beta-adrenoceptor mediated signal transduction in congestive heart failure in cardiomyopathic (UM-X7.1) hamsters

Kaura D, Takeda N, Sethi R, Wang X, Nagano M, Dhalla NS
Division of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Winnipeg, Manitoba, Canada.
Mol Cell Biochem 1996 Apr 12-26;157(1-2):191-6

In view of the lack of information regarding the status of beta-adrenoceptor mediated signal transduction mechanisms at severe stages of congestive heart failure, the status of beta-adrenoceptors, G-proteins and adenylyl cyclase activities was examined in 220-275 day old cardiomyopathic hamster hearts. Although no changes in the Kd values for beta1- and beta2,-adrenoceptors were seen, the number of beta1-adrenoceptors, unlike that of beta2-adrenoceptors, was markedly decreased in cardiac membranes from failing hearts. The activation of adenylyl cyclase in the failing hearts by different concentrations of isoproterenol was also attenuated in comparison to the control preparations. The basal adenylyl cyclase activity in cardiac membranes from the failing hearts was not altered; however, the stimulated enzyme activities, when measured in the presence of forskolin, NaF or Gpp(NH)p were depressed significantly. The functional activity of Gs-proteins (measured by cholera toxin stimulation of adenylyl cyclase) was depressed whereas that of Gi-proteins (measured by pertussis toxin stimulation of adenylyl cyclase) was increased in the failing hearts. Not only were the Gs- and Gi-protein contents (measured by immunoblotting) increased, the bioactivities of these proteins as determined by ADP-ribosylations in the presence of cholera toxin and pertussis toxin, respectively, were also higher in failing hearts in comparison to the control values. Northern blot analysis revealed that the signals for Gs- and Gi-protein mRNAs were augmented at this stage of heart failure. These results indicate that the loss of adrenergic support at severe stages of congestive heart failure in cardiomyopathic hamsters may involve a reduction in the number of beta1-adrenoceptors, and an increase in Gi-protein contents as well as bioactivities in addition to an uncoupling of Gs-proteins from the catalytic site of adenylyl cyclase in cardiac membrane.

Pharmacology and inotropic potential of forskolin in the human heart.

Bristow MR, Ginsburg R, Strosberg A, Montgomery W, Minobe W
J Clin Invest 1984 Jul;74(1):212-23

We evaluated the effects of the diterpene compound forskolin in human myocardial adenylate cyclase preparations, isolated trabeculae and capillary muscles derived from failing human hearts, and acutely instrumented dogs. forskolin was a potent, powerful activator of human myocardial adenylate cyclase and produced maximal effects that were 4.82 (normally functioning left ventricle) and 6.13 (failing left ventricle) fold greater than isoproterenol. In contrast to isoproterenol, forskolin retained full activity in membrane preparations derived from failing hearts. In cyclase preparations, forskolin demonstrated unique substrate and Mg2+ kinetic properties that could be distinguished from hormone receptor-coupled agonists or fluoride ion. The adenylate cyclase stimulatory effect of forskolin was synergistic with isoproterenol, apparently due to the location of forskolin activation being beyond the level of hormone receptor-agonist in the receptor-cyclase complex. Forskolin was a potent positive inotrope in failing human myocardium, producing a stimulation of contraction that was similar to isoproterenol. Finally, in open chest dogs Forskolin was a positive inotropic agent that reduced preload and afterload. We conclude that forskolin belongs to a class of agents that may have therapeutic potential in the treatment of congestive heart failure.

[Effects of forskolin on canine congestive heart failure]

Sonoki H, Uchida Y, Masuo M, Tomaru T, Katoh A, Sugimoto T
Nippon Yakurigaku Zasshi 1986 Nov;88(5):389-94

Forskolin is a diterpene of the labdane family which activates adenylate cyclase. The effects of forskolin were investigated in a congestive heart failure (CHF) model that we newly established using anesthetized dogs. The model was made by the intramural injection of protease into the left ventricular free wall, saline loading, and dextran and methoxamine infusion. By this maneuver, aortic blood flow (AoBF) was decreased; left atrial pressure (LAP), systemic vascular resistance (SVR) and left ventricular endodiastolic pressure (LVEDP) were markedly increased; and systemic blood pressure was unchanged. A bolus injection of 5.0 micrograms/kg forskolin reversed the hemodynamic findings of CHF. It reduced LAP (17.5----7.9 mmHg) (mean, N = 7), SVR (19980----10390 dyne sec/cm5), time constant T (90.7----59.2 msec) and LVEDP (22.8----16.8 mmHg); and it increased Vmax (2.32----2.82 l/sec) and AoBF (0.50----0.72 l/min). Forskolin improved the CHF mainly through its vasodilator and positive inotropic actions.

Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure. CoQ10 Drug Surveillance Investigators.

Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G
Department of Internal Medicine, V. Buzzi Hospital, Reggio Emilia.
Mol Aspects Med 1994;15 Suppl:s287-94

Digitalis, diuretics and vasodilators are considered the standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of Coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2664 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing study in 173 Italian centers. The daily dosage of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two-to seven-point scales. The results show a low incidence of side effects: 38 adverse effects were reported in 36 patients (1.5%) of which 22 events were considered as correlated to the test treatment. After three months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 78.1%, oedema 78.6%, pulmonary rales77.8%, enlargement of liver area 49.3%, jugular reflux 71.81%, dyspnoea 52.7%, palpitations 75.4%, sweating 79.8%, subjective arrhytmia 63.4%, insomnia 662.8%, vertigo 73.1% and nocturia 53.6%. Moreover we observed a contemporary improvement of at least three symptoms in 54% of patients; this could be interpreted as an index of improved quality of life.

[Coenzyme Q10 (ubiquinone) in the treatment of heart failure. Are any positive effects documented?]

Spigset O
Avdelningen for klinisk farmakologi, Norrlands Universitetssjukhus, Umea.
Tidsskr Nor Laegeforen 1994 Mar 20;114(8):939-42

Coenzyme Q10 is an endogenous substance which has a well established role as electron carrier in the mitochondrial synthesis of adenosine triphosphate (ATP). In addition, coenzyme Q10 also has antioxidant and membrane stabilizing properties. Based on biopsy samples from patients undergoing cardiac surgery and blood samples from patients with congestive heart failure, the existence of a relative Q10 deficiency in patients with cardiac failure has been suggested. A total number of eight double blind, placebo controlled studies in patients with heart failure have been published. Most of these studies include a small number of patients, and various methodological problems have been attributed to these. The results, judged as improvement in ejection fraction or work capacity, are inconsistent. In one large study, Coenzyme Q10 was found to have a positive effect on morbidity, and in another on quality of life. However, although some of the results appear to be promising, more studies are needed, including studies designed with mortality as a primary end point, before the effect of the substance in patients with heart failure can be established. (30 Refs.)

Italian multicenter study on the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 Drug Surveillance Investigators.

Baggio E, Gandini R, Plancher AC, Passeri M, Carmosino G
Department of Internal Medicine, V. Buzzi Hospital, Milan.
Clin Investig 1993;71(8 Suppl):S145-9

Digitalis, diuretics, and vasodilators are considered standard therapy for patients with congestive heart failure, for which treatment is tailored according to the severity of the syndrome and the patient profile. Apart from the clinical seriousness, heart failure is always characterized by an energy depletion status, as indicated by low intramyocardial ATP and coenzyme Q10 levels. We investigated safety and clinical efficacy of coenzyme Q10 (CoQ10) adjunctive treatment in congestive heart failure, which had been diagnosed at least 6 months previously and treated with standard therapy. A total of 2500 patients in NYHA classes II and III were enrolled in this open noncomparative 3-month postmarketing drug surveillance study in 173 Italian centers. The daily dose of CoQ10 was 50-150 mg orally, with the majority of patients (78%) receiving 100 mg/day. Clinical and laboratory parameters were evaluated at the entry into the study and on day 90; the assessment of clinical signs and symptoms was made using from two- to seven-point scales. Preliminary results on 1113 patients (mean age 69.5 years) show a low incidence of side effects: 10 adverse reactions were reported in 8 (0.8%) patients, of which only 5 reactions were considered as correlated to the test treatment. After 3 months of test treatment the proportions of patients with improvement in clinical signs and symptoms were as follows: cyanosis 81%, edema 76.9%, pulmonary rales 78.4%, enlargement of the liver area 49.3%, jugular reflux 81.5%, dyspnea 54.2%, palpitations 75.7%, sweating 82.4%, arrhythmia 62%, insomnia 60.2%, vertigo 73%, and nocturia 50.7%.

Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment.

Langsjoen PH, Langsjoen PH, Folkers K
Clin Investig 1993;71(8 Suppl):S140-4

Symptoms of fatigue and activity impairment, atypical precordial pain, and cardiac arrhythmia frequently precede by years the development of congestive heart failure. Of 115 patients with these symptoms, 60 were diagnosed as having hypertensive cardiovascular disease, 27 mitral valve prolapse syndrome, and 28 chronic fatigue syndrome. These symptoms are common with diastolic dysfunction, and diastolic function is energy dependent. All patients had blood pressure, clinical status, Coenzyme Q10 (CoQ10) blood levels and echocardiographic measurement of diastolic function, systolic function, and myocardial thickness recorded before and after CoQ10 replacement. At control, 63 patients were functional class III and 54 class II; all showed diastolic dysfunction; the mean CoQ10 blood level was 0.855 micrograms/ml; 65%, 15%, and 7% showed significant myocardial hypertrophy, and 87%, 30%, and 11% had elevated blood pressure readings in hypertensive disease, mitral valve prolapse and chronic fatigue syndrome respectively. Except for higher blood pressure levels and more myocardial thickening in the hypertensive patients, there was little difference between the three groups. CoQ10 administration resulted in improvement in all; reduction in high blood pressure in 80%, and improvement in diastolic function in all patients with follow-up echocardiograms to date; a reduction in myocardial thickness in 53% of hypertensives and 36% of the combined prolapse and fatigue syndrome groups; and a reduced fractional shortening in those high at control and an increase in those initially low.

Effect of coenzyme Q10 therapy in patients with congestive heart failure: a long-term multicenter randomized study.

Morisco C, Trimarco B, Condorelli M
Facolta di Medicina e Chiruriga, Universita degli Studi di Napoli Federico II.
Clin Investig 1993;71(8 Suppl):S134-6

The improved cardiac function in patients with congestive heart failure treated with coenzyme Q10 supports the hypothesis that this condition is characterized by mitochondrial dysfunction and energy starvation, so that it may be ameliorated by Coenzyme Q10 supplementation. However, the main clinical problems in patients with congestive heart failure are the frequent need of hospitalization and the high incidence of life-threatening arrhythmias, pulmonary edema, and other serious complications. Thus, we studied the influence of Coenzyme Q10 long-term treatment on these events in patients with chronic congestive heart failure (New York Heart Association functional class III and IV) receiving conventional treatment for heart failure. They were randomly assigned to receive either placebo (n = 322, mean age 67 years, range 30-88 years) or COENZYME Q10 (n = 319, mean age 67 years, range 26-89 years) at the dosage of 2 mg/kg per day in a 1-year double-blind trial. The number of patients who required hospitalization for worsening heart failure was smaller in the Coenzyme Q10 treated group (n = 73) than in the control group (n = 118, P < 0.001). Similarly, the episodes of pulmonary edema or cardiac asthma were reduced in the control group (20 versus 51 and 97 versus 198, respectively; both P < 0.001) as compared to the placebo group. Our results demonstrate that the addition of coenzyme Q10 to conventional therapy significantly reduces hospitalization for worsening of heart failure and the incidence of serious complications in patients with chronic congestive heart failure.

Role of metabolic therapy in cardiovascular disease.

Rengo F, Abete P, Landino P, Leosco D, Covelluzzi F, Vitale D, Fedi V, Ferrara N
Istituto di Medicina Interna, Cardiologia e Chirurgia Cardiovascolare, Catiedra di Geriatria, Facolta di Medicina, Napoli.
Clin Investig 1993;71(8 Suppl):S124-8

The pathophysiological basis for the use of metabolic therapy in the treatment of heart failure is analyzed. Bioenergetical processes related to ATP bioavailability play a central role in regulating myocardial contractility at rest and on effort. Furthermore, a significant correlation has been demonstrated in diseased heart between ATP content, revealed at endomyocardial biopsy, and systolic and diastolic left ventricular indexes evaluated with invasive and noninvasive methods. Several international investigations demonstrate the beneficial effects of ubiquinone (Coenzyme Q10) in the treatment of heart failure. Here the results of a study are reported that was conducted on patients with heart failure treated with ubiquinone. After 7 months of oral drug administration (100 mg/day), a significant improvement was observed in echocardiographic indexes of systolic function, cardiothoracic ratio, and clinical signs and symptoms of congestive heart failure. In conclusion, the introduction of metabolic drugs, such as ubiquinone, in the treatment of heart failure opens new horizons in the therapeutic approach to an ailment that entails substantial human and social costs.

Usefulness of taurine in chronic congestive heart failure and its prospective application.

Azuma J, Sawamura A, Awata N
Third Department of Internal Medicine, Osaka University Medical School, Japan.
Jpn Circ J 1992 Jan;56(1):95-9

We compared the effect of oral administration of taurine (3 g/day) and coenzyme Q10 (CoQ10) (30 mg/day) in 17 patients with congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy, whose ejection fraction assessed by echocardiography was less than 50%. The changes in echocardiographic parameters produced by 6 weeks of treatment were evaluated in a double-blind fashion. In the taurine-treated group significant treatment effect was observed on systolic left ventricular function after 6 weeks. Such an effect was not observed in the CoQ10-treated group.

Co-enzyme Q10: a new drug for cardiovascular disease.

Greenberg S, Frishman WH
Department of Medicine, Mt. Sinai Hospital and Medical Center, New York, New York.
J Clin Pharmacol 1990 Jul;30(7):596-608

Co-enzyme Q10 (ubiquinone) is a naturally occurring substance which has properties potentially beneficial for preventing cellular damage during myocardial ischemia and reperfusion. It plays a role in oxidative phosphorylation and has membrane stabilizing activity. The substance has been used in oral form to treat various cardiovascular disorders including angina pectoris, hypertension, and congestive heart failure. Its clinical importance is now being established in clinical trails worldwide. (133 Refs.)

Coenzyme Q10: a new drug for myocardial ischemia?

Greenberg SM, Frishman WH
Department of Medicine, Mt. Sinai Hospital and Medical School, New York, New York
Med Clin North Am 1988 Jan;72(1):243-58

A biochemical rationale for using CoQ in treating certain cardiovascular diseases has been established. CoQ subserves an endogenous function as an essential cofactor in several metabolic pathways, particularly oxidative respiration. As an exogenous source in supraphysiologic doses, CoQ may have pharmacologic effects that are beneficial to tissues rendered ischemic and then reperfused. Its mechanism of action appears to be that of a free radical scavenger and/or direct membrane stabilizer. Initial clinical studies performed abroad and in the United States indicate that CoQ may be effective in treating certain patients with ischemic heart disease, congestive heart failure, toxin-induced cardiotoxicity, and possibly hypertension. The most intriguing property of CoQ is its potential to protect and preserve ischemic myocardium during surgery. Currently, CoQ is still considered an experimental agent and only further studies will determine whether it will be useful therapy for human cardiovascular disease states. (105 Refs.)

Cardiac performance and Coenzyme Q10 in thyroid disorders

Suzuki H, Naitoh T, Kuniyoshi S, Banba N, Kuroda H, Suzuki Y, Hiraiwa M, Yamazaki N, Ishikawa M, Hashigami Y, et al
Endocrinol Jpn 1984 Dec;31(6):755-61

To investigate the relationship between serum levels of Coenzyme Q10 and cardiac performance in thyroid disorders, we studied the cardiac performance and assessed serum levels of thyroid hormones and Coenzyme Q10 in 20 patients with hyperthyroidism, 5 patients with hypothyroidism and 10 normal subjects. A significant inverse correlation between thyroid hormones and Coenzyme Q10 levels was found by performing partial correlation analysis. Because low serum levels of Coenzyme Q10 were found in thyrotoxic patients and congestive heart failure may occur as a result of severe hyperthyroidism, 120 mg of Coenzyme Q10 was administered daily for one week to 12 hyperthyroid patients and the change in cardiac performance was assessed. Further augmentation of cardiac performance was found in hyperthyroid hearts, which were already augmented, after the administration of Coenzyme Q10. It appears, therefore, that the Coenzyme Q10 dose actually has a therapeutic value for congestive heart failure induced by severe thyrotoxicosis.

A clinical study of the effect of Coenzyme Q on congestive heart failure.

Ishiyama T, Morita Y, Toyama S, Yamagami T, Tsukamoto N
Jpn Heart J 1976 Jan;17(1):32-42

Expecting activation of myocardial energy liberation, COENZYME Q was applied as a treatment to 55 patients suffering from congestive heart failure. Daily doses of 50 to 100 mg of coenzyme Q7 were injected intravenously in 21 cases for 3 to 35 days. Daily doses of 60 mg of coenzyme Q7 were administered perorally in 17 cases for 14 to 196 days. Daily doses of 30 mg of Coenzyme Q10 were administered perorally in 17 cases for 7 to 182 days. Clinical effects were evaluated within 4 weeks by the criteria using a scoring method of severity of congestive heart failure which was devised by the authors. In summary a certain effect was found in 20 cases and a mild effect was observed in 29 cases. No significant changes were observed in heart rate and blood pressure. Exanthema appeared in 2 patients of the group of COENZYME Q7 intravenous injection. In conclusion the therapeutic effect of COENZYME Q was thought to be mild but stable in supplement to digitalis therapy in cases of congestive heart failure.

[Magnesium in cardiology]

Weiss M
Medizinische Abteilung, Inselspital Bern.
Schweiz Rundsch Med Prax 1995 May 2;84(18):526-32

Magnesium acts as a cofactor of numerous enzymes and is important for the maintenance of a high intracellular potassium concentration and the transmembrane action potential. Of the total magnesium content of about 1000 mmol, only 0.3% are located in plasma. Hypomagnesemia and probable magnesium deficiency are found in 7 to 11% of hospitalized patients but are only rarely accompanied by relevant clinical symptoms. Prolonged diuretic therapy and secondary aldosteronism are frequent causes of hypomagnesemia in cardiology. Intravenous magnesium is a vasodilatator and prolongs the AH interval. In animal studies magnesium has been shown to have cardioprotective and platelet-inhibiting properties. The only verified indication for intravenous magnesium is the initial treatment of torsade de pointes. Magnesium may suppress digitalis-induced tachyarrhythmias and convert paroxysmal supraventricular tachycardia and monomorphic ventricular tachycardia to sinus rhythm. Its role in the treatment of acute myocardial infarction and of ventricular arrhythmias in congestive heart failure is unclear. (81 Refs.)

Magnesium therapy in acute myocardial infarction when patients are not candidates for thrombolytic therapy

Shechter M, Hod H, Chouraqui P, Kaplinsky E, Rabinowitz B
Heart Institute, Sheba Medical Center, Tel-Hashomer, Israel.
Am J Cardiol 1995 Feb 15;75(5):321-3

Thrombolytic therapy reduces in-hospital mortality. However, 70% to 80% of patients do not receive thrombolysis and their in-hospital mortality is high. During the last decade some clinical trials demonstrated that magnesium sulfate reduced in-hospital mortality. The aim of this study was to evaluate the effects of magnesium sulfate in patients with acute myocardial infarction (AMI) who were considered unsuitable for thrombolytic therapy. Intravenous magnesium sulfate was evaluated in 194 patients with AMI ineligible for thrombolytic therapy in a randomized, double-blind, placebo-controlled study. Group I consisted of 96 patients who received 48-hour intravenous magnesium. Group II consisted of 98 patients who received isotonic glucose as a placebo. Magnesium reduced the incidence of arrhythmias, congestive heart failure, and conduction disturbances compared with placebo (27% vs 40%, p = 0.04; 18% vs 23%, p = 0.27; 10% vs 15%, p = 0.21, respectively). Left ventricular ejection fraction 72 hours and 1 to 2 months after admission was higher in patients who received magnesium sulfate than in those taking placebo (49% vs 43% and 52% vs 45%; p = 0.01, respectively). In-hospital mortality was significantly reduced in patients receiving magnesium sulfate than in those receiving placebo (4% vs 17%; p < 0.01), and also in the subgroup of elderly patients (> 70 years) (9% vs 23%; p = 0.09). In conclusion, magnesium sulfate should be considered as an alternative therapy to thrombolysis in patients with AMI.

[Oral magnesium supplementation to patients receiving diuretics--normalization of magnesium, potassium and sodium, and potassium pumps in the skeletal muscles]

Dorup I, Skajaa K, Thybo NK
Aarhus Universitet, Fysiologisk Institut.
Ugeskr Laeger 1994 Jul 4;156(27):4007-10, 4013

In 76 consecutive patients who had received diuretics for 1-17 years for arterial hypertension or congestive heart failure, muscle concentrations of magnesium, potassium, and sodium-potassium pumps were significantly reduced compared to 31 age- and sex-matched controls. Thirty-six patients with muscle magnesium and/or potassium below the control level received oral magnesium hydroxide supplement for 2-12 weeks (N = 20) or 26 weeks (N = 16). After short term (2-12 weeks) magnesium supplementation muscle parameters were increased, but far from normalized. After magnesium supplementation for 26 weeks, the muscle concentrations of magnesium, potassium and sodium-potassium pumps were normalized in most cases. Oral magnesium supplementation may restore diuretic-induced disturbances in the concentrations of magnesium, potassium and sodium-potassium pumps in skeletal muscle. A supplemental period of at least six months seems required before complete normalization can be expected.

Effects of intravenous magnesium sulfate on arrhythmias in patients with congestive heart failure.

Gottlieb SS, Fisher ML, Pressel MD, Patten RD, Weinberg M, Greenberg N
Division of Cardiology, University of Maryland School of Medicine, Baltimore 21201.
Am Heart J 1993 Jun;125(6):1645-50

Intravenous magnesium is an effective treatment for ventricular tachycardia of some etiologies, and in patients with congestive heart failure low serum magnesium concentrations are associated with frequent arrhythmias and high mortality. This suggests that magnesium administration may decrease the frequency of ventricular arrhythmias in patients with heart failure. We therefore assessed the impact of an intravenous magnesium infusion upon the frequency of ventricular premature depolarizations in 40 patients with New York Heart Association (NYHA) class II to IV heart failure and serum magnesium < or = 2.0 mg/dl. Within 1 week of a baseline 6-hour ambulatory electrocardiographic recording, an infusion of 0.2 mEq/kg of MgSO4 was given over 1 hour and a repeat 6-hour recording was obtained. There was an inverse relationship between the change in magnesium concentration and the change in frequency of premature ventricular depolarizations; premature ventricular depolarizations declined by 134 +/207 hr-1 in patients in whom serum magnesium concentration increased > or = 0.75 mg/dl, but increased by 72 +/- 393 hr-1 in patients with a change < 0.75 mg/dl (p < 0.05). For all patients, the frequency of premature ventricular depolarizations was 283 +/- 340 hr-1 pretreatment and 220 +/269 hr-1 following magnesium infusion (p = 0.21). Patients with > or = 300 premature ventricular depolarizations hr-1 demonstrated a decrease from 794 +/- 309 to 369 +/- 223 hr-1 (p < 0.001). Intravenous magnesium administration decreased the frequency of couplets from 233 +/- 505 to 84 +/- 140 (p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Magnesium-potassium interactions in cardiac arrhythmia. Examples of ionic medicine.

Iseri LT, Ginkel ML, Allen BJ, Brodsky MA
College of Medicine University of California, Irvine.
Magnes Trace Elem 1991-92;10(2-4):193-204

Ionic biology involving Ca2+, Na+, K+ and Mg2+ across the cell membrane and in the development of the action potential is reviewed with reference to cardiac arrhythmia. K+ and Mg2+ deficiency which frequently occur together lead to abnormal ionic transfer of Na+, K+ and Ca2+ with development of automaticity, triggered impulses and reentrant tachycardia. Tachycardia occurring in acute myocardial ischemia, congestive heart failure, hypertensives on diuretics and digitalis toxicity is examined according to the concept of ionic imbalance. A protocol for prevention and treatment of cardiac tachyarrhythmia is proposed with this concept in mind.

Clinical clues to magnesium deficiency.

Cohen L, Kitzes R
Department of Medicine B, Lady Davis Carmel Hospital, Haifa, Israel.
Isr J Med Sci 1987 Dec;23(12):1238-41

Two cases of congestive heart failure with coexistent magnesium and potassium depletion are described. The prolonged QTc intervals and ventricular premature beats of the first patient and the idionodal tachycardia of the second patient disappeared only after magnesium repletion, which normalized both extra- and intracellular potassium and magnesium levels. The third patient had a case of urosepsis while on total parenteral nutrition. He developed diarrhea, hypocalcemia, hypokalemia, hypomagnesemia, weakness, muscular fasciculations and athetoid movements. The neurological manifestations were relieved and the biochemical abnormalities normalized only after magnesium repletion.

Platelet taurine in patients with arterial hypertension, myocardial failure or infarction.

Paasonen MK, Penttila O, Himberg JJ, Solatunturi E
Acta Med Scand Suppl 1980;642:79-84

The content of taurine in the hypertrophied left ventricle is increased in congestive heart failure an in spontaneously hypertensive (SH) rats. In SH rats the taurine content of and taurine uptake by the platelets are also increased. The present results indicate that, as in the heart, the taurine content may also increase in the platelets of those patients with congestive heart failure. The taurine content and uptake are not increased in the platelets of hypertensive patients as they are in the platelets of SH rats. It is likely that in acute myocardial infarction, a considerable amount of taurine is released from the heart into the plasma. However, there is no simultaneous increase in the platelet taurine content. From this work on can only conclude that platelets may reflect taurine changes in the heart in some pathological states, e.g. congestive heart failure.

Physiological and experimental regulation of taurine content in the heart.

Huxtable RJ, Chubb J, Azari J
Fed Proc 1980 Jul;39(9):2685-90

High concentrations of taurine are found in the heart and these are increased still further in congestive heart failure. It appears that taurine is largely derived by influx from the circulation, and this influx is stimulated by cyclic AMP, whereas influx of alpha-amino acids is unaffected. Influx occurs via a saturable transport system that has strict requirements for ligands. Other substances are transported by this system, including beta-alanine, hypotaurine, guanidoethyl sulfonate, and, to a lesser extent, guanidinopropionate; and these are competitive antagonists for taurine transport. Guanidinoethyl sulfonate, in vivo, markedly lowers taurine concentrations over the course of a few days in all tissues examined in the rat and mouse (but not in the guinea pig). The concentrations of other amino acids are unaffected. Guanidinoethyl sulfonate may prove to be a useful substance in the study of the biological role of taurine, in view of its ability to regulate taurine content in a number of species. Despite the numerous pharmacological actions of taurine, its physiological function in the heart remains problematic. One function appears to be the modulation of calcium movements. The inotropic actions of taurine and beta-adrenergic activation may be linked via the cyclic AMP-dependent regulation of taurine influx.

A relation between myocardial taurine contest and pulmonary wedge pressure in dogs with heart failure.

Newman WH, Frangakis CJ, Grosso DS, Bressler R
Physiol Chem Phys 1977;9(3):259-63

Myocardial taurine levels were correlated with pulmonary wedge pressure (PWP) in dogs with congestive heart failure (CHF). Heart failure was induced by creating an infrarenal aortocaval fistula. PWP ranged from 6.6 to 28 mm Hg, suggesting a wide range in severity of heart failure in those dogs. Compared to taurine levels of normal dogs, levels of the CHF group were significantly elevated in both left and right ventricles. Linear regression analysis of ventricular taurine content yielded a highly significant direct relation to PWP. The results suggest that myocardial taurine content increases as heart failure becomes more severe.

Adrenergic stimulation of taurine transport by the heart.

Huxtable R, Chubb J
Science 1977 Oct 28;198(4315):409-11

A high-affinity transport system that is specific for beta-amino acids has been delineated in rat hearts. This system transports the cardiotonic sulfonic amino acid taurine. beta-Adrenergic stimulation increases the transport capacity without effect on alpha-amino acid uptake, as does stimulation with adenosine 3',5'-monophosphate or theophylline. The existence of such an uptake system for taurine in the heart accounts for the high intra- to extracellular concentration gradient that is maintained, and suggests that cardiac stress is associated with increased taurine uptake. This may explain why taurine is the only amino acid to be markedly elevated in congestive heart failure. taurine is a modifier of calcium fluxes in the heart, as are beta-adrenergic agonists. The presence of this uptake system suggests a link between beta-adrenergic stimulation of calcium and taurine fluxes.

Effects of L-Carnitine administration on left ventricular remodeling after acute anterior myocardial infarction

Iliceto S, Scrutinio D, Bruzzi P, D'Ambrosio G, Boni L, Di Biase M, Biasco G, Hugenholtz PG, Rizzon P
Institute of Cardiology, University of Bari, Italy.
J Am Coll Cardiol 1995 Aug;26(2):380-7

OBJECTIVES. This study was performed to evaluate the effects of L-Carnitine administration on long-term left ventricular dilation in patients with acute anterior myocardial infarction.

BACKGROUND. Carnitine is a physiologic compound that performs an essential role in myocardial energy production at the mitochondrial level. Myocardial Carnitine deprivation occurs during ischemia, acute myocardial infarction and cardiac failure. Experimental studies have suggested that exogenous Carnitine administration during these events has a beneficial effect on function.

METHODS. The L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial was a randomized, double-blind, placebo-controlled, multicenter trial in which 472 patients with a first acute myocardial infarction and high quality two-dimensional echocardiograms received either placebo (239 patients) or L-Carnitine (233 patients) within 24 h of onset of chest pain. Placebo or L-Carnitine was given at a dose of 9 g/day intravenously for the first 5 days and then 6 g/day orally for the next 12 months. Left ventricular volumes and ejection fraction were evaluated on admission, at discharge from hospital and at 3, 6 and 12 months after acute myocardial infarction.

RESULTS. A significant attenuation of left ventricular dilation in the first year after acute myocardial infarction was observed in patients treated with L-Carnitine compared with those receiving placebo. The percent increase in both end-diastolic and end-systolic volumes from admission to 3-, 6- and 12-month evaluation was significantly reduced in the L-Carnitine group. No significant differences were observed in left ventricular ejection fraction changes over time in the two groups. Although not designed to demonstrate differences in clinical end points, the combined incidence of death and congestive heart failure after discharge was 14 (6%) in the L-Carnitine treatment group versus 23 (9.6%) in the placebo group (p = NS). Incidence of ischemic events during follow-up was similar in the two groups of patients.

CONCLUSIONS. L-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event.

The myocardial distribution and plasma concentration of Carnitine in patients with mitral valve disease.

Nakagawa T, Sunamori M, Suzuki A
Department of Thoracic-Cardiovascular Surgery, Tokyo Medical University, School of Medicine, Japan.
Surg Today 1994;24(4):313-7

The myocardial distribution and concentration of Carnitine and its fractions was studied in 11 patients with mitral valve disease not associated with congestive heart failure (CHF). The plasma concentration of Carnitine was found to be identical to the normal values documented in the literature. The left ventricular papillary muscle had the highest concentrations of total, short-acyl, long-acyl, and free Carnitine, being significantly higher than those of the right ventricle, while the right atrial appendage had the lowest values of all fractions of Carnitine. The proportion of long-acyl Carnitine to total Carnitine was significantly greater in the left ventricle than in either the right atrium or the atrial septum, and other Carnitine fractions were identical in all cardiac chambers. Our results suggest that in the compensated heart with mitral valve disease, Carnitine and its fractions are greatest in the left ventricle in the muscles of all cardiac chambers, and that long-acyl Carnitine is most likely to be linked to the cardiac muscle demanding a higher cardiac performance.

Myocardial Carnitine metabolism in congestive heart failure induced by incessant tachycardia.

Pierpont ME, Foker JE, Pierpont GL
Department of Pediatrics, University of Minnesota, School of Medicine, Minneapolis.
Basic Res Cardiol 1993 Jul-Aug;88(4):362-70

Persistent tachycardia induces congestive heart failure (CHF), but the mechanism(s) of progressive ventricular dysfunction is (are) unclear. This study was designed to define possible metabolic causes of myocardial dysfunction in rapid ventricular pacing induced CHF. Twelve adult mongrel dogs were paced to 250 beats/min for 19 days. Plasma Carnitine, norepinephrine and renin were measured at 0, 1, 2, and 3 weeks. Myocardial high energy phosphates, Carnitine, glycogen, glucose, non-collagenous protein and collagen were measured at 19 days. Cardiac output, arterial pressure and pulmonary wedge pressure, measured at baseline and with CHF, showed a decrease in cardiac output and increase in pulmonary wedge pressure. Neurohumoral activation was evident by progressively increasing plasma norepinephrine and renin activity and depletion of myocardial norepinephrine. Plasma free Carnitine rose significantly from 12.6 +/- 2.0 control to 28.3 +/- 3.8 nmol/ml at 19 days (p < 0.001), whereas myocardial total Carnitine was lower in paced than in control dogs (6.0 +/- 1.9 vs. 14.1 +/- 3.5 nmol/mg non-collagenous protein, p < 0.001). Myocardial ATP ATP and ADP were unchanged, while AMP decreased 22%, and creatine phosphate decreased 30% compared to control animals. Myocardial glucose was normal but glycogen was decreased 54% (p < 0.005). The low myocardial Carnitine and elevated plasma Carnitine in pacing induced CHF suggests altered Carnitine transport or membrane integrity.

[The clinical and hemodynamic effects of propionyl-L-Carnitine in the treatment of congestive heart failure]

Pucciarelli G, Mastursi M, Latte S, Sacra C, Setaro A, Lizzadro A, Nolfe G
Servizio di Cardiologia, USL n. 42, Ospedale Elena D'Aosta, Napoli.
Clin Ter 1992 Nov;141(11):379-84

In order to evaluate the clinical and hemodynamic effects of propionyl-L-Carnitine (PLC) a randomized, double-blind study versus placebo was performed in 50 patients of both sexes, between 48 and 69 years of age, affected by mild-moderate congestive heart failure. All patients participating in said study were on digitalis and diuretic treatment. 25 of these belonged to the control group, while the other 25 were treated with an oral dose of 1 g b.i.d of propionyl-L-Carnitine. At the end of six months of treatment maximum exercise time on the treadmill increased 11.1% after 90 days and 16.4% after 180 in the group treated with PLC. From a hemodynamic standpoint, after 30, 90 and 180 days the ejection fraction increased by 7.3%, 10.7% and 12.1%. At the same time, moreover, the systemic vascular resistances were reduced by 14.9%, 20% and 20.6%. In the patients treated with placebo, however, the above-mentioned parameters showed no significant variation. Finally, no unexpected events or toxic effects were observed in any of the patients in either group. As a consequence of these results it is possible to affirm that propionyl-L-Carnitine, due to its clinical and hemodynamic effects, represents a drug of notable therapeutic interest in patients with congestive heart failure, in whom it may be usefully combined with the usual pharmacological therapy.

L-Carnitine treatment for congestive heart failure--experimental and clinical study.

Kobayashi A, Masumura Y, Yamazaki N
Third Department of Internal Medicine, Hamamatsu University School of Medicine, Japan
Jpn Circ J 1992 Jan;56(1):86-94

To evaluate the therapeutic efficacy of l-Carnitine in heart failure, the myocardial Carnitine levels and the therapeutic efficacy of l-Carnitine were studied in cardiomyopathic BIO 14.6 hamsters and in patients with chronic congestive heart failure and ischemic heart disease. BIO 14.6 hamsters and patients with heart failure were found to have reduced myocardial free Carnitine levels (BIO 14.6 vs FI, 287 +/- 26.0 vs 384.8 +/83.8 nmol/g wet weight, p less than 0.05; patients with heart failure vs without heart failure, 412 +/- 142 vs 769 +/- 267 nmol/g p less than 0.01). On the other hand, long-chain acylCarnitine level was significantly higher in the patients with heart failure (532 +/- 169 vs 317 +/- 72 nmol/g, p less than 0.01). Significant myocardial damage in BIO 14.6 hamsters was prevented by the intraperitoneal administration of l-Carnitine in the early stage of cardiomyopathy. Similarly, oral administration of l-Carnitine for 12 weeks significantly improved the exercise tolerance of patients with effort angina. In 9 patients with chronic congestive heart failure, 5 patients (55%) moved to a lower NYHA class and the overall condition was improved in 6 patients (66%) after treatment with l-Carnitine. L-Carnitine is capable of reversing the inhibition of adenine nucleotide translocase and thus can restore the fatty acid oxidation mechanism which constitutes the main energy source for the myocardium. Therefore, these results indicate that l-Carnitine is a useful therapeutic agent for the treatment of congestive heart failure in combination with traditional pharmacological therapy.

The therapeutic potential of Carnitine in cardiovascular disorders.

Pepine CJ
Division of Cardiology, University of Florida, Gainesville.
Clin Ther 1991 Jan-Feb;13(1):2-21; discussion 1

The naturally occurring compound L-Carnitine plays an essential role in fatty acid metabolism. It is only by combining with Carnitine that the activated long-chain fatty acyl coenzyme A esters in the cytosol are able to be transported to the mitochondrial matrix where beta-oxidation occurs. Carnitine also functions in the removal of compounds that are toxic to metabolic pathways. Clinical evidence indicates that Carnitine may have a role in the management of a number of cardiovascular disorders. Supplemental administration of Carnitine has been shown to reverse cardiomyopathy in patients with systemic Carnitine deficiency. Experimental evidence obtained in laboratory animals and the initial clinical experience in man indicate that Carnitine may also have potential in the management of both chronic and acute ischemic syndromes. Peripheral vascular disease, congestive heart failure, cardiac arrhythmias, and anthracycline-induced cardiotoxicity are other cardiovascular conditions that may benefit from Carnitine administration, although at this time data on the use of Carnitine for these indications are very preliminary. (53 Refs.)

[Dilated cardiomyopathy due to primary Carnitine deficiency]

Squarcia U, Agnetti A, Caffarra A, Cavalli C, Marbini A
Pediatr Med Chir 1986 Mar-Apr;8(2):157-61

A case of a 3 and a half years old girl with severe congestive heart failure, and typical picture of dilated cardiomyopathy is presented. The serum level of Carnitine (17.2 micromoles/l, versus 44.1 +/- 12.2 micromoles/l, normal value for age) and the histologic and biochemical evaluation of quadriceps muscle tissue confirmed the diagnosis of primary deficit of Carnitine. L-Carnitine (2 gr. three times a day p.o.) was added to anti-congestive therapy. After 8 weeks of therapy, the general and cardiocirculatory conditions are much improved. The physiopathology of dilated cardiomyopathy due to deficit of Carnitine are discussed. An early diagnosis, and an early substitutive therapy with L-Carnitine dramatically improve the outcome of the disease.

Characterization of inwardly rectifying K+ channel in human cardiac myocytes. Alterations in channel behavior in myocytes isolated from patients with idiopathic dilated cardiomyopathy.

Koumi S, Backer CL, Arentzen CE
Department of Medicine, Northwestern University School of Medicine, Chicago, Ill., USA.
Circulation 1995 Jul 15;92(2):164-74

BACKGROUND: Little is known about the characteristics of the inwardly rectifying K+ channel (IK1) and the influence of preexisting heart disease on the channel properties in the human heart.

METHODS AND RESULTS: We studied the characteristics of cardiac IK1 in freshly isolated adult human atrial and ventricular myocytes by using the patch-clamp technique. Specimens were obtained from the atria and ventricles of 48 patients undergoing cardiac surgery or transplantation and from four explanted donor hearts. The action potential in ventricular myocytes exhibited a longer duration (391.4 +/-30.2 milliseconds at 90% repolarization, n = 10) than in atrium (289.4 +/- 23.0 milliseconds, n = 18, P < .001) and had a fast late repolarization phase (phase 3). The final phase of repolarization in ventricle was frequency independent. Whole-cell IK1 in ventricle exhibited greater slope conductance (84.0 +/- 7.9 nS at the reversal potential, EK; n = 27) than in atrium (9.7 +/-1.2 nS at EK; n = 8, P < .001). The steady-state current-voltage (I-V) relation in ventricular IK1 demonstrated inward rectification with a region of negative slope. This negative slope region was not prominent in atrial IK1. The macroscopic currents were blocked by Ba2+ and Cs+. The channel characteristics in ventricular myocytes from patients with congestive heart failure after idiopathic dilated cardiomyopathy (DCM) exhibited distinct properties compared with those from patients with ischemic cardiomyopathy (ICM). The action potential in ventricular myocytes from patients with DCM had a longer duration (490.8 +/- 24.5 milliseconds, n = 11) compared with that for ICM (420.6 +/- 29.6 milliseconds, n = 11, P < .01) and had a slow repolarization phase (phase 3) with a low resting membrane potential. The whole-cell current slope conductance for DCM was smaller (41.2 +/- 9.0 nS at EK, n = 7) than that for ICM (80.7 +/- 17.0 nS, n = 6, P < .05). In single-channel recordings from cell-attached patches, ventricular IK1 channels had characteristics similar to those of atrial IK1; channel openings occurred in long-lasting bursts with similar conductance and gating kinetics. In contrast, the percent of patches in which IK1 channels were found was 34.7% (25 of 72) of patches in atrium and 88.6% (31 of 35) of patches in ventricle. Single IK1 channel activity for DCM exhibited frequent long-lasting bursts separated by brief interburst intervals at every holding voltage with the open probability displaying little voltage sensitivity (approximately 0.6). Channel activity was observed in 56.2% (18 of 32) of patches for DCM and 77.4% (24 of 31) of patches for ICM. Similar results were obtained from atrial IK1 channels for DCM. In addition, channel characteristics were not significantly different between ICM and explanted donor hearts (donors). IK1 channels in cat and guinea pig had characteristics virtually similar to those of humans, with the exception of lower open probability than that in humans.

CONCLUSIONS: These results suggest that the electrophysiological characteristics of human atrial and ventricular IK1 channels were similar to those of other mammalian hearts, with the possible exception that the channel open probability in humans may be higher, that the whole-cell IK1 density is higher in human ventricle than in atrium, and that IK1 channels in patients with DCM exhibited electrophysiological properties distinct from IK1 channels found in patients with ICM and in donors.

Impaired forearm vasodilation to hyperosmolal stimuli in patients with congestive heart failure secondary to idiopathic dilated cardiomyopathy or to ischemic cardiomyopathy.

Bank AJ, Rector TS, Burke MN, Tschumperlin LK, Kubo SH
Cardiovascular Division, University of Minnesota Medical School, Minneapolis 55455.
Am J Cardiol 1992 Nov 15;70(15):1315-9

Patients with congestive heart failure (CHF) have impaired peripheral vasodilation during exercise. Hyperosmolality is one local stimulus that produces vasodilation during exercise in normal subjects. This study addressed the hypothesis that vasodilation to hyperosmolal stimuli is impaired in patients with CHF. Forearm blood flow responses to intrabrachial artery infusions of isoosmolar (280 mosm/kg) and hyperosmolal (480 and 660 mosm/kg) solutions of saline and glucose were compared in 9 patients with CHF and 13 normal subjects. Forearm blood flow was measured by strain gauge plethysmography. In the normal subjects, hyperosmolal infusions of 480 and 660 mosm/kg increased forearm blood flow by 3.12 +/0.40 and 6.80 +/- 0.67 ml/min/100 ml forearm volume, respectively (both p< 0.001 compared with isoosmolal infusions). In contrast, in the patients with CHF, these infusions increased forearm blood flow by 2.19 +/- 0.44 and 4.06 +/- 0.92 ml/min/100 ml forearm volume (p < 0.05 normal vs CHF). The impaired forearm blood flow responses in heart failure occurred despite significantly greater (p < 0.05, normal vs CHF) increases in venous osmolality (17.3 +/- 6.5 vs 9.6 +/- 1.3 mosm/kg for the 660 mosm/kg infusion). There were no differences between groups in forearm venous hematocrit, calcium, and sodium or potassium changes during hyperosmolal infusions. It is concluded that peripheral vasodilation to hyperosmolal stimuli is impaired in patients with CHF.

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

Langsjoen H, Langsjoen P, Langsjoen P, Willis R, Folkers K
University of Texas Medical Branch, Galveston 77551, USA.
Mol Aspects Med 1994;15 Suppl:s165-75

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

Bioenergetics in clinical medicine. Studies on coenzyme Q10 and essential hypertension.

Yamagami T, Shibata N, Folkers K
Res Commun Chem Pathol Pharmacol 1975 Jun;11(2):273-88

The specific activities (S.A.) of the succinate dehydrogenase-coenzyme Q10 (CoQ10) reductase of a control group of 65 Japanese adults and 59 patients having essential hypertension were determined. The mean S.A. of the hypertensive group was significantly lower (p less than 0.001) and the mean % deficiency of enzyme activity was significantly higher (p less than 0.001) than the values for the control group. These data on Japanese in Osaka agree with data on Americans in Dallas. Some patients showed no CoQ10-deficiency, and others showed definite deficiencies. Emphasizing the CoQ10-enzyme for patient selection, CoQ10 was administered to hypertensive patients. Four individuals showed significant but partial reductions of blood pressure. Monitoring the CoQ10-enzyme before, during, and after administration of CoQ10 indicated responses. The maintenance of high blood pressure could be primarily due to contraction of the arterial wall. Contraction or relaxation of an arterial wall is dependent upon bioenergetics, which also provide the energy for biosynthesis of angiotensin II, renin, aldosterone, and the energy for sodium and potassium transport. A clinical benefit from administration of CoQ10 to patients with essential hypertension could be based upon correcting a deficiency in bioenergetics, and point to possible combination treatments with a form of CoQ and anti-hypertensive drugs.

Can antioxidants prevent ischemic heart disease?

Maxwell SR
Queen Elizabeth Hospital, Edgbaston, Birmingham, U.K.
J Clin Pharm Ther 1993 Apr;18(2):85-95

Ischemic heart disease remains a major cause of mortality in developed countries. A number of important risk factors for the development of coronary atherosclerosis have been identified including hypertension, hypercholesterolaemia, insulin resistance and smoking. However, these factors can only partly explain variations in the incidence of ischaemic heart disease either between populations or within populations over time. In addition, population interventions based upon these factors have had little impact in the primary prevention of heart disease. Recent evidence suggests that one of the important mechanisms predisposing to the development of atherosclerosis is oxidation of the cholesterol-rich low-density lipoprotein particle. This modification accelerates its uptake into macrophages, thereby leading to the formation of the cholesterol-laden 'foam cell'. In vitro, low-density lipoprotein oxidation can be prevented by naturally occurring antioxidants such as vitamin C, vitamin E and beta-carotene. This article explores the evidence that these dietary anti-oxidants may influence the rate of progression of coronary atherosclerosis in vivo and discusses the need for formal clinical trials of antioxidant therapy.

Antioxidant therapy in the aging process.

Deucher GP
Clinica Guilherme Paulo Deucher, Sao Paulo, Brazil.
EXS 1992;62:428-37

A total of 1,265 patients with age-related diseases such as diabetes, arthritis, vascular disease and hypertension as well as 1,100 persons in diminished health without apparent disease, were treated with the metal chelator EDTA and antioxidants such as vitamin C, E, beta-carotene, selenium, zinc and chromium. Good results were observed in the majority of patients. This is encouraging for the initiation of controlled clinical trials.