Circulation: Heart Failure最新文献

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.

Recent findings emphasize the potential role of invasive hemodynamic assessment in guiding transcatheter mitral and tricuspid valve percutaneous interventions. Right heart catheterization-derived parameters offer insights into hemodynamic changes associated with valvular heart diseases, pulmonary hypertension phenotyping, and right ventricular to pulmonary artery coupling. This might improve prognostic stratification for candidates to transcatheter therapies. This review provides a clinical overview of available data regarding the utility of preoperative right heart catheterization-derived parameters in patients undergoing mitral and tricuspid percutaneous repair or replacement.

Background: The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines introduced elevated natriuretic peptide (NP) levels as a criterion for defining stage B heart failure (HF), or pre-HF, to identify individuals at greatest risk for future HF. Given the known NP deficiency in obesity, we aimed to assess whether a single NP cut point would disproportionately up-classify individuals with versus without obesity to stage B HF.

Methods: Participants free of HF from 5 community-based cohorts were included. We examined the reclassification of individuals to stage B HF using the 2022 versus 2013 guidelines, stratified by obesity class. Cox proportional hazards models were used to assess the association of NPs with incident HF across obesity classes.

Results: Among 32 735 participants, 35% had normal weight, 40% were overweight, 17% had obesity class 1, and 8% had obesity class 2/3. When applying the 2022 versus 2013 criteria, the proportion of individuals up-classified to stage B HF using the NP criterion was 62% among those with normal weight, 51% for those overweight, 47% for individuals with obesity class 1, and 42% for individuals with obesity class 2/3. Over a median follow-up of 13 years, 3077 HF events occurred. Both higher NP and body mass index were associated with greater HF risk, as expected (P<0.0001 for both). Importantly, body mass index modified the association of NP with HF risk, such that higher NP concentration was associated with greater HF risk among individuals with lower body mass index. The optimal NT-proBNP (N-terminal pro-B-type natriuretic peptide) cut point to predict future HF risk was lower among individuals with obesity (80 pg/mL; 95% CI, 53-121) compared with normal-weight individuals (109 pg/mL; 95% CI, 80-157).

Conclusions: The application of a single NP cut point resulted in fewer individuals with obesity being up-classified to stage B HF compared with normal-weight individuals. Adjusting NP cut points for individuals with obesity may improve the accuracy of HF risk stratification.