Milton Packer M.D.

Simpson, J., P. S. Jhund, L. H. Lund, S. Padmanabhan, B. L. Claggett, L. Shen, M. C. Petrie, W. T. Abraham, A. S. Desai, K. Dickstein, L. Kober, M. Packer, J. L. Rouleau, G. Mueller-Velten, S. D. Solomon, K. Swedberg, M. R. Zile and J. J. V. McMurray (2020). “Prognostic Models Derived in PARADIGM-HF and Validated in ATMOSPHERE and the Swedish Heart Failure Registry to Predict Mortality and Morbidity in Chronic Heart Failure.” JAMA Cardiol Jan 29. [Epub ahead of print].

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Importance: Accurate prediction of risk of death or hospitalizations in patients with heart failure (HF) may allow physicians to explore how more accurate decisions regarding appropriateness and timing of disease-modifying treatments, advanced therapies, or the need for end-of-life care can be made. Objective: To develop and validate a prognostic model for patients with HF. Design, Setting, and Participants: Multivariable analyses were performed in a stepwise fashion. Harrell C statistic was used to assess the discriminative ability. The derivation cohort was Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure trial (PARADIGM-HF) participants. The models were validated using the Aliskiren Trial to Minimize Outcomes in Patients with Heart Failure Trial (ATMOSPHERE) study and in the Swedish Heart Failure Registry (SwedeHF). A total of 8399 participants enrolled in PARADIGM-HF. Data were analyzed between June 2016 and June 2018. Main Outcomes and Measures: Cardiovascular death, all-cause mortality, and the composite of cardiovascular death or HF hospitalization at both 1 and 2 years. Results: Complete baseline clinical data were available for 8011 patients in PARADIGM-HF. The mean (SD) age of participants was 64 (11.4) years, 78.2% were men (n = 6567 of 8011), and 70.6% were New York Heart Association class II (n = 5919 of 8011). During a mean follow-up of 27 months, 1546 patients died, and 2031 had a cardiovascular death or HF hospitalization. The common variables were: male sex, race/ethnicity (black or Asian), region (Central Europe or Latin America), HF duration of more than 5 years, New York Heart Association class III/ IV, left ventricular ejection fraction, diabetes mellitus, beta-blocker use at baseline, and allocation to sacubitril/valsartan. Ranked by chi2, N-terminal pro brain natriuretic peptide was the single most powerful independent predictor of each outcome. The C statistic at 1 and 2 years was 0.74 (95% CI, 0.71-0.76) and 0.71 (95% CI, 0.70-0.73) for the primary composite end point, 0.73 (95% CI, 0.71-0.75) and 0.71 (95% CI, 0.69-0.73) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.67-0.74) for all-cause death, respectively. When validated in ATMOSPHERE, the C statistic at 1 and 2 years was 0.71 (95% CI, 0.69-0.72) and 0.70 (95% CI, 0.68-0.71) for the primary composite end point, 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.69-0.72) for cardiovascular death, and 0.71 (95% CI, 0.69-0.74) and 0.70 (95% CI, 0.68-0.72) for all-cause death, respectively. An online calculator was created to allow calculation of an individual’s risk (http://www.predict-hf.com). Conclusions and Relevance: Predictive models performed well and were developed and externally validated in large cohorts of geographically representative patients, comprehensively characterized with clinical and laboratory data including natriuretic peptides, who were receiving contemporary evidence-based treatment.

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, 6; no abstract available.)

Packer, M. (2020). “Potential Role of Atrial Myopathy in the Pathogenesis of Stroke in Rheumatoid Arthritis and Psoriasis: A Conceptual Framework and Implications for Prophylaxis.” J Am Heart Assoc 9(3): e014764.

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Both rheumatoid arthritis (RA) and psoriasis are accompanied by an increased risk of stroke, which cannot be explained by an increased prevalence of traditional cardiovascular risk factors that are focused on atherosclerosis. Instead, the risk of stroke is likely to be related to an effect of systemic inflammation to promote the development of an atrial myopathy, resulting in blood stasis within the left atrium (LA), thrombus formation, and systemic thromboembolism. The systemic inflammatory process in RA and psoriasis can directly impair the integrity of the endothelium of the coronary microcirculation of the atrial myocardium. In addition, systemic inflammation can cause expansion of the epicardial adipose tissue adjacent to the LA; the secretion of proinflammatory adipocytokines from the epicardial fat depot can exaggerate the adverse structural and functional changes in the LA, leading to the atrial myopathy that provides the substrate for thromboembolic stroke. Interventions that are directed toward alleviation of the atrial myopathy and the resulting risk of thrombus formation are worthy of further evaluation in reducing the burden of cerebrovascular disease in patients with RA and psoriasis. (Excerpt from text, n.p.; no abstract available.)

Packer, M. (2020). “Interplay of AMPK/SIRT1 Activation and Sodium Influx Inhibition Mediates the Renal Benefits of SGLT2 Inhibitors in Type 2 Diabetes: a Novel Conceptual Framework.” Diabetes Obes Metab. Jan 9. [Epub ahead of print].

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Long-term treatment with SGLT2 inhibitors slows the deterioration of renal function in patients with diabetes. This benefit cannot be ascribed to an action on blood glucose, ketone utilization, uric acid or systolic blood pressure. SGLT2 inhibitors produce a striking amelioration of glomerular hyperfiltration. Although initially ascribed to an action of these drugs to inhibit proximal tubular glucose reabsorption, SGLT2 inhibitors exert renoprotective effects even in patients with meaningfully impaired levels of glomerular function that are sufficient to abolish their glycosuric actions. Instead, the reduction in intraglomerular pressures may be related to an action of SGLT2 inhibitors to interfere with the activity of sodium-hydrogen exchanger isoform 3 (NHE-3), thereby inhibiting proximal tubular sodium reabsorption and promoting tubuloglomerular feedback. Yet, experimentally, such an effect may not be sufficient to prevent renal injury. It is therefore noteworthy that the diabetic kidney exhibits an important defect in AMPK and SIRT1 signaling, which may contribute to the development of nephropathy. These enzymes exert direct effects to mute oxidative stress and inflammation, and they also stimulate autophagy, a lysosomally-mediated degradative pathway that maintains cellular homeostasis in the kidney. SGLT2 inhibitors induce both AMPK and SIRT1, and they have been shown to stimulate autophagy, thereby ameliorating cellular stress and glomerular and tubular injury. Enhanced AMPK/SIRT1 signaling may also contribute to the action of SGLT2 inhibitors to interfere with sodium transport mechanisms. The dual effects of SGLT2 inhibitors on AMPK/SIRT1 activation and renal tubular sodium transport may explain their protective effects on the kidney in type 2 diabetes.

Packer, M. (2020). “Concerns about the use of metformin as a first-line agent to slow the progression of chronic kidney disease in diabetes.” Diabetes Res Clin Pract Jan 16. [Epub ahead of print].

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A major imperative in the treatment of diabetes is to slow the onset and prevent the progression of diabetes-related renal injury. Currently, metformin is used routinely as first-line therapy to lower blood glucose, and many physicians assume that the drug′s glycemic effects have important renoprotective benefits . . . [But] there is little evidence to suggest that glycemic control with metformin has favorable effects on the development of serious chronic kidney disease in patients with diabetes . . . Further work is needed to explore the potential interactions between metformin and SGLT2 inhibitors in clinical trials. If these analyses confirm that metformin attenuates the benefits of dapagliflozin and canagliflozin on the kidneys, then physicians should reconsider the current practice of using metformin as first-line treatment, given the fact that the effectiveness of metformin in preventing chronic kidney disease in patients with type 2 diabetes has not been established. (Excerpt from text, p. 1-2; no abstract available.)