Ferric Carboxymaltose in Heart Failure with Iron Deficiency.

BACKGROUND: Ferric carboxymaltose therapy reduces symptoms and improves quality of life in patients who have heart failure with a reduced ejection fraction and iron deficiency. Additional evidence about the effects of ferric carboxymaltose on clinical events is needed. METHODS: In this double-blind, randomized trial, we assigned ambulatory patients with heart failure, a left ventricular ejection fraction of 40% or less, and iron deficiency, in a 1:1 ratio, to receive intravenous ferric carboxymaltose or placebo, in addition to standard therapy for heart failure. Ferric carboxymaltose or placebo was given every 6 months as needed on the basis of iron indexes and hemoglobin levels. The primary outcome was a hierarchical composite of death within 12 months after randomization, hospitalizations for heart failure within 12 months after randomization, or change from baseline to 6 months in the 6-minute walk distance. The significance level was set at 0.01. RESULTS: We enrolled 3065 patients, of whom 1532 were randomly assigned to the ferric carboxymaltose group and 1533 to the placebo group. Death by month 12 occurred in 131 patients (8.6%) in the ferric carboxymaltose group and 158 (10.3%) in the placebo group; a total of 297 and 332 hospitalizations for heart failure, respectively, occurred by month 12; and the mean (±SD) change from baseline to 6 months in the 6-minute walk distance was 8±60 and 4±59 m, respectively (Wilcoxon-Mann-Whitney P = 0.02; unmatched win ratio, 1.10; 99% confidence interval, 0.99 to 1.23). Repeated dosing of ferric carboxymaltose appeared to be safe with an acceptable adverse-event profile in the majority of patients. The number of patients with serious adverse events occurring during the treatment period was similar in the two groups (413 patients [27.0%] in the ferric carboxymaltose group and 401 [26.2%] in the placebo group). CONCLUSIONS: Among ambulatory patients who had heart failure with a reduced ejection fraction and iron deficiency, there was no apparent difference between ferric carboxymaltose and placebo with respect to the hierarchical composite of death, hospitalizations for heart failure, or 6-minute walk distance. (Funded by American Regent, a Daiichi Sankyo Group company; HEART-FID ClinicalTrials.gov number, NCT03037931.).

Roles of ß-adrenoceptor Subtypes and Therapeutics in Human Cardiovascular Disease: Heart Failure, Tachyarrhythmias and Other Cardiovascular Disorders.

ß-Adrenoceptors (ß-ARs) provide an important therapeutic target for the treatment of cardiovascular disease. Three ß-ARs, ß1-AR, ß2-AR, ß3-AR are localized to the human heart. Activation of ß1-AR and ß2-ARs increases heart rate, force of contraction (inotropy) and consequently cardiac output to meet physiological demand. However, in disease, chronic over-activation of ß1-AR is responsible for the progression of disease (e.g. heart failure) mediated by pathological hypertrophy, adverse remodelling and premature cell death. Furthermore, activation of ß1-AR is critical in the pathogenesis of cardiac arrhythmias while activation of ß2-AR directly influences blood pressure haemostasis. There is an increasing awareness of the contribution of ß2-AR in cardiovascular disease, particularly arrhythmia generation. All ß-blockers used therapeutically to treat cardiovascular disease block ß1-AR with variable blockade of ß2-AR depending on relative affinity for ß1-AR vs ß2-AR. Since the introduction of ß-blockers into clinical practice in 1965, ß-blockers with different properties have been trialled, used and evaluated, leading to better understanding of their therapeutic effects and tolerability in various cardiovascular conditions. ß-Blockers with the property of intrinsic sympathomimetic activity (ISA), i.e. ß-blockers that also activate the receptor, were used in the past for post-treatment of myocardial infarction and had limited use in heart failure. The ß-blocker carvedilol continues to intrigue due to numerous properties that differentiate it from other ß-blockers and is used successfully in the treatment of heart failure. The discovery of ß3-AR in human heart created interest in the role of ß3-AR in heart failure but has not resulted in therapeutics at this stage.

Baseline characteristics of patients in the randomized study to investigate the efficacy and safety of ferric carboxymaltose as treatment for heart failure with iron deficiency: HEART-FID trial.

BACKGROUND: Prior clinical trials have investigated intravenous iron in patients with heart failure (HF) and iron deficiency, but the safety and efficacy of this therapy remains unclear. METHODS: We report the baseline demographics and clinical characteristics of patients enrolled in the HEART-FID study and compare HEART-FID participants with patients within other contemporary clinical trials of patients with HF with reduced ejection fraction (HFrEF), including other intravenous iron trials. RESULTS: In the 3,065 participants randomized in HEART-FID, median (IQR) age was 69.7 (62.0-76.5) years, 1,037 (33.8%) were female, 322 (10.5%) were Black, median ejection fraction was 32% (25%-37%), 1,837 (60.0%) had ischemic etiology, and baseline median NT-proBNP was 1,462 (721-2,966) pg/mL. Median baseline hemoglobin was 12.6 (11.6-13.6) g/dL, and median 6-minute walk test distance was 272 (196-350) m, similar to prior intravenous iron HFrEF trials. Common comorbidities included atrial fibrillation/flutter (43.7%), and type 2 diabetes (45.2%). Compared with several recent HFrEF trials, patients enrolled in HEART-FID had similar baseline demographics and clinical characteristics, though a greater proportion of women and Black participants were recruited in HEART-FID. In HEART-FID, HFrEF therapy included a beta-blocker in 92.5%, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker/angiotensin receptor-neprilysin inhibitors (ARNI) in 86.1% (with 29.7% ARNI), and a mineralocorticoid antagonist (MRA) in 55.6%. CONCLUSIONS: Patients enrolled in HEART-FID were similar to those enrolled in other contemporary HFrEF trials and registries, including trials of intravenous iron in HFrEF. However, the HEART-FID cohort is substantially larger and more racially diverse than prior trials of intravenous iron in HFrEF. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03037931).

Impact of Patient and Model of Care Factors on Titration and Tolerability of Sacubitril/Valsartan: An Early Australian Real-World Experience.

BACKGROUND: Sacubitril/valsartan was shown to be superior to enalapril in the Prospective Comparison of angiotensin receptor neprilysin inhibitor with an angiotensin converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) study. However, the study design raised uncertainty about the potential real-world tolerability amongst less well selected cohorts. We aimed to examine the real-world tolerability and factors associated with successful titration of sacubitril/valsartan. METHODS: We performed a retrospective single centre analysis in a tertiary referral centre of 235 consecutive patients prescribed sacubitril/valsartan between August 2016 and January 2018. RESULTS: At baseline, our patients were younger, had lower baseline systolic blood pressure (SBP), reduced ischaemic aetiology and a higher rate of mineralocorticoids receptor antagonist compared to PARADIGM-HF. At last assessment, 120 patients (51%) reached target dose (97/103 mg bi-daily [BD]), 67 patients (29%) were stable on a mid-range dose (≥49/51 mg BD), 22 patients (9%) tolerated the low dose (24/26 mg BD) and 26 patients (11%) discontinued, comparable to PARADIGM-HF. Adverse effects were similar to PARADIGM-HF and hypotension remained the primary reason of sub-maximal titration. Several baseline characteristics were associated with successful titration to target dose including; higher baseline body mass index, systolic blood pressure (SBP) and sodium, male gender and treatment coordinated by multidisciplinary heart failure (HF) clinic. CONCLUSION: Comparable results to PARADIGM-HF in attaining target dose of sacubitril/valsartan and tolerability profile can be achieved in a real-world setting. Several baseline characteristics involving patient factors, markers of disease severity and systems of care predict successful titration to the target dose 97/103 mg BD.

Right Heart Catheterisation: How To Do It.

Right heart catheterisation (RHC) is a minimally invasive procedure that provides direct haemodynamic measurement of intracardiac and pulmonary pressures. It is the gold standard investigation for the diagnosis and management of pulmonary hypertension. This article will describe how to perform right heart catheterisation, indications and contraindications.

Evaluation of Novel Metrics of Symptom Relief in Acute Heart Failure: The Worst Symptom Score.

OBJECTIVE: To characterize a novel "worst"-symptom visual analogue scale (WS-VAS) versus the traditional dyspnea visual analogue scale (DVAS) in an acute heart failure (AHF) trial. BACKGROUND: AHF trials assess symptom relief as a pivotal endpoint with the use of dyspnea scores. However, many AHF patients' worst presenting symptom (WS) may not be dyspnea. We hypothesized that a WS-VAS may reflect clinical improvement better than DVAS in AHF. METHODS AND RESULTS: AHF patients (n = 232) enrolled in the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE-AHF) Trial indicated their WS at enrollment and completed DVAS and WS-VAS at enrollment and 24, 48, and 72 hours. Dyspnea was the WS in 61%, body swelling in 29%, and fatigue in 10% of patients. Clinical characteristics differed by WS. In all patients, DVAS scores were higher (less severe symptoms) than WS-VAS and the change in WS-VAS over 72 hours was greater than the change in DVAS (P < .001). Changes in DVAS were smaller in patients with body swelling and fatigue than in patients with dyspnea as their WS (P = .002), whereas changes in the WS-VAS were similar regardless of patients' WS. Neither score, nor its change, was associated with available decongestion markers (change in N-terminal pro-B-type natriuretic peptide, weight or cumulative 72-hour urine volume). CONCLUSIONS: Many AHF patients have symptoms other than dyspnea as their most bothersome symptom. The WS-VAS better reflects symptom improvement across the spectrum of AHF phenotypes. Symptom relief and decongestion were not correlated in this AHF study.

Characterization of serum phosphate levels over time with intravenous ferric carboxymaltose versus placebo as treatment for heart failure with reduced ejection fraction and iron deficiency: An exploratory prospective substudy from HEART-FID.

AIMS: Ferric carboxymaltose (FCM) is guideline-recommended for iron deficiency (ID) in heart failure with reduced ejection fraction (HFrEF). Despite a well-established safety profile, the magnitude and clinical significance of FCM-induced hypophosphataemia in HFrEF remains unclear. This pre-specified substudy of HEART-FID evaluated serum phosphate, 1,25-dihydroxyvitamin D, and plasma parathyroid hormone (PTH) subsequent to FCM. METHODS AND RESULTS: HEART-FID was a randomized, double-blind, placebo-controlled trial of ambulatory patients with HFrEF and ID randomized to FCM versus placebo. This substudy assessed mean change from baseline across eight visits over 6 months for the following endpoints: serum phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and PTH, in addition to the clinical severity of potential hypophosphataemia. Overall, 133 patients (n = 62 FCM, n = 71 placebo) were prospectively enrolled. Mean age was 68 ± 11 years, 55 (41.4%) were women, and 29 (21.8%) had chronic kidney disease. Phosphate levels decreased in 34 (57.6%) patients in the FCM group compared with 7 (10.3%) in the placebo group. Mean change in phosphate levels reached a nadir at day 21 (-0.36 ± 0.27 mmol/L) subsequent to FCM infusion with 28 (51%) having moderate-to-severe hypophosphataemia. Reductions in 1,25-dihydroxyvitamin D were also observed, whilst PTH increased. These biochemical changes returned to baseline levels by day 91. Serum levels of 25-hydroxyvitamin D remained stable throughout the study. No serious adverse events associated with hypophosphataemia were reported. CONCLUSIONS: Transient moderate-to-severe hypophosphataemia was frequent subsequent to FCM infusion, accompanied by 1,25-dihydroxyvitamin D decrease and PTH increase. Serum levels of 25-hydroxyvitamin D remained stable. No evidence of symptomatic hypophosphataemia was reported, collectively indicating FCM-related hypophosphataemia to be clinically benign and transient in HFrEF.

Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM).

BACKGROUND: Timing of initial treatment for acute decompensated heart failure (ADHF) varies across hospitals and its impact on outcomes remains poorly defined. We examined the association between time to first intravenous (IV) heart failure (HF) therapy and patient outcomes. METHODS: Using the ADHERE-EM linked to Medicare claims data, we identified patients ≥65 years old who were hospitalized for ADHF and received IV HF therapy during index admission. Cox proportional hazard model was used to assess the association of time to treatment with a composite of 30-day all-cause mortality or re-admission. Generalized linear mixed models were used to examine the association of time to treatment with in-hospital all-cause mortality, index hospitalization length of stay, and total days alive and out-of-hospital at 30 days. RESULTS: Of 6,971 patients, the median time to first IV HF therapy was 2.3-hours (interquartile range 1.1, 4.4). The cumulative incidence of 30-day all-cause mortality or readmission was 27.4%. After adjusting for covariates, time to treatment was not associated with increased risk of composite 30-day all-cause mortality or re-admission (HR 1.00; 95% CI 1.00-1.00; P = .221). However, every hour delay in treatment was associated with a modest increased risk of in-hospital mortality (adjusted OR 1.01; 95% CI 1.00-1.02; P = .001) and an approximately 1.4-hour increase in index admission length of stay (P < .001). CONCLUSION: Among older patients presenting with ADHF, delay in initiating IV HF therapy was associated with modestly higher risk for in-hospital mortality and longer length of stay, but was not associated with 30-day outcomes.

ST Elevation Myocardial Infarction Complicated by Cardiogenic Shock: Systematic Review of Survival Predictors.

Background: Cardiogenic shock complicating acute myocardial infarction is associated with reduced survival despite advancements in the treatment of acute coronary syndromes. Characterizing predictors of morbidity and mortality in this setting is crucial to improving risk stratification and management. Notwithstanding, the interplay of factors determining survival in this condition remains poorly studied. Methods: Embase, MEDLINE, and CINAHL databases were searched for original studies evaluating predictors of short-term (30-day or in-hospital) survival in ST elevation myocardial infarction with cardiogenic shock (STEMI-CS). Included studies were analyzed by way of vote counting, identifying variables that predicted mortality or survival. Results: Twenty-four studies, consisting of 14,735 patients (5649 nonsurvivors and 9086 survivors) were included. All studies were observational by design (17 retrospective and 7 prospective) with clinical and statistical heterogeneity. Unsuccessful revascularization, reduced left ventricular ejection fraction, renal impairment, and other variables were identified as key independent predictors of mortality. Conclusion: Several key variables have been shown to independently increase mortality in STEMI-CS populations. Future prospective studies examining the prognostic role of multivariate scoring systems incorporating these domains are required.

Ultrasound Enhancing Agents with Transthoracic Echocardiography for Maximal Wall Thickness in Hypertrophic Cardiomyopathy.

Objectives: To determine whether ultrasound enhancing agent (UEA) changes maximal wall thickness (WT) in hypertrophic cardiomyopathy (HCM), and if it improves correlation with magnetic resonance imaging (MRI). Patients and Methods: A total of 107 patients with HCM were prospectively enrolled at a single tertiary referral center between July 10, 2014, and August 31, 2017, and underwent transthoracic echocardiography (TTE) with and without UEA and MRI. Maximal WT measurements were compared, and variability among the 3 modalities was evaluated using a simple linear regression analysis and paired t tests and Bland-Altman plots. Interobserver variability for each technique was assessed. Results: Most (63%) of cardiac imagers found UEA helpful in determining maximal WT by TTE, with 49% reporting change in WT. Of 52 patients where UEA changed WT measurement, 32 (62%) reported an increase and 20 (38%) reported a decrease in WT. The UEA did not alter the median discrepancy in WT between MRI and TTE. However, where UEA increased reported WT, the difference between MRI and TTE improved in 79% of cases (P=.001) from 2.0-0.5mm. In those with scar on MRI, UEA improved agreement of WT between TTE and MRI compared with that of TTE without UEA (79% vs 39%; P=.011). Interclass correlation coefficient for WT for TTE without UEA, with UEA, and MRI was 0.84; (95% CI, 0.61-0.92), 0.88; (95%CI, 0.82-0.92), and 0.97; (95%CI, 0.96-0.98), respectively. Conclusion: Although use of UEA did not eliminate differences in WT discrepancy between modalities, the addition of UEA to TTE aided in WT determination and improved correlation with MRI in those with greater WT and in all patients with myocardial scars.

Prognostic Value of Left and right ventricular deformation strain analysis on Acute Cellular rejection in Heart Transplant recipients: A 6-year outcome study.

PURPOSE: Two-dimensional (2D) strain analysis is a sensitive method for detecting myocardial dysfunction in acute cellular rejection (ACR) from post-transplant complications. This study aims to evaluate the utility of novel left (LV) and right ventricular (RV) strain parameters for prognostic risk stratification associated with ACR burden at 1-year post transplantation. METHODS: 128 Heart transplant patients, assessed between 2012 and 2018, underwent transthoracic echocardiography and endomyocardial biopsy. 2D strain analysis was performed and history of rejection burden was assessed and grouped according to ACR burden at 1-year post transplantation. The primary endpoint was all-cause mortality at 6-years follow up. RESULTS: 21 patients met primary the endpoint. Multivariate analysis of 6-year all-cause mortality showed LV global longitudinal strain (LV GLS) (Hazard Ratio [HR] = 1.21, CI = 1.06-1.49), LV early diastolic strain rate (LV ESr) (HR = 1.31, CI = 1.12-1.54), RV GLS (HR = 1.12, CI = 1.02-1.25) and RV ESr (HR = 1.26, CI = 1.12-1.47) were significant predictors of outcome. Univariate analysis also showed LV GLS, LV ESr, RV GLS and RV ESr were significant predictors of outcome. Optimal cut-off for predicting 6-year mortality for LV GLS by receive operator characteristic was 15.5% (sensitivity: 92%, specificity: 79%). Significant reductions (p < 0.05) in LV GLS, RV GLS and LV and RV ESr between rejection groups were seen. CONCLUSIONS: Non-invasive LV and RV strain parameters are predictors of mortality in post-transplant patient with ACR. LV GLS and LV ESr are superior to other strain and conventional echo parameters.

Who 'nose', is it the angiotensin receptor neprilysin inhibitor?: a case series of persistent nasal pruritus in heart failure patients receiving sacubitril/valsartan.

BACKGROUND: Sacubitril/valsartan is approved for the treatment of chronic heart failure with reduced left ventricular ejection fraction of ≤40% to decrease mortality and morbidity. Nasal pruritus is not a recognized adverse effect in the product information. In this case series, we encountered three patients who presented with nasal pruritus that improved after discontinuation of sacubitril/valsartan. CASE SUMMARY: Three patients aged 58-73 years-old presented with pruritus at the nasal septum post-initiation of sacubitril/valsartan. The pruritus did not subside despite the use of anti-histamines. Within 3-6 months, all individuals discontinued sacubitril/valsartan with complete resolution of their nasal pruritus. DISCUSSION: Many physicians may not aware of this unusual but reversible adverse effect of sacubitril/valsartan. Despite the positive prognostic value of sacubitril/valsartan, the constant nasal pruritus had impacted the quality of life of our patients, leading them to discontinue sacubitril/valsartan permanently.

Hypophosphatemia Is Common After Intravenous Ferric Carboxymaltose Infusion Among Patients With Symptomatic Heart Failure With Reduced Ejection Fraction.

Administration of intravenous ferric carboxymaltose (FCM) for iron-deficient patients suffering heart failure with reduced ejection fraction (HFrEF) has been associated with transient hypophosphatemia. We sought to investigate and model the effect of intravenous FCM on phosphate levels in iron-deficient patients with HFrEF. In this single-center retrospective study, serum phosphate levels, recorded for clinical reasons, were collected out to 60 days following intravenous FCM. Hypophosphatemia was defined as a nadir serum phosphate level <0.64 mmol/L. This was further categorized as severe (0.4 to <0.64 mmol/L) and extreme (<0.4 mmol/L). Factors associated with hypophosphatemia and change in serum phosphate over time were explored. Of 173 patients included, 47 (27%) experienced hypophosphatemia, 44 (25%) were classified as severe, and 3 (2%) extreme. Risk of hypophosphatemia was increased for patients with a creatinine clearance between 60 and <90 mL/min (odds ratio, 2.3; 95% confidence interval, 1.0-5.5), while <60 mL/min was protective. The median time to nadir in patients who experienced hypophosphatemia was 8 (interquartile range, 4-16) days, with a return to baseline levels at 6 weeks. Biochemically relevant hypophosphatemia is common following a single dose of intravenous FCM. The median time to nadir was 8 days, and creatinine clearance may influence phosphate levels following intravenous FCM. These observations support the need to increase awareness among clinicians administering intravenous FCM to iron-deficient patients with HFrEF.

Effects of omecamtiv mecarbil on failing human ventricular trabeculae and interaction with (-)-noradrenaline.

Omecamtiv mecarbil (OM) is a novel medicine for systolic heart failure, targeting myosin to enhance cardiomyocyte performance. To assist translation to clinical practice we investigated OMs effect on explanted human failing hearts, specifically; contractile dynamics, interaction with the ß1 -adrenoceptor (AR) agonist (-)-noradrenaline and spontaneous contractions. Left and right ventricular trabeculae from 13 explanted failing hearts, and trabeculae from 58 right atrial appendages of non-failing hearts, were incubated with or without a single concentration of OM for 120 min. Time to peak force (TPF) and 50% relaxation (t50% ) were recorded. In other experiments, trabeculae were observed for spontaneous contractions and cumulative concentration-effect curves were established to (-)-noradrenaline at ß1 -ARs in the absence or presence of OM. OM prolonged TPF and t50% in ventricular trabeculae (600 nM, 2 µM, p < .001). OM had no significant inotropic effect but reduced time dependent deterioration in contractile strength compared to control (p < .001). OM did not affect the generation of spontaneous contractions. The potency of (-)-noradrenaline (pEC50 6.05 ± 0.10), for inotropic effect, was unchanged in the presence of OM 600 nM or 2 µM. Co-incubation with (-)-noradrenaline reduced TPF and t50% , reversing the negative diastolic effects of OM. OM, at both 600 nM and 2 µM, preserved contractile force in left ventricular trabeculae, but imparted negative diastolic effects in trabeculae from human failing heart. (-)-Noradrenaline reversed the negative diastolic effects, co-administration may limit the titration of inotropes by reducing the threshold for ischemic side effects.

Randomized Placebo-Controlled Trial of Ferric Carboxymaltose in Heart Failure With Iron Deficiency: Rationale and Design.

BACKGROUND: Iron deficiency (ID) has a prevalence of ≈40% to 50% among patients in heart failure (HF) with reduced ejection fraction and is associated with worse prognosis. Several trials demonstrated that intravenous ferric carboxymaltose leads to early and sustained improvement in patient-reported outcomes and functional capacity in patients with HF with reduced ejection fraction with ID, yet morbidity and mortality data are limited. METHODS: The objective of the HEART-FID trial (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) is to assess efficacy and safety of ferric carboxymaltose compared with placebo as treatment for symptomatic HF with reduced ejection fraction with ID. HEART-FID is a multicenter, randomized, double-blind, placebo-controlled trial enrolling ≈3014 patients at ≈300 international centers. Eligible patients are aged ≥18 years in stable chronic HF with New York Heart Association functional class II to IV symptoms, ejection fraction ≤40%, ID (ferritin <100 ng/mL or ferritin 100-300 ng/mL with a transferrin saturation <20%), and documented HF hospitalization or elevated N-terminal pro-brain natriuretic peptide. Consented patients are assigned to ferric carboxymaltose or placebo at baseline, with repeated visits/assessments every 6 months for additional study drug based on hemoglobin and iron indices for the trial duration. The primary end point is a hierarchical composite of death and HF hospitalization at 12 months and change from baseline to 6 months in the 6-minute walk test distance. CONCLUSIONS: The HEART-FID trial will inform clinical practice by clarifying the role of long-term treatment with intravenous ferric carboxymaltose, added to usual care, in ambulatory patients with symptomatic HF with reduced ejection fraction with ID. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037931.

Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure.

Heart failure (HF) is a global pandemic with significant mortality and morbidity. Despite current medications, 50% of individuals die within 5 years of diagnosis. Of these deaths, 30-50% will be a result of sudden cardiac death from ventricular arrhythmias. This review discusses two stress-induced mechanisms, phosphorylation from chronic ß-adrenoceptor (ß-AR) stimulation and thiol modifications from oxidative stress, and how they modulate the cardiac ryanodine receptor type 2 (RyR2) and foster an arrhythmogenic phenotype. Calcium (Ca2+) is the ubiquitous secondary messenger of excitation-contraction coupling and provides a common pathway for contractile dysfunction and arrhythmia genesis. In a healthy heart, Ca2+ is released from the sarcoplasmic reticulum (SR) by RyR2. The open probability of RyR2 is under the dynamic influence of co-proteins, ions, and kinases that are in strict balance to ensure normal physiological functioning. In HF, chronic ß-AR activity and production of reactive oxygen species and reactive nitrogen species provide two stress-induced mechanisms uncoupling RyR2 control, resulting in pathological diastolic SR Ca2+ leak. This increased cytosolic [Ca2+] promotes Ca2+ extrusion via the local Na+/Ca2+ exchanger, resulting in net sarcolemmal depolarization, delayed after depolarization and ventricular arrhythmia. Experimental models researching oxidative stress and phosphorylation have aimed to identify how post-translational modifications to the RyR2 macromolecular complex, and the associated Na+/Ca2+ cycling proteins, result in pathological Ca2+ handling and diastolic leak. However, the causative molecular changes remain controversial and undefined. Through understanding the molecular mechanisms that produce an arrhythmic phenotype, novel therapeutic targets to treat HF and prevent its malignant course can be identified.

Correction to "Understanding How Phosphorylation and Redox Modifications Regulate Cardiac Ryanodine Receptor Type 2 Activity to Produce an Arrhythmogenic Phenotype in Advanced Heart Failure".

[This corrects the article DOI: 10.1021/acsptsci.0c00003.].

A Rare Case of Severe Nontropical Isolated Right Ventricular Endomyocardial Fibrosis.

We present a case of late presentation nontropical endomyocardial fibrosis isolated to the right ventricle and tricuspid valve (TV). In response to deteriorating hemodynamics, surgical debulking and TV removal were performed before initiation of centralized venoarterial extracorporeal membrane oxygenation support. Definitive endomyocardial resection with a TV prosthesis was then successfully completed. (Level of Difficulty: Advanced.).

Nesiritide in patients hospitalized for acute heart failure: does timing matter? Implication for future acute heart failure trials.

AIMS: It remains unclear if early administration of i.v. nesiritide in patients hospitalized with acute heart failure (AHF) is associated with improved clinical outcomes. METHODS AND RESULTS: We analysed data from 7007 patients enrolled in ASCEND-HF to examine the associations between time to treatment with study medication (nesiritide or placebo) and clinical endpoints: (i) moderate to marked dyspnoea relief on a 7-point Likert scale at 6 h; (ii) 30-day all-cause mortality or re-hospitalization; and (iii) 30-day all-cause mortality. The median time to study drug administration was 16.7 h (25th, 75th percentiles = 6.5, 23.1), with significant regional variation (e.g. median of 13.0 h in Asia-Pacific vs. 18.4 h in North America). After risk adjustment, each hour delay in study medication after the first 10 h from initial hospital presentation was associated with modestly reduced odds of dyspnoea relief [(adjusted odds ratio (OR) 0.98, 95% confidence interval (CI) 0.98-0.99; P < 0.0001]. Every hour delay in study medication was associated with modestly higher all-cause mortality or re-hospitalization (unadjusted OR 1.01, 95% CI 1.01-1.02; P < 0.001) due to pre-randomization therapies and known predictors of 30-day outcomes (adjusted P = 0.12). There was no significant association between time to study drug and all-cause mortality (P > 0.08). CONCLUSION: In a large international AHF trial, time to treatment with study medication varied markedly across regions. Earlier administration of study medication was associated with modestly better dyspnoea relief, but not 30-day clinical outcomes. The association between timing of treatment with study medication and study endpoints may have implications for the interpretation of AHF studies and future trial design.