Circulation: Heart Failure最新文献

Background: The purpose of the current study was to investigate the clinical implications of elevated donor-derived cell-free DNA (dd-cfDNA) levels in heart transplantation recipients without evidence of rejection observed on endomyocardial biopsy.

Methods: We retrospectively analyzed dd-cfDNA samples from all consecutive heart transplantation recipients between 2019 and 2023, excluding those with multiorgan transplants. Each sample was paired with an endomyocardial biopsy (<30 days). A positive biopsy was defined based on International Society for Heart and Lung Transplantation criteria of ≥1R/1B or antibody-mediated rejection >0. Elevated dd-cfDNA was defined as ≥0.12%, with a subanalysis using a threshold of 0.20%. Graft dysfunction was defined as an ejection fraction<50%. We excluded dd-cfDNA samples with concurrent histologically positive biopsy results, focusing on those with positive dd-cfDNA and negative biopsy findings. A mixed model Cox regression approach was applied to assess for mortality and graft dysfunction.

Results: Of 643 dd-cfDNA samples from 227 patients, 238 samples (37%) from 110 patients showed positive dd-cfDNA results with negative endomyocardial biopsy. The median age was 56 years, with 27% females and 53% White patients. The median time from heart transplantation to sample collection was 5 months (interquartile range, 3-12). Among the positive samples, the median dd-cfDNA level was 0.24% (interquartile range, 0.16%-0.53%) with 63% exceeding 0.20%. A higher prevalence of prior treated antibody-mediated rejection was observed in the dd-cfDNA positive group (15% versus 5%; P=0.002). Patients with elevated dd-cfDNA results ≥ 0.20% demonstrated a near 5-fold increased risk of mortality (hazard ratio, 4.6 [95% CI, 1.6-13.4]; P=0.005) and a 3-fold risk of graft dysfunction (hazard ratio, 3.4 [95% CI, 1.0-11.9]; P=0.054) compared with those with negative dd-cfDNA.

Conclusions: In our cohort, patients with positive dd-cfDNA levels and negative biopsy results had higher rates of adverse outcomes, including graft dysfunction and mortality.

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.