Heart failure, TMAO/L-Carnitine, Magnesium, CoQ10, D-Ribose, Taurine, Berberine, External counter-pulsation therapy, H2RA therapy

Heart Failure – A Metabolic Approach

By Joel Kahn, MD, and Daniel Chong, ND

Heart failure (HF) is a syndrome of cardiac dysfunction in which the heart can no longer pump enough blood around the body to support its organs and systems. Identified risk factors for HF include conditions that damage the heart, such as hypertension, coronary heart disease, heart attack, and diabetes; also lifestyle factors such as smoking, obesity, lack of exercise, and a high-fat and/or high-sodium diet.¹ While HF may occasionally come on suddenly for certain reasons, the majority of cases are typically chronic and worsen over time without care. For the purposes of this article, HF will refer to chronic HF specifically. If untreated or poorly treated HF continues to worsen, it will eventually become congestive heart failure (CHF), in which fluid may back up into the lungs, liver, gastrointestinal tract, arms, and/or legs. HF afflicts over five million persons in the United States, at a cost of over $30 billion yearly.² It also accounts for over 1 million hospital admissions yearly and is the cause of one out of every nine deaths.² With over 800,000 hospital admissions for HF occurring each year, despite only a minority ending up truly requiring acute care, hospital initiatives have been launched to decrease readmissions for HF within the first 30 days of discharge.³

The Awesome Foursome

An orthomolecular approach to improving energy production in the heart was proposed at least a few decades ago.^4,5 However, Dr Stephen Sinatra may be given credit for popularizing a metabolic therapy approach to HF in 1990s when he began using supplements in his cardiology practice to restore cardiac energy production. Based on earlier research findings, Dr Sinatra recommended coenzyme Q10 (CoQ10), L-carnitine, and magnesium, and identified beneficial responses.⁶ His aforementioned colleague, Dr James Roberts, suggested adding D-ribose powder to the combination, and the “Awesome Foursome” was created, as detailed in their book.⁷ These agents will be featured here as primary therapeutic interventions that seek to address the unique needs of this crucial organ.

Coenzyme Q10

An antioxidant and critical component of cardiac energy production, CoQ10 is concentrated in healthy heart muscle and can become deficient in the myocardiocytes of patients suffering from HF.⁸ The most definitive evidence to date can be found in the Q-SYMBIO study, which was a placebo-controlled, double-blind, randomized trial of patients with chronic HF.⁹ In this study, 420 HF patients were randomized to CoQ10 (100 mg TID) or placebo and followed for two years. At 16 weeks, there were no differences between the two groups in heart function, six-minute walk test, or circulating biomarkers (brain natriuretic peptide, or BNP). However, the long-term, primary endpoint of a composite of major adverse cardiovascular events was reached by 26% of the placebo, vs only 15% of the CoQ10 group.⁹ In addition, cardiovascular mortality, all-cause mortality, and incidence of hospital stays for chronic HF were significantly lower in the CoQ10 treatment arm.

D-Ribose

D-ribose shares the structure of the backbone of ATP and is a 5-carbon sugar, affording it some unique properties that show promise in the treatment of HF. Animal research has shown that heart cells subjected to ischemia (acute or chronic) experience a reduction in ATP production capacity.¹⁰ What’s more, while recovery from the effects of ischemia is typically sluggish due to certain rate-limiting enzymatic steps in the pentose phosphate pathway (PPP), supplemental D-ribose appears able to enter the PPP and bypass the rate-limiting steps, leading to improved efficiency of ATP production.^10,11

Importantly, human clinical trials have shown related effects. A 1992 study of stable but severe coronary artery disease patients found that supplementing these patients with D-ribose enabled them to increase their “ischemic threshold” and exercise longer with fewer symptoms.¹² Additional studies have demonstrated similar effects of D-ribose on the enhancement of depleted cellular energy stores following ischemia.¹³ The same authors also reviewed preclinical and clinical trials examining D-ribose that demonstrated its ability to improve diastolic heart function, quality of life, and ventilatory parameters.¹⁴

Magnesium

Magnesium is a crucial cofactor in many pathways involved with cardiac bioenergetics, yet it is understudied (and underutilized) in conventional cardiology.¹⁵ Compounding this problem, recent research has shown that nearly half of all Americans do not consume recommended amounts of magnesium from the foods they are eating.¹⁵ The likely deficiency created by such poor intake is then amplified by various pharmaceutical agents frequently prescribed to these same people, such as certain types of antacids, antibiotics, and birth control pills. HF patients – the very people who may need magnesium the most – are also frequently prescribed medications for their condition that further worsen the likelihood of magnesium deficiency, namely diuretics and the cardiac glycoside, digoxin.¹⁶ It is interesting to note in one study that higher serum magnesium levels in patients hospitalized for HF were actually associated with increased all-cause mortality.¹⁷ However, after adjusting for baseline differences, this association was no longer significant, and factors such as advanced age and poor renal function were considered more likely than magnesium to be related to the excess risk.¹⁷

Given that magnesium has effects on over 300 enzymatic processes and is the second most abundant intracellular cation (next to potassium) in the human body, the mineral certainly plays a significant role in human health beyond its impact on heart function.¹⁸ Key heart-related functions of magnesium, all of which would impact HF, include impacting potassium’s role in electrical conductance and modulating heart cell function by contributing to the maintenance of the sodium/potassium and calcium gradients of the cardiac cell membrane. Thus, through various means, magnesium exerts a powerful influence on the electrical and contractile functions of the myocardium.¹⁸ Its physiological contributions to cardiac function, in turn, suggest the important role a deficiency would play in HF, and an equally important role optimization of tissue magnesium levels would play in its treatment. Research in support of this conclusion has thus far been promising, including cardiac arrhythmias—frequently seen in HF patients—responding positively to both long-term oral supplementation¹⁹ and acute IV administration of magnesium.²⁰

A recent double-blind, placebo-controlled study also showed magnesium orotate supplementation over the course of one year to improve survival rate in severe HF patients by nearly 25%, while also significantly improving their symptoms and quality of life.²¹

L-Carnitine

Considering the significant impact dysfunctional mitochondria appear to have in the pathogenesis of HF, as well as research on its use thus far, L-carnitine should be a consideration if other therapeutic interventions do not yield sufficient results. However, new data suggests that reevaluation of this perspective may be appropriate.²² Researchers at the Cleveland Clinic recently commenced a hunt for new dietary factors and metabolites related to developing clogged arteries, or atherosclerosis, and eventually published data in 2013, identifying a compound known as trimethylamine-N-oxide or TMAO, which can rise in the bloodstream after meals, and can be considered pro-atherogenic, or plaque-causing.²³ The study detailed how, in the omnivores studied, the amino acid L-carnitine, found in meat (especially red meat) and choline, found mainly in egg yolks, could be metabolized by the gut microbiome into the metabolite TMA, which was then converted into TMAO in their livers.

The study also found a strong correlation between the blood levels of TMAO and rates of atherosclerosis and kidney disease. Interestingly, they also published more data that year, this time involving volunteers eating a vegan diet, to see if they would also produce TMAO after consuming L-carnitine, like the omnivores did.²⁴ To accomplish this, the vegan volunteers agreed to eat steak like the omnivores did (for research purposes only). Unlike the omnivores however, the vegans produced far less TMAO after the steak challenge. From this data, the researchers hypothesized that the microbiome of vegans was different than omnivores and does not produce TMA (and subsequently TMAO) when exposed to L-carnitine, as observed in the omnivores. They reported that “the present studies suggest reduction in carnitine and total choline ingestion with attendant reductions in TMAO levels may contribute to the cardiovascular health benefits observed in vegan/vegetarians.”

Interestingly, published data relating TMAO levels and cardiovascular health also appear to be of interest in the treatment of congestive heart failure. In a review of TMAO and outcomes of cardiovascular disease, TMAO levels were significantly associated with a 1.18 to 1.79-fold increased mortality rate in people with chronic heart failure.²⁵ Also of note, in patients with type 2 diabetes, higher TMAO levels were significantly associated with a higher overall mortality rate of 2.1 to 2.7-fold.

In another study of TMAO metabolites and congestive heart failure, 22 patients admitted for congestive heart failure and 11 age-, sex-, and comorbidity-matched, hospitalized control subjects without a history of HF were studied.²⁶ Plasma concentration of TMAO was found to be increased in heart failure patients compared to those without heart failure.

Again, these findings provide important evidence that, while L-carnitine supplementation is potentially therapeutic for people with HF, it should be used with caution, and if included in a treatment plan, TMAO levels should be closely monitored over time.

Additional Supplements and Other Alternative Therapies

Taurine is a sulfur-containing amino acid that may augment the role of conventional medications for HF because of its role in inhibiting the harmful effects of catecholamines and angiotensin II in HF.²⁷ In a randomized study of placebo vs taurine supplementation in HF, at a dose of only 500 mg TID over two weeks, various aspects of exercise performance increased significantly in patients receiving the active supplement.²⁸

Berberine is a quaternary ammonium salt found in medicinal plants such as goldenseal, Oregon grape root, and coptis. In a study of 156 patients with CHF, in which all patients were given conventional medications for the disease, those who were also given 1.2-2 g of berberine per day experienced improvements in ejection fraction, exercise capacity, and dyspnea, as well as a decrease in the frequency of complex premature ventricular contractions (PVCs), compared to the placebo group.²⁹ Long-term follow-up also revealed a significant decrease in mortality rate in the berberine-supplemented group.²⁹

Various known physiological effects of berberine, including inhibition of smooth muscle contraction, reduction of inflammation, platelet aggregation inhibition, and inhibition of ventricular tachyarrhythmias, may help explain its apparently potent effects on HF patients.^30,31 Nonetheless, there is some suggestion that long-term use of berberine may inhibit cytochrome P450, resulting in various potentially negative effects on the clearance of drugs and possibly other toxins; thus, caution is warranted until further study can elucidate the impact of such findings.³²

External Counter-Pulsation Therapy

One therapy for congestive heart failure that is under recognized and rarely recommended is external counter-pulsation (ECP). Years ago, a device known as an intra-aortic balloon pump, or IABP, was developed to aid failing hearts. While effective, it required insertion of a catheter inside of an artery in order to provide a rhymical inflation of a balloon pump timed to the heartbeat. Soon, however, researchers in China and subsequently New York found they could duplicate the support of the failing heart with external pressure cuffs and external counter-pulsation (ECP) was developed. Although first developed for anginal chest pain in the setting of badly blocked heart arteries, studies extended the evaluation to include congestive heart failure.

A registry was published that involved treating patients with advanced heart failure with ECP. Article co-author, Dr. Joel Kahn, participated in those early studies. Data were retrospectively analyzed from 127 New York Heart Association class II-IV CHF patients. The patients were divided into three groups based on the pressures applied during ECP. In the year following ECP using the most intense therapy, all-cause mortality was only 1.9% (one of 54 patients), whereas over the same time period the mortality rate was 7-8% with the lower pressure ECP group. For the Low, Mid, and High ECP pressure therapy groups, respectively: 1) average left ventricular ejection fractions increased 23%, 20%, and 17%; 2) NYHA class declined 36%, 29%, and 29%; and 3) all-cause hospitalizations, including terminal admissions, were reduced 86%, 83%, and 57% in the year following ECP therapy from the prior year. Also of note, there were no adverse effects or withdrawals from the ECP therapy and no significant difference in sex-based outcomes.

H2RA Therapy

Another novel therapy of congestive heart failure is to utilize the H2 histamine antagonist ((H2RAs) receptor system which exists on heart tissue.³³ Histamine H2 antagonists have long been suggested to have beneficial effects on congestive heart failure (CHF). However, full agreement about the cardioprotective effects of H2RAs is still not reached yet. A total of 10 studies (472 participants) were included in a meta-analysis. H2RAs exhibited significant negative inotropic and chronotropic effects to reduce heart rate. Furthermore, although H2RAs did not affect the blood pressure in health volunteers, they significantly decreased the blood pressure of CHF patients. Additionally, H2RAs were also associated with significant increase in pre-ejection period and the ratio of pre-ejection period to left ventricular ejection time. In summary, the findings showed that H2RAs exerted negative inotropic and chronotropic effects to reduce heart rate and blood pressure, which, similar to beta-adrenergic receptor blockers, might decrease myocardial oxygen demand and eventually result in improvement of CHF symptoms.

If you have CHF, and you decide with your doctor to try adding H2RAs to your treatment arsenal, please also be aware there is limited data suggesting the possibility that this class of medication may negatively affect B12 absorption. Therefore, it would be prudent to consider monitoring serum B12 and/or methylmalonic acid (MMA) levels if taking long term.

Case Study

AB is currently an 87-year-old woman who lives independently and enjoys friends and family events. Three years ago, she was admitted to a local hospital with shortness of breath, fatigue, and edema, and was diagnosed with congestive heart failure.

Exam and Treatment: An echocardiogram identified an enlarged heart, a reduced ejection fraction of 35%, and moderately severe mitral regurgitation. A coronary angiogram showed normal arteries. She was begun on diuretics, carvedilol, and an ACE inhibitor. She was considered for a mitral valve clipping to reduce the amount of valve insufficiency. After several consultations for this new procedure, she consulted with Dr. Kahn, and a metabolic cardiology program was instituted on top of the standard medications. She began CoQ10 (400 mg/d), L-carnitine (500 mg BID), D-ribose powder (5 g TID), and magnesium taurate (250 mg/d).

Follow-up: AB remained free of dyspnea over the coming months, and a follow-up echocardiogram four months later demonstrated her left ventricle to be of normal size, her ejection fraction to be 60%, and only mild mitral insufficiency remaining. Now, almost three years later, she remains only on carvedilol plus the metabolic supplements, and is free of CHF.

Summary

Heart failure is a serious disorder that can cause great suffering and shorten life. Current therapies with lifestyle alterations and pharmaceutical agents are of value but can simultaneously worsen certain aspects of the problem and often leave patients limited in quality of life. A thorough and detailed understanding of myocardial bioenergetics, plus a decades-long history of data—some from rigorously performed studies—now exists, providing strong support for the use of nutraceuticals in support of this all too common condition. In fact, for these reasons, coupled with the fact that such therapeutic agents have almost no side effects and rarely interact negatively with pharmaceutical prescriptions, HF can be considered an ideal candidate for this therapeutic approach. In addition, advanced lab tests (eg, NT-proBNP)³⁴ along with ejection fraction testing afford physicians the means necessary to properly and objectively monitor patients and ensure they are experiencing a positive response to the prescribed therapies. As highlighted in the case study featured in this review, an integrated approach can garner excellent results, even in relatively severe cases, improving myocardial bioenergetics, left ventricular function, and quality of life.

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