Circulation: Heart Failure最新文献

Background: Cardiogenic shock (CS) is a severe complication of acute myocardial infarction (AMI) leading to poor outcomes. Specific biomarkers, with subsequent validation of their prognostic relevance in CS, are urgently needed to improve therapies and outcomes. Accordingly, the present study investigated the plasma proteome using proximity extension assay technology to identify novel specific biomarkers with subsequent validation of their prognostic relevance in CS.

Methods: Using proximity extension assay (Olink Explore, 2942 proteins), the proteomic signature in the plasma of 9 AMI patients without shock and 8 AMI patients with CS (AMICS; exploration cohort) at admission was analyzed. Candidate biomarkers were measured in the plasma of 421 patients with AMICS from the CULPRIT-SHOCK cohort (Culprit Lesion Only PCI Versus Multivessel PCI in Cardiogenic Shock; REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01927549, validation cohort). Their prognostic relevance was assessed for 180-day survival as the primary end point.

Results: Proteome profiling was successful for 2925 proteins and identified VEGFR1 (vascular endothelial growth factor receptor 1, also known as Flt1) as elevated in AMICS compared with nonshock AMI in the exploration cohort (P<0.001). In patients from the independent validation cohort, nonsurvivors had markedly higher VEGFR1 levels (6.8 versus 3.8 ng/L; P<0.001). In Cox regression, VEGFR1 levels were independently associated with a higher 180-day mortality risk even after adjusting for the Simplified Acute Physiology Score II (per ng/L; adjusted hazard ratio, 1.06 [95% CI, 1.03-1.09]; P<0.001) and yielded incremental prognostic information in addition to serum lactate levels (P<0.001). The levels of VEGFR1 in surviving (30 days; n=29) and nonsurviving (n=21) patients with AMICS were determined at different time points (days 0, 1, and 5) in a third cohort, showing continuously higher levels in nonsurvivors.

Conclusions: Plasma proteomic screening identified VEGFR1 as an early biomarker in patients with AMICS that provided independent prognostic information in a large cohort of well-defined patients with AMICS.

The discovery of the PLN-R14del (deletion of arginine 14 [p.Arg14del] within the phospholamban protein) genetic mutation, characterized by a deletion of R14 in phospholamban, in a large Greek family marked a significant milestone in understanding the cause of its associated cardiomyopathy. Since its initial identification in 2006, this mutation has been found in numerous patients across 11 countries. PLN-R14del carriers commonly exhibit both dilated cardiomyopathy and arrhythmogenic cardiomyopathy, accounting for a significant portion of annual heart transplants in the Netherlands. Under physiological conditions, PLN plays a crucial role in regulating the calcium pump SERCA2a (sarco[endo]plasmic reticulum calcium ATPase 2a) within cardiomyocytes. While the normal function of PLN has been extensively studied, the precise mechanisms underlying the pathogenesis of PLN-R14del-induced heart disease remain uncertain and subject to ongoing debate. The current review systematically summarizes existing literature on the PLN-R14del mutation, elucidating its pathological phenotypes and discussing its implications in PLN-R14del cardiomyopathy. Current knowledge is consolidated, and unresolved questions are addressed with the aim to contribute to a deeper understanding of PLN-R14del-associated cardiac pathology. Finally, this review provides guidance for future research to advance diagnosis and therapeutic approaches for affected individuals.

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.