Research Spotlight

Packer, M., C. S. P. Lam, L. H. Lund and M. M. Redfield (2020). “Interdependence of Atrial Fibrillation and Heart Failure With a Preserved Ejection Fraction Reflects a Common Underlying Atrial and Ventricular Myopathy.” Circulation 141(1): 4-6.

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Atrial fibrillation (AF) and heart failure with a preserved ejection fraction (HFpEF) are closely intertwined disorders that afflict millions of people, many of whom are obese or have diabetes mellitus or other proinflammatory conditions. Conceivably, the convergence of AF and HFpEF might be explained by 2 distinctly different frameworks. On the one hand, it is possible that each phenotype might lead sequentially to the other (ie, the increased left ventricular [LV] filling pressure in HFpEF may cause left atrial [LA] dilatation that triggers AF, and conversely, the rapid heart rate that accompanies AF might lead to LV fibrosis, although there is little evidence to support this hypothesis). On the other hand, and more likely, the 2 disorders may be parallel manifestations of the same underlying myocardial disease, which causes AF (because it affects the LA) and HFpEF (because it afflicts the LV) . . . AF and HFpEF demonstrate an exceptionally high degree of clinical and epidemiological convergence. Regardless of which disorder presents first, both are or will soon become evident in the same patients. AF and HFpEF appear to both be manifestations of a common underlying atrial and ventricular myopathy that is triggered when a systemic inflammatory or metabolic disorder causes coronary microvascular dysfunction and fibrosis of the atrial and ventricular myocardium, a process that may be mediated or exacerbated by inflammation in the adjoining epicardial adipose tissue. (Excerpts from text, p. 4-5; no abstract available.)

Packer, M. (2020). “Is Long-Standing Atrial Fibrillation a Biomarker of or Contributor to the Symptoms or Progression of Chronic Heart Failure?” Am J Med 133(1): 17-18.

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There is consensus that atrial fibrillation is a biomarker of the disease process in heart failure. Prolonged atrial distension due to chronic increases in left ventricular filling pressures contributes to the genesis of the arrhythmia. The disease process in the ventricles can also affect the atrial myocardium. Additionally, the atria are susceptible to fibrosis that results from the inflammation of epicardial adipose tissue that is seen in obesity or diabetes. The degree of atrial fibrosis is particularly marked in patients with persistent and long-standing atrial fibrillation. When the left atrium is severely fibrotic, restoration of sinus rhythm does not fully restore force transmission to the left ventricle. Patients with heart failure are at increased risk of stroke and systemic thromboembolism, whether in sinus rhythm or atrial fibrillation. The risk of stroke is higher in those with atrial fibrillation, perhaps because their atrial disease is more severe. Unless contraindicated, patients with atrial fibrillation should receive non-vitamin K-dependent oral anticoagulants, which have been shown to be noninferior or superior to warfarin in preventing stroke, but carry a lower risk of intracranial bleeding, particularly in patients with heart failure. However, even in sinus rhythm, the use of these drugs (e.g., rivaroxaban) in chronic heart failure appears to reduce the risk of stroke. Does atrial fibrillation itself contribute to the progression of heart failure? (Excerpt from text, p. 17; no abstract available.)

Packer, M. (2020). “HFpEF Is the Substrate for Stroke in Obesity and Diabetes Independent of Atrial Fibrillation.” JACC Heart Fail 8(1): 35-42.

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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.

Packer, M. (2020). “Do amiodarone and dronedarone prevent thrombo-embolic stroke by treating the atrial myopathy of patients with atrial fibrillation? A provocative hypothesis.” Europace Jan 3. [Epub ahead of print].

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Aside from the relief of arrhythmia-related symptoms, the major reason to treat AF is to prevent the occurrence of systemic thromboembolism, since there remains uncertainty as to the role of AF in the progression of cardiomyopathy or heart failure. There is a growing interest in the use of catheter ablation as a first-line treatment for AF, since it is generally more effective than drug therapy in abolishing the arrhythmia, and it often spares patients from receiving potentially toxic antiarrhythmic agents. However, any preference for catheter ablation should be tempered by the possibility that certain Class III antiarrhythmic drugs may have an effect to reduce the risk of stroke because of a direct benefit on the underlying atrial myopathy. Oral anticoagulation is the most important treatment for the prevention of stroke, but many patients with AF are not prescribed these drugs or remain at risk of stroke despite receiving long-term anticoagulation. Additionally, because it exacerbates the underlying atrial myopathy, AF ablation without concomitant Class III antiarrhythmic drugs may not provide optimal protection against stroke, even in those who are prescribed oral anticoagulants. Therefore, in patients with AF who are at meaningful risk of stroke, physicians may well be advised to assess the presence and severity of an underlying atrial myopathy as a means of guiding their treatment decisions. (Excerpt from text, p. 2-3; no abstract available.)

Packer, M. (2019). “Do most patients with obesity or type 2 diabetes, and atrial fibrillation, also have undiagnosed heart failure? A critical conceptual framework for understanding mechanisms and improving diagnosis and treatment.” Eur J Heart Fail Dec 17. [Epub ahead of print].

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Obesity and diabetes can lead to heart failure with preserved ejection fraction (HFpEF), potentially because they both cause expansion and inflammation of epicardial adipose tissue and thus lead to microvascular dysfunction and fibrosis of the underlying left ventricle. The same process also causes an atrial myopathy, which is clinically evident as atrial fibrillation (AF); thus, AF may be the first manifestation of HFpEF. Many patients with apparently isolated AF have latent HFpEF or subsequently develop HFpEF. Most patients with obesity or diabetes who have AF and exercise intolerance have increased left atrial pressures at rest or during exercise, even in the absence of diagnosed HFpEF. Among patients with AF, those who also have latent HFpEF have increased risk for systemic thromboembolism and death. The identification of HFpEF in patients with obesity or diabetes alters the risk-to-benefit relationship of commonly prescribed treatments. Bariatric surgery and statins can ameliorate AF and reduce the risk for HFpEF. Conversely, antihyperglycaemic drugs that promote adipogenesis or cause sodium retention (insulin and thiazolidinediones) may increase the risk for heart failure in patients with an underlying ventricular myopathy. Patients with obesity and diabetes who undergo catheter ablation for AF are at increased risk for AF recurrence and for post-ablation increases in pulmonary venous pressures and worsening heart failure, especially if HFpEF coexists. Therefore, AF may be the earliest indicator of HFpEF in patients with obesity or type 2 diabetes, and recognition of HFpEF alters the management of these patients.