Cardiovascular Disease
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This study describes how beneficial Over-The-Counter (OTC) supplements can be in heart health; especially anti-oxidants. CoQ10 is a very powerful anti-oxidant.

Metabolic and nutritional support in acute cardiac failure.

Berger MM, Mustafa I.

Intensive Care Unit and Burns Centre, University Hospital, Lausanne, Switzerland. mette.berger@chuv.hospvd.ch

PURPOSE OF REVIEW: Cardiovascular disease is one of the most important causes of morbidity and mortality in western countries, generating an increasing number of admissions to intensive care units. Cardiac failure has long been associated with nutritional disorders, malnutrition and cachexia being frequent during the late phases of congestive heart failure: undernutrition is also a determinant of outcome, even after cardiac transplantation. RECENT FINDINGS: It has been shown that early metabolic support can improve the recovery of the ischaemic heart. This paper reviews recent findings on substrates that can support the failing myocardium, which are mainly glucose-insulin, glutamine, taurine, selenium, thiamine, folic acid, and omega-3 fatty acids. Ischaemia-reperfusion generates tissue lesions that can be partly prevented through substrate manipulation. SUMMARY: Shifting the substrate metabolism from lipids to carbohydrates and reinforcing the antioxidant status reduces the deleterious biological and clinical consequences of acute ischaemic events. The use of the glucose-insulin-potassium infusion has become widespread with the re-discovery of its value in modulating cellular metabolism and accelerating recovery of the ischaemic myocardium. Antioxidants have gained acceptance in the perioperative phase, as well as in chronic heart failure. This constitutes another piece of evidence in favour of early metabolic and nutritional intervention. There also appears to be room for the prevention of acute deterioration of cardiac function after surgery with the preoperative administration of oral supplements containing omega-3 fatty acids.

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"De novo" means, basically, "in house". This paper laments how slowly ATP is generated de novo in cardiac tissue, and how supplementing ribose speeds things up.

[6-13]

Adenine nucleotide synthesis de novo in mature rat cardiac myocytes.

Dow JW, Nigdikar S, Bowditch J.

Inadequate oxygenation of cardiac muscle leads to rapid loss of high energy compounds essential for contractile function. ATP can be regenerated by synthesis de novo, a route operating at a relatively slow rate in the heart. Myocytes isolated from mature rat heart have been used to measure the rate of ATP synthesis de novo from both [14C]glycine and [14C]ribose. Incorporation of glycine into ATP is accelerated 10-fold in the presence of 1 mM ribose. Myocytes also accumulate both precursors into IMP and four other metabolites on the de novo synthesis pathway. These metabolites represent 80% of the glycine entering the pathway. The potential of de novo synthesis for restoration of adenine nucleotides appears to be limited by the rates of early reactions, adenylosuccinate synthetase being only one of the enzymes operating at a sufficiently slow rate to make this pathway an inherently weak route for the restoration of normal energy status in post-ischemic myocardium. Interventions are being sought to alleviate these apparent metabolic delays.

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We are more and more using a class of substances called purines to help protect and treat ailing heart muscle. Here ribose is shown to actually regulate how these substances are incorporated into ATP.

Enhanced ATP and GTP synthesis from hypoxanthine or inosine after myocardial ischemia

E. Harmsen, P. P. de Tombe, J. W. de Jong and P. W. Achterberg

Increasing therapeutic use is made of purines for the treatment of ischemic heart disease, but little is known about regulatory mechanisms involved. Therefore we perfused isolated rat hearts with 0.02 mmol/l [8-14C]hypoxanthine or inosine. Under normoxic conditions about 1% is taken up by the heart and partially used for synthesis of ATP and GTP at a rate of 0.4 and 0.1 nmol X min-1 X g dry wt-1, respectively. After relatively mild ischemia (coronary flow reduction of 70% for 20 min), no increase in myocardial purine uptake is observed, but ATP and GTP synthesis rates are doubled (P less than 0.001). D-Ribose stimulates the hypoxanthine incorporation rate in normoxic perfused rat hearts to 1.1 and 0.5 nmol X min-1 X g dry wt-1 for ATP and GTP, respectively, which is further increased during postischemic perfusion. About 80% of the [8-14C]inosine or [8-14C]hypoxanthine passes through the heart unchanged, while 15% is converted to (hypo)xanthine and uric acid. We conclude from these experiments that inosine and hypoxanthine incorporation into ATP and GTP is at least partly regulated by the availability of 5-phosphoribosyl-1-pyrophosphate.

http://ajpheart.physiology.org/cgi/content/abstract/246/1/H37

 [6-30]

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According to this study, it looks as though a high LDL ("bad cholesterol") to ubiquinone (another name for CoQ10) ratio is a legitimate risk factor for cardiovascular disease. Statin drugs lower CHOL, and LDL, but also CoQ10. We should keep this in mind.

[4-28}

Coenzyme Q10 and coronary artery disease.

Hanaki Y, Sugiyama S, Ozawa T, Ohno M.

Department of Cardiology, Toyohashi National Hospital.

It has been postulated that oxidatively modified low-density lipoprotein (LDL) contributes to the genesis of atherosclerosis. Ubiquinone has been suggested to be an important physiological lipid-soluble antioxidant and is found in LDL fractions in the blood. We measured plasma level of ubiquinone using high-performance liquid chromatography and plasma levels of total cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides in 245 normal subjects (186 males, 59 females) and in 104 patients (55 males, 49 females) who had coronary artery disease not receiving pravastatin and 29 patients (12 males, 17 females) receiving pravastatin. In the normal subjects, the plasma ubiquinone levels did not vary with age. In the patient groups, the plasma total cholesterol and LDL levels were higher and the plasma ubiquinone level lower than in the normal subject group. The LDL/ubiquinone ratio was higher in the patient groups. We found that ubiquinone level, either alone or when expressed in relation to LDL levels, was significantly lower in the patient groups compared with the normal subject group. The 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor is thought to prevent atherosclerosis, however, it also inhibits ubiquinone production. The present study revealed that HMG CoA reductase inhibitor decreased plasma cholesterol level, and that it did not improve either the ubiquinone level or the LDL/ubiquinone ratio. From these results, the LDL/ubiquinone ratio is likely to be a risk factor for atherogenesis, and administration of ubiquinone to patients at risk might be needed

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More evidence of how statin drugs deplete all-important CoQ10.

[4-24]

Evidence of plasma CoQ10-lowering effect by HMG-CoA reductase inhibitors: a double-blind, placebo-controlled study.

Ghirlanda G, Oradei A, Manto A, Lippa S, Uccioli L, Caputo S, Greco AV, Littarru GP.

Institute of Internal Medicine, Catholic University Medical School, Rome, Italy.

Inhibitors of HMG-CoA reductase are new safe and effective cholesterol-lowering agents. Elevation of alanine-amino transferase (ALT) and aspartate-amino transferase (AST) has been described in a few cases and a myopathy with elevation of creatinine kinase (CK) has been reported rarely. The inhibition of HMG-CoA reductase affects also the biosynthesis of ubiquinone (CoQIO). We studied two groups of five healthy volunteers treated with 20 mg/day of pravastatin (Squibb, Italy) or simvastatin (MSD) for a month. Then we treated 30 hypercholesterolemic patients in a double-blind controlled study with pravastatin, simvastatin (20 mg/day), or placebo for 3 months. At the beginning, and 3 months thereafter we measured plasma total cholesterol, CoQIO, ALT, AST, CK, and other parameters (urea, creatinine, uric acid, total bilirubin, gamma GT, total protein). Significant changes in the healthy volunteer group were detected for total cholesterol and CoQIO levels, which underwent about a 40% reduction after the treatment. The same extent of reduction, compared with placebo was measured in hypercholesterolemic patients treated with pravastatin or simvastatin. Our data show that the treatment with HMG-CoA reductase inhibitors lowers both total cholesterol and CoQIO plasma levels in normal volunteers and in hypercholesterolemic patients. CoQIO is essential for the production of energy and also has antioxidative properties. A diminution of CoQIO availability may be the cause of membrane alteration with consequent cellular damage.

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This paper describes why everyone who takes a statin drug--no if's, ands or buts--MUST also then take CoQ10.

Frankly, we cannot understand why all doctors who prescribe them do not tell their patients about this.

It's also good to remember the reason WHY the patient was prescribed a statin: heart disease or diabetes. Both these disease processes produce conditions which deplete, and therefore require supplementation of, CoQ10.

[4-17]

Proc. Natl. Acad. Sci. USA

Vol. 87, pp. 8931-8934, November 1990

Medical Sciences

Lovastatin decreases coenzyme Q levels in humans

(hypercholesterolemia/3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors/ubiquinone/drug side effects)

Karl Folkers*1\ Per Langsjoen*, Richard Willis*, Phillip Richardson*, Li-Jun Xia*, Chun-Qu Ye*,

AND HlROO TAMAGAWA*

'University of Texas at Austin, Austin, TX 78712; and *The Health Center at Tyler, The University of Texas at Tyler, Tyler, TX 75710

Contributed by Karl Folkers, June 20, 1990

ABSTRACT       Lovastatin is clinically used to treat patients with hypercholesterolemia and successfully lowers cholesterol levels. The mechanism of action of lovastatin is inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, an enzyme involved in the biosynthesis of cholesterol from acetyl-CoA. Inhibition of this enzyme could also inhibit the intrinsic bio­synthesis of coenzyme Qlo (CoQ10), but there have not been definitive data on whether lovastatin reduces levels of CoQ10 as it does cholesterol. The clinical use of lovastatin is to reduce a risk of cardiac disease, and if lovastatin were to reduce levels of CoQio, this reduction would constitute a new risk of cardiac disease, since it is established that CoQio is indispensable for cardiac function. We have conducted three related protocols to determine whether lovastatin does indeed inhibit the biosyn­thesis of CoQ10. One protocol was done on rats, and is reported in the preceding paper [Willis, R. A., Folkers, K., Tucker, J. L., Ye, C.-Q., Xia, L.-J. & Tamagawa, H. (1990) Proc. Natl. Acad. Sci. USA 87, 8928-8930]. The other two protocols are reported here. One involved patients in a hospital, and the other involved a volunteer who permitted extraordinary mon­itoring of CoQio and cholesterol levels and cardiac function. All data from the three protocols revealed that lovastatin does indeed lower levels of CoQ10. The five hospitalized patients, 43-72 years old, revealed increased cardiac disease from lovastatin, which was life-threatening for patients having class IV cardiomyopathy before lovastatin or after taking lovastatin. Oral administration of CoQ10 increased blood levels of CoQ10 and was generally accompanied by an improvement in cardiac function. Although a successful drug, lovastatin does have side effects, particularly including liver dysfunction, which presum­ably can be caused by the lovastatin-induced deficiency of CoQ10.

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Here we see CoQ10's amazing ability to lower high blood pressure--without dropping it too low. Taking a safe, naturally occurring substance already found in every cell of the body, instead of expensive synthetic drugs—all of which carry negative side effects!

[4-8]

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

Burke BE, Neuenschwander R, Olson RD.

Research Service, Department of Veterans Affairs Medical Center, Boise, Idaho 83702, USA.

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

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After this study, does anyone think we SHOULDN'T give CoQ10 to those with high blood pressure?

[4-45]

Treatment of essential hypertension with coenzyme Q10.

Langsjoen P, Langsjoen P, Willis R, Folkers K.

Institute for Biomedical Research, University of Texas at Austin 78712, USA.

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

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We now know when heart tissue is starved from oxygen--either by a heart attack, or during surgery--the real damage occurs not necessarily from the original oxygen depletion, but rather through chemical changes as oxygen rushes back in. CoQ10 is shown here to help this situation; again, by its tremendous impact on mitochondrial function.

[4-13]

Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possible prevention by coenzyme Q10.

Domae N, Sawada H, Matsuyama E, Konishi T, Uchino M.

Cumulative dose-dependent toxic effects, particularly cardiomyopathy, induced by doxorubicin and the possible prevention by coenzyme Q10 (CoQIO) were studied in rabbits. In rabbits given doxorubicin alone, there was considerable body weight loss, alopecia, pancytopenia, significant increase in serum creatine phosphokinase and LDH, and ECG changes characterized by tachycardia, flat and inverted T wave, the premature ventricular contractions. In rabbits given doxorubicin plus CoQIO, the only change was pancytopenia. In rabbits treated with doxorubicin alone, the most prominent histologic changes were observed in mitochondria of myocytes, and these changes were characterized by loss of outer membrane, disarrangement of cristae, and formation of numerous concentric lamellae. In addition to mitochondrial changes, there were numerous vacuolizations and extensive depositions of both electron-dense and membranous laminated bodies in the sarcoplasm and disarrangement of Z-band and filamentous changes of myofibrils. Numerous vacuolizations in the capillary endothelial cytoplasm in the myocardium were also conspicuous. On the other hand, few significant morphologic changes were seen in the nuclei of myocytes. There were few ECG and histopathologic changes in rabbits treated with both doxorubicin and CoQIO. These findings suggest that the cardiomyopathy of doxorubicin may be prevented or is at least inhibited by CoQIO. The mechanisms of both doxorubicin-induced cardiomyopathy and its prevention by CoQIO are discussed.

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"Ischemic insult" means ill changes caused by starvation for oxygen. Ribose is here shown to increase ATP building block production in cardiac tissues after ischemic insult

 [6-34]

Metabolic recovery following temporary regional myocardial ischemia in the rat.

Ibel H, Zimmer HG.

The restoration of the cardiac ATP content after an ischemic insult takes a long period of time. Ribose, via stimulation of adenine nucleotide biosynthesis, accelerated the replenishment of the adenine nucleotide pool in the heart, in the kidney, however, it had no effect. In the myocardium, the ribose-mediated restoration of the adenine nucleotide content was dependent on the duration of the previous ischemic period and was not influenced by the beta-receptor blocker atenolol.

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It is necessary to cut off the flow of blood to the heart during some types of cardiac surgery. This study shows that taking CoQ10--and at dosages much less than provided by recommended daily dose of CardioFuel--for only a few days, dramatically reduces the fall off in cardiac output which occurs following such procedures, where the heart muscle is temporarily starved for oxygen.

This study shows how CoQ10 helps the heart recover after it is starved for oxygen (which always happens for a period of time during this surgery) while replacing cardiac valves. Doing so may reduce the need for “inotropic agents—drugs which forcibly increase cardiac output—which further reduce crucial ATP levels within the heart.

[1-9]

Coenzyme Q10: the prophylactic effect on low cardiac output following cardiac valve replacement

J Tanaka, R Tominaga, M Yoshitoshi, K Matsui, M Komori, A Sese, H Yasui and K Tokunaga

A randomized, prospective study of the effectiveness of preoperative administration of coenzyme Q10 on the prophylaxis of postoperative low cardiac output state was performed in 50 patients with acquired valvular diseases necessitating valve replacement. There were 25 patients in the treatment group and 25 in the control group. Patients in the treatment group received 30 to 60 mg of coenzyme Q10 orally for six days before operation. Preoperative clinical variables, operative procedures, total cardiopulmonary bypass time, and aortic cross-clamping time were similar for the two groups. Postoperatively, mild to severe low cardiac output state developed in 28 of 50 patients (56%) and necessitated the administration of considerable amounts of inotropic agent. The treatment group showed a significantly lower incidence of low cardiac output state during the recovery period than the control group (p less than 0.05). These results suggest that preoperative administration of coenzyme Q10 will increase the tolerance of human hearts to ischemia during aortic cross-clamping.

http://ats.ctsnetjournals.org/cgi/content/abstract/33/2/145

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Angina is chest pain from the heart. Stable angina is pain that is brought on by, and commensurate with, physical activity. Here carnitine reduced angina in a dozen test subjects on a treadmill, made them perform better, reduced their chest pain, and even made their EKG’s look better. A couple of them didn’t even complain of chest pain at all after taking carnitine!

[5-36]

Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris.

Kamikawa T, Suzuki Y, Kobayashi A, Hayashi H, Masumura Y, Nishihara K, Abe M, Yamazaki N.

The effects of L-carnitine (900 mg, p.o. daily) on exercise performance were studied in 12 patients with stable effort angina using a multistage treadmill exercise test. Exercise tests were performed at the end of the placebo period and after 4 and 12 weeks of carnitine therapy. While 12 patients experienced angina during treadmill tests in the placebo period, 2 patients were free of angina after treatment with carnitine. The mean exercise time was 11.4 +/- 0.7 min (mean +/- SE) in the placebo period. This increased significantly to 12.2 +/- 0.5 min (p less than 0.05) after 4 weeks and 12.8 +/- 0.5 min (p less than 0.01) after 12 weeks of treatment with carnitine. The time required for 1 mm ST depression to occur was 6.4 +/- 0.9 min in the placebo period. This increased significantly to 7.6 +/- 0.9 min (p less than 0.01) after 4 weeks and 8.8 +/- 1.0 min after 12 weeks of treatment with carnitine. There was significantly less ST segment depression during the same exercise load after 12 weeks of treatment as compared with that in the placebo period (p less than 0.05). The heart rate and the pressure rate product at the same work load showed no significant difference among the 3 testing periods. The results of this study suggest that L-carnitine may improve exercise tolerance in patients with effort angina.

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This one focuses on the benefits of carnitine for ischemic (“oxygen starved”) heart disease. The result is more fuel available, better blood supply, fewer arrhythmias, and less free radical damage. Also shows how the propionyl-L-carnitine variety (included in CardioFuel) gets into heart cell mitochondria better.

[5-42]

Influence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass.

Lango R, Smolenski RT, Narkiewicz M, Suchorzewska J, Lysiak-Szydlowska W.

Chair and Department of Anesthesiology and Intensive Care, Medical University of Gdansk, Debinki 80-211, Gdansk, Poland. rlango@amg.gda.pl

Carnitine and its derivatives have recently been shown to protect cardiac metabolism and function in ischemic heart disease and other clinical conditions of myocardial ischemia. Potential mechanisms of this effect include an increase in glucose metabolism, a reduction of toxic effects of long-chain acyl-CoA and acyl-carnitine in myocytes, an increase in coronary blood flow and anti-arrhythmic effect. It has also been shown that propionyl-L-carnitine which penetrates faster than carnitine into myocytes is effective in inhibiting production of free radicals. Beneficial effects of carnitine supplementation have been demonstrated under a variety of clinical conditions such as acute cardiac ischemia, during extracorporeal circulation, in carnitine-dependent cardiomyopathy as well as in patients with chronic circulatory failure and in cardiogenic shock. However, further studies are required before carnitine administration could be recommended as a routine procedure in ischemic heart disease or before cardiopulmonary bypass.

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Like CoQ10 did in the previous studies, carnitine also helps the heart recover after it has been starved of oxygen.

[5-26]

Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart.

Felix C, Gillis M, Driedzic WR, Paulson DJ, Broderick TL.

Department of Pharmacology, Faculty of Medicine, Dalhousie University, B3H 4H7, Halifax, NS, Canada.

The effects of propionyl-L-carnitine (PLC) on isolated mitochondrial respiration in the ischemic reperfused diabetic heart were studied. Oral PLC treatment of STZ-diabetic rats was initiated for a period of 6 weeks. After treatment, isolated working hearts from diabetic rats were perfused under aerobic conditions then subjected to 25 min of no-flow ischemia followed by 15 min of aerobic reperfusion. At the end of reperfusion, heart mitochondria was isolated using differential centrifugation and respiration measured in the presence of pyruvate, glutamate, and palmitoylcarnitine. Our results indicate that diabetes was characterized by a pronounced decrease in heart function under aerobic conditions as well as during reperfusion following ischemia. Treatment with PLC resulted in a significant improvement in heart function under these conditions. The depressions in state 3 mitochondrial respiration with both pyruvate and glutamate seen in reperfused hearts from diabetic rats were prevented by PLC. State 3 respiration in the presence of palmitoylcarnitine was also improved in the ischemic reperfused diabetic rat heart. Our results show that PLC improves recovery of mechanical function following ischemia in the diabetic rat heart. The beneficial effects of PLC are associated with enhanced mitochondrial oxidation of fuels.

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Men and women with congestive heart failure, when given the same dose of carnitine included in CardioFuel, lowered heart rate and water retention, and needed fewer drugs to strengthen the heart. It also improved their lipid profile. Most importantly, they felt better!

[5-28]

Evaluation of the therapeutic efficacy of L-carnitine in congestive heart failure.

Ghidini O, Azzurro M, Vita G, Sartori G.

Reparto Medicina Interna, Ospedale Bussolengo, Verona, Italy.

To evaluate the therapeutic efficacy of L-carnitine in elderly subjects suffering from heart failure, secondary to ischemic and/or hypertensive heart disease, 38 patients (22 men, 16 women) were studied, aged from 65 to 82 years. In addition to traditional therapy (digitalis, diuretics, antiarrhythmic agents) given in all cases, 21 patients received oral L-carnitine on the basis of a randomized protocol in 1-g doses twice daily for 45 days (the other 17 received placebo). In the group treated with L-carnitine, a distinct improvement was observed in both subjective and objective conditions; reduced heart rate, edema and dyspnea, increased diuresis and a marked reduction in daily digitalis consumption. L-carnitine treatment also induced a significant reduction in serum cholesterol and triglyceride levels. No adverse reactions attributable to L-carnitine administration were observed in any of the patients.

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Here live rat hearts were starved for nutrients. Carnitine not only improved intracellular energy supply, but also protected the hearts once they were reperfused--to the point of allowing four such starvation-reperfusion cycles. The hearts without carnitine couldn't survive the first one!

[5-45]

Effects of L-carnitine and its acetyl and propionyl esters on ATP and PCr levels of isolated rat hearts perfused without fatty acids and investigated by means of 31P-NMR spectroscopy.

Loster H, Keller T, Grommisch J, Grunder W.

Institute of Clinical Chemistry and Pathobiochemistry, University of Leipzig, Germany.

31P-NMR in vivo spectroscopy is a non-invasive and non-hazardous technique which investigates chemical composition and metabolism of living objects, for example by determining phosphocreatine (PCr) and ATP concentrations. In the present study we investigated the influence of L-carnitine, acetyl-L-carnitine and propionyl-L-carnitine on the energetic state of the Langendorff rat heart subjected to an ischemic period of 20 min followed by a reperfusion period of 60 min. To avoid an overlapping of the effects of fatty acids and glucose, the hearts were perfused with a Tyrode solution containing no fatty acids. Ischemia causes a rapid decrease in the PCr signal, followed by a decrease in the ATP signal after a prolonged period of ischemia. At the same time, a drastic increase in the Pi signal was observed. A partial recovery of the ATP and PCr signals was observed in the reperfusion period. With L-carnitine a markedly improved recovery of the high energy phosphates (e.g. increased PCr/P ratios) was found. With acetyl-L-carnitine this effect was enhanced in the first postischemic phase. It was followed, however, by a more rapid decrease in the PCr/Pi ratio in the late reperfusion period. The effect of propionyl-L-carnitine was not significantly improved in the first minutes of the reperfusion period, but during the whole reperfusion phase a stabilization of the PCr/Pi ratio was observed. Intracellular pH can be calculated from determination of the Pi-chemical shift. This shows that L-carnitine and its derivatives have a protective effect against intracellular pH decrease during ischemia. L-carnitine improves the energetic state of the heart, which leads to increased ischemia tolerance. Hearts under L-carnitine were able to tolerate up to four ischemia-reperfusion periods in succession, whereas the controls were not able to do so. These NMR results confirm the hypothesis that L-carnitine and its esters have a protective effect in the reperfusion period of the ischemic rat heart. This could be of importance for the treatment of ischemic cardiac diseases.

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How much the important left ventricle of the heart enlarges after a heart attack predicts how well--and how long--the patient will survive. Carnitine may decrease the amount of tissue which dies during the heart attack, as well as help the heart maintain its normal size later on. Other benefits are described as well, adding up to a recommendation that anyone who has had a heart attack should get on, and stay on, carnitine.

[5-19]

Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico.

Colonna P, Iliceto S.

Institute of Cardiology, University of Cagliari, Italy.

Left ventricular dilatation after acute myocardial infarction (MI) is a powerful predictor of progressive functional deterioration, culminating in heart failure and death. The most important determinants of post-MI left ventricular remodeling are the size of the infarct, the degree of residual stenosis in the infarct-related artery, and the viability of the infarct zone. In addition to reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may represent a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function. Ongoing studies with early metabolic intervention with carnitine in the acute phase of infarction may prove successful in protecting the microcirculation against ischemic damage and enhancing its ability to respond to blood flow resumption. The results of the multicenter, randomized, double-blind Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial suggest that the early and long-term administration of L-carnitine attenuates progressive left ventricular dilatation after acute anterior MI. Results show significant, consistent reductions in end-diastolic volume and end-systolic volume in patients who received L-carnitine compared with placebo. The ongoing CEDIM-2 trial (projected 4000 patients with acute MI) will assess the efficacy of L-carnitine in reducing the combined incidence of death and heart failure at 6 months. In addition to standard reperfusion therapy and angiotensin-converting enzyme inhibition, metabolic intervention with L-carnitine may be a therapeutic approach for preventing left ventricular dilatation and preserving cardiac function by limiting infarct size, decreasing residual stenosis in the infarct-related artery, and increasing viability of the infarct zone.

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This study shows how giving carnitine to those who have had a heart attack reduces heart rate, lowers blood pressure, decreases subsequent chest pain and improves cardiac output, as well as the lipid profile. Why is this not being recommended to everyone who has had an MI?

[5-21]

Controlled study on L-carnitine therapeutic efficacy in post-infarction.

Davini P, Bigalli A, Lamanna F, Boem A.

Department of Cardiovascular Medicine, Santa Chiara Hospital, U.S.L., Pisa, Italy.

A controlled study was carried out on 160 patients of both sexes (age between 39 and 86 years) discharged from the Cardiology Department of the Santa Chiara Hospital, Pisa, with a diagnosis of recent myocardial infarction. L-carnitine was randomly administered to 81 patients at an oral dose of g 4/die for 12 months, in addition to the pharmacological treatment generally used. For the whole period of 12 months, these patients showed, in comparison with the controls, an improvement in heart rate (p < 0.005), systolic arterial pressure (p < 0.005) and diastolic arterial pressure (NS); a decrease of anginal attacks (p < 0.005), of rhythm disorders (NS) and of clinical signs of impaired myocardial contractility (NS), and a clear improvement in the lipid pattern (p < 0.005). The above changes were accompanied by a lower mortality in the treated group (1.2%, p < 0.005), while in the control group there was a mortality of 12.5%. Furthermore, in the control group there was a definite prevalence of deaths caused by reinfarction and sudden death. On the basis of these results, it is concluded that L-carnitine represents an effective treatment in post-infarction ischaemic cardiopathy, since it can improve the clinical evolution of this pathological condition as well as the patient's quality of life and life expectancy.

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CoQ10 is so good for the heart, it even brings great benefit for end stage heart failure patients--those waiting for a heart transplant.

[4-6]

Coenzyme Q10 in patients with end-stage heart failure awaiting cardiac transplantation: a randomized, placebo-controlled study.

Berman M, Erman A, Ben-Gal T, Dvir D, Georghiou GP, Stamler A, Vered Y, Vidne BA, Aravot D.

Department of Cardiothoracic Surgery, Heart-Lung Transplant Unit, Rabin Medical Center, Beilinson Campus, Potah Tikva, Israel. mariusby@yahoo.com

BACKGROUND: The number of patients awaiting heart transplantation is increasing in proportion to the waiting period for a donor. Studies have shown that coenzyme Q10 (CoQlO) has a beneficial effect on patients with heart failure. HYPOTHESIS: The purpose of the present double-blind, placebo-controlled, randomized study was to assess the effect of CoQlO on patients with end-stage heart failure and to determine if CoQlO can improve the pharmacological bridge to heart transplantation. METHODS: A prospective double-blind design was used. Thirty-two patients with end-stage heart failure awaiting heart transplantation were randomly allocated to receive either 60 mg U/day of Ultrasome--CoQ10 (special preparation to increase intestinal absorption) or placebo for 3 months. All patients continued their regular medication regimen. Assessments included anamnesis with an extended questionnaire based partially on the Minnesota Living with Heart Failure Questionnaire, 6-min walk test, blood tests for atrial natriuretic factor (ANF) and tumor necrosis factor (TNF), and echocardiography. RESULTS: Twenty-seven patients completed the study. The study group showed significant improvement in the 6-min walk test and a decrease in dyspnea, New York Heart Association (NYHA) classification, nocturia, and fatigue. No significant changes were noted after 3 months of treatment in echocardiography parameters (dimensions and contractility of cardiac chambers) or ANF and TNF blood levels. CONCLUSIONS: The administration of CoQlO to heart transplant candidates led to a significant improvement in functional status, clinical symptoms, and quality of life. However, there were no objective changes in echo measurements or ANF and TNF blood levels. Coenzyme Q10 may serve as an optional addition to the pharmacologic armamentarium of patients with end-stage heart failure. The apparent discrepancy between significant clinical improvement and unchanged cardiac status requires further investigation.

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Here they sampled the hearts of those who received heart transplants--in other words, the worst cardiac tissue around. They found the several forms of carnitine were very deficient in these failed hearts, and in fact, on an almost molecule by molecule basis, the less carnitine, the less blood the heart could push out per beat.

[5-46]Myocardial carnitine and carnitine palmitoyltransferase deficiencies in patients with severe heart failure.

Martin MA, Gomez MA, Guillen F, Bornstein B, Campos Y, Rubio JC, de la Calzada CS, Arenas J.

Centro de Investigacion, Hospital Universitario 12 de Octubre, Madrid, Spain.

We studied myocardial tissue from 25 cardiac transplant recipients, who had end-stage congestive heart failure (CHF), and from 21 control donor hearts. Concentrations of total carnitine (TC), free carnitine (FC), short-chain acylcarnitines, long-chain acylcarnitines (LCAC) as well as carnitine palmitoyltransferase (CPT) activities were measured in myocardial tissue homogenates and referred to the concentration of non-collagen protein. Compared to controls, the concentrations of TC and FC as well as total CPT activities were significantly lower in patients. LCAC levels and the LCAC to FC ratio values were significantly greater in patients than in controls. While the malonyl-CoA sensitive fraction of CPT, which represents CPT I activity, was similar in patients and controls, the residual CPT activity after inhibition by malonyl-CoA, representing CPT II activity, was significantly reduced in patients compared to controls. Moreover, the activity of CPT in the presence of Triton X-100, which also represents the activity of CPT II, was significantly lower in patients than in controls. Malonyl-CoA concentrations required for half-maximal inhibition of CPT activity were significantly greater in patients than in controls. There was a linear relationship between ejection fraction (EF) values and concentrations of TC, FC, or total CPT activities. Values for LCAC and the LCAC to FC ratio were inversely related to EF values. We conclude that failing heart shows decreased total CPT and CPT II activities and carnitine deficiency that may be related to ventricle function.

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Hearts harvested for transplantation are preserved in cold solutions. Here is another example of the wonderful things CoQ10 can do for cardiac tissue, with the common link being oxygen starvation.

[4-9]

Effectiveness of coenzyme Q10 on myocardial preservation during hypothermic cardioplegic arrest

Ying-Fu Chen, MD, Young-Tso Lin, MD, Su-Chuan Wu, BS

Kaohsiung, Taiwan

From the Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical College, Kaohsiung, Taiwan.

Received for publication Oct. 22, 1992. Accepted for publication April 16, 1993. Address for reprints: Ying-Fu Chen, MD, Division of Cardiovascular Surgery, Department of Surgery, Kaohsiung Medical College, 100 Shih-Chuan 1st Rd., Kaohsiung, Taiwan.

Abstract

A prospective, randomized, double-blind trial assigned 11 patients to receive coenzyme Q10 and 11 to receive none. Patients pretreated with coenzyme Q10 had a lower left atrial pressure and a lesser

incidence of low cardiac output. They also had a wider pulse pressure. The right and left ventricular myocardial ultrastructure was better preserved in patients receiving preoperative treatment with coenzyme Q10. There was no demonstrable benefit to the atrial myocardium. (J

THORAC CARDIOVASC SURG 1994;107:242-7)

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One day Interventional Cardiologists may lay in some ribose as they are conducting certain types of heart imaging studies.

[6-31]

Ribose infusion accelerates thallium redistribution with early imaging compared with late 24-hour imaging without ribose.

Hegewald MG, Palac RT, Angello DA, Perlmutter NS, Wilson RA.

Department of Medicine, Oregon Health Sciences University, Portland 97201-3098.

To determine if early (4-h) thallium-201 imaging with ribose infusion would enhance detection of thallium redistribution better than late (24-h) imaging without ribose infusion, 15 patients with coronary artery disease underwent thallium stress tests by both methods within 2 weeks. All 15 patients had quantitative coronary angiography. After immediate postexercise planar imaging during the first of two exercise tests, patients were randomized to receive either intravenous ribose (3.3 mg/kg per min) or a control infusion of saline solution for 30 min. Images performed at 4 h for the ribose study were compared with those at 24 h for the saline control study. During the second test, exercise was carried to the same rate-pressure product and each patient received the opposite infusion. Four-hour postexercise images after ribose infusion identified 21 reversible defects not seen in the 24-h saline study. Three reversible defects were seen only in saline studies, but not with ribose at 4 h (p less than 0.01); 15 reversible defects were seen with both tests. When analyzed with respect to the 31 vascular territories supplied by a coronary artery with a greater than 50% stenosis, 8 territories had reversible defects present in the ribose but not the saline study and the saline study did not demonstrate reversible defects in territories that were seen in the ribose study (p less than 0.01). In 14 of these territories, reversible defects were seen with both tests. In 6 of 15 patients, additional vascular territories with reversible defects were identified after ribose infusion. It is concluded that ribose enhances the detection of thallium redistribution at 4 h compared with 24-h control images in patients with coronary artery disease and, therefore, substantially improves the identification of viable ischemic myocardium.

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This study shows how sick hearts which require valve replacement have lower levels of carnitine. It also showed the actual heart tissue is using up the carnitine, as the carnitine concentration in the blood may still be normal.

[5-50]Carnitine levels in patients with chronic rheumatic heart disease.

Narin F, Narin N, Andac H, Ergin A, Coskun A, Ustdal M, Ceyran H.

Erciyes University Medical Faculty, Department of Biochemistry, Kayseri, Turkiye.

OBJECTIVE: Carnitine, a small aminoacid derivative plays a major role in fatty acid oxidation. Myocardial carnitine deficiency may cause malfunction of the heart. Rheumatic valvular heart disease can be associated with myocardial dysfunction. We have investigated myocardial and plasma-free carnitine levels in patients with chronic rheumatic heart disease. MATERIAL AND METHODS: Eleven patients with chronic rheumatic heart disease requiring valve replacement were selected for study. Ten patients with no cardiac failure, myocardial wall motion abnormalities and myocardial infarction and for whom coronary bypass surgery was planned were selected as the control group. Carnitine levels of myocardial tissue obtained from the right atrium and plasma during the operation were evaluated using spectrophotometric method. Myocardial-free carnitine levels expressed as mumol/g (dry weight) were determined according to Ceberblad and Lindstedt technique. RESULTS: Myocardial-free carnitine levels in patients were found to be 0.72 +/- 0.37 mumol/g (dry weight) in comparison with 1.44 +/- 1.03 mumol/g (dry weight) in the control group. Myocardial-free carnitine levels in patients were statistically decreased when compared to control group. Plasma-free carnitine levels in patients were 80.91 +/- 28.22 mumol/L and 89.52 +/- 48.21 mumol/L in the control group, respectively. There was no significant difference between plasma-free carnitine levels of the groups. CONCLUSION: In our study, myocardial-free carnitine levels were decreased while plasma-free carnitine levels were normal in patient with chronic rheumatic heart disease.

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Another catch-all paper listing benefits of carnitine with respect to heart disease--including its ability to help clear cell toxins.

[5-57]

The therapeutic potential of carnitine in cardiovascular disorders.

Pepine CJ.

Division of Cardiology, University of Florida, Gainesville.

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.

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Claudication is terrible leg pain brought on by physical exercise, due to oxygen starvation because the blood supply of the legs is compromised. Carnitine here allowed people walk faster and longer on a treadmill, and therefore would improve their QOL (Quality of Life).

[5-32]

Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication.

Hiatt WR, Regensteiner JG, Creager MA, Hirsch AT, Cooke JP, Olin JW, Gorbunov GN, Isner J, Lukjanov YV, Tsitsiashvili MS, Zabelskaya TF, Amato A.

Department of Medicine, Section of Vascular Medicine, Divisions of Geriatrics and Cardiology, University of Colorado Health Sciences Center, Denver 80203, USA.

PURPOSE: We tested the hypothesis that propionyl-L-carnitine would improve peak walking time in patients with claudication. Secondary aims of the study were to evaluate the effects of propionyl-L-carnitine on claudication onset time, functional status, and safety. SUBJECTS AND METHODS: In this double-blind, randomized, placebo-controlled trial, 155 patients with disabling claudication from the United States (n = 72) or Russia (n = 83) received either placebo or propionyl-L-carnitine (2g/day orally) for 6 months. Subjects were evaluated at baseline and 3 and 6 months after randomization with a graded treadmill protocol at a constant speed of 2 miles per hour, beginning at 0% grade, with increments in the grade of 2% every 2 minutes until maximal symptoms of claudication forced cessation of exercise. Questionnaires were used to determine changes in functional status. RESULTS: At baseline, peak walking time was 331 +/- 171 seconds in the placebo group and 331 +/- 187 seconds in the propionyl-L-carnitine group. After 6 months of treatment, subjects randomly assigned to propionyl-L-carnitine increased their peak walking time by 162 +/- 222 seconds (a 54% increase) as compared with an improvement of 75 +/- 191 seconds (a 25% increase) for those on placebo (P <0.001). Similar improvements were observed for claudication onset time. Propionyl-L-carnitine treatment significantly improved walking distance and walking speed (by the Walking Impairment Questionnaire), and enhanced physical role functioning, reduced bodily pain, and resulted in a better health transition score (by the Medical Outcome Study SF-36 Questionnaire). The incidence of adverse events and study discontinuations were similar in the two treatment groups. CONCLUSIONS: Propionyl-L-carnitine safely improved treadmill exercise performance and enhanced functional status in patients with claudication.

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A study describing how carnitine may benefit the heart function of diabetics.

[5-13]

Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat.

Broderick TL, Driedzic W, Paulson DJ.

Midwestern University, Department of Physiology, Glendale, Arizona 85308, USA.

Previous studies have shown that propionyl-L-carnitine (PLC) can exert cardiac antiischemic effects in models of diabetes. In the nonischemic diabetic rat heart, PLC improves ventricular function secondary to stimulation in the oxidation of glucose and palmitate. Whether this increase in the oxidation of these substrates can explain the beneficial effects of PLC in the ischemic reperfused diabetic rat heart has yet to be determined. Diabetes was induced in male Sprague-Dawley rats by an intravenous injection of streptozotocin (60 mg/kg). Treatment was initiated by supplementing the drinking water with propionyl-L-carnitine at the concentration of 1 g/L. After a 6-week treatment period, exogenous substrate oxidation and recovery of mechanical function following ischemia were determined in isolated working hearts. In aerobically perfused diabetic hearts, compared with those of controls, rates of glucose oxidation were lower, but those of palmitate oxidation were similar. Diabetes was also characterized by a pronounced decrease in heart function. Following treatment with by propionyl-L-carnitine, however, there was a marked increase in rates at which glucose and palmitate were oxidized by diabetic hearts and a significant improvement in heart performance. Postischemic recovery of function in diabetic hearts was also improved with PLC. This improvement in contractile function was accompanied by an increase in both glucose and palmitate oxidation. Our findings show that postischemic diabetic rat heart function can be improved following chronic PLC treatment. This beneficial effect of propionyl-L-carnitine can be explained, in part, by an improvement in the oxidation of glucose and palmitate.