Applied nutritional investigationEffects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure
Introduction
Heart failure (HF) is characterized by a poor quality of life (QoL), adverse prognosis, and high medical costs. [1] Despite advances in drug therapy and development of new devices to improve patient prognosis, individuals with chronic heart failure (CHF) continue to have an unsatisfactory QoL and reduced exercise tolerance. A hallmark of HF is the reduced ability to perform aerobic exercise. This reduction in functional capacity and exercise tolerance is mediated by several factors including alterations of endothelial and vasodilatory function, abnormalities in skeletal muscle metabolism, and reduction in muscle blood flow during exercise [2]. Improving these parameters remains a major unmet need of HF treatment. Recently, the role of the nutritional status and cachexia in HF has been extensively shown [3], [4], [5]. Supplementation of essential amino acids (AAs) has demonstrated promising results with regard to improvement of functional capacity and, in some cases, in left ventricular ejection fraction (LVEF) [6], [7], [8]. Although these studies were small in size and heterogeneous with regard to the analyzed molecules, they highlight the need for a deeper knowledge of the effects of nutritional support and the correction of macro- and micronutrient deficiencies in patients with HF. The failing heart is exposed to several mechanisms (hemodynamic, neurohormonal, and inflammatory) that contribute to left-ventricular remodeling and to progressive decrease in cardiac function [9]. Recently, it has been proposed that one mechanism of action of these stressors may involve myocytes metabolism (metabolic remodeling) in the failing heart, where AAs become essential for energy production through the Krebs cycle [10], [11]. AAs also regulate protein turnover and synthesis, and contribute to the maintenance of hormonal balance by increasing the activity of anabolic hormones. An adequate intake of AAs, therefore, may be of primary importance in patients with HF and AA supplementation may represent a proper treatment, by reverting the alterations of cardiac and systemic metabolism [12].
Levo-carnosine (l-carnosine) is a cytoplasmic dipeptide (β-alanyl-l-histidine) found in high concentrations in the tissues of longeval mammals, especially in muscles, heart, and brain [13], [14], [15]. In vitro studies have shown the ability of carnosine to slow the aging of human fibroblasts [16], [17]. Other studies also have demonstrated that the levels of carnosine decrease with age, with a loss of 63%, from 10 to 70 y and carnosine levels in mammals also seem to be directly correlated with life expectancy [18]. Carnosine is considered a multifunctional molecule with antioxidant and antiaging action, and operates as a selective inhibitor of protein glycosylation and protein–protein cross-linking [19], [20], [21], [22]. In humans, the carnosinase enzyme degrades circulating carnosine. Recent studies have shown that the diabetic nephropathy is associated with a (CTG)n polymorphism in the carnosine dipeptidase-1 gene (CNDP1), and patients homozygous for (CTG)5 have a lower risk for developing diabetic nephropathy and also have lower plasma levels of carnosinase [23]. Studies included small groups of patients have demonstrated that oral supplementation of carnosine in subjects with deficient carnosinase enzyme activity increases carnosinemia and could have a protective effect on the kidneys of patients with diabetes by reducing glycation end products and oxidative stress [24], [25]. Recently, the administration of carnosine has been associated with a nephroprotective effect in patients with diabetic nephropathy, and nephropathy induced by contrast medium. This favorable effect seems to be related to the reduction of plasma levels of proinflammatory cytokines and the synthesis of fibronectin and type IV collagen [26]. In preliminary studies, carnosine has been shown to induce Na,K-ATPase activation and to prevent membrane depolarization with a potential role in the management of HF and myocardial infarction [27]. In a rabbit model in which HF was induced by infusing doxorubicin, the administration of carnosine reduced cardiotoxic effects compared with rabbits treated with doxorubucine alone [28]. Carnosine plays a key role against the oxidative damage that occurs during exercise under anaerobic conditions. During exercise, there is an increase of lactic acid with a subsequent dissociation into lactate and H+, which reduce pH levels. These protons are usually buffered by the bicarbonate system, which has an acid dissociation constant (pKa) of 6.1, whereas l-carnosine has a pKa value of 6.83, closer to the physiological pH (7.38–7.42) [29]. Carnosine plays an effective buffering action through the imidazole group of histidine, which binds a proton reducing the pH value. The pKa of carnosine is closer to the physiological pH and could be used sooner as a buffer during exercise [30], [31]. An increase in muscle l-carnosine levels may improve contractility and reduce fatigue [32]. Other mechanisms include regulatory effects on myocardial calcium levels, an increase in sensitivity of calcium-release channels and of the contractile apparatus, with favorable effects on cardiac contractility and function [33], [34], [35]. Thus, carnosine is potentially useful as an addition to the standard treatment of patients with HF. The aim of this study was to test the oral supplementation of l-carnosine and its effects on QoL and exercise performance in patients with stable CHF.
Section snippets
Study patients
We studied patients with HF of ≥6-mo duration, with New York Heart Association (NYHA) class II or III symptoms, an LVEF ≤45% by echocardiography and the ability to perform a cardiopulmonary exercise test. Patients had to be on optimal medical therapy, including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and β-blockers, if not contraindicated, at stable dose for at least 4 wk before entering the study. Patients were excluded if they had symptoms of myocardial
Results
The study group included 50 consecutive ambulatory patients (mean age, 62.01 ± 9.55 y) with CHF due to left-ventricular systolic dysfunction (mean LVEF, 33.21 ± 7.57), who were referred to our institute between June and November 2012 and randomized to receive l-carnosine (500 mg OD) on top of standard therapy or standard treatment.
At study entry, the two groups were balanced with respect to demographic, clinical, and biochemical variables, as well as medical therapy (Table 1).
All patients were
Discussion
To our knowledge, this study is the first to analyze the effects of oral supplementation in a 500 mg/d dose of l-carnosine in ambulatory patients with HF and severe left-ventricular systolic dysfunction, focusing on the effect on exercise tolerance and QoL. The administration of l-carnosine was performed in patients on optimized therapy for HF and who were clinically stable. l-carnosine is a dietary supplement in the formulation of orodispersible tablet. Carnosine is a molecule composed of two
Conclusion
This investigation demonstrated that once-daily oral supplementation of 500 mg l-carnosine, added to conventional therapy, may improve exercise performance and QoL in ambulatory patients with stable CHF. This study did not test l-carnosine against placebo and enrolled a relatively small number of patients. More data are necessary to confirm these promising results and placebo-controlled studies enrolling a larger number of patients are needed to evaluate potential effects of l-carnosine on
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