Milton Packer M.D.

Packer, M. (2019). “Critical role of the epicardium in mediating cardiac inflammation and fibrosis in patients with type 2 diabetes.” Diabetes Obes Metab 21(8): 1765-1768.

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The neurohormonal imbalances that characterize diabetes may play a key role in epicardial adipogenesis, leading to the possibility that mineralocorticoid receptor antagonists and neprilysin inhibitors may be useful in reducing epicardial adipose mass, and thereby preventing or treating HFpEF, especially in patients with type 2 diabetes. Ongoing large‐scale trials are poised to test these hypotheses. In addition, imaging of epicardial adipose tissue (ideally using three‐dimensional cardiac magnetic resonance) has the potential to quantify an important source of proinflammatory cytokines in patients with type 2 diabetes, thereby identifying those at particular risk of cardiovascular or renal injury. Such patients might be particularly responsive to treatments (i.e. SGLT‐2 inhibitors) that effectively target the derangements in epicardial adipose fat depots. (Excerpt from text, p. 1766; no abstract available.)

Packer, M. (2019). “Is Long-Standing Atrial Fibrillation a Biomarker of or Contributor to the Symptoms or Progression of Chronic Heart Failure?” Am J Med Jun 17. [Epub ahead of print].

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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? Atrial tachyarrhythmias can lead to cardiomyopathy, but if high ventricular rates can be minimized, irregularity of the ventricular response does not adversely affect cardiac performance. In patients whose rate is < 100 per minute, the outcomes of patients with atrial fibrillation are not influenced by the rapidity of the ventricular response. Additionally, although it is commonly believed that patients with heart failure with atrial fibrillation fare worse than those in sinus rhythm, this risk is confined to those with paroxysmal or recent-onset arrhythmias. Longstanding atrial fibrillation is not associated with an increased risk of death or hospitalization for heart failure, as compared with sinus rhythm. (Excerpt from article in press, unpaginated; no abstract available.)

Packer, M. (2019). “Effect of catheter ablation on pre-existing abnormalities of left atrial systolic, diastolic, and neurohormonal functions in patients with chronic heart failure and atrial fibrillation.” Eur Heart J 40(23): 1873-1879.

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The critical role of the left atrium (LA) in cardiovascular homoeostasis is mediated by its reservoir, conduit, systolic, and neurohormonal functions. Atrial fibrillation is generally a reflection of underlying disease of the LA, especially in patients with heart failure. Disease-related LA remodelling leads to a decline in both atrial contractility and distensibility along with an impairment in the control of neurohormonal systems that regulate intravascular volume. Catheter ablation can lead to further injury to the atrial myocardium, as evidenced by post-procedural troponin release and tissue oedema. The cardiomyocyte loss leads to replacement fibrosis, which may affect up to 30-35% of the LA wall. These alterations further impair atrial force generation and neurohormonal functions; the additional loss of atrial distensibility can lead to a ‘stiff LA syndrome’, and the fibrotic response predisposes to recurrence of the atrial arrhythmia. Although it intends to restore LA systole, catheter ablation often decreases the chamber’s transport functions. This is particularly likely in patients with long-standing atrial fibrillation and pre-existing LA fibrosis, especially those with increased epicardial adipose tissue (e.g. patients with obesity, diabetes and/or heart failure with a preserved ejection fraction). Although the fibrotic LA in these individuals is an ideal substrate for the development of atrial fibrillation, it may be a suboptimal substrate for catheter ablation. Such patients are not likely to experience long-term restoration of sinus rhythm, and catheter ablation has the potential to worsen their haemodynamic and clinical status. Further studies in this vulnerable group of patients are needed.

Balmforth, C., J. Simpson, L. Shen, P. S. Jhund, M. Lefkowitz, A. R. Rizkala, J. L. Rouleau, V. Shi, S. D. Solomon, K. Swedberg, M. R. Zile, M. Packer and J. J. V. McMurray (2019). “Outcomes and Effect of Treatment According to Etiology in HFrEF: An Analysis of PARADIGM-HF.” JACC Heart Fail 7(6): 457-465.

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OBJECTIVES: The purpose of this study was to compare outcomes (and the effect of sacubitril/valsartan) according to etiology in the PARADIGM-HF (Prospective comparison of angiotensin-receptor-neprilysin inhibitor [ARNI] with angiotensin-converting-enzyme inhibitor [ACEI] to Determine Impact on Global Mortality and morbidity in Heart Failure) trial. BACKGROUND: Etiology of heart failure (HF) has changed over time in more developed countries and is also evolving in non-Western societies. Outcomes may vary according to etiology, as may the effects of therapy. METHODS: We examined outcomes and the effect of sacubtril/valsartan according to investigator-reported etiology in PARADIGM-HF. The outcomes analyzed were the primary composite of cardiovascular death or HF hospitalization, and components, and death from any cause. Outcomes were adjusted for known prognostic variables including N terminal pro-B type natriuretic peptide. RESULTS: Among the 8,399 patients randomized, 5,036 patients (60.0%) had an ischemic etiology. Among the 3,363 patients (40.0%) with a nonischemic etiology, 1,595 (19.0% of all patients; 47% of nonischemic patients) had idiopathic dilated cardiomyopathy, 968 (11.5% of all patients; 28.8% of nonischemic patients) had a hypertensive cause, and 800 (9.5% of all patients, 23.8% of nonischemic patients) another cause (185 infective/viral, 158 alcoholic, 110 valvular, 66 diabetes, 30 drug-related, 14 peripartum-related, and 237 other). Whereas the unadjusted rates of all outcomes were highest in patients with an ischemic etiology, the adjusted hazard ratios (HRs) were not different from patients in the 2 major nonischemic etiology categories; for example, for the primary outcome, compared with ischemic (HR: 1.00), hypertensive 0.87 (95% confidence interval [CI]: 0.75 to 1.02), idiopathic 0.92 (95% CI: 0.82 to 1.04) and other 1.00 (95% CI: 0.85 to 1.17). The benefit of sacubitril/valsartan over enalapril was consistent across etiologic categories (interaction for primary outcome; p = 0.11). CONCLUSIONS: Just under one-half of patients in this global trial had nonischemic HF with reduced ejection fraction, with idiopathic and hypertensive the most commonly ascribed etiologies. Adjusted outcomes were similar across etiologic categories, as was the benefit of sacubitril/valsartan over enalapril. (Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure; NCT01035255).

Packer, M. and P. A. Grayburn (2019). “Neurohormonal and Transcatheter Repair Strategies for Proportionate and Disproportionate Functional Mitral Regurgitation in Heart Failure.” JACC Heart Fail Jun; 7(6): 518-521. Epub 2019 May 8.

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Functional mitral regurgitation (MR) is present to varying degrees in most patients with chronic heart failure (HF) and left ventricular (LV) systolic dysfunction, and in ~30% of its magnitude is hemodynamically meaningful. A critical determinant of MR in these patients is the degree of LV dilation. Remodeling and enlargement of the LV leads to displacement of the papillary muscles and widening and flattening of the mitral annulus, which (together with a reduction in closing forces) impairs the coaptation of the mitral valve (MV) leaflets. However. independent of LV end-diastolic volume (LVEDV), ventricular dyssynchrony contributes importantly to functional MR. In patients with meaningful QRS prolongation, dyssynchrony causes unequal contraction of papillary muscle bearing walls, preventing coordinated closure of the MV leaflets; amelioration of the conduction delay by cardiac resynchronization reduces MR. Additionally, irrespective of the presence of e1ec:trfc conduction delay, localized LV remodeling can cause apical and posterior displacement of the papillary muscles and dyssynchronous contraction of the leaflet-supporting structures independent of global LV dsyfunction. These observation suggest that patients with functional MR and HF include the following: 1) those whose MR can be entirely explained by the MV distortions produced by LV enlargement: and 2) those who had regional LV dysfunction inordinately interferes with the synchronous contraction of the papillary muscle segments that support normal MV coaptation. We refer to the first group as having MR that is “proportionate'” to LV enlargement and the second group as having MR that is “disproportionate” to LVEDV (i.e., the severity of MR is greater than predicted by LV volumes). (Excerpt from introduction to article in press, p. 518.)