4.9.2 Cardiovascular Disease Models

Cardiovascular disease models allow the efficacy of candidate antihypertensive, anti-ischaemic, and cardioprotective agents to be evaluated using readily...

Cardiovascular disease models allow the efficacy of candidate antihypertensive, anti-ischaemic, and cardioprotective agents to be evaluated using readily quantifiable physiological endpoints such as blood pressure, infarct size, and cardiac function.

Hypertension — DOCA-Salt and Spontaneously Hypertensive Rat (SHR) Models

Hypertension, a chronic elevation of systemic arterial blood pressure, is modelled using both chemically induced and genetic approaches. In the deoxycorticosterone acetate (DOCA)-salt model, uninephrectomised rats receive DOCA (25 mg/kg subcutaneously, twice weekly) combined with 1% saline as drinking water, producing mineralocorticoid-driven sodium and water retention and consequent volume-dependent hypertension over two to four weeks. The Spontaneously Hypertensive Rat (SHR), a genetically inbred strain that develops hypertension without any experimental intervention, models the polygenic, essential (primary) hypertension that accounts for the majority of human cases. Blood pressure in both models is measured non-invasively by tail-cuff plethysmography or, for greater precision, by radiotelemetry, with captopril or losartan serving as reference antihypertensive standards. The DOCA-salt model is particularly useful for studying mineralocorticoid- and volume-dependent hypertension mechanisms, while the SHR strain is preferred for studying the broader pathophysiology and end-organ (cardiac and renal) consequences of chronic essential hypertension, including left ventricular hypertrophy.

Myocardial Infarction — Isoproterenol-Induced Model

Myocardial infarction results from prolonged coronary ischaemia causing irreversible cardiomyocyte necrosis. The isoproterenol-induced model exploits the observation that supraphysiological doses of the beta-adrenergic agonist isoproterenol (typically 85–150 mg/kg administered subcutaneously on two consecutive days in rats) produce myocardial necrosis through a combination of excessive oxygen demand, coronary vasospasm, and direct catecholamine-mediated calcium overload toxicity, without requiring surgical coronary occlusion. Cardiac injury is assessed through serum cardiac biomarkers (creatine kinase-MB, cardiac troponin, and lactate dehydrogenase), electrocardiographic changes (ST-segment elevation), and histopathological evidence of myocardial necrosis and inflammatory infiltrate. Standard cardioprotective reference agents vary by mechanism under investigation but commonly include beta-blockers or antioxidant compounds, reflecting the oxidative-stress component of isoproterenol-induced injury. The principal advantage of this model is its technical simplicity relative to surgical infarction models; its main limitation is that the mechanism of injury (catecholamine toxicity) differs mechanistically from the coronary thrombotic occlusion that underlies most human myocardial infarction.

Heart Failure — Coronary Artery Ligation Model

Chronic heart failure following myocardial infarction is modelled surgically by permanent ligation of the left anterior descending coronary artery in rats or mice, producing a discrete infarct followed, over subsequent weeks, by progressive ventricular remodelling, dilation, and contractile dysfunction that closely mirrors the pathophysiological sequence of post-infarction heart failure in humans. Cardiac function is assessed longitudinally using echocardiography (ejection fraction, fractional shortening, and chamber dimensions), invasive haemodynamic measurement (via a pressure-volume catheter for load-independent contractility indices), and terminal histopathological assessment of infarct size and interstitial fibrosis. ACE inhibitors, angiotensin receptor blockers, and beta-blockers, the cornerstone pharmacological classes of human heart failure therapy, serve as standard reference comparators. This model offers excellent translational relevance to the most common clinical aetiology of heart failure but demands substantial surgical expertise, longer study durations (typically four to eight weeks to allow remodelling to develop), and specialised, often costly, imaging or haemodynamic equipment.