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PCSK9 Inhibition in Acute Myocardial Infarction: A Novel Opportunity

Cory Trankle and Antonio Abbate*

VCU Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, USA

*Corresponding Author:
Antonio Abbate
Department of Pharmacotherapy and
Outcome Sciences School of Pharmacy
Virginia Commonwealth University 410 N 12th St
Box 980533 Richmond, VA, 23298, USA
Tel: + 8043988796
E-mail: antonio [email protected]

Received Date: November 28, 2015; Accepted Date: December 02, 2015; Published Date: January 20, 2016

Citation: Trankle C, Abbate A (2016) PCSK9 Inhibition in Acute Myocardial Infarction: A Novel Opportunity. Transl Med 6:e135. doi:10.4172/2161-1025.1000e135

Copyright: © 2016 Trankle C. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Editorial

Acute myocardial infarction (AMI) remains a leading cause of mortality and morbidity across the nation and worldwide. While major advances in reperfusion strategies over the past several decades have significantly reduced early mortality rates after AMI, patients who survive the index event are at increasingly risk for adverse cardiac remodeling and the sequelae of heart failure and sudden cardiac death [1]. This problem is accelerated by the aging population, making heart failure a major public health concern. Heart failure indeed currently affects approximately 5 million Americans, with increasing rates of prevalence and incidence.

Anticoagulants, antiplatelet agents, and neurohormonal blockers are standard of care in the treatment of patients with AMI, given their established effects on morbidity and mortality. Drugs lowering low density lipoprotein (LDL) cholesterol, primarily hydroxyl-methylglutaryl- coA reductase inhibitors – statins – have been studied as a means not only to reduce LDL cholesterol (and hence the incidence of recurrent AMI), but also as an adjunct to acute AMI therapy to reduce the acute complications. In the MIRACL trial, atorvastatin 80 mg, administered within 24 to 96 hours after presentation with acute coronary syndrome (ACS), significantly reduced the composite endpoint of death, nonfatal AMI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial infarction from 17.4% to 14.8% in the first 16 weeks when compared to placebo (relative risk = 0.84 [0.70 – 1.00], p=0.048) [2].

In the ARMYDA trial, high-dose atorvastatin for 7 days prior to elective percutaneous intervention (PCI) significantly reduced periprocedural myocardial infarction (MI) rates from 18% to 5% (p=0.025) [3]. This was followed by the ARMYDA-ACS trial, showing that initiation of high dose atorvstatin therapy in patients presenting with non-ST elevation ACS sent to early (<48 hours) angiography reduced the composite primary endpoint of death, MI, or target vessel revascularization from 17% to 5% compared to placebo (p=0.010) at 30 days[4].

Proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors are a promising new treatment strategy for LDL cholesterol lowering, demonstrating potent LDL lowering effects in addition to or compared to statins, in stable patients in primary or secondary prevention [5,6]. PCSK9 is predominantly produced in the liver, intestine, and kidney, where it is secreted into the plasma and binds the extracellular component of LDL receptors (LDL-R). Once bound, the LDLR-PCSK9 complex is internalized and directed it to the lysosome for degradation [7]. PCSK9 inhibitors have been formulated as monoclonal antibodies, designed to bind PCSK9 and prevent this series of events. As an effect, LDL-R concentrations on the surface of hepatocytes are increased, and more LDL is removed from the circulation.

Two PCSK9 inhibitors, alirocumab (Praluent™) and evolocumab (Repatha™), are currently approved by the United States of America Food & Drug Administration for primary prevention in patients with heterozygous familial hypercholesterolemia or secondary prevention in patients with clinically stable atherosclerotic cardiovascular disease who require additional lowering of LDL-cholesterol [8,9].

To date, there have been no studies of alirocumab, evolocumab, or any other PCSK9 inhibitor given acutely in patients with AMI. Considering the residual risk of complications and death in patients with AMI, there is an urgent clinical need to investigate new strategies for risk reduction in AMI. A rapid reduction of LDL cholesterol within 2-4 weeks of an AMI could provide additional benefit on top of current standard care, including high-dose statins.

Moreover, a cross-talk between lipoprotein metabolism and systemic inflammation exists. In multiple in vitro studies, PCSK9 has demonstrated influence on receptors other than LDLR, including the VLDL receptor (PCSK9 facilitates its degradation) [10], LDL-R-related protein 1 (LRP-1) [11] and CD36 [12].

LRP-1 is a receptor that is known to bind over 40 ligands, including bacterial toxins and apoptotic cell debris [13], facilitating endosomal transport into phagocytes for degradation [14]. The receptor has been shown to promote resolution of inflammation, at least in part due to its indirect control on the IKK/NF-κB pathway by downregulation of the cell surface expression of tumor necrosis factor-1 receptor [15]. PCSK9 appears to have a similar effect on LRP-1 as it does on LDL-R (i.e. facilitating LRP-1 degradation) [16], suggesting that PCSK9 inhibition would prevent this component of the inflammatory cascade in response to the molecular triggers of LRP-1 (e.g. lipopolysaccharides encountered on Gram negative bacterial surfaces, cell debris released during an acute MI), and thus PCSK9 inhibitors could promote an antiinflammatory effect.

Macrophages are known to play an important role in atherosclerosis formation [17] and the associated inflammatory pathways [18]. High levels of plasma LDL lead to oxidative modification of those LDL particles in the arterial intima, thus forming oxLDL particles [19]. This oxidized form of LDL is then recognizable to scavenger receptors (SR) on the surface of macrophages, principally SR-CD36 and SR-A18. Once CD36 binds oxLDL, the activated receptor interacts with Tolllike receptor 4 (TLR4) and TLR6 to activate NF-κB and ultimately the inflammasome complex [20], which serves to dramatically amplify the inflammatory response. PCSK9-mediated increases in levels of circulating LDL leaves those LDL particles vulnerable to oxidation. The resulting oxLDL is scavenged by CD36, leading to stimulation of further CD36 upregulation [21]. PCSK9 silencing RNA suppresses oxLDLinduced NF-κB activation of inflammatory pathways in macrophages [22], which appears to be at least partially related to a direct upregulation of CD36 in this cell line [23]. On the other hand, PCSK9 appears to have an opposite effect on CD36 in hepatic cells (i.e. PCSK9 facilitates CD36 degradation) [24], suggesting another mechanism by which oxLDL particles are removed from the circulation, thus reducing the overall inflammatory burden.

The suggested effects of PCSK9 activity on LDL receptors and CD36 in liver cells, as well as LRP-1 and CD36 in macrophages, are summarized in Figure 1.

translational-medicine-hepatocytes

Figure 1: LDL and oxLDL particles bind to their respective receptors on hepatocytes, facilitating their endosomal uptake and elimination. PCSK9 binding to the receptors promotes lysosomal degradation, rather than recycling to the cell surface, making the receptors unavailable for LDL and oxLDL scavenging. Microbial products (e.g. lipopolysaccharide on Gram negative bacterial surfaces) or cell debris bind LRP1 receptor facilitating pathogen clearance and inhibiting the inflammatory response. PCSK9 binding to LRP1 promotes lysosomal degradation of the receptor, thus making the receptor unavailable for pathogen scavenging. Like LDL-R, LRP1 also binds circulating lipoproteins. In macrophages, CD36 functions as a co-factor for TLRs inducing a pro-inflammatory response to ox-LDL. Abbreviations: LDL-R: low density lipoprotein receptor; oxLDL: oxidized LDL; PCSK9: proprotein convertase subtilisin/kexin 9; LRP-1: LDL receptor related protein 1; TLR: Toll-like receptor.

Overlapping pathways between lipoprotein metabolism and inflammation has a theoretical basis in the innate immune response to pathologic lipoproteic signals (i.e. cell debris during myocardial injury or lipopolysaccharide in Gram negative bacteria). Indeed, in a mouse model of septic shock due to intraperitoneal injection of lipopolysaccharide, PCSK9-knockout mice or mice receiving PCSK9 modulators had a more favorable outcome than their counterparts [25]. Accordingly, retrospective evidence from a large clinical study of septic shock showed a correlation between estimated PCSK9 activity (extrapolated from detected gain of function or loss of function genetic mutations), the measured inflammatory biomarker levels, and survival during septic shock [25].

To our knowledge, there has been no published data from clinical trials on the effects of PCSK9 inhibitors on the inflammatory response in patients with AMI. Efficacy data of PCSK9 inhibitors derives from the primary and secondary prevention studies enrolling patients who are not expected to have high levels of inflammatory biomarkers, thus making any effect of PCSK9 inhibitors on inflammation difficult to detect [26]. Chronic low-grade systemic inflammation (which associates with increased cardiovascular risk in primary and secondary prevention) may indeed be a different pathologic process than the acute inflammatory response to AMI.

Patients suffering from an AMI may, therefore, derive benefit from PSCK9 inhibitors, by way of rapid LDL reduction (stabilizing the LDL-R), a reduction the pro-inflammatory signaling of ox-LDL (reducing the CD36 receptor), and/or facilitation of removal of the proinflammatory apoptotic debris and anti-inflammatory cellular signaling (via the LRP1 receptor). They have proven safe and well tolerated in stable outpatient populations, but whether this remains true for patients in the acute setting remains to be seen. Testing this hypothesis in future clinical trial would clarify whether a new therapeutic agent to prevent post-AMI heart failure is already within our reach.

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