Protecting the heart after an acute coronary syndrome is a key therapeutic goal to support cardiac recovery and prevent progression to heart failure. A potential strategy is to target cardiac glucose metabolism at the early stages after ischemia when glycolysis is critical for myocyte survival. Building on our discovery that high-density lipoprotein (HDL) modulates skeletal muscle glucose metabolism, we now demonstrate that a single dose of reconstituted HDL (rHDL) delivered after myocardial ischemia increases cardiac glucose uptake, reduces infarct size, and improves cardiac remodeling in association with enhanced functional recovery in mice. These findings applied equally to metabolically normal and insulin-resistant mice. We further establish direct effects of HDL on cardiomyocyte glucose uptake, glycolysis, and glucose oxidation via the Akt signaling pathway within 15 min of reperfusion. These data support the use of infusible HDL preparations for management of acute coronary syndromes in the setting of primary percutaneous interventions.
Rationale: Decades of research have examined immune modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure, but have failed to translate to clinical benefit. Objective: To determine anti-inflammatory actions of apoA-I nanoparticles (n-apoA-I) that contribute to cardiac tissue recovery after myocardial infarction. Methods and Results: Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apoA-I (CSL111, 80mg/kg) delivered immediately after reperfusion, reduced the systemic and cardiac inflammatory response. N-apoA-I treatment lowered the number of circulating leukocytes by 30{plus minus}7% and their recruitment into the ischemic heart by 25{plus minus}10% (all p<5.0E-2). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I by 52{plus minus}17% (p=1.01E-2). N-apoA-I reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60-80%, and lowered surface expression of integrin CD11b on monocytes by 20{plus minus}5% (all p<5.0E-2). Fluorescently labeled n-apoA-I entered the infarct and peri-infarct regions and co-localized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apoA-I binds to neutrophils and monocytes, with preferential binding to the pro-inflammatory monocyte subtype and partially via scavenger receptor BI (SR-BI). In patients with type 2 diabetes mellitus, we also observed that intravenous infusion of the same n-apoA-I (CSL111, 80mg/kg) similarly reduced the level of circulating leukocytes by 12{plus minus}5% (all p<5.0E-2). Conclusions: A single intravenous bolus of n-apoA-I delivered immediately post-myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apoA-I and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.
Background Although acute coronary syndromes (ACS) are a major cause of morbidity and mortality, relationships with biologically active lipid species potentially associated with plaque disruption/erosion in the context of their lipoprotein carriers are indeterminate. The aim was to characterize lipid species within lipoprotein particles which differentiate ACS from stable coronary artery disease. Methods and Results Venous blood was obtained from 130 individuals with de novo presentation of an ACS (n=47) or stable coronary artery disease (n=83) before coronary catheterization. Lipidomic measurements (533 lipid species; liquid chromatography electrospray ionization/tandem mass spectrometry) were performed on whole plasma as well as 2 lipoprotein subfractions: apolipoprotein A1 (apolipoprotein A, high‐density lipoprotein) and apolipoprotein B. Compared with stable coronary artery disease, ACS plasma was lower in phospholipids including lyso species and plasmalogens, with the majority of lipid species differing in abundance located within high‐density lipoprotein (high‐density lipoprotein, 113 lipids; plasma, 73 lipids). Models including plasma lipid species alone improved discrimination between the stable and ACS groups by 0.16 (C‐statistic) compared with conventional risk factors. Models utilizing lipid species either in plasma or within lipoprotein fractions had a similar ability to discriminate groups, though the C‐statistic was highest for plasma lipid species (0.80; 95% CI, 0.75–0.86). Conclusions Multiple lysophospholipids, but not cholesterol, featured among the lipids which were present at low concentration within high‐density lipoprotein of those presenting with ACS. Lipidomics, when applied to either whole plasma or lipoprotein fractions, was superior to conventional risk factors in discriminating ACS from stable coronary artery disease. These associative mechanistic insights elucidate potential new preventive, prognostic, and therapeutic avenues for ACS which require investigation in prospective analyses.
Aim: We have recently demonstrated that reconstituted high-density lipoprotein (rHDL) delivered immediately after myocardial infarction reduces infarct size and improves heart function in mice ( Heywood SE, Sci Transl Med, 2017 ). We now examine potential immunomodulatory actions of HDL that may underlie these effects. Methods: In male C57BL/6 mice, a single intravenous bolus of rHDL (CSL-111, 80mg/kg of human apoA-I, or saline) was delivered at the time of reperfusion following 30mins of surgically-induced ischemia. Effects on the inflammatory response were studied throughout the 5 days post ischemia-reperfusion. Results: Twenty-four hours after ischemia-reperfusion, rHDL reduced the number of circulating leukocytes (versus saline p<0.05) and increased the number in spleen (p<0.05). rHDL inhibited the recruitment cascade of the entire spectrum of inflammatory cells into the left ventricle (LV) including neutrophils (1 day post ischemia), T and B cells (3 days after), and monocytes (5 days after) (p<0.05 for all). This was associated with lower cardiac expression of chemokines that attract neutrophils (CXCL1, CXCL2, CXCL5) and monocytes (CCL2) (ELISA, p<0.05 for all). Histochemistry at 6 and 24 hours after ischemia-reperfusion showed fluorescently labeled rHDL localized to the infarct and peri-infarct regions. There were also greater quantities of rHDL (human apoA-I) in the LV and spleen of mice subjected to ischemia versus sham-operated mice (ELISA, p<0.05); no rHDL was observed in the right ventricle. In addition, flow cytometry studies using the fluorescent rHDL indicated binding to both circulating leukocytes as well as those recruited into the ischemic LV (mostly neutrophils and monocytes). rHDL had a greater association with the circulating pro-inflammatory monocyte subtype (Ly6C high ) than the anti-inflammatory subtype (Ly6C low ; p<0.05) 24 hours post ischemia. Furthermore, there was less recruitment of Ly6C High monocytes 5 days post ischemia in the LV of mice treated with rHDL (p<0.05). Conclusion: rHDL limits the myocardial post-ischemic inflammatory response by effects in both the LV and by directly modulating inflammatory cells. These finding suggest a novel treatment modality for acute coronary syndromes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.