Sam, Flora

Left atrial (LA) myopathy plays a critical role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate LA function in a murine model of hypertension-induced HFpEF, with and without obesity, by analyzing left ventricular (LV) pressure signals to quantify the contribution of LA systole to total LV volume. HFpEF was induced in C57BL/6J mice using the SAUNA model, which involves uninephrectomy, chronic aldosterone infusion, and high-salt drinking water for four weeks. To model obesity-associated HFpEF, a high-fat diet (HFD) was added to the SAUNA protocol. Invasive hemodynamic measurements were obtained, and a novel method was developed to assess atrial systole using the second-order derivative of the LV pressure signal during diastolic filling. SAUNA HFpEF mice exhibited preserved LVEF, moderate hypertension, pulmonary congestion, and diastolic dysfunction as evidenced by a prolonged time constant of relaxation (Tau). In sham control mice, atrial systole accounted for 23.0 ± 2.4% of LV volume, whereas this contribution was significantly reduced to 13.9 ± 2.3% in SAUNA HFpEF mice ( P < 0.01). In obese sham controls, atrial systole contributed 53.1 ± 2.2%, which was markedly decreased to 36.8 ± 3.6% in obese-SAUNA HFpEF mice ( P < 0.003). This novel method enables precise quantification of LA systolic contribution to LV filling in mice and highlights the pathophysiological effects of hypertension and obesity on LA function in HFpEF.

Heart failure with preserved ejection fraction (HFpEF), a major public health problem that is rising in prevalence, is associated with high morbidity and mortality and is considered to be the greatest unmet need in cardiovascular medicine today because of a general lack of effective treatments. To address this challenging syndrome, the National Heart, Lung, and Blood Institute convened a working group made up of experts in HFpEF and novel research methodologies to discuss research gaps and to prioritize research directions over the next decade. Here, we summarize the discussion of the working group, followed by key recommendations for future research priorities. There was uniform recognition that HFpEF is a highly integrated, multiorgan, systemic disorder requiring a multipronged investigative approach in both humans and animal models to improve understanding of mechanisms and treatment of HFpEF. It was recognized that advances in the understanding of basic mechanisms and the roles of inflammation, macrovascular and microvascular dysfunction, fibrosis, and tissue remodeling are needed and ideally would be obtained from (1) improved animal models, including large animal models, which incorporate the effects of aging and associated comorbid conditions; (2) repositories of deeply phenotyped physiological data and human tissue, made accessible to researchers to enhance collaboration and research advances; and (3) novel research methods that take advantage of computational advances and multiscale modeling for the analysis of complex, high-density data across multiple domains. The working group emphasized the need for interactions among basic, translational, clinical, and epidemiological scientists and across organ systems and cell types, leveraging different areas or research focus, and between research centers. A network of collaborative centers to accelerate basic, translational, and clinical research of pathobiological mechanisms and treatment strategies in HFpEF was discussed as an example of a strategy to advance research progress. This resource would facilitate comprehensive, deep phenotyping of a multicenter HFpEF patient cohort with standardized protocols and a robust biorepository. The research priorities outlined in this document are meant to stimulate scientific advances in HFpEF by providing a road map for future collaborative investigations among a diverse group of scientists across multiple domains.