Cardiology

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].

Full text of this article.

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.

Singh, M., J. A. Spertus, S. M. Gharacholou, R. C. Arora, R. J. Widmer, A. Kanwar, R. M. Sanjanwala, G. A. Welle and M. A. Al-Hijji (2020). “Comprehensive Geriatric Assessment in the Management of Older Patients With Cardiovascular Disease.” Mayo Clin Proc 95(6): 1231-1252.

Full text of this article.

Cardiovascular disease (CVD) disproportionately affects older adults. It is expected that by 2030, one in five people in the United States will be older than 65 years. Individuals with CVD now live longer due, in part, to current prevention and treatment approaches. Addressing the needs of older individuals requires inclusion and assessment of frailty, multimorbidity, depression, quality of life, and cognition. Despite the conceptual relevance and prognostic importance of these factors, they are seldom formally evaluated in clinical practice. Further, although these constructs coexist with traditional cardiovascular risk factors, their exact prevalence and prognostic impact remain largely unknown. Development of the right decision tools, which include these variables, can facilitate patient-centered care for older adults. These gaps in knowledge hinder optimal care use and underscore the need to rigorously evaluate the optimal constructs for providing care to older adults. In this review, we describe available tools to examine the prognostic role of age-related factors in patients with CVD.

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].

Full text of this article.

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].

Full text of this article.

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.

Full text of this article.

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.