Clinical Outcomes In Heart Failure Research Articles

Associations of serially measured PCSK9, LDLR and MPO with clinical outcomes in heart failure.

Aim: To investigate the temporal evolution of plasma proprotein convertase subtilisin/kexin type 9(PCSK9), low-density lipoprotein receptor (LDLR) and myeloperoxidase (MPO) in relation to clinical outcome in chronic heart failure (CHF). Methodology &results: Trimonthly blood sampling was performed during a median follow-up of 2.2 (IQR 1.4-2.5) years in 263 CHF patients. Seventypatients reached the primary end point (PE) (cardiovascular death, heart transplantation, left ventricular assist device implantation or HF-hospitalization). MPO level was independently associated with the PE; the adjusted (for clinical factors) hazard ratio (aHR) per standard deviation difference in MPO was 1.71 (95% CI: 1.23-2.43) at any time during follow-up. PCSK9 level (HR: 1.45 [1.04-2.06]) and LDLR (HR: 0.66 [0.49-0.87]) were statistical significantly associated with the PE but only in unadjusted analyses. Slope of temporal MPO evolution (aHR: 1.34 [1.12-1.76]per 0.1 standard deviation/year difference in slope) and LDLR (aHR: 0.78 [0.61-0.90]) however, were associated with PE. Conclusion: Temporal patterns of MPO and LDLR are independently associated with clinical outcome in CHF, which illustrates the importance of assessing temporal evolutions. Clinical trial registration information: registered in ClinicalTrials.gov, number NCT01851538. https://clinicaltrials.gov/ct2/show/NCT01851538.

Loop Diuretic Prescription and Long-Term Outcomes in Heart Failure: Association Modification by Congestion

BackgroundThe effect of loop diuretics on clinical outcomes in heart failure has not been evaluated in randomized controlled trials. In hospitalized patients with heart failure, a discharge loop diuretic prescription has been shown to be associated with improved 30-day outcomes, which appears to be more pronounced in subgroups with congestion. In the current study, we examined these associations and association modifications during longer follow-up. MethodsWe assembled a propensity score-matched cohort of 2191 pairs of hospitalized heart failure patients discharged with, vs without, a prescription for loop diuretics, balanced on 74 baseline characteristics (mean age 78 years; 54% women; 11% African American). ResultsHazard ratio (HR) and 95% confidence interval (CI) for 6-year combined endpoint of heart failure readmission or all-cause mortality was 1.02 (0.96-1.09). HRs and 95% CIs for this combined endpoint in patients with no, mild-to-moderate, and severe pulmonary rales were 1.19 (1.07-1.33), 0.95 (0.86-1.04), and 0.77 (0.63-0.94), respectively (P for interaction, < .001). Respective HRs (95% CIs) for no, mild-to-moderate, and severe lower extremity edema were 1.16 (1.06-1.28), 0.94 (0.85-1.04), and 0.71 (0.56-0.89; interaction P < .001). ConclusionsThe association between a discharge loop diuretic prescription and long-term clinical outcomes in hospitalized patients with heart failure is modified by admission congestion with worse, neutral, and better outcomes in patients with no, mild-to-moderate, and severe congestion, respectively. If these findings can be replicated, congestion may be used to risk-stratify patients with heart failure for potential optimization of loop diuretic prescription and outcomes.

Atrial fibrillation burden and heart failure: Data from 39,710 individuals with cardiac implanted electronic devices

Atrial fibrillation (AF) and heart failure (HF) often accompany one another, and each is independently associated with poor outcomes. However, the association between AF burden and outcomes is poorly understood. The purpose of this study was to describe the association between device-based AF burden and HF clinical outcomes. We used a nationwide, remote monitoring database of cardiac implantable electronic devices (CIEDs) linked to Medicare claims. We included patients with nonpermanent AF, undergoing new CIED implant, stratified by baseline HF. The outcomes were new-onset HF, HF hospitalization, and all-cause mortality at 1 and 3 years. We identified 39,710 patients who met inclusion criteria (25,054 with HF; 14,656 without HF). Patients with HF were younger (mean age 76.3 vs 78.5 years; P <.001), more often male (65% vs 54%; P <.001), and had higher mean CHA2DS2-VASc scores (5.4 vs 4.1; P <.001). Among those without HF, increasing device-based AF burden was significantly associated with increased risk of new-onset HF (adjusted hazard ratio [HR] 1.09 per 10% AF burden; 95% confidence interval [CI] 1.06-1.12; P <.001) and all-cause mortality (adjusted HR 1.05 per 10% AF burden; 95% CI 1.01-1.10; P = .012). Among patients with HF, increasing AF burden was significantly associated with increased risk of HF hospitalization (adjusted HR 1.05 per 10% AF burden; 95% CI 1.04-1.06; P <.001) and all-cause mortality (adjusted HR 1.06 per 10% AF burden; 95% CI 1.05-1.08; P <.001). Among older patients with AF receiving a CIED, increasing AF burden is significantly associated with increasing risk of adverse HF outcomes and all-cause mortality.

High percent body fat mass predicts lower risk of cardiac events in patients with heart failure: an explanation of the obesity paradox

BackgroundAlthough high body mass index (BMI) is a risk factor of heart failure (HF), HF patients with a higher BMI had a lower mortality rate than that in HF patients with normal or lower BMI, a phenomenon that has been termed the “obesity paradox”. However, the relationship between body composition, i.e., fat or muscle mass, and clinical outcome in HF remains unclear.MethodsWe retrospectively analyzed data for 198 consecutive HF patients (76 years of age; males, 49%). Patients who were admitted to our institute for diagnosis and management of HF and received a dual-energy X-ray absorptiometry scan were included regardless of left ventricular ejection fraction (LVEF) categories. Muscle wasting was defined as appendicular skeletal muscle mass index < 7.0 kg/m2 in males and < 5.4 kg/m2 in females. Increased percent body fat mass (increased FM) was defined as percent body fat > 25% in males and > 30% in females.ResultsThe median age of the patients was 76 years (interquartile range [IQR], 67–82 years) and 49% of them were male. The median LVEF was 47% (IQR, 33–63%) and 33% of the patients had heart failure with reduced ejection fraction. Increased FM and muscle wasting were observed in 58 and 67% of the enrolled patients, respectively. During a 180-day follow-up period, 32 patients (16%) had cardiac events defined as cardiac death or readmission by worsening HF or arrhythmia. Kaplan-Meier survival curves showed that patients with increased FM had a lower cardiac event rate than did patients without increased FM (11.4% vs. 22.6%, p = 0.03). Kaplan-Meier curves of cardiac event rates did not differ between patients with and those without muscle wasting (16.5% vs. 15.4%, p = 0.93). In multivariate Cox regression analyses, increased FM was independently associated with lower cardiac event rates (hazard ratio: 0.45, 95% confidence interval: 0.22–0.93) after adjustment for age, sex, diabetes, muscle wasting, and renal function.ConclusionsHigh percent body fat mass is associated with lower risk of short-term cardiac events in HF patients.

Pharmacist-led heart failure patient focus group using mobile apps-based intervention mix

AbstractObjectivesThe impact of clinical pharmacists on inpatient heart failure (HF) care has been proven in many studies. Evidence regarding the use of mobile apps by pharmacists to achieve positive clinical outcomes in HF is limited. The purpose of this study is to examine the impact of a pharmacist-led HF patient focus group using mobile apps-based intervention mix.MethodsIn this pre–post-exploratory study, using an intervention mix of hospital discharge counselling, MyTherapy app, WhatsApp and occasional phone calls to improve clinical outcomes in HF. Patient medication adherence, health-related quality of life (HRQoL) and 30-day all-cause hospital readmission rate were assessed. The Wilcoxon Signed-Rank Test was used to find statistical significance of improvements in medication adherence and HRQoL using SPSS software version 26.Key findingsThe intervention mix of initial hospital-discharge counselling, MyTherapy app, follow-up with the WhatsApp group and occasional phone calls established an effective communication with patients. All 10 patients had improvements in their clinical outcomes. Significant improvements in medication adherence and HRQoL were found (Z-value −2.810 and Z-value −2.805, respectively; 95% confidence interval). No patients were readmitted in 30 days or within 3 months of study.ConclusionsA pharmacist-led HF patient focus group using mobile apps-based intervention mix was found to be effective in improving clinical outcomes in HF patients. Further research should be performed on long-term effects of our approach.

Does Weight Loss Improve Clinical Outcomes in Overweight and Obese Patients with Heart Failure?

Obesity increases the risk of new onset heart failure (HF), and particularly HF with preserved ejection fraction (HFpEF). Despite the observations of favorable clinical outcomes in HF patients with obesity in general, sometimes referred to as the "obesity paradox," it is important to recognize that severe obesity is associated with worse clinical outcomes. This review summarizes the effects of obesity treatment on cardiovascular health and HF clinical outcomes. Treatment for obesity utilizes a variety of modalities to achieve purposeful weight loss including lifestyle intervention, medications, and bariatric surgery. There are a cluster of benefits of obesity treatment in terms of clinical outcomes in HF. The mechanisms of these benefits include both weight loss-dependent and weight loss-independent mechanisms. Obesity treatment is safe and associated with favorable clinical outcomes across the spectrum of the HF population. The potential benefits are facilitated through multiple mechanisms.

Abstract 13812: Pulmonary Function Predicts Cardiac Function, Structure &amp; Clinical Outcome in Chronic Heart Failure: Results From the Myovasc Study

Introduction: A growing body of evidence suggests a relevance of pulmonary function in the pathophysiology of heart failure (HF). Comprehensive data on the role of forced expiratory volume in 1 second (FEV1) in the development &amp; progression of HF is limited. Hypothesis: Given this background, we hypothesized, that (FEV1) is associated with deteriorated left ventricular (LV) functional as well as structural status, &amp; predicts specific clinical outcome in HF. Methods: Data from the MyoVasc Study (n=3,289) were analysed. Comprehensive clinical phenotyping including body plethysmography for the evaluation of FEV1 &amp; standardized echocardiography were performed during a five-hour investigation in a dedicated study center. Worsening of HF (comprising transition from asymptomatic to symptomatic HF, HF hospitalization, &amp; cardiac death) was assessed during a structured follow-up with subsequent validation &amp; adjudication of endpoints. Results: Information on FEV1 was available in 2,998 individuals (age 35-84 years; 34.1% female, mean FEV1 92.4[% predicted]). In multivariable regression analysis adjusted for age, sex, height, cardiovascular risk factors (CVRF) &amp; clinical profile, FEV1 per-1SD was an independent predictor of reduced LV ejection fraction (β:-1.6[95%CI -2.0;-1.3]), elevated E/E’-ratio (β:0.82[0.64;0.99]), &amp; increased LV mass/Height 2.7 (β:1.6[1.1;2.1]) (for all, P&lt;0.001). During a median follow-up of 2.3 (interquartile range 1.1; 4.0) years, FEV1 per-1SD predicted worsening of HF (hazard ratio(HR) 1.46[1.30;1.65], P&lt;0.001) independent of age, sex, height, CVRF &amp; comorbidities. This finding was consistent among the single components of the primary study endpoint: FEV1 per-1SD predicted an increased risk for transition to symptomatic HF (HR 1.57[1.19;2.06]), HF hospitalization (HR 1.35[1.16;1.57]) &amp; for cardiac death (HR 1.84[1.49;2.26]) (for all, P&lt;0.001). FEV1 per-1SD remained an independent predictor of worsening of HF after additional adjustment for NT-proBNP (HR 1.25[1.08;1.45], P=0.002). Conclusion: Impaired FEV1 is directly linked to the pathophysiology of HF &amp; represents a strong &amp; independent predictor of HF outcome highlighting its potential value to advance risk prediction in HF.

Heart Failure in Diabetes Mellitus: An Updated Review.

Diabetes mellitus (DM) and heart failure (HF) are comorbid conditions associated with significant morbidity and mortality worldwide. Despite the availability of novel and effective therapeutic options and intensive glycaemic control strategies, mortality and hospitalisation rates continue to remain high and the incidence of HF persists. In this review, we described the impact of currently available glucose-lowering therapies in DM with a focus on HF clinical outcomes. Non-conventional modes of management and alternative pathophysiological mechanisms with the potential for therapeutic targeting are also discussed.

Prevalence of microvascular dysfunction and association with clinical outcomes in heart failure with preserved ejection fraction

Abstract Introduction Heart failure with preserved ejection fraction (HFpEF) accounts for approximately 50% of symptomatic heart failure. A recently proposed paradigm for the pathophysiology of HFpEF postulates a central inflammatory aetiology with coronary microvascular function at its core. However, the pathophysiological and clinical significance of microvascular dysfunction in HFpEF remains uncertain. Purpose Utilising cardiovascular magnetic resonance (CMR), we sought to (1) quantify coronary microvascular function, (2) evaluate the impact of microvascular dysfunction and fibrosis on long-term clinical outcomes and (3) examine the relationship between myocardial perfusion and fibrosis. Methods In a prospective, observational study, 147 subjects (104 HFpEF without a prior history or CMR evidence of coronary artery disease, and 43 asymptomatic controls) underwent multiparametric CMR, comprising left ventricular volumetric assessment, absolute quantitation of myocardial blood flow [MBF] during adenosine stress (140mcg/kg/min) and at rest, and evaluation of diffuse myocardial fibrosis (extracellular volume [ECV]). The primary endpoint was the composite of death or hospitalisation with heart failure. Results 104 HFpEF patients (mean age 73±9 years, mean ejection fraction 56%) and 43 controls (mean age 73±5 years, mean ejection fraction 58%) were studied. There was no significant difference in resting MBF (1.10±0.42ml/min/g in HFpEF subjects vs 1.00±0.38 ml/min/g in controls, p=0.23), though hyperaemic MBF was lower in HFpEF subjects (1.66±0.68 ml/min/g vs 1.97±0.59 ml/min/g, p=0.01). Myocardial perfusion reserve [MPR] was also lower in HFpEF subjects (1.73±0.75 vs 2.22±0.76; p&amp;lt;0.01). Microvascular dysfunction (defined as MPR&amp;lt;2.0) was present in 70% of HFpEF patients (versus 33% of controls, p&amp;lt;0.01). During median follow-up of 3.4 years, there were 46 composite events. MPR was predictive of clinical outcome (one unit increase – hazard ratio [HR] 0.57; 95% CI 0.35–0.92; p=0.02), as was ECV (one standard deviation [SD] increase – HR 1.65; 95% CI 1.14–2.39; p=0.01). However, there was no significant linear correlation between MPR and diffuse fibrosis (r&amp;lt;0.01, p=0.99). Conclusion Microvascular dysfunction is highly prevalent in HFpEF and is associated with adverse clinical outcomes. The lack of correlation between abnormal myocardial perfusion and fibrosis challenges the assertion of a direct causal link between these entities. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): NIHR, BHF

Discharge heart rate and beta-blockers treatments in hospitalized heart failure patients with coexisted atrial fibrillation

Abstract Background Beta-blockers are widely used to improve clinical outcomes in heart failure (HF) patients. However, the effects of beta-blockers on clinical outcomes in those who have coexisted atrial fibrillation (AF) remains uncertain. Purpose We investigated the associations between beta-blockers and clinical outcomes according to discharge heart rate. Methods The study cohort included 1631 HF patients hospitalized primarily with AF, which was from the China PEACE Prospective Heart Failure Study. Clinical outcome was 1-year combined all-cause mortality and HF hospitalization after discharge. The associations between beta-blockers and clinical outcome were assessed using Cox proportional hazard and standardization mortality weighting regression models, with stratified discharge heart rate group predefined by restricted cubic spline. Results The median age was 68 (IQR: 60- 77) years, 41.9% were women, discharge heart rate was (median (IQR)) 75 (69- 84) beats per minute (bpm), and 60.2% received beta-blockers at discharge. According to the result of restricted cubic spline plot, these patients were divided into 3 groups: lowest &amp;lt;65 bpm, middle 65–86 bpm and highest ≥87 bpm (Fig.1). In the Cox proportional hazard analysis, a significant interaction between discharge heart rate and beta-blocker use was observed (P&amp;lt;0.001 for interaction). Stratified analysis showed beta-blocker prescription at discharge was associated with reduced risk for clinical outcomes in patients with high heart rates (hazard ratio 0.336, 95% CI: 0.144–0.786, p=0.012) but not in those with lowest and middle heart rates (hazard ratio: 1.32; 95% CI, 0.95–1.63; hazard ratio: 1.02; 95% CI, 0.68–1.55, respectively). Conclusion The associations between beta-blockers and clinical outcomes may be significantly influenced by baseline heart rate. Hospitalized HF patients with AF benefit the most from beta-blockers use if they had high heart rate (≥87 bpm) at discharge. Figure 1 Funding Acknowledgement Type of funding source: Other. Main funding source(s): This work was supported by the National Key Research and Development Program (2017YFC1310803) from the Ministry of Science and Technology of China; the CAMS Innovation Fund for Medical Science (2017-I2M-B&amp;R-02); the 111 Project from the Ministry of Education of China (B16005).

Atrial fibrillation and the prognostic performance of biomarkers in heart failure

Abstract Background Consideration of circulating biomarkers for risk stratification in heart failure (HF) is recommended in authoritative international guidelines but the influence of atrial fibrillation (AF) on the prognostic performance of many markers is unclear. Therefore we investigated the interactions between AF and biomarkers in prediction of important clinical outcomes in HF. Methods NT-proBNP, pro-atrial natriuretic peptide (MR-proANP), C-type natriuretic peptide (CNP), NT-proCNP, high-sensitivity troponin-T, high-sensitivity troponin-I, mid-regional-propeptide adrenomedullin (MR-proADM), co-peptin (PAVP), growth differentiation factor-15 (GDF-15), sST2, Galectin-3 and procalcitonin levels were measured in a prospectively designed, multicenter, longitudinal study of adults with HF. AF was defined as a documented history of AF based on medical records, and/or presence of AF/atrial flutter on baseline 12-lead ECG. The primary outcome considered was the composite of HF-hospitalization or all-cause mortality on prospective follow-up at 2-years. Cox proportional-hazards models were used in the prognostic evaluation of biomarkers, and each was tested for interaction with AF. Results Among 1,099 patients with HF (mean age 62±12 years, 28% female, mean left ventricular ejection fraction 35±16%), 261 (24%) patients had AF. Median levels of NT-proBNP, GDF-15, ST2, MR-proADM, proANP and CNP were higher in AF (p&amp;lt;0.05). Above-median levels of all 12 biomarkers were independently associated with increased risk of the primary outcome. Significant interactions with AF were detected for Galectin-3 and sST2. Galectin-3 (&amp;gt;7.7ng/mL) was associated with increased HF-hospitalizations (adjusted hazard ratio [AHR] 1.75, 95% C.I. 1.10–2.77) and all-cause mortality (AHR 1.95, 95% C.I. 1.04–3.63) only among patients with AF. The prognostic performance of sST2 (&amp;gt;35.6ng/mL) was also stronger in AF especially for the primary outcome (AF: AHR 2.06 95% C.I. 1.32–3.21; non-AF: AHR 1.49 95% C.I. 1.18–1.88) and HF-hospitalization (AF: AHR 1.65, 95% C.I. 1.01–2.69; non-AF: AHR 1.32, 95% C.I. 1.02–1.71). The association of Galectin-3 with the composite outcome was not modified by HF type (HFpEF vs HFrEF) (p for 3-way interaction=0.61) except for sST2 (p for 3-way interaction=0.018) where the association appeared stronger in patients with HFpEF and AF (HR 3.12, 95% C.I. 1.26–7.78) compared to those with HFrEF and AF (HR 1.83, 95% C.I. 1.01–3.33) although numbers of events in each subgroup were small. Notably, no such interactions were observed for the most frequently measured prognostic markers in HF including NT-proBNP and the high-sensitivity cardiac troponins. Conclusion AF modified the prognostic utility of guideline-endorsed HF-biomarkers, wherein prognostic associations of Galectin-3 and ST2 were limited to, or stronger in, patients with AF. Application of markers for prognostic purposes in HF requires consideration of the presence or absence of AF. Figure 1 Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): National Medical Research Council of Singapore

A decrease in tricuspid regurgitation pressure gradient during follow-up in patients with heart failure

Abstract Objective This study aimed to investigate the prognostic impact of the decrease in tricuspid regurgitation pressure gradient (TRPG) at 6-month follow-up in patients after discharge with heart failure (HF). Background No previous study has reported the association between TRPG decrease during follow-up and clinical outcomes in HF. Methods Among 748 patients with 6-months follow-up echocardiography after discharge from the acute decompensated heart failure in 19 centers in Japan, we analyzed 721 patients with available TRPG data and divided into two groups: the decrease in TRPG group (N=179) and no decrease in TRPG group (N=542). We defined the decrease in TRPG as &amp;gt;10mmHg decrease compared in the initial hospitalization. The primary outcome measure was a composite of all cause deaths and hospitalization due to HF. Results The patients in the decrease in TRPG group had a lower prevalence of hypertension, dyslipidemia, atrial fibrillation, and a reduced EF, higher levels of blood albumin and lower levels of sodium than those in no decrease in TRPG group. The median follow-up duration after the follow up echocardiography was 302 (inter quartile range: 206–490), with a 90.9% follow up rate at 6-month. The cumulative 6-month incidence of the primary outcome measure was significantly lower in the decrease in TRPG group than in no decrease in TRPG group (12.2% vs. 18.9%, P=0.0011). After adjusting confounders, the excess risk of the decrease in TRPG relative to no decrease in TRPG for the primary outcome measure remained significant (HR: 0.60, 95% CI 0.34–0.99). There were no significant interactions between the subgroup factors and the effect of the decrease in TRPG for primary outcomes. Conclusions HF patients with the decrease in TRPG at 6-month after discharge had a lower risk of clinical outcome than those without decrease in TRPG. Funding Acknowledgement Type of funding source: None

Serum potassium and heart failure: association, causation, and clinical implications

Dyskalemia (hypo- and hyperkalemia) is a common clinical encounter in patients with heart failure (HF), linked to underlying pathophysiologic alterations, pharmacological treatments, and concomitant comorbidities. Both hypo- and hyperkalemia have been associated with a poor outcome in HF. However, it is not known if this association is causal. In order to investigate this relation, we implemented the Bradford Hill criteria for causation examining the available literature. Of note, hypokalemia and low-normal potassium levels (serum potassium <4.0mmol/L) appear to be associated with adverse clinical outcomes in HF in a cause-and-effect manner. Conversely, a cause-and-effect relationship between hyperkalemia (serum potassium >5.0mmol/L) and adverse clinical outcomes in HF appears unlikely. We also examined the benefits of renin-angiotensin-aldosterone system inhibitors (RAASi) therapy uptitration in patients with HF and reduced ejection fraction. In fact, hyperkalemia often limits RAASi use, thereby negating or mitigating their clinical benefits. Finally, serum potassium levels in HF should be maintained within the range of 4.0-5.0mmol/L, and although the correction of hyperkalemia does not appear to improve clinical outcomes per se, it may enable the optimal titration of RAASi, offering indirect clinical benefit.

Mir-30d Regulates Cardiac Remodeling by Intracellular and Paracrine Signaling.

Previous translational studies implicate plasma extracellular microRNA-30d (miR-30d) as a biomarker in left ventricular remodeling and clinical outcome in heart failure (HF) patients, although precise mechanisms remain obscure. To investigate the mechanism of miR-30d-mediated cardioprotection in HF. In rat and mouse models of ischemic HF, we show that miR-30d gain of function (genetic, lentivirus, or agomiR-mediated) improves cardiac function, decreases myocardial fibrosis, and attenuates cardiomyocyte (CM) apoptosis. Genetic or locked nucleic acid-based knock-down of miR-30d expression potentiates pathological left ventricular remodeling, with increased dysfunction, fibrosis, and cardiomyocyte death. RNA sequencing of in vitro miR-30d gain and loss of function, together with bioinformatic prediction and experimental validation in cardiac myocytes and fibroblasts, were used to identify and validate direct targets of miR-30d. miR-30d expression is selectively enriched in cardiomyocytes, induced by hypoxic stress and is acutely protective, targeting MAP4K4 (mitogen-associate protein kinase 4) to ameliorate apoptosis. Moreover, miR-30d is secreted primarily in extracellular vesicles by cardiomyocytes and inhibits fibroblast proliferation and activation by directly targeting integrin α5 in the acute phase via paracrine signaling to cardiac fibroblasts. In the chronic phase of ischemic remodeling, lower expression of miR-30d in the heart and plasma extracellular vesicles is associated with adverse remodeling in rodent models and human subjects and is linked to whole-blood expression of genes implicated in fibrosis and inflammation, consistent with observations in model systems. These findings provide the mechanistic underpinning for the cardioprotective association of miR-30d in human HF. More broadly, our findings support an emerging paradigm involving intercellular communication of extracellular vesicle-contained miRNAs (microRNAs) to transregulate distinct signaling pathways across cell types. Functionally validated RNA biomarkers and their signaling networks may warrant further investigation as novel therapeutic targets in HF.

Boron improves cardiac contractility and fibrotic remodeling following myocardial infarction injury

Myocardial fibrosis is a major determinant of clinical outcomes in heart failure (HF) patients. It is characterized by the emergence of myofibroblasts and early activation of pro-fibrotic signaling pathways before adverse ventricular remodeling and progression of HF. Boron has been reported in recent years to augment the innate immune system and cell proliferation, which play an important role in the repair and regeneration of the injured tissue. Currently, the effect of boron on cardiac contractility and remodeling is unknown. In this study, we investigated, for the first time, the effect of boron supplementation on cardiac function, myocardial fibrosis, apoptosis and regeneration in a rat model myocardial infarction (MI)-induced HF. MI was induced in animals and borax, a sodium salt of boron, was administered for 7 days, p.o., 21 days post-injury at a dose level of 4 mg/kg body weight. Transthoracic echocardiographic analysis showed a significant improvement in systolic and diastolic functions with boron treatment compared to saline control. In addition, boron administration showed a marked reduction in myocardial fibrosis and apoptosis in the injured hearts, highlighting a protective effect of boron in the ischemic heart. Interestingly, we observed a tenfold increase of nuclei in thin myocardial sections stained positive for the cell cycle marker Ki67 in the MI boron-treated rats compared to saline, indicative of increased cardiomyocyte cell cycle activity in MI hearts, highlighting its potential role in regeneration post-injury. We similarly observed increased Ki67 and BrdU staining in cultured fresh neonatal rat ventricular cardiomyocytes. Collectively, the results show that boron positively impacted MI-induced HF and attenuated cardiac fibrosis and apoptosis, two prominent features of HF. Importantly, boron has the potential to induce cardiomyocyte cell cycle entry and potentially cardiac tissue regeneration after injury. Boron might be beneficial as a supplement in MI and may be a good candidate substance for anti-fibrosis approach.

Reappraisal of Urinary Sodium Excretion as a Predictor of Clinical Outcomes in Heart Failure

Reappraisal of Urinary Sodium Excretion as a Predictor of Clinical Outcomes in Heart Failure

Why is Diuresis-related Weight Loss Not a Consistent Predictor of Clinical Outcomes in Heart Failure? -need to Account For Variability in Volume Status

Introduction Change in body weight is a common metric used to assess adequacy of decongestive therapy in patients hospitalized for heart failure (HF). However, the findings of clinical studies linking this metric to clinical decongestion and outcomes are mixed. We propose this reflects the failure to take into account biologic variability in intravascular volume status which would impact response to therapy. Methods Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by median diuresis-related weight loss and analyzed for 1-year outcome of HF-related mortality or 1st re-hospitalization, and the relation of change in weight to change in PV admission to discharge. Results The cohort was composed of 138 patients with median weight loss of 6 (IQR -3.2, -8.1) kg during hospitalization (5 IQR 4, 6 days). Greater than median weight loss (Figure 1) did not result in better outcomes. At the time of hospital discharge the subgroup with greater weight loss (N=61) paradoxically demonstrated greater absolute (4.8±1.0 vs. 4.2±1.0 liters, p<0.001) and relative PV expansion(+44±29% vs. +33±23% above normal, p=0.023). Also demonstrated was marked heterogeneity in PV status in both subgroups (Figure 2). Volumes for the cohort ranged from 17% with normal PV, 23% mild-moderate PV expansion, to 60% with persisting severe (≥ +25%) PV expansion at hospital discharge. In a cohort subgroup of 62 patients where PV was measured at hospital admission and discharge there was no clinically significant association between change in weight and change in PV (r=0.327, p=0.01). Conclusions Diuresis-related changes in weight reflect clinical decongestion but do not consistently reflect better HF outcomes and, importantly, do not accurately reflect changes in intravascular volume. A basis for this discordance is the significant patient-to-patient variability in volume both at admission and discharge which confounds interpretation of surrogate metrics of decongestion. Failure to account for the marked heterogeneity in volume status contributes to the observed discordance between metrics of clinical decongestion and HF outcomes. Change in body weight is a common metric used to assess adequacy of decongestive therapy in patients hospitalized for heart failure (HF). However, the findings of clinical studies linking this metric to clinical decongestion and outcomes are mixed. We propose this reflects the failure to take into account biologic variability in intravascular volume status which would impact response to therapy. Data were prospectively collected in hospitalized patients requiring diuresis. Plasma volume (PV) was measured using I-131-labelled albumin indicator-dilution methodology. The cohort was stratified by median diuresis-related weight loss and analyzed for 1-year outcome of HF-related mortality or 1st re-hospitalization, and the relation of change in weight to change in PV admission to discharge. The cohort was composed of 138 patients with median weight loss of 6 (IQR -3.2, -8.1) kg during hospitalization (5 IQR 4, 6 days). Greater than median weight loss (Figure 1) did not result in better outcomes. At the time of hospital discharge the subgroup with greater weight loss (N=61) paradoxically demonstrated greater absolute (4.8±1.0 vs. 4.2±1.0 liters, p<0.001) and relative PV expansion(+44±29% vs. +33±23% above normal, p=0.023). Also demonstrated was marked heterogeneity in PV status in both subgroups (Figure 2). Volumes for the cohort ranged from 17% with normal PV, 23% mild-moderate PV expansion, to 60% with persisting severe (≥ +25%) PV expansion at hospital discharge. In a cohort subgroup of 62 patients where PV was measured at hospital admission and discharge there was no clinically significant association between change in weight and change in PV (r=0.327, p=0.01). Diuresis-related changes in weight reflect clinical decongestion but do not consistently reflect better HF outcomes and, importantly, do not accurately reflect changes in intravascular volume. A basis for this discordance is the significant patient-to-patient variability in volume both at admission and discharge which confounds interpretation of surrogate metrics of decongestion. Failure to account for the marked heterogeneity in volume status contributes to the observed discordance between metrics of clinical decongestion and HF outcomes.

Outcomes of Cardiac Resynchronization Therapy in Patients with Hypothyroidism and Heart Failure

BackgroundHypothyroidism is known to be associated with adverse clinical outcomes in heart failure. The association between hypothyroidism and cardiac resynchronization therapy outcomes in patients with severe heart failure is not clear.MethodsThe study included 1316 patients who received cardiac resynchronization therapy between 2002 and 2015. Baseline demographics and cardiac resynchronization therapy outcomes, including left ventricular ejection fraction, New York Heart Association class, appropriate implantable cardioverter-defibrillator therapy, and all-cause mortality, were collected from the electronic health record.ResultsOf the study cohort, 350 patients (26.6%) were classified as the hypothyroidism group. The median duration of follow-up was 3.6 years (interquartile range, 1.7–6.2 years). Hypothyroidism was not associated with a higher risk of all-cause mortality in patients receiving CRT for heart failure. The risk of appropriate implantable cardioverter-defibrillator therapy significantly increased in association with increased baseline thyroid-stimulating hormone level in the entire cohort (hazard ratio, 1.23 per 5mIU/L increase; 95% CI, 1.01–1.5; P = 0.04) as well as in the hypothyroid group (hazard ratio, 1.44 per 5mIU/L increase; 95% CI, 1.13–1.84; P = 0.004).ConclusionsCRT improves cardiac function in hypothyroid patients. The ventricular arrhythmic events requiring ICD therapies are associated with baseline TSH level, which might be considered as an important biomarker to stratify the risk of sudden death for patients with heart failure and hypothyroidism.

Modulation of P2Y6R expression exacerbates pressure overload-induced cardiac remodeling in mice

Cardiac tissue remodeling caused by hemodynamic overload is a major clinical outcome of heart failure. Uridine-responsive purinergic P2Y6 receptor (P2Y6R) contributes to the progression of cardiovascular remodeling in rodents, but it is not known whether inhibition of P2Y6R prevents or promotes heart failure. We demonstrate that inhibition of P2Y6R promotes pressure overload-induced sudden death and heart failure in mice. In neonatal cardiomyocytes, knockdown of P2Y6R significantly attenuated hypertrophic growth and cell death caused by hypotonic stimulation, indicating the involvement of P2Y6R in mechanical stress-induced myocardial dysfunction. Unexpectedly, compared with wild-type mice, deletion of P2Y6R promoted pressure overload-induced sudden death, as well as cardiac remodeling and dysfunction. Mice with cardiomyocyte-specific overexpression of P2Y6R also exhibited cardiac dysfunction and severe fibrosis. In contrast, P2Y6R deletion had little impact on oxidative stress-mediated cardiac dysfunction induced by doxorubicin treatment. These findings provide overwhelming evidence that systemic inhibition of P2Y6R exacerbates pressure overload-induced heart failure in mice, although P2Y6R in cardiomyocytes contributes to the progression of cardiac fibrosis.

The effect of beta-blockers in acute heart failure according to heart rate.

Background/AimsBeta-blockers (BBs) have been shown to improve clinical outcomes in heart failure (HF) patients. We evaluated the prescribing status of BBs in patients with HF with reduced ejection fraction (HFrEF) at discharge according to the presence or not of bradycardia, and its effect on prognosis.MethodsStudy data were obtained from a multicenter cohort of 3,200 patients hospitalized for HF. Patients were classified into four groups according to the presence of bradycardia and use of BBs at discharge. The primary outcome was the incidence of all-cause death during follow-up.ResultsOf 1,584 patients with HFrEF, 281 patients died during follow-up (median 523 days, mean 578.5 ± 429.7 days). In patients with bradycardia, the all-cause death rate did not significantly differ according to the use of BBs, but in those patients without bradycardia, the incidence of all-cause death was significantly lower in the BBs group than the no BBs group. Among these four groups, patients with heart rate (HR) ≥ 60 beats/min with no BBs group had the lowest cumulative death-free survival rate. In addition, HR ≥ 60 beats/min with BBs use was independently associated with a 31% reduced risk of all-cause death in patients with HFrEF.ConclusionsBBs had a beneficial effect on clinical prognosis only in those HFrEF patients without bradycardia. Therefore, BBs should be given by clinicians to HF patients without bradycardia to improve their clinical outcomes.