Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine

R e v i e w s e R i e s : g u t m i c R o b i o m eSeries Editor: Martin J. Blaser IntroductionCardiovascular disease (CVD) remains the leading cause of death in both the United States and industrialized societies, with growing incidence in developing countries (1). Factors contributing to CVD arise from genetic sources, environmental sources, or a combination of genetic and environmental sources (2). Despite extensive investigations in search of causal genetic variants, such as large-scale GWAS, less than one-fifth of attributable cardiovascular risk has been accounted for from genetic determinants (3, 4). At the same time, major advances in the treatment of atherosclerosis beyond high-potency lipid-lowering agents has not yet materialized (5). Indeed, even with high-potency statin therapy, at least a 50% residual risk remains (6), with the majority of events unchecked. Therefore, there is still ample room for improving our understanding of the processes contributing to CVD pathogenesis, and for improved prevention and treatment of CVD. While the recognizable contribution of genetics to CVD will no doubt significantly increase with time, a reassessment of environmental contributions to CVD pathogenesis and risks for adverse events is certainly worthwhile.Our largest environmental exposure is what we eat. Technically speaking, food is a foreign object that we take into our bodies in kilogram quantities every day. From the latest National Health and Nutrition Examination Survey (NHANES, 2009(NHANES, -2010, the majority of individuals sampled achieved an intermediate or poor Healthy Eating Index (1). However, dietary composition is often difficult to assess, and even precise quantification of dietary intake may not necessarily reveal the many known and unknown factors that may influence the contributions of specific dietary nutrients to disease susceptibility (7). There has also been an overwhelming lack of appreciation at the bedside regarding the intricate and complicated processes that transform ingested food into the myriad metabolites that enter the circulation and fulfill or adversely affect various functional and metabolic processes in the body.Over the past decade we have increasingly begun to appreciate the ecological diversity of microbes living symbiotically within us, a large proportion of which reside within our intestines. We now know that the human gut harbors more than 100 trillion microbial cells, far outnumbering the human host cells of the body (8). Indeed, a sobering fact is that Homo sapiens DNA is estimated to represent less than 10% of the total DNA within our bodies, due to the staggeringly large numbers of microbes that reside in and on us, primarily within our gut (9). Our microbial symbiont guests have coevolved with us and affect a wide range of physiologic and metabolic processes of the body. The major taxa present in gut microbiota consist primarily of 2 major bacterial phyla, Firmicutes and Bacteroidetes, whose proportions appear to remain remarkably stable over time within individu...

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“…Omnivores obtain most L-carnitine from their diet. In cells, carnitine functions in the transport of fatty acids into mitochondria (65).…”

Section: R E V I E W S E R I E S : G U T M I C R O B I O M Ementioning

confidence: 99%

The contributory role of gut microbiota in cardiovascular disease

2014

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“…11 Carnitine is a natural and essential vitamin-like substance that plays an essential role in myocardial energy production at the mitochondrial level. 12 It transfers long chain fatty acids across the inner mitochondrial membrane for b-oxidation and abnormalities in carnitine metabolism are thought to contribute to cardiac dysfunction. 13,14 Many studies have demonstrated a beneficial effect of levo-carnitine (LC) supplementation in various types of cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Effect of intravenous l-carnitine in Chinese patients with chronic heart failure

Jing

Peng

et al. 2016

Eur Heart J Suppl

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Chronic heart failure (CHF) may be associated with an energy deficit in cardiac muscle. As levo-carnitine (LC) is involved in the production of myocardial energy, it is hypothesized that LC supplementation may ameliorate CHF symptoms. This multicentre, randomized, double-blind, and placebo-controlled study included 265 patients with CHF. Patients were randomized to receive either LC or placebo, twice a day. Endpoints were measured after 7 days of treatment. Primary endpoint was a reduction of at least one NYHA class. Secondary endpoints were changes in 6-min walk distance (6-MWD) compared with baseline, either alone or in combination with NYHA class decrease, left ventricular ejection fraction, and NT-proBNP level, together with adverse events. The primary endpoint was reached in 60.9% of patients treated with LC, compared with only 44.7% of the placebo group (P ¼ 0.012). Among the secondary endpoints, 6-MWD, alone or in combination with NYHA class, improved significantly in the LC group compared with placebo (P ¼ 0.0497 and P ¼ 0.003, respectively). values of plasma-free carnitine were observed in patients with NYHA classes III and IV where the effect of LC supplementation was greatest (P ¼ 0.002). Treatment with LC significantly improved CHF symptoms in Chinese patients, probably by correcting a status of carnitine insufficiency.

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“…However, it has been suggested that L-carnitine may have to be administered at doses that achieve supra-physiological concentrations in plasma and target tissues to fully exploit its pharmacologic potential. 12,13 This study found that Fc and Tc levels in non-medicated patients undergoing HD were lower than those in the control group. The Fc, Ac, and Tc levels of patients increased significantly after 1 g L-carnitine was administered intravenously.…”

Section: Discussionmentioning

confidence: 71%

Clinical significance of different carnitine levels for improving the prognosis of patients undergoing hemodialysis

Zhang

et al. 2016

Renal Failure

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Objective: To investigate plasma-free carnitine (Fc), acylcarnitine (Ac), and total carnitine (Tc) levels in patients undergoing hemodialysis (HD), and to explore their clinical significance. Methods: A total of 20 subjects were in the normal control group and 133 patients undergoing HD were divided into medicated (received carnitine treatment) and non-medicated groups. The medicated group was further divided into three subgroups according to Fc level: , and ! 300 lmol/L. We used non-derivative tandem mass spectrometry to determine carnitine levels, and clinical symptoms such as weakness, hypotension, and muscle cramps were recorded during dialysis. Results: Fc and Tc levels were significantly lower in the non-medicated group than in the control group, whereas Fc, Ac, and Tc levels were higher in the medicated than non-medicated group (p< .05). The medicated group had fewer symptoms during dialysis than the non-medicated group such as weakness, hypotension, and muscle cramps (p< .05). An additional comparison showed that the incidence rates of hypotension and muscle cramps in the Fc < 80-199 lmol/L group were significantly lower than those in the Fc ! 300 lmol/L medicated and non-medicated groups. Conclusions: Patients undergoing HD have low carnitine levels. L-Carnitine can effectively increase Fc concentration and improve clinical symptoms; however, only the proper Fc range can reduce complications caused by dialysis. Thus, this range needs to be determined. ARTICLE HISTORY

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Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine

Cited by 122 publications

References 100 publications

The contributory role of gut microbiota in cardiovascular disease

The contributory role of gut microbiota in cardiovascular disease

Effect of intravenous l-carnitine in Chinese patients with chronic heart failure

Clinical significance of different carnitine levels for improving the prognosis of patients undergoing hemodialysis

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