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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.

Purpose The posterior wall of left atrium plays an important role in atrial fibrillation (AF) recurrence, but the benefit of left atrial posterior wall isolation (PWI) remains still unclear. The objective was to evaluate the benefit of PWI in radiofrequency ablation. Methods PubMed and the Web of Science were searched in September 2015. Studies comparing catheter ablation with PWI [PWI(+)] vs. ablation without PWI [PWI(−)] were included. We performed a meta-analysis to assess atrial arrhythmia recurrence, procedure-related complications, and procedural time. Results Five studies with 594 AF patients were included. Compared with PWI(−), PWI(+) resulted in a significantly lower atrial arrhythmia recurrence rate (relative risk [RR] 0.81, 95 % confidence interval [CI] 0.68–0.97, p  = 0.02), which was largely driven by the decreased AF recurrence (RR 0.55, 95 % CI 0.35–0.86, p  = 0.009). Recurrence rates of atrial tachycardia/flutter (AT/AFL) were comparable between two groups (RR 1.16, 95 % CI 0.85–1.58, p  = 0.34). There were no significant differences in procedure-related complications (RR 1.07, 95 % CI 0.45–2.53, p  = 0.89) and procedural times (weight mean difference 0.88, 95 % CI −7.29–9.06, p  = 0.83). Conclusions This meta-analysis shows that with comparable procedure-related complications and procedural time, ablation with PWI reduces AF recurrence.

Background The association between urbanization and myocardial infarction in China was not fully understood. We aim to evaluate the association between urbanization level and the risk of myocardial infarction. Methods Participants’ data from China Health and Nutrition Survey were analyzed. The survey is an ongoing open cohort with a multistage, random cluster process to draw a sample of over 30,000 individuals in 15 provinces and municipal cities. A multi-component score, urbanization index, was used to measure urbanization level. Urbanization index was categorized by cut-off values of 40, 60, and 80. Baseline characteristics were presented as percentage for categorical variables, and mean or median for continuous variables depending on normality. The association of urbanization index and myocardial infarction risk was evaluated longitudinally by a multilevel mixed-effects parametric survival model with urbanization index as a time-dependent variable using Stata software. Results A total of 16,565 participants without previous myocardial infarction were involved in the cohort. At baseline, urbanization index was positively correlated with myocardial infarction risk factors, including blood pressure, body mass index, diabetes, and stroke. In the univariate model, urbanization index was associated with risk of myocardial infarction in a “U-shape” manner, with the lowest myocardial infarction risk in urbanization index ranging from 40 to 60 (Hazard Ratio 0.55 and p =  0.013). However, in the multivariate model adjusting for myocardial infarction risk factors and other confounders, urbanization index ≥ 40 was consistently associated with lower MI risks (Hazard Ratio 0.46 and p =  0.002 for urbanization index 40–60; Hazard Ratio 0.56 and p =  0.021 for urbanization index 60–80; and Hazard Ratio 0.44 and p =  0.002 for urbanization index ≥ 80). Conclusions Our study indicated that urbanization of living communities was associated with a reduced risk of myocardial infarction.

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 noncoding 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 was induced in the heart upon pathological cardiac hypertrophy and that its deletion in mice exacerbated stress-induced cardiac hypertrophy and augmented protein translation. In contrast, overexpression of CARDINAL attenuated cardiac hypertrophy in vivo and in vitro and suppressed hypertrophy-induced protein translation. Mechanistically, CARDINAL interacted with developmentally regulated GTP-binding protein 1 (DRG1) and blocked its interaction with DRG family regulatory protein 1 (DFRP1); as a result, DRG1 was 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.

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.

Heart failure is the terminal outcome of the majority of cardiovascular diseases, which lacks specific diagnostic biomarkers and therapeutic targets. It contributes to most of cardiovascular hospitalizations and death despite of the current therapy. Therefore, it is important to explore potential molecules improving the diagnosis and treatment of heart failure. MicroRNAs (miRNAs) are small non-coding RNAs that have been reported to be involved in regulating processes of heart failure. After the discovery of miRNAs in exosomes, the subcellular distribution analysis of miRNAs is raising researchers' attention. Growing evidence demonstrates that exosomal miRNAs may be promising diagnostic and therapeutic molecules for heart failure. This review summarizes the role of exosomal miRNAs in heart failure in the prospect of molecular and clinical researches.

Deficiency of the myocardial microcirculation plays a role in the pathogenesis of heart failure (HF). We aimed to investigate the association of myocardial blood flow (MBF) and the retinal microvasculature with left ventricular (LV) function and its potential mediators. In healthy controls (HCs; n = 48), patients with cardiovascular risk factors (CVRF; n = 49) and patients with compensated HF (CHF; n = 52), we assessed LV diastolic filling pressure (E/e′), LV ejection fraction (LVEF), and global longitudinal strain (GLS) associated with MBF and the retinal arteriole‐to‐venule ratio (AVR), using multivariable regression models, while considering their direct contributions to LV function and the indirect contributions running via NT‐proBNP. Compared with HC, CHF had lower MBF and smaller AVR (p ≤ 0.002). In all participants, smaller AVR was associated with higher E/e′, lower LVEF, and lower GLS (p ≤ 0.010). Per 1 dB × dB/s MBF reduction, E/e′ increased by 0.09, whereas LVEF and GLS decreased by 0.46% and 0.14%, respectively (p < 0.001). The indirect contributions running via NT‐proBNP were all significant (p < 0.001) for MBF and for AVR related to GLS (p = 0.044) with mediation proportions of ≥29%. Across subgroups, these associations were directionally similar but lost significance given the lower sample size. Furthermore, across the spectrum of LV function, estimates of the associations of MBF with E/e′ and AVR with GLS showed a decreasing versus increasing trend (p ≤ 0.034). MBF and retinal microvasculature were associated with LV function and counterbalance the impaired LV function in CHF. NT‐proBNP, the natural vasodilating and natriuretic hormone, contributes close to 30% of the maintenance of LV function.

Background The C 2 HEST 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 C 2 HEST score. Cox proportional hazard model and competing risk regression model was used to explore the relationship between C 2 HEST score and outcomes, including incident AF, stroke, all-cause death, cardiovascular death, any hospitalization, and HF hospitalization. The discriminative ability of the C 2 HEST 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 C 2 HEST score was analyzed as a continuous variable, increased C 2 HEST 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 C 2 HEST 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 C 2 HEST 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.

Background Secondhand smoke (SHS) exposure is a well-established cardiovascular risk factor, yet association between SHS and prognosis of heart failure remains uncertain. Method Data were obtained from the US National Health and Nutrition Examination Surveys III from 1988 to 1994. Currently nonsmoking adults with a self-reported history of heart failure were included. Household SHS exposure was assessed by questionnaire. Participants were followed up through December 31, 2011. Cox proportional-hazards models were used to assess the association of household SHS exposure and mortality risk. Potential confounding factors were adjusted. Results Of 572 currently nonsmoking patients with heart failure, 88 were exposed to household SHS while 484 were not. There were totally 475 deaths during follow-up. In univariate analysis, household SHS was not associated with mortality risk (hazard ratio [HR]: 0.98, 95% confidence interval [CI]: 0.76–1.26, p  = 0.864). However, after adjustment for demographic variables, socioeconomic variables and medication, heart failure patients in exposed group had a 43% increase of mortality risk compared with those in unexposed group (HR: 1.43, 95% CI: 1.10–1.86, p  = 0.007). Analysis with further adjustment for general health status and comorbidities yielded similar result (HR: 1.47, 95% CI: 1.13–1.92, p  = 0.005). Conclusion Household SHS exposure was associated with increased mortality risk in heart failure patients.

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.