Panvascular disease is characterized by the involvement of blood vessels across multiple regions of the body, and is associated with high morbidity, disability, and mortality rates. Its pathogenesis is multifaceted, necessitating risk assessment and treatment approaches that differ from those applied to single-organ diseases. Given that panvascular disease affects multiple vital organs, an integrated, multi-system management strategy offers significant advantages over conventional, organ-specific approaches. This article provides a comprehensive review of the epidemiological features, traditional and emerging risk factors, pathophysiological mechanisms, screening and risk assessment methods, as well as new strategies for the prevention and management of panvascular disease. The objective is to offer a theoretical foundation and technical support for enhancing prevention and control measures for this condition.

The impact of diabetes on incident cardiovascular disease in relation to the extent of atherosclerotic disease remains unclear. We aimed to investigate major adverse cardiovascular events (MACE) in patients with or without type 2 diabetes (T2DM) presenting with two extremes of atherosclerotic disease, those with angiographically documented minor coronary atherosclerotic lesions and those with symptomatic peripheral artery disease. We included 1238 patients from two prospective, long-term cohort studies. Patients underwent coronary angiography and/or sonography in order to assess the grade of atherosclerosis and were defined as having no signs of Atherosclerosis (n = 332; Group I), minor atherosclerosis (n = 425; Group II) and major atherosclerosis (n = 481; Group III). Cardiovascular events were recorded over a median follow-up period of 7.1 years (Q1 = 3.6 years, Q2 = 7.1 years, Q3 = 11.3 years), covering a total of 9533 patient years. We tested the hypothesis that T2DM infers the same relative risk increase irrespective of the atherosclerosis stage, considering 3-point MACE as the primary endpoint. Incident MACE was reported in 681 patients (51%). MACE occurred more frequently in patients with T2DM than in patients without T2DM (p < 0.001). Further, MACE occurred more frequently in group III (58.1%), than group II (34.1%) or group I (19.1%) (group I vs. group II vs. group III, p < 0.001). In a cox-regression-model, T2DM was a significant predictor of MACE in univariate analyses (HR = 2.43 [1.88-3.14], p < 0.001) and after multivariate adjustment for cardiovascular risk factors, as well as the different grades of atherosclerosis (HR = 1.37 [1.02-1.84], p = 0.034). Also, atherosclerosis grades predicted MACE (HR = 3.19 [2.75-3.70], p < 0.001) in univariate analyses, and also after multivariate adjustment for known cardiovascular risk factors, including T2DM (HR = 1.61 [1.31-1.98], p < 0.001). Finally, when testing for interactions between T2DM and stages of atherosclerosis on MACE we could not find any significant interaction (HR = 1.14 [0.86-1.52], p = 0.364). We conclude that T2DM infers an increased risk for MACE across anatomically and morphologically distinct stages of atherosclerosis.

In patients with atherosclerotic occlusive diseases, systematic reviews and meta-analyses of randomized controlled trials (RCTs) report that antiplatelets, statins, and antihypertensives reduce the risk of major adverse cardiac events, need for revascularization procedures, mortality, and health care resource use. However, evidence suggests that these patients are not prescribed these medications adequately or do not adhere to them once prescribed.

We aim to systematically review and meta-analyze RCTs examining the effectiveness of implementation or adherence-supporting strategies for improving health care provider prescription of, or patient adherence to, guideline-recommended cardiovascular medications in patients with atherosclerotic occlusive disease.

We designed and reported the protocol according to the PRISMA-P (Preferred Reporting Items for Systematic Review and Meta-Analysis-Protocols) statement. We will search MEDLINE, Embase, The Cochrane Central Register of Controlled Trials, PsycINFO, and CINAHL from their inception. RCTs examining implementation or adherence-supporting strategies for improving prescription of, or adherence to, guideline-recommended cardiovascular medications in adults with cerebrovascular disease, coronary artery disease, peripheral artery disease, or polyvascular disease (>1 of these diseases) will be included. Two investigators will independently review identified titles/abstracts and full-text studies, extract data, assess the risk of bias (using the Cochrane tool), and classify implementation or adherence-supporting strategies using the refined Cochrane Effective Practice and Organization of Care (EPOC) taxonomy (for strategies aimed at improving prescription) and Behavior Change Wheel (BCW; for adherence-supporting strategies). We will narratively synthesize data describing which implementation or adherence-supporting strategies have been evaluated across RCTs, and their reported effectiveness at improving prescription of, or adherence to, guideline-recommended cardiovascular medications (primary outcomes) and patient-important outcomes and health care resource use (secondary outcomes) within refined EPOC taxonomy levels and BCW interventions and policies. Where limited clinical heterogeneity exists between RCTs, estimates describing the effectiveness of implementation or adherence-supporting strategies within different refined EPOC taxonomy levels and BCW interventions and policies will be pooled using random-effects models. Stratified meta-analyses and meta-regressions will assess if strategy effectiveness varies by recruited patient populations, prescriber types, clinical practice settings, and study design characteristics. GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) will be used to communicate evidence certainty.

The search was completed on June 6, 2023. Database searches and the PubMed "related articles" feature identified 4319 unique citations for title/abstract screening. We are currently screening titles/abstracts.

These studies will identify which implementation and adherence-supporting strategies are being used (and in which combinations) across RCTs for improving the prescription of, or adherence to, guideline-recommended cardiovascular medications in adults with atherosclerotic occlusive diseases. They will also determine the effectiveness of currently trialed implementation and adherence-supporting strategies, and whether effectiveness varies by patient, prescriber, or clinical practice setting traits.

PROSPERO CRD42023461317; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=461317; PROSPERO CRD42023461299; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=461299.

Patients with polyvascular disease are considered high risk for major adverse cardiac events (MACE). This retrospective study used the Vascular Quality Initiative (VQI) database to quantify the effect of polyvascular disease on outcomes after endovascular aneurysm repair (EVAR).

The VQI database was queried from 2012 - 2022 for elective EVAR. Patients were identified as having peripheral arterial disease, coronary artery disease, or cerebrovascular disease, and then stratified based on the number of arterial beds involved (one to three). Primary outcomes were peri-operative death and MACE. Multivariable analysis was performed to find associations between comorbidities and primary outcomes.

Of the 21 160 patients with arterial disease included in the study, 83.7% were male and the mean age was 73.73 ± 8.57 years. After stratification, 16 892 patients had atherosclerosis in one arterial bed, 3 869 in two arterial beds, and 399 in three arterial beds. Pre-operatively, patients with atherosclerosis in three arterial beds were more likely to have hypertension, diabetes, and renal failure (all p < .001). Post-operatively, patients with disease in three arterial beds were more likely to experience a post-operative complication (11.5% vs. 8.3% vs. 5.4%; p < .001), including MACE (4.3% vs. 2.5% vs. 1.3%; p < .001) and death (2.8% vs. 1.1% vs. 0.5%; p < .001). On multivariable analysis, polyvascular disease was associated with MACE (odds ratio 1.54, 95% confidence interval 1.29 - 1.84; p < .001). Kaplan-Meier analysis estimates showed statistically significant differences in survival at approximately the three year follow up (p < .001).

In this review of patients undergoing elective EVAR, patients with polyvascular disease experienced worse peri-operative outcomes, including death and MACE, the latter of which was confirmed on multivariable analysis. These patients should be considered high risk and managed accordingly.

Peripheral artery disease (PAD) remains underdiagnosed in patients with coronary artery disease (CAD) and barriers persist to measure screening PAD in routine clinical practice. We assessed the prevalence of PAD in patients with CAD in Italian primary care setting using an easy automatic instrument to measure ankle brachial pressure index (ABI). A multicenter, observational study was conducted with 32 General Practitioners (GPs). Prevalence of PAD was calculated dividing the number of patients with abnormal ABI value, or with symptoms associated with PAD or history of lower limb revascularization procedures, over the total number of patients included in the study. Incidence of major CV clinical events and all-cause death was also evaluated at 12 months in both CAD and CAD + PAD groups. In total, 713 CAD patients were included in the study, 148 (20.8%) patients had also PAD, asymptomatic in nearly 15% of them (106). The 35.4% of patients had ABI value ≤ 0.9 and 46.0% > 1.3 ABI. A significantly higher incidence of major CV events and all-cause death was seen in patients with PAD than in those without. Over 80% of patients received the therapy for secondary CV prevention and difference was seen between groups. Our findings showed that the use of an easy automatic instrument to measure ABI, easily managed by nurses, allowed to detect PAD in a relevant proportion of CAD patients who otherwise would not have been recognized. This encourages performing PAD screening in primary care setting to optimize the management of major CV risk factors associated with PAD. NCTumber: NCT03921905.

The aim of this study was to assess the impact of panvascular disease (PVD) on quality of life (QOL), exercise capacity, and clinical outcomes, in patients with heart failure (HF) with reduced ejection fraction (HFrEF).

We performed a post hoc analysis of the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION; NCT00047437). Patients with PVD were defined as those having coronary heart disease, stroke, or peripheral vascular disease at baseline. Multivariable Cox proportional hazard models were constructed to evaluate the effect of PVD on the primary endpoint (all-cause mortality or hospitalization) and secondary endpoints (all-cause mortality, cardiovascular (CV) mortality or CV hospitalization, and CV mortality or HF hospitalization). Generalized estimating-equation models were constructed to evaluate the effect of PVD on QOL (Kansas City Cardiomyopathy Questionnaire score) and exercise capacity (peak oxygen consumption and 6-minute walk test distance).

Of 2119 patients with chronic HFrEF, 1202 (56.7%) had comorbid PVD. PVD was associated significantly with reduced exercise capacity (P < 0.001). Patients with PVD had a higher risk of all-cause mortality or hospitalization (hazard ratio [HR] 1.15, 95% confidence interval [CI]: 1.02-1.29), CV mortality or CV hospitalization (HR 1.22, 95% CI: 1.07-1.39), and CV mortality or HF hospitalization (HR 1.25, 95% CI: 1.05-1.48), compared with the risk for patients without PVD. Aerobic exercise training did not significantly improve the prognosis of HFrEF patients, in either the PVD or the non-PVD subgroups.

PVD may adversely affect the QOL, exercise capacity, and prognosis of patients with chronic HFrEF.

Atherosclerosis is a systemic disease that can involve multiple vascular beds. The risk factors for atherosclerosis in multiple vascular beds remain unclear. Apolipoprotein E (APOE) is involved in inflammation and lipid deposition in the process of atherosclerosis. The objective of this study was to investigate whether APOE polymorphisms are associated with atherosclerosis in multiple vascular beds.

A total of 416 patients with atherosclerosis in single vascular bed and 658 patients with atherosclerosis in multiple vascular beds were included. APOE genotypes were detected and the differences of APOE genotypes between the groups were compared. Logistic regression analysis was performed to analyze the relationship between APOE genotypes and atherosclerosis in multiple vascular beds.

APOE E3/E4 genotype frequency was lower in the patients with atherosclerosis in multiple vascular beds than that of patients with atherosclerosis in single vascular bed (11.4% vs 17.8%, P=0.004). There was no significant difference in age and gender distribution, proportion of history of smoking, alcohol consumption, hypertension, and diabetes mellitus between the two groups (all P>0.05), and among patients with different APOE alleles (all P>0.05). Logistic regression analysis indicated that APOE E3/E4 genotype (E3/E4 vs E3/E3: odds ratio (OR) 0.598, 95% confidence interval (CI): 0.419-0.854, P=0.005), and APOE ε4 allele (ε4 vs ε3: OR 0.630, 95% CI: 0.444-0.895, P=0.010) associated with atherosclerosis in multiple vascular beds.

APOE ε4 allele is associated with atherosclerosis in multiple vascular beds.

Atherosclerosis in more than 1 vs. 1 arterial bed is associated with increased risk for major adverse cardiovascular events (MACE). This study aimed to determine whether the risk of post percutaneous coronary intervention (PCI) MACE associated with polyvascular disease (PVD) differs by sex.

We analyzed 18,721 patients undergoing PCI at a tertiary-care center between 2012 and 2019. Polyvascular disease was defined as history of peripheral artery and/or cerebrovascular disease. The primary endpoint was MACE, a composite of all-cause death, myocardial infarction, or stroke at 1 year. Multivariate Cox regression was used to adjust for differences in baseline risk between patients with PVD vs. coronary artery disease (CAD) alone and interaction testing was used to assess risk modification by sex.

Women represented 29.2% (N = 5,467) of the cohort and were more likely to have PVD than men (21.7% vs. 16.1%; P < .001). Among both sexes, patients with PVD were older with higher prevalence of comorbidities and cardiovascular risk factors. Women with PVD had the highest MACE rate (10.0%), followed by men with PVD (7.2%), women with CAD alone (5.0%), and men with CAD alone (3.6%). Adjusted analyses revealed similar relative MACE risk associated with PVD vs. CAD alone in women and men (adjusted hazard ratio [aHR] 1.54, 95% confidence interval [CI] 1.20-1.99; P < .001 and aHR 1.31, 95% CI 1.06-1.62; P = .014, respectively; p-interaction = 0.460).

Women and men derive similar excess risk of MACE from PVD after PCI. The heightened risk associated with PVD needs to be addressed with maximized use of secondary prevention in both sexes.

To investigate the distribution of arteriosclerotic vessels of arteriosclerosis, differential serum lipid profiles, and differences in the proportion of dyslipidaemia between patients with single-site arteriosclerosis and multi-site arteriosclerosis (significant hardening of ≥2 arteries).

The data of 6581 single-site arteriosclerosis patients and 5940 multi-site arteriosclerosis patients were extracted from the hospital medical record system. Serum total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) A1, ApoB concentrations and C-reactive protein (CRP) between patients with single-site arteriosclerosis and multi-site arteriosclerosis were collected and analyzed.

The most diseased arteries were coronary arteries (n=7099, 33.7%), limb arteries (n=6546, 31.1%), and carotid arteries (n=5279, 25.1%). TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C levels were higher and CRP level was lower in multi-site arteriosclerosis patients than those in single-site arteriosclerosis patients. The TC, LDL-C levels in non-elderly (<65 years old) female patients were higher and TG/HDL-C, TC/HDL-C, LDL-C/HDL-C levels were lower than those in non-elderly male patients, while the TG, TC, LDL-C, and TG/HDL-C levels in elderly (≥65 years old) female patients were higher and LDL-C/HDL-C level was lower than those in elderly male patients. The proportion of dyslipidemia in descending order was as follows: low HDL-C (31.9%), elevated TG (16.9%), elevated TC (9.0%), and elevated LDL-C (4.2%). The levels of TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C in patients with peripheral arteriosclerosis were higher than those in patients with cardio-cerebrovascular arteriosclerosis.

There were differences in serum lipid levels in patients with arteriosclerosis with different age, gender and distribution of arteriosclerotic vessels.

The potential impact of peripheral artery disease (PAD) on kidney outcomes is not well understood. The aim of this study was to explore the association between PAD and end-stage kidney disease (ESKD) and chronic kidney disease (CKD).

Among 14,051 participants (mean age 54 [SD 6 years]) from the Atherosclerosis Risk in Communities study, we categorized PAD status as symptomatic PAD (intermittent claudication or leg revascularization), asymptomatic PAD (ankle-brachial index [ABI] ≤0.90 without clinical history of symptoms), and ABI 0.91-1.00, 1.01-1.10, 1.11-1.20 (reference), 1.21-1.30, and >1.30. We evaluated their associations with two kidney outcomes: ESKD (the need of renal replacement therapy or death due to kidney disease) and CKD (ESKD cases or an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2 with a ≥25 % decline from the baseline) using multivariable Cox proportional hazards models.

Over ∼30 years of follow-up, there were 598 cases of incident ESKD and 4686 cases of incident CKD. After adjusting for potential confounders, both symptomatic PAD and asymptomatic PAD conferred a significantly elevated risk of ESKD (hazard ratio 2.28 [95 % confidence interval 1.23-4.22] and 1.75 [1.19-2.57], respectively). Corresponding estimates for CKD were 1.54 (1.14-2.09) and 1.63 (1.38-1.93). Borderline low ABI 0.91-1.00 also showed elevated risk of adverse kidney outcomes after adjustment for demographic variables. Largely consistent results were observed across demographic and clinical subgroups.

Symptomatic PAD and asymptomatic PAD were independently associated with an elevated risk of ESKD and CKD. These results highlight the importance of monitoring kidney function in persons with PAD, even when symptoms are absent.

Objective: Polyvascular disease (polyVD) often coexists with coronary artery disease (CAD). We aim to investigate the prevalence of polyVD using the method of ultrasound and find its association with adverse outcomes in coronary artery bypass grafting (CABG) patients. Methods: This retrospective and cross-sectional study included 1344 patients with a mean age of 61.4 years. Presence of peripheral artery atherosclerotic plaque and stenosis was assessed using the method of ultrasound. Receiver operating characteristic (ROC) analysis and multivariate logistic regression analysis were performed to investigate the association of polyVD with in-hospital all-cause death. Results: 52.1% of the patients had polyVD and among which 31.9% had one additional arterial bed involvement and 20.2% had two or three additional arterial beds involvement. Patients with two or three involved arterial beds had worse baseline characteristics. In-hospital all-cause death rate increased with the number of involved arterial beds (1.1% in patients with only CAD vs 3.7% in patients with two or three involved arterial beds), and this trend was more prominent in elderly patients. Multivariate logistic regression analysis confirmed that polyVD patients with two or three involved arterial beds had about three times the risk for all-cause death. Conclusions: Prevalence of polyVD assessed by ultrasound was high in CABG patients and it was significantly associated with in-hospital all-cause death. Our study may provide additive information for preoperative risk stratification in CABG patients.

Percutaneous coronary intervention (PCI) has demonstrated its safety and efficacy in treating left main (LM) coronary artery disease (CAD) in select patients. Polyvascular disease (PolyVD) is associated with adverse events in all-comers with CAD. However, there is little data examining the interplay between PolyVD and LM-PCI, which we sought to investigate in a retrospective single-center study. We included patients who underwent unprotected LM-PCI at a tertiary center from 2012 to 2019. The study population was stratified based on the presence or absence of PolyVD (i.e., medical history of cerebrovascular and/or peripheral artery disease in addition to LM-CAD). The primary outcome was major adverse cardiovascular events (MACE) combining all-cause mortality and spontaneous myocardial infarction within 1 year after index PCI. Overall, 869 patients were included, and 23.8% of the population had PolyVD. Subjects with PolyVD were older and had a greater burden of co-morbidities. After 1-year follow-up, PolyVD patients exhibited significantly higher rates of both MACE (22.8% vs 9.4%, p <0.001) and bleeding events compared with those without PolyVD. MACE was primarily driven by an increase in all-cause mortality (18.3% vs 7.1%, p <0.001). Results persisted after adjusting for confounders. In conclusion, in patients who underwent LM-PCI, the presence of PolyVD is linked to an increased risk of MACE and bleeding after 1 year of follow-up, which highlights the vulnerability of this population.

Individuals suffering from polyvascular atherosclerotic disease (PolyVD) face a higher likelihood of adverse cardiovascular events. Additionally, inflammation, assessed by high-sensitivity C-reactive protein (hsCRP), affects residual risk following percutaneous coronary intervention (PCI). We aimed to explore the interplay between PolyVD and hsCRP in terms of clinical outcomes after PCI.

Patients undergoing PCI for chronic coronary disease at a tertiary center between January 2012 and February 2020 were included for the current analysis. PolyVD was defined by additional history of cerebrovascular and/or peripheral artery disease. HsCRP levels were defined as elevated when the measured baseline concentration was > 3 mg/L. The primary outcome of interest was major adverse cardiovascular events (MACE), a composite of all-cause mortality, spontaneous MI, or target vessel revascularization.

Overall, 10,359 participants were included in the current study, with 17.4% affected by PolyVD and 82.6% included in the non-PolyVD subgroup. Patients with PolyVD had higher hsCRP levels than those without. Among the PolyVD group, a larger proportion (33.6%) exhibited elevated hsCRP compared to the non-PolyVD group (24.7%). Patients with both PolyVD and elevated hsCRP levels had significantly higher adverse event rates than all other subgroups at 1-year follow-up. Furthermore, an independent association between elevated hsCRP and MACE was observed within the PolyVD population, while this was not the case for individuals without PolyVD.

A residual risk of adverse outcomes after PCI linked to inflammation appears to be present among individuals with PolyVD. This could help define further target populations for anti-inflammatory treatment options.

Ischemic cardio-cerebrovascular disease is the leading cause of mortality worldwide. However, studies focusing on elderly and very elderly patients are scarce. Hence, our study aimed to characterize and investigate the long-term prognostic implications of ischemic cardio-cerebrovascular diseases in elderly Chinese patients.

This retrospective cohort study included 1026 patients aged ≥ 65 years who were categorized into the mono ischemic cardio-cerebrovascular disease (MICCD) (either coronary artery disease or ischemic stroke/transient ischemic attack) (n = 912) and the comorbidity of ischemic cardio-cerebrovascular disease (CICCD) (diagnosed with both coronary artery disease and ischemic stroke/transient ischemic attack at admission) (n = 114). The primary outcome was all-cause death. The mortality risk was evaluated using the Cox proportional hazards risk model with multiple adjustments by conventional and propensity-score-based approaches.

Of the 2494 consecutive elderly patients admitted to the hospital, 1026 (median age 83 years [interquartile range]: 76.5-86.4; 94.4% men) met the inclusion criteria. Patients with CICCD consisted mostly of very elderly (79.2% vs. 66.1%, P < 0.001) individuals with a higher burden of comorbidities. Over a median follow-up of 10.4 years, 398 (38.8%) all-cause deaths were identified. Compared with the MICCD group, the CICCD group exhibited a higher adjusted hazard ratio (HR) (95% confidential interval, CI) of 1.71 (1.32-2.39) for long-term mortality after adjusting for potential confounders. The sensitivity analysis results remained robust. After inverse probability of treatment weighting (IPTW) modeling, the CICCD group displayed an even worse mortality risk (IPTW-adjusted HR: 2.07; 95% CI 1.47-2.90). In addition, anemia (adjusted HR: 1.48; 95% CI 1.16-1.89) and malnutrition (adjusted HR: 1.43; 95% CI 1.15-1.78) are also independent risk factors for all-cause mortality among elderly and very elderly patients.

Our results thus suggest that elderly patients with ischemic cardio-cerebrovascular disease and anemia or malnutrition may have higher mortality, which may be predicted upon admission. These findings, however, warrant further investigation.

Polyvascular disease has a significant global burden and is associated with increased risk of major adverse cardiac events with each additional vascular territory involved. The purpose of this review is to highlight the risk factors, associated outcomes, emerging genetic markers, and evidence for screening and treatment of polyvascular disease.

Polyvascular disease is the presence of atherosclerosis in two or more vascular beds. It has a significant global burden, with a prevalence of 30-70% in patients with known atherosclerosis. Patients with polyvascular disease experience elevated rates of cardiovascular death, myocardial infarction and stroke, especially among high-risk subgroups like those with type 2 diabetes mellitus and there is a step-wise increased risk of adverse outcomes with each additional vascular territory involved. Genetic analyses demonstrate that some individuals may carry a genetic predisposition, while others exhibit higher levels of atherogenic lipoproteins and inflammatory markers. Routine screening for asymptomatic disease is not currently recommended by major cardiovascular societies unless patients are high-risk. While there are no established protocols for escalating treatment, existing guidelines advocate for lipid-lowering therapy. Additionally, recent studies have demonstrated benefit from antithrombotic agents, such as P2Y12 inhibitors and low-dose anticoagulation, but the optimal timing and dosage of these agents has not been established, and the ischemic benefit must be balanced against the increased risk of bleeding in the polyvascular population. Due to the high prevalence and risks associated with polyvascular disease, early identification and treatment intensification are crucial to reduce disease progression. Future research is needed to develop screening protocols and determine the optimal timing and dosing of therapy to prevent ischemic events.

Patients with polyvascular disease (PVD) are at very high cardiovascular risk and require intensive lipid-lowering therapy. This analysis describes the lipid-lowering efficacy and safety of inclisiran versus placebo in patients with and without PVD.

In this post hoc analysis of the ORION-9, ORION-10, and ORION-11 trials, patients were randomized 1:1 to receive 284 mg inclisiran (300 mg inclisiran sodium) or placebo on day 1, day 90, and 6-monthly thereafter. Percentage change in low-density lipoprotein cholesterol (LDL-C) from baseline to day 510 and corresponding time-adjusted change from day 90 and up to day 540 were evaluated per patients' PVD status. Safety was assessed over 540 days.

Of 3454 patients, 470 (13.6%) had PVD, and 2984 (86.4%) did not. Baseline characteristics were generally balanced between the treatment arms in both cohorts. A greater proportion of patients with PVD had comorbidities versus those without. The mean (95% confidence interval [CI]) placebo-corrected LDL-C percentage change from baseline to day 510 was -48.9% (-55.6 to -42.2) in patients with PVD and -51.5% (-53.9 to -49.1) in patients without. Proportions of patients with reported treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events were similar between treatment arms, irrespective of PVD status, except for an excess of mild or moderate clinically relevant TEAEs at the injection site with inclisiran.

Twice-yearly inclisiran dosing (after the initial and 3-month doses) was well tolerated and provided effective and sustained lipid-lowering in patients, irrespective of PVD status.

This post hoc subanalysis aimed to investigate the impact of polyvascular disease (PolyVD) in patients with acute myocardial infarction (AMI) in the contemporary era of percutaneous coronary intervention (PCI).

The Japan Acute Myocardial Infarction Registry (JAMIR), a multicenter prospective registry, enrolled 3,411 patients with AMI between December 2015 and May 2017. Patients were classified according to complications of a prior stroke and/or peripheral artery disease into an AMI-only group (involvement of 1 vascular bed [1-bed group]; n=2,980), PolyVD with one of the complications (2-bed group; n=383), and PolyVD with both complications (3-bed group; n=48). The primary endpoint was all-cause death. Secondary endpoints were major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and major bleeding. In the 1-, 2-, and 3-bed groups, the cumulative incidence of all-cause death was 6.8%, 17.5%, and 23.7%, respectively (P<0.001); that of MACE was 7.4%, 16.4%, and 33.8% (P<0.001), respectively; and that of major bleeding was 4.8%, 10.0%, and 13.9% (P<0.001), respectively. PolyVD was independently associated with all-cause death (hazard ratio [HR] 2.21; 95% confidence interval [CI], 1.48-3.29), MACE (HR 2.07; 95% CI 1.40-3.07), and major bleeding (HR 1.68; 95% CI 1.04-2.71).

PolyVD was significantly associated with worse outcomes, including thrombotic and bleeding events, in the contemporary era of PCI in AMI patients.

Polyvascular disease is strongly associated with increased risk of cardiovascular morbidity and mortality. However, its prevalence in patients undergoing carotid and lower extremity surgical revascularization and its impact on outcomes are unknown.

The Vascular Quality Initiative was queried for carotid endarterectomy (CEA) or infrainguinal lower extremity bypass (LEB), 2013-2019. Polyvascular disease was defined as presence of atherosclerotic occlusive disease in more than one arterial bed: carotid, coronary, and infrainguinal. Primary outcomes were (1) composite perioperative myocardial infarction (MI) or death and (2) 5-year survival. Patient characteristics and perioperative outcomes were evaluated using the χ2 test and multivariable logistic regression. Survival was analyzed using Kaplan-Meier method and Cox proportional hazards multivariable models.

Polyvascular disease was identified in 47% of CEA (39.0% in 2 arterial beds, 7.6% in 3 arterial beds; n = 93,736) and 47% of LEB (41.0% in 2 arterial beds, 5.7% in 3 arterial beds; n = 25,223). For both CEA and LEB, patients with polyvascular disease had more comorbidities including hypertension, congestive heart disease, chronic obstructive pulmonary disease, smoking, diabetes mellitus, and end-stage renal disease (P < .0001). Perioperative MI/death rates increased with increasing number of vascular beds affected following CEA (0.9% in 1 bed vs 1.5% in 2 beds vs 2.7% in 3 beds; P < .001) and LEB (2.2% in 1 bed vs 5.3% in 2 beds vs 6.6% in 3 beds; P < .001). Polyvascular disease was associated independently with perioperative MI/death after CEA (odds ratio, 1.59; 95% confidence interval [CI], 1.40-1.81;P < .0001) and LEB (odds ratio, 1.78; 95% CI, 1.52-2.08; P < .0001). Five-year survival was decreased in patients with polyvascular disease after CEA (82% in 3 beds vs 88% in 2 beds vs 92% in 1 bed; P < .01) and LEB (72% in 3 beds vs 75% in 2 beds vs 84% in 1 bed; P < .01) in a dose-dependent manner, with the lowest 5-year survival observed in those with three arterial beds involved. Polyvascular disease was independently associated with 5-year mortality after CEA (hazard ratio, 1.33; 95% CI, 1.24-1.40; P = .0001) and LEB (hazard ratio, 1.30; 95% CI, 1.20-1.41; P = .0001).

Polyvascular disease is common in patients undergoing CEA and LEB and is associated with a higher risk of perioperative MI/death and decreased long-term survival. After revascularization, patients with polyvascular disease should be considered for more aggressive cardioprotective medications and closer follow-up.

Carotid stenosis (CS) is an important cause of ischemic stroke. Secondary prevention lies in performing a carotid endarterectomy (CEA) procedure, the recommended treatment in most cases. When 2 or more vascular regions are simultaneously affected by atherosclerosis, mainly the carotid arteries, coronary arteries, or limb arteries, a multivessel disease polyvascular disease (PVD) is present. This study aims to assess the potential role of PVD as a long-term predictor of major adverse cardiovascular events (MACE) and all-cause mortality in patients submitted to CEA.

From January 2012 to December 2021, patients submitted to CEA for carotid stenosis in a tertiary care and referral center were eligible from a prospective database. A posthoc survival analysis was performed using the Kaplan-Meier survival curve method. The primary outcome was the incidence of long-term MACE and all-cause mortality. Secondary outcomes included acute myocardial infarction (AMI), major adverse limb events (MALE), stroke, and acute heart failure (AHF).

A total of 207 patients were enrolled, with a median follow-up of 63 months. The mean age was 70.4 ± 8.9, and 163 (78.7%) were male. There were 65 (31.4%) patients that had 2 arterial vascular territories affected, and 29 (14.0%) patients had PVD in 3 arterial beds. On multivariable analysis, both MACE and all-cause mortality had as independent risk factors age (aHR 1.039, P = 0.003; aHR 1.041, P = 0.019), chronic kidney disease (aHR 2.524, P = 0.003; aHR 3.377, P < 0.001) and PVD2 (aHR 3.381, P < 0.001; aHR 2.665, P = 0.013). PVD1 was only associated with MACE as a statistically significant risk factor (aHR 2.531, 1.439-4.450, P < 0.001).

PVD in patients with cerebrovascular disease (CVD) was revealed to carry a 2-fold increased risk for all-cause mortality and MACE during long-term follow-up. PVD may be a simple yet valuable tool in predicting all-cause mortality, MACE, AMI, and MALE after CEA.

The aim of this study was to investigate baseline characteristics and outcome of patients after endovascular therapy (EVT) for acute large vessel occlusion (LVO) in relation to their history of symptomatic vascular disease and sex.

Consecutive EVT-eligible patients with LVO in the anterior circulation admitted to our stroke center between 04/2015 and 04/2020 were included in this observational cohort study. All patients were treated according to a standardized acute ischaemic stroke (AIS) protocol. Baseline characteristics and successful reperfusion, recurrent/progressive in-hospital ischaemic stroke, symptomatic in-hospital intracranial hemorrhage, death at discharge and at 3 months, and functional outcome at 3 months were analyzed according to previous symptomatic vascular disease and sex.

995 patients with LVO in the anterior circulation (49.4% women, median age 76 years, median admission NIHSS score 14) were included. Patients with multiple vs. no previous vascular events showed higher mortality at discharge (20% vs. 9.3%, age/sex - adjustedOR = 1.43, p = 0.030) and less independency at 3 months (28.8% vs. 48.8%, age/sex - adjustedOR = 0.72, p = 0.020). All patients and men alone with one or multiple vs. patients and men with no previous vascular events showed more recurrent/progressive in-hospital ischaemic strokes (19.9% vs. 6.4% in all patients, age/sex - adjustedOR = 1.76, p = 0.028) (16.7% vs. 5.8% in men, age-adjustedOR = 2.20, p = 0.035). Men vs. women showed more in-hospital symptomatic intracranial hemorrhage among patients with one or multiple vs. no previous vascular events (23.7% vs. 6.6% in men and 15.4% vs. 5.5% in women, OR = 2.32, p = 0.035/age - adjustedOR = 2.36, p = 0.035).

Previous vascular events increased the risk of in-hospital complications and poorer outcome in the analyzed patients with EVT-eligible LVO-AIS. Our findings may support risk assessment in these stroke patients and could contribute to the design of future studies.

Objectives: To review the evidence on the effectiveness and safety of low-dose-rivaroxaban 2.5 mg twice daily (LDR) in patients with coronary artery disease (CAD) and/or peripheral artery disease (PAD) taking antiplatelets. Methods: We performed a systematic review and meta-analysis of randomized controlled trials (RCTs). Efficacy endpoints were cardiovascular events (CVEs), myocardial infarction, stroke, all-cause, and cardiovascular death. Any, major, fatal bleeding, and intracranial hemorrhage (ICH) were safety endpoints. Numbers needed to treat (NNT), and numbers needed to harm (NNH) were also calculated. Results: Seven RCTs were included with 45,836 patients: 34,276 with CAD and 11,560 with PAD. Overall, 4247 CVEs and 3082 bleedings were registered. LDR in association with either any antiplatelet drug or aspirin (ASA) alone reduced the risk of CVEs (hazard ratio [HR] 0.86, 95% confidence interval [95%CI] 0.78-0.94) and ischemic stroke (HR 0.68, 95%CI 0.55-0.84). LDR + ASA increased the risk of major bleeding (HR 1.71, 95%CI 1.38-2.11) but no excess of fatal bleeding or ICH was found. The NNT to prevent one CVE for LDR + ASA was 63 (43-103) and the NNH to cause major bleeding was 107 (77-193). Conclusions: The combination of LDR with either antiplatelet drugs or low-dose aspirin reduces CVEs and ischemic stroke in patients with CAD/PAD. There was an increased risk of major bleeding but no excess of fatal or ICH was found. LDR seems to have a favorable net clinical benefit compared to ASA treatment alone.

Peripheral arterial disease (PAD) affects 12 % of adult population and is increasing globally and in India. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease. The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death. The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of <55 mg/dl. High Intensity Statin is mainstay of treatment but optimal management is inadequate. Statin treatment reduces all-cause mortality by 39 %, CV death by 41 %, CV outcomes by 34 %, ischaemic stroke by 28 %, acute limb ischaemia by 30 % and amputations by 35 %. Ezetimibe when added to statins in IMPROVE-IT trial, showed significant reduction of MACE. PCSK9 inhibitor (FOURIER TRIAL) showed reduction in primary end point in PAD vs Non PAD patients (3.5 % vs 1.6 %). There is a critical need for an Indian multi-disciplinary task force for research on the direct impact of lipid-lowering agents on limb salvage rates and major limb-related events in PAD patients.

Despite the known higher risk of cardiovascular disease in individuals with type 2 diabetes, the pathophysiology and optimal management of diabetic foot ulcers (DFUs), a leading complication associated with diabetes, is complex and continues to evolve. Complications of type 2 diabetes, such as DFUs, are a major cause of morbidity and mortality and the leading cause of major lower extremity amputation in the United States. There has recently been a strong focus on the prevention and early treatment of DFUs, leading to the development of multidisciplinary diabetic wound and amputation prevention clinics across the country. Mounting evidence has shown that, despite these efforts, amputations associated with DFUs continue to increase. Furthermore, due to increasing patient complexity of management secondary to comorbid conditions, such as cardiovascular disease, the management of peripheral artery disease associated with DFUs has become increasingly difficult, and care delivery is often episodic and fragmented. Although structured, process-specific approaches exist at individual institutions for the management of DFUs in the cardiovascular patient population, there is insufficient awareness of these principles in the general medicine communities. Furthermore, there is growing interest in better understanding the mechanistic underpinnings of DFUs to better define personalized medicine to improve outcomes. The goals of this scientific statement are to provide salient background information on the complex pathogenesis and current management of DFUs in cardiovascular patients, to guide therapeutic and preventive strategies and future research directions, and to inform public policy makers on health disparities and other barriers to improving and advancing care in this expanding patient population.

Patients with peripheral artery disease (PAD) have a higher risk of cardiovascular events. We examined the histology of atheromatous plaques in the femoral artery and investigated their association with subsequent cardiovascular events in patients with PAD. Patients who underwent femoral artery endarterectomy between March 2010 and January 2021 were included. We analyzed the expression of myeloperoxidase (MPO), citrullinated histone, and programmed cell death ligand 1 (PD-L1) in femoral artery plaques by immunohistochemistry. Data on the subsequent occurrence of major adverse cardiovascular events (MACEs), major adverse limb events (MALEs), and all-cause mortality were retrospectively collected. A total of 37 patients were included. The median age was 71 (range, 42-90) years, and 25 patients (67.6%) were male. During the median follow-up of 24 months, 10 patients experienced MACEs and 16 patients had MALEs. Patients with MACEs had a higher number of MPO-stained cells (p = 0.044) and lower PD-L1 staining intensity (p = 0.021) in atheromatous plaques compared with those of patients with a stable prognosis. When the patients were grouped according to the immunologic score based on the MPO-stained cell number and PD-L1 staining intensity, those with a higher score had a significantly higher cumulative risk of MACEs (p = 0.014). The immunologic profile of excised peripheral artery plaques may be associated with future cardiovascular events in patients with PAD.

The inflammatory burden as measured by high-sensitivity C-reactive Protein (hsCRP) is recognized as a cardiovascular risk factor, which can however be affected by lifestyle-related risk factors (LRF). Up-to-date the interplay between hsCRP, LRF and presence and extent of atherosclerotic disease is still largely unknown, which we therefore sought to investigate in a contemporary population-based cohort. We included participants from the cross-sectional population-based Hamburg City Health Study. Affected vascular beds were defined as coronary, peripheral, and cerebrovascular arteries. LRF considered were lack of physical activity, overweight, active smoking and poor adherence to a Mediterranean diet. We computed multivariable analyses with hsCRP as the dependent variable and LRF as covariates according to the number of vascular beds affected. In the 6765 individuals available for analysis, we found a stepwise increase of hsCRP concentration both according to the number of LRF present as well as the number of vascular beds affected. Adjusted regression analyses showed an independent association between increasing numbers of LRF with hsCRP levels across the extent of atherosclerosis. We demonstrate increasing hsCRP concentrations according to both the number of LRF as well as the extent of atherosclerosis, emphasizing the necessity of lifestyle-related risk factor optimization.

Chronic limb-threatening ischemia (CLTI), a severe manifestation of peripheral arterial disease (PAD), is associated with a 1-year limb amputation rate of approximately 15-20% and substantial mortality. A key feature of CLTI is the compromised regenerative ability of skeletal muscle; however, the mechanisms responsible for this impairment are not yet fully understood. In this study, we aim to delineate pathological changes at both the cellular and transcriptomic levels, as well as in cell-cell signaling pathways, associated with compromised muscle regeneration in limb ischemia in both human tissue samples and murine models of CLTI.

We performed single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients and from a murine model of CLTI. In both datasets, we analyzed gene expression changes in macrophage and muscle satellite cell (MuSC) populations as well as differential cell-cell signaling interactions and differentiation trajectories.

Single-cell transcriptomic profiling and immunofluorescence analysis of CLTI patient skeletal muscle demonstrated that ischemic-damaged tissue displays a pro-inflammatory macrophage signature. Comparable results were observed in a murine CLTI model. Moreover, integrated analyses of both human and murine datasets revealed premature differentiation of MuSCs to be a key feature of failed muscle regeneration in the ischemic limb. Furthermore, in silico inferences of intercellular communication and in vitro assays highlight the importance of macrophage-MuSC signaling in ischemia induced muscle injuries.

Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and a murine CLTI model, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

Vascular diseases such as atherosclerosis usually affect multiple organs. Genetic factors have a certain proportion in the risk factors of atherosclerosis. The purpose was to investigate the relationship of cytochrome P450 2C19 (CYP2C19) polymorphisms with multi-site atherosclerosis.

The study included 410 patients with single-site atherosclerosis and 529 patients with multi-site atherosclerosis. The relationship between CYP2C19 rs4244285 and rs4986893 polymorphisms and single-site atherosclerosis and multi-site atherosclerosis was analyzed.

The proportion of CYP2C19 rs4244285 A allele (35.9% vs 29.9%, P=0.007) and rs4986893 G allele (97.7% vs 94.8%, P=0.001) in multi-site atherosclerosis group was significantly higher than that in single-site atherosclerosis group. The distribution of CYP2C19 genotypes was significantly different between the two groups (P=0.002). The results of univariate logistic regression indicated that CYP2C19 *1/*3 genotype (*1/*3 vs *1/*1: odds ratio (OR) 0.456, 95% confidence interval (CI): 0.231-0.902, P=0.024) may decrease risk of multi-site atherosclerosis, while *2/*2 genotype (*2/*2 vs *1/*1: OR 1.780, 95% CI: 1.100-2.880, P=0.019) may increase risk of multi-site atherosclerosis. Multivariate logistic regression (adjusted for gender, age, smoking, drinking, hypertension, and diabetes) indicated that CYP2C19 *1/*3 genotype (*1/*3 vs *1/*1: OR 0.459, 95% CI: 0.231-0.909, P=0.026) may be an independent protective factor for multi-site atherosclerosis, while *2/*2 genotype (*2/*2 vs *1/*1: OR 1.767, 95% CI: 1.091-2.864, P=0.021) may be an independent risk factor for multi-site atherosclerosis.

CYP2C19 *1/*3 genotype may be an independent protective factor for multi-site atherosclerosis, while *2/*2 genotype may be an independent risk factor for multi-site atherosclerosis.

Peripheral artery disease (PAD) is underdiagnosed due to poor patient and clinician awareness. Despite this, no widely accepted PAD screening is recommended.

The authors used machine learning to develop an automated risk stratification tool for identifying patients with a high likelihood of PAD.

Using data from the electronic health record (EHR), ankle-brachial indices (ABIs) were extracted for 3,298 patients. In addition to ABI, we extracted 60 other patient characteristics and used a random forest model to rank the features by association with ABI. The model identified several features independently correlated with PAD. We then built a logistic regression model to predict PAD status on a validation set of patients (n = 1,089), an external cohort of patients (n = 2,922), and a national database (n = 2,488). The model was compared to an age-based and random forest model.

The model had an area under the curve (AUC) of 0.68 in the validation set. When evaluated on an external population using EHR data, it performed similarly with an AUC of 0.68. When evaluated on a national database, it had an AUC of 0.72. The model outperformed an age-based model (AUC: 0.62; P < 0.001). A random forest model with inclusion of all 60 features did not perform significantly better (AUC: 0.71; P = 0.31).

Statistical techniques can be used to build models which identify individuals at high risk for PAD using information accessible from the EHR. Models such as this may allow large health care systems to efficiently identify patients that would benefit from aggressive preventive strategies or targeted-ABI screening.

Despite evidence-based therapies, patients presenting with atherosclerosis involving more than one vascular bed, such as those with peripheral artery disease (PAD) and concomitant coronary artery disease (CAD), constitute a particularly vulnerable group characterized by enhanced residual long-term risk for major adverse cardiac events (MACE), as well as major adverse limb events (MALE). The latter are progressively emerging as a difficult outcome to target, being correlated with increased mortality. Antithrombotic therapy is the mainstay of secondary prevention in both patients with PAD or CAD; however, the optimal intensity of such therapy is still a topic of debate, particularly in the post-acute and long-term setting. Recent well-powered randomized clinical trials (RCTs) have provided data in favor of a more intense antithrombotic therapy, such as prolonged dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor or a therapy with aspirin combined with an anticoagulant drug. Both approaches increase bleeding and selection of patients is a key issue. The aim of this review is, therefore, to discuss and summarize the most up-to-date available evidence for different strategies of anti-thrombotic therapies in patients with chronic PAD and CAD, particularly focusing on studies enrolling patients with both types of atherosclerotic disease and comparing a higher- versus a lower-intensity antithrombotic strategy. The final objective is to identify the optimal tailored approach in this setting, to achieve the greatest cardiovascular benefit and improve precision medicine.

Low bile acid excretion (BAE) is associated with a higher risk of coronary artery disease (CAD) and cerebrovascular disease (stroke). This study investigated BAE in patients with peripheral vascular disease (PVD) and carotid artery disease (CA) and those without these diseases, compared to patients with CAD, stroke, or no evidence of atherosclerosis. Patients with complaints of chest pain-suspected CAD, syncope, stroke/TIA, severe headache, intermittent claudication, or falls were enrolled. All received a 4-day standard diet with 490 mg of cholesterol and internal standard copper thiocyanate. Fecal BAE was measured using gas-liquid chromatography. One hundred and three patients, sixty-eight (66%) men and thirty-five women (34%), mean age range 60.9 ± 8.9 years, were enrolled in this prospective, 22-year follow-up study. Regression analysis showed that advanced age, total BAE, and excretion of the main fractions were the only significant independent factors that predicted prolonged survival (p < 0.001). Twenty-two years' follow-up revealed only 15% of those with BAE <262.4 mg/24 h survived, compared to >60% of participants without atherosclerosis and a mean BAE of 676 mg/24 h. BAE was lower in patients with polyvascular atherosclerosis than in those with involvement of 1-3 vascular beds. Pearson correlations were found between total BAE and various fractions of BA, as well as HDL cholesterol. BAE and short-term survival were decreased among patients with PVD compared to those with CAD or stroke. Low BAE should be considered a valuable and independent risk factor for PVD.

Arteriosclerosis in multiple arteries has long been associated with heightened cardiovascular risk. Acetaldehyde dehydrogenase 2 (ALDH2) and methylenetetrahydrofolate reductase (MTHFR) play an important role in the pathogenesis of arteriosclerosis by participating in the oxidation and reduction reactions in vascular endothelial cells. The purpose was to investigate the relationship of ALDH2 and MTHFR gene polymorphisms with arteriosclerosis in multiple arteries.

410 patients with arteriosclerosis in single artery and 472 patients with arteriosclerosis in multiple arteries were included. The relationship between ALDH2 rs671 and MTHFR rs1801133 polymorphisms and arteriosclerosis in single artery and arteriosclerosis in multiple arteries was analyzed.

The proportion of ALDH2 rs671 A allele (35.6% vs. 30.9%, P = 0.038) and MTHFR rs1801133 T allele (32.6% vs. 27.1%, P = 0.012) in patients with arteriosclerosis in multiple arteries was significantly higher than that in arteriosclerosis in single artery, respectively. The proportion of history of alcohol consumption in patients with ALDH2 rs671 G/G genotype was higher than those in ALDH2 rs671 G/A genotype and A/A genotype (P < 0.001). The results of logistic regression analysis indicated that ALDH2 rs671 A/A genotype (A/A vs. G/G: OR 1.996, 95% CI: 1.258-3.166, P = 0.003) and MTHFR rs1801133 T/T genotype (T/T vs. C/C: OR 1.943, 95% CI: 1.179-3.203, P = 0.009) may be independent risk factors for arteriosclerosis in multiple arteries (adjusted for age, sex, smoking, drinking, hypertension, and diabetes).

ALDH2 rs671 A/A and MTHFR rs1801133 T/T genotypes may be independent risk factors for arteriosclerosis in multiple arteries.

Chronic limb-threatening ischemia (CLTI), representing the end-stage of peripheral arterial disease (PAD), is associated with a one-year limb amputation rate of ∼15-20% and significant mortality. A key characteristic of CLTI is the failure of the innate regenerative capacity of skeletal muscle, though the underlying mechanisms remain unclear. Here, single-cell transcriptome analysis of ischemic and non-ischemic muscle from the same CLTI patients demonstrated that ischemic-damaged tissue is enriched with pro-inflammatory macrophages. Comparable results were also observed in a murine CLTI model. Importantly, integrated analyses of both human and murine data revealed premature differentiation of muscle satellite cells (MuSCs) in damaged tissue and indications of defects in intercellular signaling communication between MuSCs and their inflammatory niche. Collectively, our research provides the first single-cell transcriptome atlases of skeletal muscle from CLTI patients and murine models, emphasizing the crucial role of macrophages and inflammation in regulating muscle regeneration in CLTI through interactions with MuSCs.

Background Acute myocardial infarction (AMI) infrequently occurs after acute stroke. The Heart-brain team approach has a potential to appropriately manage this poststroke cardiovascular complication. However, clinical outcomes of AMI complicating acute stroke (AMI-CAS) with the heart-brain team approach have not been characterized. The current study investigated cardiovascular outcomes in patients with AMI-CAS managed by a heart-brain team. Methods and Results We retrospectively analyzed 2390 patients with AMI at our institute (January 1, 2007-September 30, 2020). AMI-CAS was defined as the occurrence of AMI within 14 days after acute stroke. Major adverse cerebral/cardiovascular events (cardiac-cause death, nonfatal myocardial infarction, and nonfatal stroke) and major bleeding events were compared in subjects with  AMI-CAS and those without acute stroke. AMI-CAS was identified in 1.6% of the subjects. Most AMI-CASs (37/39=94.9%) presented ischemic stroke. Median duration of AMI from the onset of acute stroke was 2 days. Patients with AMI-CAS less frequently received primary percutaneous coronary intervention (43.6% versus 84.7%; P<0.001) and dual-antiplatelet therapy (38.5% versus 85.7%; P<0.001), and 33.3% of them did not receive any antithrombotic agents (versus 1.3%; P<0.001). During the observational period (median, 2.4 years [interquartile range, 1.1-4.4 years]), patients with AMI-CAS exhibited a greater likelihood of experiencing major adverse cerebral/cardiovascular events (hazard ratio [HR], 3.47 [95% CI, 1.99-6.05]; P<0.001) and major bleeding events (HR, 3.30 [95% CI, 1.34-8.10]; P=0.009). These relationships still existed even after adjusting for clinical characteristics and medication use (major adverse cerebral/cardiovascular event: HR, 1.87 [95% CI, 1.02-3.42]; P=0.04; major bleeding: HR, 2.67 [95% CI, 1.03-6.93]; P=0.04). Conclusions Under the heart-brain team approach, AMI-CAS was still a challenging disease, reflected by less adoption of primary percutaneous coronary intervention and antithrombotic therapies, with substantially elevated cardiovascular and major bleeding risks. Our findings underscore the need for a further refined approach to mitigate their ischemic/bleeding risks.

The innovative pharmacological combination of low-dose rivaroxaban plus aspirin provides clinicians with an ideal opportunity to intensify the medical treatment of patients with coronary artery disease (CAD) and comorbid peripheral artery disease (PAD). We aimed to determine the cost-effectiveness of PAD screening using the ankle-brachial index (ABI) test in patients with CAD (with rivaroxaban administered if the PAD screening was positive) compared with no-screening strategy in China.

A Markov decision model using a 1-month cycle was developed to simulate the 25-year effectiveness and cost of PAD screening on 75-year-old patients with CAD in China, evaluating the quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER). One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the impact of variations in the key parameters for ICERs.

Our model found an incremental cost of RMB4,959 (US$740) and an incremental QALY of 0.054 after one-time ABI screening, leading to an ICER of RMB91,936 (US$13,717) per QALY gained over a 25-year period. The reduction in all-cause mortality related to rivaroxaban and its cost were the factors most affecting the ICER. The screening would become cost-effective by decreasing the monthly cost of rivaroxaban to RMB184.5 (US$27.5) or by using domestic-brand rivaroxaban according to the threshold of a willingness to pay RMB72,447 (US$10,809) per QALY gained.

Our study demonstrated that ABI screening for PAD to decide on low-dose rivaroxaban administration was not cost-effective for patients with CAD in China. Nevertheless, policy-guided cost changes for domestic-brand rivaroxaban could easily resolve this issue.

Little is known about the outcomes and processes of care of patients with non-ST-segment myocardial infarction (NSTEMI) who present with 'polyvascular' disease.

We analysed 287 279 NSTEMI patients using the Myocardial Ischaemia National Audit Project registry. Clinical characteristics and outcomes were analysed according to history of affected vascular bed-coronary artery disease (CAD), cerebrovascular disease (CeVD), and peripheral vascular disease (PVD)-with comparison to a historically disease-free control group, comprising 167 947 patients (59%). After adjusting for demographics and management, polyvascular disease was associated with increased likelihood of major adverse cardiovascular events (MACEs) [CAD odds ratio (OR): 1.06; 95% confidence interval (CI): 1.01-1.12; P = 0.02] (CeVD OR: 1.19; 95% CI: 1.12-1.27; P < 0.001) (PVD OR: 1.22; 95% CI: 1.13-1.33; P < 0.001) and in-hospital mortality (CeVD OR: 1.24; 95% CI: 1.16-1.32; P < 0.001) (PVD OR: 1.33; 95% CI: 1.21-1.46; P < 0.001). Patients without vascular disease were less frequently discharged on statins (PVD 88%, CeVD 86%, CAD 90%, and control 78%), and those with moderate [ejection fraction (EF) 30-49%] or severe left ventricular systolic dysfunction (EF < 30%) were less frequently discharged on angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) (CAD 82%, CeVD 77%, PVD 77%, and control 74%). Patients with polyvascular disease were less likely to be discharged on dual antiplatelet therapy (DAPT) (PVD 78%, CeVD 77%, CAD 80%, and control 87%).

Polyvascular disease patients had a higher incidence of in-hospital mortality and MACEs. Patients with no history of vascular disease were less likely to receive statins or ACE inhibitors/ARBs, but more likely to receive DAPT.