The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction

Packer, Milton

doi:10.1002/ejhf.1294

Cited by 43 publications

(41 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…A wide range of systemic inflammatory states lead to the accumulation and inflammation of epicardial adipose tissue and perivascular fat, which act as transducers for the transmission of the inflammatory process to the myocardium and aorta . The inflammation of myocardial and vascular tissues causes disruption of the microvascular blood supply, cardiac and adventitial fibrosis and impaired distensibility of the cardiac chambers and great vessels . The inflammatory process can also trigger the release of various cell‐signalling molecules and enzymes from adipose tissue, including aldosterone, neprilysin and leptin; the resulting sodium retention and expansion of plasma volume lead to a disproportionate increase in cardiac filling pressures when the left ventricle cannot expand as a result of microvascular rarefaction and fibrosis .…”

Section: Discussionmentioning

confidence: 99%

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Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Anker

Butler

Filippatos

et al. 2019

European J of Heart Fail

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213

169

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Background The principal biological processes that characterize heart failure with a preserved ejection fraction (HFpEF) are systemic inflammation, epicardial adipose tissue accumulation, coronary microcirculatory rarefaction, myocardial fibrosis and vascular stiffness; the resulting impairment of left ventricular and aortic distensibility (especially when accompanied by impaired glomerular function and sodium retention) causes increases in cardiac filling pressures and exertional dyspnoea despite the relative preservation of left ventricular ejection fraction. Independently of their actions on blood glucose, sodium–glucose co‐transporter 2 (SGLT2) inhibitors exert a broad range of biological effects (including actions to inhibit cardiac inflammation and fibrosis, antagonize sodium retention and improve glomerular function) that can ameliorate the pathophysiological derangements in HFpEF. Such SGLT2 inhibitors exert favourable effects in experimental models of HFpEF and have been found in large‐scale trials to reduce the risk for serious heart failure events in patients with type 2 diabetes, many of whom were retrospectively identified as having HFpEF. Study design The EMPEROR‐Preserved Trial is enrolling ≈5750 patients with HFpEF (ejection fraction >40%), with and without type 2 diabetes, who are randomized to receive placebo or empagliflozin 10 mg/day, which is added to all appropriate treatments for HFpEF and co‐morbidities. Study aims The primary endpoint is the time‐to‐first‐event analysis of the combined risk for cardiovascular death or hospitalization for heart failure. The trial will also evaluate the effects of empagliflozin on renal function, cardiovascular death, all‐cause mortality and recurrent hospitalization events, and will assess a wide range of biomarkers that reflect important pathophysiological mechanisms that may drive the evolution of HFpEF. The EMPEROR‐Preserved Trial is well positioned to determine if empagliflozin can have a meaningful impact on the course of HFpEF, a disorder for which there are currently few therapeutic options.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Anker

Butler

Filippatos

et al. 2019

European J of Heart Fail

Self Cite

213

169

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“…Furthermore, both obesity and type 2 diabetes are accompanied by an expansion of epicardial adipose tissue, which is capable of transducing the effects of these disorders to the underlying cardiac structures, further augmenting the myocardial inflammatory process . The epicardium and myocardium are intimately connected through an unobstructed shared microcirculation; therefore, when metabolic disorders act to cause proliferation and dysfunction of adipocytes in the epicardium, the secretion of adipocytokines leads to inflammation and fibrosis of the underlying myocardial tissues . If the dysfunctional epicardial adipose tissue is adjacent to the LV, the result is an impairment of LV distensibility, leading to HFpEF .…”

Section: Pathophysiological Mechanisms Leading To Hfpefmentioning

confidence: 99%

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

Packer

2019

European J of Heart Fail

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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.

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“…Both obesity and diabetes cause an expansion and proinflammatory transformation of epicardial adipose tissue; its secretion of adipocytokines can lead to microvascular dysfunction and fibrosis of the underlying myocardium . If the derangement of epicardial fat adjoins the left atrium (LA), the resulting electroanatomical remodeling causes atrial myopathy and AF (Figure ) . The severity of electroanatomical abnormalities is closely related to the volume and inflammatory state of adjacent epicardial fat .…”

Section: Mechanisms Leading To Af In Obesity and Diabetesmentioning

confidence: 99%

“…The expansion and inflammation of epicardial adipose tissue in obesity and diabetes affects not only the LA, but also the left ventricle (LV), impairing its distensibility and its ability to tolerate volume, leading to the features of heart failure with preserved ejection fraction (HFpEF) . AF frequently precedes the diagnosis of HFpEF, and conversely, most patients with HFpEF develop AF during their clinical course .…”

Section: Patients With Obesity or Diabetes Who Have Af Are Likely To mentioning

confidence: 99%

Heightened risk of intensive rate control in patients with atrial fibrillation who are obese or have type 2 diabetes: A critical review and re‐evaluation

Packer

2019

Cardiovasc electrophysiol

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Atrial fibrillation (AF) is common in patients with obesity and diabetes; the arrhythmia (if long‐standing) is typically managed by rate control and anticoagulation. However, the coexistence of these two metabolic disorders complicates therapeutic options for rate control. The likely pathogenesis of AF in these patients is an expansion of epicardial adipose tissue whose inflammation is transmitted to the left atrium causing electromechanical remodeling. However, this same process is also transmitted to the left ventricle (LV), impairing its distensibility and its ability to tolerate volume, leading to heart failure with preserved ejection fraction. Unfortunately, the latter diagnosis (although commonly present in patients with AF and a coexistent metabolic disorder) is often ignored. To achieve rate control, physicians prescribe intensive treatment with atrioventricular (AV) nodal–blocking drugs, often at doses that are titrated to blunt exercise as well as resting heart rate responses. However, strict rate control (target rate, <80/min) is associated with somewhat worse outcomes than lenient rate control (target rate, <110/min). Furthermore, any rate slowing that facilitates diastolic filling may aggravate filling pressures that are already disproportionately increased because the LV is stiff and overfilled as a result of cardiac inflammation. Rate slowing in AF with beta blockers may not achieve the benefit expected from the blockade of adrenergically mediated cardiotoxicity, and some AV nodal–blocking drugs (digoxin and dronedarone) can increase the risk of death in patients with AF. Finally, cardiac fibrosis in obesity and diabetes may affect the conduction system, which can predispose to serious bradyarrhythmias if patients are prescribed AV nodal–blocking drugs.

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The epicardial adipose inflammatory triad: coronary atherosclerosis, atrial fibrillation, and heart failure with a preserved ejection fraction

Cited by 43 publications

References 16 publications

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

Evaluation of the effects of sodium–glucose co‐transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR‐Preserved Trial

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

Heightened risk of intensive rate control in patients with atrial fibrillation who are obese or have type 2 diabetes: A critical review and re‐evaluation

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