Cardiology

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.)

Packer, M. (2020). “Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction in Patients With Nonalcoholic Fatty Liver Disease.” Am J Med 133(2): 170-177.

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The most common causes of chronic liver disease in the developed world-nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)-are the hepatic manifestations of an insulin-resistant state that is linked to visceral adiposity and systemic inflammation. NAFLD and NASH lead to an expansion of epicardial adipose tissue and the release of proinflammatory adipocytokines that cause microcirculatory dysfunction and fibrosis of the adjoining myocardium, resulting in atrial fibrillation as well as heart failure with a preserved ejection fraction (HFpEF). Inflammatory changes in the left atrium lead to electroanatomical remodeling; thus, NAFLD and NASH markedly increase the risk of atrial fibrillation. Simultaneously, patients with NAFLD or NASH commonly show diastolic dysfunction or latent HFpEF. Interventions include 1) weight loss by caloric restriction, bariatric surgery, or intensive exercise, and 2) drugs that ameliorate fat-mediated inflammation in both the liver and heart (eg, statins, metformin, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and pioglitazone). Patients with NAFLD or NASH commonly have an inflammation-related atrial and ventricular myopathy, which may contribute to symptoms and long-term outcomes.

McMurray, J. J. V., A. M. Jackson, C. S. P. Lam, M. M. Redfield, I. S. Anand, J. Ge, M. P. Lefkowitz, A. P. Maggioni, F. Martinez, M. Packer, M. A. Pfeffer, B. Pieske, A. R. Rizkala, S. V. Sabarwal, A. M. Shah, S. J. Shah, V. C. Shi, D. J. van Veldhuisen, F. Zannad, M. R. Zile, M. Cikes, E. Goncalvesova, T. Katova, A. Kosztin, M. Lelonek, N. Sweitzer, O. Vardeny, B. Claggett, P. S. Jhund and S. D. Solomon (2020). “Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.” Circulation 141(5): 338-351.

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BACKGROUND: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Maurer, M. S. and M. Packer (2020). “Impaired systemic venous capacitance: the neglected mechanism in patients with heart failure and a preserved ejection fraction?” Eur J Heart Fail Jan 16. [Epub ahead of print].

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The cardinal feature of HFpEF is an increase in LV filling pressure in the face of a LV ejection fraction that is not meaningfully reduced. In patients with a hypertrophic or infiltrative cardiomyopathy, the increase in LV filling pressures is primarily driven by an upward and leftward shift of the LV end‐diastolic pressure–volume relation. In contrast, in inflammatory‐metabolic HFpEF, LV end‐diastolic volumes (when indexed for age and sex) are not reduced; there is little evidence for a consistent shift in the end‐diastolic pressure–volume relation; and LV filling pressures are increased because the left ventricle is overfilled. The mechanisms leading to the increase in LV filling pressures and central blood volume in HFpEF have not been fully elucidated. Sodium retention and plasma volume expansion often play a role and can be ameliorated with diuretics. However, abnormalities of systemic venous capacitance likely play a critical (and unappreciated) role in driving an increase in central blood volume in HFpEF, explaining why diuretics are typically insufficient to ameliorate the increase in LV filling pressures. Mineralocorticoid receptor antagonists and neprilysin inhibitors may exert favourable effects on systemic venous capacitance, thus contributing to their action to lower LV filling pressures and wall stress in HFpEF. Additionally, treatments that block sympathetically‐mediated vasoconstriction of the splanchnic venous bed may also alleviate pulmonary congestion in patients with decompensated heart failure, a finding that also might be applicable to patients with HFpEF. Admittedly, the assessment of the effects of drugs on systemic venous capacitance is challenging, since it is extremely difficult to reliably evaluate the function of the splanchnic venous system in the clinical setting. Despite its potential importance, little work has been dedicated to understanding the role of changes in the functions of the systemic venous system in HFpEF. In the 1970s, the systemic venous system was the focus of considerable work in understanding the pathogenesis of HFrEF. It is time that we understood that, as in the case of HFrEF, HFpEF is a disorder of the entire circulation, inclusive of the peripheral circulation, and not simply a disorder of LV structure and function. (Excerpt from text, p. 3; no abstract available.)

Lam, P. H., M. Packer, G. C. Fonarow, C. Faselis, R. M. Allman, C. J. Morgan, S. N. Singh, B. Pitt and A. Ahmed (2020). “Early Effects of Starting Doses of Enalapril in Patients with Chronic Heart Failure in the SOLVD Treatment Trial.” Am J Med 133(2): e25-e31.

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BACKGROUND: In the Studies of Left Ventricular Dysfunction (SOLVD) treatment trial, similar clinical benefits were observed between starting doses of enalapril and the target dose achieved by postrandomization up-titration. In our current analysis, protecting the randomization, we examined the early effects of starting doses of enalapril. METHODS: There were 2569 patients with mild-to-moderate chronic heart failure with reduced ejection fraction (ejection fraction less-than-or-equal-to 35%) randomized to receive starting doses (5-10 mg/day) of placebo (n = 1284) or enalapril (n = 1285). At day 14, both study drugs were blindly up-titrated to the target dose (20 mg/day). Overall, 96% (2458/2569) of the patients returned for dose up-titration, which was achieved in 59% (1444/2458), 48% (696/1444) of whom were in the enalapril group. Hazard ratios (HRs) and 95% confidence intervals (CIs) for outcomes in the enalapril group were estimated. RESULTS: HRs (95% CIs) for all-cause mortality, heart failure hospitalization, and the combined endpoint of heart failure hospitalization or all-cause mortality at 14 days after randomization were 0.80 (0.32-2.03), 0.63 (0.35-1.12), and 0.65 (0.39-1.06), respectively. Corresponding HRs (95% CIs) at 30 days were 0.82 (0.41-1.67), 0.43 (0.27-0.68), and 0.43 (0.27-0.68), respectively. The magnitude of these early effects of starting doses of enalapril is similar to its previously reported long-term effects at the target dose. CONCLUSION: These data suggest that in stable ambulatory patients with heart failure with reduced ejection fraction, the magnitude of the early effect of starting doses of enalapril is similar to that observed during longer-term therapy with the target doses of the drug.