Although observational studies have demonstrated associations between elevated plasma homocysteine levels and the risk of cardiovascular diseases, controversy remains. This study investigated the causal association of plasma homocysteine levels with congestive heart failure and cardiomyopathy risk. We performed a two-sample Mendelian randomization (MR) study of congestive heart failure (n = 218,792), cardiomyopathy (n = 159,811), and non-ischemic cardiomyopathy (n = 187,152). Genetic summary data on the association of single-nucleotide polymorphisms with homocysteine were extracted from the most extensive genome-wide association study of 44,147 individuals. MR analyses, including the random-effect inverse variance-weighted (IVW) meta-analysis, weighted median, simple median, maximum likelihood, penalized weighted median, MR-PRESSO, and MR-Egger regression, were used to estimate the associations between the selected single-nucleotide polymorphisms and congestive heart failure or cardiomyopathy. The MR analyses revealed no causal role of higher genetically predicted plasma homocysteine levels with congestive heart failure risk (random-effect IVW, odds ratio [OR] per standard deviation (SD) increase in homocysteine levels = 1.753, 95% confidence interval [CI] = 0.674-4.562, P = 0.250), cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 0.805, 95% CI = 0.583 to 1.020, P = 0.189), or non-ischemic cardiomyopathy (random-effect IVW, OR per SD increase in homocysteine levels = 1.064, 95% CI = 0.927-1.222, P = 0.379). The results were consistent with other analytical methods and sensitivity analyses. Genetically predicted homocysteine level was not associated with congestive heart failure or cardiomyopathy risk. It is unlikely that homocysteine-lowering therapy decreases the incidence or improves the outcomes of congestive heart failure and cardiomyopathy.

Patients with diabetes mellitus have accelerated progression of heart failure and often have impaired cardiac sympathetic innervation. The present study examines the implications for heart failure progression of cardiac sympathetic denervation, assessed by I-123 metaiodobenzylguanidine imaging, in diabetic compared with nondiabetic subjects. We evaluated 343 diabetic and 618 nondiabetic subjects with New York Heart Association class II or III heart failure and a left ventricular ejection fraction ≤35% over a median follow-up of 17 months. A multivariable Cox proportional hazards model was used to examine the influence of clinical variables, b-type natriuretic peptide, plasma norepinephrine, left ventricular ejection fraction, and I-123 metaiodobenzylguanidine imaging parameters on time to a heart failure event. The late heart-to-mediastinum (H/M) ratio and the interaction term of diabetes mellitus with the prospectively selected late H/M ratio <1.6 were independent predictors of heart failure progression, providing incremental prognostic information beyond that available from all other variables. In diabetic subjects, late H/M ratio <1.6 was associated with a 2.99-fold greater 2-year rate of heart failure progression (33.5%) than late H/M ratio ≥1.6 (11.2% event rate). The combination of diabetes mellitus and I-123 metaiodobenzylguanidine H/M ratio is an independent predictor of heart failure progression, confirming the high risk of diabetic subjects with impaired cardiac sympathetic nerve function.

BackgroundPatients with diabetes mellitus (DM) are at increased risk of developing heart failure (HF). The “Heart OMics in AGEing” (HOMAGE) trial suggested that spironolactone had beneficial effect on fibrosis and cardiac remodelling in an at risk population, potentially slowing the progression towards HF. We compared the proteomic profile of patients with and without diabetes among patients at risk for HF in the HOMAGE trial.MethodsProtein biomarkers (n = 276) from the Olink®Proseek-Multiplex cardiovascular and inflammation panels were measured in plasma collected at baseline and 9 months (or last visit) from HOMAGE trial participants including 217 patients with, and 310 without, diabetes.ResultsTwenty-one biomarkers were increased and five decreased in patients with diabetes compared to non-diabetics at baseline. The markers clustered mainly within inflammatory and proteolytic pathways, with granulin as the key-hub, as revealed by knowledge-induced network and subsequent gene enrichment analysis. Treatment with spironolactone in diabetic patients did not lead to large changes in biomarkers. The effects of spironolactone on NTproBNP, fibrosis biomarkers and echocardiographic measures of diastolic function were similar in patients with and without diabetes (all interaction analyses p > 0.05).ConclusionsAmongst patients at risk for HF, those with diabetes have higher plasma concentrations of proteins involved in inflammation and proteolysis. Diabetes does not influence the effects of spironolactone on the proteomic profile, and spironolactone produced anti-fibrotic, anti-remodelling, blood pressure and natriuretic peptide lowering effects regardless of diabetes status. Trial registration NCT02556450.

Objective. To determine the risk of developing chronic heart failure (CHF) in patients with hypertension (HTN) depending on the actual arterial stiffness.Material and Methods. The study included 175 patients with HTN without a verified diagnosis of heart failure. The average age was 48.5 ± 6.8 years. Patients underwent general clinical examination, volume sphygmoplethysmography assessments of cardio-ankle vascular index (CAVI), echocardiography study (left ventricular (LV) ejection fraction, LV diastolic function, LV myocardial mass index, indexed LV volume by echocardiography), and tests for serum N-terminal pro-B-type natriuretic peptide (NT-proBNP). Patients were divided into two groups depending on CAVI. Group 1 included 141 (80.6%) patients with CAVI &lt; 9; group 2 included 34 (19.4%) patients with CAVI &gt; 9.Results. In patients of group 1, the level of NT-proBNP was 0.008 [0.006; 5.770], which was significantly lower than the corresponding value in group 2, where the level of NT-proBNP was 13.08 [0.01; 350.65] ng/mL (p = 0.041). Indicators of odds ratio (OR) and relative risk (RR) were also significant. The chance of developing CHF with CAVI &gt; 9 increased by almost 7 times (OR = 6.9; 95% CI = 2.8–16.8), and OR of CHF onset was 4.1 (95% CI = 2.2–7.6). Sensitivity and specificity rates were 55.9% and 84.4%, respectively. Correlation analysis revealed a medium degree of dependence and direct relationships between NT-proBNP level and CAVI values (r = 0.35; p &lt;0.05).Conclusion. Serum level of NT-proBNP depended on the actual arterial stiffness. Patients with CAVI &gt; 9 indicative of an increase in true arterial stiffness had a greater risk of developing heart failure assessed based on the level of NT-proBNP in the blood. Further studies are required to assess the effects of arterial stiffness, registered within the intermediate values of CAVI index, on the risk of heart failure onset.

To examine the association of serum gamma-glutamyltransferase (GGT) with incident heart failure. We related serum GGT to the incidence of heart failure in 3544 (mean age, 44.5 years; 1833 women and 1711 men) Framingham Study participants who were free of heart failure and myocardial infarction. On follow-up (mean, 23.6 years), 188 participants (77 women) developed new-onset heart failure. In multivariable Cox proportional hazards regression models adjusting for standard risk factors and alcohol consumption as time-varying covariates (updated every 4 years), each SD increase in log-GGT was associated with a 1.39-fold risk of heart failure (95% CI, 1.20 to 1.62). The linearity of the association was confirmed by multivariable-adjusted splines, and the relations remained robust on additional adjustment for hepatic aminotransferases and C-reactive protein. Participants with a serum GGT level at the median or greater had a 1.71-fold risk of heart failure (95% CI, 1.21 to 2.41) compared with individuals with GGT concentrations less than the median. GGT marginally increased the model C-statistic from 0.85 to 0.86 but improved the risk reclassification modestly (net reclassification index, 5.7%; P=0.01). In this prospective study of a large community-based sample, higher serum GGT concentrations within the "normal" range were associated with greater risk of heart failure and incrementally improved prediction of heart failure risk.

The epidemic of obesity impacts significantly the prevalence of cardiovascular diseases, including heart failure. Obesity facilitates proinflammatory status onset, that leads to changes in metabolism of free fatty acids, lipids, glucose, influencing myocardial function and heart failure progression from diastolic to systolic. Also, there is data confirming influence of obesity on central and peripheral hemodynamics. To understand these mechanisms is necessary for development of prevention activities against chronic heart failure and other cardiovascular events.

Although plasma palmitoleic acid has been positively associated with blood pressure, inflammation, and insulin resistance, its association with heart failure has not been investigated. We assessed whether plasma phospholipid cis-palmitoleic acid was associated with heart failure risk. This ancillary study of the Physicians' Health Study used a risk set sampling method to select 788 matched pairs. For each case of incident heart failure, we randomly selected a control among subjects that were free of heart failure and alive at the time of index case diagnosis and matched on age, year of birth, race, and time of blood collection. Plasma phospholipid fatty acids were measured using gas chromatography. Heart failure was ascertained using annual follow-up questionnaire and validated in a subsample. In a multivariable conditional logistic regression, odds ratios (95% CI) for heart failure were 1.0 (ref), 1.06 (0.75-1.48), 1.20 (0.85-1.68), and 1.58 (1.11-2.25) across consecutive quartiles of cis-palmitoleic acid (P for trend 0.009). Each SD increase in plasma cis-palmitoleic acid was associated with 17% higher odds of heart failure (95% CI: 2% to 33%) in a multivariable model. In a secondary analysis, each SD increase of log-stearoyl-coA desaturase activity (16:1n-7/16:0 ratio) was positively associated with the risk of heart failure (odds ratio: 1.14 [95% CI: 1.00 to 1.29]), whereas oleic acid and cis-vaccenic acid concentrations were not related to heart failure risk. Our data showed a positive association between plasma phospholipid cis- palmitoleic acid and heart failure risk in male physicians.

Introduction: In patients with acute myocardial infarction (AMI) early risk assessment of development of complications is of great importance. It is proven that aldosterone level has a major role in progression of cardiovascular pathology. Aim: Determination of influence of aldosterone plasma level in the progression of heart disease in patients without signs of heart failure after AMI. Material and Methods: Research included 207 patients, hospitalized in the acute phase of myocardial infarction, and who were divided into two groups: 127 patients with no clinical signs of heart failure and 60 patients with heart failure. Results: The serum aldosterone concentration was 73.4% higher in the group of decompensated patients, 128 pg/mL (75.4-236 pg/mL) in decompensated and 73.7 pg/mL (42.7 -115.25 pg/mL) in compensated. In the group of compensated patients, changes in aldosterone levels showed a statistically significant effect on the incidence of post-infarction angina (p=0.0001) as well as reinfarction (p=0.009). There is a connection between changes in aldosterone plasma level and positive stress test (p=0.012). Conclusion: In patients with AMI, elevated serum aldosterone level can be prognostic factor of the progression of coronary heart disease, development of heart failure, as well of development of post-infarction angina, myocardial reinfarction and pathological finding on the stress test.

We conduct a large-scale meta-analysis of heart failure genome-wide association studies (GWAS) consisting of over 90,000 heart failure cases and more than 1 million control individuals of European ancestry to uncover novel genetic determinants for heart failure. Using the GWAS results and blood protein quantitative loci, we perform Mendelian randomization and colocalization analyses on human proteins to provide putative causal evidence for the role of druggable proteins in the genesis of heart failure. We identify 39 genome-wide significant heart failure risk variants, of which 18 are previously unreported. Using a combination of Mendelian randomization proteomics and genetic cis-only colocalization analyses, we identify 10 additional putatively causal genes for heart failure. Findings from GWAS and Mendelian randomization-proteomics identify seven (CAMK2D, PRKD1, PRKD3, MAPK3, TNFSF12, APOC3 and NAE1) proteins as potential targets for interventions to be used in primary prevention of heart failure.

Limited data are available on the association between adiponectin and incident heart failure. In the current ancillary study to the Physicians' Health Study, we used a prospective nested-case control design to examine whether plasma adiponectin concentration was related to the risk of heart failure. We selected 787 incident heart failure cases and 787 matched controls for the current analysis. Each control was selected using a risk set sampling technique at the time of the occurrence of the index case and matched on year of birth, age at blood collection, and race. Adiponectin was measured using ELISA. Heart failure occurrence was self-reported in annual follow-up questionnaire. Validation of self-reported heart failure in this cohort has been published. The mean age was 58.7 years. In a conditional logistic regression adjusting for age, race, time of blood collection, year of birth, hypertension, atrial fibrillation, smoking, alcohol intake, and exercise, estimates of the relative risk (95% confidence interval) were 1.0 (ref), 0.74 (0.53–1.04), 0.67 (0.48–0.94), 0.70 (0.50–0.99), and 0.92 (0.65–1.30) from the lowest to the highest quintile of adiponectin, respectively, p for quadratic trend 0.004. Additional adjustment for potential mediating factors including diabetes, C-reactive protein, and body mass index led to the attenuation of the estimate of effect [1.0 (ref), 0.81 (0.57–1.15), 0.75 (0.53–1.06), 0.83 (0.58–1.18), and 1.26 (0.87–1.81) across consecutive quintiles of adiponectin]. Our data are consistent with a J-shaped association between total adiponectin and the risk of heart failure among US male physicians.