HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation

Both obesity and type 2 diabetes are important risk factors for the development of heart failure with a preserved ejection fraction (HFpEF), and both disorders increase the risk of systemic thromboembolic events. Traditionally, the risk of stroke has been explained by the strong association of these disorders with atrial fibrillation (AF). However, adiposity and diabetes are risk factors for systemic thromboembolism, even in the absence of AF, because both can lead to the development of an inflammatory and fibrotic atrial and ventricular myopathy, the 2 major elements of HFpEF. Atrial myopathy: 1) exacerbates pulmonary venous hypertension and exertional dyspnea; 2) leads to decreased flow, thrombogenesis, and systemic thromboembolization; and 3) often clinically manifests as AF; however, the relationship between AF and thromboembolism is unclear. Atrial fibrosis predisposes to thrombus formation, even in the absence of AF, and most thromboembolic events bear a poor temporal relationship to the occurrence of AF, whereas HFpEF (and the accompanying atrial disease) predicts stroke in patients with or without AF. Furthermore, rhythm control does not reduce the risk of stroke, although it reduces the burden of AF. These observations support the primacy of atrial myopathy as a critical component of HFpEF, rather than AF, as the mediator of systemic thromboembolism in obesity or diabetes. The well-established association between AF and stroke is likely explained by the fact that AF is a biomarker of more advanced inflammatory atrial disease but not necessarily a direct causal mechanism.