Minoxidil produces several cardiac lesions in animals. Some are characteristic of agents that cause tachycardia and diastolic hypotension (beta-agonists like isoproterenol, arterial dilators like hydralazine) while others are produced by a narrower range of agents with arterial dilating properties. The significance of these lesions for humans is not clear, as they have not been recognized in patients treated with oral minoxidil at systemically active doses, despite formal review of over 150 autopsies of treated patients.

(a)
    The most characteristic lesion of minoxidil, seen in rat, dog, and minipig (but not monkeys) is focal necrosis of the papillary muscle and subendocardial areas of the left ventricle. These lesions appear rapidly, within a few days of treatment with doses of 0.5 to 10 mg/kg/day in the dog and minipig, and are not progressive, although they leave residual scars. They are similar to lesions produced by other peripheral arterial dilators, by theobromine, and by beta-adrenergic receptor agonists such as isoproterenol, epinephrine, and albuterol. The lesions are thought to reflect ischemia provoked by increased oxygen demand (tachycardia, increased cardiac output) and relative decrease in coronary flow (decreased diastolic pressure and decreased time in diastole) caused by the vasodilatory effects of these agents coupled with reflex or directly induced tachycardia. Papillary muscle/subendocardial necrosis   

(b)
    After acute oral minoxidil treatment (0.5 to 10 mg/kg/day) in dogs and minipigs, hemorrhagic lesions are seen in many parts of the heart, mainly in the epicardium, endocardium, and walls of small coronary arteries and arterioles. In minipigs the lesions occur primarily in the left atrium while in dogs they are most prominent in the right atrium, frequently appearing as grossly visible hemorrhagic lesions. With exposure of 1–20 mg/kg/day in the dog for 30 days or longer, there is replacement of myocardial cells by proliferating fibroblasts and angioblasts, hemorrhage and hemosiderin accumulation. These lesions can be produced by topical minoxidil administration that gives systemic absorption of 0.5 to 1 mg/kg/day. Other peripheral dilators, including an experimental agent, nicorandil, and theobromine, have produced similar lesions. Hemorrhagic lesions   

(c)
    A less fully studied lesion is focal epicarditis, seen in dogs after 2 days of oral minoxidil. More recently, chronic proliferative epicarditis was observed in dogs treated topically twice a day for 90 days. In a one year oral dog study, serosanguinous pericardial fluid was seen. Epicarditis   

(d)
    Oral and topical studies in rats, dogs, monkeys (oral only), and rabbits (dermal only) show cardiac hypertrophy and dilation. This is presumed to represent the consequences of prolonged fluid overload; there is preliminary evidence in monkeys that diuretics partly reverse these effects. Hypertrophy and Dilation   


Autopsies of over 150 patients who died of various causes after receiving minoxidil for hypertension have not revealed the characteristic hemorrhagic (especially atrial) lesions seen in dogs and minipigs. While areas of papillary muscle and subendocardial necrosis were occasionally seen, they occurred in the presence of known pre-existing coronary artery disease and were also seen in patients never exposed to minoxidil in another series using similar, but not identical, autopsy methods.