (plus or minus2.8). During follow-up there were 97 incident strokes, including 73 completed strokes and 24 transient ischemic attacks. Age-adjusted risk of stroke decreased across increasing quintile of servings per day (log rank P for trend, .01). Age-adjusted RR for all stroke, including transient ischemic attack, was 0.78 (95% confidence interval (CI), 0.62 to 0.98) for each increase of three servings per day. For completed stroke the RR was 0.74 (95% CI, 0.57 to 0.96); for completed stroke of ischemic origin the RR was 0.76 (95% CI, 0.57 to 1.02); and for completed stroke of hemorrhagic origin, 0.49 (95% CI, 0.25 to 0.95). Adjustment for body mass index, cigarette smoking, glucose intolerance, physical activity, blood pressurerially change the results.

Conclusion. - Intake of fruits and vegetables may protect against development of stroke in men.

The effect of caffeine on ventricular ectopic activity in patients with malignant ventricular arrhythmia

Graboys TB, Blatt CM, Lown B
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
Arch Intern Med 1989 Mar;149(3):637-9

We evaluated the effect of caffeine on ventricular ectopic activity in a group of 50 consecutive patients with malignant ventricular arrhythmia. The clinical arrhythmia in these patients (mean age, 61 years) was recurrent ventricular tachycardia in 21 (42%), ventricular fibrillation in three (6%), and symptomatic nonsustained ventricular tachycardia in 26 (52%). Forty-two (84%) had either ischemic heart disease or cardiomyopathy. Each patient underwent two short-term drug trials on successive days, receiving either decaffeinated coffee mixed with 200 mg of caffeine or the decaffeinated drink alone. Continuous electrocardiographic recordings were made during the 30-minute control period, the three-hour observation period, and the hourly bicycle exercise tests. Forty-five patients (90%) exhibited ventricular couplets and 29 patients (58%) had salvos of ventricular tachycardia during the testing. However, no differences between the caffeine and decaffeinated trials were observed in either individual or group data on total or repetitive ventricular arrhythmia. Serum catecholamine levels reflected the average increase in serum caffeine level but were not associated with enhanced arrhythmia. We found no evidence that a modest dose of caffeine is arrhythmogenic, even among patients with known life-threatening arrhythmia.

Coffee, cocktails and coronary candidates

Kannel WB
N Engl J Med 1977 Aug 25;297(8):443-4

In this issue of this journal, Yano et al. publish that they found no even be beneficial.e in moderation is harmful, and they report that Pharmacologic effects of caffeine and other unspecified ingredients of coffee have been cited to explain an alleged relation to myocardial infarction. In contrast to some retrospective studies, all prospective studies have failed to implicate coffee as an independent contributor to death from coronary heart disease or myocardial infarction. The report of the Boston Collaborative Drug Surveillance program provoked much speculation regarding whether coffee consumption raises the risk of myocardial infarction. Neither the press nor the health professionals heeded the authors' caution that the possible role of coffee drinking in acute myocardial infarction requires 'reevaluation'. The authors referred briefly to possible selective biases in retrospective studies, but neither they nor their readers apparently paid sufficient heed. As regards the use of ethanol, modern methods of evaluation have not substantiated the old concept of a beneficial effect on coronary blood flow. The hazard of alcohol in cardiac disease has long been attributed to coexisting malnutrition. Recent evidence supports a cardiotoxic role for alcohol taken in large amounts; there is ample evidence that alcohol abuse can cause cardiomyopathy, and it has been associated with dysrhythmias and deterioration of left ventricular performance. However, the data linking alcohol to coronary morbidity and mortality have been inexplicably inconsistent. But, although heavy use of alcohol is clearly toxic to the heart muscle, this fact does not preclude a beneficial effect of moderate use on the coronary vessels. Lipid abnormalities, particularly hypertriglyceridemia, have been documented in response to an alcohol challenge, but these abnormalities are transient and appear to have no lasting ill effects. For the present, one can state that physicians, in protecting patients against atherosclerotic cardiovascular disease, have no good reason to restrict social drinking in moderation. Although one does not want to make too much of the apparent benefits, what data there are show, if anything, a lower incidence in those who drink a little. There is also insufficient evidence to support the restriction of coffee drinking. For patients who have an irritable myocardium subject to dysrhythmia, restriction of coffee and alcohol seems indicated.

Concentrations of magnesium, calcium, potassium, and sodium in human heart muscle after acute myocardial infarction.

Speich M; Bousquet B; Nicolas G
Clin Chem 1980 Nov;26(12):1662-5

Atomic absorption spectrometry was used to measure magnesium, calcium, and sodium, and emission spectrometry to measure potassium, in myocardium (left and right ventricles) of 26 control subjects who died of acute trauma. Results were expressed in mumol/g of proteins. Mg/Ca and K/Na ratios were also determined. The same measurements were made in 24 patients who died from acute myocardial infarction. Samples were also taken from the necrotic area. Mg/Ca and K/Na ratios were significantly higher in the left ventricle of both populations, thus providing evidence of anatomical and physiological differences between the two ventricles. As a result of cytolysis and anoxia, the Mg/Ca ratio was very significantly inverted, and the K/Na ratio very significantly smaller, In these clinical conditions arrhythmias could certainly be considered likely, and there is reason to believe that magnesium depletion may be a cause of arrhythmias.

[Therapeutic efficacy of pantothenic acid preparations in ischemic heart disease patients]

Borets VM, Lis MA, Pyrochkin VM, Kishkovich VP, Butkevich ND
Vopr Pitan 1987 Mar-Apr;(2):15-7

The therapeutic effectiveness of the pantothenic acid drugs: calciipantothenas and pantethine, was studied in 182 patients with coronary heart disease and stable angina of effort. It is shown that both the drugs produce favourable effects on certain parameters of hemodynamics, on the metabolism of lipids, riboflavin and ascorbic acid. It is recommended that the administration of calciipantothenas in a dose of 300 mg/day, during 3 weeks, be included into the combined treatment of coronary patients with no manifest disorders of lipid metabolism. Patients with manifest hyperlipidemia should be administered pantethine in a dose of 500 mg/day.

Antifibrillatory effect of tetrahydroberberine.

Sun AY, Li DX
Department of Pharmacology, Nanjing Medical College, China.
Chung Kuo Yao Li Hsueh Pao 1993 Jul;14(4):301-5

Electric stimulation and drug-induced ventricular fibrillation (VF), monophasic action potentials (MAPhydroberberine (THB) in rabbits, rats or guinea pigs. At doses of 5, 10, and 20 mg.kg-1, i.v. THB increased the ventricular fibrillation threshold, and the BaCl2-induced VF was also prevented or terminated by THB in rabbits. Centrogenic VF induced by icv aconitine in rats was inhibited by pretreatment with THB in a dose-dependent manner, whereas VF induced by iv ouabain in guinea pig was inhibited to a lesser degree. For MAP, the duration at 90% repolarization (MAPD90) was prolonged remarkably, whereas the MAPD20, the MAP amplitude, and the maximal velocity of phase 0 were shortened or decreased slightly. The amplitudes of early afterdepolarization produced by cesium chloride (CsCl) were attenuated, while the cumulative threshold doses of CsCl for sustained ventricular tachycardia were elevated by THB. These results indicated that THB had an potent antifibrillatory effect, which might be attributed to its blockade of potassium, calcium, and sodium currents.

Effects of tetrahydroberberine on ischemic and reperfused myocardium in rats.

Zhou J, Xuan B, Li DX
Department of Pharmacology, Nanjing Medical College, China.
Chung Kuo Yao Li Hsueh Pao 1993 Mar;14(2):130-3

The effects of tetrahydroberberine (THB) on ischemic and reperfused myocardium were studied in comparison with verapamil (Ver). In anesthetized rats, THB and its analogues, l-THP and l-SPD, reduced the infarct size after 4 h of left anterior descending coronary artery (LAD) ligation. In Langendorff hearts, in common with Ver, THB 1 and 10 mumol.L-1 markedly decreased the incidences of ventricular tachycardia (VT) and ventricular fibrillation (VF) in the reperfusion period. The malondialdehyde content and xanthine oxidase activity were also decreased in global ischemic-reperfused hearts pretreated with THB (P < 0.01, or P < 0.05). It suggested that THB could protect the myocardium from ischemic and reperfusion injury.

[Ventricular tachyarrhythmias treated with berberine]

Huang W
Shanghai Xu Hui District Central Hospital.
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1990 Jun;18(3):155-6, 190

The effects of berberine on 100 cases with ventricular tachyarrhythmias observed with 24 to 48 hour ambulatory monitoring were reported. The results showed that 62% of patients had 50% or greater, and 38% of patients had 90% or greater VPC suppression. The mean value of VPCs in whole group was significantly decreased by berberine from 452 +/- 421.8 beats per hour to 271 +/- 352.7 beats per hour (P less than 0.001). These results revealed that berberine is effective for ventricular tachyarrhythmias. There were no severe side effects, only mild gastroenterologic symptoms were observed in some patients.

[Effects of berberine on ischemic ventricular arrhythmia]

Huang WM, Wu ZD, Gan YQ
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1989 Oct;17(5):300-1, 319

The effects of berberine on ischemic ventricular arrhythmias induced by ligating the left anterior descending coronary artery (LAD) of canine were reported. The results showed that berberine was able to get 99% suppression (P less than 0.001) on the total ventricular premature beats (VPCs) by 12 hours after ligature of LAD, the paired VPCs, ventricular tachycardias and VPCs with R on T were also significantly suppressed; and the ventricular tachycardia induced by programmed ventricular stimulation was effectively inhibited by berberine. In addition, the results revealed that the decrease of cardiac output caused by ligature of LAD was obviously attenuated by berberine. The mechanisms of the antiarrhythmic effect of berberine on ischemic ventricular tachyarrhythmias were discussed.

[Protective effects of berberine on spontaneous ventricular fibrillation in dogs after myocardial infarction]

Xu Z, Cao HY, Li Q
Chung Kuo Yao Li Hsueh Pao 1989 Jul;10(4):320-4

The effects of berberine (Ber 5 mg/kg iv) on ventricular tachyarrhythmias and electrophysiologic consequences in both normal and ischemic myocardium were studied in the open-chest dogs subjected to programmed electrical stimulation (PES) and intimal surface an of the circumflex coronary artery on 5-8 d after acute myocardial infarction. Its effects were compared with procainamide (PA). Both drugs distinctly lengthened the QTc interval and the effective refractory period (ERP) of normal and infarct myocardium in both ventricles and decreased the dispersion of ERP in infarct myocardium (IDR) as well as the dispersion of ERP in left ventricle (VDR). The PES-induced ventricular tachycardia (VT) or ventricular fibrillation (VF) was prevented in 4 out of 6 Ber treated and 5 out of 6 PA treated dogs. Ber prevented spontaneous VF in 4 dogs (n = 5). PA prevented spontaneous VF in 3 dogs (n = 5). Normal saline (NS) did not prevent PES-induced VT/VF and spontaneous VF. The results suggest that Ber may be effective in preventing the onset of reentrant ventricular tachyarrhythmias and sudden coronary death after myocardial ischemic damage.

Protective effects of berberine and phentolamine on myocardial reoxygenation damage.

Huang Z, Chen S, Zhang G, Xu S, Huang W, Han Y, Du X
Department of Cardiology, Changzheng Hospital, Shanghai.
Chin Med Sci J 1992 Dec;7(4):221-5

The protective effects of berberine and phentolamine against anoxia and reoxygenation damage in isolated rat hrberine (24.5 mumol/L) in both a noxic and aerobic perfusion media resulted in a significant reduction of CPK release during the reoxygenation period, and the ultrastructural damage was reduced as compared with the control group; the myocytes in the berberine-treated group displayed mild intracellular edema, well-registered myofibrils without contracted bands, and swollen mitochondria with partially broken cristae but without dense bodies. Berberine did not inhibit calcium and sodium accumulation or magnesium and potassium loss. Treatment with phentolamine (6.6 mumol/L), an alpha-adrenoceptor antagonist, had similar effects, though the CPK release profile was shifted to the right and downwards. These results suggest that although berberine and phentolamine have some beneficial effects on myocardial reoxygenation injury, they may not abolish the injury. Therefore alpha-adrenoceptor stimulation may not be the major mechanism behind the injury.

Beneficial effects of berberine on hemodynamics during acute ischemic left ventricular failure in dogs.

Huang WM, Yan H, Jin JM, Yu C, Zhang H
Cardiovascular Research Laboratory, Xu Hui District Central Hospital, Shanghai.
Chin Med J (Engl) 1992 Dec;105(12):1014-9

In 18 dogs ischemic left ventricular failure characterized by a 30 percent reduction in peak rate of rise of left ventricular pressure (+dp/dt) and elevation of left ventricular end-diastolic pressure (LVEDP) to 15 mmHg or more was produced by ligation of the proximal left anterior descending coronary artery followed by serial occlusions of the distal left circumflex coronary artery. In 10 days, administration of berberine in an intravenous bolus injection (1 mg/kg, within 3 minutes) followed by a constant infusion (0.2 mg/kg/min, 30 minutes) increased the cardiac output (CO) from 1.25 +/- 0.12 to 1.61 +/- 0.17 L/min (P < 0.05), and +dp/dt from 810 +/- 85 to 1021 +/- 130 mmHg/s (P < 0.01), and decreased LVEDP from 16.5 +/- 1.3 to 12.0 +/- 1.0 mmHg (P < 0.05), diaso 84 +/- 5 mmHg (P < 0.01), syste mic vascular resistance from 7303 +/- 278 to 5442 +/- 231 dynes.x/cm5 (P < 0.01), but did not affect the heart rate. Injection of 5% glucose with the same volume did not improve CO and dp/dt (P > 0.05) but increased the LVEDP from 17.1 +/- 1.4 to 17.8 +/- 1.6 mmHg (P < 0.01) in 8 dogs. The levels of plasma concentration of berberine was determined with high-performance liquid chromatography. The changes in plasma drug level were found parallel to hemodynamic effects of berberine. The results of this study showed that berberine was able to improve the impaired left ventricular function by its positive inotropic effect and mild systemic vasodilatation.

[The role and mechanism of berberine on coronary arteries]

Huang W
Xu Hui District Central Hospital, Shanghai.
Chung Hua Hsin Hsueh Kuan Ping Tsa Chih 1990 Aug;18(4):231-4, 254-5

Berberine increased coronary artery flow of anesthetized open-chest canines and isolated guinea pig hearts with ventricular fibrillation induced by electric stimulus. The rabbits were protected by berberine from ischemic ECG changes caused by posterior pituitary hormones. Spasm of isolated swine coronary arterial rings responded to ergometrine was able to be prevented and treated effectively by berberine. On isolated swine coronary arterial strips, berberine shifted norepinephrine cumulative dose-response curve rightward parallelly without decreasing the maximal response. The pA2 value was 6.7. Contraction treatment effects post-PBMV, the cardiac function tended to decline with time, the decrease of ejection fraction, stroke volume and cardiac output were 0.03 +/- 0.007, 5.44 +/- 1.04 ml and 0.44 +/- 0.08 L/min respectively. This might be due to the unsuccessful control of activity of rheumatism after PBMV and it is necessary to pay attention to in the future.

Effect of tincture of Crataegus on the LDL-receptor activity of hepatic plasma membrane of rats fed an atherogenic diet.

Rajendran S, Deepalakshmi PD, Parasakthy K, Devaraj H, Devaraj SN
Department of Biochemistry, University of Madras, India.
Atherosclerosis 1996 Jun;123(1-2):235-41

Tincture of Crataegus, (TCR), is a hypocholesterolemic and antiatherosclerotic drug made from berries of hawthorn, Crataegus oxyacantha. Its main constituents are flavonoids, triterpene saponins and a few cardioactive amines. TCR, when administered simultaneously to rats fed an atherogenic diet, significantly increased the binding of 125I-LDL to the liver plasma membranes, in vitro. Scatchard analysis of the specific binding data revealed that under the influence o to a greater number of 125I -LDL molecules indicating an enhancement in the LDL-receptor activity. TCR was also shown to increase bile acid excretion and to depress hepatic cholesterol synthesis in atherogenic diet fed rats. With these observations in view, the hypocholesterolemic action of TCR appears to be due to an upregulation of hepatic LDL-receptors resulting in greater influx of plasma cholesterol into the liver. TCR also prevents the accumulation of cholesterol in the liver by enhancing cholesterol degradation to bile acids and by simultaneously suppressing cholesterol biosynthesis. The various constituents of TCR may act synergistically to bring about the observed effects.

Effect of a hawthorn extract on contraction and energy turnover of isolated rat cardiomyocytes.

Popping S, Rose H, Ionescu I, Fischer Y, Kammermeier H
Institute of Physiology, Medical Faculty, Rheinisch-Westfalische Technische Hochschule, Aachen, Germany.
Arzneimittelforschung 1995 Nov;45(11):1157-61

The hawthorn extract LI 132 (crataegus), prepared from leaves and flowers, and standardised to 2.2% flavonoids, was investigated with respect to its effect on

(1) the contraction,
(2) the energy-turnover and
(3) the apparent refractory period (t(ref)) of isolated cardiac myocytes from adult rats.

(1) The contractile behaviour of attached myocytes was analyzed by an image processing system.

(2) The energy turnover was calculated from the decrease in oxygen content in the myocyte suspension, brought about by cellular respiration. It was differentiated between energy turnover related to cell shortening and that required for ionic transport processes by application of the contraction-inhibiting agent 2,3-butanedione monoxime.

(3) The apparent refractory period (t(ref)) was evaluaacing the myocytes with increasing stimulation rates and determining the frequency at which failure of single contractions occurred. For these purposes, the myocytes were incubated in a stimulation chamber, which is part of a computer-assisted system allowing to simultaneously evaluate the mechanics and energetics of electrically induced contraction. Within a range of 30-180 microg/ml, the hawthorn extract exhibited a positive inotropic effect on the contraction amplitude accompanied by a moderate increase of energy turnover both for mechanical and ionic processes. In comparison with other positive inotropic interventions, such as application of the beta-adrenergic agonist isoprenaline, or of the cardiac glycoside ouabain (g-strophantin), or elevation of the extracellular Ca++-concentration, the effects of the hawthorn extract were significantly more economical with respect to the energetics of the myocytes. Furthermore the extract prolonged the apparent refractory period in the presence and the absence of isoprenaline, which be indicative for an antiarrhythmic potential.

[Crataegus Special Extract WS 1442. Assessment of objective effectiveness in patients with heart failure (NYHA II)]

Weikl A; Assmus KD; Neukum-Schmidt A; Schmitz J; Zapfe G; Noh HS; Siegrist J
Hauptkrankenhaus Deggendorf.
Fortschr Med 1996 Aug 30;114(24):291-6

METHOD: In a multicenter, placebo-controlled double-blind study, the efficacy of the Crataegus-Specialextrakt WS 1442 in patients with NYHA stage II cardiac insufficiency was investigated. A total of 136 patients with this diagnosis were admitted to the study and, following a 2-week run-in phase, treated with Crataegus-Specialextract or placebo over a period of 8 weeks. The primary target parameter was the change in the difference of the pressure, heart rate product (systolic blood pressure x heart rate/100) (PHRP 50 W load vs. rest) measured at the beginning and end of treatment.

RESULTS: On the basis of this variable, a clear improvement in the performance of the heart was shown in the group receiving the test substance, while the condition of the placebo group progressively worsened. The therapeutic difference between the groups was statistically significant. The positive result for the objective efficacy parameter was confirmed by a statistically obvious superiority of Crataegus in the patient's own assessment of improvement in the main symptoms (reduced performance, shortness of breath, ankle edema etc.). In addition, active treatment led, in comparison with placebo, to a considerably better quality of life for the patient, in particular with respect to mental well-being. The tolerability of the active substance proved to be very good-as shown by comprehensive laboratory investigations and the recording of undesirable events.

CONCLUSION: All in all, the results of the present clinical investigation confirm those of previous studies showing that Crataegus-Specialextrakt WS 1442 is an effective and low-risk phytotherapeutic form of treatment in patients with NYHA II cardiac insufficiency.

[Crataegus Special Extract WS 1442 in NYHA II heart failure. A placebo controlled randomized double-blind study]

Leuchtgens H
Fortschr Med 1993 Jul 20;111(20-21):352-4

In 30 patients with stage NYHA II cardiac insufficiency, a placebo-controlled randomized double-blind study was carried out to determine the efficacy of the Crataegus special extract WS 1442. Treatment duration was 8 weeks, and the substance was administered at a dose of 1 capsule taken twice a day. The main target parameters were alteration in the pressure-x-rate product (PRP) under standardised loading on a bicycle ergometer, and a score of subjective improvement of complaints elicited by a questionnaire. Secondary parameters were exercise tolerance and the change in heart rate and arterial blood pressure. The active substance group showed a statistically significant advantage over placebo in terms of changes in PRP (at a load of 50 W) and the score, but also in the secondary parameter heart rate. In both groups, systolic and diastolic blood pressure was mildly reduced. No adverse reactions occurred.

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Abnormal membrane concentrations of 20 and 22-carbon essential fatty acids: a common link between risk factors and coronary and peripheral vascular disease?

Horrobin DF
Scotia Research Institute, Kentville, Nova Scotia, Canada.
Prostaglandins Leukot Essent Fatty Acids 1995 Dec;53(6):385-96

Although elevated levels of cholesterol are associated with increased risks of coronary and peripheral vascular disease, the association frequently fails to provide a causative explanation at the individual level. New hypotheses are required which, whether or not they are correct, will provide new lines of research. It is proposed here that the causes of vascular disease are abnormal membrane phospholipid concentrations of the 20-carbon and 22-carbon essential fatty acids (EFAs) of the n-6 and n-3 series. These levels become abnormal with ageing, with stress and in resp to smoking, high cholesterol levels and high saturated fat intakes. They are also abnormal in patients with diabetes and hypertension. The effects of these EFAs and their metabolites include lowering of triglycerides, elevation of high-density lipoprotein (HDL)-cholesterol, reduction of blood pressure, vasodilatation, reduction of fibrinogen levels and inhibition of platelet aggregation and of cardiac arrhythmias. Prospective studies have shown that abnormal levels of these fatty acids are predictive of future coronary death. Controlled trials of treatment have demonstrated that provision of the fatty acids reduces both coronary and total mortality. Further experimental and clinical investigations of the roles of appropriate membrane concentrations of these fatty acids are justified. (157 Refs.)

Differential changes in left and right ventricular adenylyl cyclase activities in congestive heart failure

Sethi R, Dhalla KS, Beamish RE, Dhalla NS
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Am J Physiol 1997 Feb;272(2 Pt 2):H884-93

The status of beta-adrenergic receptors and adenylyl cyclase in crude membranes from both left and right ventricles was examined when the left coronary artery in rats was occluded for 4, 8, and 16 wk. The adenylyl cyclase activity in the presence of isoproterenol was decreased in the uninfarcted (viable) left ventricle and increased in the right ventricle subsequent to myocardial infarction. The density of beta1-adrenergic receptors, unlike beta2-receptors, was reduced in the left ventricle, whereas no change in the characteristics of beta1- and beta2-adrenergic receptors was seen in the right ventricle. The catalytic activity of adenylyl cyclase was depressed in the viable left ventricle but was unchanged in the right ventricle. In comparison to sham controls, the basal, as well as NaF-, forskolin-, and 5'-guanylyl imidodiphosphate (Gpp(NH)p)-stimulated adenylyl cyclase activities were decreased in the left ventricle and increased in the right ventricle of the experimental animals. Opposite alterations in the adenylyl cyclase activities in left and right ventricles from infarcted animals were also seen when two types of purified sarcolemmal preparations were employed. These changes in adenylyl cyclase activities in the left and right ventricles were dependent on the degree of heart failure. Furthermore, adenosine 3',5'-cyclic monophosphate contents were higher in the right ventricle and lower in the left ventricle from infarcted animals injected with saline, isoproterenol, or forskolin in comparison to the controls. The results suggest differential changes in the viable left and right ventricles with respect to adenylyl cyclase activities during the development of congestive heart failure due to myocardial infarction.

Chronic opiate-receptor inhibition in experimental congestive heart failure in dogs

Yatani A, Imai N, Himura Y, Suematsu M, Liang CS
Department of Medicine, University of Rochester Medical Center, New York 14642, USA.
Am J Physiol 1997 Jan;272(1 Pt 2):H478-84

Acute administration of opiate-receptor antagonists has previously been shown to improve cardiac output, sortie blood pressure, systolic ventricular performance, and the baroreflex function in conscious dogs with right-sided congestive heart failure (RHF). However, whether similar changes occur after chronic opiate-receptor inhibition in congestive heart failure is not known. To determine the chronic effects of opiate-receptor antagonism on RHF, we administered naltrexone (200 mg/day), a long-acting, orally active opiate- receptor blocking agent, to RHF and sham-operated animals for 6 wk. Naltrexone had no effects on resting heart rate, right atrial pressure, aortic pressure, or cardiac output in RHF dogs but increased the first derivative of right and left ventricular pressure with respect to time (dP/dt) at rest and improved the dP/dt responses to isoproterenol. The inotropic responses to isoproterenol and forskolin in isolated right ventricular trabeculate muscle also were improved by chronic naltrexone in RHF. Myocardial beta-receptor density was reduced in the failing right ventricle compared with the control (58 plus or minus 3 vs. 108 plus or minus 6 fmol/mg protein, P < 0.01) but was unaffected by addition of naltrexone. Finally, naltrexone prevented the decline in baroreflex sensitivity that occurred in RHF (-0.2 plus or minus 0.5 vs. -6.0 plus or minus 0.5 ms/mmHg, P < 0.01). These effects of naltrexone did not occur in the sham-operated animals. Chronic opiate-receptor blockade with naltrexone attenuates the development of reduced adrenergic inotropic responsiveness and barereflex subsensitivity that occur in RHF. Because there was a similar improvement in the forskolin response in the absence of significant alterations in myocardial beta-adrenoceptor density after naltrexone treatment, the improvement in adrenergically mediated inotropic effects probably is mediated via a postreceptor mechanism.