The following are key points to remember from this state-of-the-art article about heart failure with preserved ejection fraction (HFpEF) as the substrate for stroke in obesity and diabetes independent of atrial fibrillation (AF):

1. 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.
2. Adiposity and diabetes are risk factors for systemic thromboembolism, even in the absence of AF, since both can lead to the development of an inflammatory and fibrotic atrial and ventricular myopathy, the two major elements of HFpEF.
3. The development of a left atrial myopathy is central to the pathogenesis of both AF and HFpEF. The atrial myopathy: 1) exacerbates pulmonary venous hypertension and exertional dyspnea; 2) leads to decreased flow, thrombogenesis, and systemic thromboembolization; and 3) is often clinically manifest as AF; however, the relationship between AF and thromboembolism is unclear.
4. 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.
5. AF and HFpEF are closely linked in epidemiological studies. AF is a powerful predictor of the development of HFpEF; the presence of AF increases the likelihood of subsequent HFpEF (by up to fourfold) across diverse populations, and it precedes the diagnosis of HFpEF by 4-10 years. At the same time, most patients with HFpEF are destined to develop AF, if AF is not already evident. Among those in sinus rhythm, one-third with a diagnosis of HFpEF will develop AF during the following 3-5 years; eventually, two-thirds of patients with HFpEF will manifest clinically overt AF during the natural history of the disease. These epidemiological studies underestimate the true convergence of AF and HFpEF. Asymptomatic paroxysms of AF occur for years before a formal diagnosis of AF.
6. Elusive role of AF as a proximate cause of thromboembolic stroke: Physicians have long believed that the chaotic contraction seen in AF drives thrombus formation; however, it is the decrease in flow velocity in the left atrium (due to atrial myopathy) that predisposes to spontaneous echo contrast and thromboembolization; indeed, mitral regurgitation protects against left atrial stasis even though it promotes chamber dilatation and increases the likelihood of AF. The fibrotic process in the left atrium is a primary determinant of the impairment of the chamber’s reservoir and conduit functions, even in the absence of AF; inflammation and fibrosis may also enhance the thrombogenic potential of the atrial endocardium. Accordingly, atrial fibrosis is independently associated with left atrial thrombus, and the extensive atrial fibrosis in patients with long-standing AF predisposes to the occurrence of stroke, independently of left atrial chamber size.

Perspective: This article is a must read for all clinicians involved in the management of HFpEF, particularly, those who are designing clinical trials on HFpEF patients. The premise that AF is a risk marker for stroke has been discussed earlier in N Engl J Med 1990;323:1556-8, and nearly two decades later, this postulate holds true.

Keywords: Adiposity, Arrhythmias, Cardiac, Atrial Fibrillation, Biomarkers, Diabetes Mellitus, Dilatation, Dyspnea, Endocardium, Heart Failure, Hypertension, Inflammation, Mitral Valve Insufficiency, Obesity, Risk Factors, Secondary Prevention, Stroke, Stroke Volume, Thromboembolism, Thrombosis, Vascular Diseases

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