Impact of diabetes mellitus on mortality and atrial fibrillation in hypertrophic cardiomyopathy: A systematic review and meta-analysis

Table 2 Possible pathophysiological factors behind the increased risk in diabetes mellitus patients

Mechanism	Explanation	Associated outcome(s)	Supporting evidence with references
Myocardial fibrosis	Chronic hyperglycemia and insulin resistance promote myocardial and atrial collagen deposition. This stiffens the myocardium and disrupts conduction	AF, ACM	Fibrosis contributes to arrhythmogenic substrate and diastolic dysfunction, increasing AF risk and overall mortality[13,14,29,34,37]
Atrial remodeling and LA dilation	Elevated LV filling pressures and impaired diastolic function lead to left atrial enlargement and structural remodeling	AF	LA dilation facilitates reentry circuits and AF development in HCM patients with DM[14,20,36]
Microvascular dysfunction	DM causes capillary rarefaction and endothelial dysfunction, reducing perfusion and increasing ischemia risk	ACM	Ischemia and oxygen mismatch promote myocardial injury, fibrosis, and adverse outcomes[14,29,30]
Autonomic imbalance	DM leads to sympathetic overactivity and reduced vagal tone, predisposing to electrical instability	AF, SVT, NSVT	Increased sympathetic tone and reduced HR variability raise arrhythmia susceptibility[14,31]
Oxidative stress and inflammation	Hyperglycemia generates ROS and pro-inflammatory cytokines that damage cardiomyocytes	AF, ACM	Oxidative stress leads to apoptosis, impaired function, and fibrotic remodeling[32,33,39]
Disrupted calcium handling	ROS activates CaMKII, resulting in abnormal calcium influx and delayed afterdepolarizations	AF, VT, NSVT	Calcium overload causes ectopic activity and proarrhythmic conditions[32]
Elevated microRNA-29 expression	Insulin resistance induces microRNA-29, which stimulates myocardial hypertrophy and fibrosis	AF, ACM	microRNA-29a is a profibrotic biomarker found elevated in HCM and DM[34]
Structural remodeling	Combined effects of HCM and DM cause exaggerated hypertrophy, LV wall thickness, and chamber dilation	AF, ACM	Reflects a more advanced phenotype with increased mortality and arrhythmic burden[14,20,30]
Proarrhythmic medication patterns	High beta-blocker used in patients developing AF suggests suboptimal rhythm control despite standard therapy	AF	Patients with AF had higher baseline beta-blocker use than those in sinus rhythm, questioning its protective role[20]
Comorbidities (HTN, OSA, CAD)	These amplify myocardial stress, systemic inflammation, and fibrosis when combined with DM	AF, ACM	Hypertension, CAD, and sleep apnea synergistically raise cardiovascular risk in HCM-DM populations[14,16,34]

LA: Left atrium; HTN: Hypertension; OSA: Obstructive sleep apnea; CAD: Coronary artery disease; LV: Left ventricle; DM: Diabetes mellitus; ROS: Reactive oxygen species; CAMKII: Calcium-dependent protein kinase 2; HCM: Hypertrophic cardiomyopathy; AF: Atrial fibrillation; ACM: All-cause mortality; SVT: Supraventricular tachycardia; NSVT: Non-sustained ventricular tachycardia; VT: Ventricular tachycardia; HR: Heart rate.