Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit?

Metabolic remodelling is an integral part of the pathogenesis of heart failure. Although much progress has been made in our current understanding of the metabolic impairment involving carbohydrates and fatty acids in failing hearts, relatively little is known about the changes and potential impact of amino acid metabolism in the onset of heart diseases. Although most amino acid catabolic activities are found in the liver, branched-chain amino acid (BCAA) catabolism requires activity in several non-hepatic tissues, including cardiac muscle, diaphragm, brain and kidney. In this review, the new insights into the regulation of cardiac BCAA catabolism and functional impact on cardiac development and physiology will be discussed along with the potential contribution of impairment in BCAA catabolism to heart diseases. A particular focus will be the new information obtained from recently developed genetic models with BCAA catabolic defects and metabolomic studies in human and animal models. These studies have revealed the potential role of BCAA catabolism in cardiac pathophysiology and have helped to distinguish BCAA metabolic defects as an under-appreciated culprit in cardiac diseases rather than an epiphenomenon associated with metabolic remodelling in the failing heart.     

Epilepsy and the gut: Perpetrator or victim?

The brain and the gut are linked together with a complex, bi-path link known as the gut-brain axis through the central and enteric nervous systems. So, the brain directly affects and controls the gut through various neurocrine and endocrine processes, and the gut impacts the brain via different mechanisms. Epilepsy is a central nervous system (CNS) disorder with abnormal brain activity, causing repeated seizures due to a transient excessive or synchronous alteration in the brain’s electrical activity. Due to the strong relationship between the enteric and the CNS, gastrointestinal dysfunction may increase the risk of epilepsy. Meanwhile, about 2.5% of patients with epilepsy were misdiagnosed as having gastrointestinal disorders, especially in children below the age of one year. Gut dysbiosis also has a significant role in epileptogenesis. Epilepsy, in turn, affects the gastrointestinal tract in different forms, such as abdominal aura, epilepsy with abdominal pain, and the adverse effects of medications on the gut and the gut microbiota. Epilepsy with abdominal pain, a type of temporal lobe epilepsy, is an uncommon cause of abdominal pain. Epilepsy also can present with postictal states with gastrointestinal manifestations such as postictal hypersalivation, hyperphagia, or compulsive water drinking. At the same time, antiseizure medications have many gastrointestinal side effects. On the other hand, some antiseizure medications may improve some gastrointestinal diseases. Many gut manipulations were used successfully to manage epilepsy. Prebiotics, probiotics, synbiotics, postbiotics, a ketogenic diet, fecal microbiota transplantation, and vagus nerve stimulation were used successfully to treat some patients with epilepsy. Other manipulations, such as omental transposition, still need more studies. This narrative review will discuss the different ways the gut and epilepsy affect each other.     

Fusobacterium nucleatum: an emerging gut pathogen?

The Gram-negative, non-sporulating, obligately anaerobic species, Fusobacterium nucleatum, is rapidly gaining notoriety as a pathogen with a surprising number of associated diseases. Recently, we have found that F. nucleatum is a more common resident of the GI tract than originally thought, and thus, through several studies, we have attempted to determine its gut-relevant potential for virulence. We have found that F. nucleatum possesses a number of pathogenic traits with relevance to gut diseases such as inflammatory bowel disease (IBD), however, we have also documented strain-associated differences in virulence. An intriguing picture emerges that paints F. nucleatum as both conferring beneficial as well as detrimental effects on host cells; and we suggest that the ultimate effects of F. nucleatum infection in the gut are a consequence of the microbes with which this species aggregates.     

A unifying hypothesis for the functional gastrointestinal disorders: really multiple diseases or one irritable gut?

The functional gastrointestinal disorders are defined by the Rome criteria as a heterogeneous group of symptom-based conditions that have no structural or biochemical explanation. However, this definition now seems outdated, because structural and molecular abnormalities have begun to be recognized in subsets of patients with the irritable bowel syndrome (IBS), the prototypic functional bowel disease. A complex classification system based arbitrarily on symptom criteria does not fit in with a number of emerging facts. For example, the symptom overlap of IBS with gastroesophageal reflux disease is not due to chance, and the emergence of post-infectious IBS, dyspepsia, or both after Salmonella gastroenteritis fits better with a 1-disease model. A new paradigm seems to be needed. All of these disorders may arise after infection or gut inflammation, but the phenotype depends on localized neuromuscular dysfunction in the predisposed human host (the "irritable gut").     

Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?

Hepatic encephalopathy (HE) is a serious complication of acute and chronic liver disease associated with severe morbidity and mortality. We performed updated random effects meta-analyses to evaluate the evidence for non-absorbable disaccharides (lactulose and lactitol), rifaximin and branched chain amino acids (BCAA). A meta-analysis of randomized trials showed that, compared with placebo or no intervention, non-absorbable disaccharides have beneficial effects on HE manifestations and prevention of HE episodes. The addition of rifaximin to non-absorbable disaccharides versus rifaximin alone was more beneficial than non-absorbable disaccharides used alone on both outcome measures. Likewise, a meta-analysis of randomised controlled trials found that oral BCAA supplements have beneficial effects on manifestations of HE compared with control supplements. The effect was found in a variety of clinical settings. No convincing effects of intravenous BCAA for episodic HE were identified. In conclusion, evidence-based treatment recommendations for patients with HE should include non-absorbable disaccharides combined with rifaximin or BCAA. Additional evidence is needed to evaluate the effect of combining all three interventions.     

Is the local acid output an important factor for Helicobacter pylori colonization?

BACKGROUND/AIMS: Low local acid production is considered to be an important factor for Helicobacter pylori colonization. The increased bacterial density and inflammation are expected in cardiac mucosa because of low acid secretion. We aimed to investigate the bacterial density and the histologic pattern of gastritis in the cardia, and to compare with those of the antrum and corpus. METHODOLOGY: The biopsy specimens taken from the antrum, corpus and cardia in 97 patients during endoscopy were examined histopathologically. RESULTS: The mean scores for bacterial density in the cardia, corpus and antrum were 1.32 +/- 0.35, 1.09 +/- 0.86, 1.42 +/- 0.97, respectively. Bacterial density of the cardia was significantly higher than that in corpus, but was similar to the antrum. The mean scores for the degree of gastritis in the cardia, corpus and antrum were 1.56 +/- 0.79, 1.64 +/- 0.75, 1.85 +/- 0.77, respectively. Gastritis was significantly more severe in the antrum than in the corpus and cardia. The activity scores of gastritis in the three regions were statistically similar. CONCLUSIONS: Although bacterial density in the cardiac mucosa were found to be high, the degree of gastritis was low.     

Is branched-chain amino acid nutritional supplementation beneficial or detrimental in heart failure?

Sarcopenia or cachexia is often complicated in heart failure. Nutritional support, particularly branched-chain amino acid(BCAA) supplementation, is a candidate treatment for improving sarcopenia or cachexia in elderly patients. However, the efficacy of BCAA supplementation in patients with heart failure has not been established, and the issue is comparatively more complex. Indeed, there are conflicting reports on the efficacy of BCAA supplementation. The evidence for including BCAA supplementation in treating patients with heart failure was reviewed, and the complexity of the issue was discussed.     

Uric acid in hypertension and renal disease: the chicken or the egg?

After uric acid was recognized as the causative factor in gout, increased prevalence of renal disease and hypertension in this patient population caught the attention of the medical community. Thus, it has been proposed that uric acid might have caused these disorders. However, uric acid suffered a long period of ignorance in which it was considered a metabolically inert substance. However, recent years has witnessed a resurrection of interest. Experimental studies showed an association between increased uric acid and renal arteriolar disease and hypertension. These preliminary results were supported with clinical studies. However, controversy regarding the precise pathophysiologic role of uric acid in inducing hypertension and renal disease remains to be elucidated. Despite being limited at this time, a few randomized intervention studies showed that even treatment of asymptomatic hyperuricemia was beneficial in terms of blood pressure regulation and kidney function. In this review, we focus on the pathophysiologic role of uric acid in the development and progression of renal disease and hypertension. We also discuss recent clinical evidence suggesting a causal role of uric acid in these disease states.     

Fluoroquinolones in paediatrics: a risk for the patient or for the community?

Fluoroquinolones are an important group of antibiotics widely used in adult patients because of their excellent tissue penetration and their bactericidal activity. They are not authorised for paediatric use (except the limited indication of pseudomonas infections in cystic fibrosis), however, because of the potential for joint toxicity reported from experiments with young animals. Despite the absence of official approval, fluoroquinolones are widely used in paediatrics as second-line antibiotics when all other treatments have failed. Most of the information available about paediatric use concerns ciprofloxacin, which is used in children much more often than the other members of this class. The published paediatric series have shown that frequency of articular side-effects varies according to age: all the surveys have reported frequencies of around 0.1% in adults and 2-3% in children. Outside of cystic fibrosis and severe infections in which no other treatment is possible, the only paediatric situations where fluoroquinolones are superior to standard treatments for children, in speed of recovery and comfort as well as in efficacy, are typhoid fever, severe shigella dysenteries, and enterobacteria meningitis. Should the use of new fluoroquinolones active against pneumococci be authorised for upper respiratory infections (including recurrent otitis) in children, the potential emergence and dissemination of pneumococci strains in which multidrug resistance includes fluoroquinolones would create a real risk in the community. It is, therefore, important to continue the policy of second-line use in children, only after failure of an earlier treatment, and when other antibiotics approved for paediatric use cannot be used.     

Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?

Elevated serum uric acid (SUA) levels are commonly seen in patients with the metabolic syndrome (MetS). Several mechanisms, both direct and indirect, connect the increased SUA levels with the established diagnostic criteria of MetS. It is possible that the increased cardiovascular disease risk associated with the MetS is partially attributed to elevated circulating SUA concentration. Several drugs used in the treatment of MetS may alter SUA levels. Thus, lifestyle measures together with the judicious selection of drugs for the treatment of hypertension, dyslipidemia, and insulin resistance associated with MetS may result in a reduction of SUA levels and possibly cardiovascular disease risk. This review summarizes the pathophysiologic association between SUA and MetS and focuses on the prevention of hyperuricemia and its cardiovascular consequences.