Explore the vast range of titles available.

In the last few years, in the context of a growing interest in investigating novel pathways involved in heart failure (HF) pathophysiology, the association between the gastrointestinal (GI) system and HF represents an important model of attention, the so called ‘gut hypothesis’.1–3 Despite being classically identified as a ‘simple’ intestinal dysfunction, the main hypothesis is currently focused on the role of inflammation and oxidative stress as a consequence of the intestinal wall ischaemia and/or congestion induced by HF, determining a gut barrier dysfunction and resulting in an increased gut bacterial translocation.1–3 With this in mind, two main mechanisms have been proposed to link gut dysfunction and HF; (i) metabolism dependent, via gut-derived metabolites entering the systemic circulation and exerting pro-atherogenic effects and pro-inflammatory effects and (ii) metabolism independent, via bacterial components (e.g. lipopolysaccharides and endotoxins) translocating in the systemic circulation and contributing to the systemic inflammatory state with its well-known negative effects on HF.4 To date, most of the research has identified a choline and L-carnitine metabolic by-product, trimethylamine N-oxide (TMAO), derived by the gut microbiota from the precursor trimethylamine (TMA) and subsequent oxidation via the liver enzyme flavin-containing monooxygenase 3 (FMO3) (see Figure 1), as the key useful prognostic biomarker in several cardiovascular diseases (e.g. coronary artery disease, acute myocardial infarction, and HF), with an interesting role in risk stratification.5,6 Notably, TMAO, produced through the anaerobic metabolism of choline and carnitine containing molecules, is widely considered as the possible missing link between the consumption of a Western diet and the well-known increased cardiovascular diseases risk observed in the Western population.7 Indeed, TMAO is produced through the anaerobic metabolism of choline and L-carnitine, of which eggs and red meat are rich in the Western diet (i.e., based on high fat foods), and diet can be considered as one the of most important factors affecting the gut microbiota composition.8 [IMAGE OMITTED. SEE PDF] Amongst the cardiovascular diseases, HF represents a widely investigated disease for association with the gut, with evidence available in both reduced (HFrEF)9–21 and preserved (HFpEF)22–27 phenotypes, as well as in acute12,13,28–30 and chronic setting9–11,14–25,27 (see Table 1). From a pathophysiological point of view, TMAO pathway affects HF in different ways.1,3 First, TMAO increases the risk of conditions determining HF (i.e. cardiac ischemic diseases), through its pro-atherosclerotic effects mediated by an increase in the expression of macrophage scavenger receptors with development of foam cells in the arterial wall, increasing thrombosis, increasing platelet reactivity, and causing endothelial dysfunction.1,3 Second, TMAO increases HF susceptibility, directly acting on myocardial remodelling and fibrosis; in addition, it has been speculated that TMAO, being an organic osmolyte, altered cellular osmosis; lastly, it has been showed that TMAO worsens cardiomyocyte contractility, by acting on calcium cellular fluxes.1,3 Worthy to be mentioned is the relationship between TMAO and renal function, with a possible effect on renal fibrosis and tubular injury further aggravating HF clinic.1,3 Table 1 Main reports for associations between trimethylamine N-oxide and outcome in heart failure patients First author; year of publication Location Study population Follow-up length Main findings Trimethylamine N-oxide levels (μmol/L) Tang WH 20149 USA CHF, N = 720 5 years TMAO levels are associated with all-cause mortality 5.0 (3.0–8.5) Tang WH 201510 USA CHF, N = 112 5 years TMAO levels are associated with all-cause mortality and heart transplantation 5.8 (3.6–12.1) Trøseid M 201511 Norway CHF N = 115 5.2 years TMAO levels are associated with all-cause mortality and heart transplantation 13.5 ± 18.5 (CAD), 7.1 ± 5.6 (DCM) Suzuki T 201612 UK AHF, N = 972 1 years TMAO levels are associated with all-cause mortality and a composite mortality/rehospitalization 5.6 (3.4–10.5) Schuett K 201722 Germany CHF (pEF and rEF), N = 823 9.7 years TMAO levels are associated with all-cause mortality and cardiovascular mortality 4.7 (3.4–6.8) rEF, 4.7 (3.2–6.9) pEF Hayashi T 201813 Japan Decomp HF, N = 22 Cross-sectional TMAO levels (during decompensation and during compensation phases) and gut microbiome composition were altered compared with control subjects 17.3 ± 11.7 (Decomp), 17.7 ± 12.6 (Comp) Salzano A 201923 UK CHF (pEF and rEF), pEF = 118 vs rEF = 38 vs C = 40, N = 196 5 years TMAO levels are associated with mortality in pEF Use of levels of TMAO for risk stratification of long-term mortality in pEF 6.6 (4.3–12.2) pEF, 8.4 (3.7–13.8) rEF Suzuki T 201914 11 European countries Worsening or new-onset HF, N = 2234 3 years TMAO levels are associated with all-cause mortality and a composite of mortality/rehospitalization 5.9 (3.6–10.8) Yazaki Y 201931 11 European countries Worsening or new-onset HF, N = 2234 2 years TMAO levels of HF patients differed by region TMAO levels associated with risk of mortality CE > NW/S 6.2 (4.8–7.8) CE, 7.2 (5.5–8.8) NW, 6.5 (5.0–8.2) S Zhou X 202016 China HFrEF after MI, N = 1208 4 years TMAO levels are associated with major adverse cardiac events (MACE): all-cause mortality, HF rehospitalization, or recurrent MI, and all-cause mortality 4.5 Yazaki Y 202028 UK AHF, N = 1087 1 year TMAO levels are associated with a composite of all-cause mortality and/or rehospitalization 5.2–22.8 (Japanese), 3.6–10.8 (Caucasian), 3.1–8.4 (South Asian) Guo F 202024 China HFpEF, N = 228 5 years TMAO levels are independent predictor of new onset HF TMAO levels are independent risk factor of renal dysfunction 12.65 (9.32–18.66) Emoto T 202125 CHF (pEF and rEF), CHF = 22 vs C = 11, N = 33 TMAO levels are increased in Japanese HF compared to Caucasian/South Asian HF abundance of cntA/B positively correlated with TMAO 4.5–34.5 Papandreou C 202117 Spain CHF (pEF and rEF), AF = 509 vs C = 618, CHF = 326 vs C = 426, N = 1879 10 years TMAO levels are not associated with AF and HF incidence 3.0–8.5 Kinugasa Y 2021 26 Japan HFpEF, N = 146 5 years TMAO levels are associated with a composite endpoint of cardiac mortality and hospitalization for HF 20.37 Israr MZ 202130 UK AHF, N = 806 1 years TMAO levels are associated with all-cause mortality and a composite of all-cause mortality and/or rehospitalization caused by HF 10.2 (5.8–18.7) Dong Z 202127 China HFpEF, CHF = 61 vs C = 57, N = 118 1 years TMAO levels are independent risk factor for HFpEF 6.84 Yuzefpolskaya M 202118 USA CHF, N = 341 2 years + 8 months TMAO levels increased with HF severity and were similarly elevated, long term after LVAD and HT. TMAO levels positively related to biomarkers of inflammation (TNF-α and ET-1), endotoxemia (sCD14), and oxidative stress 6.96 (HF), 5.81 (LVAD), 5.35 (HT) Mollar A 202119 Spain Decomp HF, N = 102 1 years TMAO related with recent HF Wargny M 202232 France AHF, AHF = 209 vs C = 1140, N = 1468 7.3 years TMAO is not associated with occurrence of HF requiring hospitalization (HFrH) and composite event HFrH and/or cardiovascular mortality and all-cause mortality. 8.8 (5.3–17.0) Li N 202229 China AMI and HF, N = 985 1 years TMAO levels independently correlated with poor prognosis (i.e.: MACE, and all-cause mortality) and recurrence of MI in patients with AMI complicated by HF, especially in those with higher hsCRP levels TMAO the difference for rehospitalization due to HF is not statistically significant 6.7 (4.0, 11.7) Wei H 202220 China HFrEF, N = 955 8 years TMAO levels are associated with the composite outcome of cardiovascular death or heart transplantation 2.52 (1.18–4.06) Israr MZ 202221 UK HFrEF, N = 1783 3 years TMAO levels are associated with the composite outcome of HF hospitalization or death at 3 years 6.4 (3.9–11.6) From a clinical point of view, since the first investigations regarding the association between TMAO and HFrEF as of about 10 years ago,9 several studies have demonstrated that TMAO levels were higher in CHF when compared with healthy controls showing associations between TMAO and clinical and biochemical parameters (i.e., renal function, age, comorbidities, and CRP), severity of disease (NYHA classes),15,18 and clinical outcomes (death, HF hospitalization, composite).9–21 As a prototype, in the BIOSTAT-CHF (BIOlogy Study to TAilored Treatment in Chronic Heart Failure) population, in which 2234 patients with new-onset or progressively worsening HF have been investigated, TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) at different time-points (1, 2, and 3 years).14 Despite being the most prevalent phenotype in HF, only a few studies (when compared with the numerosity of study about HFrEF phenotype) have investigated the association of TMAO with outcome in HFpEF subjects.22–27 The Developing Imaging And plasMa biOmarkers iN Describing Heart Failure With Preserved Ejection Fraction (DIAMONDHFpEF) cohort showed that TMAO was associated with adverse outcome in HFpEF and that its use allows a better stratification of HFpEF patients when used in combination with BNP.23 Considering that natriuretic peptides are not as highly elevated in HFpEF compared with HFrEF, in this cohort elevated TMAO levels improved risk stratification of patients in which BNP levels show equivocal levels.

Heart failure with preserved ejection fraction (HFpEF) represents the most common HF phenotype of patients aged > 65 years, with an incidence and a prevalence that are constantly growing. The HFpEF cardinal symptom is exercise intolerance (EI), defined as the impaired ability to perform physical activity and to reach the predicted age-related level of exercise duration in the absence of symptoms—such as fatigue or dyspnea—and is associated with a poor quality of life, a higher number of hospitalizations, and poor outcomes. The evidence of the protective effect between exercise and adverse cardiovascular outcomes is numerous and long-established. Regular exercise is known to reduce cardiovascular events and overall mortality both in apparently healthy individuals and in patients with established cardiovascular disease, representing a cornerstone in the prevention and treatment of many cardio-metabolic conditions. Several studies have investigated the role of exercise in HFpEF patients. The present review aims to dwell upon the effects of exercise on HFpEF. For this purpose, the relevant data from a literature search (PubMed, EMBASE, and Medline) were reviewed. The analysis of these studies underlines the fact that exercise training programs improve the cardiorespiratory performance of HFpEF patients in terms of the increase in peak oxygen uptake, the 6 min walk test distance, and the ventilatory threshold; on the other hand, diastolic or systolic functions are generally unchanged or only partially modified by exercise, suggesting that multiple mechanisms contribute to the improvement of exercise tolerance in HFpEF patients. In conclusion, considering that exercise training programs are able to improve the cardiorespiratory performance of HFpEF patients, the prescription of exercise training programs should be encouraged in stable HFpEF patients, and further research is needed to better elucidate the pathophysiological mechanisms underpinning the beneficial effects described.

Heart failure (HF) is a clinical syndrome consisting of typical symptoms and signs due to structural and/or functional abnormalities of the heart, resulting in elevated intracardiac pressures and/or inadequate cardiac output. The vascular system plays a crucial role in the development and progression of HF regardless of ejection fraction, with endothelial dysfunction (ED) as one of the principal features of HF. The main ED manifestations (i.e., impaired endothelium-dependent vasodilation, increased oxidative stress, chronic inflammation, leukocyte adhesion, and endothelial cell senescence) affect the systemic and pulmonary haemodynamic and the renal and coronary circulation. The present review is aimed to discuss the contribution of ED to HF pathophysiology—in particular, HF with preserved ejection fraction—ED role in HF patients, and the possible effects of pharmacological and non-pharmacological approaches. For this purpose, relevant data from a literature search (PubMed, Scopus, EMBASE, and Medline) were reviewed. As a result, ED, assessed via venous occlusion plethysmography or flow-mediated dilation, was shown to be independently associated with poor outcomes in HF patients (e.g., mortality, cardiovascular events, and hospitalization due to worsening HF). In addition, SGLT2 inhibitors, endothelin antagonists, endothelial nitric oxide synthase cofactors, antioxidants, and exercise training were shown to positively modulate ED in HF. Despite the need for future research to better clarify the role of the vascular endothelium in HF, ED represents an interesting and promising potential therapeutic target.

Aims The aim of this study was to investigate whether ethnicity influences the associations between trimethylamine N‐oxide (TMAO) levels and heart failure (HF) outcomes. Methods and results Trimethylamine N‐oxide levels were measured in two cohorts with acute HF at two sites. The UK Leicester cohort consisted mainly of Caucasian (n = 842, 77%) and South Asian (n = 129, 12%) patients, whereas patients in the Japanese cohort (n = 116, 11%) were all Japanese. The primary endpoint was the measurement of all‐cause mortality and/or HF rehospitalization within 1 year post‐admission. Association of TMAO levels with outcome was compared in the entire population and between ethnic groups after adjustment for clinical parameters. TMAO levels were significantly higher in Japanese patients [median (interquartile range): 9.9 μM (5.2–22.8)] than in Caucasian [5.9 μM (3.6–10.8)] and South Asian [4.5 μM (3.1–8.4)] (P < 0.001) patients. There were no differences in the rate of mortality and/or HF rehospitalization between the ethnic groups (P = 0.096). Overall, higher TMAO levels showed associations with mortality and/or rehospitalization after adjustment for confounders ( P = 0.002). Despite no differences between ethnicity and association with mortality/HF after adjustment (P = 0.311), only in Caucasian patients were TMAO levels able to stratify for a mortality/HF event (P < 0.001). Conclusions Differences were observed in the association of mortality and/or rehospitalization based on circulating TMAO levels. Elevated TMAO levels in Caucasian patients showed increased association with adverse outcomes, but not in non‐Caucasian patients.

Trimethylamine N-oxide (TMAO), a gut-related metabolite, is associated with heart failure (HF) outcomes. However, TMAO is the final product of a complex metabolic pathway (ie, choline/carnitine) that has never been entirely investigated in HF. The present study investigates a panel of metabolites involved in the TMAO-choline/carnitine metabolic pathway for their associations with outcome in acute HF patients. In total, 806 plasma samples from acute HF patients were analyzed for TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, γ-butyrobetaine, crotonobetaine, trimethylamine, betaine aldehyde, choline, and betaine using a developed liquid chromatography-tandem mass spectrometry method. Associations with outcome of all-cause mortality (death) and a composite of all-cause mortality and/or rehospitalization caused by HF (death/HF) at 30 days and 1 year were investigated. TMAO, trimethyllysine, L-carnitine, acetyl-L-carnitine, and γ-butyrobetaine were associated with death and death/HF at 30 days (short term; hazard ratio 1.30-1.49, P≤ .021) and at 1 year (long term; hazard ratio 1.15-1.25, P≤ .026) when adjusted for cardiac risk factors. L-carnitine and acetyl-L-carnitine were superior for short-term outcomes whereas TMAO was the superior metabolite for association with long-term outcomes. Furthermore, acetyl-L-carnitine and L-carnitine were superior for in-hospital mortality and improved risk stratification when combined with current clinical risk scores (ie, Acute Decompensated HEart Failure National REgistry, Organized Program To Initiate Lifesaving Treatment In Hospitalized Patients With Heart Failure, and Get With The Guidelines-Heart Failure; odds ratio (OR) ≥ 1.52, P≤ .020). Carnitine-related metabolites show associations with adverse outcomes in acute HF, in particular L-carnitine and acetyl-L-carnitine for short-term outcomes, and TMAO for long-term outcomes. Further studies are warranted to investigate the role and implications of carnitine metabolites including intervention in the pathogenesis of HF.

•Gut-related metabolites are impaired in patients with COVID-19.•Dietary markers of gut health are associated with COVID-19 symptoms (breathlessness and temperature).•A trend of worse mortality from COVID-19 is shown in patients with reduced levels of betaine. Gut-related metabolites have been linked with respiratory disease. The crosstalk between the gut and lungs suggests that gut health may be compromised in COVID-19. The aims of the present study were to analyze a panel of gut-related metabolites (acetyl-L-carnitine, betaine, choline, L-carnitine, trimethylamine, and trimethylamine N-oxide) in patients with COVID-19, matched with healthy individuals and patients with non-COVID-19 respiratory symptoms. As results, metabolites from this panel were impaired in patients with COVID-19 and were associated with the symptoms of breathlessness and temperature, and it was possible to differentiate between COVID-19 and asthma. Preliminary results showed that lower levels of betaine appeared to be associated with poor outcomes in patients with COVID-19, suggesting betaine as a marker of gut microbiome health.

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. 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. 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). 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.

Myocarditis is a disease caused by cardiac inflammation that can progress to dilated cardiomyopathy, heart failure, and eventually death. Several etiologies, including autoimmune, drug-induced, and infectious, lead to inflammation, which causes damage to the myocardium, followed by remodeling and fibrosis. Although there has been an increasing understanding of pathophysiology, early and accurate diagnosis, and effective treatment remain challenging due to the high heterogeneity. As a result, many patients have poor prognosis, with those surviving at risk of long-term sequelae. Current diagnostic methods, including imaging and endomyocardial biopsy, are, at times, expensive, invasive, and not always performed early enough to affect disease progression. Therefore, the identification of accurate, cost-effective, and prognostically informative biomarkers is critical for screening and treatment. The review then focuses on the biomarkers currently associated with these conditions, which have been extensively studied via blood tests and imaging techniques. The information within this review was retrieved through extensive literature research conducted on major publicly accessible databases and has been collated and revised by an international panel of experts. The biomarkers discussed in the article have shown great promise in clinical research studies and provide clinicians with essential tools for early diagnosis and improved outcomes.

Although intestinal microbiota alterations (dysbiosis) have been described in heart failure (HF) patients, the possible mechanisms of intestinal barrier dysfunction leading to endotoxemia and systemic inflammation are not fully understood. In this study, we investigated the expression of the intestinal tight junction (TJ) proteins occludin and claudin-1 in patients with HF with reduced (HFrEF) or preserved ejection fraction (HFpEF) and their possible association with systemic endotoxemia and inflammation. Ten healthy controls and twenty-eight patients with HF (HFrEF (n = 14), HFpEF (n = 14)) underwent duodenal biopsy. Histological parameters were recorded, intraepithelial CD3+ T-cells and the expression of occludin and claudin-1 in enterocytes were examined using immunohistochemistry, circulating endotoxin concentrations were determined using ELISA, and concentrations of cytokines were determined using flow cytometry. Patients with HFrEF or HFpEF had significantly higher serum endotoxin concentrations (p < 0.001), a significantly decreased intestinal occludin and claudin-1 expression (in HfrEF p < 0.01 for occludin, p < 0.05 for claudin-1, in HfpEF p < 0.01 occludin and claudin-1), and significantly increased serum concentrations of IL-6, IL-8, and IL-10 (for IL-6 and IL-10, p < 0.05 for HFrEF and p < 0.001 for HFpEF; and for IL-8, p < 0.05 for both groups) compared to controls. Occludin and claudin-1 expression inversely correlated with systemic endotoxemia (p < 0.05 and p < 0.01, respectively). Heart failure, regardless of the type of ejection fraction, results in a significant decrease in enterocytic occludin and claudin-1 expression, which may represent an important cellular mechanism for the intestinal barrier dysfunction causing systemic endotoxemia and inflammatory response.