Targeting the gut microbiome in coronary artery disease

Host-microbiota interactions via numerous inflammatory and metabolic pathways contribute to the pathogenesis of a multitude of diseases such as cardiovascular and metabolic diseases.1 Alterations in the microbial flora generate increased circulating levels of microbiota-dependent metabolites associated with disease risk.2 One such metabolite, trimethylamine N-oxide (TMAO), is formed from the metabolism of phosphatidylcholine or L-carnitine into trimethylamine by bacteria, which is converted to TMAO in the liver by flavin-containing monooxygenases (FMO).3 While TMAO is the most commonly studied gut microbiota-derived metabolite demonstrating associations with heart failure,3 myocardial infarction4 and heart disease,5 precursor metabolites to TMAO have also shown similar associations with cardiovascular disease (CVD) risk such as betaine,6 choline,6 γ-butyrobetaine7 and more recently, acetyl-L-carnitine and L-carnitine.8 Given that TMAO can be generated from two pathways; 1) betaine -> choline -> TMAO and 2) carnitine -> TMAO, this demonstrates that TMAO levels are determined from a multitude of sources including dietary (e.g., carnitine from red meat and choline from eggs), microbial flora, medications (e.g., antibiotics), liver flavin monooxygenase activity, as well as age, gender and ethnicity.9., 10., 11. [Opening paragraph

Multiple hormone deficiency syndrome: a novel topic in chronic heart failure.

[First paragraph] Heart failure (HF) is described as a clinical syndrome characterized by typical symptoms (e.g., ankle swelling, fatigue or dyspnea) or signs (e.g., peripheral edema, pulmonary crackles or elevated jugular venous pressure), in which structural and/or functional cardiac abnormalities induce an impairment of cardiac output or an increase of intracardiac pressures at rest and/or during stress [1,2]. Importantly, due to different underlying etiologies, demographics, co-morbidities, and response to therapies, the main terminology used to describe HF is based on measurement of left ventricle ejection fraction (EF). Classically, patients with normal EF (typically considered as ≥50%) are said to have HF with preserved EF (HFpEF), with those with reduced EF (typically considered as <40%) termed as HF with reduced EF (HFrEF). In the latest European Society of Cardiology guidelines, cases where EF lies between 40 and 49%, previously considered as a ‘gray area’, are now defined as HF with mid-range EF (HFmEF) [1]

Impact of acute choline loading on circulating trimethylamine N-oxide levels.

Despite recent efforts to reduce cardiovascular disease risk by dietary intervention,1few markers are useful to assess the efficiency and progress of this. Circulating levels of trimethylamine N-oxide (TMAO) are associated with poor outcomes of cardiovascular disease.2–6TMAO is generated via hepatic flavin monooxygenase 3 (FMO3) mediated oxidation of trimethylamine (TMA),7derived largely from carnitine and choline through gut microbial metabolism. These substrates are found in red meat and eggs, which are representative of a Western diet. Therefore, TMAO levels could be used to monitor the effect of dietary intervention, particularly for the consumption of a Western diet. In this study, we examined the effect of acute choline loading on TMAO levels in healthy adult volunteers

Bowel Angiodysplasia and Myocardial Infarction secondary to an ischaemic imbalance: a case report.

Angiodysplasia, defined as a vascular ectasia or arteriovenous malformation, is the most frequent cause of occult bleeding in patients older than 60 years and a significant association with several cardiac condition is described. Patients with anemia and negative findings on upper endoscopy and colonoscopy should be referred for further investigation of the small bowel. The investigation of choice, when available, is wireless capsule endoscopy. Several therapeutic options are available in this cases, as we reviewed in this report. We report a case of 78-year old man admitted to our Intensive Coronary Unit for dyspnea and chest pain. A diagnosis of non-ST-segment elevation acute coronary syndrome was made and a concomintant, significant anemia was found (hemoglobin 8.2 g/dl). No cororary disease was found by an angiography though the past medical history revealed systemic hypertension, chronic kidney disease (KDOQY stage III), and diabetes mellitus type II on insuline therapy. A Wireless Video capsule examination was positive for jejunum angiodysplasia and an argon plasma coagulation was chosen as terapeutic option. No subsequent supportive therapy and interventions were required in subsequent one year of follow-up

The impairment of the Growth Hormone/Insulin-like growth factor 1 (IGF-1) axis in heart failure: A possible target for future therapy

Hormonal abnormalities are quite common in chronic heart failure (CHF). The most studied hormonal axis in CHF is the impairment of Growth Hormone (GH)/Insulin Growth Factor-1(IGF-1), which in turn is defined either by a blunted response to GH stimulation test or low serum IGF-1 values. Several independent groups reported that the presence of an abnormal GH/IGF-1 status in CHF is associated with a more severe disease, impaired functional capacity and reduced Survival rates. After the first encouraging results, double -blind controlled trials showed a neutral effect of the GH administration in patients. However, further studies reported positive results, when a GH-therapy is implemented only in those patients presenting a GH deficiency (replacement therapy)

Biomarkers in Heart Failure: Clinical Insights

Heart failure (HF) is a clinical syndrome caused by structural and/or functional cardiac abnormalities and resulting from impaired cardiac output or an in-crease of intracardiac pressures at rest and/or during stress. Typical signs and symptoms of HF include ankle swelling, fatigue, dyspnea and peripheral edema, pulmonary crackles, or increased jugular venous pressure. Usually, patients with ejection fraction (EF) greater than or equal to 50% are defined as HF with preserved EF, where as those with EF less than 40% have HF with reduced EF. Patients with EF between 40% and 49% are now classified as HF with midrange EF

The Tosca Registry: An Ongoing, Observational, Multicenter Registry for Chronic Heart Failure.

The ageing of the population in western countries, the continuous increase of the prevalence of chronic diseases, the frequent coexistence of several morbid conditions (comorbidity) requires health professionals and Institutions to face difficult challenges, including increasing costs, need for more effective and sustainable therapies, and organizational issues. The European Innovation Partnership on Active and Healthy Ageing aims at enabling European citizens to lead healthy, active and independent lives while ageing. We herein discuss some key concepts bearing a special significance in the light of the Partnership aims, and present research and educational projects active in our local environment. Among these, the multicentre project TOSCA (Trattamento Ormonale nello Scompenso CArdiaco) that, although primarily focused on the understanding of the interactions between hormones and chronic heart failure (CHF), is also aimed at developing more effective models of clinical care. We provide the scientific background and current stage of the project. In the context of a growing complexity of the patients' clinical management, the polipharmacy is a new arising challenge for clinicians, bearing direct economic, organizational and clinical implications. A better understanding, characterization and management of this issue represent an additional target of the TOSCA network

Surrogate markers of gut dysfunction are related to heart failure severity and outcome–from the BIOSTAT-CHF consortium

Background: The contribution of gut dysfunction to heart failure (HF) pathophysiology is not routinely assessed. We sought to investigate whether biomarkers of gut dysfunction would be useful in assessment of HF (eg, severity, adverse outcomes) and risk stratification. Methods: A panel of gut-related biomarkers including metabolites of the choline/carnitine- pathway (acetyl-L-carnitine, betaine, choline, γ-butyrobetaine, L-carnitine and trimethylamine-N-oxide [TMAO]) and the gut peptide, Trefoil factor-3 (TFF-3), were investigated in 1,783 patients with worsening HF enrolled in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) cohort and associations with HF severity and outcomes, and use in risk stratification were assessed. Results: Metabolites of the carnitine-TMAO pathway (acetyl-L-carnitine, γ-butyrobetaine, L-carnitine, and TMAO) and TFF-3 were associated with the composite outcome of HF hospitalization or all-cause mortality at 3 years (hazards ratio [HR] 2.04-2.93 [95% confidence interval {CI} 1.30-4.71] P≤.002). Combining the carnitine-TMAO metabolites with TFF-3, as a gut dysfunction panel, showed a graded association; a greater number of elevated markers was associated with higher New York Heart Association class (P<.001), higher plasma concentrations of B-type natriuretic peptide (P<.001), and worse outcome (HR 1.90-4.58 [95% CI 1.19-6.74] P≤ 0.008). Addition of gut dysfunction biomarkers to the contemporary BIOSTAT HF risk model also improved prediction for the aforementioned composite outcome (C-statistics P≤.011, NRI 13.5-21.1 [95% CI 2.7-31.9] P≤.014). Conclusions: A panel of biomarkers of gut dysfunction showed graded association with severity of HF and adverse outcomes. Biomarkers as surrogate markers are potentially useful for assessment of gut dysfunction to HF pathophysiology and in risk stratification

Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study.

BACKGROUND: Although mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD. METHODS: One-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6±1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6±1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay. RESULTS: GHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure (-11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (β = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (β = 2.23, SE = 1.20, p = .02) and NT-proBNP (β = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF. CONCLUSIONS: GH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality