Nutritional Supplementation and Exercise as Essential Allies in the Treatment of Chronic Heart Failure: The Metabolic and Molecular Bases.

Chronic heart failure (CHF) is one of principal health problems in industrialized countries. Despite therapeutical improvement, based on drugs and exercise training, it is still characterized by elevated mortality and morbidity. Data show that protein energy malnutrition, clinically evident primarily with sarcopenia, is present in more than 50% of CHF patients and is an independent factor of CHF prognosis. Several pathophysiological mechanisms, primarily due to the increase in blood hypercatabolic molecules, have been proposed to explain this phenomenon. Nutritional supplementation with proteins, amino acids, vitamins and antioxidants have all been used to treat malnutrition. However, the success and efficacy of these procedures are often contradictory and not conclusive. Interestingly, data on exercise training show that exercise reduces mortality and increases functional capacity, although it also increases the catabolic state with energy expenditure and nitrogen-providing substrate needs. Therefore, this paper discusses the molecular mechanisms of specific nutritional supplementation and exercise training that may improve anabolic pathways. In our opinion, the relationship between exercise and the mTOR complex subunit as Deptor and/or related signaling proteins, such as AMPK or sestrin, is pivotal. Consequently, concomitantly with traditional medical therapies, we have proposed a combination of personalized and integrated nutritional supplementation, as well as exercise to treat malnutrition, and anthropometric and functional CHF-related disorders.

Protein-Amino Acid Metabolism Disarrangements: The Hidden Enemy of Chronic Age-Related Conditions.

Proteins are macro-molecules crucial for cell life, which are made up of amino acids (AAs). In healthy people, protein synthesis and degradation are well balanced. However, in the presence of hypercatabolic stimulation (i.e., inflammation), protein breakdown increases as the resulting AAs are consumed for metabolic proposes. Indeed, AAs are biochemical totipotent molecules which, when deaminated, can be transformed into energy, lipids, carbohydrates, and/or biochemical intermediates of fundamental cycles, such as the Krebs' cycle. The biochemical consequence of hyper-catabolism is protein disarrangement, clinically evident with signs such as sarcopenia, hypalbuminemia, anaemia, infection, and altered fluid compartmentation, etc. Hypercatabolic protein disarrangement (HPD) is often underestimated by clinicians, despite correlating with increased mortality, hospitalization, and morbidity quite independent of the primary disease. Simple, cheap, repeatable measurements can be used to identify HPD. Therefore, identification and treatment of proteins' metabolic impairment with appropriate measurements and therapy is a clinical strategy that could improve the prognosis of patients with acute/chronic hypercatabolic inflammatory disease. Here, we describe the metabolism of protein and AAs in hypercatabolic syndrome, illustrating the clinical impact of protein disarrangement. We also illustrate simple, cheap, repeatable, and worldwide available measurements to identify these conditions. Finally, we provide scientific evidence for HPD nutritional treatment.

Supplementation of essential amino acids may reduce the occurrence of infections in rehabilitation patients with brain injury.

BACKGROUND: To investigate whether supplementation with oral essential amino acids (EAAs) may reduce the occurrence of nosocomial infection among patients with brain injury (BI: stroke, trauma, anoxic coma). METHODS: Patients (n = 125; 77 men, 48 women; mean age 63 ± 15 years) with stroke (68.8%), subarachnoid hemorrhage (17.6%), traumatic BI (7.2%), and anoxic BI (6.4%) 88 ± 15 days after the index event. Patients were randomly assigned to 2 months of oral EAAs (n = 63; 8 g/d) or placebo (n = 62). RESULTS: Over the first month of rehabilitation, there were 60 infections in the whole population of 125 patients (48%); however, the rate was 23.2% lower in the EAA group (23 episodes/63 patients; 36.5%) than in the placebo group (37 episodes/62 patients; 59.7%) (P < .01). The types of infection were similarly distributed between the 2 groups. Serum levels of prealbumin <20 mg/dL and C-reactive protein (CRP) >0.3 mg/dL were the best predictors of future infection (prealbumin: odds ratio [OR] = 4.17, confidence interval [CI] 1.84-9.45, P < .001; CRP: OR = 3.8, CI 1.71-8.44, P < .001). CONCLUSION: Supplementary EAAs may reduce the occurrence of nosocomial infections in rehabilitation patients with BI. Prealbumin and CRP are the best predictors of future infections.

Effect of essential amino acid supplementation on quality of life, amino acid profile and strength in institutionalized elderly patients.

BACKGROUND & AIMS: This study assessed the efficacy of supplemented essential amino acids on depressive symptoms, nutrition, muscle function, daily physical activity, and health-related quality of life (HRQoL) of institutionalized elderly patients. METHODS: Forty-one patients (58.5% women; mean age 79.8 yrs) with sequelae of coronary artery disease (73%), femoral fracture (34%), were randomly assigned to receive oral essential amino acids 4 gr 2 times a day for 8 weeks or isocaloric placebo. Before randomization and 8 weeks after the protocol started, the following variables were measured: depressive symptoms (Geriatric Depression Scale, GDS), nutritional panel (Mini Nutritional Assessment, MNA; serum albumin and prealbumin levels), muscle strength (Hand Grip, HG), Activity Daily Life (ADL), Quality of Life (SF-36, HRQoL) and amino acid profile. RESULTS: Compared with the placebo group, EAA patients improved nutrition (MNA score 22.6 ± 1.5 post vs 21.8 ± 1.6 pre; p < 0. 04, albumin g/dl 4.04 ± 0.35 post vs 3.88 ± 0.3 pre; p < 0.01), GDS(score 10.3 ± 1.75 post vs 13.85 ± 3.37 pre; p < 0.001), HG (Kg 19.75 ± 1.7 post vs 18.68 ± 1.36 pre; p = 0.001), ADL (p < 0.04) and both physical and mental components of SF-36 (p < 0.002). CONCLUSIONS: Oral supplementation with essential amino acids improved several determinants of quality of life in institutionalized elderly patients, including depressive symptoms, nutrition, muscle function and daily life activity.

To give or not to give? Lessons from the arginine paradox.

Arginine is one of the 20 amino acids (AA) found in proteins and synthesized by human cells. However, arginine is also the substrate for a series of reactions leading to the synthesis of other AA and is an obligatory substrate for two enzymes with diverging actions, arginases and nitric oxide synthases (NOS), giving origin to urea and NO, respectively. NO is a very potent vasodilator when produced by endothelial NOS (eNOS). The 'arginine paradox' is the fact that, despite intracellular physiological concentration of arginine being several hundred micromoles per liter, far exceeding the ∼5 µM K(M) of eNOS, the acute provision of exogenous arginine still increases NO production. Clinically, an additional paradox is that the largest controlled study on chronic oral arginine supplementation in patients after myocardial infarction had to be interrupted for excess mortality in treated patients. Expression and activity of arginases, which produce urea and divert arginine from NOS, are positively related to exogenous arginine supplementation. Therefore, the more arginine is introduced, the more it is destroyed, eventually leading to impaired NO production. In this review, conditions influencing the low arginine concentrations found in plasma will be reviewed, revising the paradigm that simple replenishment of what is lacking will always produce beneficial consequences.

Effects of oral amino acid supplementation on long-term-care-acquired infections in elderly patients.

The very high general infection rate (IRI) observed in our Geriatric Intensive Rehabilitation Center (GIRC) led us to investigate whether patient supplementation with essential amino acids (EAAs), modulators of immuno-competence, could reduce IRI. Eighty elderly patients admitted to our GIRC (n=40; age 79.5 ± 7.71; male/female 14/26) or placebo (n=40; age 82.13 ± 6.15; male/female 13/27) were allocated to an 8 g/day oral EAAs group and were surveyed for infections (>48 h from admission) over the first month of their hospital stay. The IRI was 67% for the entire population of patients, 82.5% (33/40 patients) in the placebo group and 52% (21/40 patients) in the EAA group (p<0.02). When patients were divided into infection group (IG) and without-infection group (WIG), independently of post randomization allocation, the WIG had higher levels of serum albumin (p<0.001), blood hemoglobin (Hb) concentration (p=0.01), dietary protein (p=0.008) calorie intakes (p=0.05) but lower serum C-reactive protein (CRP) (p<0.001). The factor of CRP>0.8 mg/dl and Hb ≤ 12 in females, ≤13 in males was associated 4 times and 3.6 times risk of infection, respectively, by sex. EAAs supplementation may lower the risk of infection by 30% in the rehabilitative elderly population. CRP and blood hemoglobin levels can be considered risk markers of future infection.

Effects of voluntary wheel running and amino acid supplementation on skeletal muscle of mice.

The aims of the present study were as follows: (1) to examine the adaptational changes to chronic endurance voluntary exercise and (2) to investigate the effects of amino acid supplementation on the adaptational changes induced by endurance training in hindlimb (gastrocnemius, tibialis, soleus) and respiratory (diaphragm) muscles of mice. Male C57Bl6 mice were divided in four groups: control sedentary, sedentary supplemented with amino acid mixture (BigOne, 1.5 mg g day(-1) in drinking water for 8 weeks), running (free access to running wheels for 8 weeks), and running supplemented with amino acid mixture. Myosin heavy chain (MHC) isoform distribution was determined in all muscles considered. Fiber cross-sectional area (CSA) was measured in the soleus muscle. In all muscles except the tibialis, endurance training was associated with an overall shift towards the expression of slower MHC isoforms. Amino acid supplementation produced a shift towards the expression of faster MHC isoforms in the soleus and diaphragm muscles, and partially antagonized the effects of training. Immunohistochemical analysis of CSA of individual muscle fibers from the soleus muscle suggests that voluntary running produced a decrease in the size of type 1 fibers, and amino acid supplementation during training resulted in an increase in size in both type 1 and type 2A fibers. Collectively, these results suggest that the endurance adaptations induced by voluntary running depend on the muscle type, and that amino acid supplementation is able to modulate both fiber size and MHC isoform composition of skeletal muscles in sedentary and exercised mice.

Effects of oral amino acid supplementation on myocardial function in patients with type 2 diabetes mellitus.

BACKGROUND: Diabetes mellitus is associated with an increased rate of cardiac amino acid catabolism that could interfere with cardiac function. METHODS: We assessed the effects of an oral amino acids mixture (AAM) on myocardial function in patients with type 2 diabetes mellitus (DM2). We studied 65 consecutive patients with DM2 who had normal resting left ventricular ejection fraction (LVEF) and did not have obstructive coronary artery disease (CAD). After baseline evaluations, patients were randomized to receive, in a single-blinded fashion, AAM (12 grams/day) or placebo for 12 weeks, after which, treatment was crossed over for another similar period. At baseline and at the end of each treatment, 2-dimensional ecocardiography at rest and during isometric exercise (handgrip) was performed, as were biochemical assays. Twenty adults, matched for age, sex, and body mass index served as control subjects. RESULTS: At baseline and during AAM or placebo treatment, resting left ventricular dimensions and LVEF in patients with DM2 did not differ from those of control subjects. In patients with DM2, at baseline and during placebo treatment, peak handgrip LVEF decreased significantly in comparison with the resting value (63% +/- 9% vs 56% +/- 9%, P <.001; and 62% +/- 6% vs 55% +/- 8%, P <.001). During AAM treatment, peak handgrip LVEF did not differ from resting value (66% +/- 11% vs 64% +/- 9%, P = not significant). Thus, exercise LVEF was higher during AAM treatment than both baseline and placebo treatment (66% +/- 11% vs 56% +/- 9% and vs 55% +/- 8%, P <.001). In contrast to placebo treatment, after the AAM supply, a decreased glycated hemoglobin level was observed (7.0% +/- 1.3% vs 7.6% +/- 1.8%, P <.05). CONCLUSIONS: Myocardial dysfunction is easily inducible with isometric exercise in patients with DM2 who have normal resting LV function and do not have CAD. An increased amino acid supply prevents this phenomenon and improves metabolic control.

Malnutrition, muscle wasting and cachexia in chronic heart failure: the nutritional approach.

Malnutrition, muscle wasting and cachexia are often present in chronic heart failure (CHF). However, malnutrition in CHF patients is not always as severe as muscle wasting. Data in the literature show that 24% of CHF patients have malnutrition (albumin < 3.5 mg/dl) but 68% have muscle atrophy. This apparent discrepancy can be explained by considering the metabolic role of the striate muscle. In fact, the striate muscle maintains the body metabolic performance by continuous exchanges of fuels (amino acids) with the liver. This happens in case of malnutrition or starvation. In such situations, glucose is produced by gluconeogenesis when amino acids are metabolized in the liver. Malnutrition, muscle wasting and the frequent progression through cachexia can be reduced by specific therapy such as cytokine and/or catabolic hormone antagonists. This is because cytokines and catabolic hormones, with consequent insulin resistance, cause muscle wasting. An alternative and/or complementary therapy may be exogenous amino acid supplementation. In fact, amino acids: a) are rapidly absorbed regardless of pancreatic activity, b) reduce insulin resistance, c) induce the hepatic synthesis of anabolic molecules such as growth hormone and insulin-like growth factor, and d) modulate the catabolic hormonal-mediated effects on adipocytes. Research on the best suitable qualitative and quantitative amino acid composition for an alternative and/or complementary therapy is still being studied in different research centers.