Dr. Ron’s Research Review – April 17, 2013

© 2013

This week’s research review focuses on the carnitine controversy.

A recent study showed that intestinal microbiota metabolize dietary l-carnitine, a trimethylamine abundant in red meat, to produce TMAO (trimethylamine-N-oxide), which accelerates atherosclerosis in mice. (Koeth, Wang et al. 2013)

Increased Carnitine

Miyata hypothesized that plasma carnitine level is increased due to the leakage from damaged cardiomyocytes or deficient carnitine transport into cells in heart failure patients with sleep disordered breathing. (Miyata, Yoshihisa et al. 2012)

El-Aroussy proposed that elevated plasma levels of carnitine could serve as a marker for myocardial damage and impaired left ventricular functions. (El-Aroussy, Rizk et al. 2000)

Carnitine for the Heart

A recent article found that L-carnitine and vitamin E have a protective role on the testis of atherosclerotic rats. (Salama, Kasem et al. 2013)

Another article found that L-carnitine has a protective role in heart dysfunction induced by choline-deficiency in adult rats. (Strilakou, Lazaris et al. 2013)

L-carnitine was shown to have systemic antioxidant properties in two different models of arterial hypertension. (Mate, Miguel-Carrasco et al. 2010)

Dr. Ron


Abstracts

Plasma carnitine levels as a marker of impaired left ventricular functions

         (El-Aroussy, Rizk et al. 2000) Download

L-Carnitine plays a role in the utilization of fatty acids and glucose in the myocardium. Previous studies have indicated carnitine deficiency in patients with congestive heart failure. However, the extent of altered carnitine metabolism and left ventricular function is not fully determined. This study is designed to determine if plasma L-carnitine levels can serve as a marker for impaired left ventricular function in patients with congestive heart failure. To test this hypothesis, plasma and urinary levels of L-carnitine were measured in 30 patients with congestive heart failure (CHF) and in 10 control subjects. CHF was due to dilated cardiomyopathy (DCM) and rheumatic heart disease (RHD). Cardiac functions such as percentage of fractional shortening (%FS), ejection fraction (EF), left ventricular mass index (LVMI), were determined by echocardiography. All patients and control subjects had normal renal functions. Plasma carnitine was significantly higher in patients with DCM (37.05+/-7.62, p < 0.0001) and with RHD (47.2+/-8.04, p < 0.0001) vs. the control subjects (14.4+/-5.30 mg/L). Urinary carnitine was significantly higher in DCM (49.13+/-14.11, p < 0.0001) and in RHD 43.53+/-15.5, p < 0.0001), than the control (25.1+/-5.78 mg/L). Plasma carnitine level correlated significantly with impaired left ventricular systolic functions in these patients: % FS < 25 % (r = -0.38 and p = 0.038), EF < 0.55 (r = -0.502 and p = 0.005) and LMVI > 124 gm/m2 (r = 0.436, and p = 0.016). These data suggest that elevated plasma and urinary carnitine levels in patients with CHF could serve as a marker for myocardial damage and impaired left ventricular functions.

Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis

         (Koeth, Wang et al. 2013) Download

Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary l-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of l-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma l-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary l-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.

Systemic antioxidant properties of L-carnitine in two different models of arterial hypertension

         (Mate, Miguel-Carrasco et al. 2010) Download

In spite of a wide range of drugs being available in the market, treatment of arterial hypertension still remains a challenge, and new therapeutic strategies could be developed in order to improve the rate of success in controlling this disease. Since oxidative stress has gained importance in the last few years as one of the mechanisms involved in the origin and development of hypertension, and considering that L-carnitine (LC) is a useful compound in different pathologies characterized by increased oxidative status, the aim of the present study was to investigate the systemic antioxidant effect of LC and its correlation to blood pressure in two experimental models of hypertension: (1) spontaneously hypertensive rats (SHR) and (2) rats with hypertension induced by N(omega)-nitro-L-arginine methyl ester (L-NAME). Treatment with captopril was also performed in SHR in order to compare the antioxidant and antihypertensive effects of LC and captopril. The antioxidant defense capacity, in terms of antioxidant enzyme activity, glutathione system availability and plasma total antioxidant capacity, was measured in both animal models with or without an oral, chronic treatment with LC. All the antioxidant parameters studied were diminished in SHR and in L-NAME-treated animals, an alteration that was in general reversed after treatments with LC and captopril. In addition, LC produced a significant but not complete reduction of systolic and diastolic blood pressure levels in these two models of hypertension, whereas captopril was able to normalize blood pressure. Both LC and captopril prevented the reduction in nitric oxide (NO) levels observed in hypertensive animals. This suggests a decrease in the systemic oxidative stress and a higher availability of NO induced by LC in a similar way to captopril's effects, which could be relevant in the management of arterial hypertension eventually.

Plasma Carnitine Level in Heart Failure Patients With Sleep Disordered Breathing

         (Miyata, Yoshihisa et al. 2012) Download

Background: Carnitine plays an important role in the utilization of fatty acids and glucose in the myocardium. Although myocardial carnitine level decreases in the failing heart, it is still unclear about circulating levels of carnitine in chronic heart failure (CHF). Sleep disordered breathing (SDB) has a critical association with mortality and morbidity of CHF patients. We hypothesized that plasma carnitine level is increased due to the leakage from damaged cardiomyocytes or deficient carnitine transport into cells in CHF patients with SDB. Therefore, we examined the relation of plasma carnitine level with SDB in CHF.

Methods and Results: We performed polysomnography and measured apnea-hypopnea index (AHI), central apnea index, obstructive apnea index, minimum SPO2, mean SPO2 and plasma levels of carnitine and B-type natriuretic peptide (BNP) in 106 CHF patients. These patients were divided into the four groups according to AHI: group Normal (no SDB: AHI<5 times/hr, n=14), group Mild (mild SDB: 5<AHI<15 times/hr, n=23), group Moderate (moderate SDB: 15<AHI<30 times/hr, n=31) and group Severe (severe SDB: 30<AHI times/hr, n=38). Levels of plasma carnitine were significantly higher in group Severe than in groups Normal and Mild (Normal: 61.5 ± 7.4 µmol/l, Mild: 66.9 ± 19.9 µmol/l, Moderate: 70.5 ± 19.7 µmol/l, Severe: 78.2 ± 13.6 µmol/l, P<0.01, vs. Normal; P<0.05, vs. Mild). There was a positive correlation between plasma carnitine level and AHI (R=0.29, P<0.01). There were no correlations between plasma carnitine level and the other polysomnographic data such as CAI, OAI, minimum SPO2 and mean SPO2. In addition, there was no significant correlation between levels of carnitine.

Conclusions: Severe SDB is associated with higher plasma carnitine level, and thus circulating carnitine may be a novel marker for the severity of SDB in CHF.


Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats

         (Salama, Kasem et al. 2013) Download

Atherosclerosis is a condition caused by lipid build-up and inflammation in the arteries, so hyperlipidemia is the major reason for atherosclerosis. Testis was found to be negatively affected by hyperlipidemia which leads to its impaired functions. Vitamin E and <sc>l</sc>-carnitine have well-known lipid-lowering and antioxidative activities. Triton WR 1339 is a non-ionic detergent, which induces severe hyperlipidemia by inhibition of lipoprotein lipase. The present study evaluates the protective role of vitamin E and <sc>l</sc>-carnitine on the testis in atherosclerosis and detects the most effective choice for protection against atherosclerosis; vitamin E, <sc>l</sc>-carnitine or a combination of both. A total of 80 albino male rats were divided into eight groups (10 rats for each group): control (G(1)), triton (G(2)), <sc>l</sc>-carnitine (G(3)), triton + <sc>l</sc>-carnitine (G(4)), vitamin E (G(5)), triton + vitamin E (G(6)), <sc>l</sc>-carnitine + vitamin E (G(7)) and triton + <sc>l</sc>-carnitine + vitamin E (G(8)). Data showed a significant increase in the levels of total cholesterol (TC), triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), 17 beta hydroxysteroid dehydrogenase (17 beta HSD), testicular catalase and malondialdehyde (MDA) in G(2) when compared with G(1), whereas high-density lipoprotein cholesterol (HDL-C), serum testosterone, testicular 17 ketosteroid reductase (17 KSR), total thiol and glutathione-S-transferase (GST) data showed a significant decrease in G(2) when compared with G(1). Treatment with <sc>l</sc>-carnitine or/and vitamin E helps in improving the adverse effect of triton; also the histological changes confirm this finding. So the present study recommends all people to include <sc>l</sc>-carnitine and vitamin E in their diet to be protected against atherosclerosis.

Heart dysfunction induced by choline-deficiency in adult rats: the protective role of L-carnitine

         (Strilakou, Lazaris et al. 2013) Download

Choline is a B vitamin co-factor and its deficiency seems to impair heart function. Carnitine, a chemical analogue of choline, has been used as adjunct in the management of cardiac diseases. The study investigates the effects of choline deficiency on myocardial performance in adult rats and the possible modifications after carnitine administration. Wistar Albino rats (n=24), about 3 months old, were randomized into four groups fed with a) standard diet (control-CA), b) choline deficient diet (CDD), c) standard diet and carnitine in drinking water 0.15%w/v (CARN), d) choline deficient diet and carnitine (CDD+CARN). After four weeks of treatment, we assessed cardiac function under isometric conditions using the Langendorff preparations [Left Ventricular Developed Pressure (LVDP-mmHg), positive and negative first derivative of LVDP were evaluated], measured serum homocysteine and Brain Natriuretic Peptide (BNP) levels and performed histopathology analyses. In the CDD group a compromised myocardium contractility compared to control (P=0.01), as assessed by LVDP, was noted along with a significantly impaired diastolic left ventricular function, as assessed by (-) dp/dt (P=0.02) that were prevented by carnitine. Systolic force, assessed by (+) dp/dt, showed no statistical difference between groups. A significant increase in serum BNP concentration was found in the CDD group (P<0.004) which was attenuated by carnitine (P<0.05), whereas homocysteine presented contradictory results (higher in the CDD+CARN group). Heart histopathology revealed a lymphocytic infiltration of myocardium and valves in the CDD group that was reduced by carnitine. In conclusion, choline deficiency in adult rats impairs heart performance; carnitine acts against these changes.


References

El-Aroussy, W., A. Rizk, et al. (2000). "Plasma carnitine levels as a marker of impaired left ventricular functions." Mol Cell Biochem 213(1-2): 37-41. [PMID: 11129956]

Koeth, R. A., Z. Wang, et al. (2013). "Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis." Nat Med. [PMID: 23563705]

Mate, A., J. L. Miguel-Carrasco, et al. (2010). "Systemic antioxidant properties of L-carnitine in two different models of arterial hypertension." J Physiol Biochem 66(2): 127-36. [PMID: 20506010]

Miyata, M., A. Yoshihisa, et al. (2012). "Plasma Carnitine Level in Heart Failure Patients With Sleep Disordered Breathing." Circulation 126(A10919). [PMID:

Salama, A. F., S. M. Kasem, et al. (2013). "Protective role of L-carnitine and vitamin E on the testis of atherosclerotic rats." Toxicol Ind Health. [PMID: 23406956]

Strilakou, A. A., A. C. Lazaris, et al. (2013). "Heart dysfunction induced by choline-deficiency in adult rats: the protective role of L-carnitine." Eur J Pharmacol. [PMID: 23562624]