Circulation: Heart Failure最新文献

Background: Hypertrophic cardiomyopathy (HCM) is an important cause of morbidity and mortality in children, but treatment options are limited. Aficamten, a next-in-class cardiac myosin inhibitor, directly targets the hypercontractility underlying HCM. Aficamten improved exercise capacity, health status, and symptoms in adults with obstructive HCM in the pivotal, phase 3 SEQUOIA-HCM trial (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM; NCT05186818).

Methods: CEDAR-HCM (Clinical Evaluation of dosing With Aficamten to Reduce Obstruction in Pediatric Population With HCM) is an international, multicenter, randomized, double-blind, placebo-controlled trial followed by an open-label extension to evaluate the efficacy, safety, and pharmacokinetics of aficamten in pediatric participants with symptomatic obstructive HCM. The trial will enroll ≈55 adolescents (12 to <18 years) and subsequently expand to include at least 10 children (6 to <12 years) with nonsyndromic obstructive HCM, left ventricular ejection fraction ≥60%, Valsalva left ventricular outflow tract gradient ≥50 mm Hg, and New York Heart Association functional class ≥II. Participants will be randomized 2:1 to aficamten or placebo in addition to standard of care therapy or as monotherapy, with echocardiogram-guided dose adjustments targeting a Valsalva left ventricular outflow tract gradient <30 mm Hg while maintaining left ventricular ejection fraction ≥50%. The primary end point is the change in Valsalva left ventricular outflow tract gradient from baseline to week 12. Secondary end points include change in resting left ventricular outflow tract gradient, cardiac biomarkers, New York Heart Association functional class, and assessment of pharmacokinetics. After completing the 12-week randomized period, eligible participants will continue into a long-term open-label extension.

Results: The trial is currently enrolling.

Conclusions: Results of CEDAR-HCM will provide insight into the safety and efficacy of aficamten in adolescents and in children as young as 6 years of age.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT06412666.

Background: MGP (matrix Gla-protein), a known inhibitor of vascular calcification, becomes biologically active by vitamin K-dependent carboxylation. Circulating levels of dpucMGP (dephospho-uncarboxylated matrix Gla-protein), the inactive form of MGP, have been associated with large artery stiffening and reduced skeletal muscle mass in heart failure (HF). Whether dpucMGP is related to adverse outcomes in patients with HF is unknown.

Methods: In this cohort study, we measured plasma dpucMGP among 2247 PHFS (Penn HF Study) participants. We examined the relationship between dpucMGP and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with dpucMGP. We assessed the association between dpucMGP levels and (1) death or HF-related hospital admission; (2) all-cause death.

Results: Participants' median age was 61 years (interquartile range, 53-70 years), 64% were male, and 71% were White. dpucMGP exhibited prominent proteomic associations with acute phase response, coagulation, complement system, fibrosis, cell signaling, and metabolic pathways. Greater dpucMGP was associated with older age, renal dysfunction, and warfarin use, whereas Black ethnicity was associated with lower dpucMGP. Increased dpucMGP levels were associated with an increased risk of death or HF-related hospital admission (standardized hazard ratio, 1.23 [95% CI, 1.17-1.28]; P<0.0001) and all-cause death (standardized hazard ratio, 1.32 [95% CI, 1.25-1.40]; P<0.0001), particularly among participants with nonischemic HF. Associations between dpucMGP and outcomes were dependent on warfarin use, and higher dpucMGP levels were found to mediate the association between warfarin use and adverse outcomes (death [total effect: P=0.005; indirect effect: P<0.001] and death or HF-related hospital admission [total effect: P<0.001; indirect effect: P=0.002]).

Conclusions: Higher dpucMGP is associated with multiple biological pathways and with an increased risk for adverse outcomes in HF. Greater dpucMGP levels mediated the relationship between warfarin use and adverse outcomes. Further studies are required to determine the role of therapeutic interventions to reduce dpucMGP levels in this patient population.

Background: Arrhythmogenic cardiomyopathy (ACM) is a fatal genetic heart disease primarily caused by mutations in desmosomal genes, leading to impaired cell-cell adhesion, ventricular arrhythmias, and progressive heart failure. Although gene therapy for specific ACM populations shows promise, it remains unclear whether mutation-agnostic pathways dysregulated across desmosomal mutations could be exploited for therapeutic intervention in this genetically broad and severe population. The reduction in expression of the ventricular gap junction protein Cx43 (connexin-43) is a common molecular alteration underlying desmosomal junctional deficits and arrhythmias, suggesting a potential common underlying mechanism and a therapeutic target for ACM. We hypothesized that restoration of Cx43 expression could be a mutation-agnostic intervention for ACM.

Methods: We exploited adeno-associated-viral-mediated gene therapy to restore the gap junction protein, Cx43, in genetic mouse models and human stem cell models of ACM, harboring loss or mutations in desmosomal genes, including desmoplakin (Dsp), plakophilin-2 (PKP2), and desmoglein-2 (DSG2).

Results: Administration of AAV-Cx43 (adeno-associated-viral-mediated connexin-43) gene therapy alleviated the severe biventricular dilatation, contractile dysfunction, and arrhythmias, while prolonging lifespan in 2 severe desmosomal ACM mouse models, either harboring Dsp loss and a prevalent human PKP2 mutation. Viral-mediated restoration of Cx43 could also alleviate physiological deficits in ACM human induced pluripotent stem cell-derived cardiomyocytes harboring PKP2 and DSG2 mutations. Mechanistically, Cx43 targets desmosomal protein expression and relocalization to the cell junction to support their mechanical stabilization and coupling.

Conclusions: By using mouse and human models of desmosomal ACM harboring different mutational backgrounds, we show the sufficiency of Cx43 gene therapy and its restoration to modify and alleviate ACM deficits. These data suggest that noncanonical functions of Cx43, including mechanical modulation and reassembly of the desmosome, are a therapeutic target with the potential to treat diverse ACM populations.

Background: Circulating microRNAs are promising biomarkers of acute cellular rejection (ACR) and antibody-mediated rejection (AMR) in heart transplantation. The study objective was to assess the characteristics and diagnostic performance of previously identified microRNAs and clinical rejection scores (CRS) in distinct blood samples obtained at the time of an endomyocardial biopsy (EMB).

Methods: In the 5-center, prospective, longitudinal cohort study, GRAfT (Genomic Research Alliance for Transplantation), microRNA sequencing was performed on blood samples. The previously identified microRNAs associated with ACR (n=12) and AMR (n=17) were used to fit a logistic regression model to the current cohort, and the scores were scaled from 0 to 100. Diagnostic performance of ACR and AMR microRNA panels was assessed by the area under the receiver-operating characteristic curve. An adjusted Cox proportional hazard model evaluated the effect of CRS on long-term outcomes.

Results: In 173 heart transplant recipients (29% female sex, 41% Black race, median follow-up 374 days after transplant), 922 blood samples were sequenced, 720 paired with EMB. Among 14 episodes of ACR, the median ACR CRS was 78 compared with 42 without ACR, P<0.001. Among 25 episodes of AMR, median AMR CRS was 75 compared with 53 without AMR, P<0.001. The area under the receiver-operating characteristics curve for the CRS was 0.93 for ACR and 0.92 for AMR. Using a CRS threshold of 65, the ACR CRS had 79% sensitivity, 97% specificity, and 100% negative predictive value; the AMR CRS had 84% sensitivity, 86% specificity, and 99% negative predictive value. The ACR and AMR CRS were both <65 in 589 (82%) of the tests. After adjustment, a 10-point increase in CRS was associated with ≥42% increase in hazard of the composite outcome: subsequent ACR or AMR by EMB, allograft dysfunction, or death (ACR hazard ratio, 1.42 [95% CI, 1.20-1.69]; P<0.001; AMR hazard ratio, 1.45 [95% CI, 1.14-1.86]; P=0.003).

Conclusions: Circulating microRNAs reliably identified ACR and AMR on EMB. An elevated microRNA CRS was associated with an increased risk of subsequent rejection, allograft dysfunction, or death. This biomarker, with further validation, can serve as a noninvasive test to screen and diagnose ACR and AMR without the need for an EMB.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02423070.

Background: Up-titration of guideline-directed medical therapy (GDMT) is known to enhance left ventricular function in heart failure (HF) with reduced ejection fraction. However, data regarding its effect on right ventricular (RV) function remain sparse. We aimed to assess the impact of GDMT up-titration on the RV, especially RV to pulmonary artery coupling, and its prognostic value in these patients.

Methods: All consecutive patients (n=291) with left ventricular ejection fraction <50% followed for GDMT up-titration in a dedicated HF clinic in a tertiary center from January 2019 to June 2022 with an echocardiography at baseline (before up-titration) and at follow-up (end of up-titration) were included.

Results: The median age is 65 (55-74) years; 24% are female. Ischemic cardiomyopathy was the main cause of HF (47%), and left ventricular ejection fraction was 30% (22%-34%). After 2 years, 49 patients (17%) reached the primary end point (all-cause death or hospitalization for acute HF). RV size and function significantly improved after GDMT up-titration (all, P<0.001), including RV to pulmonary artery coupling assessed by tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (0.62 versus 0.81 mm/mm Hg; P<0.001). Tricuspid annular plane systolic excursion/systolic pulmonary artery pressure <0.65 mm/mm Hg at follow-up remained associated with the primary end point after adjustment with comorbidities (hazard ratio, 5.9 [95% CI, 2.8-12.1]; P<0.001), clinical and biological severity (hazard ratio, 6.4 [95% CI, 2.4-17.8]; P<0.001), and echocardiography (hazard ratio, 3.6 [95% CI, 1.6-8.4]; P=0.002). In addition, tricuspid annular plane systolic excursion/systolic pulmonary artery pressure was associated with an incremental prognostic value (C-index improvement, P<0.01), over and above prognostic factors, including left ventricular ejection fraction.

Conclusions: This study highlights the independent and incremental prognostic value of tricuspid annular plane systolic excursion/systolic pulmonary artery pressure in HF with reduced ejection fraction during GDMT up-titration, suggesting to also consider RV to pulmonary artery coupling with echocardiography as a treatment goal.