Heart failure with preserved ejection fraction in humans and mice: embracing clinical complexity in mouse models

Figures

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  Figure 1. Diagnostic HFpEF scoring algorithms used to score HFpEF animal models. Both algorithms first include a pretest assessment to evaluate signs and symptoms and clinical features of HFpEF that include congestion, increased comorbidity burden and reduced exercise tolerance. The second step of the HFA-PEFF19 score assesses three domains that include functional aspects [echocardiographic diastolic function (E/e′ and GLS)], morphological aspects (left atrial enlargement, LV mass and wall thickness and concentric hypertrophy) as well as levels of circulating natriuretic peptides.2 , 28 The H2FPEF27 score combines clinical and echocardiographic patient characteristics: obesity, hypertension, AF, pulmonary hypertension, age >60 years and diastolic function (E/e′). A higher score represents a higher likelihood of having HFpEF (HFA-PEFF ≥5 points; H2FPEF >6 points), while a lower score is used to rule out HFpEF. For patients with an intermediate score, both algorithms recommend additional testing to refine the diagnosis by exercise echocardiography or invasive measurements of cardiac filling pressures in a non-resting state.19 , 27 AF, atrial fibrillation; GLS, global longitudinal strain; HF,…

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  Figure 2. HFA-PEFF and H2FPEF scores obtained by HF models. All HF models have been scored for cardiac and extra-cardiac domains of HFA-PEFF and H2FPEF scores. Based upon these scores, mouse HF models are differentiated into more or less likely to fulfil the criteria of the HFA-PEFF or H2FPEF score. If we solely record the scores, several of so-called HFpEF models would have obtained high scores due to functional or morphological features, while signs of lung congestion or exercise impairment were absent and levels of natriuretic peptides low. ANGII, angiotensin II; DOCA, deoxycorticosterone acetate; DOCP, desoxycorticosterone pivalate; db/db, leptin receptor-deficient model; HFpEF, heart failure with preserved ejection fraction; l-NAME, N(ω)-nitro-l-arginine methyl ester; ob/ob, leptin-deficient model.

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  Figure 3. HFpEF in mice: a novel approach to develop a multifactorial pre-clinical HFpEF mouse model. The following clinical HFpEF features are essential to develop a reliable and accurate pre-clinical HFpEF model: (1) pulmonary congestion and elevated natriuretic peptides; (2) a distinct cardiac phenotype with preserved systolic LV function with concentric hypertrophy, fibrosis, atrial enlargement and diastolic dysfunction; (3) extra-cardiac comorbidities such as hypertension, obesity, T2DM and renal dysfunction and skeletal muscle weakness; and (4) incorporate and evaluate the effect of sex and aging. LV, left ventricle. Parts of the figure were drawn by using pictures from Smart Servier Medical Art (http://smart.servier.com), licensed under a Creative Commons Attribution 3.0 Generic License (https://creativecommons.org/licenses/by/3.0/).