Large Animal Models of Heart Failure

Highlights • Preclinical large animal models play a critical and expanding role in translating basic science findings to the development and clinical approval of novel cardiovascular therapeutics.• This state-of-the-art review outlines existing methodologies and physiological phenotypes of several HF models developed in large animals. A comprehensive list of porcine, ovine, and canine models of disease are presented, and the translational importance of these studies to clinical success is highlighted through a brief overview of recent devices approved by the FDA alongside associated clinical trials and preclinical animal reports.• Increasing the use of large animal models of HF holds significant potential for identifying new mechanisms underlying this disease and providing valuable information regarding the safety and efficacy of new therapies, thus, improving physiological and economical translation of animal research to the successful treatment of human HF.

HF negatively affects the economy, costing several billions of dollars each year (z$70 billion by 2030).
A defining characteristic of HF is the inability of the heart to pump enough blood to the body, which leads to poor quality of life for patients with this condition.
In the past 30 years, the diagnosis of HF has evolved 2 primary categories: 1) HF with reduced ejection fraction (HFrEF), characterized by a resting ejection fraction (EF) of #40% and traditionally referred to as systolic HF; and 2) HF with preserved ejection fraction (HFpEF), characterized by a resting EF of $50% and traditionally referred to as diastolic HF (2,3).
Recently, a third category of HF was introduced to the field, referred to as HF with midrange EF, characterized by a resting EF range from 40% to 50% (4).
The combination of numerous risk factors (physical inactivity), comorbidities (obesity, hypertension, type 2 diabetes, chronic kidney disease), and disease modifiers (age, sex) associated with HF has made improving therapeutic options for treating the overall syndrome difficult. Contributing to these difficulties is the lack of ideal animal models that reliably replicate most of the pathophysiological features often found in human HF. Large animal models of HF (e.g., pigs, sheep, etc.) have some advantages in terms of clinical translation given key determinants of myocardial work and energy consumption, such as left ventricular (LV) wall tension, heart rate, and vascular wall-tolumen ratios are more similar to humans (5-13).
Thus, it could be argued that the use of preclinical

HF INDUCED BY PRESSURE OVERLOAD
Chronic pressure overload resulting from aortic valve stenosis or systemic hypertension may ultimately lead to HF (14,15). Over time, sustained increases in myocardial work required to overcome chronic elevations in afterload can induce structural, physiological, and molecular changes that result in pathological cardiac remodeling (16)(17)(18). In addition, vascular dysfunction in numerous organs, including the heart, brain, skeletal muscle, and renal systems, are negatively affected and may further contribute to cardiovascular dysfunction. To maintain normal function (often measured as EF), the heart transitions to a compensated stage characterized by concentric LV hypertrophy and increased myocardial stiffness associated with decreased myocardial relaxation, increased LV filling pressure, pulmonary congestion, and decreased cardiac reserve (16,17,19,20).     Aortic banding was also used to induce chronic pressure overloadÀinduced HF in both 3-and 8month-old Yucatan miniature swine using a 50-or 70-mm Hg systolic pressure gradient, respectively, placed on the ascending aorta over 6 months (see

HF INDUCED BY MYOCARDIAL INFARCTION
Cardiac cell death associated with aberrant heart dysfunction is the main characteristic of a myocardial infarction (MI), which can ultimately lead to HF (68,69). This catastrophic event occurs due to interruption of blood flow to a discrete area of the myocardium that results from partial or complete      Table 2.
The impact of TandemHeart on hemodynamics and cardiac morphology has been investigated in porcine models of acute MI or ventricular arrhythmia (151À155). For example, TandemHeart was implanted during LCx occlusion (30 min) and effectively unloaded the LV while maintaining systemic pressure, which was evident via decreased stroke volume, end-diastolic volume, and EDP (151). Impella devices have also been investigated in swine (152,(156)(157)(158)(159)(160)(161) and ovine (162,163)  At comparable flow rates, TandemHeart decreased LV preload (end-diastolic volume), stroke volume, and contractility (dP/dt max , stroke work, pre-load recruitable stroke work) to a greater extent than the Impella.
Although the preceding studies reflect successful translational interactions and outcomes between large animal and human studies, the process is not infallible. One example is the CentriMag Circulatory ventricular assist device (Abbott Laboratories, Abbott Park, Illinois), which was recalled due to a calibrating system error linked to electromagnetic interference, which caused the device to stop (https://www.fda. gov/medical-devices/medical-device-recalls/abbottrecalls-centrimag-circulatory-support-system-motordue-pump-and-motor-issues). Difficulties with the device occurred after FDA approval, despite several preclinical studies in both sheep (164À166) and pigs (167), 3 registered clinical trials (