Modeling Principle

The pig myocarditis model is a SCI gold-standard large-animal myocardial inflammatory injury pathological model constructed by virus induction or immune mediation, which accurately simulates the complete pathological process of clinical viral myocarditis and autoimmune myocarditis, including myocardial inflammatory infiltration, cardiomyocyte edema and necrosis, oxidative stress injury, immune disorder, long-term myocardial fibrosis and cardiac dysfunction. It completely compensates for the significant research deficiencies of rodent small animals such as mice and rats in cardiac anatomical structure, heart rate rhythm, myocardial fiber arrangement and immune response mechanism compared with humans. Porcine cardiac anatomical structure, myocardial thickness, ventricular cavity proportion, coronary circulation distribution, myocardial energy metabolism pattern and cardiovascular immune regulatory pathways are highly homologous to humans. The heart rate range, myocardial systolic and diastolic rhythm, and inflammatory injury repair mechanism are highly consistent with clinical human myocardial lesions. The laws of myocardial edema, inflammatory infiltration, cell necrosis and fibrotic remodeling after lesions fully conform to the disease progression of clinical myocarditis patients, making it the non-human mammalian gold-standard large-animal model with the highest clinical fitting degree and translational reliability in cardiovascular inflammatory disease translational research. Standardized modeling virus or immune adjuvant is injected intraperitoneally or intravenously to break the body's myocardial immune tolerance, trigger a systemic immune inflammatory cascade reaction, and promote a large number of inflammatory cells to directionally infiltrate myocardial tissues. Massive release of inflammatory factors induces oxidative stress injury, mitochondrial dysfunction, apoptosis and necrosis of cardiomyocytes, activates TLR4/NF-κB inflammatory pathway, NLRP3 inflammasome and TGF-β myocardial fibrosis pathway, gradually forming local myocardial inflammatory lesions, diffuse myocardial injury and interstitial edema. With disease progression, abnormal collagen deposition, scar remodeling and cardiac dysfunction gradually occur in myocardial interstitium, which fully recapitulates the classic pathological evolution chain of human myocarditis: immune activation-inflammatory infiltration-cardiomyocyte injury-persistent inflammation-myocardial fibrosis-cardiac dysfunction. With stable myocardial injury phenotype, clear inflammatory temporal gradient, minimal individual differences and excellent modeling reproducibility, and no spontaneous cardiac inflammation and congenital cardiovascular abnormalities, this model serves as an authoritative SCI standardized large-animal model for the elucidation of myocarditis pathogenesis, preclinical evaluation of new drugs and cardiovascular targeted preparations for acute myocardial protection, inflammation blockade, anti-myocardial fibrosis and cardiac function improvement.

Modeling Success Criteria

Macroscopic Signs and Electrocardiographic Phenotypes

The experimental pigs in the blank control group had stable vital signs, regular heart rate and rhythm, normal electrocardiogram waveforms, no premature beats, ST segment deviation, T wave inversion and other abnormalities, with ruddy myocardial color, uniform texture and smooth surface without congestion and edema. The model group showed systemic inflammatory manifestations such as listlessness, decreased activity and reduced appetite after modeling. The electrocardiogram showed characteristic abnormalities, including sinus arrhythmia, ventricular premature beats, ST segment elevation/depression, flat or inverted T wave. Mild congestion, edema and local punctate or patchy inflammatory lesions were visible in myocardial tissues with no large-area necrosis and bleeding. The macroscopic signs and electrocardiographic abnormalities were consistent with the typical phenotypes of clinical acute myocarditis, confirming the preliminary formation of the model.

Quantitative Serum Myocardial Injury Indexes

Compared with the blank control group, the core serum myocardial injury indexes of the model group were extremely significantly increased at each time point: the levels of cardiac troponin cTnI/cTnT, creatine kinase CK, isoenzyme CK-MB, lactate dehydrogenase LDH and aspartate aminotransferase AST were significantly upregulated, presenting typical injury characteristics of cardiomyocyte necrosis, cell membrane rupture and content release. The variation rule of these biochemical indexes is highly consistent with the serological diagnostic criteria of acute myocardial injury in clinical myocarditis patients, serving as the core quantitative gold standard basis for successful modeling.

Myocardial Histopathological Characteristics

HE staining of myocardial tissues showed characteristic pathological injuries of myocarditis in the model group: in the acute stage, myocardial fibers were swollen and disorderly arranged, partial muscle fibers were dissolved and broken, and massive diffuse infiltration of inflammatory cells (neutrophils, lymphocytes, macrophages) and obvious interstitial edema were observed in myocardial interstitium; in the subacute stage, inflammatory cell infiltration persisted, accompanied by a large number of cardiomyocyte apoptosis, necrosis and local lesion formation; in the chronic stage, inflammatory cell infiltration was reduced, with abnormal proliferation and disordered deposition of collagen fibers in myocardial interstitium. Masson staining and Sirius red staining showed obvious myocardial fibrosis and scar tissue formation, which fully recapitulates the characteristic pathological evolution process of human myocarditis: inflammatory infiltration-myocardial necrosis-persistent inflammation-interstitial fibrosis, with highly specific pathological phenotypes and high modeling stability.

Core Inflammatory and Fibrosis Pathway Indexes

The expression of core pro-inflammatory factors TNF-α, IL-6 and IL-1β in myocardial tissues of the model group was significantly upregulated, the TLR4/NF-κB inflammatory pathway and NLRP3 inflammasome were continuously activated, a large amount of oxidative stress products ROS and MDA accumulated in myocardium, the activities of antioxidant factors SOD and GSH-Px were significantly decreased, and the cardiomyocyte apoptosis rate was greatly increased. In the later stage of the disease course, the TGF-β/Smad fibrosis pathway was abnormally activated with disordered collagen anabolism, which fully conforms to the core pathogenic mechanism of myocarditis: immune inflammation activation-oxidative stress injury-cardiomyocyte apoptosis-long-term fibrotic remodeling, serving as the core academic basis for successful model construction.

Model Advantages

As a SCI-certified exclusive large-animal gold-standard model for myocarditis, it completely solves the research shortcomings of rodent small animals that their myocardial fiber structure, heart rate rhythm, immune response and fibrosis process are greatly different from humans, failing to truly simulate the clinical myocarditis course and long-term cardiac function damage. Porcine myocardial tissue structure, coronary circulation, myocardial energy metabolism and immune inflammatory regulation mechanism are highly homologous to humans, and the laws of inflammatory infiltration, characteristics of cardiomyocyte damage, fibrosis remodeling mode and electrocardiographic abnormal phenotypes are completely consistent with the disease course of clinical patients with viral/immune myocarditis. Standardized virus/immune induction modeling is adopted with pure modeling mechanism and no mechanical trauma interference. The disease course is clearly staged with distinct pathological phenotype stratification in acute, subacute and chronic stages, which perfectly recapitulates the complete clinical course of myocarditis: acute inflammation-persistent injury-chronic fibrosis. It has high modeling rate, minimal inter-group differences, excellent reproducibility and stable cardiac function damage phenotype. It is specially suitable for new drug target verification, active ingredient screening of traditional Chinese medicine and large-animal preclinical translational evaluation of cardiovascular preparations for myocarditis anti-inflammation, anti-oxidation, cardiomyocyte apoptosis inhibition, myocardial fibrosis resistance and cardiac function improvement. With clear project mechanism, extremely high translational value and high recognition in high-score SCI journals, it is fully applicable for National Natural Science Foundation declaration, master and doctoral project opening, academic papers and cardiovascular translational medical research.

Research Applications

Thepig myocarditis model is corely applied to basic cardiovascular research on virus/immune-mediated myocardial inflammatory infiltration, myocardial oxidative stress injury, cardiomyocyte apoptosis, NLRP3/NF-κB inflammatory pathway activation and myocardial interstitial fibrotic remodeling. It is specially used for screening and evaluating traditional Chinese medicine compounds, natural active ingredients, small chemical molecules and cardiovascular targeted preparations with effects of inhibiting myocardial inflammatory cascade, anti-oxidative damage, reducing cardiomyocyte apoptosis, blocking myocardial fibrosis progression, protecting myocardial function and improving electrocardiographic disorder. It is widely used in the exploration of myocarditis pathogenic targets, elucidation of inflammatory immune regulation mechanisms and large-animal preclinical translational verification of anti-inflammatory and cardiac protective drugs, serving as an indispensable standardized large-animal gold-standard model in the fields of viral myocarditis, immune myocardial injury, myocardial fibrosis and inflammatory cardiomyopathy research.

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