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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, 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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