BACKGROUND—Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However, it is unclear whether mtDNA damage directly promotes atherogenesis ...or is a consequence of tissue damage, which cell types are involved, and whether its effects are mediated only through reactive oxygen species.
METHODS AND RESULTS—mtDNA damage occurred early in the vessel wall in apolipoprotein E–null (ApoE) mice, before significant atherosclerosis developed. mtDNA defects were also identified in circulating monocytes and liver and were associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE mice deficient for mitochondrial polymerase-γ proofreading activity (polG/ApoE). polG/ApoE mice showed extensive mtDNA damage and defects in oxidative phosphorylation but no increase in reactive oxygen species. polG/ApoE mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG/ApoE bone marrow increased the features of plaque vulnerability, and polG/ApoE monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden.
CONCLUSIONS—We show that mtDNA damage in vessel wall and circulating cells is widespread and causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.
In a randomized trial, optical coherence tomography–guided PCI resulted in a larger minimum stent area than angiography-guided PCI, but there was no between-group difference in target-vessel failure ...at 2 years.
Abstract
Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the ...individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term ‘vulnerable plaque’ was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of ‘vulnerability’ of a specific lesion to the more comprehensive goal of identifying patient ‘cardiovascular vulnerability’. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and ‘local’ diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of ‘high-risk’ plaques occurring in ‘vulnerable’ patients.
The purpose of this study was to determine whether thin-capped fibroatheromata (TCFA) identified by virtual histology intravascular ultrasound (VH-IVUS) are associated with major adverse cardiac ...events (MACE) on individual plaque or whole patient analysis.
Post-mortem studies have identified TCFA as the substrate for most myocardial infarctions. However, little is known about the natural history of individual TCFA and their link with MACE. VH-IVUS provides a method of identifying plaques in vivo that are similar (although not identical) to histologically defined TCFA, and has been validated in human atherectomy and post-mortem studies.
One hundred seventy patients with stable angina or troponin-positive acute coronary syndrome referred for percutaneous coronary intervention (PCI) were prospectively enrolled and underwent 3-vessel VH-IVUS pre-PCI and also post-PCI in the culprit vessel. MACE consisted of death, myocardial infarction, or unplanned revascularization.
In all, 30,372 mm of VH-IVUS were analyzed. Eighteen MACE occurred in 16 patients over a median follow-up of 625 days (interquartile range: 463 to 990 days); 1,096 plaques were classified, and 19 lesions resulted in MACE (13 nonculprit lesions and 6 culprit lesions). Nonculprit lesion factors associated with nonrestenotic MACE included VHTCFA (hazard ratio HR: 7.53, p = 0.038) and plaque burden >70% (HR: 8.13, p = 0.011). VHTCFA (HR: 8.16, p = 0.007), plaque burden >70% (HR: 7.48, p < 0.001), and minimum luminal area <4 mm(2) (HR: 2.91, p = 0.036) were associated with total MACE. On patient-based analysis, the only factor associated with nonrestenotic MACE was 3-vessel noncalcified VHTCFA (HR: 1.79, p = 0.004).
VH-IVUS TCFA was associated with nonrestenotic and total MACE on individual plaque analysis, and noncalcified VHTCFA was associated with nonrestenotic and total MACE on whole-patient analysis, demonstrating that VH-IVUS can identify plaques at increased risk of subsequent events. The preservation of the association between VHTCFA and MACE despite various analyses emphasizes its biological importance.
Invasive imaging modalities, in particular intravascular ultrasound (IVUS) and optical coherence tomography (OCT), have become established tools for the in vivo study of coronary atherosclerosis. ...Their use in clinical studies has confirmed histopathological observations that certain important plaque features, such as thin fibrous caps and large lipid cores, are associated with plaque rupture, the precipitating event for the majority of myocardial infarctions. Serial imaging studies have also successfully been used for the evaluation of potential disease modifying pharmacological agents. Recent prospective IVUS studies have confirmed specific baseline imaging features associated with subsequent adverse clinical outcomes, although absolute event rates were too low for clinical utility. Development of hybrid IVUS–OCT imaging or integration of novel techniques, including near-infrared spectroscopy, plaque structural and endothelial shear stress, have great potential to improve our current ability to identify and stratify atheromatous plaques at risk of rupture.
Objective
The LightLab Clinical Initiative was designed to examine adoption of optical coherence tomography (OCT) imaging during routine percutaneous coronary intervention (PCI) practice, and enable ...identification and reduction of barriers to broader adoption of intracoronary imaging in real‐world practice.
Background
Intracoronary imaging guidance during PCI has been shown to improve clinical outcomes and features as a recommendation in societal guidelines, yet widespread routine adoption remains low. Perceived barriers to utilization include familiarity with, and ability to interpret imaging, concerns over added procedure time and contrast load, alongside a lack of actionable outcome data.
Methods and Results
LightLab was a multicenter prospective observational data‐gathering project, conducted between January 2019, and June 2021, with 17 participating hospitals and physicians. Data were gathered in real‐time, where OCT guidance was employed during PCI using a standardized OCT‐guided workflow algorithm, MLD MAX (where MLD stands for plaque Morphology, lesion Length, vessel Diameter and MAX for Medial dissection, stent Apposition, stent eXpansion) which was developed to simplify and integrate information from OCT throughout the PCI procedure. Integration of this workflow/algorithm was implemented through a series of phases, focusing on physician decision‐making, efficiency, and safety improvements during the procedure.
Conclusions
Through real‐time, prospective procedural data acquisition in the cardiac catheterization laboratory setting, the LightLab Clinical Initiative demonstrates the impact of a standardized OCT‐guided workflow on procedural metrics, including time, contrast use, radiation exposure, as well as financial efficiencies such as device utilization. These results can potentially mitigate underlying concerns over the utility of adoption of intracoronary imaging guidance during PCI.
Randomised trials have demonstrated improvement in clinical outcomes with intravascular ultrasound (IVUS)-guided percutaneous coronary intervention (PCI) compared with angiography-guided PCI. The ...ILUMIEN III trial demonstrated non-inferiority of an optical coherence tomography (OCT)- versus IVUS-guided PCI strategy in achieving similar post-PCI lumen dimensions. ILUMIEN IV is a large-scale, multicentre, randomised trial designed to demonstrate the superiority of OCT- versus angiography-guided stent implantation in patients with high-risk clinical characteristics (diabetes) and/or complex angiographic lesions in achieving larger post-PCI lumen dimensions and improving clinical outcomes.
ILUMIEN IV is a prospective, single-blind clinical investigation that will randomise between 2,490 and 3,656 patients using an adaptive design to OCT-guided versus angiography-guided coronary stent implantation in a 1:1 ratio. The primary endpoints are: (1) post-PCI minimal stent area assessed by OCT in each randomised arm, and (2) target vessel failure, the composite of cardiac death, target vessel myocardial infarction, or ischaemia-driven target vessel revascularisation. Clinical follow-up will continue for up to two years. The trial is currently enrolling, and the principal results are expected in 2022.
The large-scale ILUMIEN IV randomised controlled trial will evaluate the effectiveness of OCT-guided versus angiography-guided PCI in improving post-PCI lumen dimensions and clinical outcomes in patients with diabetes and/or with complex coronary lesions.
NCT03507777.
Abstract
Healthcare has entered a brave new world in the early part of the 21st century: the landscape has changed and continues to change rapidly, evolving at a rate as never seen before. Fuelled by ...technological advancement, big data analytics, and the explosion of apps and sensors, as well as by telemedicine and remote monitoring needs driven by the COVID-19 pandemic, the healthcare ecosystem is metamorphosing literally before our eyes. So, what is the role for the Medtech industry as healthcare systems reshape themselves to address emerging patients’ needs and desires, and how can the use of data and novel technologies be leveraged to bring about the kind of change needed to deliver truly holistic patient care?
BACKGROUND—Postprocedural myocardial infarction (type 4a) has been shown to be an adverse prognostic indicator after elective percutaneous coronary intervention (PCI). The Cardiac Remote Ischemic ...Preconditioning in Coronary Stenting (CRISP Stent) study demonstrated that remote ischemic preconditioning reduced procedural symptoms, ECG ST-segment deviation, and cardiac troponin I release after elective PCI and reduced the major adverse cardiac and cerebral event (MACCE) rate at 6 months. We were interested to confirm if this early benefit in MACCE rate in the remote ischemic preconditioning group was sustained long-term.
METHODS AND RESULTS—Patients were telephoned by researchers blinded to the randomization details. MACCE, defined as all-cause mortality, nonfatal myocardial infarction, transient ischemic attack or stroke, and heart failure requiring hospital admission, were adjudicated by case note and national database review. One hundred ninety-two (89.3%) of the 225 patients with elective PCI randomized in the original study were available for long-term follow-up (mean time to event or last follow-up1579.7±603.6 days). There were a total of 59 (30.7%) MACCEs. Patients with an MACCE had a higher mean cardiac troponin I after PCI (±SD)2.07±6.99 versus 0.91±2.07 ng/mL (P=0.05). The MACCE rate at 6 years remained lower in the remote ischemic preconditioning group (hazard ratio, 0.58; 95% confidence interval, 0.35–0.97; P=0.039; absolute risk reduction=0.13 and number needed to treat=8 to prevent the MACCE at 6 years).
CONCLUSIONS—Remote ischemic preconditioning reduces the incidence of postprocedural cardiac troponin I after elective PCI and confers an MACCE-free survival benefit at both short- and long-term follow-up.
CLINICAL TRIAL REGISTRATION—URLhttp://www.ukcrn.org.uk. Unique identifierUKCRN 4074
Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes ...(ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (
p
= 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%,
p
= 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%,
p
= 0.47) and revascularization (9.9 vs. 12.1%,
p
= 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS.
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