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Aims: The PIONEER-HF and PARAGLIDE-HF trials aimed to determine the efficacy and safety of the in-hospital initiation of sacubitril/valsartan in patients hospitalized for AHF. However, whether the inclusion and exclusion criteria of the trials apply to patients encountered in real-world routine care is unclear. This study aimed to investigate the applicability of the PIONEER-HF and PARAGLIDE-HF trials to real-world AHF patients., Methods and Results: We identified 28 293 AHF hospitalized patients between August 2008 to August 2017 from the Chang Gung Research Database and classified them into four groups based on left ventricular ejection fraction (LVEF) and trial criteria. Cox proportional hazards models were used to compare the risk of HF hospitalization and cardiovascular (CV) death. We defined PIONEER-HF eligible (n = 3683) and non-eligible (n = 3502) patients with an LVEF ≤40%, and PARAGLIDE-HF eligible (n = 5191) and non-eligible (n = 5832) patients with an LVEF >40%. Over a mean follow-up of 3.5 years, the PIONEER-HF non-eligible and eligible groups exhibited similar rates of HF hospitalization and CV death (41.1% vs. 41.8%, adjusted hazard ratio [aHR]: 0.95; 95% CI: 0.88-1.04). No significant difference was found in the composite outcome between PARAGLIDE-HF non-eligible and eligible groups (36.7% vs. 38.6%; aHR: 0.97; 95% CI: 0.90-1.04)., Conclusions: Using trial criteria, only 31.3% of AHF patients were eligible for sacubitril-valsartan. Yet, non-eligible patients demonstrated similar outcomes to eligible patients, indicating a need for further evaluation of sacubitril-valsartan benefits in non-eligible AHF patients., (© 2024 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The echocardiographic parameter E/e' has been associated with cardiovascular (CV) events. However, few studies have analyzed multiple associated CV outcomes using E/e' in a diverse population of both inpatients and outpatients with and without cardiac diseases and risk factors., Methods: Medical records of 75,393 patients without atrial fibrillation (AF) with first available E/e' were retrieved from our hospital database. Patients with mitral valve disease were excluded, and the remainder were studied in protocol 1 (70,819 patients). Patients with hypertension, diabetes mellitus, hyperlipidemia, CV diseases, prior CV events, CV surgeries, and left ventricular ejection fraction <50% or missing left ventricular ejection fraction were further excluded, and the remaining patients were studied in protocol 2 (14,665 patients). The study outcomes are major adverse CV events (MACE), which included myocardial infarction (MI), AF, ischemic and hemorrhagic stroke (IHS), hospitalization for heart failure (HHF), and cardiac death. The primary outcomes were MACE and each of the MACE components., Results: At the end of maximal 5-year follow-up (median 22.18 months with interquartile range 7.20-49.08 months for MACE in protocol 1 and 23.46 months with interquartile range 8.15-49.02 months for MACE in protocol 2), compared with an E/e' value of <8, an intermediate value of E/e' 8 to 15 and a high value of E/e' >15 were significantly associated with MACE, MI, AF, IHS, HHF, and cardiac death in protocol 1 (all P < .0001). In protocol 2, an intermediate E/e' value of 8 to 15 and a high value of E/e' >15 were significantly associated with MACE, MI, AF, IHS, HHF, and CV death (all P < .05), except an intermediate value E/e' 8 to 15 was not associated with AF., Conclusions: In a diverse population of inpatients and outpatients with and without cardiac diseases and risk factors, the echocardiographic parameter E/e' was associated with CV events and is a useful marker of risk., (Copyright © 2022 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Cheyne-Stokes respiration (CSR), a kind of central sleep apnea, is referred to as a poor prognostic factor in heart failure patients with reduced ejection fraction (HFrEF). Matrix metalloproteinase (MMP) and B-type natriuretic peptide (BNP) play important roles in HFrEF patients and are markers of poor prognosis. However, there is no literature mentioning the changes in MMP and BNP in HFrEF patients with CSR., Methods: From June 2018 to June 2019, 41 adult patients with stable heart failure and left ventricular ejection fraction < 50% were enrolled from the cardiology clinic. After history-taking and medication review to exclude possible central nervous system- or medication-related central sleep apnea, an overnight polysomnography study was performed, and CSR was identified. The morning serum MMP-2, MMP-9, and BNP levels were determined using enzyme-linked immunosorbent assay and fluorescence immunoassay techniques. A positive airway pressure device was applied to 7 patients for 3 months., Results: The serum MMP-2 and BNP levels were significantly higher in HFrEF patients with CSR than in patients without CSR. In addition, elevated serum MMP-2 levels correlated well with the severity of sleep apnea and intermittent hypoxia, which were represented as the apnea-hypopnea index and the oxygen desaturation index. No positive correlation was found between those markers and left ventricular ejection fraction. Finally, the treatment of sleep apnea with continuous positive airway pressure for 3 months tended to reduce the elevated serum MMP-2 levels., Conclusions: Higher serum MMP-2 and BNP levels were found in HFrEF patients with CSR. Elevated MMP-2 levels were correlated with the severity of sleep apnea and intermittent hypoxia., Citation: Chuang L-P, Pang J-HS, Lin S-W, et al. Elevated serum matrix metalloproteinase-2 levels in heart failure patients with reduced ejection fraction and Cheyne-Stokes respiration. J Clin Sleep Med . 2022;18(5):1365-1373., (© 2022 American Academy of Sleep Medicine.)

Aims: This study aimed to compare the efficacy of angiotensin receptor-neprilysin inhibitor (ARNI) therapy with angiotensin receptor blocker (ARB) therapy for cardiovascular outcomes in patients with heart failure (HF) with reduced ejection fraction., Methods and Results: Data were obtained from the Chang Gung Research Database. The cohort entry date of the ARB group was assigned as that of the ARNI group to avoid immortal time bias. Additionally, 1:1 propensity score matching based on age, sex, and baseline left ventricular ejection fraction was conducted. The expectation-maximization imputation method with inverse probability of treatment weighting was used to compare outcomes between the two groups. The primary outcome was a composite of cardiovascular death and hospitalization for worsening HF. Patients who received ARNI therapy had a significantly lower risk of the primary composite outcome occurring than patients who received ARBs (hazard ratio, 0.74; 95% confidence interval, 0.57-0.96). The reduction of hospitalization for worsening HF contributed most to the primary outcome benefits. In addition to the primary outcome, the ARNI group had a significantly lower risk of non-fatal myocardial infarction. The improvement of ejection fraction was not significantly different between the groups. The medication doses of ARNI were lower than in clinical trials., Conclusions: In patients with HF with reduced ejection fraction, sacubitril/valsartan was superior to ARB therapy in reducing the occurrence of the primary outcome endpoint of hospitalization for worsening HF and cardiovascular death., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Patients with multivessel disease (MVD) often pursue complete revascularization (CR) during percutaneous coronary intervention (PCI) to improve prognosis. However, angiographic CR is not always feasible and is associated with some procedure-related complications in heart failure (HF) patients with MVD. Clinical selective incomplete revascularization (IR) may be reasonable for these high-risk patients, but its role in long-term outcomes remains uncertain., Methods: Six hundred patients with HF and MVD submitted to PCI were enrolled. Major adverse cardiac events (MACEs) were defined as a composite of recurrent myocardial infarction, any revascularization, and all-cause mortality at 5 years., Results: During a mean follow-up period of 3.7 ± 1.9 years, there was no significant difference in 5-year MACEs between selective IR and successful angiographic CR in HF patients with MVD. However, patients who failed CR had a significantly greater incidence of 5-year MACEs than those in the other two groups (failed CR: 46.4% vs. selective IR: 27.7% vs. successful CR: 27.8%, p < 0.001)., Conclusions: Long-term outcomes of selective IR were comparable with those of successful angiographic CR in HF patients with MVD. However, patients that failed CR showed 2.53-fold increased risk of MACEs compared to patients undergoing either selective IR or successful angiographic CR. A more comprehensive planning strategy should be devised before PCI in HF patients with MVD., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Chieh-Yu Chang et al.)

Background: Coronary artery disease is the most common cause of heart failure (HF) in developed countries. The aim of this study was to elucidate the mechanisms of reduction of arrhythmias after sacubitril/valsartan (LCZ696) therapy in a myocardial infarction (MI)-HF rabbit model., Methods and Results: Chronic MI in rabbits with HF were divided into 3 groups: placebo control, valsartan 30 mg/day and LCZ696 60 mg/day. After 4 weeks of therapy, an electrophysiologic study and a dual voltage-calcium optical mapping study were performed. The LCZ696 group had significantly better left ventricular ejection fraction and lower ventricular tachyarrhythmia inducibility than the valsartan and placebo groups. The most common ventricular tachyarrhythmia pattern was 1 or 2 ectopic beats originating from the peri-infarct areas, followed by re-entrant beats surrounding phase singularity points. Compared to the valsartan and placebo groups, the LCZ696 group had significantly shorter action-potential duration, shorter intracellular calcium tau constant, faster conduction velocity, and shorter pacing cycle length to induce arrhythmogenic alternans. LCZ696 therapy reduced the phosphorylated calmodulin-dependent protein kinase II (CaMKII-p) expression., Conclusions: In a rabbit model with chronic MI and HF, LCZ696 therapy ameliorated postinfarct heart function impairment and electrophysiologic remodeling and altered CaMKII-p expression, leading to reduced ventricular tachyarrhythmia inducibility., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Acute statin therapy reduces myocardial ischemia/reperfusion (IR) injury-induced ventricular fibrillation (VF), but the underlying electrophysiological mechanisms remain unclear. This study sought to investigate the antiarrhythmic effects of a single bolus rosuvastatin injection in failing rabbit hearts with IR injury and to unveil the underlying molecular mechanisms. Rabbits were divided into rosuvastatin, rosuvastatin + L-NAME, control, and L-NAME groups. Intravenous bolus rosuvastatin (0.5 mg/kg) and/or L-NAME (10 mg/kg) injections were administered 1 hour and 15 minutes before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, an IR model was created by coronary artery ligation for 30 minutes, followed by reperfusion for 15 minutes. Plasma NO end product levels were measured during IR. Then, hearts were excised and Langendorff-perfused for optical mapping studies. Cardiac tissues were sampled for Western blot analysis. Rosuvastatin increased plasma NO levels during IR, which was abrogated by L-NAME. Spontaneous VF during IR was suppressed by rosuvastatin (P < 0.001). Intracellular calcium (Cai) decay and conduction velocity were significantly slower in the IR zone. Rosuvastatin accelerated Cai decay, ameliorated conduction inhomogeneity, and reduced the inducibility of spatially discordant alternans and VF significantly. Western blots revealed significantly higher expression of enhancing endothelial NO-synthase and phosphorylated enhancing endothelial NO-synthase proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were downregulated in the IR zone, which was attenuated or reversed by rosuvastatin. Acute rosuvastatin therapy before ischemia reduced IR-induced VF by improving SERCA2a function and ameliorating conduction disturbance in the IR zone.

Background: This study investigated the predictors of subsequent cardiovascular events in stable post-myocardial infarction patients in Taiwan., Methods: A total of 11,183 patients were recruited who had survived one year post-myocardial infarction without subsequent events of recurrent myocardial infarction or stroke from the Taiwan National Health Insurance Research Database. Their composite cardiovascular event rates were identified., Results: The composite cardiovascular events rate in three year follow-up in the post-myocardial infarction population was 13.8%. Corresponding event rates were 5.8% recurrent myocardial infarction, 5.0% stroke, and 5.2% death. Independent factors associated with a higher risk of ischemic events or death included heart failure (hazard ratio (HR)=1.19), hypertension (HR=1.16), age (65-75 vs <65 years: HR=1.29; 75-85 vs <65 years: HR=1.50; >85 vs <65 years: HR=1.70), diabetes (HR=1.33), prior stroke (HR=1.24), chronic kidney disease (HR=1.4), atrial fibrillation (HR=1.27), and underutilization of guideline-based medication (HR=1.73). Composite risk for myocardial infarction, stroke and death increased progressively from 4.9% in patients with zero risk factor to 100.0% in patients with eight risk factors., Conclusions: For acute myocardial infarction patients surviving one year without subsequent events of recurrent myocardial infarction or stroke, the risk of cardiovascular events remained high. Eight predictors identified patients at increased risk for subsequent cardiovascular events within the next three years. These results suggest an unmet need, particularly in patients with additional risk factors.

Background: LCZ696 (valsartan/sacubitril) therapy significantly reduced mortality in patients with heart failure (HF). Although a clinical trial (PARADISE-MI Trial) has been ongoing to examine the effects of LCZ696 in myocardial infarction (MI) patients, the effects of LCZ696 on remodeling of cardiac electrophysiology in animal models remain largely unclear., Methods: We performed coronary artery ligation to create MI in Sprague-Dawley rats. Echocardiography was performed one week after MI to confirm the development of HF with left ventricular ejection fraction ≤ 40%. MI rats were randomly assigned to receive medical therapy for 4 weeks: LCZ696, enalapril, or vehicle. The sham-operation rats received sham operation without MI creation. In vivo electrophysiological exams were performed under general anesthesia. Western blot analyses were conducted to quantify ion channel proteins., Results: The HF-vehicle group did not show significant changes in LVEF. Both enalapril and LCZ696 therapy significantly improved LVEF. The HF-vehicle group had higher ventricular arrhythmia (VA) inducibility than the sham group. As compared with the HF-vehicle group, LCZ696 therapy significantly reduced VA inducibility, but enalapril therapy did not. Western blot analyses showed significant downregulation of Na V 1.5, ERG, KCNE1, and KCNE2 channel proteins in the HF vehicle group compared with the sham group. LCZ696 therapy upregulated protein expression of ERG, KCNE1, and KCNE2., Conclusion: As compared with enalapril therapy, LCZ696 therapy led to improvement of LVEF, reduced VA inducibility, and upregulated expression of K + channel proteins., Competing Interests: The authors have no conflicts of interest., (Copyright © 2019 Po-Cheng Chang et al.)

Objective: Whether the cardiovascular (CV) outcomes of second-generation limus-eluting stents (LESs) differ from those of paclitaxel-eluting stents (PESs) in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) is still unclear., Methods: We used the Taiwan National Health Insurance Research Database to analyse data of 516 patients with AMI and CS diagnosed from January 2007 to December 2011. We used propensity score matching to adjust for the imbalance in covariate baseline values between these two groups. We evaluated clinical outcomes by comparing 197 subjects who used second-generation LESs to 319 matched subjects who used PESs., Results: The risk of the primary composite outcomes (i.e., myocardial infarction, coronary revascularisation or CV death) was significantly lower in the second-generation LES group than in the PES group [37.3% vs. 51.8%; hazard ratio (HR), 0.73; 95% CI: 0.56-0.95] at the 12-month follow-up. The patients who received second-generation LESs had a lower risk of coronary revascularisation (HR 0.62; 95% CI: 0.41-0.93) than those who used PESs. However, the risks of myocardial infarction (HR 0.56; 95% CI: 0.26-1.24), ischemic stroke (HR 0.73; 95% CI: 0.23-2.35), or CV death (HR 0.90; 95% CI: 0.63-1.28) were not significantly different between the two groups., Conclusions: Among patients with CS-complicating AMI, second-generation LES implantation significantly reduced the risk of coronary revascularisation and composite CV events compared to PES implantation at the 12-month follow-up., Competing Interests: The authors have declared that no competing interests exist.

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca rise and EAD-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

Cerebral tissue oxygen saturation (SctO2) reflects cerebral perfusion and tissue oxygen consumption, which decline in some patients with heart failure with reduced ejection fraction (HFrEF) or stroke, especially during exercise. Its physiologic basis and clinical significance remain unclear. We aimed to investigate the association of SctO2 with oxygen transport physiology and known prognostic factors during both rest and exercise in patients with HFrEF or stroke. Thirty-four HFrEF patients, 26 stroke patients, and 17 healthy controls performed an incremental cardiopulmonary exercise test using a bicycle ergometer. Integrated near-infrared spectroscopy and automatic gas analysis were used to measure cerebral tissue oxygenation and cardiac and ventilatory parameters. We found that SctO2 (rest; peak) were significantly lower in the HFrEF (66.3±13.3%; 63.4±13.8%,) than in the stroke (72.1±4.2%; 72.7±4.5%) and control (73.1±2.8%; 72±3.2%) groups. In the HFrEF group, SctO2 at rest (SctO2rest) and peak SctO2 (SctO2peak) were linearly correlated with brain natriuretic peptide (BNP), peak oxygen consumption ([Formula: see text]), and oxygen uptake efficiency slope (r between -0.561 and 0.677, p < 0.001). Stepwise linear regression showed that SctO2rest was determined by partial pressure of end-tidal carbon dioxide at rest (PETCO2rest), hemoglobin, and mean arterial pressure at rest (MAPrest) (adjusted R = 0.681, p < 0.05), while SctO2peak was mainly affected by peak carbon dioxide production ([Formula: see text]) (adjusted R = 0.653, p < 0.05) in patients with HFrEF. In conclusion, the study delineates the relationship of cerebral saturation and parameters associated with oxygen delivery. Moreover, SctO2peak and SctO2rest are correlated with some well-recognized prognostic factors in HFrEF, suggesting its potential prognostic value.

Seismocardiogram (SCG) or mechanocardiography is a noninvasive cardiac diagnostic method; however, previous studies used only a single sensor to detect cardiac mechanical activities that will not be able to identify location-specific feature points in a cardiac cycle corresponding to the four valvular auscultation locations. In this study, a multichannel SCG spectrum measurement system was proposed and examined for cardiac activity monitoring to overcome problems like, position dependency, time delay, and signal attenuation, occurring in traditional single-channel SCG systems. ECG and multichannel SCG signals were simultaneously recorded in 25 healthy subjects. Cardiac echocardiography was conducted at the same time. SCG traces were analyzed and compared with echocardiographic images for feature point identification. Fifteen feature points were identified in the corresponding SCG traces. Among them, six feature points, including left ventricular lateral wall contraction peak velocity, septal wall contraction peak velocity, transaortic peak flow, transpulmonary peak flow, transmitral ventricular relaxation flow, and transmitral atrial contraction flow were identified. These new feature points were not observed in previous studies because the single-channel SCG could not detect the location-specific signals from other locations due to time delay and signal attenuation. As the results, the multichannel SCG spectrum measurement system can record the corresponding cardiac mechanical activities with location-specific SCG signals and six new feature points were identified with the system. This new modality may help clinical diagnoses of valvular heart diseases and heart failure in the future.

Peripartum cardiomyopathy (PPCM) is the development of heart failure during late pregnancy to months postpartum with potential fatal outcome. However, the disease is not well-studied in Asia.We aimed to investigate the epidemiology and clinical outcomes of PPCM in Taiwan.Electronic medical records were retrieved from Taiwan National Health Insurance Research Database from 1997 to 2011. Patients with PPCM were separated into 3 groups based on the timing of diagnosis. Early: PPCM diagnosed first to ninth month of pregnancy. Traditional: PPCM diagnosed last month of pregnancy till fifth month post-delivery. Late: PPCM diagnosed sixth to twelfth month post-delivery. Primary outcomes defined as cardiac death, all-cause mortality, and major adverse cardiovascular events (MACE) within 1 year.A total of 3,506,081 deliveries during 1997 to 2011 were retrieved and 925 patients with PPCM were identified. Overall incidence of PPCM was 1:3,790 during the 15 years. Early, Traditional, and Late group each had 88, 742, and 95 patients. Cardiac death occurred in 31 patients, all-cause mortality in 72 patients, and MACE in 65 patients. Late group had 2- to 3-fold event rates in cardiac death, all-cause mortality, and MACE compared with Early and Traditional groups. Cumulative incidence showed significant differences for cardiac death (P = .0011), all-cause mortality (P = .0031), and MACE (P = .0014) among 3 groups. Multivariate Cox model showed Late group had significantly worse outcomes after adjusted for clinical variables compared with 2 other groups.Our study is the largest national cohort among Asian countries that showed timing of diagnosis of PPCM had different outcomes. Late diagnosis portended significantly increased morbidity and mortality, even after adjusted for clinical variables.

Background/aims: Hyponatremia is a well-known risk factor for poor outcomes in Western studies of heart failure (HF) patients. We evaluated the predictive value of hyponatremia in hospitalized Asian HF patients., Methods: The Clinical Characteristics and Outcomes in the Relation with Serum Sodium Level in Asian Patients Hospitalized for Heart Failure (the COAST) study enrolled hospitalized patients with systolic HF (ejection fraction < 45%) at eight centers in South Korea, Taiwan, and China. The relationship between admission sodium level and clinical outcomes was analyzed in 1,470 patients., Results: The mean admission sodium level was 138 ± 4.7 mmol/L, and 247 patients (16.8%) had hyponatremia defined as Na(+) < 135 mmol/L. The 12-month mortality was higher in hyponatremic patients (27.9% vs. 14.6%, p < 0.001), and hyponatremia was an independent predictor of 12-month mortality (hazard ratio, 1.72; 95% confidence interval, 1.12 to 2.65). During hospital admission, 57% of hyponatremic patients showed improvement without improvement in their clinical outcomes (p = 0.620). The proportion of patients with optimal medical treatment was only 26.5% and 44.2% at admission and discharge, respectively, defined as the combined use of angiotensin-converting-enzyme inhibitor/angiotensin receptor blocker and β-blocker. Underuse of optimal medical treatment was more pronounced in hyponatremic patients., Conclusions: In hospitalized Asian HF patients, hyponatremia at admission is common and is an independent predictor of poor clinical outcome. Furthermore, hyponatremic patients receive less optimal medical treatment than their counterparts.

Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n = 9 in each group). Simultaneous voltage and intracellular Ca(2+) (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.

Purpose: Although high-intensity interval aerobic training (HIT) effectively improves aerobic fitness, the risk of cardiac arrest transiently increases during strenuous physical exertion in patients with cardiovascular disease. For safety and efficacy concerns, this investigation explored the effect of a modified HIT (mHIT) on exertional ventilatory-hemodynamic efficiency in heart failure patients with reduced ejection fraction (HFREF)., Methods: HFREF patients were prospectively assigned to two groups: mHIT and usual healthcare (UC). The former comprised supervised continuous aerobic training at ventilatory anaerobic threshold for 50 min/day, 3 days/week for 4 weeks, and then 3-min intervals at 40 and 80% VO₂ reserve for 50 min/day, 3 days/week for 8 weeks. The latter received optimal medical treatment only. Ventilatory and hemodynamic responses during exercise were measured before and after the intervention. Paired-t and repeated measures ANOVA with post hoc tests were adopted., Results: Each group had an N of 33. The mHIT and UC group had matched baseline characteristics including health-promotion concept and behavior score. The mHIT for 12 weeks (1) increased VO₂, cardiac output, and notably, cardiac power output at peak workload (1,151 ± 573 vs. 1,306 ± 596 L/min/mmHg); (2) reduced V E/VO2 (32.4 ± 4.6 vs. 30.0 ± 4.0), breathing frequency, ventilation, and enhanced stroke volume compliance at identical submaximal intensity (50% peak workload at pre-intervention evaluation). No significant changes in ventilatory and hemodynamic responses to exercise were observed following the UC., Conclusions: The mHIT regimen improves peak cardiac pumping capacity with reducing cardiac after-load and simultaneously increases ventilation efficiency during exercise in patients with HFREF. Thereby, aerobic fitness is ameliorated.

Data on the effectiveness of implantable implantable cardioverter defibrillators (ICDs) with respect to reducing mortality in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) are lacking. The purpose of this meta-analysis was to compare the mortality of patients with ESRD who have received and not received an ICD. A search was conducted on January 31, 2013 of Medline, Cochrane, EMBASE, and Google Scholar. Studies were selected for inclusion based on the following criteria. 1) Randomized controlled trial. 2) ESRD patients with heart failure. 3) Device therapy (ICD, CRT-defibrillator [CRT-D]) used to treat heart failure. 4) Primary outcome is survival analysis. 5) Retrospective study if survival analysis was performed. The primary outcome was overall survival (OS), and the secondary outcome was 2-year survival. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated, and a χ2-based test of homogeneity was performed. Three studies were included in the analysis. The combined OR for OS was 2.245 (95% CI 1.871 to 2.685, P<0.001), indicating that patients with an ICD had a significantly higher OS than those without an ICD. The combined OR for 2-year survival was 2.312 (95% CI 1.921 to 2.784, P<0.001), indicating that patients with an ICD had a significantly higher 2-year survival rate than those without an ICD. The use of ICD in patients with ESRD is associated with an increase in the OS and the 2-year survival rate.

Introduction: Dantrolene prevents arrhythmogenic Ca(2+) release during heart failure (HF). However, direct evidence to support its antiarrhythmic effects in failing hearts with acute myocardial infarction (AMI) is lacking., Methods and Results: HF was induced by right ventricular pacing (312 beats/min, 4 weeks) in 19 rabbits. AMI was induced by coronary artery ligation in rabbits surviving chronic pacing (n = 17). The hearts were quickly excised and Langendorff-perfused for simultaneous membrane potential and intracellular Ca(2+) (Cai ) optical mapping when ventricular fibrillation (VF) occurred or 4 hours after AMI. The VF inducibility was defined as the ability to provoke sustained VF (>2 minutes) by pacing. Dantrolene (10 μM) was administered after baseline studies. Spontaneous VF occurred in 5 rabbits (SVF group). The ventricular premature beat (VPB) burden was significantly higher in the SVF group than the non-SVF group (P < 0.05). Dantrolene suppressed VPB burden (P = 0.03) and prolonged action potential duration (APD; P < 0.05) to reduce VF inducibility (P < 0.05). However, dantrolene shortened immediate postshock APD50 even if VF storm was suppressed., Conclusion: In failing hearts with AMI, VPB burden plays a pivotal role in SVF occurrence. Dantrolene suppresses VPBs and/or prolongs repolarization to inhibit spontaneous VF and reduce VF inducibility., (© 2013 Wiley Periodicals, Inc.)

Background: Piceatannol, a hydroxystilbene natural product, has been reported to exert antiarrhythmic action via INa inhibition and slow INa inactivation in ischemia-reperfused (IR) rat hearts. The present study aimed to clarify the proarrhythmic property of piceatannol during regional IR injury in failing rabbit hearts., Methods: Heart failure (HF) was induced by rapid right ventricular pacing for 4 weeks. The IR model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo. Simultaneous voltage and intracellular Ca(2+) (Cai) optical mapping was then performed in isolated Langendorff-perfused hearts (n=11 in each HF and control group). Action potential duration (APD) restitution, arrhythmogenic alternans and VF inducibility were evaluated by a dynamic pacing protocol. Conduction velocity was measured along lines across the IR and non-IR zones during pacing. Piceatannol (10 μM) was administered after baseline studies., Results: In the HF group, piceatannol decreased conduction velocity, induced rate-dependent regional inhomogeneity of conduction delay and wavelength shortening, slowed Cai decay, and facilitated arrhythmogenic alternans instead of APD prolongation to increase VF inducibility. In the control group, the proarrhythmic effects of piceatannol on APD restitution, arrhythmogenic alternans and conduction delay were offset by its antiarrhythmic effects (APD and wavelength prolongation), resulting in a neutral effect on VF inducibility., Conclusions: Piceatannol (10 μM) is proarrhythmic in failing rabbit hearts with regional IR injury. The increased VF inducibility by piceatannol in HF suggests that its undesirable effects are more pronounced than its benefits in failing hearts., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: Early (e')/late (a') diastolic mitral annular velocity ratio is a powerful independent predictor of poor prognosis in patients with left ventricular (LV) dysfunction. Doppler tissue imaging, however, may change over time according to intervention and medical treatment. The aim of the present study was to prospectively evaluate whether, in clinically stable patients with chronic heart failure (CHF), the decrease of an initially high e'/a' ratio on long-term therapy predicts a more favorable outcome., Methods and Results: One hundred and eighty-one adult patients with CHF and high e'/a' ratio (≥ 0.74) underwent repeat echocardiography 6 months after the initial examination, and were then followed up for a mean period of 20 months. After 6 months, e'/a' ratio did not change in 95 patients, whereas it was significantly decreased (<0.74) in the remaining 86 patients. During follow-up, 55 participants (30%) had cardiac events. According to multivariate Cox regression analysis, decrease in e'/a' ratio, initial New York Heart Association class III or IV, and change in LV mass index as well as in systolic mitral annular velocities emerged as independent predictors of survival., Conclusions: The decrease of an initially high e'/a' ratio on long-term therapy predicts a more favorable outcome in clinically stable patients with CHF.

Background: Although previous studies have established the ability of mitral annular velocities and velocity dispersion indices to differentiate between ischemic cardiomyopathy (ICM) and nonischemic cardiomyopathy, prospective data are lacking on both the use of heterogeneity of mitral annular velocities to predict the ischemic etiology in patients with left ventricular dysfunction and further cardiovascular prognosis., Methods: A total of 232 patients with left ventricular ejection fractions < 40% were admitted between 2008 and 2010. Doppler tissue imaging was performed on six mitral annular sites for three consecutive beats and then averaged for each site. Systolic (Vs') and early (Ve') and late (Va') diastolic mitral annular velocity dispersion indices among the six mitral annular sites were calculated., Results: Ve' was a significant predictor (P < .01) of ICM in multivariate logistic regression models adjusted for clinical variables and conventional echocardiography. The optimal cutoff value for predicting ICM was Ve' ≥ 16.7 with an area under the receiver operating characteristic curve of 0.92. Its sensitivity and specificity were 87% and 85%, respectively. During follow-up (median, 32 months), 64 participants experienced cardiac mortality. The adjusted hazard ratio in Cox proportional-hazards analysis for death in the third tertile in comparison with the first tertile of Ve' was 2.92 (P = .02)., Conclusions: A high degree of heterogeneity of e', expressed as Ve', provides incremental value over clinical variables and conventional echocardiography to predict the prevalence of low left ventricular ejection fractions patients with ICM. Furthermore, elevated Ve' could also identify patients at a high risk for cardiac mortality., (Copyright © 2011 American Society of Echocardiography. Published by Mosby, Inc. All rights reserved.)

Objectives: The purpose of this study was to provide direct evidences that rotor ablation suppresses atrial fibrillation (AF) inducibility., Background: Micro-re-entrant wavefronts have been suggested to serve as sources of rapid activations during AF. Whether AF inducibility is suppressed by elimination of rotors remains unknown., Methods: We used optical mapping to study Langendorff-perfused left pulmonary vein (PV)-left atrium (LA) preparations from 13 dogs with pacing-induced heart failure. Atrial arrhythmias were induced by pacing and mapped during acetylcholine infusion (1 μmol/l). Rotors were identified from optical recordings. Epicardial ablation was performed targeting the rotor anchoring sites in preparations with sustained (>10 min) or incessant spontaneous AF. Non-rotor ablation was performed in 4 preparations. Repeated pacing was performed to test the AF inducibility after ablation., Results: Sustained AF (n = 12) and incessant spontaneous AF (n = 1) were induced after acetylcholine infusion. Pulmonary vein focal discharge was found in 9 preparations (9.2 ± 4.2 beats/s), and rotor anchoring was found at the left superior PV-LA junction in 13 preparations (9.1 ± 4.6 beats/s) and at the ligament of Marshall-PV-LA junction in 1 preparation. Epicardial rotor ablation successfully inhibited the inducibility of sustained AF in 12 of 13 preparations (p < 0.01), including 4 with the maximal dominant frequency sites located on the PV-LA junctional rotor zones (direct elimination of mother rotors). The longest AF duration was shortened significantly by rotor ablation (Wilcoxon Z = 3.60, p = 0.002, n = 13), but not by non-rotor ablation (Wilcoxon Z = 1.00, p = 0.317, n = 4)., Conclusions: Epicardial ablation of the rotor anchoring sites suppresses AF inducibility. The arrhythmogenicity at the maximal dominant frequency sites is directly/indirectly suppressed by the rotor ablation., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: This study assesses the prognostic values of left ventricular (LV) filling patterns, as determined by tissue Doppler imaging (TDI), on cardiac events in patients with LV systolic dysfunction. Normally observed in patients with an advanced form of cardiac disease, an abnormal diastolic pattern by Doppler echocardiography reflects a poor prognosis. Recent studies using TDI have significantly contributed to efforts to evaluate diastolic function and demonstrate the prognostic importance of TDI-derived indices of the LV function., Methods and Results: One hundred seventy-three consecutive adult patients, mean (standard deviation) age of 62.4 (14.3), with a diagnosis of dilated cardiomyopathy and LV ejection fraction <45% were enrolled. During a follow-up period of 321 +/- 100 days, 9 patients expired from cardiac complications and 29 underwent readmission for decompensated heart failure. In multivariate analysis, only the mean value of early (Em) and late (Am) diastolic velocities ratio assessed by TDI, and LV end-diastolic pressure were found to be independent predictors of a cardiac event. The optimal cutoff value for forecasting cardiac event was Em/Am > or = 0.74 with an area under the receiver operating characteristic curve of 0.82; sensitivity and specificity were 84% and 76%, respectively (P < 0.001; standard error = 0.046)., Conclusions: Em/Am ratio is the important predictor of cardiac event, which allows normalization for other risk factors in patients with a clinical diagnosis of chronic heart failure with LV dysfunction comparing with conventional Doppler echocardiography.

Background: Heart failure increases autonomic nerve activities and changes intracellular calcium (Ca(i)) dynamics., Objective: The purpose of this study was to investigate the hypothesis that abnormal Ca(i) dynamics are responsible for triggered activity in the pulmonary veins (PVs) during acetylcholine infusion in a canine model of heart failure., Methods: Simultaneous optical mapping of Ca(i) and membrane potential was performed in isolated Langendorff-perfused PV-left atrial (LA) preparations from nine dogs with ventricular pacing-induced heart failure. Mapping was performed at baseline, during acetylcholine (1 micromol/L) infusion (N = 9), and during thapsigargin and ryanodine infusion (N = 6)., Results: Acetylcholine abbreviated the action potential. In four tissues, long pauses were followed by elevated diastolic Ca(i), late phase 3 early afterdepolarizations, and atrial fibrillation (AF). The incidence of PV focal discharges during AF was increased by acetylcholine from 2.4 +/- 0.6 beats/s (N = 4) to 6.5 +/- 2.2 beats/s (N = 8; P = .003). PV focal discharge and PV-LA microreentry coexisted in 6 of 9 preparations. The spatial distribution of dominant frequency demonstrated a focal source pattern, with the highest dominant frequency areas colocalized with PV focal discharge sites in 35 (95%) of 37 cholinergic AF episodes (N = 8). Thapsigargin and ryanodine infusion eliminated focal discharges in 6 of 6 preparations and suppressed the inducibility of AF in 4 of 6 preparations. PVs with focal discharge have higher densities of parasympathetic nerves than do PVs without focal discharges (P = .01), and periodic acid-Schiff (PAS)-positive cells were present at the focal discharge sites., Conclusion: Ca(i) dynamics are important in promoting triggered activity during acetylcholine infusion in PVs from pacing-induced heart failure. PV focal discharge sites have PAS-positive cells and high densities of parasympathetic nerves.

We report here on three patients who underwent biventricular pacing (BVP) for severe heart failure and the problems encountered with pseudo-bipolar left ventricular (LV) lead configuration. With this configuration, right ventricular anode capture with simultaneous biventricular stimulation was noted at higher output during the isolated LV pacing mode in these patients, which forced us to program the LV pacing to unipolar configuration in one patient. The implication of this phenomenon in sequential BVP therapy is discussed.

A 46-year-old male patient who had long-term right ventricular (RV) pacing for symptomatic complete heart block, initially by an epicardial, later with an endocardial pacing lead at the RV apex, developed congestive heart failure (CHF) and chronic atrial fibrillation 7 years following the pacemaker implantation and was medically treated. During follow-up, his pacemaker was upgraded to a cardiac resynchronisation therapy (CRT) device, because of uncontrolled CHF symptoms, New York Heart Association (NYHA) functional class IV, while on drugs. The patient's symptomatic status improved to NYHA functional class II with CRT. After 17 months of CRT, the battery became depleted, because of the high capture threshold of the left ventricular lead. The patient was then given dual site RV pacing (RV outflow tract+RV apex) in place of CRT, which showed similar efficacy at 12 weeks follow-up.

Aims: Whether therapeutic hypothermia (TH) is proarrhythmic in preexisting failing hearts with acute ischemia–reperfusion (IR) injury is unknown. Additionally, the effectiveness of rotigaptide on improving conduction slowing in hearts with IR injury is ambiguous. We investigated the electrophysiological effects of TH and rotigaptide in failing rabbit hearts with acute IR injury and determined the underlying molecular mechanisms. Methods and Results: Heart failure was induced by right ventricular pacing (320 beats/min, 4 weeks). Rabbits with pacing-induced heart failure were randomly divided into TH (n = 14) and non-TH (n = 7) groups. The IR rabbit model was created by ligating the coronary artery for 60 min, followed by reperfusion for 15 min in vivo. Then, the hearts were excised quickly and Langendorff-perfused for simultaneous voltage and intracellular Ca2+ (Cai) optical mapping. Electrophysiological studies were conducted, and vulnerability to ventricular fibrillation (VF) was evaluated using pacing protocols. TH (33°C) was instituted after baseline studies, and electrophysiological studies were repeated. Rotigaptide (300 nM) was infused for 20 min, and electrophysiological studies were repeated under TH. Cardiac tissues were sampled for Western blotting. TH increased the dispersion and beat-to-beat variability of action potential duration (APD), aggravated conduction slowing, and prolonged Cai decay to facilitate spatially discordant alternans (SDA) and VF induction. Rotigaptide reduced the dispersion and beat-to-beat variability of APD and improved slowed conduction to defer the onset of arrhythmogenic SDA by dynamic pacing and elevate the pacing threshold of VF during TH. However, the effect of rotigaptide on TH-enhanced VF inducibility was statistically insignificant. TH attenuated IR-induced dysregulation of protein expression, but its functional role remained uncertain. Conclusion: Therapeutic hypothermia is proarrhythmic in failing hearts with acute IR injury. Rotigaptide improves TH-induced APD dispersion and beat-to-beat variability and conduction disturbance to defer the onset of arrhythmogenic SDA and elevate the VF threshold by dynamic pacing, but these beneficial electrophysiological effects are unable to suppress TH-enhanced VF inducibility significantly. [ABSTRACT FROM AUTHOR]

Abstract: Background: Piceatannol, a grape‐derived polyphenol, has been linked to proarrhythmic properties by aggravating inhomogeneous conduction delay in the ischemia‐reperfusion (IR) zone to enhance arrhythmogenic alternans in heart failure (HF) rabbits. The underlying molecular mechanisms of piceatannol‐induced conduction disturbance were unclear in this model. Methods: HF was induced by 4 weeks’ rapid ventricular pacing. IR injury was induced in vivo using a protocol of left coronary artery ligation and release. Left ventricular cardiomyocytes were isolated enzymatically for whole‐cell patch‐clamp studies. Piceatannol (10 μM) was administrated to test its inhibitory effect on sodium current (INa). Immunoblots studies and immunoenzymological staining were conducted in tissues sampled from the IR and remote zones. Results: Peak INa density was less in failing cardiomyocytes than control cardiomyocytes. IR injury further reduces peak INa density in both groups. Piceatannol showed a greater INa inhibitory effect in HF than control cardiomyocytes. Western blots showed reduced NaV 1.5 protein expression in the HF group compared to the control group but no significant difference between remote and IR zones. Immunostaining showed that IR led to cytosolic redistribution of NaV 1.5, especially in failing hearts. Conclusions: Downregulation of NaV 1.5 protein expression and reduced peak INa density are found in the failing hearts. Piceatannol exerts a greater inhibitory effect on peak INa in the failing cardiomyocytes than in the controls. IR injury further decreases peak INa density, which is more prominent in the failing hearts than in the control hearts. [ABSTRACT FROM AUTHOR]

A 46-year-old male patient who had long-term right ventricular (RV) pacing for symptomatic complete heart block, initially by an epicardial, later with an endocardial pacing lead at the RV apex, developed congestive heart failure (CHF) and chronic atrial fibrillation 7 years following the pacemaker implantation and was medically treated. During follow-up, his pacemaker was upgraded to a cardiac resynchronisation therapy (CRT) device, because of uncontrolled CHF symptoms, New York Heart Association (NYHA) functional class IV, while on drugs. The patient's symptomatic status improved to NYHA functional class II with CRT. After 17 months of CRT, the battery became depleted, because of the high capture threshold of the left ventricular lead. The patient was then given dual site RV pacing (RV outflow tract + RV apex) in place of CRT, which showed similar efficacy at 12 weeks follow-up. [ABSTRACT FROM PUBLISHER]

Introduction: Eleclazine is a highly selective late sodium current inhibitor, possibly effective in reducing ventricular fibrillation (VF) in heart failure (HF) with ischemia-reperfusion (IR) injury. The electrophysiological effects of eleclazine at therapeutic hypothermia (TH) are unknown. We investigated the effects of eleclazine in suppressing VF in failing rabbit hearts with IR injury undergoing TH. Method: HF was induced by right ventricular pacing. An IR model was created using coronary artery ligation for 60 min, followed by reperfusion for 30 min. Hearts were excised and Langendorff-perfused for optical mapping and electrophysiological studies. Electrophysiological studies were repeated after TH (33°C) for 30 min or eleclazine (1 μm) infusion for 20 min. Results: In failing IR-injured hearts, eleclazine reduced action potential duration (APD) dispersion and accelerated intracellular Ca2+ uptake to suppress arrhythmogenic alternans but also exacerbated rate-dependent conduction slowing, resulting in neutral effects on VF inducibility at normothermia. TH increased VF severity. Eleclazine after TH ameliorated TH-induced APD dispersion and further depressed conduction to reduce VF inducibility and severity. TH after eleclazine also slowed conduction to a greater extent to reduce VF inducibility and severity by extrastimulus pacing. In control IR-injured hearts, eleclazine increased VF severity by dynamic pacing at normothermia, which was counteracted by TH. Conclusions: Eleclazine does not prevent VF at normothermia but reduces VF inducibility and severity by extrastimulus pacing at TH in isolated failing hearts with regional IR injury. [ABSTRACT FROM AUTHOR]

Simple Summary: We described the existence of an integrated Beclin 1, TLR9, and SIRT3 network involving autophagy, oxidative stress, and mitochondria that is essential for empagliflozin to protect against doxorubicin toxicity in the heart. Empagliflozin treatment increases the abundance of mitochondrial SIRT3 and enhances the activation of TLR9 to bind with Beclin 1, triggering communication to the autophagic, immune system, and inflammatory machinery. From a therapeutic standpoint, SIRT3 loss-of-function variant DCM patients lose the empagliflozin-protective effects, since SIRT3 is implicated in modern world diseases, such as aging, circadian disturbance, and obesity. Large cardiovascular outcome trials have reported favorable effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on heart failure. To study the potential mechanism of the SGLT2 inhibition in heart failure, we used the murine doxorubicin-induced cardiomyopathy model and identified the toll-like receptor 9 (TLR9), NAD-dependent deacetylase sirtuin-3 (SIRT3), and Beclin 1, acting in a complex together in response to empagliflozin treatment. The interactions and implications in mitochondrial function were evaluated with TLR9 deficient, SIRT3 deficient, Beclin 1 haplodeficient, and autophagy reporter mice and confirmed in a patient with SIRT3 point mutation and reduced enzymatic activity. The SGLT2 inhibitor, empagliflozin, protects the heart from doxorubicin cardiomyopathy in mice, by acting through a novel Beclin 1-toll-like receptor (TLR) 9-sirtuin-(SIRT) 3 axis. TLR9 and SIRT3 were both essential for the protective effects of empagliflozin. The dilated cardiomyopathy patient with SIRT3 point mutation and reduced enzymatic activity is associated with reduced TLR9 activation and the absence of mitochondrial responses in the heart after the SGLT2 inhibitor treatment. Our data indicate a dynamic communication between autophagy and Beclin 1-TLR9-SIRT3 complexes in the mitochondria in response to empagliflozin that may serve as a potential treatment strategy for heart failure. [ABSTRACT FROM AUTHOR]