Research Spotlight

Patel, M. R., J. H. Calhoon, G. J. Dehmer, J. A. Grantham, T. M. Maddox, D. J. Maron and P. K. Smith (2018). “Correction to: ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2017 Appropriate Use Criteria for Coronary Revascularization in Patients With Stable Ischemic Heart Disease.” J Nucl Cardiol May 10. [Epub ahead of print].

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To more clearly reflect the relationship between iFR (instantaneous wave-free ratio) and FFR (fractional flow reserve), this Correction document highlights the following changes to the original document published in the Journal of Nuclear Cardiology; the version available at JACC has been updated to reflect the changes, with JACC’s Correction document available at.

Packer, M. and P. R. Kowey (2018). “Building Castles in the Sky: Catheter Ablation in Patients With Atrial Fibrillation and Chronic Heart Failure.” Circulation May 30. [Epub ahead of print].

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Atrial fibrillation is part of the medical history in >30% of patients with heart failure and a reduced ejection fraction and in >50% of those with a preserved ejection fraction. In general, the arrhythmia does not cause heart failure; but does it contribute to progression of the disease? The treatment of atrial fibrillation has advanced over the past 20 years, as we have moved from antiarrhythmic drugs to catheter ablation. Yet, is intervention beneficial? It is important to relieve disabling symptoms due to paroxysms of the arrhythmia, but this is a valid goal whether heart failure exists or not. However, for most patients with heart failure and atrial fibrillation, control of the ventricular response and systemic anticoagulation are all that is required.

Packer, M. (2018). “Worsening Heart Failure During the Use of DPP-4 Inhibitors: Pathophysiological Mechanisms, Clinical Risks, and Potential Influence of Concomitant Antidiabetic Medications.” JACC Heart Fail 6(6): 445-451.

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Although dipeptidyl peptidase (DPP)-4 inhibitors have been reported to have a neutral effect on thromboembolic vaso-occlusive events in large-scale trials, they act to potentiate several endogenous peptides that can exert deleterious cardiovascular effects. Experimentally, DPP-4 inhibitors may augment the ability of glucagon-like peptide-1 to stimulate cyclic adenosine monophosphate in cardiomyocytes, and potentiation of the effects of stromal cell-derived factor-1 by DPP-4 inhibitors may aggravate cardiac fibrosis. These potentially deleterious actions of DPP-4 inhibitors might not become clinically apparent if these drugs were to promote sodium excretion. However, the natriuretic effect of DPP-4 inhibitors is modest, because they act on the distal (rather than proximal) renal tubules. Accordingly, both clinical trials and observational studies have reported an increase in the risk of heart failure in patients with type 2 diabetes who were receiving DPP-4 inhibitors. This risk may be muted in trials with a high prevalence of metformin use or with low and declining background use of insulin and thiazolidinediones. Still, the most vulnerable patients (i.e., those with established heart failure) were not well represented in these studies. The only trial that specifically evaluated patients with pre-existing left ventricular dysfunction observed important drug-related adverse structural and clinical effects. In conclusion, an increased risk of worsening heart failure appears to be a class effect of DPP-4 inhibitors, even in patients without a history of heart failure. Additional clinical trials are urgently needed to elucidate the benefits and risks of DPP-4 inhibitors in patients with established left ventricular dysfunction.

Packer, M. (2018). “Potential mechanisms underlying differences in the effect of incretin-based antidiabetic drugs on the risk of major atherosclerotic ischemic events.” J Diabetes Complications 32(6): 616-617.

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Incretin-based drugs exert antihyperglycemic effects in type 2 diabetes by mimicking or potentiating the effects of glucagon-like peptide-1 (GLP-1), which acts on the pancreas to stimulate the release of insulin. Long-acting GLP-1 receptor agonists (e.g., exenatide, liraglutide and semaglutide) are resistant to endogenous degradation and produce prolonged stimulation of the GLP-1 receptor. Conversely, drugs that inhibit dipeptidyl peptidase-4 (DPP-4) (e.g., sitagliptin and saxagliptin) enhance the actions of endogenous GLP-1 and may also augment non-GLP-1 peptides that are normally degraded by DPP-4. Although the two classes of drugs are commonly considered to have similar effects, it is more useful to regard their actions as being distinct but overlapping. GLP-1 receptor agonists can produce substantially greater stimulation of the GLP-1 receptor than can be achieved by the potentiation of physiological levels of endogenous GLP-1 by DPP-4 inhibitors. In contrast, due to their enhancement of non-GLP-1 peptides, DPP-4 inhibitors produce additional biological effects that are likely to have clinical relevance. Most efforts to understand the similarities and differences between GLP-1 receptor agonists and DPP-4 inhibitors have focused on their actions to lower blood glucose. Presumably because of their greater capacity to enhance GLP-1 signaling, long-acting GLP-1 analogs produce a greater reduction in glycated hemoglobin than DPP-4 inhibitors.1 It is therefore noteworthy that, in large-scale cardiovascular outcome trials carried out in patients with clinically stable type 2 diabetes, treatment with GLP-1 receptor agonists (i.e., liraglutide, semaglutide and exenatide) for a median of 2–4 years have had favorable effects on the risk of major adverse cardiovascular events. Treatment with these drugs has decreased the combined risk of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke, with the most marked effects being reported with semaglutide and the least pronounced effects being observed with exenatide (Table 1). In contrast, no benefit on the risk of atherosclerotic ischemic events has been observed in large-scale cardiovascular outcomes trials with the DPP-4 inhibitors (sitagliptin, saxagliptin and omarigliptin). Although the trials of the two types of incretin-based drugs were of similar size, design, duration and statistical power, DPP-4 inhibitors had no demonstrable influence on the combined risk of cardiovascular death, myocardial infarction and stroke. Why should two classes of antidiabetic drugs that both signal through the GLP-1 receptor exert different effects on the risk of major adverse cardiovascular outcomes? (Excerpt from text, p. 616; no abstract available.)

Packer, M. (2018). “Epicardial Adipose Tissue May Mediate Deleterious Effects of Obesity and Inflammation on the Myocardium.” J Am Coll Cardiol 71(20): 2360-2372.

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Epicardial adipose tissue has unique properties that distinguish it from other depots of visceral fat. Rather than having distinct boundaries, the epicardium shares an unobstructed microcirculation with the underlying myocardium, and in healthy conditions, produces cytokines that nourish the heart. However, in chronic inflammatory disorders (especially those leading to heart failure with preserved ejection fraction), the epicardium becomes a site of deranged adipogenesis, leading to the secretion of proinflammatory adipokines that can cause atrial and ventricular fibrosis. Accordingly, in patients at risk of heart failure with preserved ejection fraction, drugs that promote the accumulation or inflammation of epicardial adipocytes may lead to heart failure, whereas treatments that ameliorate the proinflammatory characteristics of epicardial fat may reduce the risk of heart failure. These observations suggest that epicardial adipose tissue is a transducer of the adverse effects of systemic inflammation and metabolic disorders on the heart, and thus, represents an important target for therapeutic interventions.