Baylor Heart and Vascular Institute

Suzuki, K., B. Claggett, M. Minamisawa, M. Packer, M. R. Zile, J. Rouleau, K. Swedberg, M. Lefkowitz, V. Shi, J. J. V. McMurray, S. D. Zucker and S. D. Solomon (2020). “Liver function and prognosis, and influence of sacubitril/valsartan in patients with heart failure with reduced ejection fraction.” Eur J Heart Fail May 14. [Epub ahead of print].

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AIMS: The prevalence of liver function abnormalities is common in patients with heart failure (HF) with reduced ejection fraction (HFrEF). We assessed the impact of liver function on prognosis and the effect of sacubitril/valsartan on measures of liver function in patients with HFrEF. METHODS AND RESULTS: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled trial. We included 8232 HFrEF patients with available measures of liver function, including transaminases, alkaline phosphatase (ALP) and bilirubin; the primary endpoint was a composite of HF hospitalization and cardiovascular (CV) death. At screening, 11.6% of study patients had total bilirubin above the upper limit of normal (20.5 μmol/L) and 9.2% had ALP above the upper limit of normal (123 IU/L). Although ALP and albumin were associated with an increased risk of outcomes, among conventional test of liver function, total bilirubin was the strongest predictor for the primary endpoint [hazard ratio (HR) 1.10; 95% confidence interval (CI) 1.04-1.15; P < 0.001], HF hospitalization (HR 1.14; 95% CI 1.07-1.22; P < 0.001); CV death (HR 1.07; 95% CI 1.00-1.14; P = 0.040), and all-cause death (HR 1.08; 95% CI 1.02-1.14; P = 0.009). All conventional measures of liver function were significantly improved in the sacubitril/valsartan group compared with the enalapril group after randomization (between-group reduction: total bilirubin 2.4%, 95% CI 0.7-4.2%, P = 0.007; aspartate aminotransferase 7.9%, 95% CI 6.7-9.0%, P < 0.001; alanine aminotransferase 7.7%; 95% CI 6.2-9.3%, P < 0.001; ALP 5.4%, 95% CI 4.4-6.4%, P < 0.001). CONCLUSION: Total bilirubin was a significant and independent predictor of CV death or HF hospitalization and all-cause mortality in patients with HFrEF enrolled in PARADIGM-HF. Sacubitril/valsartan improved measures of liver function compared with enalapril.

Packer, M. and M. Metra (2020). “Guideline-directed medical therapy for heart failure does not exist: a non-judgmental framework for describing the level of adherence to evidence-based drug treatments for patients with a reduced ejection fraction.” Eur J Heart Fail May 20. [Epub ahead of print].

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Numerous guideline documents have issued recommendations to clinicians concerning the treatment of chronic heart failure and a reduced ejection fraction. However, guidelines do not describe what constitutes an acceptable standard of care, and thus, practitioners who adhere to only a small fraction of the recommendations might claim that they are treating patients ‘in accordance with the guidelines’. As a result, <1% of patients with heart failure are receiving all life-prolonging treatments at trial-proven doses. A major impediment to the widespread adoption of trial-based treatments is a lack of any existing framework that would allow physicians to describe the adequacy of care. To address this deficiency, we propose a novel simple approach that would ask practitioners if a patient had been treated using the dosing algorithm that had been shown to be effective for each drug class. The proposed framework recognizes that all landmark survival trials in heart failure were 'strategy trials', i.e. the studies mandated a standardized forced-titration treatment plan that required timely uptitration to specified target dose unless patients experienced clinically meaningful, intolerable or serious adverse events, which persisted or recurred despite adjustment of other medications. Adherence to trial-proven regimens might be improved if physicians were asked to describe the degree to which a patient's treatment adhered to or deviated from the strategies that had been used to demonstrate the survival benefits of neurohormonal antagonists. The proposed framework should also promote practitioner self-awareness about the lack of evidence supporting the current widespread use of subtarget doses that are non-adherent with trial-proven forced-titration strategies.

Packer, M., C. S. P. Lam, L. H. Lund, M. S. Maurer and B. A. Borlaug (2020). “Characterization of the Inflammatory-Metabolic Phenotype of Heart Failure and a Preserved Ejection Fraction: a Hypothesis to Explain Influence of Sex on the Evolution and Potential Treatment of the Disease.” Eur J Heart Fail May 22. [Epub ahead of print].

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Accumulating evidence points to the existence of an inflammatory-metabolic phenotype of heart failure with a preserved ejection fraction (HFpEF), which is characterized by biomarkers of inflammation, an expanded epicardial adipose tissue mass, microvascular endothelial dysfunction, normal-to-mildly increased left ventricular volumes and systolic blood pressures, and possibly, altered activity of adipocyte-associated inflammatory mediators. A broad range of adipogenic metabolic and systemic inflammatory disorders – e.g., obesity, diabetes and metabolic syndrome as well as rheumatoid arthritis and psoriasis – can cause this phenotype, independent of the presence of large vessel coronary artery disease. Interestingly, when compared with men, women are both at greater risk of and may suffer greater cardiac consequences from these systemic inflammatory and metabolic disorders. Women show disproportionate increases in left ventricular filling pressures following increases in central blood volume and have greater arterial stiffness than men. Additionally, they are particularly predisposed to epicardial and intramyocardial fat expansion and imbalances in adipocyte-associated proinflammatory mediators. The hormonal interrelationships seen in inflammatory-metabolic phenotype may explain why mineralocorticoid receptor antagonists and neprilysin inhibitors may be more effective in women than in men with HFpEF. Recognition of the inflammatory-metabolic phenotype may improve an understanding of the pathogenesis of HFpEF and enhance the ability to design clinical trials of interventions in this heterogenous syndrome.

Packer, M. (2020). “What causes sudden death in patients with chronic heart failure and a reduced ejection fraction?” Eur Heart J 41(18): 1757-1763.

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Sudden death characterizes the mode of demise in 30-50% of patients with chronic heart failure and a reduced ejection fraction. Occasionally, these events have an identifiable pathophysiological trigger, e.g. myocardial infarction, catecholamine surges, or electrolyte imbalances, but in most circumstances, there is no acute precipitating mechanism. Instead, adverse left ventricular remodelling and fibrosis creates an exceptionally fragile and highly vulnerable substrate, which can be characterized using the model developed in theoretical physics of ‘self-organizing criticality’. This framework has been applied to describe the genesis of avalanches, nodes of traffic congestion unrelated to an accident, the abrupt system-wide failure of electrical grids, and the initiation of cancer and neurodegenerative diseases. Self-organizing criticality within the ventricular myocardium relies on complex adaptations to progressive stress and stretch, which evolve inevitably to an abrupt end (termed ‘cascading failure’), even though the rate of deterioration of the underlying disease process has not changed. The result is acute circulatory collapse (i.e. sudden death) in the absence of an identifiable triggering event. Cascading failure in a severely remodelled or fibrotic heart can become manifest electrically as a first-time ventricular tachyarrhythmia that is responsive to the shock delivered by an implantable cardioverter-defibrillator (ICD). Alternatively, it may present as an acute mechanical failure, which is manifest as (i) asystole, bradyarrhythmia, or electromechanical dissociation; or (ii) incessant ventricular fibrillation that persists despite repetitive ICD discharges; in both instances, the sudden deaths cannot be prevented by an ICD. This conceptual framework explains why anti-remodelling and antifibrotic interventions (i.e. neurohormonal antagonists and cardiac resynchronization) reduce the risk of sudden death in patients with heart failure in the absence of an ICD and provide incremental benefits in those with an ICD. The adoption of anti-remodelling and antifibrotic treatments may explain why the incidence of sudden death in clinical trials of heart failure has declined dramatically over the past 10-15 years, independent of the use of ICDs.

Packer, M. (2020). “Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.” Eur Heart J May 27;ehaa360. [Epub ahead of print].

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The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.