Personalized Intervention Based on Early Detection of Atherosclerosis: JACC State-of-the-Art Review.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required-moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health.

Aortic aneurysms in a general population cohort: prevalence and risk factors in men and women.

BACKGROUND AND AIMS: The prevalence and difference in risk factors for having thoracic and abdominal aortic aneurysms in men compared to women in the general population is not well-described. This study aimed to test the hypotheses i) that cardiovascular risk factors for thoracic and abdominal aortic aneurysms differ and ii) that the prevalence of thoracic and abdominal aortic aneurysms is sex specific. METHODS: Aortic examination using computed tomography angiography was performed in 11,294 individuals (56% women), with a mean age of 62 [range 40-95] years participating in the Copenhagen General Population Study. Thoracic aortic aneurysms were defined as ascending aortic diameter ≥45 mm and descending aortic diameter ≥35 mm, abdominal aortic aneurysms were defined as abdominal aortic diameter ≥30 mm. Demographic data were obtained from questionnaires. RESULTS: Overall prevalence of aortic aneurysms in the study population included: total population 2.1%, men 4.0% and women 0.7% (p-test men vs. women p<0.001). Aortic aneurysms were independently associated with male sex, increasing age, and body surface area. While thoracic aortic aneurysms were associated with hypertension, odds ratio=2.0[95%CI:1.5-2.8], abdominal aortic aneurysms were associated with hypercholesterolemia and smoking, odds ratios=2.4[95%CI:1.6-3.6] and 3.2[95%CI:1.9-5.4]. CONCLUSIONS: Subclinical aortic aneurysms are four times more prevalent in men than women. In both sexes, increasing age and body surface area are risk factors for aortic aneurysms of any anatomical location. Whereas arterial hypertension is a risk factor for thoracic aortic aneurysms, hypercholesterolemia and smoking are risk factors for abdominal aortic aneurysms.

Exercise Therapy for Chronic Symptomatic Peripheral Artery Disease: A Clinical Consensus Document of the European Society of Cardiology Working Group on Aorta and Peripheral Vascular Diseases in Collaboration With the European Society of Vascular Medicine and the European Society for Vascular Surgery.

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.

Exercise therapy for chronic symptomatic peripheral artery disease.

All guidelines worldwide strongly recommend exercise as a pillar of the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended for clinicians to promote and assist for the set-up of comprehensive exercise programmes to best advice in patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are narratively described based on the current best evidence. The document ends by highlighting disparities in access to supervised exercise programmes across Europe and the series of gaps for evidence requiring further research.

Exercise therapy for chronic symptomatic peripheral artery disease.

All guidelines worldwide strongly recommend exercise as a pillar in the management of patients affected by lower extremity peripheral artery disease (PAD). Exercise therapy in this setting presents different modalities, and a structured programme provides optimal results. This clinical consensus paper is intended to promote and assist the set up of comprehensive exercise programmes and best advice for patients with symptomatic chronic PAD. Different exercise training protocols specific for patients with PAD are presented. Data on patient assessment and outcome measures are described based on the current best evidence. The document ends by highlighting supervised exercise programme access disparities across Europe and the evidence gaps requiring further research.

3-D Contrast-Enhanced Fusion Ultrasound for Accurate Volume Assessment of Vessel Lumen and Plaque in Carotid Artery Disease as Compared With Computed Tomography Angiography.

OBJECTIVE: Three-dimensional contrast-enhanced fusion ultrasound (CEFUS) of atherosclerotic carotid arteries provides spatial visualization of the vessel lumen, creating a lumenography. As in 3-D computed tomography angiography (CTA), 3-D CEFUS outlines the contrast-filled lumen. Plaque and vessel contours are distinguished in 3-D CEFUS, allowing plaque volume quantification as a valid estimate of carotid plaque burden. Three-dimensional CEFUS is unproven in intermodality studies, vindicating the assessment of 3-D CEFUS applicability and comparing 3-D CEFUS and 3-D CTA lumenography as a proof-of-concept study. METHODS: Using an ultrasound system with magnetic tracking, a linear array transducer and SonoVue contrast agent, 3-D CEFUS acquisitions were generated by spatial stitching of serial 2-D images. From 3-D CEFUS and 3-D CTA imaging, the atherosclerotic carotid arteries were reconstructed with lumenography in an offline software program for lumen and plaque volume quantification. Bland-Altman analysis was used for inter-image modality agreement. RESULTS: The study included 39 carotid arteries. Mean lumen and plaque volume in 3-D CEFUS were 0.63 cm3 (standard deviation [SD]: 0.26) and 0.62 cm3 (SD: 0.26), respectively. Lumen volume differences between 3-D CEFUS and 3-D CTA were non-significant, with a mean difference of 0.01 cm3 (SD: 0.02, p = 0.26) and limits of agreement (LoA) range of ±0.11 cm3. Mean plaque volume difference was -0.12 cm3 (SD: 0.19, p = 0.006) with a LoA range of ±0.39 cm3. CONCLUSION: There was strong agreement in lumenography between 3-D CEFUS and 3-D CTA. The interimage modality difference in plaque volumes was substantial because of challenging vessel wall definition in 3-D CTA. Three-dimensional CEFUS is viable in quantifying carotid plaque volume burden and can potentially monitor plaque development over time.

Proteomic analysis of the extracellular matrix of human atherosclerotic plaques shows marked changes between plaque types.

Cardiovascular disease is the leading cause of death, with atherosclerosis the major underlying cause. While often asymptomatic for decades, atherosclerotic plaque destabilization and rupture can arise suddenly and cause acute arterial occlusion or peripheral embolization resulting in myocardial infarction, stroke and lower limb ischaemia. As extracellular matrix (ECM) remodelling is associated with plaque instability, we hypothesized that the ECM composition would differ between plaques. We analyzed atherosclerotic plaques obtained from 21 patients who underwent carotid surgery following recent symptomatic carotid artery stenosis. Plaques were solubilized using a new efficient, single-step approach. Solubilized proteins were digested to peptides, and analyzed by liquid chromatography-mass spectrometry using data-independent acquisition. Identification and quantification of 4498 plaque proteins was achieved, including 354 ECM proteins, with unprecedented coverage and high reproducibility. Multidimensional scaling analysis and hierarchical clustering indicate two distinct clusters, which correlate with macroscopic plaque morphology (soft/unstable versus hard/stable), ultrasound classification (echolucent versus echogenic) and the presence of hemorrhage/ulceration. We identified 714 proteins with differential abundances between these groups. Soft/unstable plaques were enriched in proteins involved in inflammation, ECM remodelling, and protein degradation (e.g. matrix metalloproteinases, cathepsins). In contrast, hard/stable plaques contained higher levels of ECM structural proteins (e.g. collagens, versican, nidogens, biglycan, lumican, proteoglycan 4, mineralization proteins). These data indicate that a single-step proteomics method can provide unique mechanistic insights into ECM remodelling and inflammatory mechanisms within plaques that correlate with clinical parameters, and help rationalize plaque destabilization. These data also provide an approach towards identifying biomarkers for individualized risk profiling of atherosclerosis.

Precision medicine for cardiometabolic disease: a framework for clinical translation.

Cardiometabolic disease is a major threat to global health. Precision medicine has great potential to help to reduce the burden of this common and complex disease cluster, and to enhance contemporary evidence-based medicine. Its key pillars are diagnostics; prediction (of the primary disease); prevention (of the primary disease); prognosis (prediction of complications of the primary disease); treatment (of the primary disease or its complications); and monitoring (of risk exposure, treatment response, and disease progression or remission). To contextualise precision medicine in both research and clinical settings, and to encourage the successful translation of discovery science into clinical practice, in this Series paper we outline a model (the EPPOS model) that builds on contemporary evidence-based approaches; includes precision medicine that improves disease-related predictions by stratifying a cohort into subgroups of similar characteristics, or using participants' characteristics to model treatment outcomes directly; includes personalised medicine with the use of a person's data to objectively gauge the efficacy, safety, and tolerability of therapeutics; and subjectively tailors medical decisions to the individual's preferences, circumstances, and capabilities. Precision medicine requires a well functioning system comprised of multiple stakeholders, including health-care recipients, health-care providers, scientists, health economists, funders, innovators of medicines and technologies, regulators, and policy makers. Powerful computing infrastructures supporting appropriate analysis of large-scale, well curated, and accessible health databases that contain high-quality, multidimensional, time-series data will be required; so too will prospective cohort studies in diverse populations designed to generate novel hypotheses, and clinical trials designed to test them. Here, we carefully consider these topics and describe a framework for the integration of precision medicine in cardiometabolic disease.

Stroke risk management in carotid atherosclerotic disease: A Clinical Consensus Statement of the ESC Council on Stroke and the ESC Working Group on Aorta and Peripheral Vascular Diseases.

Carotid atherosclerotic disease continues to be an important cause of stroke, often disabling or fatal. Such strokes could be largely prevented through optimal medical therapy and carotid revascularization. Advancements in discovery research and imaging along with evidence from recent pharmacology and interventional clinical trials and registries and the progress in acute stroke management have markedly expanded knowledge base for clinical decisions in carotid stenosis. Nevertheless, there is variability in carotid-related stroke prevention and management strategies across medical specialities. Optimal patient care can be achieved by (1) establishing a unified knowledge foundation and (2) fostering multi-specialty collaborative guidelines. The emergent Neuro-Vascular Team concept, mirroring the multi-disciplinary Heart Team, embraces diverse specializations, tailores personalized, stratified medicine approaches to individual patient needs, and integrates innovative imaging and risk-assessment biomarkers. Proposed approach integrates collaboration of multiple specialists central to carotid artery stenosis management such as neurology, stroke medicine, cardiology, angiology, ophthalmology, vascular surgery, endovascular interventions, neuroradiology and neurosurgery. Moreover, patient education regarding current treatment options, their risks and advantages, is pivotal, promting patient's active role in clinical care decisions. This enables optimization of interventions ranging from lifestyle modification, carotid revascularization by stenting or endarterectomy, as well as pharmacological management encompassing statins, novel lipid-lowering and antithrombotic strategies and targeting inflammation and vascular dysfunction. This consensus document provides a harmonized multi-specialty approach to multimorbidity prevention in carotid stenosis patients, based on comprehensive knowledge review, pinpointing research gaps in an evidence-based medicine approach. It aims to be a foundational tool for interdisciplinary collaboration and prioritized patient-centric decision-making.

Effect of pharmacologic anti-atherosclerotic therapy on carotid intraplaque neovascularization: A systematic review.

Intraplaque neovascularization (IPN), a key feature of vulnerable carotid plaque, is associated with adverse cardiovascular (CV) events. Statin therapy has been shown to diminish and stabilize atherosclerotic plaque, but its effect on IPN is uncertain. This review investigated the effects of common pharmacologic anti-atherosclerotic therapies on carotid IPN. Electronic databases (MEDLINE, EMBASE and Cochrane Library) were searched from inception until July 13, 2022. Studies evaluating the effect of anti-atherosclerotic therapy on carotid IPN among adults with carotid atherosclerosis were included. Sixteen studies were eligible for inclusion. Contrast-enhanced ultrasound (CEUS) was the most common IPN assessment modality (n=8), followed by dynamic contrast-enhanced MRI (DCE-MRI) (n=4), excised plaque histology (n=3) and superb microvascular imaging (n=2). In fifteen studies, statins were the therapy of interest and one study assessed PCSK9 inhibitors. Among CEUS studies, baseline statin use was associated with a lower frequency of carotid IPN (median OR = 0.45). Prospective studies showed regression of IPN after 6-12 months of lipid-lowering therapy, with more regression observed in treated participants compared to untreated controls. Our findings suggest that lipid-lowering therapy with statins or PCSK9 inhibitors is associated with IPN regression. However, there was no correlation between change in IPN parameters and change in serum lipids and inflammatory markers in statin-treated participants, so it is unclear whether these factors are mediators in the observed IPN changes. Lastly, this review was limited by study heterogeneity and small sample sizes, so larger trials are needed to validate findings.

One-year volume growth of abdominal aortic aneurysms measured by extended field-of-view ultrasound.

BACKGROUND: Measurement of volume has the potential to detect subtle growth not recognized in the current surveillance paradigm of abdominal aortic aneurysms (AAAs). Currently available three-dimensional ultrasound allows for estimation of AAA volume, but for most patients, the AAA extends beyond the ultrasound field-of-view and only allows visualization of a partial AAA volume. A new extended field-of-view three-dimensional ultrasound protocol (XFoV US) has been found to improve the proportion of patients with visualization of the full AAA volume. METHODS: To investigate the applicability of the XFoV US protocol in estimating AAA volume growth in follow-up, 86 patients with AAAs were recruited from the surveillance program at a university hospital. All were imaged by XFoV US at baseline and at one-year follow-up. RESULTS: Assessment of full volume, based on visualization of the AAA neck and bifurcation at both baseline and one-year follow-up, was achieved in 67/86 (78%) of patients. One-year mean growth in maximum diameter was 2.8 mm (6%/year), in centerline length 2.9 mm (4%/year), and in volume 15.9 mL (19%/year). In 17/67 (25%) of patients, volume growth was detected in diameter-stable AAAs. Baseline XFoV US volume was associated with one-year AAA volume growth, while, conversely, maximum baseline diameter was not associated with one-year AAA diameter growth. CONCLUSIONS: This study concludes that the XFoV US protocol provides a safe and repeatable modality for assessing AAA volume growth, and that AAA volume is a promising predictive measure of AAA growth.

Rivaroxaban in patients with symptomatic peripheral artery disease after lower extremity bypass surgery with venous and prosthetic conduits.

BACKGROUND: Patients with peripheral artery disease (PAD) requiring lower extremity revascularization (LER) have a high risk of adverse limb and cardiovascular events. The results from the VOYAGER PAD (efficacy and safety of rivaroxaban in reducing the risk of major thrombotic vascular events in subjects with symptomatic peripheral artery disease undergoing peripheral revascularization procedures of the lower extremities) trial have demonstrated that rivaroxaban significantly reduced this risk with an overall favorable net benefit for patients undergoing surgical revascularization. However, the efficacy and safety for those treated by surgical bypass, including stratification by bypass conduit (venous or prosthetic), has not yet been described. METHODS: In the VOYAGER PAD trial, patients who had undergone surgical and endovascular infrainguinal LER to treat PAD were randomized to rivaroxaban 2.5 mg twice daily or placebo on top of background antiplatelet therapy (aspirin 100 mg to be used in all and clopidogrel in some at the treating physician's discretion) and followed up for a median of 28 months. The primary end point was a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, and cardiovascular death. The principal safety outcome was major bleeding using the TIMI (thrombolysis in myocardial infarction) scale. The index procedure details, including conduit type (venous vs prosthetic), were collected at baseline. RESULTS: Among 6564 randomized patients, 2185 (33%) had undergone surgical LER. Of these 2185 patients, surgical bypass had been performed for 1448 (66%), using a prosthetic conduit for 773 patients (53%) and venous conduit for 646 patients (45%). Adjusting for the baseline differences and anatomic factors, the risk of unplanned limb revascularization in the placebo arm was 2.5-fold higher for those receiving a prosthetic conduit vs a venous conduit (adjusted hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.65-3.90; P < .001), and the risk of acute limb ischemia was three times greater (adjusted HR, 3.07; 95% CI, 1.84-5.11; P < .001). The use of rivaroxaban reduced the primary outcome for the patients treated with bypass surgery (HR, 0.78; 95% CI, 0.62-0.98), with consistent benefits for those receiving venous (HR, 0.66; 95% CI, 0.49-0.96) and prosthetic (HR, 0.87; 95% CI, 0.66-1.15) conduits (Pinteraction = .254). In the overall trial, major bleeding using the TIMI scale was increased with rivaroxaban. However, the numbers for those treated with bypass surgery were low (five with rivaroxaban vs nine with placebo; HR, 0.55; 95% CI, 0.18-1.65) and not powered to show statistical significance. CONCLUSIONS: Surgical bypass with a prosthetic conduit was associated with significantly higher rates of major adverse limb events relative to venous conduits even after adjustment for patient and anatomic characteristics. Adding rivaroxaban 2.5 mg twice daily to aspirin or dual antiplatelet therapy significantly reduced this risk, with an increase in the bleeding risk, but had a favorable benefit risk for patients treated with bypass surgery, regardless of conduit type. Rivaroxaban should be considered after lower extremity bypass for symptomatic PAD to reduce ischemic complications of the heart, limb, and brain.

Antithrombotic therapy following revascularization for chronic limb-threatening ischaemia: a European survey from the ESC Working Group on Aorta and Peripheral Vascular Diseases.

AIMS: Chronic limb-threatening ischaemia (CLTI) entails dismal outcomes and is an absolute indication to lower extremity revascularization (LER) whenever possible. Antithrombotic therapy is here crucial, but available evidence on best strategies (choice of drugs, combinations, duration) is scarce. We conducted a European internet-based survey on physicians' use of antithrombotic therapy after revascularization for CLTI, under the aegis of the ESC Working Group on Aorta and Peripheral Vascular Disease in collaboration with other European scientific societies involved in CLTI management and agreeing to send the survey to their affiliates. METHODS AND RESULTS: 225 respondents completed the questionnaire. Antithrombotic therapy following surgical/endovascular LER varies widely across countries and specialties, with dedicated protocols reported only by a minority (36%) of respondents. Dual antiplatelet therapy with aspirin and clopidogrel is the preferred choice for surgical (37%) and endovascular (79%) LER. Dual pathway inhibition (DPI) with aspirin and low-dose rivaroxaban is prescribed by 16% of respondents and is tightly related to the availability of reimbursement (OR 6.88; 95% CI 2.60-18.25) and to the choice of clinicians rather than of physicians performing revascularization (OR 2.69; 95% CI 1.10-6.58). A ≥ 6 months-duration of an intense (two-drug) postprocedural antithrombotic regimen is more common among surgeons than among medical specialists (OR 2.08; 95% CI 1.10-3.94). Bleeding risk assessment is not standardised and likely underestimated. CONCLUSION: Current antithrombotic therapy of CLTI patients undergoing LER remains largely discretional, and prescription of DPI is related to reimbursement policies. An individualised assessment of thrombotic and bleeding risks is largely missing.

European Society of Cardiology quality indicators for the cardiovascular pre-operative assessment and management of patients considered for non-cardiac surgery. Developed in collaboration with the European Society of Anaesthesiology and Intensive Care.

AIMS: To establish a set of quality indicators (QIs) for the cardiovascular (CV) assessment and management of patients undergoing non-cardiac surgery (NCS). METHODS AND RESULTS: The Quality Indicator Committee of the European Society of Cardiology (ESC) and European Society of Anaesthesiology and Intensive Care (ESAIC) in collaboration with Task Force members of the 2022 ESC Guidelines on CV assessment and management of patients undergoing NCS followed the ESC methodology for QI development. This included (1) identification, by constructing a conceptual framework of care, of domains of the CV assessment, and management of patients with risk factors or established cardiovascular disease (CVD) who are considered for or undergoing NCS, (2) development of candidate QIs following a systematic literature review, (3) selection of the final set of QIs using a modified Delphi method, and (4) evaluation of the feasibility of the developed QIs. In total, eight main and nine secondary QIs were selected across six domains: (1) structural framework (written policy), (2) patient education and quality of life (CV risk discussion), (3) peri-operative risk assessment (indication for diagnostic tests), (4) peri-operative risk mitigation (use of hospital therapies), (5) follow-up (post-discharge assessment), and (6) outcomes (major CV events). CONCLUSION: We present the 2022 ESC/ESAIC QIs for the CV assessment and management of patients with risk factors or established CVD who are considered for or are undergoing NCS y. These indicators are supported by evidence from the literature, underpinned by expert consensus, and align with the 2022 ESC Guidelines on CV assessment and management of patients undergoing NCS.

Cancer should not contravene the revascularization of chronic limb-threatening ischaemia.

OBJECTIVES: This study aimed to examine the frequency of cancer among patients with chronic limb-threatening ischaemia (CLTI) due to peripheral artery disease (PAD) and to determine how active cancer affected outcomes after open or endovascular revascularization. In addition, we aimed to investigate all-cause mortality and cause of death in the PAD population. DESIGN: Observational single-centre cohort study based on a retrospective analysis of prospectively entered registry data. MATERIALS: All consecutive patients treated for CLTI due to PAD at a single university centre between the 1st of January 2011 and the 31st of December 2015 were included. Data from the Danish Vascular Registry (Karbase) regarding demographics, surgical procedure, and complications were linked with data from the Danish Cancer Registry and Cause of Death Registry. METHODS: The primary endpoint was major amputation-free survival. Secondary endpoints were postoperative complications within 30 days, cancer-free survival, all-cause mortality and cause of death in the cohort. Major amputation-free survival, cancer-free survival and mortality were described with Kaplan-Meier (KM) survival estimates. RESULTS: We included 920 patients, of which 116 (13%) were in the active cancer group at the time of revascularization. There was no difference in amputation-free survival between those with cancer (86.8% 1-year KM estimate) and those without cancer (85.2% 1-year KM estimate) (p = 0.50). Likewise, we found no difference in 30-day postoperative complication rate. The risk of developing cancer in the included CLTI cohort was similar to the age-matched background population (6.1% vs 6.4%) (p = 0.69). All-cause mortality was higher in CLTI patients with cancer, mainly due to cancer, compared with CLTI patients without cancer who mainly died from cardiovascular disease. Three-year KM survival estimates were 48.3% (95% CI 40.0%-58.3%) and 64.4% (95% CI 61.2%-67.8%) (p = 0.014) for cancer and non-cancer patients, respectively. CONCLUSIONS: Although cancer in patients with CLTI is related to higher medium- to long-term mortality, active cancer per se should not contravene revascularization, as postoperative complications and risk of amputation are not overrepresented.