From joints to vessels: How rheumatoid arthritis therapy alters the fate of the heart

Table 5 The negative effects of methotrexate on the cardiovascular system

Effect	Pathogenesis
Cardiomyopathy	Folate depletion → impaired myocardial energy metabolism Oxidative stress and mitochondrial dysfunction
	Accumulation of adenosine → vasodilation and reduced contractility
Accelerated atherosclerosis	Hyperhomocysteinemia (due to folate antagonism) → endothelial dysfunction
Vascular toxicity	Endothelial injury due to oxidative stress
	Reduced nitric oxide bioavailability
	Increased homocysteine → vascular smooth muscle proliferation
Hypertension	Renal toxicity → sodium retention
	Endothelial dysfunction → impaired vasoregulation
Heart failure	Direct myocardial toxicity (similar to cardiomyopathy)
	Fluid retention due to renal impairment
Arrhythmias	Electrolyte imbalances (e.g., hypokalemia from nephrotoxicity) QT prolongation (rare, linked to high-dose MTX)

MTX: Methotrexate.