Peripheral Arterial Disease Research Articles

Dual pathway inhibition in peripheral arterial disease

Despite its high worldwide prevalence and the intuitable negative prognostic connotation, for a long time peripheral artery disease (PAD) has not been the subject of particular interest by the cardiac scientific community. The availability of a new therapeutic strategy (low-dose rivaroxaban associated with acetylsalicylic acid) has reignited interest in PAD. The clear evidence derived from the COMPASS and VOYAGER PAD trials, with the possibility of using dual pathway inhibition, has given new energy to the therapeutic front against symptomatic PAD also associated with coronary artery disease. This review article aims to revisit the pathophysiological concepts underlying PAD and the path of the various clinical trials that have led to new scientific evidence.

What Is the Best Experimental Model for Developing Novel Therapeutics in Peripheral Artery Disease?

More than 200 million people worldwide have peripheral artery disease (PAD). PAD affects the quality of life and is associated with significant morbidity and mortality. Standard treatment for severe cases of PAD is surgical or endovascular revascularization. However, up to 30% of patients are not candidates for open or endovascular procedures, due to high operative risk or unfavorable vascular involvement. Furthermore, revascularization procedures may be insufficient to adequately improve microvascular tissue perfusion, wound healing, or limb salvage. Accordingly, regardless of advances in treatment modalities, outcomes of patients with PAD have remained unfavorable. Therefore, new medical therapeutic approaches are much needed. Small animal models are indispensable tools for the understanding of PAD physiopathology and the development of novel medical therapies. Development of animal models that more closely mimic the pathophysiology (with occlusive atherothrombosis and chronic development of limb ischemia) can incorporate the cardiovascular risk factors associated with this disease state, and focus on more clinically relevant outcomes is critical. In practice, this means using both animals that develop atherosclerosis and methods for the application of gradual arterial occlusion to induce hind limb ischemia. Doing so will likely help identify novel targets for intervention and overcome some principal challenges confronted by previous clinical trials. While various rodent models are discussed, the optimal animal model is yet to be defined.

The Differential Diagnosis of Leg Ulcers.

Chronic wounds on the leg (below the knee) are called leg ulcers. They have many causes, and thus patients with leg ulcers are treated by many different kinds of medical specialist. Appproximately 80% of sufferers have chronic venous insufficiency (CVI) and/or peripheral arterial occlusive disease (PAOD). Knowledge of the relevant differential diagnoses is important for appropriate treatment, particularly for patients with atypical findings or an intractable course. This article is based on publications retrieved by a selective search in PubMed, including current guidelines and expert recommendations. The diagnostic evaluation of a leg ulcer can be structured according to the ABCDE rule. This involves individualized, targeted history-taking (anamnesis); bacteriological testing; clinical examination; ancillary testing, particularly for perfusion (defective vascular system); and extras, such as biopsies. Specifically, we present in this article the main aspects of the complex diagnostic evaluation of venous leg ulcers, arterial leg ulcers, vasculitis, vasculopathy, calciphylaxis, pyoderma gangrenosum, necrobiosis lipoidica, ecthyma, and squamous cell carcinoma. There remain many unsolved problems, including interactions between the various areas of clinical treatment and the relative paucity of relevant high-quality research. A timely differential-diagnostic evaluation for the many diseases that can cause leg ulcers, which require treatment from representatives of many different medical specialties and health professions, is a prerequisite for their effective individualized treatment.

Treatment Modalities and Risks of Complication for Patients With Localized Renal Cell Carcinoma Aged 75 and Older.

Partial (PN)/radical (RN) nephrectomy is the standard treatment for localized renal-cell carcinoma (RCC). The potential risks of these procedures are concerns for the elderly. We evaluated perioperative outcomes/survival for patients aged ≥ 75 years with localized RCC who underwent PN, RN, or thermal ablation (TA). Localized RCC patients undergoing PN/RN/TA (2000-2023) were retrospectively reviewed. Logistic-regression assessed factors associated with major complications. Kaplan-Meier estimated survival. A total of 278 patients (≥ 75 years) with RCC who received intervention (107RN, 101PN, and 70TA) were identified. Median age was 78 years. PN patients were younger than other cohorts (77 vs. 79, p = 0.006). Patients with cancer comorbidities underwent TA than PN/RN (93% vs. 88%/76%, respectively). Median tumor size was 4.0, 3.0, and 2.6 cm in RN, PN, and TA cohorts, respectively. RN patients had more complex masses compared to other cohorts (9 vs. 7, p < 0.001). Postoperative complications were significantly greater among PN patients (p = 0.03), but there was no significant difference in Clavien ≥ 3 complications. Peripheral vascular disease (PVD) was associated with Clavien ≥ 3 complications on multivariable analysis (p = 0.03). RN was performed at a stable rate while PN decreased in favor of TA. There was no significant difference in RCC-/non-RCC-specific survival among treatment modalities. It is important to make informed decisions about treating RCC in the elderly to reduce morbidity/mortality. PVD could be a determining factor favoring TA for amenable tumors.

Heel Raises and Calf Stretches Exercises Versus Medication Only in Ischemic Intermittent Claudication: A Randomized Controlled Trial.

Intermittent claudication is a primary symptom of peripheral artery disease (PAD). a chronic progressive disease caused primarily by atherosclerosis. It is usually characterized by leg pain, aches, cramps, or fatigue when walking, which improves with rest. Physical therapy, including a supervised exercise program, is often recommended as the first treatment for sprains. This study aims to evaluate the short-term effects of incorporating heel raise and calf stretch exercises with standard medical therapy compared to medical therapy alone in managing intermittent claudication. From May 2022 to November 2023, 160 patients with Stage II Fontaine PAD were randomly assigned to two equal groups. Group A (80 patients) received heel raise and calf stretch exercises in addition to medical treatment, while Group B (80 patients) received only medical treatment. Both groups underwent treadmill walking tests before and after three months to measure absolute walking distance (ACD), peak walking time (PWT), and Walking Impairment Questionnaire (WIQ) scores, including distance, speed, and symptom severity. At baseline, there were no significant differences between the groups in terms of ACD, peak walking time, ankle-brachial index, distance, speed, and symptoms. At follow-up, Group A showed significantly greater improvements in ACD (312.00 ± 45.43 m), peak walking time (8.54 ± 1.55 min), distance (29.46 ± 4.63 km), speed (20.01 ± 3.13 kph), and WIQ symptoms (22.10 ± 1.02) compared to Group B, which had ACD (276.55 ± 29.07 m), peak walking time (6.72 ± 1.70 min), distance (23.68 ± 3.89 km), speed (15.71 ± 2.71 kph), and WIQ symptoms (20.80 ± 1.47) (P < .001). The ankle-brachial index remained similar between the groups (P > .05). We concluded that integrating standard physical therapy exercises, such as calf raises and leg stretches, with medical therapy significantly enhances walking function in patients with ischemic intermittent claudication.

Peripheral artery disease, antithrombotic treatment and outcomes in European and Asian patients with atrial aibrillation: a report from 2 prospective observational registries

Abstract Background In patients with atrial fibrillation (AF), the impact of peripheral artery disease (PAD) on oral anticoagulant (OAC) therapy use and the risk of outcomes remains unclear. Objective To analyse the epidemiology of PAD in a large cohort of European and Asian AF patients, and the impact on treatment patterns and risks of adverse outcomes. Methods We analysed AF patients from two large prospective observational registries. We identified patients with PAD as reported by the investigators. Logistic regression analysis was used to assess factor associated with the presence of PAD at baseline. OAC prescription and risk of outcomes were analyzed according to the presence of PAD, using adjusted Logistic and Cox regression analyses. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACEs). Interaction analyses were also performed according to different subgroups. Results 15,497 patients with AF (mean age 68.9, SD 11.6 years; 38.6% female, 30% from Asia) were included in the analysis. PAD was found in 941 patients (6.1%), with higher prevalence among European individuals compared to Asian (8.1% vs 1.2%, p&amp;lt;0.001). Patients with PAD were older, more likely with permanent AF, more symptomatic and with higher thromboembolic and bleeding risk. On logistic regression analysis, European patients had 6-fold higher odds of presenting with PAD compared with Asians (Figure 1, Panel A). Other comorbidities and increasing age were associated with higher odds of prevalent PAD (Figure 1 Panel A). Conversely, female sex was associated with lower odds of having PAD at baseline. With age modelled as a continuous variable, and odds of PAD at baseline, there was a non-linear relationship, with the odds of PAD increasing almost linearly until 70 years, plateauing afterwards (Figure 1 Panel B). After adjustments, PAD was associated with lower use of OAC (OR 0.69, 95% CI 0.57-0.85). On Cox regression analysis, PAD was associated with a higher risk of the primary composite outcome (HR 1.28, 95%CI: 1.08-1.52) and all-cause death (HR 1.40, 95%CI: 1.16-1.69). A significant interaction was observed between PAD and age, with greater risks of PAD found in younger patients (&amp;lt;65 years) for the primary outcome (pint=0.014, Figure 2, panel A). Consistent results were observed when we analysed the interaction between PAD and age, modelled as a restricted cubic spline, where the risk of the primary outcome followed a J-curve across age, while patients without PAD showed an approximately linear relationship (pint&amp;lt;0.001, Figure 2, Panel B). Conclusions In patients with AF, PAD is associated with lower use of OAC and higher risk of adverse outcomes, with a greater risk seen in younger patients.Figure 1Figure 2

Baseline patient reported outcomes in patients with peripheral artery disease and type 2 diabetes from STRIDE: a phase 3, 52-week, randomised, double-blind, placebo-controlled trial

Abstract Introduction Lower extremity peripheral artery disease (PAD) is caused by atherosclerotic steno-occlusive arterial lesions in the lower extremities and can lead to intermittent claudication, severe functional impairment and reduced health-related quality of life (HRQoL). People living with type 2 diabetes (T2D) are at higher risk of developing PAD than those without T2D. The most common clinical manifestation of PAD, functional impairment, can be stratified based on severity using Fontaine classification (stages I-IV). There are a limited number of therapies approved for the management of PAD related functional impairment and no glucose-lowering medication has been shown to improve functional capacity in people with PAD and T2D. STRIDE is a phase 3 clinical trial investigating once-weekly subcutaneous (s.c.) semaglutide treatment in people with PAD (Fontaine IIa claudication) and T2D. Purpose To report the patient-reported outcomes (PROs) at baseline from STRIDE and elucidate the impact that PAD has on the functional capacity and HRQoL in this early-stage symptomatic PAD population with T2D. Methods STRIDE enrolled 792 participants with PAD (Fontaine IIa claudication) and T2D who were randomised to receive either 1 mg once-weekly s.c. semaglutide or placebo for 52 weeks. The primary outcome of STRIDE is the change in maximum walking distance at week 52 on a constant load treadmill. Baseline PRO assessments included two Patient Global Impression of Severity (PGI-S) questions and three patient-reported questionnaires: the six items version of the Vascular Quality of Life questionnaire (VascuQoL-6), the Walking Impairment Questionnaire (WIQ) and the Medical Outcomes Short Form 36 (SF-36). Results Baseline responses to both PGI-S questions showed that two thirds of patients reported a moderate-to-severe limitation in their ability to walk (64.9%) and reported that the impact of poor blood circulation in their legs on their HRQoL was also moderate-to-severe (62.5%) (Figure 1A and B). The baseline VascuQoL-6 median score was 15 (score range: 6-24, with a low score indicating more severe impact) and details of impact on the six domains are presented in Table 1. Baseline responses to the WIQ indicated that 20.1% of participants found the degree of difficulty to walk 200 meters either ‘much difficulty’ or were ‘unable to do so’ and 21.8% reported the same when climbing 2 flights of stairs. The secondary supportive outcome assessed in the SF-36 questionnaire was the domain physical functioning where a median baseline value of 38.09 was observed (score range: 19.03-57.60, with a low score indicating more impact). Conclusion Participants in STRIDE, characterized as having early-stage symptomatic PAD, have reported moderate-to-high impact on their physical functioning and HRQoL at baseline. These findings highlight the need for better therapies that improve the functional capacity and HRQoL in people with PAD and T2D.

National dispensing of evidence-based treatment for New Zealand patients before and after peripheral arterial or percutaneous coronary procedures; undertreatment in plain sight

Abstract Background/Introduction Cardiovascular management guidelines recommend that those undergoing arterial procedures for atherosclerotic disease should be on a long-term antithrombotic agent, statin and blood pressure (BP) lowering (triple therapy) to prevent or delay future ischaemic events or death. Internationally, treatment gaps have been reported for people having peripheral arterial disease (PAD) procedures. Purpose We aimed to investigate national rates of triple therapy dispensing before and after admission for a percutaneous coronary intervention (PCI) compared to a PAD procedure. Methods All people aged 18-84 years admitted for a publicly-funded PCI or PAD procedure in New Zealand between 1 January 2015 and 30 June 2020 were identified. Data were linked to national community dispensing records for antithrombotic agents, statins and BP lowering and the adjusted relative risk (adjRR) of dispensing individual medication classes and triple therapy investigated 6 months prior-procedure and 0-6 months and 7-12 months post-procedure. Analyses were controlled for age, sex, prioritised ethnicity, socioeconomic deprivation index, diabetes and prior cardiovascular disease. Results During the study period, 26,383 people were admitted for a PCI procedure and 10,938 people for PAD. Compared to PCI, those with PAD were more likely to be women, older (median age 69 vs 66 years), of Māori or Pacific ethnicity, living in more deprived communities, more likely to have diabetes (33% vs 24%) and a prior admission for cardiovascular disease (63% vs 52%). Triple therapy in the 6 months prior to procedure was 48% for PAD compared to 37% for PCI (adjRR 1.04; 1.03-1.05); however, in the 6 months post-discharge, improved for PCI more than PAD (PAD 58% vs PCI 91%, [adjRR 0.82; 0.81-0,83]) with decreased dispensing in both cohorts by 7-12 months post procedure (PAD 55% vs PCI 83%, [adjRR 0.84; 0.83-0,84]). Conclusions Patients undergoing atherosclerotic arterial procedures are at high risk of future fatal and nonfatal cardiovascular events. Less than half the patients who were admitted for a PCI or PAD procedure had been dispensed triple therapy in the 6 months prior to admission. Post procedure, 91% of PCI patients were on triple therapy but this substantial increase did not occur for PAD patients. The risk management gap for those who have peripheral arterial compared to coronary procedures indicates clear clinical and system-related deficiencies and a national quality improvement approach is required to address these issues. Figure 1. Adjusted relative risk of being dispensed preventive medications for patients who had a PAD procedure, compared to patients who had a PCI procedure [after adjusting for age, sex, ethnicity, NZDep, history of CHD (including prior PCI and CABG), stroke/TIA, haemorrhagic stroke, heart failure, PVD, and diabetes]

"The medicine is not something that interests me at all." Beliefs, health-related behaviors, and medication adherence in patients with symptomatic peripheral arterial disease

Abstract Background Despite evidence-based guidelines recommending secondary prevention with antithrombotics and lipid-lowering therapies, adherence to optimal pharmacological therapies remains suboptimal in patients with symptomatic lower extremity peripheral arterial disease (PAD), potentially contributing to excess morbidity and mortality. However, the behavioral factors and health beliefs underlying this behavior are still poorly understood. Purpose To explore the health-related behaviors and beliefs of patients with symptomatic PAD regarding secondary preventive therapy. Methods Using a qualitative design, we conducted individual semi-structured interviews with patients diagnosed with symptomatic PAD. Participants were recruited from four departments of vascular surgery in Denmark from December 2022 to January 2024. Data analysis was performed using framework analysis based on the six domains of the Health Belief Models1 (HBM) as analytical framework: perceived susceptibility, severity, benefits, barriers, cues to action, and self-efficacy. The HBM is widely used for conceptualizing individual’s attitudes and beliefs to explain and predict health behaviours. Results Sixteen patients participated in the study: seven adherent and nine non-adherent patients. Based on the HBM components, the following findings emerged (Figure 1). Patients expressed low perceived awareness of the severity of PAD and its potential consequences, not recognizing PAD as a systemic condition associated with broader cardiovascular risk. The perception of PAD centered around the experience of excruciating leg pain and its impact on everyday life. This focus on symptoms affected the perceived benefits of secondary preventive therapies. Patients lacked knowledge about the importance and goal of treatment and did not link the secondary preventive therapy to PAD, often associating it only with other cardiovascular diseases. Barriers included inadequate understanding of the chronic progressive nature of PAD and its severity, experience and fear of side-effects, prescription confusion, pill burden, financial constraints, and allergies. Fear of recurring pain, complications, and early death served as strong internal adherence triggers. Paradoxically, despite expressing fear, some patients were only adherent to antithrombotic therapy, not assigning the same importance to statins. Other cues to action included practical arrangements as well as establishing a trusting patient-provider relationship and receiving comprehensive and logical explanations. Conclusions This study provided new perspectives on the multifaceted challenges hindering adherence to secondary preventive therapy among patients with symptomatic PAD. Notably, the insufficient knowledge regarding the chronic progressive nature of PAD and its cardiovascular implications, underscores the need for enhanced patient education and tailored interventions to ensure optimal secondary preventive therapy.Figure 1

Developing a multi-center registry of peripheral artery disease using natural language processing: unlocking the power of the electronic health record

Abstract Background Although peripheral artery disease (PAD) is common and associated with a high risk of mortality, contemporary PAD research remains limited due to poor accuracy of diagnosis codes in the electronic health record (EHR). We previously developed and validated a novel natural language processing (NLP) algorithm that can extract ankle brachial index (ABI) and toe-brachial index (TBI) values from clinical documents and identify patients with PAD with high accuracy (positive predictive value 92.4%). Purpose Scale the NLP system for developing a nationwide registry of PAD in the Veterans Health Administration (VHA), the largest integrated health system in the U.S. that provides care to ~9 million Veterans across 130 sites. Describe the baseline characteristics and mortality outcomes among participants and identify predictors of long-term mortality. Methods A total of 1,182,025 documents from vascular and radiology procedures during 2013-2020 were processed by the NLP system. After excluding non-ABI vascular studies, patients with a known diagnosis of PAD prior to 2015, patients younger than 40 years of age, and those who do not regularly follow-up in the VHA, we identified 107,711 patients with newly diagnosed PAD during 2015-2020. Patients were followed longitudinally using the VA’s electronic health record data. The primary outcome was all-cause mortality. We used Cox proportional hazards regression to examine predictors of long-term mortality. Results The mean age was 70.5 years; 97.3% were males, and 18.5% were of Black race. The mean ABI value was 0.78 (SD: 0.26) and the mean TBI value was 0.51 (SD: 0.19). There was a high prevalence of hypertension (83.6%), heart failure (20.8%), diabetes (53.6%), renal failure (22.1%) and chronic obstructive pulmonary disease (32.4%, Table 1). At 1-year, 9.6% of patients had died and this proportion increased to 25.4% at 3 years. Although nearly all patient variables were significantly associated with mortality, older age, severe PAD at diagnosis, diabetes, heart failure, renal failure and COPD were the strongest predictors of long-term mortality. Black race was associated with lower hazard of long-term mortality. Conclusions Using a previously validated novel NLP algorithm that extracts ABI and TBI values from clinical documents, we have successfully developed a registry of newly diagnosed PAD in the VHA. Ongoing studies from our cohort will yield important insights into the association between clinical management of PAD and clinical outcomes, with the goal of identifying opportunities for improving care.

Associations of smoking status with long-term cardiovascular events in different arterial territories: the EPIC Norfolk prospective population cohort

Abstract Background Smoking cessation is associated with a reduced risk of cardiovascular disease (CVD) events, mainly in ischemic heart disease (IHD) and stroke. However, the impact of smoking status (never, former or current smoking) on long-term CVD events across different arterial territories remains understudied. Knowledge of such associations is important, as it may assist in risk communication and smoking cessation motivation. We therefore investigated associations between smoking status and territory-specific CVD events in a large cohort with ≥20 years follow-up. Methods We included participants without baseline CVD from the European Prospective Investigation of Cancer (EPIC) Norfolk prospective population cohort. The strengths of associations between smoking, former smoking and never smoking with the first occurrence of a CVD event were evaluated using a competing risk-adjusted regression model. CVD events were defined as hospitalisation or death due to IHD, ischemic stroke, haemorrhagic stroke, peripheral arterial disease (PAD) or aortic aneurysm (AA). Patients were followed-up until the first event, non-CVD death (competing risk) or end of study (15-03-2018). The model was adjusted for sex, age, systolic blood pressure, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), diabetes, renal function and body mass index. We compared former and current smoking (at baseline) with never smoking. Results We included 23,581 participants (56% women) with a median baseline age of 58 years [interquartile range (IQR) 51-66]. During median follow up of 21.3 years (IQR 19.0-22.8), 26.4% experienced ≥1 CVD event. The first event of occurrence was IHD in 17.3%, ischemic stroke in 3.6%, haemorrhagic stroke in 1.4%, PAD in 3.1% and AA in 1.4%. Current (vs. never) smoking was associated with IHD [adjusted hazard rate (aHR) 1.53, 95% confidence interval (CI) 1.36-1.72], PAD (aHR 1.29, 95%CI 1.07-1.56) and AA (aHR 4.81, 95%CI 3.54-6.54). Current smoking was not significantly associated with ischemic stroke (aHR 1.20, 95% CI 0.95-1.52) and haemorrhagic stroke (aHR 1.18, 95% CI 0.81-1.70). In former (vs. never) smoking individuals, the association with AA remained statistically significant but less pronounced [aHR 1.69, 95%CI 1.29-2.23]. Conversely, former smoking was not associated with IHD (aHR 1.07, 95%CI 0.99-1.16) or PAD (aHR 1.09, 95%CI 0.95-1.26) (Figure 1). Conclusion After 20-years of follow-up, former smokers, compared to never-smokers, remain at considerably higher risk for CVD events, particularly for aortic aneurysm. This knowledge may assist in treatment decisions and risk communication.

Natural language processing realises the potential of electronic health records: identifying risk factors for disease progression and major adverse limb events in intermittent claudication

Abstract Background/Introduction Peripheral Arterial Disease (PAD) is a common pathology, affecting 4.5% of the UK population. Symptomatic PAD manifests as intermittent claudication (IC). Predictors of IC progression to Chronic-Limb-Threatening Ischaemia (CLTI) and complications including Major Adverse Limb Events (MALE), such as smoking history and diabetes, have been described previously in resource-intensive cohort studies. Novel Natural Language Processing (NLP) approaches transform routinely collected, unstructured health records into datasets for real-world analysis of PAD. Purpose This study leverages NLP based interrogation of electronic health records to efficiently identify risk factors for disease progression and MALE in patients presenting with IC. Methods A retrospective cohort study of patients with PAD at a large, tertiary vascular referral centre identified using the SNOMED terms of IC in the Medcat-NLP-AI toolkit. Demographics, Index of Multiple Deprivation (IMD), and indicators of disease progression, and revascularisation and amputation (MALE) were analysed using Kaplan-Meier survival and Cox Proportional-Hazards analysis. Results 5,027 patients (Mean age 73.7(61.8-85.6), Males 66.1% (n=2,781) were identified. Self-reported population ethnicity was 4.72% Asian, 15.5% Black, 79.7% White. All-cause mortality was 19.5% (n=979) after 10 years of follow-up, with 5.85% of patients progressing to CLTI (n=294). 2.32% of Asian patients, 5.78% of Black patients and 5.04% of White patients progressed to CLTI, respectively. 5.09% of Asian patients, 8.99% of Black patients, and 7.36% of White patients underwent amputation. Multivariate analysis of risk factors for progression to CLTI, demonstrated that diabetes (HR 2.36, 95%CI: 1.22 - 4.48, p = .01) and smoking history (HR 1.76, 95%CI: 1.19 - 2.59, p = .004) independently predicted progression. No risk factors for MALE reached significance. Conclusions Diabetes and smoking behaviour are well-described in the literature as risk factors for progression to CLTI. This study demonstrates the utility of NLP as a resource efficient, validated, methodological tool. Disparities in MALE may exist between patients within a universal healthcare system, although our sample size was insufficient to demonstrate statistical significance. A larger, multicentre analysis is warranted. NLP represents a valuable tool for efficiently identifying and analysing risk factors for PAD progression and holds potential to refine management algorithms.KM curves of CLTI-free survival (DM)

Factors affecting in-hospital clinical outcomes in patients with acute limb ischemia undergoing endovascular therapy or fogarty thrombectomy: a large-scale analysis based on the JROAD-DPC database

Abstract Background The etiology of acute limb ischemia (ALI) involves embolism as well as atherosclerotic thrombosis. Although endovascular therapy (EVT) or Fogarty thrombectomy (Fogarty TE) is the recommended revascularization method for ALI, treatment choice based on patient characteristics remains controversial. Purpose This study aimed to evaluate the differences in clinical outcomes between primary treatments and identify predictive factors affecting clinical outcomes in patients with ALI. Methods This retrospective study used data from the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC) database, from April 2012 to March 2020. We analyzed 18,701 patients with ALI and categorized them into medication and invasive treatment groups (EVT alone, Fogarty TE alone, bypass surgery alone, and hybrid treatment). The EVT-alone and Fogarty TE-alone groups were compared after propensity score matching, considering 19 clinically relevant covariates. The primary outcomes were in-hospital mortality, major amputation, and bleeding complications (anemia requiring transfusion or endoscopic hemostasis). The secondary outcomes were major adverse cardiovascular events (myocardial infarction, coronary intervention, heart failure, stroke, and cerebral hemorrhage), major amputation and/or death, hospitalization duration, and total cost during hospitalization. Results The EVT-alone group had more patients at a higher risk of atherosclerotic disease, including peripheral artery disease (PAD), chronic kidney disease (CKD), or hemodialysis. The Fogarty TE-alone group had more patients at a higher risk of embolism, including AF or AFL. After propensity score matching, in-hospital mortality (odds ratio [OR]: 1.58, 95% confidence interval [CI]: 1.29–1.92, p&amp;lt;.0001), bleeding complications (OR: 1.28, 95% CI: 1.12–1.46, p=0.0002), and major amputation rates (OR: 1.44, 95% CI: 1.17–1.76, p=0.0004) were significantly higher in the EVT-alone group than in the Fogarty TE-alone group. Major amputation and/or death rates and total hospitalization costs were higher in the EVT-alone group than in the Fogarty TE-alone group. In interaction analyses, EVT demonstrated a favorable trend of lower risks of death and/or major amputation in patients with PAD, CKD, and diabetes mellitus (all risk factors for atherosclerotic disease), especially in those with PAD and CKD. Conclusions Fogarty TE may be the preferred primary treatment for patients with ALI, particularly those without PAD or CKD.Study flowchartForest plot analyzing interaction effect

Prognostic significance of coronary flow velocity reserve in patients with peripheral arterial disease

Abstract Background Patients with lower extremity peripheral arterial disease (PAD) have a higher risk of cardiovascular events. Stress echocardiography (SE) based on regional wall motion abnormality (RWMA) is imperfect for risk stratification in PAD, but it can be complemented with an assessment of coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending coronary artery. Purpose To assess the value of SE with RWMA and CFVR to predict survival in PAD. Methods In a retrospective analysis of prospectively acquired data in an observational, multicenter study, we recruited 359 patients (age 69±8 years, 240 [67%] males) with PAD referred for dipyridamole SE in 3 accredited laboratories. We assessed RWMA and CFVR (abnormal value &amp;lt;2.0). All patients were followed up for a median of 4.7 (interquartile range: 2.0 to 8.2 years). All-cause death was the outcome end-point. Results The positivity rate was 37/359 (10%) for RWMA and 159/359 (44%) for CFVR. During follow-up, 97 (27%) deaths were registered. At multivariable analysis, inducible RWMA and/or CFVR &amp;lt;2.0 (HR 2.58, 95% CI 1.65-4.04; p&amp;lt;0.0001), age ≥70 years, diabetes, dialysis treatment, and ejection fraction ≤50% were associated with decreased survival. The annual mortality was 7.4% in patients with RWMA and/or CFVR &amp;lt;2.0 and 2.7% in those with no RWMA and CFVR &amp;gt;2.0 (Figure, p&amp;lt;0.0001). Conclusion In patients with PAD, SE shows more than 4-fold higher prevalence of abnormal CFVR compared to RWMA. The prognostic value of CFVR outperforms RWMA, showing the importance of coronary microvascular dysfunction and diffuse, subcritical coronary atherosclerosis in determining the outcome.

Remnant cholesterol, not LDL cholesterol, explains peripheral artery disease risk conferred by apolipoprotein B: a cohort study

Abstract Background Elevated apolipoprotein B (apoB)-containing lipoproteins (=remnants + low-density lipoproteins [LDL]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied risk of chronic limb-threatening ischemia and myocardial infarction. Methods ApoB, remnant cholesterol, and LDL cholesterol were measured in 93,461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1,207 had PAD, 552 had chronic limb threatening ischemia, and 2,022 had myocardial infarction in the national Danish Patient Registry. Remnant and LDL cholesterol were calculated from a standard-lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25,347 of the individuals. Results were replicated in 302,167 individuals without statin use from the UK Biobank (2004-2010). Results In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% confidence interval: 1.5-2.4) and 1.1 (1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (1.4-2.1) and 0.9 (0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32-100%) and 8% (0-46%), respectively; corresponding results were 63% (30-100%) and 0% (0-33%) for risk of chronic limb-threatening ischemia, and 41% (27-55%) and 54% (38-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. Conclusions PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

The risk factors for in-stent restenosis following drug-eluting stent implantation in end-stage renal disease patients receiving renal replacement therapy

Abstract Background Chronic renal disease is a recognized risk factor for in-stent restenosis (ISR) following percutaneous coronary intervention (PCI) with a drug-eluting stent (DES). However, the specific risk of ISR among individuals with end-stage renal disease (ESRD) remains unclear or insufficiently studied. Purpose It is imperative to identify the risk factors associated with ISR among patients with ESRD and coronary artery disease following the implantation of DES. This identification is crucial for generating evidence-based strategies aimed at preventing ISR. Methods ESRD patients undergoing renal replacement therapy with concomitant coronary artery disease who underwent PCI with their initial DES implantation at our hospital between January 2013 and December 2022 were included in the study cohort. Clinical data, laboratory test results, and PCI specifics were compared between patients with and without ISR. Univariate and multivariate analyses utilizing Cox proportional hazard regression were employed to identify independent risk factors for DES-ISR. Results Among the 321 patients with ESRD who underwent PCI with DES implantation, totaling 874.5 patient-years of follow-up, 53 cases of ISR occurred during this period, yielding an incidence rate of 6.1 per 100 patient-years. Several baseline characteristics, angiographic findings, and procedural details were found to elevate the risk of ISR significantly. These included underlying diabetes mellitus, peripheral artery disease (PAD), high serum parathyroid hormone levels, LDL-C levels, acute coronary syndrome as the clinical presentation, the presence of triple vessel disease, duration of dual antiplatelet therapy less than 1 year, target lesion involving the left main (LM) or left anterior descending (LAD) artery, target vessel size less than 3 mm, ostial lesion, bifurcation lesion, number of stents implanted equal to or more than 3, and stent size less than 3 mm. In the multivariate Cox proportional hazard model, bifurcation lesion (HR 14.70, 95% CI 4.66-46.38), PCI of LM or LAD (HR 5.29, 95% CI 1.14-24.60), target vessel size less than 3 mm (HR 4.10, 95% CI 1.77-9.50), PAD (HR 3.92, 95% CI 1.52-10.08), and ostial lesion (HR 2.92, 95% CI 1.16-7.38) were identified as independent risk factors for ISR (all p-values &amp;lt; 0.05). Conclusions Among ESRD patients with coronary artery disease, bifurcation lesion, PCI involving the LM or LAD, target vessel size less than 3 mm, PAD, and ostial lesion are identified as independent risk factors for ISR. These findings hold significance in enhancing risk stratification and decision-making concerning treatment planning for this population.Univariate analysis risk factors for ISR

Ankle brachial index,a non invasive tool predicts cardiovascular events after acute myocardial infarction:a 3 year follow -up study

Abstract Background / Introduction The ankle-brachial index (ABI) is a non-invasive tool that was initially used for the diagnosis of lower-extremity peripheral artery disease (PAD). It has been proven that ABI is a marker of atherosclerosis in other vascular sites and can therefore be used to predict cardiovascular events regardless the presence or not of PAD symptoms. Purpose This study aims to examine the prognostic value of ABI in the setting of acute myocardial infarction (MI), as up till now there is not enough relevant evidence. Method We followed up 441 patients [79% male;mean age 62 years;67% hypertnesive; 30% with diabetes mellitus (DM); 52% current smokers] who were hospitalized because of MI for a period of three years. All patients underwent baseline estimation of clinical and laboratory parameters during theri hospitalization.The ABI was measured according to established methodology using a certified automated device and abnormal ABI defined as a value ≤ 0.9. The primary endpoint was a composite of all-cause and cardiovascular death, as well as major cardiovascular events including decompensated heart failure, new acute coronary syndrome, cerebrovascular event, malignant arrhythmia, PAD event and new onset renal dysfunction. All events were assessed both in-hospital and within 3 years of follow-up. Results Our study population had a mean ABI of 1.1 (IQR: 1.00 to 1.18). With the use of reduced multivariate regression models ABI was proven to be a prognostic indicator for the in-hospital composite endpoint. Patients with an abnormal ABI had a threefold risk of in-hospital events [HR 2.93, 95% CI: 1.48-5.81, p=0.002]. After conducting multivariate analysis ABI maintained its predictive power of all-cause mortality [HR 2.88, 95% CI: 1.53 – 5.42, p=0.001], regardless of hypertension DM, LDL levels and smoking status of the study population in 3 years follow-up. Conclusion An impaired ABI is associated with greater risk of in-hospital events in patients with acute MI. Moreover, ABI emerges as an independent predictor of long-term all-cause mortality in those patients.The findings of this study suggest that subclinical and clinical PAD are associated with poor outcomes among patients with acute MI; thus, routine ABI tests enhance risk stratification and might carry important prognostic significance in these patients regardless of PAD symptoms.

Targeting the histone methyltransferase SETD7 rescues diabetes-induced impairment of angiogenic response by transcriptional repression of semaphorin 3G

Abstract Background Peripheral artery disease (PAD) is highly prevalent in patients with diabetes (DM) and associates with a high rate of limb amputation and poor prognosis. Surgical and catheter-based revascularization have failed to improve outcome in DM patients with PAD. Hence, a need exists to develop new treatment strategies able to promote blood vessel growth in this setting. Mono-methylation of histone 3 at lysine 4 (H3K4me1) - a specific epigenetic signature induced by the histone methyltransferase SETD7 - favours an open chromatin thus enabling gene transcription. Purpose To investigate whether SETD7-dependent epigenetic changes modulate angiogenic response in diabetes. Methodology Primary human aortic endothelial cells (HAECs) were exposed to normal glucose (NG, 5 mM) or high glucose (HG, 25 mM) concentrations for 48 hours. Unbiased gene expression profiling was performed by RNA sequencing (RNA-seq) followed by Ingenuity Pathway Analysis (IPA). In vitro assays, namely cell migration and tube formation were employed to study angiogenic properties in HAECs. SETD7 and H3K4me1 levels were investigated by Western blot and Chromatin immunoprecipitation (ChIP). Pharmacological blockade of SETD7 was achieved by using the highly selective inhibitor (R)-PFI-2. Mice with streptozotocin-induced diabetes were orally treated with (R)-PFI-2 or vehicle and underwent hindlimb ischemia by femoral artery ligation for 14 days. Blood flow recovery was analysed at 30 minutes, 7 and 14 days by laser Doppler imaging. Our experimental findings were also translated in gastrocnemius muscle samples from patients with and without diabetes. Results RNA-seq in HG-treated HAECs revealed a profound upregulation of the methyltransferase SETD7, an enzyme involved in mono-methylation of lysine 4 at histone 3 (H3K4me1). SETD7 upregulation in HG-treated HAECs was associated with increased H3K4me1 levels as well as with impaired endothelial cell migration and tube formation. Both SETD7 gene silencing and pharmacological inhibition by (R)PFI-2 rescued hyperglycemia-induced impairment of HAECs migration and tube formation, while SETD7 overexpression blunted the angiogenic response. RNA-seq and ChIP assays showed that SETD7-dependent H3K4me1 regulates the transcription of the angiogenesis inhibitor semaphorin-3G (SEMA-3G). Moreover, SEMA-3G overexpression blunted migration and tube formation in SETD7-depleted HAECs. In diabetic mice with hindlimb ischemia, treatment with (R)-PFI-2 improved limb vascularization and perfusion as compared to vehicle. Finally, SETD7/SEMA3G axis was upregulated in muscle specimens from T2D patients as compared to controls. Conclusion Targeting SETD7 represents a novel epigenetic-based therapy to boost neovascularization in diabetic patients with PAD.

Causes and predictors of long-term mortality in patients referred to a cardiac rehabilitation program

Abstract Introduction Cardiac rehabilitation (CR) programs have proven to reduce short-term mortality in patients with ischemic heart disease (IHD) and hospitalization rates in patients with heart failure (HF) (1-3). However, there is insufficient evidence about long-term mortality (&amp;gt;24-36 months) for patients receiving treatments based on recent clinical practice recommendations. Purpose To assess the long-term prognosis and predictors of mortality in a heterogenous group of patients referred to cardiac rehabilitation, and to obtain a detailed overview of death causes. Methods An inferential analysis of consecutive patients referred for exercise-based CR at a single site between January 2016 and January 2021 was performed. Included subjects were classified attending to four indications for referral: IHD, HF, valvular heart disease (VHD) and cancer therapy-related cardiovascular toxicity (CTR-CVT). Patients who did not initiate the CR program or were referred for other indications were excluded. The primary endpoint was all cause death. The secondary endpoint was cardiovascular (CV) death. A survival analysis was performed using Kaplan Meier estimates for each referral indication and a Cox proportional hazards model was fitted to investigate mortality predictors. The initiation of the exercise program was considered the inclusion date, and patients were followed until they met the primary endpoint or censored by January 2024. Results A total of 1180 patients were included in the analysis (81% male, mean age 61 ± 11 years), with a median follow-up of 5.3 years. Most of the patients had been referred due to IHD (87%), while the proportion for HF, VHD, and CTR-CVT was 9.9%, 1.8% and 1.4%, respectively. Seventy-eight patients (6.6%) died during follow-up, with a Kaplan-Meier estimated survival of 94.5% at 5 years (95% CI 93.2%-95.9%). Nineteen patients (24.4%) died due to a cardiovascular event, mostly sudden cardiac death (47%). The predominant non-CV causes of death were infectious disease (36%) and cancer (34%). A multivariate Cox model analysis (Table 1) showed an increased risk of all cause death for patients referred due to HF (HR 2.95, 95% CI 1.33 - 6.55), VHD (HR 5.55, 95% CI 1.19 - 25.9) and CTR-CVT (22.47, 95% IC 7.32 - 68.95) when compared to IHD (Figure 1). Other significant predictors of mortality were LVEF &amp;lt;40%, male sex, age, diabetes, peripheral vascular disease, and multivessel coronary disease. Only LVEF &amp;lt;40%, VHD, CTR-CVT and peripheral vascular disease were independent predictors of CV death. Conclusion Patients who initiated an exercise-based CR program had a low risk of all cause death at 5 years. Indications for CR other than IHD were associated with higher mortality rates after adjusting for confounder variables, likely due to a selection bias of patients in advanced stages of the disease.Table 1.Cox models for all-cause deathFigure 1.KM plot for all-cause death

Incidence of cardiovascular diseases among breast cancer patients: a nationwide registry study 2013-2020

Abstract Background and aims There is evidence to suggest that breast cancer (BC) treatment is associated with an increased risk of developing cardiovascular disease (CVD). Several countries have introduced clinical measures to reduce the impact of breast cancer treatment on cardiovascular function including activated breathing control during radiotherapy, lower radiation doses, and maximum anthracycline doses. The overall aim of this study was therefore to investigate whether breast cancer patients still exhibit higher rates of cardiovascular disease than the general population. Methods We conducted a registry-based cohort study using linked data from four nationwide health registries. Out study population included all Norwegian patients diagnosed with BC between 2013-2020 and matched them by age to 10 controls without BC. Health outcomes were measured from 2008 to 2021. We estimated the cumulative incidence from index date, for ten selected CVDs. For BC patients, the index date was defined as date of BC diagnosis. For controls, the index date was defined as the date of BC diagnosis for the matched BC patient. A wash-out period of 5 years was applied to identify incident cases of CVD. Results The study population included 27,535 patients with BC and 269,9994 matched controls. Median age in both groups was 62 years (IQR: 20). Prior to index date, there were no significant differences in the prevalence of heart valve disease, chronic ischemic heart disease heart failure and peripheral vascular disease in BC patients compared to controls (p&amp;gt;0.05) (Table 1). Hypertensive heart disease, pulmonary embolism, atrial fibrillation, and other cardiac arrythmias were more prevalent in BC patients, while angina pectoris and acute myocardial infarction were more prevalent among controls. After the index date, the incidence proportion for heart valve disease, hypertensive heart disease, pulmonary embolism, atrial fibrillation, other cardiac arrythmias, and heart failure were higher in BC patients compared to controls (p&amp;lt;0.001) (Table 2). No significant differences were found for angina pectoris, acute myocardial infarction, chronic ischemic heart disease, and peripheral vascular disease. Conclusion Breast cancer is still associated with an increased risk of developing several CVDs in current clinical practice, compared to matched controls without breast cancer.Baseline characteristicsIncidence of CVD