Circulation: Heart Failure最新文献

Background: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease, presenting diverse clinical phenotypes and outcomes based on the underlying gene affected. The influence of sex on the gene-specific long-term prognosis of patients with genetic DCM remains unclear. This study aims to determine the effect of sex on the long-term prognosis per underlying genogroup.

Methods: A retrospective cohort study was conducted using data from 4 international referral centers. Baseline and longitudinal clinical data of patients with DCM, with a median follow-up of 6.7 years (interquartile range, 3.5-11.9 years), were collected. The study included men and women with DCM who had undergone genetic testing. Patients were categorized into 7 genotype groups: cytoskeletal/Z-disk, desmosomal, nuclear envelope, motor sarcomeric, TTN, other genetic, and genotype negative. The main outcomes measured were left ventricular reverse remodeling, mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias.

Results: Among 1716 patients, 1130 (66%) were men and 510 (30%) had a (likely) pathogenic variant. Ventricular remodeling was gene-dependent in women, with TTN patients exhibiting the highest rate (P=0.003) and desmosomal patients the lowest (P=0.04) compared with the genotype-negative group. After a median follow-up of 6.7 years, 334 men (29%) and 140 women (24%) reached the primary end point. Men with a (likely) pathogenic variant had the poorest prognosis, showing a higher rate of major adverse events (adjusted hazard ratio, 1.48 [95% CI, 1.12-1.95]; P=0.02) and malignant ventricular arrhythmias (adjusted hazard ratio, 1.83 [95% CI, 1.16-2.88]; P=0.009) compared with genotype-negative women. Prognosis varied by gene in men (log-rank P<0.0001) but not in women (log-rank P=0.1). The cytoskeletal/Z-disk, desmosomal, and nuclear envelope groups had the worst prognosis in men.

Conclusions: The genetic architecture and sex are critical predictors of left ventricular reverse remodeling and long-term prognosis in DCM. These factors should be integrated into individualized risk prediction models to enhance clinical outcomes in patients with DCM.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown beneficial effects in heart failure (HF) management, but data on their use in geriatric populations with high comorbidity remain limited. This observational study aimed to assess the real-world efficacy and safety of SGLT2i in elderly patients with HF.

Methods: This prospective multicenter study included 496 patients hospitalized for acute heart failure across 3 geriatric units. The mean age was 90 years, and the mean Charlson Comorbidity Index score was 8.2. Participants were divided into 2 groups: the SGLT2i group (n=260) receiving SGLT2i (empagliflozin or dapagliflozin) alongside standard HF treatment, and the Control group (n=236) receiving only standard HF treatment. The primary outcomes were all-cause mortality, HF rehospitalizations, and adverse events over 1 year.

Results: SGLT2i use was associated with lower risks of all-cause mortality (hazard ratio, 0.67 [95% CI, 0.46-0.98]; P=0.031), HF rehospitalization (hazard ratio, 0.64 [95% CI, 0.42-0.97]; P=0.037), and the composite outcome (hazard ratio, 0.60 [95% CI, 0.44-0.82]; P=0.001) at 1 year, after multivariable adjustment. No significant interaction was observed between left ventricular ejection fraction status and SGLT2i use (P for interaction=0.12). Although urinary and genital infections were more frequently reported in the SGLT2i group, treatment discontinuation remained low (2.7%).

Conclusions: In this elderly population with high comorbidity, SGLT2i therapy was associated with substantial reductions in mortality and HF rehospitalization, and showed good tolerability and an acceptable safety profile.

Background: Right ventricular functional adaptation to afterload is a major determinant of outcome in pulmonary arterial hypertension (PAH). We aimed to investigate if right ventricular-pulmonary artery (PA) coupling evaluated by the ratio of tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (sPAP) improves risk assessment scores for survival prediction.

Methods: A total of 677 consecutive patients with PAH (55% idiopathic) were prospectively enrolled with follow-up clinical, right heart catheterization, and echocardiographic evaluations within 12 months (interquartile range, 180-344 days) after initiation of targeted therapies in 11 Italian centers. European Society of Cardiology/European Respiratory Society guidelines-derived risk scores and REVEAL 2.0 (US Registry to Evaluate Early and Long-Term PAH Disease Management 2.0) risk scores were collected at baseline and follow-up. 254 consecutive patients with PAH retrospectively enrolled in a German reference center served as a validation cohort.

Results: A low-risk status at a median of 3.7 years (interquartile range, 1.2-6.8) follow-up was significantly associated with each unit (0.1 mm/mm Hg) increase in TAPSE/sPAP under targeted therapies (European Society of Cardiology/European Respiratory Society score: odds ratio, 1.78; P≤0.001; REVEAL 2.0 score: odds ratio, 1.43; P≤0.001). At follow-up, the TAPSE/sPAP ratio increased the prognostic information of each risk stratum of the European Society of Cardiology/European Respiratory Society risk score, except the highest risk stratum, with 0.5 mm/mm Hg, 0.35 mm/mm Hg, and 0.30 mm/mm Hg, from the lowest to the intermediate-high risk score, identified as the best cutoff value. TAPSE/sPAP ratio increased the prognostic information of the REVEAL 2.0 score at follow-up, with 0.35 mm/mm Hg identified as the best cutoff value to discriminate within a score of 5 to 8, with no added value for scores <5 and >8. These results were confirmed in the validation cohort.

Conclusions: Assessment of right ventricular-PA coupling by the TAPSE/sPAP ratio in PAH improves risk assessment scores except in the lowest or most advanced stage of the disease.

Background: Doxorubicin (DOX) cardiotoxicity increases cardiovascular risk in cancer patients, mainly through mitochondrial damage. However, the underlying mechanisms remain unclear, and whether mitochondrial short open reading frame-encoded peptides can mitigate DOX-induced cardiotoxicity is unknown.

Methods: Five adeno-associated viruses expressing mitochondrial short open reading frame-encoded peptides under the cardiac troponin T promoter, including MODICA (mito-SEP protector against DOX-induced cardiac injury), were screened in a DOX-induced cardiotoxicity mouse model (n=3-5 per group). Male and female mice were randomized to adeno-associated virus-CTRL or adeno-associated virus-MODICA, respectively, combined with saline or DOX treatment. Sample sizes were: males-saline-CTRL (n=4), saline-MODICA (n=4), DOX-CTRL (n=11), DOX-MODICA (n=10); females-saline-CTRL (n=8), saline-MODICA (n=10), DOX-CTRL (n=10), DOX-MODICA (n=13). MODICA-heterozygous mice generated by CRISPR/Cas9 were also included: saline-WT (n=7), saline-heterozygous (n=4), DOX-WT (n=11), DOX-heterozygous (n=8). Echocardiography was performed at baseline and after 2 weeks of DOX treatment; myocardial tissue and serum samples were collected for molecular and histological analyses.

Results: The mitochondrial short open reading frame-encoded peptide MODICA was identified through biochemical analysis and functional screening in a DOX-induced cardiac injury model. MODICA localizes to the outer mitochondrial membrane and is significantly downregulated by DOX (1.00±0.08 versus 0.42±0.09; P<0.001). Cardiac-specific overexpression of MODICA via adeno-associated viruses significantly attenuated DOX-induced cardiac injury in both males and females (fractional shortening: males 38.86% versus 51.54%, P<0.001; females 39.81% versus 51.39%, P<0.001, DOX-CTRL versus DOX-MODICA) and was supported by bulk RNA-seq analysis. Conversely, MODICA deficiency exacerbated DOX-induced injury, resulting in reduced fractional shortening (40.37% versus 31.85%, P<0.001; DOX-WT versus DOX-heterozygous) and increased cardiac fibrosis (P=0.009). Proteomic analyses revealed that MODICA interacts with apoptosis-related voltage-dependent anion channel proteins, inhibiting their DOX-induced oligomerization (P<0.001) on the outer mitochondrial membrane, thereby reducing mitochondrial permeability, decreasing cardiomyocyte apoptosis and improving calcium handling.

Conclusions: Our study shows that the mitochondrial short open reading frame-encoded peptide MODICA alleviates DOX-induced cardiac dysfunction and may represent a therapeutic target against DOX cardiotoxicity.

Background: Influenza contributes substantially to disease burden in individuals with heart failure (HF) and is an established trigger of cardiovascular and HF events. Standard-dose inactivated influenza vaccine (SD-IIV) is recommended for HF, though immune responses may be attenuated. High-dose inactivated influenza vaccine (HD-IIV) was developed to enhance immunogenicity, but its effectiveness compared with SD-IIV against hospitalization for influenza and cardiovascular disease by HF status remains uncertain.

Methods: This was a prespecified analysis of a pragmatic, prospective, individually randomized, open-label trial with registry-based end point-evaluation conducted in Denmark across the 2022/2023 to 2024/2025 influenza seasons. Citizens ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Outcomes included hospitalization for influenza-related illness, laboratory-confirmed influenza, any cardiovascular disease, cardio-respiratory disease, and HF, assessed by HF status. Effect of HD-IIV versus SD-IIV in reducing risk of outcomes assessed was expressed as risk ratios.

Results: The trial randomized 332 438 participants (48.6% female; mean age, 73.7±5.8 years), including 10 410 with HF at baseline (27.4% female; mean age, 76.0±6.3 years). Overall, HD-IIV was associated with a statistically significant lower incidence of hospitalization for influenza-related illness, laboratory-confirmed influenza, cardio-respiratory disease, cardiovascular disease, and HF compared with SD-IIV. In participants with HF, effect estimates were similar: risk ratio for influenza-related hospitalization was 0.48 (95% CI, 0.20-1.06; P_interaction=0.64), for laboratory-confirmed influenza hospitalization 0.55 (95% CI, 0.29-1.02; P_interaction=0.59), for cardio-respiratory hospitalization 0.89 (95% CI, 0.77-1.02; P_interaction=0.34), for cardiovascular hospitalization 0.86 (95% CI, 0.72-1.02; P_interaction=0.34), and for HF hospitalization 0.82 (95% CI, 0.61-1.11; P_interaction=0.83). Findings were consistent across HF subgroups by disease duration, recency of hospitalization, most recent NT-proBNP (N-terminal pro-B-type natriuretic peptide), and presence of device therapy.

Conclusions: In this prespecified exploratory analysis of the largest individually randomized influenza vaccine trial ever conducted, HD-IIV was associated with lower rates of influenza and cardiovascular hospitalizations compared with SD-IIV, with effect estimates similar across HF status at baseline and HF subgroups.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: https://clinicaltrials.gov/study/NCT05517174.

Background: There are currently no robust clinical markers for assessing prognosis in patients with heart failure (HF) with recovered left ventricular ejection fraction (LVEF). This study sought to investigate whether NT-proBNP (N-terminal pro-B-type natriuretic peptide) measured at the time of LVEF recovery is an independent predictor of prognosis among patients with HF with recovered LVEF.

Methods: This retrospective cohort study (2009-2024) included 3935 patients with HF with recovered LVEF (previous LVEF of ≤40% with subsequent improvement to ≥50%) and available NT-proBNP data at the time of LVEF recovery. Patients were categorized into 7 different NT-proBNP groups, which were compared using Kaplan-Meier analysis and multivariable Cox regression to evaluate the outcome of LVEF relapse (decrease in LVEF by ≥10% to <50%) and the composite outcome of HF hospitalization or all-cause death.

Results: The median value of NT-proBNP at the time of LVEF recovery was 1341 pg/mL (interquartile range, 400-4207). The probability of remaining free from LVEF relapse and the composite outcome decreased across NT-proBNP groups. After multivariable adjustment, NT-proBNP was an independent predictor of both LVEF relapse and the composite outcome, with higher NT-proBNP levels associated with higher risk of both outcomes in a dose-response manner. Even near-normal NT-proBNP levels (125-299 pg/mL) were associated with poorer prognosis relative to normal levels (<125 pg/mL), with a 46% higher risk of LVEF relapse and 82% higher risk of the composite outcome. This relationship was consistent and similar across age, sex, atrial fibrillation status, and renal function, but was modified by body mass index, with higher body mass index associated with higher risk. Notably, NT-proBNP was predictive of the composite outcome even when patients sustained LVEF recovery without experiencing LVEF relapse.

Conclusions: NT-proBNP is an independent and robust predictor of prognosis in patients with HF with recovered LVEF and may therefore be used to guide further optimization of pharmacotherapy.