Differential biomarker expression in heart failure patients with and without mitral regurgitation: Insights from BIOSTAT-CHF.

BACKGROUND: Mitral regurgitation (MR) frequently coexists with heart failure (HF). OBJECTIVES: To better understand potential pathophysiological differences between patients with HF with or without moderate-severe MR, we compared differentially expressed circulating biomarkers between these two groups. METHODS: The Olink Proteomics® Multiplex Cardiovascular (CVD) -II, CVD-III, Immune Response and Oncology-II panels of 363 unique proteins from different pathophysiological domains were used to investigate the biomarker profiles of HF patients from index and validation cohorts of the BIOSTAT-CHF study stratified according to the presence of moderate-to-severe MR or no-mild MR. RESULTS: The index cohort included 888 patients (46%) with moderate-to-severe MR and 1029 (54%) with no-mild MR at baseline. The validation cohort included 522 patients (33%) with moderate-to-severe MR and 1076 (66%) with no-mild MR at baseline. Compared to patients with no-mild MR, those with moderate-to-severe MR had lower body mass index, higher comorbidity burden, signs and symptoms of more severe HF, lower systolic blood pressure, and larger left atrial and ventricular dimensions, in both cohorts. NT-proBNP, CA125, fibroblast growth factor 23 (FGF23) and growth hormone 1 (GH1) were up-regulated, whereas leptin (LEP) was down-regulated in patients with moderate-severe MR versus no-mild MR, in both index and validation cohorts. CONCLUSION: Circulating biomarkers differently expressed in HF patients with moderate-severe MR versus no-mild MR were related to congestion, lipid and mineral metabolism and oxidative stress. These findings may be of value for the development of novel treatment targets in HF patients with MR.

Prognostic significance of serum potassium in patients hospitalized for acute heart failure.

AIM: We investigated the prognostic significance of serum potassium abnormalities at discharge in patients hospitalized for acute heart failure (AHF). METHODS AND RESULTS: In a retrospective analysis, we included 926 patients hospitalized for AHF, stratified by serum potassium levels at discharge as hypokalaemia (<3.5 mEq/L), normokalaemia (3.5-5.0 mEq/L), and hyperkalaemia (>5.0 mEq/L). The primary endpoint was all-cause death at 1 year since hospital discharge. At discharge, 40 patients had hypokalaemia (4.3%), 840 normokalaemia (90.7%), and 46 hyperkalaemia (5.0%). Patients with hyperkalaemia at discharge were more frequently men, had more signs of congestion, and lower LVEF while patients with hypokalaemia were more likely to be women with HFpEF. Treatment with ACEi/ARBs and MRAs ≥50% of target dose at discharge was similar across groups. One year all-cause death occurred in 10% of the patients with hypokalaemia, 13.9% of those with normokalaemia, and 30.4% of those with hyperkalaemia (P = 0.006). After adjustment for covariates, including renal function, background treatment, and baseline potassium level, hyperkalaemia resulted an independent predictor of the primary endpoint (HR 1.96, 95% IC [1.01-3.82]; P = 0.048). CONCLUSIONS: In patients with AHF, the presence of hyperkalaemia at discharge is an independent predictor of 1 year all-cause death.

Distinct pathophysiological pathways in women and men with heart failure.

AIMS: Clinical differences between women and men have been described in heart failure (HF). However, less is known about the underlying pathophysiological mechanisms. In this study, we compared multiple circulating biomarkers to gain better insights into differential HF pathophysiology between women and men. METHODS AND RESULTS: In 537 women and 1485 men with HF, we compared differential expression of a panel of 363 biomarkers. Then, we performed a pathway over-representation analysis to identify differential biological pathways in women and men. Findings were validated in an independent HF cohort (575 women, 1123 men). In both cohorts, women were older and had higher left ventricular ejection fraction (LVEF). In the index and validation cohorts respectively, we found 14/363 and 12/363 biomarkers that were relatively up-regulated in women, while 21/363 and 14/363 were up-regulated in men. In both cohorts, the strongest up-regulated biomarkers in women were leptin and fatty acid binding protein-4, compared to matrix metalloproteinase-3 in men. Similar findings were replicated in a subset of patients from both cohorts matched by age and LVEF. Pathway over-representation analysis revealed increased activity of pathways associated with lipid metabolism in women, and neuro-inflammatory response in men (all p < 0.0001). CONCLUSION: In two independent cohorts of HF patients, biomarkers associated with lipid metabolic pathways were observed in women, while biomarkers associated with neuro-inflammatory response were more active in men. Differences in inflammatory and metabolic pathways may contribute to sex differences in clinical phenotype observed in HF, and provide useful insights towards development of tailored HF therapies.

Congestion in Patients with Advanced Heart Failure: Assessment and Treatment.

Heart failure (HF) is characterized by frequent hospital admissions due to acute decompensation and shortened life span with a progressive clinical course leading to an advanced stage where traditional therapies become ineffective. Due to aging of the population and improved therapies, only a small of proportion of patients with advanced HF are candidates for surgical treatments, such as mechanical circulatory support or heart transplantation. In most cases, prompt identification and management of congestion is paramount to improving symptoms and quality of life and avoiding progression to severe multiorgan dysfunction and death.

Vericiguat for Heart Failure with Reduced Ejection Fraction.

PURPOSE OF REVIEW: The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway plays an important role in the regulation of cardiovascular function, and it is disrupted in heart failure (HF), resulting in decreased protection against myocardial injury. Impaired NO-sGC-cGMP signaling in HF is secondary to reduced NO bioavailability and altered redox state of sGC, which becomes less responsive to NO. The sGC activator cinaciguat increases cGMP levels by direct NO-independent activation of sGC and may be particularly effective in conditions of increased oxidative stress and endothelial dysfunction, and therefore reduced NO levels, at the expense of a greater risk of hypotension. Conversely, sGC stimulators (riociguat and vericiguat) enhance sGC sensitivity to endogenous NO, thus exerting a more physiological action. RECENT FINDINGS: Clinical trials have suggested the benefit of vericiguat in patients with high-risk HF; in particular, a lower incidence of death from cardiovascular causes or HF hospitalization. Adding vericiguat may be considered in individual patients with HF, and reduced left ventricular ejection fraction (HFrEF) particularly those at higher risk of HF hospitalization.

Impact of mitral regurgitation in patients with worsening heart failure: insights from BIOSTAT-CHF.

AIMS: Few data regarding the prevalence and prognostic impact of mitral regurgitation (MR) in patients with worsening chronic or new-onset acute heart failure (HF) are available. We investigated the role of MR in the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF). METHODS AND RESULTS: We performed a retrospective post-hoc analysis including patients from both the index and validation BIOSTAT-CHF cohorts with data regarding MR status. The primary endpoint was a composite of all-cause death or HF hospitalization. Among 4023 patients included, 1653 patients (41.1%) had moderate-severe MR. Compared to others, patients with moderate-severe MR were more likely to have atrial fibrillation and chronic kidney disease and had larger left ventricular (LV) dimensions, lower LV ejection fraction (LVEF), worse quality of life, and higher plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP). A primary outcome event occurred in 697 patients with, compared to 836 patients without, moderate-severe MR [Kaplan-Meier 2-year estimate: 42.2% vs. 35.3%; hazard ratio (HR) 1.28; 95% confidence interval (CI) 1.16-1.41; log-rank P < 0.0001]. The association between MR and the primary endpoint remained significant after adjusting for baseline variables and the previously validated BIOSTAT-CHF risk score (adjusted HR 1.11; 95% CI 1.00-1.23; P = 0.041). Subgroup analyses showed a numerically larger impact of MR on the primary endpoint in patients with lower LVEF, larger LV end-diastolic diameter, and higher plasma NT-proBNP. CONCLUSIONS: Moderate-severe MR is common in patients with worsening chronic or new-onset acute HF and is strongly associated with outcome, independently of other features related to HF severity.

Quality of life in men and women with heart failure: association with outcome, and comparison between the Kansas City Cardiomyopathy Questionnaire and the EuroQol 5 dimensions questionnaire.

AIMS: We sought to analyse quality of life (QoL) measures derived from two questionnaires widely used in clinical trials, the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQoL 5 dimensions (EQ-5D), and to compare their prognostic value in men and women with heart failure and reduced ejection fraction (HFrEF). METHODS AND RESULTS: From the BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) we compared KCCQ and EQ-5D at baseline and after 9 months in 1276 men and 373 women with new-onset or worsening symptoms of HFrEF, who were sub-optimally treated and in whom there was an anticipated up-titration of guideline-derived medical therapies. Women had significantly worse baseline QoL (median) as compared with men, both when assessed with KCCQ overall score (KCCQ-OS, 44 vs. 53, P < 0.001) and EQ-5D utility score (0.62 vs. 0.73, P < 0.001). QoL improved equally in women and men at follow-up. All summary measures of QoL were independently associated with all-cause mortality, with KCCQ-OS showing the most remarkable association with mortality up to 1 year compared to the EQ-5D scores (C-statistic 0.650 for KCCQ-OS vs. 0.633 and 0.599 for EQ-5D utility score and EQ-5D visual analogue scale, respectively). QoL was associated with all outcomes analysed, both in men and women (all P for interaction with sex >0.2). CONCLUSION: Amongst patients with HFrEF, women reported significantly worse QoL than men. QoL was independently associated with subsequent outcome, similarly in men and women. The KCCQ in general, and the KCCQ-OS in particular, showed the strongest independent association with outcome.

In-hospital and long-term mortality for acute heart failure: analysis at the time of admission to the emergency department.

AIMS: Acute heart failure (AHF) leads to a drastic increase in mortality and rehospitalization. The aim of the study was to identify prognostic variables in a real-life population of AHF patients admitted to the emergency department with acute shortness of breath. METHODS AND RESULTS: We evaluated potential predictors of mortality in 728 consecutive patients admitted to the emergency department with AHF. Possible predictors of all-cause and cardiovascular (CV) mortality were investigated by Cox and Fine and Gray models at multivariable analysis. Among the 728 patients, 256 died during the entire follow-up, 142 of these due to CV cause. The 1 year mortality rate was 20%, with the highest risk of death during the index hospitalization (with 8% estimate in-hospital mortality at 30 days). A higher risk of events during the index hospitalization was more evident for the CV deaths, for which we found a cumulative 1 year incidence of 12% with a cumulative incidence in the first 30 days of hospitalization of about 5%. At multivariable analysis, age (P < 0.001), New York Heart Association (NYHA) class IV vs. I-II-III (P = 0.001), systolic blood pressure (P < 0.001), non-cardiac co-morbidities (≥3 vs. 0, P = 0.05), oxygen saturation (P = 0.03), serum creatinine (P < 0.001), and left ventricular ejection fraction (LVEF) (40-49% vs. <40%, P = 0.004; ≥50% vs. <40%, P = 0.003) were independent predictors of all-cause mortality during the entire follow-up. Age (P = 0.03), systolic blood pressure (P = 0.01), oxygen saturation (P = 0.03), serum creatinine (P = 0.02), and LVEF (40-49% vs. <40%, P = 0.03; ≥50% vs. <40%, P = 0.004) were independent predictors of CV mortality during the entire follow-up. NYHA class IV vs. I-II-III (P < 0.001), serum creatinine (P = 0.01), and LVEF (40-49% vs. <40%, P = 0.02; ≥50% vs. <40%, P < 0.001) remained independent predictors for in-hospital death, while only serum creatinine (P = 0.04), LVEF (40-49% vs. <40%: 0.32, P = 0.04; ≥50% vs. <40%, P < 0.001), and NYHA class vs. I-II-III (P = 0.02) remained predictors for in-hospital CV mortality. CONCLUSIONS: In this real-life cohort of patients with AHF, the results showed a similar mortality rate comparing with other analysis and with the most important registries. Age, NYHA class IV, systolic blood pressure, creatinine levels, sodium levels, and ejection fraction were independent predictors of 1 year mortality, while LVEF <40% was the only predictor of both all-cause mortality and CV mortality.

Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.

AIMS: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors. METHODS AND RESULTS: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations. CONCLUSION: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

Identifying optimal doses of heart failure medications in men compared with women: a prospective, observational, cohort study.

BACKGROUND: Guideline-recommended doses of angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs), and ß blockers are similar for men and women with heart failure with reduced ejection fraction (HFrEF), even though there are known sex differences in pharmacokinetics of these drugs. We hypothesised that there might be sex differences in the optimal dose of ACE inhibitors or ARBs and ß blockers in patients with HFrEF. METHODS: We did a post-hoc analysis of BIOSTAT-CHF, a prospective study in 11 European countries of patients with heart failure in whom initiation and up-titration of ACE inhibitors or ARBs and ß blockers was encouraged by protocol. We included only patients with left ventricular ejection fraction less than 40%, and excluded those who died within the first 3 months. Primary outcome was a composite of time to all-cause mortality or hospitalisation for heart failure. Findings were validated in ASIAN-HF, an independent cohort of 3539 men and 961 women with HFrEF. FINDINGS: Among 1308 men and 402 women with HFrEF from BIOSTAT-CHF, women were older (74 [12] years vs 70 [12] years, p<0·0001) and had lower bodyweights (72 [16] kg vs 85 [18] kg, p<0·0001) and heights (162 [7] cm vs 174 [8] cm, p<0·0001) than did men, although body-mass index did not differ significantly. A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (99 [25%] vs 304 [23%], p=0·61) and ß blockers (57 [14%] vs 168 [13%], p=0·54). In men, the lowest hazards of death or hospitalisation for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and ß blockers, but women showed approximately 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels. These sex differences were still present after adjusting for clinical covariates, including age and body surface area. In the ASIAN-HF registry, similar patterns were observed for both ACE inhibitors or ARBs and ß blockers, with women having approximately 30% lower risk at 50% of the recommended doses, with no further benefit at higher dose levels. INTERPRETATION: This study suggests that women with HFrEF might need lower doses of ACE inhibitors or ARBs and ß blockers than men, and brings into question what the true optimal medical therapy is for women versus men. FUNDING: European Commission.

Right heart dysfunction: from pathophysiologic insights to therapeutic options: a translational overview.

: The right ventricle has become increasingly studied in cardiovascular research. In this article, we describe specific pathophysiological characteristics of the right ventricle, with special focus on functional and molecular modifications as well as therapeutic strategies in right ventricular dysfunction, underlining the differences with the left ventricle. Then we analyze the main imaging modalities to assess right ventricular function in different clinical settings. Finally, we acknowledge main therapeutic advances for treatment of right heart diseases.

Corrigendum to "Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems".

[This corrects the article DOI: 10.1155/2016/5902947.].

Prognostic value of the absolute lymphocyte count in patients admitted for acute heart failure.

BACKGROUND: Low relative lymphocyte count is an important prognostic marker in acute heart failure (AHF); however, it could be influenced by other abnormalities in white cells count. Our purpose is to evaluate if low absolute lymphocyte count (ALC) is an independent predictor of events in patients with AHF. METHODS: In a retrospective analysis, we included 309 patients with AHF, divided into two groups according to the median value of ALC at admission (1410 cells/µl). The primary end point was all-cause mortality or urgent heart transplantation within 1 year. RESULTS: Patients with low ALC were older and had more comorbidity, namely atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease and anemia. Low ALC was associated with higher all-cause mortality or urgent heart transplantation at 1 year (24.3 vs 13.0%; P = 0.012). In a multivariable model, the independent predictors of mortality at 1 year were ALC 1410 cells/µl or less at admission [hazard ratio 2.04; CI (confidence interval) 95% (1.06-3.95); P = 0.033], age [hazard ratio 1.08; CI 95% (1.04-1.12); P < 0.001], baseline serum creatinine [hazard ratio 1.25; CI 95% (1.05-1.50); P = 0.012] and baseline serum Na [hazard ratio 0.91; CI 95% (0.85-0.98); P = 0.013]. CONCLUSION: Low ALC in patients with AHF is associated with higher in-hospital mortality during the hospitalization and is an independent predictor of long-term mortality.

Heart failure 2016: still more questions than answers.

Heart failure has reached epidemic proportions given the ageing of populations and is associated with high mortality and re-hospitalization rates. This article reviews and summarizes recent advances in the diagnosis, assessment and treatment of the patients with heart failure. Data are discussed based also on the most recent guidelines indications. Open issues and unmet needs are highlighted.

Cardiorenal Interactions.

Recently, there has been increased appreciation of the identification and management of comorbidities in heart failure patients, and for therapies targeting conventional heart failure signs and symptoms. Renal dysfunction is common in patients with heart failure and is associated with high morbidity and mortality. Early identification of renal damage through novel biomarkers and the use of new pharmacological strategies aimed at preserving renal function may represent an important objective in the treatment. This article reviews the epidemiology and pathophysiology of cardiorenal syndrome in heart failure, and highlights novel biomarkers and improved therapies targeting renal dysfunction.

Nutritional Deficiency in Patients with Heart Failure.

Heart failure (HF) is the main cause of mortality and morbidity in Western countries. Although evidence-based treatments have substantially improved outcomes, prognosis remains poor with high costs for health care systems. In patients with HF, poor dietary behaviors are associated with unsatisfactory quality of life and adverse outcome. The HF guidelines have not recommended a specific nutritional strategy. Despite the role of micronutrient deficiency, it has been extensively studied, and data about the efficacy of supplementation therapy in HF are not supported by large randomized trials and there is limited evidence regarding the outcomes. The aim of the present review is to analyze the state-of-the-art of nutritional deficiencies in HF, focusing on the physiological role and the prognostic impact of micronutrient supplementation.

Nutrition and Cardiovascular Disease: Finding the Perfect Recipe for Cardiovascular Health.

The increasing burden of cardiovascular disease (CVD) despite the progress in management entails the need of more effective preventive and curative strategies. As dietary-associated risk is the most important behavioral factor influencing global health, it appears the best target in the challenge against CVD. Although for many years, since the formulation of the cholesterol hypothesis, a nutrient-based approach was attempted for CVD prevention and treatment, in recent years a dietary-based approach resulted more effective in reducing cardiovascular risk worldwide. After the publication of randomized trials on the remarkable effects of the Mediterranean diet and the Dietary Approach to Stop Hypertension (DASH) diet on CVD, new efforts were put on research about the effects of complex dietary interventions on CVD. The purpose of this paper is to review the evidence on dietary interventions in the prevention and disease modification of CVD, focusing on coronary artery disease and heart failure, the main disease responsible for the enormous toll taken by CVD worldwide.

Chemokines and Heart Disease: A Network Connecting Cardiovascular Biology to Immune and Autonomic Nervous Systems.

Among the chemokines discovered to date, nineteen are presently considered to be relevant in heart disease and are involved in all stages of cardiovascular response to injury. Chemokines are interesting as biomarkers to predict risk of cardiovascular events in apparently healthy people and as possible therapeutic targets. Moreover, they could have a role as mediators of crosstalk between immune and cardiovascular system, since they seem to act as a "working-network" in deep linkage with the autonomic nervous system. In this paper we will describe the single chemokines more involved in heart diseases; then we will present a comprehensive perspective of them as a complex network connecting the cardiovascular system to both the immune and the autonomic nervous systems. Finally, some recent evidences indicating chemokines as a possible new tool to predict cardiovascular risk will be described.

Rapid recovery of baroreceptor reflexes in acute myocardial infarction is a marker of effective tissue reperfusion.

Baroreflex sensitivity (BRS) measured several days after myocardial infarction (MI) is a powerful predictor of cardiovascular mortality. No information is available on BRS in the early hours of MI. The possibility to reliably assess BRS in the acute phase of MI and its clinical correlates were evaluated in 45 patients treated with primary percutaneous coronary intervention (pPCI). BRS (sequence method) was assessed 1, 3, 6, and 12 h after PCI. ST resolution (STRes) was considered present if ST had decreased ≥70 % 3 h after PCI. BRS was 10.7 ± 6.2 1 h after PCI; at 12 h it was 15.4 ± 5.2 and 8.4 ± 4.8 ms/mmHg in patients with and without STRes, respectively (p < 0.001). STRes was an independent predictor of 12 h BRS (p = 0.005) and of 1-12 h BRS difference (p = 0.002). BRS can be reliably assessed in the first hours of MI; it shows a rapid recovery in patients with STRes and a significant depression in patients without STres.