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Advances in our understanding of how the gut microbiota contributes to human health and diseases have expanded our insight into how microbial composition and function affect the human host. Heart failure is associated with splanchnic circulation congestion, leading to bowel wall oedema and impaired intestinal barrier function. This situation is thought to heighten the overall inflammatory state via increased bacterial translocation and the presence of bacterial products in the systemic blood circulation. Several metabolites produced by gut microorganisms from dietary metabolism have been linked to pathologies such as atherosclerosis, hypertension, heart failure, chronic kidney disease, obesity, and type 2 diabetes mellitus. These findings suggest that the gut microbiome functions like an endocrine organ by generating bioactive metabolites that can directly or indirectly affect host physiology. In this Review, we discuss several newly discovered gut microbial metabolic pathways, including the production of trimethylamine and trimethylamine N-oxide, short-chain fatty acids, and secondary bile acids, that seem to participate in the development and progression of cardiovascular diseases, including heart failure. We also discuss the gut microbiome as a novel therapeutic target for the treatment of cardiovascular disease, and potential strategies for targeting intestinal microbial processes.

The microbiome has proven to influence health and disease, but how combinations of external factors affect the microbiome is relatively unknown. Diet can cause changes, but this is usually achieved by altering macronutrient ratios and has not focused on dietary protein source or saturated fat intake levels. In addition, each individual’s unique microbiome profile can be an important factor during studies, and it has even been shown to affect therapeutic outcomes. We show here that the effects of individual differences outweighed the effect of experimental diets and that protein source is less influential than saturated fat level. This suggests that fat and protein composition, separate from macronutrient ratio and carbohydrate composition, is an important consideration in dietary studies. Interindividual variation in the composition of the human gut microbiome was examined in relation to demographic and anthropometric traits, and to changes in dietary saturated fat intake and protein source. One hundred nine healthy men and women aged 21 to 65, with BMIs of 18 to 36, were randomized, after a two-week baseline diet, to high (15% total energy [E])- or low (7%E)-saturated-fat groups and randomly received three diets (four weeks each) in which the protein source (25%E) was mainly red meat (beef, pork) (12%E), white meat (chicken, turkey) (12%E), and nonmeat sources (nuts, beans, soy) (16%E). Taxonomic characterization using 16S ribosomal DNA was performed on fecal samples collected at each diet completion. Interindividual differences in age, body fat (%), height, ethnicity, sex, and alpha diversity (Shannon) were all significant factors, and most samples clustered by participant in the PCoA ordination. The dietary interventions did not significantly alter the overall microbiome community in ordination space, but there was an effect on taxon abundance levels. Saturated fat had a greater effect than protein source on taxon differential abundance, but protein source had a significant effect once the fat influence was removed. Higher alpha diversity predicted lower beta diversity between the experimental and baseline diets, indicating greater resistance to change in people with higher microbiome diversity. Our results suggest that interindividual differences outweighed the influence of these specific dietary changes on the microbiome and that moderate changes in saturated fat level and protein source correspond to modest changes in the microbiome. IMPORTANCE The microbiome has proven to influence health and disease, but how combinations of external factors affect the microbiome is relatively unknown. Diet can cause changes, but this is usually achieved by altering macronutrient ratios and has not focused on dietary protein source or saturated fat intake levels. In addition, each individual’s unique microbiome profile can be an important factor during studies, and it has even been shown to affect therapeutic outcomes. We show here that the effects of individual differences outweighed the effect of experimental diets and that protein source is less influential than saturated fat level. This suggests that fat and protein composition, separate from macronutrient ratio and carbohydrate composition, is an important consideration in dietary studies.

Metabolites derived from dietary choline and L -carnitine, such as trimethylamine N -oxide and betaine, have recently been identified as novel risk factors for atherosclerosis in mice and humans. We sought to identify genetic factors associated with plasma betaine levels and determine their effect on risk of coronary artery disease (CAD). A two-stage genome-wide association study (GWAS) identified two significantly associated loci on chromosomes 2q34 and 5q14.1. The lead variant on 2q24 (rs715) localizes to carbamoyl-phosphate synthase 1 ( CPS1 ), which encodes a mitochondrial enzyme that catalyses the first committed reaction and rate-limiting step in the urea cycle. Rs715 is also significantly associated with decreased levels of urea cycle metabolites and increased plasma glycine levels. Notably, rs715 yield a strikingly significant and protective association with decreased risk of CAD in only women. These results suggest that glycine metabolism and/or the urea cycle represent potentially novel sex-specific mechanisms for the development of atherosclerosis. Dietary choline metabolites, such as trimethylamine N-oxide and betaine, have been associated with coronary artery disease (CAD). Here, Hartiala et al . identify two genetic loci for betaine levels on chromosomes 2q34 and 5q14.1 and find that the 2q34 locus was also associated with other pathway intermediates, and decreased risk of CAD in women.

Background Rheumatoid arthritis (RA) patients are at high risk of developing cardiovascular disease (CVD). In RA, chronic inflammation may lead to endothelial dysfunction, an early indicator of CVD, owing to diminished nitric oxide (NO) production. Because l -arginine is the sole precursor of NO, we hypothesized that levels of l -arginine metabolic products reflecting NO metabolism are altered in patients with RA. Methods Plasma samples from patients with RA ( n  = 119) and age- and sex-matched control subjects ( n  = 238) were used for this study. Using LC-MS/MS, we measured plasma levels of free l -arginine, l -ornithine, l -citrulline, l - N G -monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA). We compared global arginine bioavailability ratio (GABR) (i.e., ratio of l -arginine to l -ornithine + l -citrulline) and arginine methylation index (ArgMI) (i.e., ADMA + SDMA/MMA) in patients with RA vs. control subjects. Plasma arginase activity was measured using a sensitive arginase assay kit. The relationship of l -arginine metabolites and arginase activity to CVD risk factors was evaluated using Pearson’s chi-square test. Results Compared with healthy control subjects, the RA cohort showed significantly lower levels of plasma l -arginine (46.11 ± 17.29 vs. 74.2 ± 22.53 μmol/L, p  < 0.001) and GABR (0.36 ± 0.16 vs. 0.73 ± 0.24, p  < 0.001), elevated levels of ADMA (0.76 ± 0.12 vs. 0.62 ± 0.12 μmol/L, p  < 0.001), SDMA (0.54 ± 0.14 vs. 0.47 ± 0.13 μmol/L, p  < 0.001), and ArgMI (6.51 ± 1.86 vs. 5.54 ± 1.51, p  < 0.001). We found an approximately fourfold increase in arginase activity (33.8 ± 1.1 vs. 8.4 ± 0.8 U/L, p  < 0.001), as well as elevated levels of arginase-mediated l -arginine catalytic product l -ornithine (108.64 ± 30.26 vs. 69.3 ± 20.71 μmol/L, p  < 0.001), whereas a nitric oxide synthase (NOS) catalytic product, the l -citrulline level, was diminished in RA (30.32 ± 9.93 vs. 36.17 ± 11.64 μmol/L, p  < 0.001). Patients with RA with existing CVD had higher arginase activity than patients with RA without CVD ( p  = 0.048). Conclusions Global l -arginine bioavailability was diminished, whereas plasma arginase activity, ADMA, and SDMA levels were elevated, in patients with RA compared with healthy control subjects. Plasma SDMA was associated with hypertension and hyperlipidemia in patients with RA. This dysregulated l -arginine metabolism may function as a potential indicator of CVD risk in patients with RA.

•Myocardial thinning defined as a 50% or greater diameter reduction of the compacted myocardium compared to a contiguous segment on cardiac magnetic resonance imaging is associated with adverse cardiovascular events in patients with left ventricular noncompaction.•Myocardial thinning predicts major adverse cardiovascular events alongside factors such as ventricular tachycardia, left ventricular end-systolic volume, and left bundle branch block in patients with left ventricular noncompaction.•In our cohort, 42 patients (20%) exhibiting focal myocardial thinning ≥50% experienced 3 times worse outcomes than those without thinning (HR 3.052; 95% CI 1.569 to 5.937; p = 0.001).•Incorporating myocardial thinning into medical risk assessments can improve the prediction and management of adverse outcomes in these patients. Clinical presentations of left ventricular noncompaction (LVNC) range from asymptomatic cases to ventricular tachyarrhythmia (VT), heart failure (HF), and cerebrovascular accidents (CVA). In this multicenter study, we explored the associations between clinical and imaging characteristics and outcomes of LVNC patients and validated the predictive value of myocardial thinning identified on cardiac magnetic resonance imaging (CMR) as previously described. About 214 adult patients (54% male, mean age 41 ± 16 years) meeting the imaging criteria for LVNC were identified. Myocardial thinning was defined as a 50% or greater diameter reduction of the compacted myocardium compared to a contiguous segment on CMR. The primary endpoint was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of all-cause mortality, HF hospitalization, left ventricular assist device (LVAD) or heart transplant, cardiac resynchronization therapy (CRT), CVA/transient ischemic attacks (TIA), VT and appropriate implantable cardioverter defibrillator (ICD) therapy. Focal myocardial thinning was observed in 42 patients (20%). Over a median follow-up time of 7 years (IQR, 4 to 10 years), 54 patients (24%) experienced a primary outcome. Patients with myocardial thinning had more cumulative adverse events than those without myocardial thinning (chi-square = 29.516, log-rank < 0.001), even after matching for medical risk score. In a multivariate Cox regression model, myocardial thinning remained associated with outcomes: HR 3.052 (95% CI: 1.569 to 5.937, p = 0.001). Myocardial thinning is associated with adverse cardiovascular events in LVNC patients. Incorporating myocardial thinning into medical risk assessments can improve the prediction and management of adverse outcomes in these patients.

Background Diabetic cardiomyopathy (DbCM) is a form of Stage B heart failure (HF) at high risk for progression to overt disease. Using baseline characteristics of study participants from the Aldose Reductase Inhibition for Stabilization of Exercise Capacity in Heart Failure (ARISE-HF) Trial we sought to characterize clinical characteristics of individuals with findings consistent with DbCM. Methods Among study participants meeting inclusion criteria, clinical characteristics, laboratory testing, imaging, Kansas City Cardiomyopathy Questionnaire (KCCQ), Physical Activity Scale of the Elderly (PASE) and cardiopulmonary exercise testing (CPET) results were tabulated. Cluster phenogroups were identified. Results Among 691 study participants (mean age 67.4 years; 50% were female), mean duration of type 2 diabetes mellitus (T2DM) was 14.5 years. The median (Q1, Q3) N-terminal pro-B type natriuretic peptide and high sensitivity cardiac troponin T were 71 (35, 135) ng/L and 9 [ 6 , 12 ] ng/L. The most common echocardiographic abnormalities were reduced global longitudinal strain in 25.3% and impaired diastolic relaxation in 17.7%. Despite rather well-preserved KCCQ scores the average PASE score was markedly impaired at 155 accompanied by an average maximal oxygen consumption of 15.7 mL/Kg/minute on CPET. In K-means clustering, 4 phenogroups were identified including a higher-risk group with more advanced age, greater elevation of cardiac biomarkers, and more prevalent evidence for diastolic dysfunction and left ventricular hypertrophy. Conclusions Baseline data from the ARISE-HF Trial provide clinical characterization of individuals with T2DM and features of stage B HF, and may help clarify the diagnosis of DbCM. Trial Registration ARISE-HF, NCT04083339.

Skeletal muscle mass (SMM) plays a crucial role in risk assessment in transcatheter aortic valve replacement (TAVR) candidates, yet it remains underutilized. Traditional methods focus on weakness or performance but omit SMM. This study compared traditional and novel markers of sarcopenia and frailty in terms of their ability to predict adverse outcomes post-TAVR. Three risk models were evaluated for the composite outcome of perioperative complications, 1-year rehospitalization, or 1-year mortality: (1) sarcopenia by combining low muscle mass (LMM) and weakness/performance assessed by hand grip strength or gait speed; (2) frailty by an Adapted Green score; and (3) frailty by the Green-SMI score incorporating LMM by multilevel opportunistic pre-TAVR thoracic CT segmentation. In this study we included 184 eligible patients from January to December of 2018, (96.7%) of which were balloon expandable valves. The three risk models identified 22.8% patients as sarcopenic, 63.6% as frail by the Adapted Green score, and 53.8% as frail by the Green-SMI score. There were higher rates of the composite outcome in patients with sarcopenia (54.8%) and frailty (41.9% with the Adapted Green and 50.5% with the Green-SMI score) compared to their nonsarcopenic (30.3%) and nonfrail counterparts (25.4% with the Adapted Green and 18.8% with the Green-SMI score). Sarcopenia and frailty by Green-SMI, but not by the Adapted Green, were associated with higher risks of the composite outcome on multivariable adjustment (HR 2.2 [95% CI: 1.25-4.02], P = .007 and HR 3.4 [95% CI: 1.75-6.65], P < .001, respectively). The integration of preoperative CT-based SMM to a frailty score significantly improves the prediction of adverse outcomes in patients undergoing TAVR. Caption: Venn diagram showing intersection between the Adapted Green score incorporating weakness (assessed by hand grip strength and gait speed), LMM (from multilevel CT imaging), and Green-SMI score. Bottom panel showing key findings from the study. [Display omitted]

Lower serum chloride (Cl) levels are strongly associated with increased long-term mortality after admission for acute heart failure (AHF). However, the therapeutic implications of serum Cl levels during AHF are unknown. We sought to determine the short-term clinical response and postdischarge outcomes associated with serum Cl levels in AHF. Serum Cl was measured at randomization (n = 358) and during hospitalization from patients with AHF in the Renal Optimization Strategies Evaluation in Acute Heart Failure trial. Outcomes included diuretic response and renal function at 72 hours and death and rehospitalization at 60 and 180 days. Baseline Cl tertiles were 84 to 98; 99 to 102; and 103 to 117 meq/l. Baseline Cl level was associated with diuretic efficiency (p <0.001) but not change in cystatin C (p = 0.30) at 72 hours and was associated with 60-day death (hazard ratio [HR] 0.86, p = 0.029), 60-day death and rehospitalization (HR 0.90, p = 0.01), and 180-day death (HR 0.91, p = 0.049). These associations were attenuated with additional adjustment for loop diuretic dose (p >0.05). Chloride change correlated with weight change (ρ 0.18, p = 0.001), cystatin C change (ρ −0.35, p <0.001), and cumulative sodium excretion (ρ −0.21, p <0.001) but was not associated with any clinical outcomes (p >0.05 for all). In conclusion, serum Cl levels in AHF were inversely associated with loop diuretic response and were prognostic. However, changes in Cl levels were associated with parameters of decongestion but not with clinical outcomes.

Polygenic diseases, which are genetic disorders caused by the combined action of multiple genes, pose unique and significant challenges for the diagnosis and management of affected patients. A major goal of cardiovascular medicine has been to understand how genetic variation leads to the clinical heterogeneity seen in polygenic cardiovascular diseases (CVDs). Recent advances and emerging technologies in artificial intelligence (AI), coupled with the ever-increasing availability of next generation sequencing (NGS) technologies, now provide researchers with unprecedented possibilities for dynamic and complex biological genomic analyses. Combining these technologies may lead to a deeper understanding of heterogeneous polygenic CVDs, better prognostic guidance, and, ultimately, greater personalized medicine. Advances will likely be achieved through increasingly frequent and robust genomic characterization of patients, as well the integration of genomic data with other clinical data, such as cardiac imaging, coronary angiography, and clinical biomarkers. This review discusses the current opportunities and limitations of genomics; provides a brief overview of AI; and identifies the current applications, limitations, and future directions of AI in genomics.

IntroductionThe endothelial surface layer is covered with abundant proteoglycans, of which syndecans and glycosaminoglycans are major constituents.Recent FindingsAmong the endothelial glycocalyx (eGC) constituents, syndecan-1 (sdc1) is a main component, and an elevated serum level of sdc1 may indicate the degradation of eGC. In patients with ischemic heart disease or heart failure, elevation of serum sdc1 has been associated with worsening cardiac and renal function; however, the causal relationship between degradation of eGC and clinical outcomes is unclear.SummaryHerein, we review the previous literature on eGC in cardiovascular and noncardiovascular diseases and their clinical implications.