Author + information
- Mark F. McCarty, BA∗ ( and )
- James J. DiNicolantonio, PharmD
- ↵∗Catalytic Longevity, 7831 Rush Rose Drive, Apt. 316, Carlsbad, California 92009
The new study by Tang et al. (1) demonstrating an inverse correlation of serum levels of trimethylamine-N-oxide (TMAO) with survival in patients with heart failure (HF) is intriguing and thought provoking. Similar findings have been published recently by Norwegian researchers.
In our judgment, TMAO is more likely to be a marker than a mediator in this relationship. Fish, especially deep-ocean fish, is exceptionally high in TMAO, with a TMAO content of 1.7 g per pound or higher. As noted previously, human TMAO exposure resulting from ingestion of a pound of fish could be expected to be an order of magnitude higher than that which would result from ingestion of a pound of carnitine-rich red meat (2). Nonetheless, dietary fish consumption has been correlated inversely with the risk of HF in several prospective cohorts, including the Physicians’ Health Study; how fish intake correlates with survival in pre-existing HF does not appear to have been studied. Very likely, the long-chain omega-3 content of fish is largely responsible for its protective efficacy in this regard.
Dietary carnitine can boost the production of TMAO in the body, yet supplemental carnitine has been shown to be therapeutically beneficial in patients with HF. In controlled clinical trials, carnitine supplementation of HF patients has been found to improve exercise performance, increase left ventricular ejection fraction, slow the increase in end-diastolic and end-systolic volumes, and improve clinical indexes such as edema, dyspnea, and digitalis consumption. In 1 study of 3 years’ duration, long enough to assess an impact on mortality, survival was significantly higher in those receiving carnitine (3). Hence, it would be inappropriate to conclude from the inverse correlation of TMAO and survival in HF that dietary carnitine has an adverse influence on HF.
A corollary of these considerations is that the predictive value of TMAO in HF would likely be compromised in individuals or groups who ingest ample amounts of fish or who take supplemental carnitine.
These considerations evidently do not rule out the possibility that TMAO itself, in the high-normal clinical range, might exert an adverse effect on the clinical course of HF, but they do suggest that any impact in this regard is modest compared with the protective benefits of long-chain omega-3 or of l-carnitine. Moreover, there is reason to question whether TMAO exerts meaningful proatherogenic activity at the low micromolar levels observed in human plasma (2).
Alternatively, elevated serum TMAO may serve as a marker for other dietary or metabolic factors that are the true mediators of risk. Red meat is the richest natural dietary source of carnitine and hence tends to raise serum TMAO levels. In the Physicians’ Health Study, red meat consumption correlated positively with the risk of HF, with or without a previous myocardial infarction. A recent Swedish study correlated increased consumption of processed red meat, but not unprocessed red meat, with an increased risk of HF. Dietary choline also raises TMAO levels; red meat is a meaningful dietary source of choline as are dairy products and eggs. In the prospective ARIC (Atherosclerosis Risk in Communities) study, consumption of high-fat dairy products and eggs correlated with an increased risk of HF. Hence, increased serum TMAO may be serving as a marker for dietary choices that by independent mechanisms tend to promote HF. In this regard, among HF patients enrolled in a clinical trial evaluating sodium restriction, dietary saturated fat consumption was shown to correlate positively with 1-year mortality, whereas dietary consumption of polyunsaturates correlated inversely (4). Also, plasma phospholipid levels of saturated fats or of palmitic acid specifically have been reported to correlate with the risk of HF in ARIC and the Physicians’ Health Study.
In the Tang et al. (1) study, TMAO correlated inversely with the estimated glomerular filtration rate; because TMAO is found in urine, this likely reflects a role for renal clearance in the regulation of plasma TMAO levels. However, the authors show that TMAO retains predictive value after statistical correction of the estimated glomerular filtration rate, so TMAO is not serving solely as a marker for this parameter.
Finally, as the authors note, increased serum TMAO might conceivably be a marker for the presence of gastrointestinal flora that work in independent ways to worsen prognosis in HF.
Curiously, TMAO, like 4-phenylbutyrate or taurodeoxycholate, can act as a small-molecule chemical chaperone that suppresses endoplasmic reticulum (ER) stress. This is thought to explain the favorable impact of TMAO administration in rodent models of asthma, diabetic neuropathy, and cataract. Moreover, ER stress appears to be an exacerbating factor in HF, linked to an increased risk of apoptosis of cardiomyocytes; hence, it has been suggested that agents that counteract ER stress may have a role in the management of HF. Indeed, the orphan drug 4-phenylbutyrate was protective in a rodent model of pressure-overload cardiac hypertrophy. Could high intakes of TMAO actually play a protective role in HF? (This is not necessarily inconsistent with the findings of Tang et al. (1) because the low micromolar physiological concentrations of TMAO would be expected to have little meaningful chaperone activity.) This possibility could be evaluated in rodent studies.
Considerable evidence also points to ER stress as a driver of atherogenesis, foam cell formation, and plaque destabilizing apoptosis of intimal macrophages and smooth muscle cells. Indeed, both 4-phenylbutyrate and taurodeoxycholate are reported to exert antiatherosclerotic activity in rodent studies and to suppress induction of CD36 and scavenger receptor A in macrophages. In notable contrast, TMAO has been found to have a proatherogenic effect in mice and to up-regulate CD36 and scavenger receptor A expression in macrophages (5). Although it is quite conceivable that TMAO has some idiosyncratic adverse countervailing effect on foam cells that outweighs the benefit of its inhibitory influence on ER stress, it should be noted that only 1 research group to date has reported a proatherogenic role for TMAO; this observation needs independent confirmation before it can be accepted as established fact.
Please note: Mark McCarty is the owner of a small nutraceutical company, some of whose products contain carnitine. Dr. DiNicolantonio works for a company that sells l-carnitine, but he does not directly profit from its sale.
- American College of Cardiology Foundation