There is growing evidence that high concentrations of L-C provide beneficial effects in various diseases such as coronary artery disease, congestive heart failure, peripheral vascular diseases, type 2 diabetes, dyslipidemia, and hypertension [ 6 ]. However, the clinical guidelines about nutritional supplements in different countries are not consistent. But, as a treatment of heart failure, L-C has not been recommended in patients with current or prior symptoms of heart failure with reduced ejection fraction and heart failure with preserved ejection fraction in the American guideline [ 3 ].
The recommendation of nutritional supplements has not been proposed in the European guideline [ 2 ]. In addition, two meta-analyses of RCTs has been performed to assess the therapeutic effects of L-C in the secondary prevention of cardiovascular disease [ 8 , 9 ], but there is no meta-analysis of RCTs in CHF. Thus, we performed a meta-analysis of RCTs with critical inclusion and exclusion criteria to evaluate the efficacy and tolerance of L-C.
Literature was searched by two authors X. Song and Z. Yang independently. The search was limited to human subjects, with no restriction for language. Two authors independently selected trials and discussed with each other when inconsistencies were found. Studies that included other nutritional supplements i. The methodological qualities of the included RCTs were assessed according to Cochrane Collaboration's tool described in Handbook version 5.
Two authors X. Yang assessed the quality independently, and inconsistency was discussed with a third review author H. Zhou who acted as an arbiter. Authors were contacted by e-mail for additional information if data were unavailable. Data were processed in accordance with the Cochrane Handbook [ 10 ]. The fixed-effects model was first used for meta-analyses. The random-effects model was used in the presence of heterogeneity.
Description analysis was performed when the quantitative data could not be pooled. Intention-to-treat ITT principle was used.
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Review Manage v. The flow of selecting studies for the meta-analysis is shown in Figure S1. Briefly, among the initial reports, articles were retrieved for detailed evaluation, and 17 RCTs [ 12 — 28 ] enrolling participants that fulfilled the inclusion criteria were finally analyzed. The study and patient characteristics are shown in Table 1.
L-Carnitine and the Heart
L-C dosage ranged from 1. All studies included in this meta-analysis were randomized controlled trials. The quality assessment of the included RCTs is shown in Figure 1. Four studies [ 12 , 13 , 21 , 26 ] did not report the method of randomization, whereas the others reported a randomization number sequence or adaptive minimization randomization scheme.
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There were three studies [ 13 , 17 , 26 ] using the blind method; blind methods of all the other studies are unclear. Selective reporting was found in three studies [ 13 , 21 , 26 ] because they did not present the ITT analysis data. These studies had high performance bias and detection bias.
The other potential biases were unclear in these trials Figure 2. Because most of the studies were conducted in China, we cautiously drew the conclusion that publication bias might have been present in the meta-analysis. The differences of treatment period would influence the outcomes of chronic heart failure patients.
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Eight studies [ 14 , 18 — 20 , 22 , 24 , 27 , 28 ] had a treatment period of 2 weeks, and the follow-up period of other studies still ranged variously. In this condition, we conducted a subgroup analysis in these studies with 2 -week treatment period Figure S3. Four studies [ 13 , 18 , 21 , 23 ] reported all-cause mortality.
The improvement in cardiac function decreased NYHA class was rated as overall efficacy. The endpoint was a decrease of at least one NYHA class, with efficacy rated as effective decrease of two classes, decrease of one class or ineffective no class change. The overall efficacy consisted of excellent and effective rate. Thus, a random-effects model was used. Six studies [ 12 , 14 , 16 , 24 , 25 , 28 ] reported that there were no adverse events related to L-C.
Four reports [ 13 , 20 , 23 , 26 ] contained data on specific adverse events. No participants have withdrawn from the study for the reason of adverse events.
Meta-analysis demonstrated no differences in adverse events between patients in both groups 5. The other seven trials did not report adverse events. It is also an organ that needs energy from metabolism. CHF is currently conceived as a systemic and multiorgan syndrome with metabolic failure as basic mechanism. L-C is a natural constituent of human cells and participates in fatty acid metabolism. L-C plays an important role in lipid metabolism by acting as an obligatory cofactor for oxidation of fatty acids and facilitating the transport of long-chain fatty acids LCFAs across the mitochondrial membrane to provide enough adenosine triphosphate ATP for myocardial cells [ 30 ].
Although heart failure is not listed as one of indications in package insert of L-C, clinical application of L-C has shown significant relief of heart failure, which was confirmed in our research. Recently, DiNicolantonio et al.
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However, our study suggests that the additional use of L-C failed to reduce all-cause mortality in CHF patients. Chronic oral L-C supplementation has been shown to ameliorate factors associated with metabolic syndrome and cardiovascular disease, such as arterial hypertension, cholesterol levels, impaired glucose tolerance, and insulin resistance. L-C appears to be particularly suitable as a treatment for metabolic syndrome patients, who are often obese, insulin resistant, and hypertensive [ 31 — 33 ].
One included study [ 27 ] suggested that L-C can significantly ameliorate total cholesterol, blood sugar, and cardiac function and improve clinical symptoms of patients for heart failure patients with diabetes mellitus. Some reports [ 21 , 24 , 25 ] indicated that clinical symptom, cardiac function, and renal function in CHF patients with renal insufficiency were more likely to be ameliorated with L-C treatment. Furthermore, noteworthy is that L-C exerts cardioprotective effects through alternative mechanisms, such as oxidative stress [ 35 ], nitric oxide [ 36 ], arterial hypertension, cardiac inflammation and fibrosis [ 37 — 39 ], and interstitial remodeling [ 40 ], as well as by improving endothelial function [ 41 ].
It is noteworthy that, based on existing conventional treatment, L-C was used in treatment of energy metabolism disorder.
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It acted as a supplementation to preexisting treatment rather than a replacement. Chronic heart failure is a disease that requires multitargeted and phase dependent therapeutic methods. Our research showed that L-C represents a safe and effective adjuvant therapy which, by increasing high energy phosphate for systolic and diastolic function, may have a synergistic effect with other drugs. Through analyzing the included references, we speculated the following possible causes for the discrepancies: 1 different uses, doses of L-C utilized in these studies.
Some limitations of our meta-analysis need to be acknowledged.
Firstly, the methodological quality of included studies was less than optimal, so we were not able to exclude the potential risk of bias in these trials. Secondly, it is worth noticing that only patients were involved in the 17 RCTs, which justifies the performance of more large-scale RCTs for evaluating the impact of L-C treatment on CHF patients.
Thirdly, the follow-up duration in these studies varied widely, from 7 days to 3 years. Owing to these limitations, our results are insufficient to recommend the method as a first-line treatment or to establish the quality of life and long-term results. Therefore, further research is required to more accurately assess the results of L-C for treating CHF.
There were three main parts of the supplementary material. Figure S1 shows flow diagram of study selection, Figure S2 shows forest plots for adverse events, and Figure S3 shows forest plots for subgroup analysis of 2-week treatment period. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Center for Biotechnology Information , U.
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