JACC. Heart failure最新文献

Background: Donor-recipient heart size matching is crucial in heart transplantation; however, the often-used predicted heart mass (PHM) ratio may be inaccurate in the setting of obesity.

Objectives: In this study, the authors sought to investigate the association between echocardiographically measured donor left ventricular mass (LVM) for heart size matching and the risk of the primary 1-year composite outcome of death or retransplantation.

Methods: The Donor Heart Study was a prospective, multicenter, observational cohort study that collected echocardiograms from brain-dead donors. The measured LVM ratio (donor measured LVM/recipient predicted LVM) was defined as the exposure variable, and the association with the primary outcome was analyzed with Cox proportional hazard modeling. Secondary analyses evaluated the association of the PHM and predicted LVM (donor predicted LVM/recipient predicted LVM) ratios with the primary outcome.

Results: In 2,015 heart transplants, the measured LVM ratio demonstrated that undersized matches (<0.80) had a 47% higher risk (adjusted HR [aHR]: 1.47; 95% CI: 1.01-2.15) and oversized (>1.20) matches had a 58% increased risk (aHR: 1.58; 95% CI: 1.05-2.37) of the 1-year composite outcome compared with ideally matched transplants. However, the PHM and predicted LVM ratios were not associated with the primary outcome. Nonlinear modeling demonstrated a U-shaped relationship between the measured LVM ratio and composite outcome. The measured LVM ratio had superior predictive power for poor post-transplantation outcomes in obese recipients.

Conclusions: Measuring donor LVM with the use of echocardiography may provide a more accurate method for donor-recipient heart size matching that could improve heart transplant outcomes, especially in obese recipients.

The number of candidates on the waiting list for heart transplantation (HT) continues to far outweigh the number of available organs, and the donor heart nonuse rate in the United States remains significantly higher than that of other regions such as Europe. Although predicting outcomes in HT remains challenging, our overall understanding of the factors that play a role in post-HT outcomes continues to grow. We observe that many donor risk factors that are deemed "high-risk" do not necessarily always adversely affect post-HT outcomes, but are in fact nuanced and interact with other donor and recipient risk factors. The field of HT continues to evolve, with ongoing development of technologies for organ preservation during transport, expansion of the practice of donation after circulatory death, and proposed changes to organ allocation policy. As such, the field must continue to refine its processes for donor selection and risk prediction in HT.

Background: Safe and effective pharmacologic therapy for atrial fibrillation (AF) in heart failure (HF) is an unmet need. In AF clinical trials, the standard primary endpoint of time to first symptomatic AF event (TTFSE) has several disadvantages, which could theoretically be overcome by measurement of AF-specific symptoms burden during an entire follow-up period.

Objectives: The authors sought to develop and validate a method of measuring symptom burden of AF in a HF population.

Methods: The authors constructed a patient-reported outcome instrument (Atrial Fibrillation Symptoms Questionnaire [AFSQ]) to function in the setting of AF/HF, and used it to measure symptoms throughout long-term follow-up. The AFSQ queries the presence of 10 new or worsening symptoms, equally divided between those associated with AF or HF. In a 267 patient AF/HF trial comparing 2 AF prevention treatments, the AFSQ was linked to electrocardiography documented AF to form a 2-component clinical outcome assessment (SxB_AF) that was subjected to psychometric testing, anchor validation, and endpoint efficiency comparison to TTFSE.

Results: SxB_AF exhibited greater efficiency than time to first symptomatic event for treatment difference detection, resulting in smaller projected clinical trial sample sizes. SxB_AF correlated well with device-detected AF burden (Spearman's ρ = 0.74; P < 0.0001), while permitting gradation in symptom severity. SxB_AF also identified treatment group differences in cardiovascular serious adverse events and AF interventions and in recent-onset AF provided specificity for AF- or worsening HF-associated symptoms (P < 0.001 for each).

Conclusions: Measurement of symptoms burden throughout clinical trial follow-up is feasible in AF/HF and should be useful for evaluating patient-centered outcomes in AF prevention trials. (Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure [GENETIC-AF]; NCT01970501).

Background: In hypertrophic cardiomyopathy, histologic findings like myocyte hypertrophy and disarray, interstitial fibrosis (IF), and small intramural coronary artery dysplasia (SICAD) result in left ventricular hypertrophy, diastolic dysfunction, arrhythmogenicity, and microvascular ischemia.

Objectives: The authors sought to evaluate the association between histology and outcomes in obstructive hypertrophic cardiomyopathy (oHCM) patients undergoing surgical myectomy (SM).

Methods: The study included 1,722 symptomatic oHCM patients (mean age: 56 ± 14 years; 948 [55%] men) who underwent SM at a tertiary center between 2005 and 2018. The SM specimen was analyzed for presence and severity of: 1) myocyte hypertrophy; 2) myocyte disarray; 3) IF; and 4) SICAD. Histologic findings were graded as 0-3 (none, mild, moderate, and severe) and a score from 0-12 was calculated. Primary endpoint was a composite of death, appropriate defibrillator discharge, or cardiac transplantation during follow-up.

Results: Moderate and severe histologic findings were distributed as follows: myocyte hypertrophy (1,341 [78%]); disarray (237 [14%]); IF (448 [26%]); and SICAD (258 [15%]). The mean total histologic score was 5.1 ± 1.4. At 5.1 ± 5.2 years, there were 352 (20%) primary events (317 [18%] deaths). On spline analysis, a total histology score of >5 was associated with primary events. On Kaplan-Meier analysis, patients with a histology score >5 had greater events vs those with a score ≤5 (147/598 [25%] vs 205/1124 [18%]; log-rank P value = 0.002). On multivariable Cox analysis, total histology score >5 (HR: 1.24 [95% CI: 1.03-1.54]; P = 0.03) was independently associated with higher primary events.

Conclusions: In symptomatic oHCM patients undergoing SM, a higher histologic score was independently associated with long-term outcomes.

Background: Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF).

Objectives: This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction.

Methods: The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction.

Results: At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m²; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m². Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m² (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m² (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m² (HR: 0.66; 95% CI: 0.45-0.97).

Conclusions: In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

Gene therapy has emerged as a possible treatment for progressive, debilitating Mendelian cardiomyopathies with limited therapeutic options. This paper arises from discussions at the 2023 Cardiovascular Clinical Trialists Forum and highlights several challenges relevant to gene therapy clinical trials, including low prevalence and high phenotypic heterogeneity of Mendelian cardiomyopathies, outcome selection complexities and resulting regulatory uncertainty, and immune responses to the adeno-associated viral vectors that are being used in ongoing studies. Avenues to address these challenges such as natural history studies, external controls, novel regulatory pathways, and immunosuppression are discussed. Relevant cases of recent therapy approvals are highlighted. Ultimately, this work aims to broadly frame discussions on and provide potential future avenues for clinical trial design for rare cardiomyopathy gene therapies.