The Monocrotaline Rat Model of Pulmonary Arterial Hypertension-induced Right Heart Disease

Giulia Wan^*
*Correspondence: Giulia Wan, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria, Email:

Introduction

Pulmonary Arterial Hypertension (PAH) is a progressive vascular disease characterized by elevated pulmonary arterial pressure and vascular resistance, leading to right heart failure and death. Animal models are crucial for understanding the pathophysiology of PAH and for developing new therapies. The monocrotaline rat model is one of the most widely used models to study PAH and right heart disease. This short communication discusses the characteristics, pathophysiological mechanisms, and applications of the MCT rat model in preclinical PAH research, along with its advantages and limitations. Pulmonary Arterial Hypertension (PAH) is a severe and life-threatening condition characterized by progressive remodeling of the pulmonary vasculature, increased Pulmonary Vascular Resistance (PVR), and Right Ventricular Hypertrophy (RVH), eventually leading to right heart failure. The disease is defined by a Mean Pulmonary Artery Pressure (mPAP) greater than 20 mmHg at rest, with no left heart disease. The survival rate remains low despite therapeutic advances, highlighting the need for better understanding of its pathogenesis and development of effective treatments.

Description

Animal models are critical for studying PAH and the subsequent development of right heart disease, as they allow researchers to examine disease mechanisms and evaluate potential therapies in controlled settings. The monocrotaline rat model has become a widely used and well-established experimental system for inducing Pulmonary Hypertension (PH) and right heart failure, mimicking many of the features seen in human PAH. This model reliably induces pulmonary vascular injury, progressive PAH, and right ventricular dysfunction, providing valuable insights into the underlying mechanisms of disease. This article reviews the use of the monocrotaline rat model in PAH research, emphasizing its pathophysiological features, key applications, and limitations in studying PAH-induced right heart disease. Monocrotaline is a pyrrolizidine alkaloid derived from Crotalaria plants. In animal studies, MCT is typically administered via a single intraperitoneal or subcutaneous injection. Following systemic absorption, MCT undergoes metabolic activation in the liver, producing toxic metabolites that target the pulmonary vasculature, primarily the endothelium. These metabolites initiate a cascade of vascular injury and inflammation, leading to pulmonary arterial hypertension within 2-4 weeks of administration [1].

MCT metabolites preferentially damage the pulmonary endothelial cells, triggering endothelial dysfunction. This leads to reduced production of vasodilators like nitric oxide (NO) and prostacyclin, while enhancing vasoconstrictor pathways, including endothelin-1 (ET-1) and thromboxane A2. Endothelial injury is a hallmark of the early stages of PAH in this model. Following endothelial damage, an inflammatory response occurs in the pulmonary vasculature. Inflammatory cytokines, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and transforming growth factor-beta (TGF-β), are upregulated, leading to the recruitment of immune cells, including macrophages and lymphocytes, into the perivascular spaces. Inflammatory mediators stimulate the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs), contributing to thickening of the pulmonary arterial walls. The media and intima layers of the arteries become progressively hypertrophied, leading to increased vascular resistance and elevated pulmonary arterial pressure. This remodeling process resembles the pulmonary arterial changes seen in human PAH [2].

As the pulmonary arterial pressure rises, the Right Ventricle (RV) is subjected to increased afterload, resulting in compensatory hypertrophy. Over time, the right ventricle decompensates, leading to RV dilation, dysfunction, and ultimately, heart failure. This progression closely mirrors the right heart disease observed in clinical PAH. Following monocrotaline injection, pulmonary hypertension typically develops within 2-3 weeks. Hemodynamic measurements using right heart catheterization confirm elevated mPAP, increased pulmonary vascular resistance (PVR), and a reduced cardiac output. These findings are consistent with the hemodynamic profile of PAH in humans. Histological examination of the lung vasculature reveals medial hypertrophy, intimal hyperplasia, and perivascular inflammation, further corroborating the features of PAH in the MCT model. Right ventricular hypertrophy is a hallmark of the MCT model. The increased afterload imposed by elevated PVR forces the right ventricle to undergo compensatory hypertrophy, characterized by thickening of the ventricular walls and increased right ventricular mass. This can be quantified by calculating the RV/LV+S (right ventricle to left ventricle plus septum) weight ratio, which serves as a reliable index of RV hypertrophy [3].

Over time, the hypertrophied right ventricle becomes dysfunctional, as indicated by reduced Right Ventricular Ejection Fraction (RVEF) and impaired systolic function. This mimics the pathophysiology of human right heart failure secondary to PAH, allowing researchers to study both the compensatory and decompensatory phases of right ventricular adaptation. Inflammation is a key driver of PAH progression in the MCT model. The infiltration of immune cells into the pulmonary vasculature, coupled with the release of pro-inflammatory cytokines, contributes to the chronic remodeling of the pulmonary arteries. This results in thickened vascular walls, occlusion of small pulmonary arterioles, and increased resistance to blood flow. The structural changes in the pulmonary arteries are reminiscent of the vascular remodeling observed in PAH patients. The MCT model provides a robust platform for investigating the molecular pathways underlying vascular remodeling, including the roles of Hypoxia-Inducible Factors (HIFs), growth factors like Platelet-Derived Growth Factor (PDGF), and Bone Morphogenetic Proteins (BMPs). Understanding these pathways is essential for identifying therapeutic targets in PAH.

The monocrotaline rat model has been instrumental in advancing our understanding of PAH and right heart disease, serving as a preclinical tool for testing new therapeutic strategies. The MCT model allows researchers to study the molecular and cellular processes driving pulmonary vascular remodeling and right heart failure. For instance, studies have shown that pathways involving NO, prostacyclin, and endothelin-1 are disrupted in the MCT model, leading to endothelial dysfunction and excessive vasoconstriction. By exploring these mechanisms, researchers have identified potential targets for therapeutic intervention, such as PDE5 inhibitors, endothelin receptor antagonists, and prostacyclin analogs. The MCT model is widely used to evaluate the efficacy of novel pharmacological agents in the treatment of PAH. For example, the success of sildenafil (a PDE5 inhibitor) and bosentan (an endothelin receptor antagonist) in the MCT model contributed to their eventual use in human PAH therapy. Additionally, novel drugs targeting inflammatory pathways, vascular remodeling, or oxidative stress are frequently tested in this model to assess their impact on pulmonary pressures, vascular structure, and right heart function [4].

A major advantage of the MCT model is its ability to simulate the progression from compensated RV hypertrophy to decompensated right heart failure. This aspect of the model is particularly valuable for studying the mechanisms of right ventricular adaptation and dysfunction in PAH. Researchers use the MCT model to investigate the molecular signals involved in right ventricular remodeling, including those related to mitochondrial function, oxidative stress, and fibrosis. Given the complex pathophysiology of PAH, combination therapies targeting multiple pathways are often more effective than monotherapy. The MCT model provides an ideal platform for testing combination treatments, such as vasodilators with anti-inflammatory agents or antifibrotic drugs. By examining the synergistic effects of drug combinations, researchers can identify optimal therapeutic strategies for managing PAH. The MCT model reliably induces PAH and right ventricular hypertrophy, making it a reproducible and consistent model for PAH research. The model requires a single MCT injection, making it relatively simple to implement in preclinical studies [5].

Conclusion

The MCT model mimics many of the key features of human PAH, including endothelial dysfunction, vascular remodeling, and right ventricular failure. Compared to other models of PAH (e.g., hypoxia or genetic models), the MCT model is cost-effective and accessible for most research laboratories. The MCT model relies on toxin-induced vascular injury, which may not fully recapitulate the idiopathic or genetic forms of human PAH. This raises questions about the translatability of findings to all forms of PAH. PAH develops relatively quickly in the MCT model (within 2-4 weeks), which differs from the slower progression of human PAH.

Acknowledgement

None.

Conflict of Interest

None.

References

1. Naeije, Robert and Alessandra Manes. "The right ventricle in pulmonary arterial hypertension." Eur Respir Rev 23 (2014): 476-487.

Google Scholar, Crossref, Indexed at

2. Ekman, Inger, John GF Cleland, Bert Andersson and Karl Swedberg. "Exploring symptoms in chronic heart failure." Eur J Heart Fail 7 (2005): 699-703.

Google Scholar, Crossref, Indexed at

3. Nieminen, Markku S., Dirk Brutsaert, Kenneth Dickstein and Helmut Drexler, et al. "EuroHeart Failure Survey II (EHFS II): A survey on hospitalized acute heart failure patients: Description of population." Eur Heart J 27 (2006): 2725-2736.

Google Scholar, Crossref, Indexed at

4. Maeder, Micha T., Lukas Weber, Susanne Pohle and Joannis Chronis, et al. "Impact of the 2022 pulmonary hypertension definition on haemodynamic classification and mortality in patients with aortic stenosis undergoing valve replacement." Eur Heart J Open 4 (2024): oeae037.

Google Scholar, Crossref, Indexed at

5. Deng, Zemin, Jane H. Morse, Susan L. Slager and Nieves Cuervo, et al. "Familial primary pulmonary hypertension (Gene PPH1) is caused by mutations in the bone morphogenetic protein receptor–II gene." Am J Hum Genet 67 (2000): 737-744.

Google Scholar, Indexed at