The long non-coding RNA CARDINAL attenuates cardiac hypertrophy by modulating protein translation.

One of the features of pathological cardiac hypertrophy is enhanced translation and protein synthesis. Translational inhibition has been shown to be an effective means of treating cardiac hypertrophy, although system-wide side effects are common. Regulators of translation, such as cardiac-specific long non-coding RNAs (lncRNAs), could provide new, more targeted, therapeutic approaches to inhibit cardiac hypertrophy. Therefore, we generated mice lacking a previously identified lncRNA named CARDINAL to examine its cardiac function. We demonstrate that CARDINAL is a cardiac-specific, ribosome associated lncRNA and show that its expression is induced in the heart upon pathological cardiac hypertrophy; its deletion in mice exacerbates stress-induced cardiac hypertrophy and augments protein translation. In contrast, overexpression of CARDINAL attenuates cardiac hypertrophy in vivo and in vitro, and suppresses hypertrophy-induced protein translation. Mechanistically, CARDINAL interacts with developmentally regulated GTP binding protein 1 (DRG1) and blocks its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 is downregulated, thereby modulating the rate of protein translation in the heart in response to stress. This study provides evidence for the therapeutic potential of targeting cardiac-specific lncRNAs to suppress disease-induced translational changes and to treat cardiac hypertrophy and heart failure.

Prognostic Significance of Blood Pressure at Rest and After Performing the Six-Minute Walk Test in Patients With Acute Heart Failure.

BACKGROUND: It remains unclear whether systolic (SBP) and diastolic (DBP) pressure and BP response after six-minute walk test (6MWT) are associated with adverse outcomes in patients with acute heart failure (AHF). METHODS: We investigated these associations in 98 AHF patients (24.5% women; mean age, 70.5 years) enrolled in the ROSE trial (The Low-dose Dopamine or Low-dose Nesiritide in Acute Heart Failure with Renal Dysfunction). The primary endpoint consisted of any death or rehospitalization within 6 months after randomization. We computed hazard ratios (HRs) of the risks associated with 1-SD increase in post-exercise BP levels and BP ratios, calculated as BP immediately after 6MWT divided by BP before 6MWT. RESULTS: The BP before and after 6MWT averaged 110.6/117.5 mm Hg for SBP and 61.9/64.7 mm Hg for DBP. In multivariable-adjusted analyses including clinic BP measured at the same day of 6MWT, higher DBP after 6MWT was associated with lower risk of the primary endpoint (HR, 0.49; 95% confidence interval [CI], 0.26-0.95; P = 0.034). Both higher SBP and DBP immediately after 6MWT were associated with lower risk of 6-month mortality (HRs, 0.39/0.16; 95% CI, 0.17-0.90/0.065-0.40; P ≤ 0.026). The post-exercise SBP ratio was associated with the risk of 6-month mortality in multivariable-adjusted analyses (HR, 0.44; P = 0.023). CONCLUSIONS: Higher BP levels and BP ratios immediately after 6MWT conferred lower risk of adverse health outcomes. Our observations highlight that 6MWT-related BP level and response may refine risk estimates in patients hospitalized AHF and may help further investigation for the development of HF preventive strategies.

Associations of long-term mortality with serum uric acid at admission in acute decompensated heart failure with different phenotypes.

BACKGROUND AND AIMS: It remains unclear whether the long-term prognostic value of serum uric acid (SUA) at admission differs in acute decompensated heart failure (HF) patients across the spectrum of left ventricular ejection fraction (EF). METHODS AND RESULTS: In 2375 patients (38.9% women; mean age, 68.8 years), we assessed the risk of long-term (>1 year) all-cause mortality associated with per 1-SD increase in SUA at admission, using multivariable Cox regression in HF with preserved (HFpEF), mildly reduced (HFmrEF) and reduced (HFrEF) EF. During a median follow-up of 4.1 years, the long-term mortality rate was 39.9%. In all patients, the multivariable-adjusted hazard ratio (HR) expressing the risk of long-term mortality associated with SUA was 1.18 (95% CI, 1.11-1.26; P < 0.001). Compared with the low tertile of the SUA distribution, the sex- and age-adjusted cumulative incidence of long-term mortality was higher in the top tertile. In patients with HFpEF and HFrEF, SUA predicted the risk of long-term mortality with HRs amounting to 1.12 (95% CI, 1.02-1.21; P = 0.012) and 1.28 (95% CI, 1.12-1.47; P < 0.001), respectively. However, there were no associations between the risk of mortality and SUA in HFmrEF. Furthermore, age, sex, NYHA class, and the prevalence of coronary heart disease interacted significantly with SUA for predicting long-term mortality. CONCLUSION: Higher levels of SUA at admission were associated with higher risk of long-term mortality in patients with different HF subtypes. The risk conferred by SUA was age and sex dependent. Our observations highlight that measuring SUA at admission may help to improve risk stratification.

Prognostic Implication of Admission Mean and Pulse Pressure in Acute Decompensated Heart Failure With Different Phenotypes.

BACKGROUND: It remains unknown whether admission mean (MAP) and pulse pressure (PP) pressure are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mid-range (HFmrEF), and reduced (HFrEF) ejection fraction. METHODS: In 2,706 acute decompensated heart failure (HF) patients, we assessed the risk of 30-day, 1-year, and long-term (>1 year) mortality with 1-SD increment in MAP and PP, using multivariable logistic and Cox regression, respectively. RESULTS: During a median follow-up of 4.1 years, 1,341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. A lower MAP was associated with a higher risk of 30-day mortality in women (P = 0.023) and a higher risk of 30-day and 1-year mortality in men (P ≤ 0.006), while higher PP predicted long-term mortality in men (P ≤ 0.014) with no relationship observed in women. In adjusted analyses additionally accounted for PP, 1-SD increment in MAP was associated with 30-day mortality in HFpEF (odds ratio [OR], 0.63; 95% CI, 0.43 to 0.92; P = 0.018), with 1-year mortality in HFmrEF (OR, 0.46; 95% CI, 0.32 to 0.66; P < 0.001) and HFrEF (OR, 0.54; 95% CI, 0.40 to 0.72; P < 0.001). In the adjusted model additionally accounted for MAP, 1-SD increment in PP was associated with long-term mortality in HFpEF (hazard ratio, 1.16; 95% CI, 1.05 to 1.28; P = 0.003). CONCLUSIONS: A lower MAP was associated with a higher risk of short-term mortality in all HF subtypes, while a higher PP predicted a higher risk of long-term mortality in men and in HFpEF. Our observations highlight the clinical importance of admission blood pressure for risk stratification in HF subtypes.

Clinical information from repeated blood pressure measurements in the management of heart failure with preserved ejection fraction.

It remains unclear whether cumulative blood pressure (BP) exposure is associated with adverse outcomes in heart failure with preserved ejection fraction (HFpEF). The aim was to investigate the associations of adverse health outcomes with cumulative BP exposure as captured by weighted BP, cumulative BP and trends in BP over a 1-year timespan from baseline to a 12-month visit among 1303 patients with HFpEF (49.5% women; mean age, 71.5 years) enrolled in the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. The primary endpoints consisted of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for the management of heart failure.We computed hazard ratios with a 1-SD increase in weighted BP and cumulative BP. In the spironolactone group, compared with patients with a downward trend in BP, those with an upward trend had higher event rates. However, there were no differences in event rates between those with upward and downward trends in BP in the placebo group. In multivariable-adjusted analyses that additionally accounted for baseline BP, weighted systolic BP and cumulative systolic BP predicted (P ≤ 0.037) the primary composite endpoint (hazard ratio [HR], 1.21; 95% CI, 1.05-1.39/1.15; 1.01-1.31) and hospitalization for HF (1.29; 1.09-1.52/1.18; 1.02-1.37), respectively. Among patients aged ≤72 years, cumulative systolic BP increased (P ≤ 0.016) the risk of the primary endpoint and hospitalization for HF. Higher cumulative systolic BP exposure conferred a higher risk of the primary endpoint and hospitalization for HF, independent of baseline BP. Our findings underscore that longitudinal BP measurements may refine risk stratification for patients with HFpEF.

Distinct implications of body mass index in different subgroups of nonobese patients with heart failure with preserved ejection fraction: a latent class analysis of data from the TOPCAT trial.

BACKGROUND: Obesity is a well-defined risk factor for heart failure with preserved ejection fraction (HFpEF), but it is associated with a better prognosis in patients with diagnosed HFpEF. The paradoxically poor prognosis in nonobese patients with HFpEF may be driven by a subset of high-risk patients, which suggests that the nonobese HFpEF subpopulation is heterogeneous. METHODS: Latent class analysis (LCA) was adopted to identify the potential subgroups of 623 nonobese patients enrolled in the TOPCAT trial. The baseline characteristics of the identified nonobese subgroups were compared with each other and with the obese patients. The risks of all-cause, cardiovascular, and noncardiovascular mortality, and an HF composite outcome were also compared. RESULTS: Two subgroups of nonobese patients with HFpEF (the physiological non-obesity and the pathological non-obesity) were identified. The obese patients were younger than both nonobese subgroups. The clinical profile of patients with pathological non-obesity was poorer than that of patients with physiological non-obesity. They had more comorbidities, more severe HF, poorer quality of life, and lower levels of physical activity. Patients with pathological non-obesity showed low serum hemoglobin and albumin levels. After 2 years of follow-up, more patients in the pathological group lost ≥ 10% of body weight compared with those in the physiological group (11.34% vs. 4.19%, P = 0.009). The prognostic implications of the two subgroups were opposite. Compared to patients with obesity, patients with physiological non-obesity had a 47% decrease in the risk of HF composite outcome (hazard ratio [HR] 0.53, 95% confidence interval [CI] 0.40-0.70, P<0.001) and a trend of decreased all-cause mortality risk (HR 0.75, 95% CI 0.55-1.01, P=0.06), while patients with pathological non-obesity had a 59% increase (HR 1.59, 95% CI 1.24-2.02, P<0.001) in all-cause mortality risk. CONCLUSIONS: Two subgroups of nonobese patients with HFpEF with distinct clinical profiles and prognostic implications were identified. The low BMI was likely physiological in one group but pathological in the other group. Using a data-driven approach, our study provided an alternative explanation for the "obesity paradox" that the poor prognosis of nonobese patients with HFpEF was driven by a pathological subgroup.

Associations of short- and long-term mortality with admission blood pressure in Chinese patients with different heart failure subtypes.

It remains unknown whether systolic (SBP) and diastolic (DBP) pressure on admission are associated with short- and long-term mortality in Chinese patients with heart failure with preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. In 2706 HF patients (39.1% women; mean age, 68.8 years), we assessed the risk of 30-day, 1-year, and long-term (> 1 year) mortality with 1-SD increment in SBP and DBP, using multivariable logistic and Cox regression, respectively. During a median follow-up of 4.1 years, 1341 patients died. The 30-day, 1-year, and long-term mortality were 3.5%, 16.7%, and 39.4%, respectively. In multivariable-adjusted analyses additionally accounted for DBP or SBP, a higher SBP conferred a higher risk of long-term mortality (hazard ratio, 1.11; 95% CI, 1.02-1.22; p = .017) and a lower DBP was associated with a higher risk of all types of mortality (p ≤ .011) in all HF patients. Independent of potential confounders including DBP or SBP, in patients with HFpEF, higher SBP and lower DBP levels predicted a higher risk of long-term mortality with hazard ratios amounting to 1.16 (95% CI, 1.04-1.29; p = .007) and .89 (95% CI, .80-.99; p = .028), respectively. In patients with HFmrEF and HFrEF, irrespective of adjustments of potential confounders, DBP was associated with 1-year mortality with odds ratios ranging from .49 to .62 (p ≤ .006). In conclusion, lower DBP and higher SBP levels on admission were associated with a higher risk of different types of all-cause mortality in Chinese patients with different HF subtypes. Our observations highlight that admission BP may help to improve risk stratification.

Worsening of Renal Function Among Hospitalized Patients With Acute Heart Failure: Phenotyping, Outcomes, and Predictors.

OBJECTIVE: To define clinical phenotyping and its associated outcome of worsening of renal function (WRF) in hospitalized acute heart failure (AHF) patients. PATIENTS AND METHODS: Latent class analysis was performed in 113 AHF patients who developed WRF within 72 hours in the DOSE (Diuretic Optimization Strategies Evaluation) trial (from March 2008 to November 2009) and ROSE-AHF (Renal Optimization Strategies Evaluation in Acute Heart Failure) trial (from September 2010 to March 2013) to identify potential WRF phenotypes. Clinical characteristics and outcome (in-hospital and post-discharge) were compared between different phenotypes. RESULTS: Two WRF phenotypes were identified by latent class analysis, which we named WRF minimally responsive to diuretics (WRF-MRD) and WRF responsive to diuretics (WRF-RD). Among the population, 58 (9.5%) developed WRF-MRD and 55 (9.0%) developed WRF-RD. Patients with WRF-MRD had more comorbidities than WRF-RD. In WRF-MRD, there were an early increase in serum creatinine, a smaller amount of net fluid loss and weight loss, and a higher rate of worsening or persistent heart failure over 72 hours. In contrast, for those with WRF-RD, they had faster in-hospital net fluid loss and weight loss and a better 60-day survival after discharge even compared with patients without WRF (P=.004). Furthermore, baseline chronic obstructive pulmonary disease, diabetes, and cystatin C were independent predictors of WRF-MRD, whereas serum hemoglobin and sodium predicted WRF-RD. CONCLUSIONS: Among hospitalized AHF patients, we identified two phenotypes of WRF with distinct response to heart failure treatment, predictors, and short-term prognosis after discharge. The results could help early differentiation of WRF phenotypes in clinical practice.

Non-vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation patients with heart failure and preserved, mildly reduced, and reduced ejection fraction: A systemic review and meta-analysis.

Background: Patient prevalence of atrial fibrillation (AF) and heart failure (HF) is increasing, and anticoagulation for patients from heterogeneous backgrounds with both conditions remains controversial. In this meta-analysis, we are aiming to compare the effectiveness and safety of the non-vitamin K antagonist oral anticoagulants (NOACs) and warfarin in AF patients with HF and preserved (HFpEF), mildly reduced (HFmrEF), and reduced (HFrEF) ejection fraction. Methods and results: We systematically searched the PubMed, Cochrane, and Embase databases until January 2022. The primary effectiveness and safety outcomes were stroke or systemic embolism (SSE) and major bleeding, respectively. We abstracted risk ratios (RR) and 95% confidence intervals (CIs) and compiled them using a random-effects model. We analyzed data of 266,291 patients from 10 studies. By comparing NOACs with warfarin, patients with AF and HF have reduced the risk of SSE (RR: 0.83, 95% CI 0.76-0.91), all-cause mortality (RR: 0.85, 95% CI 0.80-0.91), major bleeding (RR: 0.79, 95% CI 0.69-0.90), and intracranial hemorrhage (RR: 0.54, 95% CI 0.46-0.63). Further analyses based on the HF subtypes showed that NOACs reduced the chances of SSE (RR: 0.71, 95% CI 0.53-0.94) in the HFrEF group and major bleeding (RR: 0.74, 95% CI 0.57-0.95) in HFmrEF and HFpEF groups. There were no differences regarding SSE (RR: 0.91, 95% CI 0.76-1.09) in HFmrEF and HFpEF groups and major bleeding (RR: 0.99, 95% CI 0.79-1.23) in the HFrEF group. Conclusion: For patients with AF and HF, NOACs have better or similar effectiveness and safety than warfarin, but the stroke prevention superiority of NOACs over warfarin varies in different HF subtypes.

Efficacy of ablation index-guided pulmonary vein isolation in patients with paroxysmal atrial fibrillation.

BACKGROUND: Ablation index (AI) is a novel technology of ablation lesion quality to help improve homogeneity of lesion size and continuity. In this study, we aim to evaluate whether AI-guided PVI improves clinical outcomes compared to CF-guided PVI in patients with paroxysmal AF (PAF). METHODS: Patients undergoing first-time radiofrequency ablation for PAF were randomized in a 2:1 ratio to two groups: AI-guided PVI and CF-guided PVI. In the AI group, AI ≥500 was recommended at the anterior/superior/inferior walls, 350-400 at the posterior wall, and inter-lesion distance ≤4 mm. The primary endpoint is the freedom from atrial arrhythmia recurrence during 12 months follow-up, without antiarrhythmic drug therapy (ADT). The key secondary endpoints include intra-procedural efficiency and peri-procedural complications. RESULTS: Two hundred twenty five patients were randomized (AI group [n = 149] and CF group [n = 76]). First-pass isolation rate in AI group was significantly higher than that in CF group (58.3% vs. 43.4%, p = .035). After a median follow-up of 12.2 months, 154/225 (68.4%) of patients were free from atrial arrhythmia recurrence without ADT, which was higher in AI group compared with CF group, but without significant difference (71.1% vs. 63.2%, p = .253). The incidence of peri-procedural complications is low and without difference between two groups. CONCLUSIONS: AI-guided ablation provided higher acute efficacy than CF-guided ablation in PV isolation for patients with paroxysmal AF. The long-term success rate in AI group was higher than CF group, but did not reach statistical significance.

Phenotypes of heart failure with preserved ejection fraction and effect of spironolactone treatment.

AIMS: The aims of this study were to explore phenotypes of heart failure with preserved ejection fraction (HFpEF) and evaluate differential effects of spironolactone treatment. METHODS AND RESULTS: A swap-stepwise algorithm was used for variable selection. Latent class analysis based on 10 selected variables was employed in a derivative set of 1540 patients from the TOPCAT trial. Cox proportional hazard models were used to evaluate the prognoses and effects of spironolactone treatment. Three phenotypes of HFpEF were identified. Phenotype 1 was the youngest with low burden of co-morbidities. Phenotype 2 was the oldest with high prevalence of atrial fibrillation, pacemaker implantation, and hypothyroidism. Phenotype 3 was mostly obese and diabetic with high burden of other co-morbidities. Compared with phenotype 1, phenotypes 2 (hazard ratio [HR]: 1.46; 95% confidence interval [CI]: 1.14-1.89; P = 0.003) and 3 (HR: 2.35; 95% CI: 1.80-3.07; P < 0.001) were associated with higher risks of the primary composite outcome. Spironolactone treatment was associated with a reduced risk of the primary outcome only in phenotype 1 (HR: 0.63; 95% CI: 0.40-0.98; P = 0.042). CONCLUSIONS: Three distinct HFpEF phenotypes were identified. Spironolactone treatment could improve clinical outcome in a phenotype of relatively young patients with low burden of co-morbidities.

PRMT4 promotes ferroptosis to aggravate doxorubicin-induced cardiomyopathy via inhibition of the Nrf2/GPX4 pathway.

Doxorubicin (DOX), a commonly used antitumor agent, is often accompanied by its dosage-dependent cardiotoxicity, which incorporates ferroptosis in its pathogenesis. Protein arginine methyltransferase 4 (PRMT4) is a transcription regulator involved in the modulation of oxidative stress and autophagy, but its role in DOX-induced cardiomyopathy (DIC) and ferroptosis remains elusive. Herein, we aimed to investigate the involvement and the underlying mechanisms of PRMT4 in the pathogenesis of DIC. Our present study revealed that the expression level of PRMT4 was markedly decreased in DOX-treated cardiomyocytes. Interestingly, it is noted that PRMT4 overexpression accelerated ferroptosis to aggravate DIC, while its gene disruption or pharmaceutical inhibition exhibited the opposite effect. Mechanistically, our observation demonstrated that PRMT4 interacted with the nuclear factor erythroid 2-related factor 2 (Nrf2) to promote its enzymatic methylation, which restricted the nuclear translocation of Nrf2 and subsequently suppressed the transcription of glutathione peroxidase 4 (GPX4). Importantly, the detrimental role of PRMT4 in DOX-induced cardiomyocyte ferroptosis was abolished by Nrf2 activation or Fer-1 administration. Collectively, our data reveal that PRMT4 inhibits Nrf2/GPX4 signaling to accelerate ferroptosis in DIC, suggesting that targeting PRMT4 may present as a potential preventive strategy against the development of DIC.

Ischemic risk in patients with heart failure with preserved ejection fraction: A post hoc analysis of the TOPCAT data.

BACKGROUND AND AIMS: Heart failure with preserved ejection fraction (HFpEF) patients have a high burden of comorbidities that could predispose them to ischemic vascular event. The profile of ischemic risk among HFpEF patients is not fully understood. We aim to evaluate the risk, risk factors, and prognostic significance of ischemic events among HFpEF patients. METHODS: A total of 1767 HFpEF patients from Americas in the TOPCAT trial were included in our analysis. Ischemic event was defined as myocardial infarction or ischemic stroke during follow-up. Multivariate competing risks regression model was used to identify risk factors of ischemic event. Time-dependent Cox models were constructed to evaluate the association of incident ischemic event and mortality risk. RESULTS: During a median follow-up period of 2.9 years, 164 (9.3%) patients had at least 1 ischemic event. The crude incidence rate was 3.3% per year. Body mass index, prior myocardial infarction, insulin use, peripheral artery disease, hypertension, and current smoking were independent risk factors of ischemic event in HFpEF patients. HF hospitalization turned out to be an important trigger of ischemic event. Risk of ischemic event increased 4.7-fold (hazard ratio 4.70, 95% confidence interval: 2.23-9.89, p < 0.001) within the first month after the first HF hospitalization, and dropped rapidly thereafter. Incident ischemic event was associated with significant higher short-term risks of all-cause mortality and cardiovascular mortality. CONCLUSIONS: HFpEF patients from Americas were at a high risk of ischemic events, which was associated with mortality risk. A subset of baseline characteristics and HF hospitalization during follow-up could predict ischemic event.

Clinical Significance of Mean and Pulse Pressure in Patients With Heart Failure With Preserved Ejection Fraction.

It remains debated whether pulse pressure is associated with left ventricular traits and adverse outcomes over and beyond mean arterial pressure (MAP) in patients with heart failure (HF) with preserved ejection fraction. We investigated these associations in 3428 patients with HF with preserved ejection fraction (51.5% women; mean age, 68.6 years) enrolled in the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). We computed association sizes and hazards ratios with 1-SD increase in MAP and pulse pressure. In multivariable-adjusted analyses, association sizes (P≤0.039) for MAP were 0.016 cm and 0.014 cm for septal and posterior wall thickness, -0.15 for E/A ratio, -0.66 for E/e', and -0.64% for ejection fraction, independent of pulse pressure. With adjustment additionally applied for MAP, E/A ratio and longitudinal strain increased with higher pulse pressure with association sizes amounting to 0.067 (P=0.026) and 0.40% (P=0.023). In multivariable-adjusted analyses of both placebo and spironolactone groups, lower MAP and higher pulse pressure predicted the primary composite end point (P≤0.028) and hospitalized HF (P≤0.002), whereas MAP was also significantly associated with total mortality (P≤0.007). Sensitivity analyses stratified by sex, median age, and region generated confirmatory results with exception for the association of adverse outcomes with pulse pressure in patients with age ≥69 years. In conclusion, the clinical application of MAP and pulse pressure may refine risk estimates in patients with HF with preserved ejection fraction. This finding may help further investigation for the development of HF with preserved ejection fraction preventive strategies targeting pulsatility and blood pressure control.

An electrographic AV optimization for the maximum integrative atrioventricular and ventricular resynchronization in CRT.

BACKGROUND: Atrioventricular (AV) delay could affect AV and ventricular synchrony in cardiac resynchronization therapy (CRT). Strategies to optimize AV delay according to optimal AV synchrony (AVopt-AV) or ventricular synchrony (AVopt-V) would potentially be discordant. This study aimed to explore a new AV delay optimization algorithm guided by electrograms to obtain the maximum integrative effects of AV and ventricular resynchronization (opt-AV). METHODS: Forty-nine patients with CRT were enrolled. AVopt-AV was measured through the Ritter method. AVopt-V was obtained by yielding the narrowest QRS. The opt-AV was considered to be AVopt-AV or AVopt-V when their difference was < 20 ms, and to be the AV delay with the maximal aortic velocity-time integral between AVopt-AV and AVopt-V when their difference was > 20 ms. RESULTS: The results showed that sensing/pacing AVopt-AV (SAVopt-AV/PAVopt-AV) were correlated with atrial activation time (Pend-As/Pend-Ap) (P < 0.05). Sensing/pacing AVopt-V (SAVopt-V/PAVopt-V) was correlated with the intrinsic AV conduction time (As-Vs/Ap-Vs) (P < 0.01). The percentages of patients with more than 20 ms differences between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were 62.9% and 57.1%, respectively. Among them, opt-AV was linearly correlated with SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The sensing opt-AV (opt-SAV) = 0.1 × SAVopt-AV + 0.4 × SAVopt-V + 70 ms (R2 = 0.665, P < 0.01) and the pacing opt-AV (opt-PAV) = 0.25 × PAVopt-AV + 0.5 × PAVopt-V + 30 ms (R2 = 0.560, P < 0.01). CONCLUSION: The SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V were correlated with the atrial activation time and the intrinsic AV conduction interval respectively. Almost half of the patients had a > 20 ms difference between SAVopt-AV/PAVopt-AV and SAVopt-V/PAVopt-V. The opt-AV could be estimated based on electrogram parameters.

Effect of aggressive diuresis in acute heart failure with reduced and preserved ejection fraction.

AIMS: Heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) had distinct haemodynamic characteristics in the setting of acute heart failure. The aim of our study is to evaluate the differential response to aggressive diuresis in HFrEF and HFpEF. METHODS AND RESULTS: Patients in the Diuretic Optimization Strategies Evaluation trial with left ventricular ejection fraction measurement were included (n = 300) and classified into HFrEF [left ventricular ejection fraction (LVEF) < 40%] (n = 193) and HFpEF (LVEF ≥ 40%) (n = 107). Effect of high-dose vs. low-dose furosemide strategy was compared separately in HFrEF and HFpEF. In HFrEF, high-dose strategy did not increase change in creatinine or cystatin C at 72 h [treatment difference: -0.05, 95% confidence interval (CI): -0.14 to 0.03 mg/dL; P = 0.23 for creatinine, and treatment difference: -0.06, 95% CI: -0.15 to 0.02 mg/dL; P = 0.15 for cystatin C] compared with low-dose strategy, but there were significantly more net fluid loss, weight loss, and congestion-free patients at 72 h in high-dose group. It was also associated with a significantly lower risk of composite clinical outcome of death, total hospitalizations, and unscheduled visits due to heart failure. In HFpEF, high-dose strategy significantly increased change in creatinine and cystatin C at 72 h (treatment difference: 0.16; 95% CI: 0.02-0.30 mg/dL; P = 0.03 for creatinine, and treatment difference: 0.26; 95% CI: 0.09-0.43 mg/dL; P = 0.003 for cystatin C), but did not significantly affect net fluid loss, weight loss, proportion of congestion-free patients at 72 h, and risk of the composite clinical outcome. CONCLUSIONS: Acute heart failure on the basis of HFrEF and HFpEF responded differently to aggressive diuresis. Future trials should be designed separately for HFrEF and HFpEF.

Living Alone and Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

OBJECTIVE: In patients with heart failure with preserved ejection fraction (HFpEF), whether living alone could contribute to a poor prognosis remains unknown. We sought to investigate the association of living alone with clinical outcomes in patients with HFpEF. METHODS: Symptomatic patients with HFpEF with a follow-up of 3.3 years (data collected from August 2006 to June 2013) in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial were classified as patients living alone and those living with others. The primary outcome was defined as a composite of cardiovascular death, aborted cardiac arrest, or HF hospitalization. RESULTS: A total of 3103 patients with HFpEF were included; 25.2% of them were living alone and were older, predominantly female, and less likely to be White and have more comorbidities compared with the other patients. After multivariate adjustment for confounders, living alone was associated with increased risks of HF hospitalization (hazard ratio [HR] = 1.29, 95% confidence interval [CI] = 1.03-1.61) and any hospitalization (HR = 1.26, 95% CI = 1.12-1.42). A significantly increased risk of any hospitalization (HR = 1.16, 95% CI = 1.01-1.34) was also observed in the Americas-based sample. In addition, each year increase in age, female sex, non-White race, New York Heart Association functional classes III and IV, dyslipidemia, and chronic obstructive pulmonary disease were independently associated with living alone. CONCLUSIONS: We assessed the effect of living arrangement status on clinical outcomes in patients with HFpEF and suggested that living alone was associated with an independent increase in any hospitalization.Clinical Trial Registration: ClinicalTrials.gov identifier: NCT00094302.

Visit-to-Visit Blood Pressure Variability and Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

[Figure: see text].

Comparative Effectiveness and Safety of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation Patients.

BACKGROUND AND PURPOSE: Several observational studies have compared the effect of the non-vitamin K antagonist oral anticoagulants to each other in patients with atrial fibrillation. However, confounding by indication is a major problem when comparing non-vitamin K antagonist oral anticoagulant treatments in some of these studies. This meta-analysis was conducted to compare the effectiveness and safety between non-vitamin K antagonist oral anticoagulant and non-vitamin K antagonist oral anticoagulant by only including the propensity score matching studies. METHODS: We systematically searched the PubMed and Ovid databases until May 2020 to identify relevant observational studies. Hazard ratios (HRs) and 95% CIs of the reported outcomes were collected and then pooled by a random-effects model complemented with an inverse variance heterogeneity or quality effects model. RESULTS: A total of 17 retrospective cohort studies were included in this meta-analysis. Compared with dabigatran use, the use of rivaroxaban was significantly associated with increased risks of stroke or systemic embolism (HR, 1.16 [95% CI, 1.05-1.29]) and major bleeding (HR, 1.32 [95% CI, 1.24-1.41]), whereas the use of apixaban was associated with a reduced risk of major bleeding (HR, 0.78 [95% CI, 0.67-0.90]) but not stroke or systemic embolism (HR, 0.84 [95% CI, 0.56-1.28]). Compared with rivaroxaban use, the use of apixaban was associated with a decreased risk of major bleeding (HR, 0.63 [95% CI, 0.54-0.73]) but not stroke or systemic embolism (HR, 0.83 [95% CI, 0.67-1.04]). Reanalyses with the inverse variance heterogeneity or quality effects model produced similar results as the random-effects model. CONCLUSIONS: Current observational comparisons with propensity score matching methods suggest that apixaban might be a better choice compared with dabigatran or rivaroxaban for stroke prevention in atrial fibrillation patients.

C2HEST score predicts clinical outcomes in heart failure with preserved ejection fraction: a secondary analysis of the TOPCAT trial.

BACKGROUND: The C2HEST score has been validated for predicting AF in the general population or post-stroke patients. We aimed to assess whether this risk score could predict incident AF and other clinical outcomes in heart failure with preserved ejection fraction (HFpEF) patients. METHODS: A total of 2202 HFpEF patients without baseline AF in the TOPCAT trial were stratified by baseline C2HEST score. Cox proportional hazard model and competing risk regression model was used to explore the relationship between C2HEST score and outcomes, including incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The discriminative ability of the C2HEST score for various outcomes was assessed by calculating the area under the curve (AUC). RESULTS: The incidence rates of incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization were 1.79, 0.70, 3.81, 2.42, 15.50, and 3.32 per 100 person-years, respectively. When the C2HEST score was analyzed as a continuous variable, increased C2HEST score was associated with increased risk of incident AF (HR 1.50, 95% CI 1.29-1.75), as well as increased risks of all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The AUC for the C2HEST score in predicting incident AF (0.694, 95% CI 0.640-0.748) was higher than all-cause death, cardiovascular death, any hospitalization, or HF hospitalization. CONCLUSIONS: The C2HEST score could predict the risk of incident AF as well as death and hospitalization with moderately good predictive abilities in patients with HFpEF. Its simplicity may allow the possibility of quick risk assessments in busy clinical settings.