Morbidity In Heart Failure Research Articles

Temporal trends in end-stage renal disease in patients with heart failure with or without diabetes: a nationwide study from 2002 to 2017

Abstract Background Advances in treatment of heart failure (HF) have increased survival rates. However, whether the improved life expectancy for HF patients has resulted in an increased risk of a significant comorbidity like end-stage renal disease (ESRD) is less clear. Renal dysfunction is associated with increased morbidity and mortality in HF and constitutes an important prognostic factor for HF. Further, diabetes (DM) is closely related to both HF and ESRD, but it is unknown how DM affects the risk of ESRD in patients with HF. Purpose To investigate temporal trends in ESRD in patients with HF and the subsequent risk of mortality stratified by DM. Methods Using Danish nationwide registies, we identified patients, aged 18 to 100 years, with incident HF between 2002 and 2017. The outcomes were ESRD (defined as dialysis treatment), worsening of HF (wHF, defined as rehospitalization for HF) and all-cause mortality. Three study periods were investigated 2002–2006, 2007–2011 and 2012–2017. We estimated crude 5-year incidence rates (per 1000/person-years) of the outcomes stratified by DM. Multivariate Cox regression models were performed for all outcomes stratified by DM. Further, we computed the 1-year all-cause mortality risk after diagnosis with ESRD. Results Of 124,141 patients with HF, 50,690 (41%) were women and the median age was 74.5 years [95% confidence interval (CI) 64.5–82.8]. At baseline DM was present in 20% of the patients. These patients were older, more often men and more comorbid than HF patients without DM. Over time (2002–2006 to 2012–2017) the incidence rates of ESRD (9.0 to 7.9 and 2.1 to 1.9 per 1000/person-years for DM and no-DM, respectively) and wHF (124.0 to 124.8 and 84.3 to 81.9 per 1000/person-years for DM and no-DM) remained stable, while all-cause mortality rates decreased (217.0 to 170.3 and 172.9 to 127.8 per 1000/person-years for DM and no-DM). The incidence of ESRD was lower compared with the incidence of wHF and all-cause mortality [Figure 1]. HF patients with DM had significantly higher associated rates of all three outcomes (in 2012–2017 the rates for DM vs no-DM of ESRD: 3.99 [3.27–4.86], wHF: 1.42 [1.36–1.49], all-cause mortality: 1.36 [1.31–1.41]) compared with patients without DM. We found no significant interaction between time period and DM on the rates of outcomes (p>0.05 for all) [Figure 2]. One-year all-cause mortality risk after diagnosis with ESRD was high both for HF patients with and without DM through all time periods (identical risks and 95% CI in 2012–2017: 32% [0.25–0.39]). Conclusions We did not observe a change over time in the 5-year risk of ESRD for HF patients. The incidence of ESRD remained low compared to wHF and all-cause mortality. DM was associated with increased rates of all three events, not changed over time. Conversely, all-cause mortality after diagnosis with ESRD was markedly high, irrespectively of DM. Our analyses suggest that ESRD is a less common, but fatal event in HF patients. Funding Acknowledgement Type of funding sources: None.

Metabolic syndrome and heart failure: 40 years follow up results of the Seven Countries Study

Abstract Introduction Metabolic syndrome (Met Sy) as a highly debatable cluster of traditional risk factors is known to promote cardiometabolic-related morbidity and mortality, but its precise mechanisms remain to be determined. Purpose We sought to determine influence of MetSy on heart failure (HF) morbidity and mortality in the Seven Countries' Study as one of the oldest epidemiological studies. Methods The Seven Countries Study encompassed 12,763 participants from 3 continents who were all healthy men of over 40 years at baseline and who underwent regular check ups every 5 years throughout over a 4 decades' span. Morbidity and mortality was adjudicated according to valid ICD and LPH coding. Results Using the IDF definition of the Metabolic Syndrome, 9,09% of participants were identified (Figure 1). HF was confirmed in 220 patients (16.4% alive at 40y follow up visit), while 8.2% died of HF as well in the same time-frame (Tables 1 & 2). Presence of MetSy has been shown to significantly influence HF mortality (Figures 2) with lowest survival of 22% for 300 months of follow up for patients with both MetSy and HF (Log rank test=4.405, p<0.0001). Conclusion Metabolic syndrome treatment remains in the realm of risk factors' control that now we know influence both ischemic heart disease and heart failure of other origins. Historically, just emerging biomarkers' and targeted imaging weren't available to determine such at the time of HF diagnosis. Also, the sample consisted of men only, mainly Caucasian and a modest proportion of Asian and African-American now known to carry ethnic-specific burden of cardiovascular disease. All of the above, emphasizes the importance of more diversity, equity and inclusion-dedicated long term both observational, as well as interventional research. Funding Acknowledgement Type of funding sources: None.

Obesity increases cardiovascular mortality in patients with HFmrEF.

BackgroundHigh body mass index increases the risk of heart failure morbidity and mortality. It is unclear whether a high body mass index is associated with prognosis in patients with heart failure with mildly reduced left ventricular ejection fraction (HFmrEF). We retrospectively analyzed the effect of a high body mass index on the prognosis of patients with HFmrEF.MethodsWe investigated the association between body mass index and cardiovascular death (death from any cardiovascular mechanism) in 1,691 HFmrEF patients (mean age, 68 years; 35% female) in Xiangtan Central Hospital. Using Cox proportional hazards models, body mass index was assessed as a continuous and a categorical variable.ResultsCardiovascular death occurred in 133 patients (82 males and 51 females) after 1 year of follow-up. After adjustment for established risk factors, there was a 7.5% increase in the risk of cardiovascular death for females for each increment of 1 in BMI. In contrast, changes in male body mass index were not significantly associated with cardiovascular death (P = 0.097). Obese subjects had a 1.8-fold increased risk of cardiovascular death compared with subjects with a normal body mass index. The hazard ratio for females was 2.163 (95% confidence interval: 1.150–4.066). Obesity was not significantly associated with cardiovascular death in males (P = 0.085).ConclusionAn increased body mass index is associated with an increased risk of cardiovascular death in patients with HFmrEF; however, this risk was mainly associated with female patients with HFmrEF and less with male patients with HFmrEF.

Sacubitril/Valsartan in Patients With Heart Failure and Concomitant End-Stage Kidney Disease.

Background Heart failure with reduced ejection fraction (HFrEF) is a chronic disease with substantial mortality. Management of HFrEF has seen significant breakthrough after the launch of neprilysin inhibitor. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impacton Global Mortality and Morbidity in Heart Failure) trial showed that sacubitril/valsartan significantly reduces HFrEF mortality and the heart failure hospitalization rate. However, in patients with advanced kidney disease, who have the highest prevalence of heart failure, the efficacy and safety of sacubitril/valsartan remains uncertain. We aim to study the efficiency of sacubitril/valsartan in patients with end-stage kidney disease. Methods and Results Heart function was screened by echocardiogram among all patients with end-stage kidney disease in 2 hospitals. Patients with HFrEF received either sacubitril/valsartan or conventional treatment. Fifteen echocardiographic parameters were compared before and after treatment. After 1-year sacubitril/valsartan treatment, parameters of systolic (left ventricular ejection fraction 31.3% to 45.1%, P<0.0001; left ventricular end-systolic volume 95.7 to 70.1 mL, P=0.006; left ventricular internal diameter at end-systole phase 47.2 to 40.1 mm, P=0.005), and diastolic (E/A ratio 1.3 to 0.8, P=0.009; E/Med e' ratio 25.3 to 18.8, P=0.010) function improved in patients with HFrEF and end-stage kidney disease. These parameters were unchanged in the conventional treatment group. Serum potassium did not increase in the sacubitril/valsartan group. Conclusions Sacubitril/valsartan improves left ventricular systolic and diastolic function in patients with HFrEF and end-stage kidney disease.

Abstract P2047: Identification Of Selective Small-molecule ERBB4 Agonists With Cardioprotective Effects

Introduction: Morbidity and mortality of heart failure remain high, mandating new therapeutic approaches. The neuregulin-1 (NRG1)/ERBB4 axis is cardioprotective and an attractive target for treatment. Clinical trials with recombinant NRG1 are ongoing, but require intravenous administration, limiting applicability and efficacy. Purpose: To develop selective small-molecule ERBB4 agonists with cardioprotective effects. Methods: A high-throughput screening of 10,240 compounds (cpds) was performed on a ERBB4/ERBB4 dimerization assay. Hit cpds were co-administered with NRG1 or fluorescently labeled NRG1 to determine competitive binding. Selectivity, receptor phosphorylation, toxicity and metabolic stability were determined using Luminex RTK phosphoprotein, ERBB2/ERBB3 dimerization and adenylate kinase assays or LC-MS/MS. Apoptotic and hypertrophic effects of cpds (4-32μM) on cultured cardiomyocytes were studied after exposure to 100μM H 2 O 2 and 100nM angiotensin II (AngII). Antifibrotic effects (4-32μM) were studied on TGF-β-induced collagen synthesis in cultured human fibroblasts, and in mice (n=9-10/group) treated with AngII (1000 ng/kg/min) or cpd (83 μg/kg/h) using osmotic pumps. Results: We identified 8 similar pyrimidine derivatives inducing ERBB4/ERBB4 dimerization (Emax 9-33% relative to NRG1, EC50 6E-6 to 2E-7M). Competition assays indicated allosteric receptor binding and potentiation of NRG1-induced ERBB4 receptor dimerization, up to 2.7 fold (P&lt;0.0001). Six were non-toxic and induced ERBB4 phosphorylation, but ERBB1, ERBB2 or ERBB3 phosphorylation remained unaffected and cpds did not induce ERBB2/ERBB3 dimerization, showing ERBB4 selectivity. Cpds showed a t1/2 of 170min in human liver microsomes. Cpds attenuated hypertrophic and apoptotic effects of AngII or H 2 O 2 (P&lt;0.05), and decreased collagen upregulation in vitro (P&lt;0.05). In vivo , a selected cpd attenuated AngII-induced myocardial interstitial fibrosis (-76±26%, P&lt;0.01), and cardiac Col1a1, Col3a1 (-64±22%; -71±25%, P&lt;0.01) and Nppa (-77±22%, P&lt;0.01) mRNA expression. Conclusion: We identified selective novel pyrimidine derivative small-molecule ERBB4 agonists with cardioprotective effects in vitro and in vivo .

Sacubitril/valsartan in heart failure: efficacy and safety in and outside clinical trials.

Heart failure (HF) treatment has changed substantially over the last 30years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline-directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM-HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266000 patients were treated with S/V in Germany. The estimated cumulative real-world patient exposure is >5.5 million patient-treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice.

Analysis of Worsening Heart Failure Events in an Integrated Health Care System

BackgroundThere is growing interest to disentangle worsening heart failure (WHF) from location of care and move away from hospitalization as a surrogate for acuity. ObjectivesThe purpose of this study was to describe the incidence of WHF events across the care continuum from ambulatory encounters to hospitalizations. MethodsWe studied calendar year cohorts of adults with diagnosed heart failure (HF) from 2010-2019 within a large, integrated health care delivery system. Electronic health record (EHR) data were accessed for outpatient encounters, emergency department (ED) visits/observation stays, and hospitalizations. WHF was defined as ≥1 symptom, ≥2 objective findings including ≥1 sign, and ≥1 change in HF-related therapy. Symptoms and signs were ascertained using natural language processing. ResultsWe identified 103,138 eligible individuals with mean age 73.6 ± 13.7 years, 47.5% women, and mean left ventricular ejection fraction of 51.4% ± 13.7%. There were 1,136,750 unique encounters including 743,039 (65.4%) outpatient encounters, 224,670 (19.8%) ED visits/observation stays, and 169,041 (14.9%) hospitalizations. A total of 126,008 WHF episodes were identified, including 34,758 (27.6%) outpatient encounters, 28,301 (22.5%) ED visits/observation stays, and 62,949 (50.0%) hospitalizations. The annual incidence (events per 100 person-years) of WHF increased from 25 to 33 during the study period primarily caused by outpatient encounters (7 to 10) and ED visits/observation stays (4 to 7). The 30-day rate of hospitalizations for WHF ranged from 8.2% for outpatient encounters to 12.4% for hospitalizations. ConclusionsED visits/observation stays and outpatient encounters account for approximately one-half of WHF events, are driving the underlying growth in HF morbidity, and portend a poor short-term prognosis.

Dapagliflozin Impact on the Exercise Capacity of Non-Diabetic Heart Failure with Reduced Ejection Fraction Patients.

Background: Dapagliflozin has been shown to reduce morbidity and mortality in Heart Failure with reduced Ejection Fraction (HFrEF), but its impact on exercise capacity of non-diabetic HF outpatients is unknown. Methods: Adult non-diabetic HF patients with a left ventricular ejection fraction (LVEF) <50% were randomized 1:1 to receive dapagliflozin 10 mg or to continue with HF medication. Patients underwent an initial evaluation which was repeated after 6 months. The variation of several clinical parameters was compared, with the primary endpoint being the 6 month peak oxygen uptake (pVO2) variation. Results: A total of 40 patients were included (mean age 61 ± 13 years, 82.5% male, mean LVEF 34 ± 5%), half being randomized to dapagliflozin, with no significant baseline differences between groups. The reported drug compliance was 100%, with no major safety events. No statistically significant difference in HF events was found (p = 0.609). There was a 24% reduction in the number of patients in New York Heart Association (NYHA) class III in the treatment group as opposed to a 15.8% increase in the control group (p = 0.004). Patients under dapagliflozin had a greater improvement in pVO2 (3.1 vs. 0.1 mL/kg/min, p = 0.030) and a greater reduction in NT-proBNP levels (−217.6 vs. 650.3 pg/mL, p = 0.007). Conclusion: Dapagliflozin was associated with a significant improvement in cardiopulmonary fitness at 6 months follow-up in non-diabetic HFrEF patients.

Renal denervation in patients who do not respond to cardiac resynchronization therapy

Cardiac resynchronization therapy (CRT) reduces the morbidity and mortality in advanced heart failure (HF) in about two-thirds of the patients. Approximately one-third of the patients do not respond to CRT. The overactivity of sympathetic nervous system is associated with advanced HF and deteriorates the hemodynamic state. We tested the hypothesis that controlling sympathetic overactivity by renal denervation (RDN) could be beneficial in nonresponders for CRT. In our HeartF-RDN study (ClinalTrials.gov. NCT02638324), RDN could not reverse the progression of HF in subjects with New York Heart Association Classification (NYHA) III-IV stage symptoms.

C78 PREVALENCE AND MECHANISMS OF SEVERE MITRAL AND TRICUSPID REGURGITATION IN A HEART FAILURE OUTPATIENTS POPULATION

Abstract Introduction Mitral regurgitation (MR) and tricuspid regurgitation (TR) are a known cause of morbidity and mortality in heart failure (HF) patients. Maximal up–titration of guideline–directed medical therapy (GDMT) for HF may not be enough to reduce the severity of the valve’s incompetence and patients’ symptoms. The development and successful results of transcatheter therapies for mitral/tricuspid disease have opened new therapeutic opportunities when surgery is not feasible. Accurate valve regurgitation’s mechanisms evaluation is essential to choose the best treatment option. This study aims at evaluating the prevalence and underlying mechanisms of at least moderate–to–severe (≥3+/4+) MR and/or TR in a cohort of HF outpatients. Methods We retrospectively analyzed the medical records of 1260 outpatients evaluated by our HF unit between January 2020 and June 2021. All patients with echocardiographic evidence of ≥ 3+/4+ MR and/or TR were included (treated ones were excluded), and a thorough echocardiographic images review was conducted. A full collection of patients’ clinical, laboratory and therapy regimens details was performed as well. Results Of the 1260 analyzed patients, 173 (13.7%) exhibited ≥3+/4+ MR and/or TR and were included in the registry. Table 1 shows the main clinical/echocardiographic characteristics. Mean age was 80±7 years, median ejection fraction was 45% (IQR=33–55). All patients were treated with maximal tolerated doses of GDMT and, if appropriate, with cardiac devices/myocardial revascularization. ≥3+/4+ MR and/or TR was observed in 92 (7.3%) and 117 (9.3%) patients, respectively. Patients with isolated significant MR were 56 (4.4%), with isolated significant TR were 81 (6.4%); the remaining 36 (2.8%) had both MR/TR. Among patients with significant MR, 50 (54%) had functional/secondary valvular defect (details in Figure 2): the majority (41,82%) presented a ventricular etiology (asymmetric tethering in 18/41) while 9 (18%) an atrial one (atriogenic tethering in 3/9). Conclusion Despite optimized GDMT, the prevalence of patients with hemodynamically significant valvular defects was considerably high in our HF population. This is the first registry to comprehensively detail atrioventricular valve regurgitations’ mechanisms in a wide real–life cohort of HF outpatients. Further studies are needed to identify reasons for potential undertreatment and patients who would benefit the most from percutaneous correction of their valvular defects.

MO102: Lean Tissue, as Assessed by Bioimpedance Spectroscopy, Is Dependent on Renal Function in Patients with HFREF

Abstract BACKGROUND AND AIMS Despite impressive improvements in treatment strategies, heart failure (HF) morbidity and mortality remain substantially high worldwide. Muscle wasting is common and is associated with increased morbidity and mortality in patients with HF. The aim of the study was to determine muscle mass, by bioimpedance spectroscopy (BIS), and to identify factors associated with decreased muscle mass in this population. METHOD This was a prospective observational study of outpatient adults referred for clinically indicated transthoracic echocardiograms at an academic hospital between 2016 and 2018. A left ventricular ejection fraction below 45% was required for inclusion (HFrEF). Muscle mass was assessed using BIS (with the body composition monitor—BCM® device). RESULTS Our study included 151 patients. The mean age and eGFR values of the population at baseline were 67.1 years and 66.5 mL/min/1.73 m2. The median levels for lean tissue index (LTI, lean tissue mass/height2) were 11.3 (IQR 9.4–12.9) kg/m2. LTI was positively associated with eGFR and negatively associated with uric acid, ST-2 and galectin-3 levels. Including all these variables in a stepwise multivariable regression only eGFR and ST-2 remained independently associated with LTI (see Table 1). Based on the LTI median value, we also divided the patients into two groups—group 1 (LTI ≤ 11.3 kg/m2) and group 2 (LTI &amp;gt; 11.3 kg/m2). In the univariable logistic regression age, using the haemoglobin, eGFR and ST-2 levels predicted the group appurtenance. Including all these variables in a stepwise multivariable logistic regression, only eGFR and eGFR remained independently associated with LTI groups (see Table 2). CONCLUSION A better understanding of the factors associated with decreased muscle mass is needed to develop preventive strategies for muscle wasting in patients with HF. Muscle mass, as measured by the BCM and expressed as the LTI, is strongly associated with eGFR.

Response of functional mitral regurgitation in nonischemic cardiomyopathy to left bundle branch pacing.

Functional mitral regurgitation (FMR) in patients with cardiomyopathy is correlated with morbidity and mortality in heart failure. The response of FMR to cardiac resynchronization therapy (CRT) varies. The purpose of this study was to analyze the incidence and severity of FMR in patients with nonischemic cardiomyopathy (NICM) and left bundle branch block (LBBB) and the response to left bundle branch pacing (LBBP). Patients who had undergone LBBP for NICM, LBBB, and FMR between 2019 to 2021 were included retrospectively in the study. A total of 79 patients were identified, of whom 6 were excluded (5 no consistent LBB capture, 1 prosthetic mitral valve). The remaining 73 patients were divided into 2 groups based on the severity of FMR into group I with mild FMR (n = 35 [48%]) and group II with significant FMR (n = 38 [52%]). Mean follow-up duration was comparable in both groups. Group II was characterized by higher N-terminal pro-brain natriuretic peptide levels, New York Heart Association functional class, and larger left ventricular dimensions. LBBP resulted in significant reduction in QRS duration in both group I (113.8 ± 12.7 ms; P <.0001) and group II (117.3± 10.3 m s; P <.0001). LBBP resulted in similar percentage reduction in QRS duration (-31% ± 10% vs -33% ± 8%; P = .34), left ventricular (LV) end-diastolic diameter (-8% ± 10% vs -11% ± 12%; P = .25), LV end-diastolic volume (-26%± 12% vs -31% ± 27%; P = .31), and LV end-systolic volume (-39% ± 16% vs -37% ± 30%; P = .72) in groups I and II, respectively. Percentage change (+59% ± 39% vs +59% ± 41%; P = 1) and absolute change (+19.9% ± 10.4% vs +17% ± 10.04%; P = .22) in LV ejection fraction were similar in both groups. In group II, 31 patients (82%) showed significant reduction in FMR severity during follow-up. No patients in group I showed worsening of FMR. LBBP resulted in excellent electrical resynchronization with significant reduction in FMR severity in the majority of patients with significant FMR and no worsening of FMR from baseline in any patient.

Abstract 217: Assessing Medication Non-Adherence In Heart Failure Patients: A Resident Driven Quality Improvement Initiative

Introduction: Non-adherence to guideline directed medical therapies (GDMT) is responsible for significant health care costs, morbidity, and mortality in heart failure (HF) patients. Assessing and improving medication adherence (MA) is challenging in this patient population given its multifactorial nature. We aimed to evaluate trainee assessment of MA in HF patients while identifying potential barriers to addressing MA during patient encounters. Methods: This was a single-institution study performed at a large safety net hospital in Atlanta. An anonymous questionnaire was used to assess MA strategies of interns, residents, and medical students for HF patients. This data was compiled and analyzed to identify the most commonly perceived barriers to medication non-adherence. Results: 100 surveys were returned. 99% (99/100) noted that addressing MA is important in HF patients. However, only 83% (83/100) reported that they discussed the specific reasons for non-adherence with their HF patients, with 9%, 12%, and 78% addressing MA in the outpatient, inpatient, and both settings, respectively; the lack of time was reported as the most common contributor in all settings. The most common reasons reported by trainees for patient non-adherence include misunderstanding of their regimen (71%), cost (62%), and polypharmacy (57%). Although, 40% (40/100) of survey responders believed that ≥50% of their HF patients were nonadherent, strikingly, only 12% (12/100) discussed these MA barriers at all HF patient visits. Conclusion: Improving outcomes in HF patients is multifactorial. Medicine teaching teams can play a crucial role in this process by recognizing and addressing the specific barriers to MA in HF patients while promoting GDMT adherence. Our study demonstrates that although trainees recognize the importance of MA, the unique patient characteristics that contribute to non-adherence are under appreciated. Our long-term goal is to not only identify these barriers, but to implement educational interventions, then re-assess trainee comfort level with discussing MA, to demonstrate that trainee driven interventions can improve MA in HF patients while simultaneously reducing HF related re-admissions and hospital costs.

Burden of Pediatric Heart Failure in the United States

BackgroundThere are currently limited accurate national estimates for pediatric heart failure (HF). ObjectivesThis study aims to describe the current burden of primary and comorbid pediatric HF in the United States. MethodsInternational Classification of Diseases, Clinical Modification codes were used to identify HF cases and comorbidities from the Kids’ Inpatient Database, National Inpatient Sample, National Emergency Department (ED) Sample, and National Vital Statistics System for 2012 and 2016. To describe HF events, all visits/events among pediatric and adult subjects were included in the analysis. HF events were classified into 1 of 3 groups: 1) no HF; 2) primary HF; or 3) comorbid HF. We compared patients with and without HF and calculated unique event rates with age and sex standardization. ResultsCongenital heart disease, conduction disorders/arrhythmias, and cardiomyopathy were responsible for the majority of pediatric HF-related ED visits and hospitalizations. Compared to 2012, in 2016, there was an increase in comorbid HF ED visits (rate ratio: 1.93; P < 0.001) and primary HF hospitalizations (rate ratio: 1.14; P = 0.002). Pediatric HF burden was lower compared to adult HF; however, deaths in the ED and in-hospital were significantly more likely in children presenting with HF than adults. ConclusionsThe burden of pediatric HF continues to increase. Compared to adults with HF presenting to the ED and in-hospital, outcomes are inferior and per patient resource use is higher for children hospitalized with HF. National initiatives to understand risk factors for morbidity and mortality in pediatric HF and continued surveillance and mitigation of preventable risk factors may attenuate this uptrend.

Catecholaminergic RVLM C1 neurons mediates heart failure decompensation and mortality during salt loading

Heart failure (HF) is a complex clinical syndrome affecting over 37 million people worldwide. Although advances in medical therapy have significantly improve HF condition, morbidity and mortality rate are still high and global prevalence is continuously rising. Common clinical features of HF include cardiac sympathoexcitation and disordered breathing, which are strongly associated with poor survival of HF patients. Importantly, we have previously shown that brainstem pre‐sympathetic neurons (C1) from the rostral ventrolateral medulla (RVLM), play a key role in sympathetic regulation in HF. However, the role played by RVLM‐C1 neurons during heart failure decompensation is totally unknown. Accordingly, we aimed to determine the contribution of RVLM‐C1 neurons on survival during HF decompensation. Adult male Sprague‐Dawley rats underwent volume overload induce non‐ischemic HF. After two weeks, anti‐dopamine β‐hydroxylase‐saporin toxin (DβH‐SAP: 2.5ng/150nl; or saline) was bilaterally injected into RVLM to ablate C1 neurons. Animals were then expose to high salt diet (3% Na+ in food and 2% Na+ in water) for 3 weeks to induce transition from compensated to decompensated HF state. At 6 weeks post‐HF induction, echocardiography, cardiac autonomic function, breathing function, blood pressure, and mortality were assessed. Compared to normal chow fed HF animals, HF+Na+ rats displayed an increased cardiac index (15.1 ± 0.6 vs. 18.5 ± 1.3 ml/min/100cm2, HF vs. HF+Na+, respectively) and cardiac sympathetic tone (∆HR to propranolol: 8.7 ± 3.1 vs. 23.4 ± 2.5 bpm, HF vs. HF+Na+, respectively). Furthermore, HF+Na+ animals showed a further increase in the incidence of breathing disorders compared to HF (apnea‐hypopnea index: 8.1 ± 0.6 vs. 12.5 ± 2.1 events/hr, HF vs. HF+Na+, respectively). Lastly, salt loading results in marked decompensation in HF rats being the outcome a significant increase in mortality risk (survival: 100% vs. 10% HF vs. HF+Na+, respectively). We found that partial ablation of RVLM C1 neurons in HF+Na+ prevented further deterioration in cardiac autonomic function and breathing disorders and markedly improved survival in HF rats that underwent salt loading (survival: 10% vs. 75% HF+Na+ vs. HF+DβH‐SAP+Na+, respectively). Our results strongly support the role for RVLM C1 neurons in HF decompensation during salt loading and suggest that RVLM C1 may act as a key nodal point mediating salt induced cardiorespiratory distress, decompensation and mortality in HF.

GRK5 is an essential co-repressor of the cardiac mineralocorticoid receptor and is selectively induced by finerenone.

BACKGROUNDIn the heart, aldosterone (Aldo) binds the mineralocorticoid receptor (MR) to exert damaging, adverse remodeling-promoting effects. We recently showed that G protein-coupled receptor-kinase (GRK)-5 blocks the cardiac MR by directly phosphorylating it, thereby repressing its transcriptional activity. MR antagonist (MRA) drugs block the cardiac MR reducing morbidity and mortality of advanced human heart failure. Non-steroidal MRAs, such as finerenone, may provide better cardio-protection against Aldo than classic, steroidal MRAs, like spironolactone and eplerenone. AIMTo investigate potential differences between finerenone and eplerenone at engaging GRK5-dependent cardiac MR phosphorylation and subsequent blockade. METHODSWe used H9c2 cardiomyocytes, which endogenously express the MR and GRK5.RESULTSGRK5 phosphorylates the MR in H9c2 cardiomyocytes in response to finerenone but not to eplerenone. Unlike eplerenone, finerenone alone potently and efficiently suppresses cardiac MR transcriptional activity, thus displaying inverse agonism. GRK5 is necessary for finerenone’s inverse agonism, since GRK5 genetic deletion renders finerenone incapable of blocking cardiac MR transcriptional activity. Eplerenone alone does not fully suppress cardiac MR basal activity regardless of GRK5 expression levels. Finally, GRK5 is necessary for the anti-apoptotic, anti-oxidative, and anti-fibrotic effects of both finerenone and eplerenone against Aldo, as well as for the higher efficacy and potency of finerenone at blocking Aldo-induced apoptosis, oxidative stress, and fibrosis.CONCLUSIONFinerenone, but not eplerenone, induces GRK5-dependent cardiac MR inhibition, which underlies, at least in part, its higher potency and efficacy, compared to eplerenone, as an MRA in the heart. GRK5 acts as a co-repressor of the cardiac MR and is essential for efficient MR antagonism in the myocardium

Relationship of Dapagliflozin With Serum Sodium: Findings From the DAPA-HF Trial

ObjectivesThis study aimed to assess the prognostic importance of hyponatremia and the effects of dapagliflozin on serum sodium in the DAPA-HF (Dapagliflozin And Prevention of Adverse outcomes in Heart Failure) trial. BackgroundHyponatremia is common and prognostically important in hospitalized patients with heart failure with reduced ejection fraction, but its prevalence and importance in ambulatory patients are uncertain. MethodsWe calculated the incidence of the primary outcome (cardiovascular death or worsening heart failure) and secondary outcomes according to sodium category (≤135 and >135 mmol/L). Additionally, we assessed: 1) whether baseline serum sodium modified the treatment effect of dapagliflozin; and 2) the effect of dapagliflozin on serum sodium. ResultsOf 4,740 participants with a baseline measurement, 398 (8.4%) had sodium ≤135 mmol/L. Participants with hyponatremia were more likely to have diabetes, be treated with diuretics, and have lower systolic blood pressure, left ventricular ejection fraction, and estimated glomerular filtration rate. Hyponatremia was associated with worse outcomes even after adjustment for predictive variables (adjusted HRs for the primary outcome 1.50 [95% CI: 1.23-1.84] and all-cause death 1.59 [95% CI: 1.26-2.01]). The benefits of dapagliflozin were similar in patients with and without hyponatremia (HR for primary endpoint: 0.83 [95% CI: 0.57-1.19] and 0.73 [95% CI: 0.63-0.84], respectively, P for interaction = 0.54; HR for all-cause death: 0.85 [95% CI: 0.56-1.29] and 0.83 [95% CI: 0.70-0.98], respectively, P for interaction = 0.96). Between baseline and day 14, more patients on dapagliflozin developed hyponatremia (11.3% vs 9.4%; P = 0.04); thereafter, this pattern reversed and at 12 months fewer patients on dapagliflozin had hyponatremia (4.6% vs 6.7%; P = 0.003). ConclusionsBaseline serum sodium concentration was prognostically important, but did not modify the benefits of dapagliflozin on morbidity and mortality in heart failure with reduced ejection fraction. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]: NCT03036124)

Iron Deficiency in Pediatric Dilated Cardiomyopathy is Associated with Clinical, Biochemical and Hematological Markers of Severe Disease and Adverse Outcomes

<h3>Purpose</h3> Adult studies suggest that iron deficiency (ID) is a common and treatable contributor to morbidity and mortality in heart failure. There is limited evidence as to the impact of ID in children and adolescents with dilated cardiomyopathy (DCM). <h3>Methods</h3> This was a retrospective single-centre review. All patients age < 18 years seen between 2010-2020 with a diagnosis of DCM and complete iron studies (ferritin, iron, transferrin and transferrin saturation) were included. Patients were excluded if they were on erythropoietin-stimulating agents, had received a transfusion in the preceding fortnight, or were post-heart transplant (HTx). ID was defined as ≥ 2 of ferritin < 15 μg/L, iron < 9 μmol/L, transferrin > 3 g/L or transferrin saturation < 15%. Clinical, biochemical and haematological indices, and the incidence of a composite adverse event (CAE) of mechanical circulatory support (MCS), HTx or death at 3 and 6 months were compared between children with ID and without. <h3>Results</h3> Of 138 patients with DCM, 49 patients had iron studies results available and were included. The mean (SD) age at time of iron studies was 5.8±5.2 years old, and 26 (53%) were female. Twenty-nine (59%) had ID and 29 (59%) were anemic; of these, 22 (45%) were both iron deficient and anemic. Eleven (22%) had renal impairment and 16 (32%) had biochemical liver dysfunction. Children with ID had a higher incidence of anemia (22, 76%, <i>P</i> = 0.004), microcytosis (9, 31%, <i>P</i> = 0.034), hypochromia (16, 55%, <i>P</i> = 0.005), a higher median NT-BNP (1590 pg/ml, IQR 456 - 3446, <i>P</i> = 0.001), and a lower median albumin (37 g/L, IQR 33 - 41, <i>P</i> = 0.008). Children with ID were more likely to be receiving inotropes (17, 59%, <i>P</i> = 0.002) and invasive/non-invasive ventilation (13, 45%, <i>P</i> = 0.009) than those who were iron replete. The CAE occurred in 8 children (28%; 4 MCS, 2 HTx, 2 deaths) with ID by 3 months (<i>P</i> = 0.015). By 6 months, it had occurred in 10 (34%; 1 MCS, 1 death) children with ID, and 2 (20%; 1 MCS, 1 death) children who were iron replete (<i>P</i> = 0.09). <h3>Conclusion</h3> ID occurred in more than half of our patient population with DCM who have had iron studies measured. ID is associated with severe clinical, haematological and biochemical disease and an increased composite risk of MCS, HTx or death. The need for iron replacement therapy should be considered in all patients who present with heart failure related to DCM.

Renal effects of guideline-directed medical therapies in heart failure: a consensus document from the Heart Failure Association of the European Society of Cardiology.

Novel pharmacologic treatment options reduce mortality and morbidity in a cost-effective manner in patients with heart failure (HF). Undisputedly, the effective implementation of these agents is an essential element of good clinical practice, which is endorsed by the European Society of Cardiology (ESC) guidelines on acute and chronic HF. Yet, physicians struggle to implement these therapies as they have to balance the true and/or perceived risks versus their substantial benefits in clinical practice. Any worsening of biomarkers of renal function is often perceived as being disadvantageous and is in clinical practice one of the most common reasons for ineffective drug implementation. However, even in this context, they clearly reduce mortality and morbidity in HF with reduced ejection fraction (HFrEF) patients, even in patients with poor renal function. Furthermore these agents are also beneficial in HF with mildly reduced ejection fraction (HFmrEF) and sodium-glucose cotransporter 2 (SGLT2) inhibitors more recently demonstrated a beneficial effect in HF with preserved ejection fraction (HFpEF). The emerge of several new classes (angiotensin receptor-neprilysin inhibitor [ARNI], SGLT2 inhibitors, vericiguat, omecamtiv mecarbil) and the recommendation by the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic HF of early initiation and titration of quadruple disease-modifying therapies (ARNI/angiotensin-converting enzyme inhibitor + beta-blocker + mineralocorticoid receptor antagonist and SGLT2 inhibitor) in HFrEF increases the likelihood of treatment-induced changes in renal function. This may be (incorrectly) perceived as deleterious, resulting in inertia of starting and uptitrating these lifesaving therapies. Therefore, the objective of this consensus document is to provide advice of the effect HF drugs on renal function.

Hypoglycemia-Exacerbated Mitochondrial Connexin 43 Accumulation Aggravates Cardiac Dysfunction in Diabetic Cardiomyopathy.

BackgroundDiabetic cardiomyopathy (DCM) is a complex multifaceted disease responsible for elevated heart failure (HF) morbidity and mortality in patients with diabetes mellitus (DM). Patients with DCM exhibit subclinical diastolic dysfunction, progression toward systolic impairment, and abnormal electrophysiology. Hypoglycemia events that occur spontaneously or due to excess insulin administration threaten the lives of patients with DM—with the increased risk of sudden death. However, the molecular underpinnings of this fatal disease remain to be elucidated.Methods and ResultsHere, we used the established streptozotocin-induced DCM murine model to investigate how hypoglycemia aggravates DCM progression. We confirmed connexin 43 (Cx43) dissociation from cell–cell interaction and accumulation at mitochondrial inner membrane both in the cardiomyocytes of patients with DM and DCM murine. Here, we observed that cardiac diastolic function, induced by chronic hyperglycemia, was further aggravated upon hypoglycemia challenge. Similar contractile defects were recapitulated using neonatal mouse ventricular myocytes (NMVMs) under glucose fluctuation challenges. Using immunoprecipitation mass spectrometry, we identified and validated that hypoglycemia challenge activates the mitogen-activated protein kinase kinase (MAPK kinase) (MEK)/extracellular regulated protein kinase (ERK) and inhibits phosphoinositide 3-kinase (PI3K)/Akt pathways, which results in Cx43 phosphorylation by Src protein and translocation to mitochondria in cardiomyocytes. To determine causality, we overexpressed a mitochondrial targeting Cx43 (mtCx43) using adeno-associated virus serotype 2 (AAV2)/9. At normal blood glucose levels, mtCx43 overexpression recapitulated cardiac diastolic dysfunction as well as aberrant electrophysiology in vivo. Our findings give support for therapeutic targeting of MEK/ERK/Src and PI3K/Akt/Src pathways to prevent mtCx43-driven DCM.ConclusionDCM presents compensatory adaptation of mild mtCx43 accumulation, yet acute hypoglycemia challenges result in further accumulation of mtCx43 through the MEK/ERK/Src and PI3K/Akt/Src pathways. We provide evidence that Cx43 mislocalization is present in hearts of patients with DM hearts, STZ-induced DCM murine model, and glucose fluctuation challenged NMVMs. Mechanistically, we demonstrated that mtCx43 is responsible for inducing aberrant contraction and disrupts electrophysiology in cardiomyocytes and our results support targeting of mtCx43 in treating DCM.