Large and Small Animal Models of Heart Failure With Reduced Ejection Fraction

Abstract

Heart failure (HF) describes a heterogenous complex spectrum of pathological conditions that results in structural and functional remodeling leading to subsequent impairment of cardiac function, including either systolic dysfunction, diastolic dysfunction, or both. Several factors chronically lead to HF, including cardiac volume and pressure overload that may result from hypertension, valvular lesions, acute, or chronic ischemic injuries. Major forms of HF include hypertrophic, dilated, and restrictive cardiomyopathy. The severity of cardiomyopathy can be impacted by other comorbidities such as diabetes or obesity and external stress factors. Age is another major contributor, and the number of patients with HF is rising worldwide in part due to an increase in the aged population. HF can occur with reduced ejection fraction (HF with reduced ejection fraction), that is, the overall cardiac function is compromised, and typically the left ventricular ejection fraction is lower than 40%. In some cases of HF, the ejection fraction is preserved (HF with preserved ejection fraction). Animal models play a critical role in facilitating the understanding of molecular mechanisms of how hearts fail. This review aims to summarize and describe the strengths, limitations, and outcomes of both small and large animal models of HF with reduced ejection fraction that are currently used in basic and translational research. The driving defect is a failure of the heart to adequately supply the tissues with blood due to impaired filling or pumping. An accurate model of HF with reduced ejection fraction would encompass the symptoms (fatigue, dyspnea, exercise intolerance, and edema) along with the pathology (collagen fibrosis, ventricular hypertrophy) and ultimately exhibit a decrease in cardiac output. Although countless experimental studies have been published, no model completely recapitulates the full human disease. Therefore, it is critical to evaluate the strength and weakness of each animal model to allow better selection of what animal models to use to address the scientific question proposed.

Endothelin type A receptor blockade attenuates aorto-caval fistula-induced heart failure in rats with angiotensin II-dependent hypertension

“…The evidence that kidney activity of RAAS, SNS, and endothelin system is not increased in ACF TGR seems incompatible with the neurohormonal theory of the pathophysiology of heart failure, which proposes that in heart failure the activity of the RAAS and SNS is increased and compensates for the initial insult, even though in the long run such hyperactivity is known to be deleterious and critically contributes to the progression of heart failure [17–19,54–56]. In addition, the present results are at variance with our earlier report on an increased plasma and kidney RAAS and SNS activity in hypertensive rats [15,59,75]. However, this was so 5 weeks after the creation of ACF, in the phase of advanced heart failure decompensation, with 60% mortality (Fig.…”

“…In addition, the present results are at variance with our earlier report on an increased plasma and kidney RAAS and SNS activity in hypertensive rats [15,59,75]. However, this was so 5 weeks after the creation of ACF, in the phase of advanced heart failure decompensation, with 60% mortality (Fig.…”

Prevalence and prognostic role of L wave and selected clinical and echocardiographic variables in dogs with atrial fibrillation

“…Hence, L waves have been studied mainly in humans with LV hypertrophy and ischemic heart disease that generally cause more severe diastolic dysfunction compared to MMVD and DCM in dogs. 44,[46][47][48] Despite the observed high prevalence of L waves, we could not identify a significant prognostic role in dogs with AF. Hence, neither was significantly different MST found between dogs with and without L waves nor was the presence of L waves associated with cardiac death or all-cause mortality in Cox proportional hazards models.…”

“…These discrepancies are likely because of species‐related differences as well as different structural cardiac diseases and their effect on diastolic function. Hence, L waves have been studied mainly in humans with LV hypertrophy and ischemic heart disease that generally cause more severe diastolic dysfunction compared to MMVD and DCM in dogs 44,46‐48 …”

A Small Animal Model of Diabetic Heart Failure With Reduced Ejection Fraction

“…These two diseases are most often modeled in rodents using a variety of strategies, such as induction of genetic modifications, specific diet regimens, and exposure to chemical agents as well as surgical manipulation. 6) Even though laboratory rodents are still the most widely used animal model for human pathology, in the last decade the number of zebrafish models in biomedical studies has explosively increased. Zebrafish have several advantages including ex vivo fertilization and embryogenesis, optical transparency of embryos and larvae, rapid embryonic development, low housing costs, and genetic similarity with mammals.…”