Modeling Principle

The Pig Heart Failure Model establishes a stable and highly reproducible large-animal model of heart failure with reduced ejection fraction (HFrEF) via sustained rapid right ventricular pacing, which serves as a standardized SCI-recognized heart failure model in translational cardiovascular medicine. High-frequency ventricular electrical stimulation induces persistent tachycardia leading to excessive myocardial energy consumption, impaired cardiomyocyte calcium homeostasis and sustained activation of oxidative stress, gradually resulting in deteriorated myocardial systolic function. Long-term overload pacing triggers sarcoplasmic reticulum dysfunction, desensitization of β-adrenergic signaling pathway and increased cardiomyocyte apoptosis. Secondary left ventricular dilatation, elevated wall tension and overactivation of neuroendocrine systems (upregulation of RAAS and sympathetic nervous system) drive progressive ventricular remodeling, interstitial collagen deposition and diffuse myocardial fibrosis. Ultimately, a typical phenotype of chronic systolic heart failure develops: persistent reduction of left ventricular ejection fraction, enlarged left ventricular end-diastolic volume, decreased cardiac output, pulmonary circulation congestion and impaired exercise tolerance, accompanied by peripheral edema and elevated neuroendocrine factors, which faithfully recapitulates the pathophysiological progression of clinical chronic HFrEF patients.

Rodents exhibit remarkable discrepancies from human hearts in cardiac anatomical structure, myocardial fiber arrangement, baseline heart rate, coronary circulation and neuroendocrine regulation, and cannot accurately simulate ventricular remodeling in large mammals. The heart size, coronary branch configuration, cardiomyocyte electrophysiology, ventricular pressure-volume relationship, evolutionary pattern of myocardial fibrosis and circulating RAAS response of adult miniature pigs are highly homologous to human hearts. Permanent ventricular pacing electrodes are implanted via internal jugular vein, and programmed continuous high-frequency pacing is applied to controllably induce tachycardia cardiomyopathy progressing to heart failure. Modeling cycle, pacing frequency and sustained pacing duration can be quantitatively standardized with stable time window for successful modeling and low intra-group & batch-to-batch variation. Three successive phases can be clearly identified: subclinical compensated myocardial injury phase, progressive ventricular remodeling phase and stable decompensated heart failure phase. This model is suitable for preclinical efficacy and safety evaluation of novel heart failure drugs, cardiac resynchronization therapy (CRT), implantable device intervention, myocardial protective agents, anti-fibrotic targeted regimens and stem cell cardiac repair strategies, acting as a gold-standard large-animal heart failure model widely accepted by high-impact cardiovascular journals.

Modeling Success Criteria

Echocardiographic and Invasive Hemodynamic Phenotype

LVEF of sham control group remains ≥55% throughout the experiment with normal ventricular cavity size. LVEF of model group drops to ≤40% at modeling endpoint, meeting echocardiographic diagnostic threshold of HFrEF. Left ventricular end-diastolic volume (LVEDV) increases significantly compared with baseline, left ventricular fractional shortening (LVFS) decreases obviously and cardiac output declines. Invasive hemodynamic detection reveals elevated left ventricular end-diastolic pressure, reduced maximum ventricular systolic rising rate ±dP/dtmax and impaired ventricular filling, presenting typical hemodynamic characteristics of systolic heart failure. Extremely significant statistical difference exists between groups, confirming successful and stably reproducible modeling.

Quantitative Biochemical Gold-Standard Indexes in Circulation

Serum NT-proBNP, cTnI, AngⅡ, ALD and pro-inflammatory factors TNF-α, IL-6 in model group are markedly elevated compared with sham group. Expressions of ANP and BNP in myocardium are upregulated, and expression levels of fibrosis-related proteins Collagen Ⅰ/Ⅲ and TGF-β1 increase, indicating excessive neuroendocrine activation, cardiomyocyte injury and collagen deposition, which are highly consistent with biochemical characteristics of clinical chronic heart failure patients.

Myocardial Histopathological Characteristics

Combined staining of HE, Masson, WGA and TUNEL is applied to observe progressive myocardial injury and remodeling:

1. 2 weeks after pacing: mild cardiomyocyte edema, focal cardiomyocyte apoptosis and slight interstitial collagen proliferation;
2. 4 weeks after pacing: cardiomyocyte hypertrophy, disordered arrangement, continuous interstitial collagen deposition and formation of micro fibrotic lesions;
3. Terminal stage at 5 weeks after pacing: extensive cardiomyocyte hypertrophy, myofibril lysis, diffuse interstitial fibrosis, significantly increased number of apoptotic cardiomyocytes and obvious ventricular wall remodeling, which faithfully recapitulate characteristic pathological changes of chronic HFrEF.

Gold-Standard Indexes for Ventricular Remodeling Pathways

Continuous high-frequency pacing triggers persistent tachycardia, aggravates myocardial energy exhaustion and calcium transport dysfunction, and induces cardiomyocyte apoptosis. It activates circulating and local RAAS system and sympathetic nerve pathway, upregulates TGF-β1-mediated fibroblast activation and accelerates massive collagen synthesis and deposition leading to myocardial fibrosis. Increased myocardial stiffness and impaired systolic synchrony result in left ventricular dilatation and reduced ejection capacity, eventually progressing to decompensated heart failure. This model fully reconstructs the pathological cascade: persistent tachycardia → myocardial energy metabolism disorder + calcium homeostasis imbalance → cardiomyocyte injury and apoptosis → excessive neuroendocrine activation → ventricular remodeling and myocardial fibrosis → systolic heart failure, serving as the core academic evidence verifying model reliability and reproducibility.

Model Advantages

This model is a gold-standard rapid ventricular pacing-induced pig heart failure model widely adopted by cardiovascular SCI journals. The modeling workflow is standardized, closed-loop and controllable with unified pacing parameters, minor intra-group and batch-to-batch differences and excellent reproducibility. Miniature pigs share high homology with humans in cardiac anatomy, coronary circulation, myocardial electrophysiology, ventricular remodeling response and neuroendocrine regulation. The pathological progression of tachycardia-induced cardiomyopathy develops gradually, enabling division of compensated and decompensated phases suitable for sequential intervention researches. Minimally invasive pacing implantation is a mature surgical technique supporting long-term dynamic monitoring of cardiac function evolution. Comparative studies of multiple intervention regimens including drugs, devices and cell therapy can be carried out simultaneously. Experimental data are applicable for National Natural Science Foundation projects, master & doctoral dissertations and translational researches of novel heart failure drugs, and relevant achievements are readily accepted by high-impact cardiovascular SCI journals.

Research Applications

The Pig Heart Failure Model is mainly applied to elucidate the complete pathological mechanism: persistent tachycardia leads to myocardial energy metabolism disorder, disrupted calcium regulation, cardiomyocyte apoptosis, overactivation of RAAS and sympathetic nerve, progressive ventricular dilatation, myocardial collagen deposition and fibrosis, persistent decline of systolic function evolving into chronic HFrEF. It is used to screen and verify anti-heart failure small-molecule drugs, gene delivery vectors, myocardial protective preparations, optimized CRT device parameter regimens and stem cell repair strategies with functions of inhibiting excessive neuroendocrine activation, alleviating myocardial oxidative stress, blocking cardiomyocyte apoptosis, delaying ventricular remodeling, suppressing myocardial fibrosis, improving ventricular systolic synchrony and enhancing left ventricular ejection performance. It is extensively adopted for excavation of key molecular targets of ventricular remodeling in heart failure, elucidation of fibrosis regulatory network and preclinical efficacy evaluation of novel cardiovascular implantable devices. It serves as an essential standardized reproducible large-animal model in translational medicine of chronic systolic heart failure, cardiovascular pharmacology and cardiac device development.

pig heart failure large animal model, rapid ventricular pacing induced heart failure, chronic systolic heart failure, ventricular remodeling, myocardial fibrosis, heart failure with reduced ejection fraction (HFrEF), preclinical cardiovascular translational research