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Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (15 July 2021) | Viewed by 32835

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Special Issue Editor

Prof. Sanjay Patel

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Guest Editor

Department of Cardiology, Royal Prince Alfred Hospital, 2050 Sydney, Australia
Interests: atherosclerosis-associated inflammation; acute coronary syndromes; percutaneous coronary intervention; anti-inflammatory and anti-atherosclerotic therapeutics

Special Issue Information

Dear Colleagues,

Acute coronary syndromes (ACS) are the global leading cause of morbidity and mortality. Contemporary guideline-directed therapies emphasise the modulation of cardiovascular risk factors, lipid-lowering strategies (both dietary and pharmacologic), and antiplatelet medications to prevent future cardiovascular events. Despite these measures, the incidence of major adverse cardiovascular events is as high as 20% 3 years after index ACS presentation. Recurrent events post-ACS are particularly worrisome because they are associated with significantly higher morbidity and mortality than the index event. As a result, a significant number of patients are not adequately served by current treatments, and new athero-protective strategies are needed. This treatment gap is explained, at least in part, by failure to target inflammatory and other immunomodulatory pathways implicated in coronary plaque destabilisation, inadequate patient response to high doses of conventional anti-thrombotic and lipid-modifying agents, and/or failure to optimise the outcomes and manage the complications of the percutaenous coronary intervention of culprit plaque. Additionally, current clinical risk prediction models and advanced non-invasive and invasive imaging modalities are imperfect in identifying vulnerable plaques that may be the substrates for future events, as well as the individual patients that may be vulnerable to these adverse events.

This Special Issue aims to publish the most recent original research, reviews and comments on a) state-of-the-art non-invasive and invasive imaging to identify vulnerable plaques and patients at risk of future ACS; b) intra-coronary imaging to identify the underlying lesions and mechanisms for ACS, and to optimise the primary PCI outcomes; c) therapeutic strategies targeting inflammatory and thrombotic pathways, which drive coronary plaque rupture and subsequent myocardial infarction; d) the repurposing of existing anti-inflammatory and immunomodulatory agents to reduce residual risk in ACS survivors; e) strategies to minimise infarct size/maximise myocardial salvage; f) reducing microcirculatory dysfunction and enhancing tissue perfusion during revascularisation.

Prof. Sanjay Patel
Guest Editor

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Keywords

acute coronary syndrome
immuno-modulatory agents
intra-vascular imaging
myocardial salvage
microcirculatory dysfunction

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

3 pages, 197 KiB

Open AccessEditorial

Acute Coronary Syndrome: Unravelling the Biology to Identify New Therapies

by Bradley Tucker and Sanjay Patel

Cells 2022, 11(24), 4136; https://doi.org/10.3390/cells11244136 - 19 Dec 2022

Cited by 2 | Viewed by 1289

Abstract

Acute coronary syndrome (ACS) encompasses a spectrum of presentations including unstable angina, non-ST elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI) [...] Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

Research

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11 pages, 911 KiB

Open AccessArticle

The rs508487, rs236911, and rs236918 Genetic Variants of the Proprotein Convertase Subtilisin–Kexin Type 7 (PCSK7) Gene Are Associated with Acute Coronary Syndrome and with Plasma Concentrations of HDL-Cholesterol and Triglycerides

by Gilberto Vargas-Alarcón, Oscar Pérez-Méndez, Héctor González-Pacheco, Julián Ramírez-Bello, Rosalinda Posadas-Sánchez, Galileo Escobedo and José Manuel Fragoso

Cells 2021, 10(6), 1444; https://doi.org/10.3390/cells10061444 - 09 Jun 2021

Cited by 6 | Viewed by 1854

Abstract

Dyslipidemia has a substantial role in the development of acute coronary syndrome (ACS). Previous reports, including genome-wide associations studies (GWAS), have shown that some genetic variants of the proprotein convertase subtilisin–kexin type 7 (PCSK7) gene are associated with plasma lipid levels. In the present study, we evaluated whether PCSK7 gene polymorphisms are significantly associated with the plasma lipid profile and ACS. Three PCSK7 gene polymorphisms (rs508487 T/C, rs236911 C/A, and rs236918 C/G) were determined using TaqMan genotyping assays in a group of 603 ACS patients and 622 healthy controls. The plasma lipid profile was determined in the study groups by enzymatic/colorimetric assays. Under the recessive model, the rs236918 C allele was associated with a high risk of ACS (OR = 2.11, pC = 0.039). In the same way, under the recessive and additive models, the rs236911 C allele was associated with a high risk of ACS (OR = 1.95, pC = 0.037, and OR = 1.28, pC = 0.037, respectively). In addition, under the co-dominant model, the rs508487 T allele was associated with a higher risk of ACS (OR = 1.78, pC = 0.010). The CCC and TCC haplotypes were associated with a high risk of ACS (OR = 1.21, pC = 0.047, and OR = 1.80, pC = 0.001, respectively). The rs236911 CC and rs236918 CC genotypes were associated with lower high-density lipoproteins-cholesterol (HDL-C) plasma concentrations, whereas the rs236911 CC genotype was associated with a higher concentration of triglycerides, as demonstrated in the control individuals who were not receiving antidyslipidemic drugs. Our data suggest that the PCSK7 rs508487 T/C, rs236911 C/A, and rs236918 C/G polymorphisms are associated with the risk of developing ACS, and with plasma concentrations of HDL-C and triglycerides. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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12 pages, 1522 KiB

Open AccessArticle

Pericoronary Adipose Tissue Attenuation Is Associated with High-Risk Plaque and Subsequent Acute Coronary Syndrome in Patients with Stable Coronary Artery Disease

by Jeremy Yuvaraj, Andrew Lin, Nitesh Nerlekar, Ravi K. Munnur, James D. Cameron, Damini Dey, Stephen J. Nicholls and Dennis T. L. Wong

Cells 2021, 10(5), 1143; https://doi.org/10.3390/cells10051143 - 10 May 2021

Cited by 25 | Viewed by 2494

Abstract

Background: High-risk plaques (HRP) detected on coronary computed tomography angiography (CTA) confer an increased risk of acute coronary syndrome (ACS). Pericoronary adipose tissue attenuation (PCAT) is a novel biomarker of coronary inflammation. This study aimed to evaluate the association of PCAT with HRP and subsequent ACS development in patients with stable coronary artery disease (CAD). Methods: Patients with stable CAD who underwent coronary CTA from 2011 to 2016 and had available outcome data were included. We studied 41 patients with HRP propensity matched to 41 controls without HRP (60 ± 10 years, 67% males). PCAT was assessed using semi-automated software on a per-patient basis in the proximal right coronary artery (PCAT_RCA) and a per-lesion basis (PCAT_Lesion) around HRP in cases and the highest-grade stenosis lesions in controls. Results: PCAT_RCA and PCAT_Lesion were higher in HRP patients than controls (PCAT_RCA: −80.7 ± 6.50 HU vs. −84.2 ± 8.09 HU, p = 0.03; PCAT_Lesion: −79.6 ± 7.86 HU vs. −84.2 ± 10.3 HU, p = 0.04), and were also higher in men (PCAT_RCA: −80.5 ± 7.03 HU vs. −86.1 ± 7.08 HU, p < 0.001; PCAT_Lesion: −79.6 ± 9.06 HU vs. −85.2 ± 7.96 HU, p = 0.02). Median time to ACS was 1.9 years, within a median follow-up of 5.3 years. PCAT_RCA alone was higher in HRP patients who subsequently presented with ACS (−76.8 ± 5.69 HU vs. −82.0 ± 6.32 HU, p = 0.03). In time-dependent analysis, ACS was associated with HRP and PCAT_RCA. Conclusions: PCAT attenuation is increased in stable CAD patients with HRP and is associated with subsequent ACS development. Further investigation is required to determine the clinical implications of these findings. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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16 pages, 2283 KiB

Open AccessArticle

Metabolic Signatures in Coronary Artery Disease: Results from the BioHEART-CT Study

by Stephen T. Vernon, Owen Tang, Taiyun Kim, Adam S. Chan, Katharine A. Kott, John Park, Thomas Hansen, Yen C. Koay, Stuart M. Grieve, John F. O’Sullivan, Jean Y. Yang and Gemma A. Figtree

Cells 2021, 10(5), 980; https://doi.org/10.3390/cells10050980 - 22 Apr 2021

Cited by 11 | Viewed by 3689

Abstract

Despite effective prevention programs targeting cardiovascular risk factors, coronary artery disease (CAD) remains the leading cause of death. Novel biomarkers are needed for improved risk stratification and primary prevention. To assess for independent associations between plasma metabolites and specific CAD plaque phenotypes we performed liquid chromatography mass-spectrometry on plasma from 1002 patients in the BioHEART-CT study. Four metabolites were examined as candidate biomarkers. Dimethylguanidino valerate (DMGV) was associated with presence and amount of CAD (OR) 1.41 (95% Confidence Interval [CI] 1.12–1.79, p = 0.004), calcified plaque, and obstructive CAD (p < 0.05 for both). The association with amount of plaque remained after adjustment for traditional risk factors, ß-coefficient 0.17 (95% CI 0.02–0.32, p = 0.026). Glutamate was associated with the presence of non-calcified plaque, OR 1.48 (95% CI 1.09–2.01, p = 0.011). Phenylalanine was associated with amount of CAD, ß-coefficient 0.33 (95% CI 0.04–0.62, p = 0.025), amount of calcified plaque, (ß-coefficient 0.88, 95% CI 0.23–1.53, p = 0.008), and obstructive CAD, OR 1.84 (95% CI 1.01–3.31, p = 0.046). Trimethylamine N-oxide was negatively associated non-calcified plaque OR 0.72 (95% CI 0.53–0.97, p = 0.029) and the association remained when adjusted for traditional risk factors. In targeted metabolomic analyses including 53 known metabolites and controlling for a 5% false discovery rate, DMGV was strongly associated with the presence of calcified plaque, OR 1.59 (95% CI 1.26–2.01, p = 0.006), obstructive CAD, OR 2.33 (95% CI 1.59–3.43, p = 0.0009), and amount of CAD, ß-coefficient 0.3 (95% CI 0.14–0.45, p = 0.014). In multivariate analyses the lipid and nucleotide metabolic pathways were both associated with the presence of CAD, after adjustment for traditional risk factors. We report novel associations between CAD plaque phenotypes and four metabolites previously associated with CAD. We also identified two metabolic pathways strongly associated with CAD, independent of traditional risk factors. These pathways warrant further investigation at both a biomarker and mechanistic level. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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Review

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13 pages, 699 KiB

Open AccessReview

The Role of Sodium Glucose Cotransporter-2 Inhibitors in Atherosclerotic Cardiovascular Disease: A Narrative Review of Potential Mechanisms

by Jennifer Y. Barraclough, Sanjay Patel, Jie Yu, Bruce Neal and Clare Arnott

Cells 2021, 10(10), 2699; https://doi.org/10.3390/cells10102699 - 09 Oct 2021

Cited by 7 | Viewed by 2821

Abstract

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of medication with broad cardiovascular benefits in those with type 2 diabetes, chronic kidney disease, and heart failure. These include reductions in major adverse cardiac events and cardiovascular death. The mechanisms that underlie their benefits in atherosclerotic cardiovascular disease (ASCVD) are not well understood, but they extend beyond glucose lowering. This narrative review summarises the ASCVD benefits of SGLT2 inhibitors seen in large human outcome trials, as well as the mechanisms of action explored in rodent and small human studies. Potential pathways include favourable alterations in lipid metabolism, inflammation, and endothelial function. These all require further investigation in large human clinical trials with mechanistic endpoints, to further elucidate the disease modifying benefits of this drug class and those who will benefit most from it. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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Graphical abstract

17 pages, 2708 KiB

Open AccessFeature PaperReview

Imaging Inflammation in Patients and Animals: Focus on PET Imaging the Vulnerable Plaque

by Benjamin Bartlett, Herbert P. Ludewick, Silvia Lee, Shipra Verma, Roslyn J. Francis and Girish Dwivedi

Cells 2021, 10(10), 2573; https://doi.org/10.3390/cells10102573 - 28 Sep 2021

Cited by 11 | Viewed by 2546

Abstract

Acute coronary syndrome (ACS) describes a range of conditions associated with the rupture of high-risk or vulnerable plaque. Vulnerable atherosclerotic plaque is associated with many changes in its microenvironment which could potentially cause rapid plaque progression. Present-day PET imaging presents a plethora of radiopharmaceuticals designed to image different characteristics throughout plaque progression. Improved knowledge of atherosclerotic disease pathways has facilitated a growing number of pathophysiological targets for more innovative radiotracer design aimed at identifying at-risk vulnerable plaque and earlier intervention opportunity. This paper reviews the efficacy of PET imaging radiotracers ¹⁸F-FDG, ¹⁸F-NaF, ⁶⁸Ga-DOTATATE, ⁶⁴Cu-DOTATATE and ⁶⁸Ga-pentixafor in plaque characterisation and risk assessment, as well as the translational potential of novel radiotracers in animal studies. Finally, we discuss our murine PET imaging experience and the challenges encountered. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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21 pages, 1068 KiB

Open AccessReview

Acute Coronary Syndromes (ACS)—Unravelling Biology to Identify New Therapies—The Microcirculation as a Frontier for New Therapies in ACS

by Kaivan Vaidya, Bradley Tucker, Sanjay Patel and Martin K. C. Ng

Cells 2021, 10(9), 2188; https://doi.org/10.3390/cells10092188 - 25 Aug 2021

Cited by 7 | Viewed by 2799

Abstract

In acute coronary syndrome (ACS) patients, restoring epicardial culprit vessel patency and flow with percutaneous coronary intervention or coronary artery bypass grafting has been the mainstay of treatment for decades. However, there is an emerging understanding of the crucial role of coronary microcirculation in predicting infarct burden and subsequent left ventricular remodelling, and the prognostic significance of coronary microvascular obstruction (MVO) in mortality and morbidity. This review will elucidate the multifaceted and interconnected pathophysiological processes which underpin MVO in ACS, and the various diagnostic modalities as well as challenges, with a particular focus on the invasive but specific and reproducible index of microcirculatory resistance (IMR). Unfortunately, a multitude of purported therapeutic strategies to address this unmet need in cardiovascular care, outlined in this review, have so far been disappointing with conflicting results and a lack of hard clinical end-point benefit. There are however a number of exciting and novel future prospects in this field that will be evaluated over the coming years in large adequately powered clinical trials, and this review will briefly appraise these. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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27 pages, 5627 KiB

Open AccessFeature PaperReview

Inflammation during Percutaneous Coronary Intervention—Prognostic Value, Mechanisms and Therapeutic Targets

by Bradley Tucker, Kaivan Vaidya, Blake J. Cochran and Sanjay Patel

Cells 2021, 10(6), 1391; https://doi.org/10.3390/cells10061391 - 04 Jun 2021

Cited by 22 | Viewed by 3324

Abstract

Periprocedural myocardial injury and myocardial infarction (MI) are not infrequent complications of percutaneous coronary intervention (PCI) and are associated with greater short- and long-term mortality. There is an abundance of preclinical and observational data demonstrating that high levels of pre-, intra- and post-procedural inflammation are associated with a higher incidence of periprocedural myonecrosis as well as future ischaemic events, heart failure hospitalisations and cardiac-related mortality. Beyond inflammation associated with the underlying coronary pathology, PCI itself elicits an acute inflammatory response. PCI-induced inflammation is driven by a combination of direct endothelial damage, liberation of intra-plaque proinflammatory debris and reperfusion injury. Therefore, anti-inflammatory medications, such as colchicine, may provide a novel means of improving PCI outcomes in both the short- and long-term. This review summarises periprocedural MI epidemiology and pathophysiology, evaluates the prognostic value of pre-, intra- and post-procedural inflammation, dissects the mechanisms involved in the acute inflammatory response to PCI and discusses the potential for periprocedural anti-inflammatory treatment. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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18 pages, 1528 KiB

Open AccessReview

The Emerging Role of CT-Based Imaging in Adipose Tissue and Coronary Inflammation

by Jeremy Yuvaraj, Kevin Cheng, Andrew Lin, Peter J. Psaltis, Stephen J. Nicholls and Dennis T. L. Wong

Cells 2021, 10(5), 1196; https://doi.org/10.3390/cells10051196 - 13 May 2021

Cited by 15 | Viewed by 3953

Abstract

A large body of evidence arising from recent randomized clinical trials demonstrate the association of vascular inflammatory mediators with coronary artery disease (CAD). Vascular inflammation localized in the coronary arteries leads to an increased risk of CAD-related events, and produces unique biological alterations to local cardiac adipose tissue depots. Coronary computed tomography angiography (CTA) provides a means of mapping inflammatory changes to both epicardial adipose tissue (EAT) and pericoronary adipose tissue (PCAT) as independent markers of coronary risk. Radiodensity or attenuation of PCAT on coronary CTA, notably, provides indirect quantification of coronary inflammation and is emerging as a promising non-invasive imaging implement. An increasing number of observational studies have shown robust associations between PCAT attenuation and major coronary events, including acute coronary syndrome, and ‘vulnerable’ atherosclerotic plaque phenotypes that are associated with an increased risk of the said events. This review outlines the biological characteristics of both EAT and PCAT and provides an overview of the current literature on PCAT attenuation as a surrogate marker of coronary inflammation. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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17 pages, 14362 KiB

Open AccessReview

Cardiac Computed Tomography Radiomics for the Non-Invasive Assessment of Coronary Inflammation

by Kevin Cheng, Andrew Lin, Jeremy Yuvaraj, Stephen J. Nicholls and Dennis T.L. Wong

Cells 2021, 10(4), 879; https://doi.org/10.3390/cells10040879 - 12 Apr 2021

Cited by 19 | Viewed by 3493

Abstract

Radiomics, via the extraction of quantitative information from conventional radiologic images, can identify imperceptible imaging biomarkers that can advance the characterization of coronary plaques and the surrounding adipose tissue. Such an approach can unravel the underlying pathophysiology of atherosclerosis which has the potential to aid diagnostic, prognostic and, therapeutic decision making. Several studies have demonstrated that radiomic analysis can characterize coronary atherosclerotic plaques with a level of accuracy comparable, if not superior, to current conventional qualitative and quantitative image analysis. While there are many milestones still to be reached before radiomics can be integrated into current clinical practice, such techniques hold great promise for improving the imaging phenotyping of coronary artery disease. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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18 pages, 2593 KiB

Open AccessFeature PaperReview

Atherothrombosis in Acute Coronary Syndromes—From Mechanistic Insights to Targeted Therapies

by Chinmay Khandkar, Mahesh V. Madhavan, James C. Weaver, David S. Celermajer and Keyvan Karimi Galougahi

Cells 2021, 10(4), 865; https://doi.org/10.3390/cells10040865 - 10 Apr 2021

Cited by 6 | Viewed by 3513

Abstract

The atherothrombotic substrates for acute coronary syndromes (ACS) consist of plaque ruptures, erosions and calcified nodules, while the non-atherothrombotic etiologies, such as spontaneous coronary artery dissection, coronary artery spasm and coronary embolism are the rarer causes of ACS. The purpose of this comprehensive review is to (1) summarize the histopathologic insights into the atherothrombotic plaque subtypes in acute ACS from postmortem studies; (2) provide a brief overview of atherogenesis, while mainly focusing on the events that lead to plaque destabilization and disruption; (3) summarize mechanistic data from clinical studies that have used intravascular imaging, including high-resolution optical coherence tomography, to assess culprit plaque morphology and its underlying pathobiology, especially the newly described role of innate and adaptive immunity in ACS secondary to plaque erosion; (4) discuss the utility of intravascular imaging for effective treatment of patients presenting with ACS by percutaneous coronary intervention; and (5) discuss the opportunities that these mechanistic and imaging insights may provide for more individualized treatment of patients with ACS. Full article

(This article belongs to the Special Issue Acute Coronary Syndrome: Unraveling the Biology to Identify New Therapies)

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