W.H. Wilson Tang , MD ∗ ( tangw{at}ccf.org ) and Stanley L. Hazen , MD, PhD ↵ ∗ Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, Ohio 44195

We thank Mr. McCarty and Dr. DiNicolantonio for their interest and their opinions regarding our discovery of a previously unappreciated role for the potential involvement of a specific gut microbiota–dependent pathway leading to higher circulating trimethylamine N-oxide (TMAO) levels that were associated with a worse prognosis independent of traditional cardiorenal indices and risk factors. We believe that the observed associations are hypothesis generating and call for further rigorous mechanistic investigations. Our reported association between elevated TMAO levels and an adverse prognosis among subjects with heart failure was recently validated in independent cohorts of patients, including among subjects with chronic systolic heart failure (left ventricular ejection fraction ≤35%) with well-characterized echocardiographic assessments (1), as well as in a Norwegian cohort with similar observations (2). There are also emerging data to demonstrate the potential interplay between TMAO and other neurohormonal systems that are implicated in the pathogenesis of heart failure and other cardiovascular diseases (3). Thus, a rapidly growing body of evidence suggests that elevated TMAO levels are strikingly linked to an adverse prognosis in heart failure patients, and further studies are warranted to determine whether the observed associations are causal, which may point toward important potential nutritional or other preventive efforts that might mitigate the observed risk.

We agree that the role of dietary choices and nutritional exposure as mechanistic underpinnings of heart failure pathophysiology has been speculated for several decades. However, unlike many commentaries, we are very careful not to make any unfounded speculations regarding any single dietary source of TMAO production as the sole culprit. The challenge in investigations of this topic is largely due to the difficulties in objective quantification in a rigorous scientific manner. Epidemiological studies are limited in their precision and accuracy to measure dietary composition. In our own published data, systemic levels of l-carnitine, choline, as well as betaine portend poorer long-term prognosis when there is a concomitant increase in circulating TMAO levels. Moreover, we recently discovered the contributory role of γ-butyrobetaine, an intermediate metabolite of l-carnitine that is vital to carnitine metabolism in vegetarians/vegans, which may potentially siphon oral l-carnitine availability upstream from the gastrointestinal tract (4). These novel observations further illustrate the complex interplay between dietary nutrients, gut microbial metabolism, and host homeostasis, above and beyond a simplistic explanation to justify or refute any therapeutic approaches. It is true that some species of fish have a high TMAO content, whereas many others do not. A similar situation is observed with the content of specific molecular species of omega-3 fatty acids in fish; many have very little.

The issue regarding l-carnitine supplementation itself being beneficial in the setting of chronic heart failure is far from being substantiated scientifically. Indeed, we find the characterization and analyses of Mr. McCarty and Dr. DiNicolantonio quite misleading. Although there may be short-term myocardial effects and theoretical benefits, the majority of human studies in this area were performed more than 2 decades ago and predominantly in the acute post-infarction setting (4). Careful review of l-carnitine supplementation studies in chronic heart failure revealed that all were short of duration and in patients not even receiving contemporary therapies (such as angiotensin-converting enzyme inhibitors and beta-blockers) (4). The study that was quoted as demonstrating the benefits of l-carnitine included 80 subjects not taking beta-blockers (with open-label l-carnitine use after 3 months) and reported 7 deaths in 3 years of follow-up (annualized mortality rate of 3.3%, surprisingly low for a population in New York Heart Association functional class III to IV). Results from Dr. DiNicolantonio's own meta-analysis actually did not demonstrate any significant effects on cardioprotection as it relates to preventing reinfarction (p = 0.45) or future development of heart failure (p = 0.21) with l-carnitine supplementation (4). When the studies with <10 events were excluded, no benefits were apparent, and the evidence is therefore largely inconsistent (4). What this particular meta-analysis also failed to emphasize is that during the 6-month follow-up of the largest randomized study performed by Tarantini et al. (n = 2,330), the primary endpoint (all-cause mortality and heart failure) was not significantly different in the l-carnitine and placebo groups (p = 0.27) (5). In fact, there were numerically more mortality events observed after the first 5 days of enrollment post-infarction in the l-carnitine–treated group compared with placebo at 180 days (40/1,141 [3.5%] vs. 31/1,117 [2.8%]) (5). This is the fundamental challenge of claiming therapeutic effects by statistical means without examining or appreciating the primary data source or validating mechanistic evidence. It would be important to first distinguish scientific evidence from testimonial beliefs and objectively examine and report what the data actually showed.

Although interventions that targeted metabolic modulation have been tried over several decades based on our understanding of the importance of impaired energetics of the failing heart, few therapeutic interventions, if any, reached the threshold of independent validation. It is not surprising that the latest American College of Cardiology/American Heart Association guidelines systematically reviewed the current evidence and do not recommend the use of otherwise unregulated nutritional supplements, including carnitine, in the treatment of chronic heart failure with systolic dysfunction due to lack of benefit. We believe that the growing body of data demonstrating mechanistic links between the gut microbiota–dependent TMAO pathway and both atherosclerosis and renal functional impairment in animal models, coupled with the independent clinical studies now reporting strong associations between elevated TMAO levels and adverse prognosis are a call for concern. The potential long-term adverse risk of high-dose, long-term l-carnitine supplementation as nutritional intervention simply cannot be overlooked and requires further investigation. In our humble opinion, the cardioprotective benefits are not firmly established, yet the risks are foreseeable and quantifiable in some individuals.

Footnotes Please note: Dr. Tang has previously received investigator-initiated research grant support from Abbott Laboratories, Inc. with no personal financial payments. Dr. Hazen is named as co-inventors on pending patents held by the Cleveland Clinic relating to cardiovascular diagnostics.