Characterization of a robust mouse model of heart failure with preserved ejection fraction

Abstract

Heart failure (HF) is a leading cause of morbidity and mortality particularly in older adults and patients with multiple metabolic comorbidities. Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome with multisystem organ dysfunction in which patients develop symptoms of HF as a result of high left ventricular (LV) diastolic pressure in the context of normal or near normal LV ejection fraction (LVEF; ≥50 percent). Challenges to create and reproduce a robust rodent phenotype that recapitulates the multiple comorbidities that exist in this disease explain the presence of various animal models that fail to satisfy all the criteria of HFpEF. Using a continuous infusion of angiotensin II and phenylephrine (AngII/PE), we demonstrate a strong HFpEF phenotype satisfying major clinically relevant manifestations and criteria of this disease, including exercise intolerance, pulmonary edema, concentric myocardial hypertrophy, diastolic dysfunction, histological signs of microvascular impairment, and fibrosis. Conventional echocardiographic analysis of diastolic dysfunction identified early stages of HFpEF development and speckle tracking echocardiography analysis including the left atrium (LA) identified strain abnormalities indicative of contraction-relaxation cycle impairment. Diastolic dysfunction was validated by cardiac catheterization and analysis of LV end diastolic pressure (LVEDP). Among mice that developed HFpEF, two major subgroups were identified with predominantly perivascular fibrosis and interstitial myocardial fibrosis. In addition to major phenotypic criteria of HFpEF that were evident at early stages of this model, accompanying RNAseq data demonstrate activation of pathways associated with myocardial metabolic changes, activation of ECM deposition, microvascular rarefaction, and pressure and volume related myocardial stress

A murine model of hypertensive heart disease in older women

“…Sham surgery was performed without the placement of a vehicle-filled osmotic minipump in all animals. Previous studies have shown that this had not caused differences in the heart ( Matsiukevich et al, 2023 ; Aidara et al, 2024 ).…”

“…One important addition that our model will probably need in the future is the inclusion of a metabolic stressor. Previous publications of HFpEF murine models ( Withaar et al, 2021a ; Schiattarella et al, 2019 ; Withaar et al, 2021b ; Tong et al, 2019 ; Matsiukevich et al, 2023 ; Aidara et al, 2024 ) added a high-fat diet to hypertensive stress. We recently observed in young female mice that the high-fat diet alone was sufficient to cause significant levels of CH, comparable to AngII.…”

“…We did not submit the animals to exercise exhaustion protocols, and lung weight remained within the normal range. We did not incorporate metabolic stress such as a high-fat diet as in other recently developed HFpEF models ( Withaar et al, 2021a ; Schiattarella et al, 2019 ; Withaar et al, 2021b ; Tong et al, 2019 ; Matsiukevich et al, 2023 ; Aidara et al, 2024 ).…”

“…Males, unlike females, displayed features of heart failure with reduced ejection fraction when subjected to HFD and AngII ( Tong et al, 2019 ). Matsiukevich et al (2023) described a new mouse model of HFpEF by targeting the α 1 adrenergic receptor with an agonist, phenylephrine, and AngII in young animals. This model displayed many features associated with HFpEF.…”

Atrial Myopathy Quantified by Speckle-tracking Echocardiography in Mice

“…15,38 Nevertheless, because the mean LA reservoir strain values in the mouse groups with atrial myopathy were approximately half of the value of young (normal) mice, the decrease in strain was proportional to decreases seen in humans studies. Furthermore, Matsiukevich et al 39 recently characterized a murine model of HFpEF using combined Ang II and phenylephrine infusion and found an LV global longitudinal strain to LA reservoir strain ratio of 25%/40%=0.63 in the untreated mice. The LV/LA ratio in our study was similar at 15%/22%=0.68.…”