Author + information
- Gary S. Francis, MD∗ ()
- ↵∗Address for correspondence:
Dr. Gary S. Francis, Cardiovascular Division, University of Minnesota, 420 Delaware Street Southeast, MMC508, Minneapolis, Minnesota 55455.
The BIOSTAT-CHF (BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study by Bayes-Genis et al. (1) in this issue of the Journal describes the prognostic value of a new biotarget in the management of atherosclerosis progression: the proprotein convertase subtilisin/kexin type 9 (PCSK9), and its interaction or “axis” with low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes. Although it is well known that PCSK9 and LDLR are associated with atherosclerotic risk (2), the interaction of cholesterol and the clinical syndrome of heart failure are unclear. To date, large-scale trials have not confirmed a firm across-the-board benefit of statins for the treatment of congestive heart failure. The relation of PCSK9 and LDLR to heart failure has not previously been explored, and very little is known regarding how PCSK9 and LDLR may relate to future heart failure events.
Patients with acute myocardial infarction have elevated serum PCSK9 levels (3), but until now we had no such data in patients with worsening heart failure. There are somewhat mixed data regarding cholesterol-lowering agents in patients with heart failure (4,5), and the value of measuring circulating inflammatory biomarkers seems to be limited in these patients (6). The authors have hypothesized that, similar to unstable coronary artery disease, there may be elevated levels of PCSK9 in patients with worsening heart failure. So, what is the role of the PCSK9-LDLR axis in predicting cardiovascular risk in patients with worsening heart failure? The authors remind us that heart failure hospitalization was reduced by rosuvastatin in CORONA (Controlled Rosuvastatin Multi-national Trial in Heart Failure) (4), and that other data support the hypothesis that statins may improve patients with heart failure (7). Therefore, it is worth exploring whether the PCSK9/LDLR axis relates to cardiovascular events in patients with worsening heart failure.
Overall, patients in this study who had ischemic heart disease and previous coronary revascularization had the highest levels of PCSK9, whereas coronary disease severity was inversely related to LDLR quartiles. A total of 2,174 patients were included in the analysis, with a median follow-up of 1.53 years. Of these patients, 88.8% had a left ventricular ejection fraction ≤40%. The findings demonstrate that the PCSK9-LDLR axis is associated with outcomes in patients with worsening heart failure. Soluble PCSK9 is positively associated with poor outcomes in patients with worsening heart failure, whereas circulating LDLR is inversely associated with the same endpoints. PCSK9 may be a risk factor across the entire cardiovascular spectrum, including subjects who are asymptomatic and patients with symptomatic atherosclerosis or worsening heart failure. This new information sets the stage for additional studies.
What might the clinician take away from this report? It should be noted that these study patients had worsening heart failure, not chronic, stable heart failure. It is unclear if the PCSK9-LDLR axis will demonstrate similar prognostication in patients with stable chronic heart failure. As the current guidelines do not recommend the use of statins to treat heart failure, their role in the management of patients with heart failure is still not entirely clear. What does seem clear from these data is that there is a positive linear association between mortality and the composite endpoint of death or unscheduled hospitalization for heart failure in patients with worsening heart failure who have an elevated PCSK9 level and a low LDLR level. What remains to be tested is whether PCSK9 inhibition in patients with worsening heart failure will lead to improved outcomes and whether there is a cause and effect relationship between the PCSK9-LDLR axis and long-term outcomes.
The data from the BIOSTAT-CHF study (1) extend our understanding of the interaction between lipid abnormalities in patients with worsening heart failure. This relationship has to some extent previously been ignored; there has been much more emphasis on correcting fluid overload and the accompanying patient discomfort, with a therapeutic focus on relieving dyspnea and edema. Studies of standard cholesterol treatment in the setting of heart failure have been mixed, at best. Data on worsening heart failure and lipid moieties are now beginning to emerge that open our minds to an alternative idea. To date, brief exposures to novel heart failure treatment regimens have not reduced important endpoints in clinical trials of patients with worsening heart failure (8). It is possible that PCSK9 is contributing to worsening heart failure, but to determine this requires further study. These findings may be even more poignant given our current dismal record of treating acute, decompensated heart failure with various fluid removal, vasodilator, and inotropic-positive strategies without lasting benefit.
Last, there is the issue of the cost of PCSK9 inhibitors. As it now stands, they are probably not cost-effective (9). Although scientific advancement is obviously important, so is affordability. Current restrictions on access to expensive drugs send a strong message to physicians and patients, as well as to innovators, that the benefits must be substantial if such drugs are going to be widely used. Nevertheless, these investigators have uncovered an interesting finding that may warrant further study, particularly if it can successfully be applied in a therapeutic manner to patients with acute, worsening heart failure.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Dr. Francis has served as a paid consultant to Amgen, which makes a CPSK9 inhibitor; and has served on data and safety monitoring boards for Merck and Novartis.
- 2017 American College of Cardiology Foundation
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