Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic ¹⁸F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Background—: Heart failure caused by wild-type transthyretin amyloidosis (ATTRwt) is an underappreciated cause of morbidity and mortality in the aging population. The aims of this study were to examine features of disease and to characterize outcomes in a large ATTRwt cohort. Methods and Results—: Over 20 years, 121 patients with ATTRwt were enrolled in a prospective, observational study. Median age at enrollment was 75.6 years (range, 62.6–87.8 years); 97% of patients were white. The median survival, measured from biopsy diagnosis, was 46.69 months (95% confidence interval, 41.95–56.77); 78% of deaths were attributable to cardiac causes. By Kaplan–Meier analysis, 5-year survival was 35.7% (95% confidence interval, 25–46). Impaired functional capacity (mean V o ₂ max, 13.5 mL·kg ⁻¹ ·min ⁻¹ ) and atrial fibrillation (67%) were common clinical features. Multivariate predictors of reduced survival were elevated serum brain natriuretic peptide (482±337 pg/mL) and uric acid (8.2±2.6 mg/dL), decreased left ventricular ejection fraction (50% median; range, 10%–70%), and increased relative wall thickness (0.75±0.19). Conclusions—: In this series of patients with biopsy-proven ATTRwt, poor functional capacity and atrial arrhythmias were common clinical features. Elevated brain natriuretic peptide and uric acid, decreased left ventricular ejection fraction, and increased relative wall thickness were associated with limited survival of only 35.7% at 5 years for the group as a whole. These data establish the natural history of ATTRwt, provide statistical basis for the design of future interventional clinical trials, and highlight the need for more sensitive diagnostic tests and disease-specific treatments for this disease.