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Supplements to Bolster Myocardial Function: Beyond Optimal Medical Therapy

James Kneller, MD, MSc, PhD, FHRS, CCDS
1535-2226
Electrophysiologists treat a cohort of arrhythmia patients, including those with resistant electrical instability (e.g., atrial fibrillation, ventricular tachycardia, PVCs) and others with a highly compromised myocardium who have failed medical therapy and proceed to ICD or CRT implantation. Pathological changes include both reversible and irreversible fibrosis, maladaptive autonomic remodeling, metabolic derangements, and cardiomyopathy.1,2 These patients frequently credit their electrophysiologist for the clinical benefit they experience, either because of a successful ablation, positive response to CRT, restoration of chronotropic competency with atrial pacing, or the wealth of diagnostic information provided by their device to guide therapy and help intercept future decompensations. It is the electrophysiologist who will continue to carefully assess patient status and adjust device parameters, considering additional beneficial interventions on an iterative basis. Beyond conventional therapies, additional compounds supporting myocardial function may be appropriate for both arrhythmia and heart failure (HF) patients, helping to compensate for arrhythmic vulnerability or a potentially reversible myopathy due to cellular metabolic deficiencies. Electrophysiologists may best appreciate the value of appropriate nutritive supplementation and extend this option to patients.

IMPROVING MYOCYTE FUNCTION

Optimal medical therapy protects the myocardium from adrenergic stress (beta blockers), adverse effects following activation of the renin-angiotensin-aldosterone system (ACE inhibitors, ARBs, spironolactone), as well as ongoing inflammation and progression of atherosclerosis (statins), promoting electrical quiescence and recovery of myocardial function. Beyond protection, certain combinations of nutritional supplements promise to improve myocyte function by addressing a variety of metabolic imbalances and deficiencies. Supplements represent a multibillion dollar industry. Many of our patients admit they already take a variety of supplements, often at considerable personal expense, and would appreciate some guidance. Clearly, our patients are looking beyond our recommendations and reaching for anything that may further relieve their symptoms. Although supplements are not presently considered standard of care, there is growing evidence for the benefit of certain agents. Large-scale, multicenter trials necessary for guideline inclusion are unlikely to be performed; nevertheless, physicians can direct patients based on the available evidence.
 
At our institution, we provide interested patients with a printed list of supplement recommendations. Patients are generally very receptive and appreciate that their doctor is considering “natural” remedies, understanding that these have not yet been evaluated by the U.S. FDA. A surprising number of patients now swear by our regimens, reporting improved well-being, energy, and activity levels, which are reason enough for us to continue. Cardiologist Dr. Stephen Sinatra (www.drsinatra.com) has been a longstanding proponent of the combination of coenzyme Q10, D-ribose, L-carnitine, and magnesium, calling these the “awesome foursome” of metabolic cardiology (Figure 1).3 Evidence supporting the use of these agents continues to build, including randomized trial data. Myocytes in congestive heart failure have undergone extensive metabolic remodeling, resulting in markedly reduced contractile reserve.4 Recovery is limited by substrate deficiencies, particularly in the setting of a pending decompensation. Supplementation may facilitate repletion of energy stores on which myocardial function and electrical quiescence depend.5 In this article, we share our supplement regimens, with rationale for each agent listed. Also included here are suggested doses for arrhythmia support (Table 1), heart failure (Table 2), and for otherwise healthy individuals (Table 3).
 
CoQ10
 
Coenzyme Q110 (CoQ110), also known as ubiquinone, is found in virtually all cells of the body, with highest concentrations in the myocardium (Figures 1, 2A, and 3A). CoQ10 is a powerful lipid-soluble antioxidant, playing a pivotal role in the synthesis of adenosine triphosphate (ATP) within the mitochondria, accounting for 95% of cellular energy.6 Age-related CoQ10 levels decline from peak levels, by 32% at age 40 and 57% at age 80, greatly limiting the potential for ATP generation.7 Statin therapy rapidly depletes CoQ10, contributing to adverse effects of statins such as exercise intolerance, myalgia, and myoglobinuria; therefore, CoQ10 supplementation may be advisable in patients taking statins.8 Low plasma CoQ10 has been shown to be an independent predictor of mortality in HF, suggesting supplementation may be particularly beneficial in this setting.5
 
The Q-SYMBIO trial represents a prospective, randomized, double-blind, placebo-controlled, multicenter evaluation of CoQ10 as an adjunctive treatment of chronic HF focusing on changes in SYMptoms, BIomarker status, and long-term Outcome.9 This trial was conducted pursuant to earlier observations that CoQ10 may improve LV contractility and functional status in patients awaiting heart transplant.10,11 In Q-SYMBIO, 420 patients with moderate to severe HF (baseline LVEF was 31±10% in both groups) were randomized to either CoQ10 100 mg 3 times daily or placebo, in addition to standard therapy. Serum CoQ10 was increased threefold in the treatment group. There was a reduction of N-terminal pro-B type natriuretic peptide (NT-proBNP; 20%) versus a proportional rise in the placebo group (12%) after 16 weeks, with greater improvement in NYHA class (58% versus 45%, respectively) after 2 years in the treatment group. Treatment with CoQ10 also significantly reduced cardiovascular mortality (9% vs 16%; P=0.026), all-cause mortality (10% vs 18%; P=0.018), and HF hospitalization (P=0.033). There was no significant change in LVEF.9
 
Ribose
Ribose is a five-carbon sugar essential to the structure of ATP and therefore to cellular energy (Figures 1, 2B, and 3B), and is highly conserved for the purpose of maintaining and rebuilding the ATP pool. Dietary sources are negligible, and the majority of ribose is obtained through a slow, multi-step biosynthetic pathway within myocytes. Ribose is depleted during times of metabolic stress, with the cumbersome process of biosynthesis limiting repletion of the energy pool and restoration of myocardial function. Supplemental D-ribose is readily absorbed through the gut, and >90% is utilized by tissues.3
 
Administration of D-ribose 5 grams, 3 times daily for 3 weeks, has demonstrated objective improvement in diastolic function, including a shortened E-wave deceleration (235±64 vs 196±42 ms; P=0.002) by echocardiography and a reduction of left atrial dimension (54±20 vs 47±18 ml; P=0.02), with enhanced atrial contribution to left ventricular filling (40±11 vs 45±9%; P=0.02).12 These changes were associated with enhanced quality of life by a SF-36 questionnaire (417±118 vs 467±128; P≤0.01). Similarly, D-ribose 5 grams, 3 times daily for 8 weeks, demonstrated a significant improvement in ventilatory parameters (VO2, tidal volume/VCO2) at anaerobic threshold, with improvement in functional status among NYHA class III-IV patients (n=16).13 Most recently, D-ribose 5 grams, 3 times daily for 6 weeks, demonstrated a similar improvement in diastolic function and cardiopulmonary testing in patients with NYHA II-IV heart failure and preserved LVEF (n=11), with improved tissue Doppler velocity (E´) demonstrated in 64% of patients, and improvement in the ratio of early diastolic filling velocity (E) to early annulus relaxation velocity (E´) in 45% of patients. Four patients also had an improvement in their maximum predicted VO2 values. Benefit was sustained following discontinuation of D-ribose.14
 
Carnitine
Fatty acids are the preferred source of metabolic energy for striated muscle, accounting for 60% of myocyte ATP production (Figures 1, 2C, and 3C). Carnitine plays a pivotal role in shuttling fatty acids across the mitochondrial membrane.15 It is the only carrier with this capability, and an abundance of L-carnitine within myocytes is a strict requirement for life. Carnitine is an amino acid that is prevalent in meat, for which it is named (Latin carne). Carnitine is derived from two amino acids, lysine and methionine, with biosynthesis occurring in a series of reactions utilizing niacin (vitamin B3), vitamin B6, vitamin C, and iron as cofactors. Many adults may be on a continuum between mild and overt deficiencies, with vegetarians being particularly at risk, as quantities of carnitine in plants are minimal and biosynthesis in humans is markedly less than that of other mammals.3
 
Carnitine deficiency may result in an isolated cardiomyopathy as well as electrical instability by causing short QT syndrome and increased QT dynamicity, which may result in ventricular fibrillation, even in the absence of any overt cardiomyopathy.15-17 There is evidence that L-carnitine supplementation prevents the development of fibrosis in hypertensive heart failure with preserved LVEF.18 A randomized study in patients with dilated cardiomyopathy and NYHA III-IV functional status found that L-carnitine (2 grams/day) may reduce cardiovascular and all-cause mortality at three years.19 In addition, L-carnitine may improve coronary blood flow and myocardial oxygen consumption during exercise in patients with obstructive coronary artery disease, and has been found to reduce PVC and tachyarrhythmias early post myocardial infarction.20,21 Furthermore, L-carnitine supplementation 2 grams daily for 12 weeks has demonstrated improvement in walking performance and muscle strength in patients with peripheral vascular disease and claudication.22
 
Magnesium
 
All enzymatic reactions involving ATP have an absolute magnesium requirement (Figures 1, 2D, and 3D). Magnesium is the second most common intracellular cation in the human body (after potassium), and is a cofactor for >300 enzymatic reactions. The human body contains 20-25 grams of magnesium, between the mineral phase in bone (65%), sequestered in muscle (34%), and within plasma and interstitial fluids (1%).3 Serum magnesium is highly conserved, with magnesium recruited from muscle and bone to preserve serum levels, such that serum levels are poorly predictive of tissue stores. Cardiomyopathy patients frequently display markedly reduced tissue levels of magnesium despite relatively preserved serum concentrations, and it is estimated that the majority of cardiac patients in the United States are magnesium deficient.23 Alcohol, caffeine, and diuretics promote excessive urinary excretion of magnesium, with the diuretic effect exacerbated in diabetes patients. In addition, chronic use of H2 receptor blockers (e.g., ranitidine) stop absorption of dietary magnesium. Physical and emotional stress results in excess cortisol secretion, which also promotes magnesium loss. Furthermore, soil depletion has reduced levels in fruits and vegetables, and increased use of soft and bottled water has diminished drinking water as a reliable source of magnesium.3
 
Magnesium deficiency is known to result in injury to heart muscle and myocardial necrosis, which is likely attributable to loss of protection from free-radical damage.24 Beyond cardiomyopathy, low magnesium levels promote endothelial dysfunction and generate a pro-inflammatory, pro-thrombotic, and pro-atherogenic environment promoting cardiovascular disease.25 We are all familiar with the utility of magnesium infusion in the setting of torsades and drug-induced long QT. Magnesium infusion (2 to 3 grams over 1 minute, followed by 10 grams over 5 hours) was also found to be an effective adjunctive agent for controlling ventricular fibrillation or malignant ventricular tachycardia in other settings.26,27 Low dietary magnesium also increases supraventricular and ventricular ectopy; magnesium infusion is useful in controlling atrial fibrillation with rapid ventricular response in both deficient and nondeficient patients.28,29

DOSAGE AND SOURCES

Dosing recommendations are obtained from available studies and recommendations made by Dr. Sinatra. Dose recommendations for arrhythmia control (Table 1), heart failure (Table 2), and health maintenance in otherwise healthy individuals (Table 3) are given. CoQ10 and D-ribose (we recommend this in powder form) are available for purchase online. Two level teaspoons are equivalent to a 5-gram dose. The powder tastes sweet, and patients frequently use it in their coffee. When a sustained positive benefit is maintained, a lower maintenance dose may be determined. An excellent form of supplemental carnitine is L-carnitine fumarate. Magnesium citrate or magnesium malate are good forms of supplemental magnesium. Magnesium oxide should be avoided due to limited absorption. Sample retail prices per month for a health maintenance program (Table 3) include CoQ10 (100 mg daily) $19.99/month, D-ribose (5 grams daily) $26.66/month, L-carnitine (1000 mg daily) $21.66/month, magnesium (675 mg daily) $8.25/month, for a total regimen cost of $76.56. Discounts and rebates occur frequently. We suggest www.swansonvitamins.com and www.iherb.com for quality products that are reasonably priced. It is important to note that we receive no financial incentive whatsoever from any online source.

SAFETY

CoQ10 is generally safe with no significant adverse reactions and very few drug interactions, even at high doses. Long-term usage may cause epigastric discomfort (0.39%), decreased appetite (0.23%), nausea (0.16%), diarrhea (0.12%), and elevated lactate dehydrogenase (LDH) or serum glutamic oxaloacetic transaminase (SGOT) (rare).3 Because data is limited, we do not recommend CoQ10 to pregnant women, nursing mothers, or to very young children. In addition, there are no known adverse reactions or drug interactions associated with ribose, likely because the biochemistry of ribose in tissue is so specific.3 It is recommended not to take D-ribose on an empty stomach. Some concern has been expressed that D-ribose may lower blood sugar, and should be introduced slowly in diabetics, where some reduction in diabetes medications may be necessary. Recent research shows how dietary sources of carnitine in patients with significant meat consumption may interact with the bacterial flora to produce substances promoting atherosclerosis and renal fibrosis. It is uncertain whether these findings also apply to supplemental L-carnitine; nevertheless, for patients who frequently eat meat, we only allow for short courses of L-carnitine as a last resort for refractory symptoms.30 The recommended dietary allowance for magnesium is 320 mg daily.28 Supplemental magnesium may cause diarrhea, and we encourage the highest tolerated dose. For patients with significant renal dysfunction, we ask patients to first discuss with their nephrologist. For patients taking warfarin, we recommend vigilance in INR monitoring, as minor dose adjustments may be necessary.
 
Our patient handouts contain the following disclaimer and precaution:
 
Disclaimer: The suggested supplements have not been evaluated by the Food & Drug Administration (FDA). Furthermore, commercially available supplements have not been evaluated and therefore quality control of commercially available products remains uncertain. Despite limited data for the use of these agents, many of our arrhythmia and heart failure patients have experienced benefit, while others have not. Benefit has been observed for products obtained from the online sources listed. Alternately, we suggest to ask your pharmacist for reliable sources of health supplements.
 
Warning: For patients taking warfarin, please have your INR checked within 1 week of starting any new medications or supplements. A minor dose adjustment may be necessary. If you are diabetic, please introduce D-ribose slowly and monitor for any changes in your blood sugar, which may require adjustment of your medications for diabetes. For patients who regularly eat meat, we advise to only supplement with L-carnitine if your response to the other agents listed is unsatisfactory, and for a maximum of three months. If magnesium supplementation results in diarrhea, find the lowest tolerated dose. Discuss any other side effects with your doctor and consider stopping the problematic supplement.

SUMMARY

I have personally experienced benefit from the supplements discussed here, and multiple patients from our practice are convinced of the benefit for arrhythmia (AF, VT, and PVCs), heart failure, and improved statin tolerance. It is uncertain which patients may respond to each of the supplements discussed, although certain patients have reported a definite positive response to certain agents. Some patients feel CoQ10 brought the greatest benefit, while others preferred D-ribose. Many of our patients already spend a considerable amount of money on supplements, and appreciate receiving guidance from their electrophysiologist. Supplements must be purchased over the counter or online.
 
Disclosure: The author has no conflicts of interest to report regarding the content herein.  

References

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