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Background: To characterize the effects of CSL112 (human APOA1 [apolipoprotein A1]) on the APOA1 exchange rate (AER) and the relationships with specific HDL (high-density lipoprotein) subpopulations when administered in the 90-day high-risk period post-acute myocardial infarction., Methods: A subset of patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo or CSL112 post-acute myocardial infarction. AER was measured in AEGIS-I plasma samples incubated with lipid-sensitive fluorescent APOA1 reporter. HDL particle size distribution was assessed by native gel electrophoresis followed by fluorescent imaging and detection of APOA1 and SAA (serum amyloid A) by immunoblotting., Results: CSL112 infusion increased AER peaking at 2 hours and returning to baseline 24 hours post-infusion. AER correlated with cholesterol efflux capacity ( r =0.49), HDL-cholesterol ( r =0.30), APOA1 ( r =0.48), and phospholipids ( r =0.48; all P <0.001) over all time points. Mechanistically, changes in cholesterol efflux capacity and AER induced by CSL112 reflected HDL particle remodeling resulting in increased small HDL species that are highly active in mediating ABCA1 (ATP-binding cassette transporter 1)-dependent efflux, and large HDL species with high capacity for APOA1 exchange. The lipid-sensitive APOA1 reporter predominantly exchanged into SAA-poor HDL particles and weakly incorporated into SAA-enriched HDL species., Conclusions: Infusion of CSL112 enhances metrics of HDL functionality in patients with acute myocardial infarction. This study demonstrates that in post-acute myocardial infarction patients, HDL-APOA1 exchange involves specific SAA-poor HDL populations. Our data suggest that progressive enrichment of HDL with SAA may generate dysfunctional particles with impaired HDL-APOA1 exchange capacity, and that infusion of CSL112 improves the functional status of HDL with respect to HDL-APOA1 exchange., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02108262., Competing Interests: Disclosures B.A. Kingwell and E. Velkoska are employees of CSL Ltd; B.H. Greene, S.J. Mears; A.V. Navdaev, S.A. Didichenko, and S.D. Wright are employees of CSL Behring; S. Wang Lorkowski and J.D. Smith received research support from CSL for these studies; C. Michael Gibson received grant support and consulting fees from CSL Behring. Independent data access and analysis: S.A. Didichenko, D. Duffy, and B.A. Kingwell had full access to all the data in the study and took responsibility for its integrity and the data analysis.

Purpose of Review: Angiotensin converting enzyme 2 (ACE2) is an important regulator of the renin-angiotensin system through actions to degrade angiotensin II. Loss of ACE2 can contribute to the development and progression of cardiovascular disease, and experimental studies have highlighted a beneficial role for novel therapeutic approaches that activate or replenish tissue ACE2. This review focuses on experimental studies that have used the off-target effects of the antitrypanosomal agent, diminazene aceturate (DIZE) to activate ACE2., Recent Findings: In cardiovascular disease, activation of the classical renin-angiotensin system and depletion of ACE2 leads to pathophysiological changes. One approach to activate ACE2 involves the drug DIZE, which has been shown to have beneficial effects in experimental models of hypertension, pulmonary hypertension, myocardial infarction, stroke, atherosclerosis, type 1 diabetes, and eye disease. The precise mechanism of action of DIZE to activate ACE2 remains under scrutiny., Summary: Activation of ACE2 may represent an important therapeutic approach in cardiovascular disease. To date, most studies have focused on the off-target actions of DIZE, in experimental models of disease. More research is required to determine the exact mechanism of action of DIZE and evaluate its therapeutic potential in comparison with currently available clinical interventions. There are no clinical studies of DIZE, and its side-effects, and toxicity make such studies unlikely. Hence, new methods of selectively activating or replenishing ACE2 will be needed in the future if this approach is to be used in a clinical context.

Objective: To determine the influence of the renal sympathetic nerves on the pathogenesis of septic acute kidney injury., Design: Interventional control study to determine the effects of renal denervation in ovine hyperdynamic sepsis., Setting: Research Institute., Subjects: Twenty-four adult Merino ewes., Interventions: The effects of infusion of angiotensin II and norepinephrine and induction of hyperdynamic sepsis by administration of live Escherichia coli were examined in control sheep and in sheep at 2 weeks after bilateral renal denervation (n = 10/group)., Measurements and Main Results: Systemic hemodynamics and renal function were measured in conscious sheep instrumented with flow probes on the pulmonary and renal arteries. Angiotensin II, but not norepinephrine, had a greater pressor effect in denervated animals. Sepsis increased cardiac output by 60%, renal blood flow by 35%, and arterial lactate by approximately four-fold. The denervated compared with the control group had a greater degree of hypotension during sepsis (68 vs 81 mm Hg; p = 0.003) and a reduction in the early polyuric response (from 496 to 160 mL at 2-8 hr of sepsis; p < 0.001). Creatinine clearance decreased similarly in both groups., Conclusions: In experimental hyperdynamic sepsis, renal denervation was associated with greater hypotension and a loss of the initial diuresis, but no significant change in creatinine clearance. In sepsis, the renal nerves help support arterial pressure and determine the initial diuretic response, but septic acute kidney injury developed similarly in the innervated and denervated groups.

Purpose of Review: Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis., Recent Findings: The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target., Summary: Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Angiotensin-converting enzyme 2, as an internal anti regulator of the renin-angiotensin hormone cascade reaction, plays a protective role in vasodilation, inhibition of fibrosis, and initiation of anti-inflammatory and antioxidative stress by degrading angiotensin II and generating angiotensin (1-7). Multiple studies have shown that plasma angiotensin-converting enzyme 2 activity is low in healthy populations without significant cardiometabolic disease, and elevated plasma angiotensin-converting enzyme 2 levels can be used as a novel biomarker of abnormal myocardial structure and/or adverse events in cardiometabolic diseases. This article aims to elaborate the determinants of plasma angiotensin-converting enzyme 2 concentration, the relevance between angiotensin-converting enzyme 2 and cardiometabolic disease risk markers, and its relative importance compared with known cardiovascular disease risk factors. Confronted with the known cardiovascular risk factors, plasma angiotensin-converting enzyme 2 (ACE2) concentration uniformly emerged as a firm predictor of abnormal myocardial structure and/or adverse events in cardiometabolic diseases and may improve the risk prediction of cardiometabolic diseases when combined with other conventional risk factors. Cardiovascular disease is the leading cause of death worldwide, while the renin-angiotensin system is the main hormone cascade system involved in the pathophysiology of cardiovascular disease. A multi-ancestry global cohort study from the general population by Narula et al revealed that plasma ACE2 concentration was strongly associated with cardiometabolic disease and might be an easily measurable indicator of renin-angiotensin system disorder. The association between this atypical hormone disorder marker and cardiometabolic disease is isolated from conventional cardiac risk factors and brain natriuretic peptide, suggesting that a clearer comprehending of the changes in plasma ACE2 concentration and activity may help us to improve the risk prediction of cardiometabolic disease, guide early diagnosis and feasible therapies, and develop and test new therapeutic targets., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Several epidemiological studies have shown a clear inverse relationship between serum levels of high-density lipoprotein cholesterol (HDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD), even at low-density lipoprotein cholesterol levels below 70 mg/dL. There is much evidence from basic and clinical studies that higher HDL-C levels are beneficial, whereas lower HDL-C levels are detrimental. Thus, HDL is widely recognized as an essential anti-atherogenic factor that plays a protective role against the development of ASCVD. Percutaneous coronary intervention is an increasingly common treatment choice to improve myocardial perfusion in patients with ASCVD. Although drug-eluting stents have substantially overcome the limitations of conventional bare-metal stents, there are still problems with stent biocompatibility, including delayed re-endothelialization and neoatherosclerosis, which cause stent thrombosis and in-stent restenosis. According to numerous studies, HDL not only protects against the development of atherosclerosis, but also has many anti-inflammatory and vasoprotective properties. Therefore, the use of HDL as a therapeutic target has been met with great interest. Although oral medications have not shown promise, the developed HDL infusions have been tested in clinical trials and have demonstrated viability and reproducibility in increasing the cholesterol efflux capacity and decreasing plasma markers of inflammation. The aim of the present study was to review the effect of HDL on stent biocompatibility in ASCVD patients following implantation and discuss a novel therapeutic direction of HDL infusion therapy that may be a promising candidate as an adjunctive therapy to improve stent biocompatibility following percutaneous coronary intervention., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Abstract: The high mortality of specific groups from COVID-19 highlights the importance of host-viral interactions and the potential benefits from enhancing host defenses. SARS-CoV-2 requires angiotensin-converting enzyme (ACE) 2 as a receptor for cell entry and infection. Although both ACE inhibitors and spironolactone can upregulate tissue ACE2, there are important points of discrimination between these approaches. The virus requires proteolytic processing of its spike protein by transmembrane protease receptor serine type 2 (TMPRSS2) to enable binding to cellular ACE2. Because TMPRSS2 contains an androgen promoter, it may be downregulated by the antiandrogenic actions of spironolactone. Furin and plasmin also process the spike protein. They are inhibited by protease nexin 1 or serpin E2 (PN1) that is upregulated by angiotensin II but downregulated by aldosterone. Therefore, spironolactone should selectively downregulate furin and plasmin. Furin also promotes pulmonary edema, whereas plasmin promotes hemovascular dysfunction. Thus, a downregulation of furin and plasmin by PN1 could be a further benefit of MRAs beyond their well-established organ protection. We review the evidence that spironolactone may be the preferred RASSi to increase PN1 and decrease TMPRSS2, furin, and plasmin activities and thereby reduce viral cell binding, entry, infectivity, and bad outcomes. This hypothesis requires direct investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)