Function In Heart Failure Patients Research Articles

Effect of Levosimendan on Ventricular Systolic and Diastolic Functions in Heart Failure Patients: A Meta-Analysis of Randomized Controlled Trials.

Levosimendan, a calcium sensitizer, exerts inotropic action through improving left ventricular ejection fraction. We noticed that only few clinical studies are published in which the effects of levosimendan on cardiac function are studied by echocardiography. When screening the literature (PubMed, Embase, and CENTRAL, from inception to August 2020), we found 29 randomized controlled trials on levosimendan containing echocardiographic data. We included those studies, describing a total of 574 heart failure patients, in our meta-analysis and extracted 14 ultrasonic parameters, pooling the effect estimates using a random-effect model. Our analysis of the diastolic parameters of the left ventricle shows that levosimendan reduce the early/late transmitral diastolic peak flow velocity ratio [standardized mean difference (SMD) -0.45 to 95% confidence interval (CI) (-0.87 to -0.03), P = 0.037] and E/e' (e': mitral annulus peak early diastolic wave velocity using tissue-doppler imaging) [SMD -0.59, 95% CI (-0.8 to -0.39), P < 0.001]. As it regards the systolic parameters of the right ventricle, levosimendan increased tricuspid annular plane systolic excursion [SMD 0.62, 95% CI (0.28 to 0.95), P < 0.001] and tricuspid annular peak systolic velocity [SMD 0.75, 95% CI (0.35 to 1.16), P < 0.001], and reduced systolic pulmonary artery pressure [SMD -1.02, 95% CI (-1.32, -0.73), P < 0.001]. As it regards the diastolic parameters of the right ventricle, levosimendan was associated with the decrease of Aa (peak late diastolic tricuspid annular velocity using tissue-doppler imaging) [SMD -0.38, 95% CI (-0.76 to 0), P = 0.047] and increase of Ea (peak early diastolic tricuspid annular velocity using tissue-doppler imaging) [SMD 1.03, 95% CI (0.63 to 1.42), P < 0.001] and Ea/Aa [SMD 0.86, 95% CI (0.18 to 1.54), P = 0.013]. We show that levosimendan is associated with an amelioration in the diastolic and systolic functions of both ventricles in heart failure patients.

MiR-132/212 Impairs Cardiomyocytes Contractility in the Failing Heart by Suppressing SERCA2a.

Compromised cardiac function is a hallmark for heart failure, mostly appearing as decreased contractile capacity due to dysregulated calcium handling. Unfortunately, the underlying mechanism causing impaired calcium handling is still not fully understood. Previously the miR-132/212 family was identified as a regulator of cardiac function in the failing mouse heart, and pharmaceutically inhibition of miR-132 is beneficial for heart failure. In this study, we further investigated the molecular mechanisms of miR-132/212 in modulating cardiomyocyte contractility in the context of the pathological progression of heart failure. We found that upregulated miR-132/212 expressions in all examined hypertrophic heart failure mice models. The overexpression of miR-132/212 prolongs calcium decay in isolated neonatal rat cardiomyocytes, whereas cardiomyocytes isolated from miR-132/212 KO mice display enhanced contractility in comparison to wild type controls. In response to chronic pressure-overload, miR-132/212 KO mice exhibited a blunted deterioration of cardiac function. Using a combination of biochemical approaches and in vitro assays, we confirmed that miR-132/212 regulates SERCA2a by targeting the 3′-end untranslated region of SERCA2a. Additionally, we also confirmed PTEN as a direct target of miR-132/212 and potentially participates in the cardiac response to miR132/212. In end-stage heart failure patients, miR-132/212 is upregulated and correlates with reduced SERCA2a expression. The up-regulation of miR-132/212 in heart failure impairs cardiac contractile function by targeting SERCA2a, suggesting that pharmaceutical inhibition of miR-132/212 might be a promising therapeutic approach to promote cardiac function in heart failure patients.

Discovery of a Hydroxypyridinone APJ Receptor Agonist as a Clinical Candidate.

Apelin-13 is an endogenous peptidic agonist of the apelin receptor (APJ) receptor with the potential for improving cardiac function in heart failure patients. However, the low plasma stability of apelin-13 necessitates continuous intravenous infusion for therapeutic use. There are several approaches to increase the stability of apelin-13 including attachment of pharmacokinetic enhancing groups, stabilized peptides, and Fc-fusion approaches. We sought a small-molecule APJ receptor agonist approach to target a compound with a pharmacokinetic profile amenable for chronic oral administration. This manuscript describes sequential optimization of the pyrimidinone series, leading to pyridinone 14, with in vitro potency equivalent to the endogenous ligand apelin-13 and with an excellent oral bioavailability and PK profile in multiple preclinical species. Compound 14 exhibited robust pharmacodynamic effects similar to apelin-13 in an acute rat pressure-volume loop model and was advanced as a clinical candidate.

Long-term administration of tolvaptan ameliorates annual decline in estimated glomerular filtration rate in outpatients with chronic heart failure.

Protective effects of tolvaptan against worsening renal function in acute heart failure have been shown. However, long-term effects of its agent on renal function remain to be elucidated. The present study investigated retrospectively whether long-term treatment with tolvaptan exerts renoprotective effects in patients with chronic heart failure, by comparing serial changes in estimated glomerular filtration rate (eGFR) for years before and after tolvaptan administration. From 63 outpatients with chronic heart failure taking diuretics including tolvaptan, 34 patients whose eGFR levels were continuously measured for more than 6months both before and after administration of tolvaptan (average dose, 7.8mg/day at the end of the follow-up period) were selected as eligible for the present analyses. All eGFR values were separately plotted before and after the initiation of treatment with tolvaptan (except hospitalization periods) along the time course axis and the slope of the linear regression curve was calculated as an annual change in eGFR. The mean follow-up periods before and after tolvaptan administration were 1197 and 784days (3.3 and 2.1years), respectively. Changing rates of eGFR per year were significantly ameliorated after treatment with tolvaptan (mean ± SD, -8.02 ± 9.35 to -1.62 ± 5.09mL/min/1.73m2/year, P = 0.001). In echocardiographic parameters, inferior vena cava (IVC) diameter significantly decreased after tolvaptan administration, and the decrease in IVC diameter was correlated with the improvement of eGFR decline slope after administration of tolvaptan (P = 0.0075). This longitudinal observational study indicated that long-term treatment with tolvaptan ameliorated annual decline in eGFR in outpatients with chronic heart failure. Our findings suggest that tolvaptan has a protective effect against chronically worsening renal function in heart failure patients.

Efficacy of upgrading to left bundle branch pacing in patients with heart failure after right ventricular pacing.

Chronic right ventricular (RV) pacing is associated with an increased incidence of heart failure and mortality. Left bundle branch (LBB) pacing could produce near-physiological electrical activation and mechanical synchrony. We aimed to report the effects of upgrading to LBB pacing in heart failure patients after chronic RV pacing. The indications included pacing-induced cardiomyopathy (PICM) in Group 1 and heart failure after RV pacing with left ventricular ejection fraction (LVEF) ≥ 50% in Group 2. LBB pacing was achieved by penetrating the pacing lead to the subendocardium of left-sided interventricular septum through the venous access. Left ventricular activation time (LVAT) was measured from the pacing stimulus to the ascending peak of lead V5 or V6. All patients underwent clinical and echocardiographic evaluations before and after upgrading. Totally 27 patients (13 in Group 1 and 14 in Group 2) were consecutively enrolled. The mean follow-up time after upgrade was 10.4 ± 6.1 months. Paced QRS duration was significantly shortened from 174.1 ± 15.8milliseconds to 116.6 ± 11.7milliseconds (p<.0001). The mean LVAT was 83.2 ± 11.7milliseconds. LVEF increased from 40.3 ± 5.2% before upgrading to 48.1 ± 9.5% at follow-up in patients with PICM. Serum N-terminal probrain natriuretic peptide levels decreased and New York Heart Association classification improved in both groups. No upgrade-related complications were observed. Upgrading to LBB pacing was feasible and effective with improved cardiac function in heart failure patients with both reduced and preserved LVEF after RV pacing.

Salivary Gland Dysfunction in Patients with Chronic Heart Failure Is Aggravated by Nitrosative Stress, as Well as Oxidation and Glycation of Proteins.

Chronic heart failure (HF) is an important clinical, social, and economic problem. A key role in HF progression is played by oxidative stress. Free oxygen radicals, formed under the conditions of hypoxia and reperfusion, participate in myocardial stunning and other forms of post-reperfusion damage. HF patients also suffer from disorders connected with saliva secretion. However, still little is known about the mechanisms that impair the secretory function of salivary glands in these patients. In the presented study, we were the first to compare the antioxidant barrier, protein glycoxidation, and nitrosative/nitrative stress in non-stimulated (non-stimulated whole saliva (NWS)) and stimulated (SWS) saliva of HF patients. The study included 50 HF patients with normal saliva (NS) secretion (n = 27) and hyposalivation (HS) (n = 23), as well as an age- and gender-matched control group (n = 50). We demonstrated that, in NWS of HF patients with HS, the concentration of low-molecular-weight non-enzymatic antioxidants decreased (↓total polyphenols, ↓ascorbic acid, ↓reduced glutathione, ↓albumin) compared to HF patients with normal saliva (NS) secretion, as well as the control group (except albumin). We also observed increased content of protein glycoxidation products (↑dityrosine, ↑kynurenine, ↑glycophore) in NWS and SWS of HF patients with HS compared to healthy controls. Interestingly, the content of dityrosine, N-formylkynurenine, and glycophore in NWS was also significantly higher in HF patients with HS compared to those with NS secretion. The concentration of NO was considerably lower, while the levels of peroxynitrite and nitrotyrosine were significantly higher in NWS and SWS of HF subjects with HS compared to the controls. Salivary gland dysfunction occurs in patients with chronic HF with the submandibular salivary glands being the least efficient. Oxidative/nitrosative stress may be one of the mechanisms responsible for the impairment of salivary gland secretory function in HF patients.

Dietary supplementation with whey protein improves systemic microvascular function in heart failure patients: a pilot study

Endothelial dysfunction is a well-known component of the pathophysiology of heart failure (HF), with proven prognostic value. Dietary supplementation with whey protein (WP) has been widely used to increase skeletal muscle mass, but it also has vascular effects, which are less understood. This study aimed to evaluate the effects of WP supplementation on the systemic microvascular function of HF patients. This was a blinded, randomized, placebo-controlled clinical trial that evaluated the effects of 12-week WP dietary supplementation on systemic microvascular function, in patients with HF New York Heart Association (NYHA) classes I/II. Cutaneous microvascular flow and reactivity were assessed using laser speckle contrast imaging, coupled with pharmacological local vasodilator stimuli. Fifteen patients (aged 64.5±6.2 years, 11 males) received WP supplementation and ten patients (aged 68.2±8.8 years, 8 males) received placebo (maltodextrin). The increase in endothelial-dependent microvascular vasodilation, induced by skin iontophoresis of acetylcholine, was improved after WP (P=0.03) but not placebo (P=0.37) supplementation. Moreover, endothelial-independent microvascular vasodilation induced by skin iontophoresis of sodium nitroprusside, was also enhanced after WP (P=0.04) but not placebo (P=0.42) supplementation. The results suggested that dietary supplementation with WP improved systemic microvascular function in patients with HF.

Acceptance of the disease and sexual functions of patients with heart failure.

Sexual activity is an important element of quality of life for many individuals suffering from heart failure. The study investigated the influence of disease acceptance on sexual function in a population of male patients with chronic heart failure. The study included 80 patients with chronic heart failure (mean age 63.3±9.2 years) who filled in the Mell-Krat Scale questionnaire to evaluate sexual needs and reactions. We also used the International Index of Erection Function (IIEF-5) inventory and the Acceptance of Illness Scale (AIS). The study showed that the acceptance of the illness was positively associated with all of the Mell-Krat components such as sexual need, F = (3.27), frequency of intercourse, F = (2.46), position and technique, F = (1.88). Also, according to the IIEF-5 questionnaire, 84.42% of respondents had erectile dysfunction. Taken together these indicated that psychological adjustments such as acceptance of disease increase quality of all aspects of sexual functions in heart failure patients, including their erectile functions. Our findings suggest that psychological adjustments to feelings of loss associated with the onset of heart failure disease is the important determinant of quality of sexual life among male adults. Our research implicates that effects of AIS on sexual functioning give reasonable information to tailor sexual counselling for males suffering from heart failure.

Association of leptin serum concentration with heart adipose tissue and parameters of systolic and diastolic function in heart failure patients

Abstract Aims Leptin has recently been related to myocardial remodeling in animal experimentation studies on heart failure (HF). Furthermore, leptin has been reported to be related to diastolic dysfunction, however only in healthy population. With the emergence of new medical therapies targeting cardiac remodeling, there needs to be a better understanding of the metabolic pathways involving leptin. Our study aims to investigate leptin's correlation to parameters of systolic and diastolic heart function, as well as epicardial and pericardial adipose tissue (EAT and PAT) in heart failure (HF) patients. Methods The study included 51 patients with chronic heart failure with reduced ejection fraction (HFrEF) of ischemic (n=22) and non-ischemic (n=29) origin (NYHA II-III, mean EF 29.56%, SD 8.1; mean BMI 28.08, SD 5.8). Serum concentrations of leptin, NT-proBNP, HbA1c, LDL, and total cholesterol were also measured. Global longitudinal strain (GLS) and other LV function parameters were assessed in transthoracic echocardiography, as well as EAT and PAT in parasternal long and short-axis views. Results We found a significant correlation between leptin serum concentration and epicardial, as well as pericardial adipose tissue (EAT r=0.336, p=0.030; PAT r=0.565, p&amp;lt;0.001). There was a significant negative correlation between leptin and GLS (r=−0.332; p=0.045), as well a positive correlation between Leptin and E/E' ration (r=0.373; p=0.039). There was no significant difference between ischemic and non-ischemic HF patients. Conclusion We provide evidence of serum leptin correlation to remodeling parameters, as well as epicardial and pericardial fat tissue in HF patients. Whether leptin has positive effects on reversing or preventing remodeling in heart failure, needs further investigation. Correlation of leptin vs. GLS Funding Acknowledgement Type of funding source: None

Circulating exosomal microRNAs as emerging non‐invasive clinical biomarkers in heart failure: Mega bio‐roles of a nano bio‐particle

Exosomes are nano-sized extracellular vesicles containing a cell-specific biologically active cargo of proteins and genetic materials. Exosomes are constitutively released from almost all cell-types and affect neighboring or distant cells through a complex intercellular exchange of the genetic information and/or regulation of certain gene expressions that change the function and behavior of recipient cells. Those released into body fluids are the major mediators of intercellular communications. The success of the biological functions of exosomes is highly mediated by the effective transfer of microRNAs (miRs). Exosomes secreted by a damaged or diseased heart can exhibit alterations in the miRs' profile that may reflect the cellular origin and (patho)physiological state, as a "signature" or "fingerprint" of the donor cell. It has been shown that the transportation of cardiac-specific miRs in exosomes can be rapidly detected and measured, holding great potential as biomarkers in heart diseases. Currently, the search for new biomarkers of heart diseases remains a large and increasing enterprise. Notably, circulating exosomal miRs (Exo-miRs) have successfully gained huge interests for their diagnostic and prognostic potentials. The present review highlights circulating Exo-miRs explored for diagnosis/prognosis and outcome prediction in patients with heart failure (HF). To this end, we explain the feasibility of exosomes as clinical biomarkers, discuss the priority of circulating Exo-miRs over non-exosomal ones as a biomarker, and then outline reported circulating Exo-miRs having the biomarker function in HF patients, together with their mechanism of action. In conclusion, circulating Exo-miRs represent emerging diagnostic (Exo-miR-92b-5p, Exo-miR-146a, Exo-miR-181c, and Exo-miR-495) and prognostic (Exo-miR-192, Exo-miR-194, Exo-miR-34a, Exo-miR-425, Exo-miR-744) biomarkers for HF.

EMERGING ROLE OF NRF2 AS A POTENTIAL THERAPEUTIC TARGET FOR CARDIOVASCULAR DISEASES

Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor playing a big part in dynamic control of the antioxidant and cytoprotective gene system via activating the antioxidant response element (ARE) expression. Several Nrf2-targeted enzymes are essential for cardiovascular disease pathogenesis and are closely correlated with atherosclerosis, myocardial ischemia, diabetic cardiomyopathy, and congestive heart failure; moreover, they function as sensitive and precise markers to represent the ventricular function in heart failure patients. Activation of Nrf2 offers cardioprotection by synchronized up-regulation of the processes of antioxidative, anti-inflammatory, and autophagy. Thus, it may be worth examining the possible role of the Nrf2 signaling in cardioprotection. This review will encapsulate the present information about the structure, regulation, and participation of Nrf2 in various cardiovascular disorders and related complications like diabetic cardiomyopathy, hypertension, and obesity. A particular focus is put on Nrf2 inducers, which are potentially attractive therapeutic candidates for several cardiovascular disorders.

Impact of β-blocker therapy on right ventricular function in heart failure patients with reduced ejection fraction. A prospective evaluation.

Beta-blocker (β-blocker) therapy has been shown to improve mortality and reduce hospitalizations in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Although the physiological action mechanisms of β-blockers are well described, their effects on right ventricular (RV) function have not been prospectively studied. This prospective study aimed to (a) evaluate whether β-blocker therapy impacts RV remodeling based on echo parameters and (b) determine the predictive echo factors of β-blocker therapy response. From September 2017 to September 2018, HF patients were prospectively enrolled using CIBIS criteria: Class II, III, or IV HF; left ventricular ejection fraction (LVEF) of ≤40%; hospitalized for HF within the previous 12months. Echo evaluation was performed before initiating β-blocker therapy and 3months after optimal dose adjustment. Based on previous studies, patients with (absolute) LVEF≥5% improvement were considered significant β-blocker therapy responders. Overall, 40 patients (pts) completed the study, characterized as follows by age: 70±10years; gender: 10 women; cardiomyopathy etiology: idiopathic in 24 and ischemic in 16; NYHA Class: II in 22 and III in 10; LVEF: 32±5%; and NTProBNP: 2665±2400pg/mL. The final population comprised 32 pts (79%), with eight (21%) excluded: two because of β-blocker therapy intolerance, one lost to follow-up, and five withdrew from the study. Under β-blocker therapy, several echo parameters significantly improved: LVEF from 31.7±9 to 40.5±9 (P<.0001); LV end-diastolic volume (EDV) from 154±54 to 143±45mL (P=.06); LV end-systolic volume (ESV) from 107±49 to 88±37mL (P=.0006); LV ES from 46±11 to 64±13mL (P=.008); LV end-diastolic diameter (EDD) from 57±9 to 54±6mm (P=.04); LV end-systolic diameter (ESD) from 48±10 to 44±7mm (P=.007); and right ventricular systolic pressure (RV SP) from 39±10 to 32±8mmHg (P=.0001). Significant modifications were observed in terms of RV echo parameters: right ventricular (RV) size decreased from 30±4 to 27±5mm (P=.03), while RV systolic function significantly improved based on tricuspid annular plane systolic excursion (TAPSE) (16.5±4 vs. 19±4mm; 0.0006); DTI-derived tricuspid lateral annular systolic velocity wave (S') (10±2 vs. 11.3±3cm/s; P=.03); and RIMP (Tei index) (0.5±0.1 vs 0.46±0.1; P=.04). RV 2D fractional area change (%) did not significantly differ despite a clear improvement tendency (35±6 vs. 37±4%; P=.1). No significant modifications were observed concerning LV diastolic parameters. Overall, β-blocker echo responders (n=23/32; 72%) exhibited the same left and right echo parameters. No echo variables predicted the β-blocker response. In HFrEF pts, β-blocker therapy significantly improves LV and RV systolic remodeling. Accordingly, β-blocker therapy could be applied as soon as possible in HFrEF patients with right ventricular dysfunction so as to limit RV remodeling.

Effects of 3-Month Astaxanthin Supplementation on Cardiac Function in Heart Failure Patients with Left Ventricular Systolic Dysfunction-A Pilot Study.

Astaxanthin has strong antioxidant properties. We conducted a prospective pilot study on heart failure (HF) patients with left ventricular (LV) systolic dysfunction to investigate improvements in cardiac function and exercise tolerance in relation to suppression of oxidative stress by 3-month astaxanthin supplementation. Oxidative stress markers—serum Diacron reactive oxygen metabolite (dROM), biological antioxidant potential (BAP), and urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) concentrations, LV ejection fraction (LVEF), and 6-min walk distance (6MWD) were assessed before and after 3-month astaxanthin supplementation. Finally, the data of 16 HF patients were analyzed. Following 3-month astaxanthin supplementation, dROM level decreased from 385.6 ± 82.6 U.CARR to 346.5 ± 56.9 U.CARR (p = 0.041) despite no changes in BAP and urinary 8-OHdG levels. LVEF increased from 34.1 ± 8.6% to 38.0 ± 10.0% (p = 0.031) and 6MWD increased from 393.4 ± 95.9 m to 432.8 ± 93.3 m (p = 0.023). Significant relationships were observed between percent changes in dROM level and those in LVEF. In this study, following 3-month astaxanthin supplementation, suppressed oxidative stress and improved cardiac contractility and exercise tolerance were observed in HF patients with LV systolic dysfunction. Correlation between suppression of oxidative stress and improvement of cardiac contractility suggests that suppression of oxidative stress by astaxanthin supplementation had therapeutic potential to improve cardiac functioning.

Acute effects of oral triglyceride load on dynamic changes in peripheral endothelial function in heart failure patients with reduced ejection fraction and healthy controls

BachgroundPostprandial hyperlipaemia impairs endothelial function, possibly via oxidative-stress-mediated mechanisms. The aim of this study was to evaluate the acute effects of an oral triglyceride load (OTGL) on peripheral endothelial function in heart failure patients with reduced ejection fraction (HFrEF) compared to healthy controls. DesignProspective cross-sectional. MethodsWe enrolled 47 patients with HFrEF and 20 healthy controls. Peripheral endothelial function was assessed with EndoPAT2000 technology using a reactive hyperaemia index (RHI) and pulse wave amplitude (PWA) at baseline (after 8-h overnight fasting) as well as 1, 2, 3 and 4-h post-OTGL consumption (250-ml cream drink). Pulse wave amplitude index (PWAI) was calculated as a ratio of PWA at each time point to the baseline PWA. ResultsRHI at baseline was lower in HFrEF patients compared to controls (1.7 ± 0.3 and 2.3 ± 0.6, respectively; P = 0.001). The OTGL accounted for a physiologic increase in PWA in healthy controls (p = 0.01), but this change was not observed in HFrEF patients. After 4 h, vasodilator response was significantly increased in healthy controls but not patients with HFrEF (2.3 ± 1.3 vs. 1.3 ± 0.8 respectively, P < 0.05). ConclusionsThe main finding of this study was the impaired postprandial dynamic changes in peripheral endothelial function in patients with HFrEF compared to healthy controls. A high-fat load that caused acute hypertriglyceridaemia significantly increased resting blood flow and peak flow at reactive hyperaemia in healthy subjects. By contrast, patients with HFrEF exhibited impaired dynamic changes in peripheral endothelial function after oral triglyceride load.

Caloric restriction in heart failure: A systematic review.

Nutrition exerts a determinant role in maintaining cardiac function, regulating insulin and mitochondrial efficiency, that are essential to support energy production for contractility. In patients with heart failure (HF), myocardial tissue efficiency is reduced because of decreased mitochondrial oxidative capacity. In HF conditions, cardiomyocytes shift toward glucose and a reduction in fatty acid utilization. Calorie restriction induces weight loss in obese patients and can be beneficial in some HF patients, although this has generated some controversy. This study aims to evaluate the impact of the CR diet on myocardial efficiency in HF patients. On Pubmed and Embase, articles related to the keywords: "chronic heart failure" with "diet," "nutrition," "insulin resistance," and "caloric restriction" have been searched, Studies, including exercise or food supplementation, were excluded. The retrieved articles showed that weight loss, through the activation of insulin and various kinase pathways, regulates the efficiency of myocardial tissue. In contrast, insulin resistance represents a strong cardiovascular risk factor that reduces myocardial function. CR diet represents the first therapy in overweight HF patients, both with preserved ejection fraction (HFpEF) and with reduced ejection fraction (HFrHF) because reducing body fat, the myocardial function increased. Insulin activity is the critical hormone that regulates mitochondrial function and cardiac efficiency. However, a severely restricted diet may represent a severe risk factor correlated with all-cause mortality, particularly in underweight HF patients. Long-term studies conducted on large populations are necessary to evaluate the effects of CR on myocardial function in HF patients.

Prognostic effect and modulation of cardiac sympathetic function in heart failure patients treated with cardiac resynchronization therapy

BackgroundCardiac autonomic dysfunction as assessed by 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy is associated with poor prognosis in heart failure (HF) patients. Although cardiac resynchronization therapy (CRT) has emerged as an effective therapy in improving outcomes on HF patients, its effect on cardiac sympathetic nervous function is still not fully understood. We aimed to study the value of pre-implantation 123I-mIBG late heart-to-mediastinum ratio (HMR) as a predictor of response and outcomes after CRT and to correlate modification in this parameter with CRT response and functional improvement. Methods and ResultsBETTER-HF (Benefit of exercise training therapy and cardiac resynchronization in HF patients) is a prospective randomized clinical trial including HF patients submitted CRT (mean LVEF 24 ± 8%, 74% NYHA class ≥ III) who underwent a clinical, echocardiographic, and scintigraphic assessment before and 6 months after CRT. One-hundred and twenty-one patients were included. Echocardiographic response was observed in 54% and composite outcome of cardiac mortality, cardiac transplant or heart failure hospitalization in 24% of patients. Baseline late HMR was an independent predictor of CRT response (regression coefficient 2.906, 95% CI 0.293-3.903, P .029) and outcomes (HR 0.066 95% CI 0.005-0.880, P .040). At follow-up, 123I-mIBG imaging showed positive changes in cardiac sympathetic nerve activity only in responders to CRT (1.36 ± 0.14 prior vs. 1.42 ± 0.16 after CRT, P .039). There was a significant correlation between improvement in late HMR and improvement in peak oxygen consumption (r 0.547, P < .001). ConclusionIn our study, baseline cardiac denervation predicted response and clinical outcomes after CRT implantation. Cardiac sympathetic function was improved only in patients who responded to CRT and these positive changes were correlated with improvement in functional capacity.

Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ

This article describes the discovery of aryl hydroxy pyrimidinones and the medicinal chemistry efforts to optimize this chemotype for potent APJ agonism. APJ is a G-protein coupled receptor whose natural agonist peptide, apelin, displays hemodynamic improvement in the cardiac function of heart failure patients. A high throughput screen was undertaken to identify small molecule hits that could be optimized to mimic the apelin in vitro response. A potent and low molecular weight aryl hydroxy pyrimidinone analog 30 was identified through optimization of an HTS hit and medicinal chemistry efforts to improve its properties.

Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure.

Heart failure (HF) is associated with aberrant skeletal muscle impairments, which are closely linked to the severity of HF. A low level of brain-derived neurotrophic factor (BDNF), a myokine produced in the skeletal muscle, is known to be involved in reduced exercise capacity and poor prognosis in HF. However, little is known about the factors or conditions of skeletal muscle associated with BDNF levels. We investigated the association between serum BDNF levels and the skeletal muscle mass and function in HF patients (n = 60, 63 ± 13 years) and age-matched controls (n = 29, 61 ± 16 years). The serum BDNF level was significantly lower in the HF patients compared to the controls (24.9 ± 0.9 versus 28.6 ± 1.3, P = 0.021). In a univariate analysis, BDNF was significantly correlated with the peak oxygen uptake, estimated glomerular filtration rate, 10-m gait speed, and muscle strength, but not with the body mass index or lean mass in the HF group. A multiple linear regression analysis revealed that BDNF was independently associated with muscle strength (β-coefficient = 2.80, 95%CI: 1.89-11.8, P = 0.008). Serum BDNF levels were associated with exercise capacity and skeletal muscle function, but not with muscle mass. These novel findings may suggest that BDNF production is controlled by muscle function and activity and consequently regulates exercise capacity, highlighting the importance of adequate training regarding skeletal muscle in HF patients.

Impact of B-Bloker therapy on right ventricular function in heart failure patients with reduced ejection fraction. A prospective evaluation

ß-Blocker Therapy has been shown to improve mortality and reduce hospitalizations in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Its effects on right ventricular (RV) function have not been prospectively well studied. Objective. The aim of this prospective study was to: – evaluate if ß-Blocker Therapy impacts RV remodelling based on echo parameters; – sought the echo predictive factors of ß-Blocker therapy response. From September 2017 to September 2018, HF patients were prospectively enrolled using CIBIS criteria: Class II, III, or IV HF; left ventricular ejection fraction (LVEF) < 40%; hospitalized for HF within the previous 12 months. Echo evaluation was performed before initiating ß-Blocker therapy and 3 months after optimal dose adjustment. Patients with improvement in LVEF ≥ 5% were considered significant ß-Blocker therapy responders. Forty patients completing the study. The final population comprised 32 pts (79%): 2 did not tolerate ß-Blocker therapy, 1 was lost of follow-up, 5 did not pursue the protocol. Several echo parameters significantly improved: LVEF from 31.7 ± 9 to 40.5 ± 9 ( P < 0.0001); LV end-diastolic volume from 154 ± 54 to 143 ± 45 ml ( P = 0.06); LV end-systolic volume from 107 ± 49 to 88 ± 37 ml ( P = 0.0006); LV ES from 46 ± 11 to 64 ± 13 ml ( P = 0.008), right ventricular size decreased (30 ± 4 vs. 27 ± 5; P = 0.03), right ventricular systolic function improved significantly based on the tricuspid annular plane systolic excursion (16.5 ± 4 vs. 19 ± 4 mm; .0006); tricuspid lateral annular systolic velocity wave (10 ± 2 vs. 11.3 ± 3 cm/s; P = 0.03); and Tei index (0.5 ± .1 vs. 0.46 ± .1; P = 0.04). ß-Blocker echo responders ( n = 23/32; 72%) exhibited the same left and right echo parameters. No echo variables predicted the ß-Blocker response ( Fig. 1 ). In HFrEF patients, ß-Blocker therapy significantly improves LV and RV systolic remodelling.

Paradoxical Prognostic Implications of Visceral Adiposity for Lethal Cardiac Events in Association with Impaired Cardiac Sympathetic Innervation in Chronic Heart Failure

Background: Obesity increases the risk for development of heart failure (HF) but, when present is likely to be related to better outcomes in patients with HF. This study aimed to clarify the paradoxical prognostic values of visceral obesity in association with cardiac sympathetic function in HF patients. Methods and Results: A total of 653 consecutive patients with systolic HF who underwent visceral adiposity area (VAA) measurements using a computed tomographic technique were divided into 3 groups: VAA 1, area <80 cm2; VAA 2, area 80-140 cm2; VAA 3, area >140 cm2. Sympathetic innervation was quantified by 123I-MIBG cardiac activity. Patients were followed up for an average of 22 months with a primary endpoint of lethal cardiac events (CE). The CE group (n=200) had a lower late heart-to mediastinum ratio (HMR) and a smaller VAA than those in the non-CE group. Rates of overall CE/HF death were inversely correlated with VAA: 39.2% ± 6.2% for VAA 1, 27.4% ± 19.9% for VAA 2 and 24.1% ± 15.3% for VAA 3. In addition to sudden cardiac death rate, lethal arrhythmic event rate increased in association with visceral fat obesity: 3.0% for VAA 1, 7.5% for VAA 2 and 8.8% for VAA 3. Late HMR identified high-risk sub-populations in each group. Conclusion: Visceral obesity has paradoxical prognostic implications in terms of HF mortality and lethal arrhythmic/sudden cardiac death events. Cardiac sympathetic denervation and quantitative visceral adiposity are synergistically associated with overall cardiac mortality, contributing to better risk stratification of HF patients.