Circulation: Heart Failure最新文献

Background: Although obesity and insulin resistance (IR) are established risk factors for left heart dysfunction, their clinical impact in group 1 pulmonary hypertension (PH) remains unclear. We sought to determine the impact of excess adiposity versus IR on biventricular hemodynamic and functional reserve in group 1 PH.

Methods: Homeostasis model of insulin resistance and adiposity indices (body mass index [BMI], fat mass, waist circumference) were measured among group 1 patients with PH recruited to PVDOMICS (Redefining Pulmonary Hypertension Through Pulmonary Vascular Disease Phenomics). Functional capacity, and dynamic pulmonary capillary wedge pressure (PCWP) and right atrial pressure responses were compared stratified by obesity (BMI≥30 kg/m²) and IR status (HOMA-IR≥2.6) using repeated-measure mixed models.

Results: Among patients with group 1 PH (n=418), 158 (38%) had BMI≥30 kg/m² (94 [60%] of whom had IR), and 260 (62%) had BMI<30 kg/m² (74 [28%] of whom had IR). Among those with waist circumference measurement (n=375), 287 (77%) had excess adiposity by elevated waist/height ratio, with 214 (57%) having elevated waist circumference. Patients with obesity had worse quality of life, exercise capacity and left heart remodeling, along with higher resting/dynamic PCWP, right atrial pressure and cardiac output (P<0.0001 for all). Higher PCWP response with obesity persisted after adjusting for IR (IR-adjusted PCWP+2.5 mm Hg [95% CI, +1.4 to +3.6]; P<0.0001). All adiposity indices were consistently associated with PCWP response, but IR was not. Similar associations were observed between adiposity indices with higher right atrial pressure and cardiac output. Greater visceral adiposity as measured by body shape index (hazard ratio, 2.01 [95% CI, 1.16-3.47]; P=0.01) or weight-adjusted waist index (hazard ratio, 1.64 [95% CI, 1.10-2.46]; P=0.01) was associated with worse survival.

Conclusions: Excess adiposity is common in group 1 PH, occurring in 4 out of 5 patients by the more sensitive waist/height ratio, in contrast to only 2 out of 5 patients having obesity by traditional BMI criteria. Excess adiposity is associated with higher biventricular filling pressures, cardiac output demand, worse functional status and reduced survival. These data support trials of adipose-reducing therapies in patients with group 1 PH and excess adiposity.

Background: Anecdotal evidence suggests that symptoms and physical activity levels in patients with heart failure (HF) fluctuate considerably, though empirical data to support this claim are sparse. We examined how stable psychosocial traits (eg, intrinsic motivation), situational psychosocial states (eg, vitality), and HF symptoms vary in stable patients with HF and their association with physical activity.

Methods: The MOVIN-HF study (Mobile Health Intervention to Increase Activity in Heart Failure) was a prospective, observational study of patients with symptomatic HF. We collected data on (1) psychosocial traits at baseline and (2) twice daily ecological momentary assessments for 28 days of participants' symptoms and current psychosocial states. Physical activity was measured by smartwatch step counts. We evaluated the association between baseline psychosocial states and mean daily step counts and between ecological momentary assessments of symptoms and psychosocial states and short-term step counts (12 hours after ecological momentary assessments). Mixed effects models quantified associations.

Results: Between February and June 2024, 30 participants enrolled in the study; the mean age was 59.7 (SD, 13.6) years, 53% were female, and most (63%) had New York Heart Association class 2 HF symptoms. Baseline psychosocial traits like motivational quality were significantly associated with daily step count. For example, each 1-point increase in intrinsic motivation was associated with 39% higher daily step count (95% CI, 3%-87%). There was also significant variability in ecological momentary assessment scores of symptoms and psychosocial states: 10 (33%) participants experienced a 50% or greater change in HF symptoms, and 18 (60%) a 50% or greater change in vitality. HF symptoms and psychosocial states (eg, vitality, competence) were significantly associated with 12-hour step count.

Conclusions: Baseline psychosocial traits are associated with daily physical activity. In addition, symptoms and psychosocial states fluctuate frequently among patients with HF and are associated with short term physical activity. These findings suggest tailored interventions may improve physical activity levels.

Background: Women with obstructive hypertrophic cardiomyopathy often present with a greater burden of disease and worse prognosis. Whether there are sex-related differences in response to aficamten is unknown.

Methods: We performed a prespecified subgroup analysis of sex differences in the double-blind, randomized-controlled SEQUOIA-HCM trial (Safety, Efficacy and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) of aficamten versus placebo in patients with obstructive hypertrophic cardiomyopathy. Baseline characteristics were compared using the t test for continuous variables and the χ² test for categorical variables. Prespecified primary (change in peak oxygen uptake) and secondary end points from baseline to end of treatment (week 24) were analyzed using linear regression models, adjusted for baseline values, β-blocker use, and exercise mode.

Results: Of the 282 participants, women (n=115) were older (64 years in women versus 56 years in men) and had lower Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, higher NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, and lower peak oxygen uptake at baseline. Women had smaller left ventricular chamber sizes, higher E/e' ratios, and higher left ventricular outflow tract gradients. At 24 weeks, there was a significant treatment-related increase in peak oxygen uptake in women (+1.5 [+0.7 to +2.4]) and men (+2.0 [+0.9 to +3.0]). Both women and men had significant treatment-related decreases in left ventricular outflow tract gradients at rest and with Valsalva, with no sex-by-treatment interaction at week 24 (P_interaction≥0.13). There was a significant improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score in women (11 [6-15]) and men (6 [2-9]; P_interaction=0.08). Women had a greater reduction in lateral E/e' ratio (P_interaction=0.01). The geometric mean proportional reduction in NT-proBNP was similar in women and men (P_interaction=0.10).

Conclusions: Women enrolled in SEQUOIA-HCM were older with worse baseline health status, higher NT-proBNP, and higher left ventricular outflow tract gradients compared with men. Despite these differences, both men and women derived significant benefits in the primary and secondary end points following treatment with aficamten.

Background: Left ventricular noncompaction cardiomyopathy (LVNC; OMIM No. 604169) is anatomically characterized by excess trabeculation and deep intertrabecular recesses. It is the third most prevalent pediatric cardiomyopathy. Despite its clinical significance, the pathogenesis of LVNC remains uncertain.

Methods: We examined Numb expression in epicardial cells (EpiCs) and epicardial-derived cells (EPDCs) using a mCherry::Numb knock-in mouse line; used Tbx18^Cre/+ and inducible WT1^CreERT2/+ to generate epicardium-specific Numb and Numblike double knockouts (epicardial Nb;Nl double knockout [EDKO]) and inducible EpiC-specific Nb;Nl knockout, respectively; monitored EpiCs/EPDCs invasion into the myocardium by lineage tracing; assessed LVNC defects via the ratio of noncompact to compact zone thickness/area; utilized single-nuclei mRNA sequencing and biochemical tools to determine the disrupted molecular mechanisms of EDKOs; and used pharmacological approaches to rescue defects in EDKOs. Cardiac structural and functional changes in adult stages were examined using echocardiography and histochemistry. Sample sizes ranged from 3 to 9 hearts across experiments.

Results: Numb is enriched in EpiCs and EPDCs. In EDKO hearts, EPDCs displayed abnormal differentiation, and their migration was arrested at the outer compact zone, resulting in the absence of EPDCs in the inner compact zone and trabeculae. The EDKO hearts displayed LVNC, and inducible EpiC-specific Nb;Nl knockouts (induced at embryonic day 10.5) recapitulated the defects. Single-nuclei mRNA sequencing revealed the upregulation of Fgfr1 (fibroblast growth factor receptor 1) in epicardium and the downregulation of Fgf (fibroblast growth factor) ligands in cardiomyocytes in EDKOs. Exogenous Fgf2 supplementation to pregnant females partially rescued epithelial-mesenchymal transition and compaction defects in EDKO hearts. Female EDKOs survived to adulthood and maintained LVNC.

Conclusions: Ablation of NFPs (numb family proteins) in EpiCs disrupted the invasion and differentiation of EPDCs and the communication between cardiomyocytes and other cells, and caused LVNC. The epithelial-mesenchymal transition and compaction defects can be partially rescued by exogenous Fgf2 supplementation. Our findings highlight an essential role for the epicardial NFPs-Fgf/Fgfr axis in regulating ventricular compaction.