Systematic review of effect of coenzyme Q10 in physical exercise, hypertension and heart failure

COENZYME Q10 IN PHYSICAL EXERCISE. We identified eleven studies in which CoQ10 was tested for an effect on exercise capacity, six showed a modest improvement in exercise capacity with CoQ10 supplementation but five showed no effect. CoQ10 IN HYPERTENSION. We identified eight published trials of CoQ10 in hypertension. Altogether in the eight studies the mean decrease in systolic blood pressure was 16 mm Hg and in diastolic blood pressure, 10 mm Hg. Being devoid of significant side effects CoQ10 may have a role as an adjunct or alternative to conventional agents in the treatment of hypertension. CoQ10 IN HEART FAILURE. We performed a randomised double blind placebo-controlled pilot trial of CoQ10 therapy in 35 patients with heart failure. Over 3 months, in the CoQ10 patients but not in the placebo patients there were significant improvements in symptom class and a trend towards improvements in exercise time. META-ANALYSIS OF RANDOMISED TRIALS OF COENZYME Q10 IN HEART FAILURE. In nine randomised trials of CoQ10 in heart failure published up to 2003 there were non-significant trends towards increased ejection fraction and reduced mortality. There were insufficient numbers of patients for meaningful results. To make more definitive conclusions regarding the effect of CoQ10 in cardiac failure we recommend a prospective, randomised trial with 200-300 patients per study group. Further trials of CoQ10 in physical exercise and in hypertension are recommended.     

Exercise training in chronic heart failure: mechanisms and therapies

Decreased exercise capacity negatively affects the individuals’ ability to adequately perform activities required for normal daily life and, therefore, the independence and quality of life. Regular exercise training is associated with improved quality of life and survival in healthy individuals and in cardiovascular disease patients. Also in patients with stable heart failure, exercise training can relieve symptoms, improve exercise capacity and reduce disability, hospitalisation and probably mortality. Physical inactivity can thus be considered a major cardiovascular risk factor, and current treatment guidelines recommend exercise training in patients with heart failure in NYHA functional classes II and III. Exercise training is associated with numerous pulmonary, cardiovascular, and skeletal muscle metabolic adaptations that are beneficial to patients with heart failure. This review discusses current knowledge of mechanisms by which exercise training is beneficial in these patients.     

How long should angiotensin-converting enzyme inhibitors be given to patients following myocardial infarction: implications of the HOPE trial

Long-term treatment with angiotensin-converting enzyme inhibitors reduces post-infarction morbidity and mortality in patients with left ventricular (LV) systolic dysfunction or symptomatic heart failure. Until recently, the effect of such treatment in patients with preserved LV function has not been known. The results from the Heart Outcome Prevention Evaluation trial have indicated that long-term treatment with ramipril leads to a significant reduction in cardiovascular events in patients with atherosclerotic disease, including those with prior myocardial infarction and preserved LV function. These results suggest that long-term angiotensin-converting enzyme inhibition should also be considered in post-infarction patients with normal cardiac function.     

Coenzyme Q10 improves contractility of dysfunctional myocardium in chronic heart failure

BACKGROUND: There is evidence that plasma CoQ(10) levels decrease in patients with advanced chronic heart failure (CHF). OBJECTIVE: To investigate whether oral CoQ(10) supplementation could improve cardiocirculatory efficiency in patients with CHF. METHODS: We studied 21 patients in NYHA class II and III (18M, 3W, mean age 59 +/- 9 years) with stable CHF secondary to ischemic heart disease (ejection fraction 37 +/- 7%), using a double-blind, placebo-controlled cross-over design. Patients were assigned to oral CoQ(10) (100 mg tid) and to placebo for 4 weeks, respectively. RESULTS: CoQ(10) supplementation resulted in a threefold increase in plasma CoQ(10) level (P < 0.0001 vs placebo). Systolic wall thickening score index (SWTI) was improved both at rest and peak dobutamine stress echo after CoQ(10) supplementation (+12.1 and 15.6%, respectively, P < 0.05 vs placebo). Left ventricular ejection fraction improved significantly also at peak dobutamine (15% from study entry P < 0.0001) in relation to a decrease in LV end-systolic volume index (from 57 +/- 7 mL/m(2) to 45 mL/m(2), P < 0.001). Improvement in the contractile response was more evident among initially akinetic (+33%) and hypokinetic (+25%) segments than dyskinetic ones (+6%). Improvement in SWTI was correlated with changes in plasma CoQ(10) levels (r = -0.52, P < 0.005). Peak VO(2) was also improved after CoQ(10) as compared with placebo (+13%, <0.005). No side effects were reported with CoQ(10). CONCLUSIONS: Oral CoQ(10) improves LV contractility in CHF without any side effects. This improvement is associated with an enhanced functional capacity.     

The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus.

A possible relationship between the pathogenesis of type 2 diabetes and coenzyme Q10 (CoQ10) deficiency has been proposed. The aim of this study was to assess the effect of CoQ10 on metabolic control in 23 type 2 diabetic patients in a randomized, placebo-controlled trial. Treatment with CoQ10 100 mg bid caused a more than 3-fold rise in serum CoQ10 concentration (p < 0.001). No correlation was observed between serum CoQ10 concentration and metabolic control. No significant changes in metabolic parameters were observed during CoQ10 supplementation. The treatment was well tolerated and did not interfere with glycemic control, therefore CoQ10 may be used as adjunctive therapy in patients with associated cardiovascular diseases.     

Marginal hazard ratio estimates in joint frailty models for heart failure trials

This work is motivated by clinical trials in chronic heart failure disease, where treatment has effects both on morbidity (assessed as recurrent non‐fatal hospitalisations) and on mortality (assessed as cardiovascular death, CV death). Recently, a joint frailty proportional hazards model has been proposed for these kind of efficacy outcomes to account for a potential association between the risk rates for hospital admissions and CV death. However, more often clinical trial results are presented by treatment effect estimates that have been derived from marginal proportional hazards models, that is, a Cox model for mortality and an Andersen–Gill model for recurrent hospitalisations. We show how these marginal hazard ratios and their estimates depend on the association between the risk processes, when these are actually linked by shared or dependent frailty terms. First we derive the marginal hazard ratios as a function of time. Then, applying least false parameter theory, we show that the marginal hazard ratio estimate for the hospitalisation rate depends on study duration and on parameters of the underlying joint frailty model. In particular, we identify parameters, for example the treatment effect on mortality, that determine if the marginal hazard ratio estimate for hospitalisations is smaller, equal or larger than the conditional one. How this affects rejection probabilities is further investigated in simulation studies. Our findings can be used to interpret marginal hazard ratio estimates in heart failure trials and are illustrated by the results of the CHARM‐Preserved trial (where CHARM is the ‘Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity’ programme).     

Coenzyme Q(10) , endothelial function, and cardiovascular disease

Since the time a precise role of coenzyme Q(10) (CoQ(10) ) in myocardial bioenergetics was established, the involvement of CoQ in the pathophysiology of heart failure was hypothesized. This provided the rationale for numerous clinical trials of CoQ(10) as adjunctive treatment for heart failure. A mild hypotensive effect of CoQ was reported in the early years of clinical use of this compound. We review early human and animal studies on the vascular effects of CoQ. We then focus on endothelial dysfunction in type 2 diabetes and the possible impact on this condition of antioxidants and nutritional supplements, and in particular the therapeutic effects of CoQ. The effect of CoQ(10) on endothelial dysfunction in ischemic heart disease is also reviewed together with recent data highlighting that treatment with CoQ(10) increases extracellular SOD activity.     

Therapy with coenzyme Q10 of patients in heart failure who are eligible or ineligible for a transplant.

Twenty years of international open and seven double blind trials established the efficacy and safety of coenzyme Q10 (CoQ10) to treat patients in heart failure. In the U.S., ca. 20,000 patients under 65 years are eligible for transplants, but donors are less than 1/10th of those eligible, and there are many more such patients over 65, both eligible and ineligible. We treated eleven exemplary transplant candidates with CoQ10; all improved; three improved from Class IV to Class I; four improved from Classes III-IV to Class II; and two improved from Class III to Class I or II. After CoQ10, some patients required no conventional drugs and had no limitation in lifestyle. The marked improvement is based upon correcting myocardial deficiencies of CoQ10 which improve mitochondrial bioenergetics and cardiac performance. These case histories, and very substantial background proof of efficacy and safety, justify treating with CoQ10 patients in failure awaiting transplantation.     

Overview of the use of CoQ10 in cardiovascular disease.

The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5 micrograms/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.     

Complex Biventricular Pacing - A Case Series

It is established that cardiac resynchronisation therapy (CRT) reduces mortality and hospitalisation and improves functional class in patients with NYHA class 3-4 heart failure, an ejection fraction of ≤ 35% and a QRS duration of ≥ 120ms. Recent updates in the American guidelines have expanded the demographic of patients in whom CRT may be appropriate. Here we present two cases of complex CRT; one with a conventional indication but occluded central veins and the second with a novel indication for CRT post cardiac transplant.     

Diabetes mellitus and cardiac function

Cardiovascular complications are the most common causes of morbidity and mortality in diabetic patients. Coronary atherosclerosis is enhanced in diabetics, whereas myocardial infarction represents 20% of deaths of diabetic subjects. Furthermore, re-infarction and heart failure are more common in the diabetics. Diabetic cardiomyopathy is characterized by an early diastolic dysfunction and a later systolic one, with intracellular retention of calcium and sodium and loss of potassium. In addition, diabetes mellitus accelerates the development of left ventricular hypertrophy in hypertensive patients and increases cardiovascular mortality and morbidity. Treating the cardiovascular problems in diabetics must be undertaken with caution. Special consideration must be given with respect to the ionic and metabolic changes associated with diabetes. For example, although ACE inhibitors and calcium channel blockers are suitable agents, potassium channel openers cause myocardial preconditioning and decrease the infarct size in animal models, but they inhibit the insulin release after glucose administration in healthy subjects. Furthermore, potassium channel blockers abolish myocardial preconditioning and increase infarct size in animal models, but they protect the heart from the fatal arrhytmias induced by ischemia and reperfusion which may be important in diabetes. For example, diabetic peripheral neuropathy usually presents with silent ischemia and infarction. Mechanistically, parasympathetic cardiac nerve dysfunction, expressed as increased resting heart rate and decreased respiratory variation in heart rate, is more frequent than the sympathetic cardiac nerve dysfunction expressed as a decrease in the heart rate rise during standing.     

Simvastatin decreased coenzyme Q in the left ventricle and skeletal muscle but not in the brain and liver in L-NAME-induced hypertension

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (statins) have been proven to reduce effectively cholesterol level and morbidity and mortality in patients with coronary heart disease and/or dyslipoproteinemia. Statins inhibit synthesis of mevalonate, a precursor of both cholesterol and coenzyme Q (CoQ). Inhibited biosynthesis of CoQ may be involved in some undesirable actions of statins. We investigated the effect of simvastatin on tissue CoQ concentrations in the rat model of NO-deficient hypertension induced by chronic L-NAME administration. Male Wistar rats were treated daily for 6 weeks with L-NAME (40 mg/kg) or with simvastatin (10 mg/kg), another group received simultaneously L-NAME and simvastatin in the same doses. Coenzyme Q(9) and Q(10) concentrations were analyzed by high performance liquid chromatography. L-NAME and simvastatin alone had no effect on CoQ concentrations. However, simultaneous application of L-NAME and simvastatin significantly decreased concentrations of both CoQ homologues in the left ventricle and slightly decreased CoQ(9) concentration in the skeletal muscle. No effect was observed on CoQ level in the liver and brain. We conclude that the administration of simvastatin under the condition of NO-deficiency reduced the level of CoQ in the heart and skeletal muscle what may participate in adverse effect of statins under certain clinical conditions.     

Thrombopoietin upregulates nucleolin mRNA and protein in thrombopoietin-dependent megakaryocytic cell line,UT-7/TPO

In a randomized, double-blind, controlled trial, the effects of oral treatment with coenzyme Q10 (CoQ10, 120 mg/day), a bioenergetic and antioxidant cytoprotective agent, were compared for 1 year, on the risk factors of atherosclerosis, in 73 (CoQ, group A) and 71 (B vitamin group B) patients after acute myocardial infarction (AMI). After 1 year, total cardiac events (24.6 vs. 45.0%, p < 0.02) including non-fatal infarction (13.7 vs. 25.3%, p < 0.05) and cardiac deaths were significantly lower in the intervention group compared to control group. The extent of cardiac disease, elevation in cardiac enzymes, left ventricular enlargement, previous coronary artery disease and elapsed time from symptom onset to infarction at entry to study showed no significant differences between the two groups. Plasma level of vitamin E (32.4 ± 4.3 vs. 22.1 ± 3.6 umol/L) and high density lipoprotein cholesterol (1.26 ± 0.43 vs. 1.12 ± 0.32 mmol/L) showed significant (p < 0.05) increase whereas thiobarbituric acid reactive substances, malondialdehyde (1.9 + 0.31 vs. 3.1 + 0.32 pmol/L) and diene conjugates showed significant reduction respectively in the CoQ group compared to control group. Approximately half of the patients in each group (n = 36 vs. 31) were receiving lovastatin (10 mg/day) and both groups had a significant reduction in total and low density lipoprotein cholesterol compared to baseline levels. It is possible that treatment with CoQ10 in patients with recent MI may be beneficial in patients with high risk of atherothrombosis, despite optimal lipid lowering therapy during a follow-up of 1 year. Adverse effect of treatments showed that fatigue (40.8 vs. 6.8%, p < 0.01) was more common in the control group than CoQ group.     

Asymmetrical dimethylarginine--more sensitive than NT-proBNP to diagnose heart failure in adults with congenital heart disease

Background

Chronic heart failure is an important cause for morbidity and mortality in adults with congenital heart disease (ACHD). While NT-proBNP is an established biomarker for heart failure of non-congenital origin, its value in ACHD has limitations. Asymmetrical dimethylarginine (ADMA) correlates with disease severity and independently predicts adverse clinical events in heart failure of non-congenital origin. Its role in ACHD has not been investigated.

Methods

In 102 patients ADMA and NT-proBNP were measured and related to NYHA class, systemic ventricular function and parameters of cardiopulmonary exercise testing.

Results

In contrast to NT-proBNP ADMA differentiated between NYHA classes I-III. Both, ADMA and NT-proBNP showed a good correlation with parameters of cardiopulmonary exercise testing with comparable receiver-operating characteristic curves for identifying patients with severely limited cardiopulmonary exercise capacity.

Conclusion

ADMA seems to be a better biomarker than NT-proBNP for the assessment of NYHA class and as a good as NT-proBNP for the estimation of maximum exercise capacity in adults with congenital heart disease. Its use in clinical routine should be evaluated.     

Debate: Statins should be used in patients with heart failure

Treatment to prevent progression of heart failure has been targeted to reverse the consequences of heart failure and to a lesser extent the cause – the atherosclerotic plaque itself. Less than 50% of patients with heart failure are treated with lipid intervention. Heart failure (New York Heart Association [NYHA] functional classes I and II) is associated with an increase in low-density lipoproteins (LDL) and triglycerides while high-density lipoproteins (HDL) is lowered. In NYHA class IV, cholesterol is reduced due to depressed production in the liver. Although lipoproteins, especially LDL and HDL, may have some protective effect in binding and neutralising endotoxins released from the intestine during terminal heart failure, observational studies in patients with heart failure strongly suggest that lipid modification with statins may reduce progression of heart failure as well as reducing heart failure mortality.     

Atrial pacing for rhythm control of atrial fibrillation

After atrial fibrillation (AF) develops, the first step is to search for and treat underlying (heart) s. Thereafter, AF should be treated. This includes prevention of cardiovascular morbidity and mortality, especially vascular events, and reduction of symptoms.1 The latter may be obtained by two treatment strategies: rhythm-control and/or rate-control treatment. Recent randomised trials have shown that rate control is not inferior to rhythm control with regard to cardiovascular morbidity and mortality.2 In these studies, predominantly elderly patients with underlying heart s (especially hypertension) were included. Patients with (severely) symptomatic AF and advanced heart failure were excluded. Since then, rate-control treatment has been adopted more frequently, even as first-choice therapy, especially in the elderly.     

Coenzyme Q10: is there a clinical role and a case for measurement?

Coenzyme Q(10) (CoQ(10)) is an essential cofactor in the mitochondrial electron transport pathway, and is also a lipid-soluble antioxidant. It is endogenously synthesised via the mevalonate pathway, and some is obtained from the diet. CoQ(10) supplements are available over the counter from health food shops and pharmacies. CoQ(10) deficiency has been implicated in several clinical disorders, including but not confined to heart failure, hypertension, Parkinson's disease and malignancy. Statin, 3-hydroxy-3- methyl-glutaryl (HMG)-CoA reductase inhibitor therapy inhibits conversion of HMG-CoA to mevalonate and lowers plasma CoQ(10) concentrations. The case for measurement of plasma CoQ(10) is based on the relationship between levels and outcomes, as in chronic heart failure, where it may identify individuals most likely to benefit from supplementation therapy. During CoQ(10) supplementation plasma CoQ(10) levels should be monitored to ensure efficacy, given that there is variable bioavailability between commercial formulations, and known inter-individual variation in CoQ(10) absorption. Knowledge of biological variation and reference change values is important to determine whether a significant change in plasma CoQ(10) has occurred, whether a reduction for example following statin therapy or an increase following supplementation. Emerging evidence will determine whether CoQ(10) does indeed have an important clinical role and in particular, whether there is a case for measurement.     

Multifactorial approach and superior treatment efficacy in renal patients with the aid of nurse practitioners. Design of The MASTERPLAN Study [ISRCTN73187232]

Background

Patients with chronic kidney disease (CKD) are at a greatly increased risk of developing cardiovascular disease. Recently developed guidelines address multiple risk factors and life-style interventions. However, in current practice few patients reach their targets. A multifactorial approach with the aid of nurse practitioners was effective in achieving treatment goals and reducing vascular events in patients with diabetes mellitus and in patients with heart failure. We propose that this also holds for the CKD population.

Design

MASTERPLAN is a multicenter randomized controlled clinical trial designed to evaluate whether a multifactorial approach with the aid of nurse-practicioners reduces cardiovascular risk in patients with CKD. Approximately 800 patients with a creatinine clearance (estimated by Cockcroft-Gault) between 20 to 70 ml/min, will be included. To all patients the same set of guidelines will be applied and specific cardioprotective medication will be prescribed. In the intervention group the nurse practitioner will provide lifestyle advice and actively address treatment goals. Follow-up will be five years. Primary endpoint is the composite of myocardial infarction, stroke and cardiovascular mortality. Secondary endpoints are cardiovascular morbidity, overall mortality, decline of renal function, change in markers of vascular damage and change in quality of life. Enrollment has started in April 2004 and the study is on track with 700 patients included on October 15th, 2005. This article describes the design of the MASTERPLAN study.     

Early mitral valve repair versus watchful waiting in patients with severe asymptomatic organic mitral regurgitation; rationale and design of the Dutch AMR trial, a multicenter, randomised trial

Background

Asymptomatic severe mitral valve (MV) regurgitation with preserved left ventricular function is a challenging clinical entity as data on the recommended treatment strategy for these patients are scarce and conflicting. For asymptomatic patients, no randomised trial has been performed for objectivising the best treatment strategy.

Methods

The Dutch AMR (Asymptomatic Mitral Regurgitation) trial is a multicenter, prospective, randomised trial comparing early MV repair versus watchful waiting in asymptomatic patients with severe organic MV regurgitation. A total of 250 asymptomatic patients (18–70 years) with preserved left ventricular function will be included. Intervention will be either watchful waiting or MV surgery. Follow-up will be 5 years. Primary outcome measures are all-cause mortality and a composite endpoint of cardiovascular mortality, congestive heart failure, and hospitalisation for non-fatal cardiovascular and cerebrovascular events. Secondary outcome measures are total costs, cost-effectiveness, quality of life, echocardiographic and cardiac magnetic resonance parameters, exercise tests, asymptomatic atrial fibrillation and brain natriuretic peptide levels. Additionally, the complication rate in the surgery group and rate of surgery in the watchful waiting group will be determined.

Implications

The Dutch AMR trial will be the first multicenter randomised trial on this topic. We anticipate that the results of this study are highly needed to elucidate the best treatment strategy and that this may prove to be an international landmark study.     

Cardioprotection by aldosterone receptor antagonism in heart failure. Part I. The role of aldosterone in heart failure

In recent years understanding of the role of aldosterone has expanded beyond the known classic effects of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine, and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a well-documented increase in aldosterone levels that occurs over several months during chronic treatment with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition, ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study" (RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a significant mortality reduction due both to decreased death from progressive heart failure and sudden cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of progressive heart failure. Although it is an effective antialdosterone agent, widespread use of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist, eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the sexual disturbances of spironolactone. Recently Eplerenone was successfully introduced for the treatment of hypertension and heart failure. Growing number of experimental studies are finding a broader role for Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred by ACE-I and/or AII receptor blockers.