JACC. Heart failure最新文献

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).

Several trials have evaluated diuretic-based strategies to improve symptoms and outcomes in patients with acute heart failure (AHF). The authors sought to summarize the effect of different combination strategies on symptoms, physical signs, physiological variables, and outcomes in patients with AHF. Twelve trials were identified that assessed the addition of thiazide diuretics, sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, vasopressin receptor antagonists, carbonic anhydrase inhibitors, or loop diuretic intensification to conventional therapy for AHF. The trials evaluated short-term markers of congestion and symptoms, and none were powered for clinical outcomes. Short-term responses (such as relief from dyspnea, physical signs of congestion, and weight change) varied greatly across studies; all diuretic strategies were accompanied by short-term increases in serum creatinine and did not demonstrate benefits on mortality or recurrent heart failure events. The available evidence suggests that intensification of loop diuretic agents produces relief of physical signs of decongestion, but the importance of different strategies for short-term decongestion strategy for health status and long-term outcomes has not been established.

Background: Systemic immune-mediated diseases (SIDs) are a well-known cause of dilated cardiomyopathy (DCM), a cardiac phenotype influenced by genetic predispositions and environmental factors.

Objectives: This study sought to examine if an underlying genetic predisposition is present in patients with DCM and SID.

Methods: Genotyped DCM-SID patients (n = 183) were enrolled at 3 European centers. Genetic variants were compared with healthy control subjects (n = 20,917), DCM patients without SID (n = 560), and individuals with a suspicion of an SID (n = 1,333). Clinical outcomes included all-cause mortality, heart failure hospitalization, and life-threatening arrhythmias.

Results: The SID diagnosis preceded the DCM diagnosis by 4.8 months (Q1-Q3: -68.4 to +2.4 months). The prevalence of pathogenic/likely pathogenic (P/LP) variants in DCM patients with an SID from the Maastricht cohort was 17.1%, compared with 1.9% in healthy control subjects (P < 0.001). In the Madrid/Trieste cohort, the prevalence was 20.5% (P < 0.001). Truncating variants showed the strongest enrichment (10.7% [OR: 24.5] (Maastricht) and 16% [OR: 116.6 (Madrid/Trieste); both P < 0.001), with truncating TTN (titin) variant (TTNtv) being the most prevalent. Left ventricular ejection fraction at presentation was reduced in TTNtv-SID patients compared with DCM patients with SID without a P/LP (P = 0.016). The presence of a P/LP variant in DCM-SID had no impact on clinical outcomes over a median follow-up of 8.4 years (Q1-Q3: 4.9-12.1 years).

Conclusions: One in 6 DCM patients with an SID has an underlying P/LP variant in a DCM-associated gene. This highlights the role of genetic testing in those patients with immune-mediated DCM, and supports the concept that autoimmunity may play a role in unveiling a DCM phenotype in genotype-positive individuals.

Randomized clinical trials (RCTs) for hypertrophic cardiomyopathy (HCM) have long been challenging caused by the condition's rarity, low event rates, and diverse clinical presentations. However, recent advances in targeted therapies have sparked increased interest in HCM research. Despite this, designing effective RCTs remains complex, particularly in identifying clinically meaningful endpoints. HCM, often linked to sequence variation in sarcomeric protein genes like MYH7 and MYBPC3, exhibits varied phenotypic expressions that influence disease progression and treatment responses. This genetic variability underscores the need for personalized approaches in clinical trials. Emerging gene therapies, such as CRISPR/Cas9, show promise in addressing these genetic factors. A major challenge in HCM RCTs is ensuring that endpoints are both statistically and clinically significant, given issues like test-retest variability and missing data. Primary endpoints often focus on symptom relief and functional improvement, while secondary and exploratory endpoints provide broader insights into treatment effects. Regulatory authorities are increasingly open to a wider range of endpoints, including patient-reported outcomes and functional measures, although the cost-risk balance is crucial, especially for high-risk interventions. Future HCM RCTs may incorporate hard clinical endpoints such as heart failure hospitalization, atrial fibrillation recurrence, and all-cause mortality, offering a more comprehensive evaluation of treatment efficacy. Integrating genetic insights and advanced technologies will be essential to improving trial design and enhancing patient outcomes in HCM.

Background: Prior analyses have suggested that a smaller left ventricular end-diastolic diameter (LVEDD) is associated with reduced survival following HeartMate 3 left ventricular assist device implantation.

Objectives: In this trial-based comprehensive analysis, the authors sought to examine clinical characteristics and association with the outcome of this specific relationship.

Methods: The authors analyzed the presence of LVEDD <55 mm among 1,921 analyzable HeartMate 3 patients within the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) trial portfolio, on endpoints of overall survival and adverse events at 2 years. Adverse events included hemocompatibility-related (stroke, bleeding, and pump thrombosis) and non-hemocompatibility-related (right heart failure, infection) outcomes.

Results: Those with a smaller LVEDD (<55 mm) (n = 108) were older (age 63 ± 11 years vs 60 ± 12 years; P = 0.005), were more often female (31% vs 20%; P = 0.096), and had more ischemic cardiomyopathy (60.2% vs 42.6%; P = 0.0004) compared with the LVEDD ≥55 mm group (n = 1,813). Death during implant hospitalization was higher (14.8 vs 5.7%; P = 0.0007) and survival at 2 years was lower (63.3% vs 81.8%; HR: 1.97 [95% CI: 1.39-2.79]; P = 0.0002) in the LVEDD <55 mm group. The LVEDD <55 mm group experienced more deaths due to hemocompatibility-related adverse events (2.8% vs 0.6%; HR: 4.61 [95% CI: 1.29-16.45]; P = 0.018) and right heart failure, both early (0-30 days; 7.4% vs 2.0%; HR: 3.70 [95% CI: 1.73-7.91]; P = 0.001) and late (>30 days; 12.0 vs 4.8%; HR: 2.58 [95% CI: 1.37-4.84]; P = 0.003). Low-flow alarms rehospitalizations were higher in the LVEDD <55 mm cohort (17.4 vs 8.3%; HR: 2.39 [95% CI: 1.59-3.59]; P < 0.001).

Conclusions: Although infrequent in occurrence, smaller LVEDD (<55 mm) is associated with increased risk for early and late mortality, a consequence of hemocompatibility-related and right heart failure-related deaths. Rehospitalizations due to low-flow alarms are also more frequent. (MOMENTUM 3 IDE Clinical Study Protocol [HM3™]; NCT02224755; MOMENTUM 3 Continued Access Protocol [MOMENTUM 3 CAP]; NCT02892955).

Background: Previous studies have examined clinical predictors of incident heart failure (HF) in men and women. However, potential mechanisms through which these clinical predictors relate to the onset of HF remain to be established.

Objectives: The authors studied the association between clinical and proteomic risk profiles of new-onset HF in men and women.

Methods: Incident HF was studied in 478,479 participants from the UK Biobank. The association between new-onset HF and 8 common modifiable traditional risk factors, including obesity, smoking status, socioeconomic status, atrial fibrillation, type 2 diabetes, hypertension, hyperlipidemia, and history of myocardial infarction, was assessed in men and women. Proteomics data (2,923 unique proteins, Olink) was available in 22,695 men and 27,421 women. Pathway over-representation analyses were performed to identify biological pathways in men and women with and without new-onset HF. Principal component analyses were performed to extract weighted scores for each pathway. Subsequently, weighted scores were used in mediation analyses to investigate how the pathways mediated the association between risk factors and new-onset HF.

Results: During a median follow-up time of 12 years, HF incident rate was 3.60 per 1,000 person-years in men and 1.72 per 1,000 person-years in women (P < 0.001). The strongest risk factor for future HF was a history of myocardial infarction (HR: 2.61; 95% CI: 2.46-2.77) in men and atrial fibrillation (HR: 4.10; 95% CI: 3.58-4.71) in women. When a risk factor was present in women, it conferred a higher risk of new-onset HF compared with the presence of the same risk factor in men. Both in men and women, the population-attributable risk was highest for hypertension (25% in men, 29% in women) and obesity (16% in men, 21% in women). Pathway analyses of protein profiles indicated several inflammatory pathways, and neutrophil degranulation in particular, to be activated both in men and women who developed HF. These inflammatory pathways modestly (22% in men and 24% in women) contributed to the association between hypertension and new-onset HF, but showed a stronger contribution (33% in men and 47% in women) to the association between obesity and new-onset HF.

Conclusions: In men and women, the most prominent risk factors for new-onset HF were hypertension and obesity, but they conferred a greater risk of new-onset HF in women. New-onset HF in both men and women was associated with pathophysiological pathways related to neutrophil degranulation and immunomodulation and these pathways partly mediated the association between hypertension, obesity, and new-onset HF.