Hyperhomocysteinemia: marker of systemic atherosclerosis in peripheral arterial disease.

AIM: Patients suffering from peripheral arterial disease (PAD) are increasingly described as having hyperhomocysteinemia more than in patients with coronary artery or cerebrovascular disease. Cases of symptomatic PAD usually present with associated coronary artery or cerebrovascular disease and renal artery disease. It can thus be postulated that multilocular atherosclerosis is linked to hyperhomocysteinemia and that the extent of atherosclerosis has a possible correlation with homocysteine concentrations. The aim of this study was to ascertain whether fasting total homocysteine concentrations in patients with PAD are associated with the extent and the localization of systemic atherosclerosis in cerebrovascular, coronary and/or renal vascular zones. METHODS: A total of 183 patients with PAD, Fontaine stages II-IV, were divided into 2 groups: Group A contained patients with isolated PAD (n=98) and Group B patients with systemic atherosclerosis in PAD (n=85). Characterization of vascular disease in various vascular zones was indication-adapted using non-invasive and/or invasive METHODS: Patients with renal insufficiency were excluded from the study. RESULTS: Homocysteine concentrations were significantly lower in patients with isolated PAD than in patients with additional systemic atherosclerosis (10.1+/-4.4 vs 16.7+/-7.04 micromol/l, p<0.0001). There were no differences in localization or extent of concomitant systemic atherosclerosis. Logistic regression analysis indicated that elevated plasma homocysteine and decreasing ABPI served independently as significant risk indicators for systemic atherosclerosis in patients with PAD (p<0.0001). CONCLUSION: Hyperhomocysteinemia is a precursoral marker of systemic atherosclerosis and thus a prognostic indicator of cardiovascular morbidity and mortality in PAD.     

前列地尔脂微球载体注射液对糖尿病下肢动脉血管病变的影响

目的观察前列地尔脂微球载体注射液(Lipo-PGE1)对糖尿病下肢动脉血管病变的影响。方法选取哈尔滨医科大学附属第二医院内分泌科2004年10月至2005年6月住院的2型糖尿病下肢动脉血管病变患者36例,采用Lipo-PGE1治疗,观察治疗前后股动脉、腘动脉、胫后动脉和足背动脉的内径和血流量。结果糖尿病下肢动脉血管病变经Lipo-PGE1治疗后,股动脉、腘动脉、胫后动脉和足背动脉内径均增加,胫后动脉和足背动脉内径在治疗前后差异有显著性意义(P<0.05及P<0.01)。股动脉、腘动脉、胫后动脉和足背动脉血流量在治疗后均增加,但差异无显著性意义。经Lipo-PGE1治疗后,36例受试者均自我感觉行走有力,有间歇性跛行的18例患者无瘤行走距离和最大耐受行走距离均明显增加。结论Lipo-PGE1对糖尿病下肢动脉血管病变具有肯定的治疗作用。其可以扩张股动脉、腘动脉、胫后动脉和足背动脉的内径,增加其血流量,但是其最主要的靶向部位在胫后动脉和足背动脉,扩张这些较小的肢端动脉,可有效改善症状。     

Multi-Bed Vascular Disease and Atherothrombosis: Scope of the Problem

While atherosclerosis has traditionally been divided into three types of disease, coronary artery or coronary heart disease (CHD), cerebrovascular disease, and peripheral vascular or peripheral arterial disease (PAD), it is now clear that atherosclerosis is a systemic disease caused by the same pathologic processes regardless of the vascular bed involved. The burden of disease is enormous both in the US and around the world with 61,800,000 Americans affected with one or more types of CVD, responsible for 958,775 deaths annually at a cost of approximately US 329.2 billion dollars annually. Despite trends of decreasing cardiovascular mortality, the global burden of cardiovascular disease is expected to rise, with CHD and stroke becoming the first and fourth most common causes of mortality and morbidity globally. Atherosclerosis is a multibed process with a substantial portion of patients afflicted with disease in more than one bed, although often assymptomatic. Now that there are multiple therapies available to modify and treat atherosclerosis and atherosclerotic risk factors, identification and treatment of these patients are important since their leading cause of death is from co-existing cardiovascular disease.     

Premature atherosclerotic peripheral artery disease: An underrecognized and undertreated disorder with a rising global prevalence

Premature atherosclerotic peripheral artery disease (PAD) of the lower extremities is characterized by disease diagnosis before the age of 50 years. The global prevalence of premature PAD has increased, and the disease is often underdiagnosed given heterogenous patient symptoms. Traditional cardiovascular risk factors like smoking, diabetes, hypertension, and hyperlipidemia as well as non-traditional risk factors like elevated lipoprotein(a), family history of PAD, hypercoagulability, and systemic inflammation are associated with premature PAD. Patients with premature PAD tend to have an aggressive vascular disease process, a high burden of cardiovascular risk factors, and other concomitant atherosclerotic vascular diseases like coronary artery disease. Prevention of cardiovascular events, improvement of symptoms and functional status, and prevention of adverse limb events are the main goals of patient management. In this review, we discuss the epidemiology, risk factors, clinical evaluation, and management of patients with premature PAD.     

Complex Evolution of Epidemiology of Vascular Diseases,Including Increased Disease Burden: From 2000 to 2015

BackgroundVascular diseases, encompassing coronary heart disease (CHD), cerebrovascular disease (CVD), and peripheral artery disease (PAD), are leading causes of the global mortality and morbidity burdens. Our objective was to evaluate the temporal trends in the burden of vascular diseases in the province of Quebec from 2000 to 2015.MethodsWe identified subjects aged ≥ 20 years with vascular diseases in the Quebec Integrated Chronic Disease Surveillance System (a combination of 5 provincial health administrative datasets). We identified Quebecers with CHD, CVD, or PAD by tracking codes identifying vascular diseases (and interventions for CHD) in the hospitalization datasets. We used the 2011 Quebec standard population for age standardization.ResultsIn 2015, the crude prevalence of vascular diseases was 7.3% (n = 473,305), and the all-cause crude mortality rate was 6.6% (n = 31,320). Age-standardized prevalence of vascular diseases increased relatively by 21.4% between 2000 (5.6%; 99% confidence interval [CI], 5.5-5.6) and 2015 (6.8%; 99% CI, 6.7-6.8), whereas the age-standardized incidence and mortality rates showed relative decreases of 46.2% and 32.6%, respectively. PAD and CVD had lower prevalence and incidence but higher mortality than CHD. Most patients with CHD only had this vascular disease in contrast to patients with PAD who generally had diseases involving more than 1 vascular bed. CHD only and CHD with PAD ranked first and second, respectively, in mortality burdens.ConclusionsDuring the last decade, the age-standardized incidence and mortality rate of vascular diseases declined, but their prevalence increased with the overall burden of vascular diseases remaining substantial in Quebec, Canada.     

Current approach to the diagnosis and treatment of femoral-popliteal arterial disease. A systematic review

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis affecting 5 million adults in the United States, with an age-adjusted prevalence of 4% to 15% and increasing up to 30% with age and the presence of cardiovascular risk factors. In this article we focus on lower extremity PAD and specifically on the superficial femoral and proximal popliteal artery (SFPA), which are the most common anatomic locations of lower extremity atherosclerosis. We summarize current evidence and perform a systematic review on the diagnostic evaluation as well as the medical, endovascular and surgical management of SFPA disease.     

Quantifying tissue perfusion after peripheral endovascular procedures: Novel tissue perfusion endpoints to improve outcomes

Peripheral artery disease(PAD) is a flow-limiting condition caused by narrowing of the peripheral arteries typically due to atherosclerosis. It affects almost 200 million people globally with patients either being asymptomatic or presenting with claudication or critical or acute limb ischemia. PAD-affected patients display increased mortality rates, rendering their management critical. Endovascular interventions have proven crucial in PAD treatment and decreasing mortality and have significantly increased over the past years. However, for the functional assessment of the outcomes of revascularization procedures for the treatment of PAD, the same tests that have been used over the past decades are still being employed. Those only allow an indirect evaluation, while an objective quantification of limb perfusion is not feasible. Standard intraarterial angiography only demonstrates post-intervention vessel patency, hence is unable to accurately estimate actual limb perfusion and is incapable of quantifying treatment outcome. Therefore, there is a significant necessity for real-time objectively measurable procedural outcomes of limb perfusion that will allow vascular experts to intraoperatively quantify and assess outcomes, thus optimizing treatment, obviating misinterpretation, and providing significantly improved clinical results. The purpose of this review is to familiarize readers with the currently available perfusion-assessment methods and to evaluate possible prospects.     

Clinical Trials of Adult Stem Cell Therapy for Peripheral Artery Disease

Peripheral artery disease (PAD) refers to noncoronary vascular disease affecting the peripheral arteries. Most commonly the term is applied to occlusive arterial disease affecting the limb arteries, typically due to atherosclerosis. Preclinical studies indicate that a variety of stem cell therapies provide growth factors and cytokines for therapeutic angiogenesis. Small clinical trials with bone marrow mononuclear cells, as well as other cell types, have shown promise. However, mechanisms of therapeutic effect, if any, are not understood. Definitive clinical trials are needed to determine if there are any beneficial effects on functional capacity or morbidity.     

Perioperative clinical variables and long-term survival following vascular surgery

Cardiovascular disease is the leading cause of death in patients with peripheral arterial disease(PAD). Coro-nary artery disease(CAD) is highly prevalent, and often times coexist, in patients with PAD. The management of patients with PAD that requires a high-risk vascular surgical procedure for intermittent claudication, critical limb ischemia or expanding abdominal aortic aneurysm requires risk stratification with the revised cardiac risk index, optimization of medical therapies, and limited use of cardiac imaging prior to surgery. Preventive re-vascularization in patients with stable CAD, with the sole intention to mitigate the risk of cardiac complica-tions in the peri-operative period, is not effective and may be associated with significant bleeding and throm-botic risks, in particular if stents are used. A strategy of universal use of cardiac troponins in the perioperative period for active surveillance of myocardial ischemia may be more reasonable and cost-effective than the current standard of care of widespread use of cardiac imaging prior to high-risk surgery. An elevated cardiactroponin after vascular surgery is predictive of long-term mortality risk. Medical therapies such as aspirin and statins are recommended for patients with post-operative myocardial ischemia. Ongoing trials are as-sessing the role of novel anticoagulants. Additional research is needed to define the role of cardiac imaging and invasive angiography in this population.     

Periphere arterielle Verschlusskrankheit

Peripheral arterial disease (PAD) is highly prevalent. Patients with PAD have often manifestations of atherosclerosis in other vascular territories and are at increased risk for cardiovascular events. Typical symptoms are intermittent claudication or rest pain and acral lesions in patients with advanced PAD. The majority of PAD patients is clinically asymptomatic, therefore it makes sense to look for PAD in patients with cardiovascular risk factors. The ankle brachial index (ABI = ankle/arm pressure) is regarded as an easy and cost effective method for baseline diagnostic. If ABI measurement confirms the suspected PAD, a detailed diagnostic pathway should follow in which duplex sonography plays a central role. In some cases additional radiologic imaging is necessary to complete the diagnostic or to plan therapeutic procedures.     

Management of Infrapopliteal Peripheral Arterial Occlusive Disease

The management of infrapopliteal peripheral arterial occlusive disease (PAD) is challenging. For patients with asymptomatic disease or claudication, exercise and optimal medical management, including antiplatelet agents, blood pressure control, statin therapy and tight glucose control for patients with diabetes mellitus, are the mainstays of therapy. However, patients with isolated tibial artery occlusive disease often have diabetes mellitus or renal insufficiency and present with critical limb ischemia (CLI). CLI is advanced occlusive disease marked by the development of rest pain, ischemic ulceration, or gangrene and is associated with a high mortality rate. Limb salvage requires an intervention in cases of CLI, but careful operative planning is required as patients often have multilevel disease and limited options for revascularization. A surgical bypass with a vein graft remains the best treatment for infrapopliteal PAD, especially in patients with a life expectancy of over 2 years. Balloon angioplasty can play an important role in limb salvage, especially for patients lacking adequate vein for bypass, at high operative risk, or with a life expectancy of less than 2 years. However, a lack of rigorous trials has left unanswered questions as to the efficacy of infrapopliteal angioplasty with or without stents compared to bypass surgery. As such, endovascular therapy is currently not a proven treatment for intermittent claudication. Patients who are unable to undergo a revascularization procedure for infrapopliteal CLI have few options besides amputation or palliation. New therapies, such as drug-eluting stents, drug-coated balloons, and stem cell therapy are under development, but their efficacy and effectiveness remain unproven.     

Epidemiology of peripheral arterial disease

Peripheral arterial disease (PAD) is not an uncommon but a commonly neglected condition by many medical practitioners. It is a disease that threatens not only the limb but also life itself! Atherosclerosis is the commonest cause of PAD in the western nations. The cardinal symptom is intermittent claudication (IC) but majority of the patients are asymptomatic. Ankle-brachial pressure index (ABI) is an effective screening tool for PAD. A diminished ABI (< 0.9) is a definite sign of PAD. Its prevalence steadily increases with age. In Germany almost a fifth of the patients aged over 65 years suffer from it. With increasing life expectancy the prevalence of PAD is on the increase. PAD is a manifestation of diffuse and severe atherosclerosis. It is a strong marker of cardiovascular disease; a very strong association exists between PAD and other atherosclerotic disorders such as coronary artery disease (CAD) and cerebrovascular disease (CVD). PAD is an independent predictor of high mortality in patients with CAD. Smoking, diabetes mellitus and advancing age are the cardinal risk factors. A relatively small number of PAD patients lose limbs by amputation. Most paitients with PAD die of either heart attacks or strokes and they die of the former conditions far earlier than controls. PAD still remains an esoteric disease and there is a significant lack of awareness of this condition by many physicians, and therefore under-diagnosed and underestimated. Measures to promote awareness of PAD among physicians and the society in general are needed. Since most patients are asymptomatic and carry potentially significant morbidity and mortality risks, screening for PAD should be made a routine practice at primary care level.     

Common carotid intima-media thickness in patients with peripheral arterial disease or abdominal aortic aneurysm: the SMART study. Second Manifestations of ARTerial disease.

Evidence is emerging that the contribution of atherosclerosis to the development of abdominal aortic aneurysm may differ from that of other manifestations of arterial disease. B-mode ultrasound may be helpful in understanding the characteristics and factors that contribute to the development of different manifestations of arterial disease. We examined whether there is a difference in common carotid intima-media thickness (IMT), an indicator of generalized atherosclerosis, in patients with peripheral arterial disease (PAD) and abdominal aortic aneurysm (AAA). IMT of the left and right common carotid artery was measured in the first 172 patients (123 PAD and 49 AAA) enrolled in the Second Manifestations of ARTerial disease (SMART) study, a cohort study among patients with a manifestation of atherosclerotic vascular disease or risk factors for atherosclerosis. Mean IMT was 0.98 +/- 0.34 mm in patients with PAD and 0.91 +/- 0.20 mm in patients with AAA, with an age and sex adjusted mean difference of 0.18 mm (95% CI 0.08; 0.28). After additional adjustments for cardiovascular risk factors, the difference remained 0.11 mm (95% Cl 0.01; 0.21). Common carotid IMT in patients with AAA is on average smaller than in patients with PAD, independent of other determinants of IMT. These findings support the view that the development of AAA cannot completely be explained by atherosclerosis and is in part due to other pathophysiological mechanisms.     

Regenerative Therapy in Peripheral Artery Disease

Patients with peripheral artery disease (PAD) and critical limb ischemia are the main candidates for limb amputations and have a poor life expectancy. Frequently, these patients are not eligible for either surgical or percutaneous interventions aimed at mechanical revascularization. Therefore, new strategies need to be identified to offer these patients a viable therapeutic option. Gene and cell therapy hold great promise for the treatment of peripheral vascular diseases because, in animal models, local delivery of growth factors and endothelial progenitor cells result in new blood vessel formation and regeneration of ischemic tissues. In this article, are reviewed phase I and phase II gene, and cell therapy clinical trials in patients with PAD.     

Intermittent claudication

Opinion statement Intermittent claudication is the most common symptom in patients with peripheral arterial disease (PAD). As such, it is mandatory for clinicians to treat both the PAD-specific symptoms (to decrease functional impairment and thereby improve quality-of-life, as well as to decrease rates of amputation) and the underlying systemic atherosclerosis (and thereby reduce cardiovascular ischemic events, especially myo-cardial infarction and stroke). Most patients with claudication can successfully decrease their exertional limb symptoms via a combination of exercise (preferably supervised) and pharmacotherapeutic interventions (eg, cilostazol). Endovascular revascularization currently serves as an effective therapy for patients with high-grade stenoses of the proximal limb arterial segments, (eg, the distal aorta, common iliac artery, or external iliac artery, and occasionally the proximal common femoral artery). Surgical revascularization usually is reserved for patients who present with severe aortoiliac disease in whom long-term patency is likely to be achieved (eg, aortobi-femoral or femoral-femoral bypass) and who have a low cardiovascular perioperative ischemic risk. Patients who undergo successful revascularization also are likely to benefit from exercise rehabilitation programs. All patients with PAD, of any severity, must successfully normalize atherosclerosis risk factors and use antiplatelet therapies. Such interventions include complete smoking cessation, glycemic control, normaliza-tion of blood pressure (less than 130/90 mm Hg), and lowering of low-density lipo-protein (LDL) cholesterol to less than 100 mg/dL. Antiplatelet agents (eg, clopidogrel, aspirin) should be prescribed to decrease rates of cardiovascular ischemic events in dall patients with PAD, unless otherwise contraindicated.     

Premature lower extremity atherosclerosis: clinical aspects

Peripheral arterial disease (PAD) involving the lower extremities is presumably a disease of the elderly. The awareness of PAD in the general population, and in younger adults in particular, is low. Atherosclerosis is the major cause of lower limb ischemia in the young. Young adults with clinical manifestations of premature lower extremity atherosclerosis (PLEA) typically have multiple cardiovascular risk factors and the majority are smokers, with strong family history of cardiovascular disease, and typically have chronic symptoms of claudication at diagnosis. Frequently these symptoms are either not reported in a timely manner by the patients or are attributed to other, presumably more common causes of leg pain in the young. More than 70% of patients with PLEA have angiographic evidence of severe aortoiliac disease. The results of surgical revascularizations in young adults are inferior to those reported in older patients. Younger adults typically require multiple revascularizations with relatively high amputation rate. We conclude that PAD should be considered in adults with multiple risk factors regardless of their age if appropriate symptoms are present. There is a need for increased public health awareness for premature lower extremity atherosclerosis.     

Canadian Cardiovascular Society 2022 Guidelines for Peripheral Arterial Disease

Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects their quality of life and longevity. Over the past 2 decades there have been substantial advances in diagnostics, pharmacotherapy, and interventions including endovascular and open surgical to aid in the management of PAD patients. To summarize the evidence regarding approaches to diagnosis, risk stratification, medical and intervention treatments for patients with PAD, guided by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, evidence was synthesized, and assessed for quality, and recommendations provided—categorized as weak or strong for each prespecified research question. Fifty-six recommendations were made, with 27% (15/56) graded as strong recommendations with high-quality evidence, 14% (8/56) were designated as strong recommendations with moderate-quality evidence, and 20% (11/56) were strong recommendations with low quality of evidence. Conversely 39% (22/56) were classified as weak recommendations. For PAD patients, strong recommendations on the basis of high-quality evidence, include smoking cessation interventions, structured exercise programs for claudication, lipid-modifying therapy, antithrombotic therapy with a single antiplatelet agent or dual pathway inhibition with low-dose rivaroxaban and aspirin; treatment of hypertension with an angiotensin converting enzyme or angiotensin receptor blocker; and for those with diabetes, a sodium-glucose cotransporter 2 inhibitor should be considered. Furthermore, autogenous grafts are more effective than prosthetic grafts for surgical bypasses for claudication or chronic limb-threatening ischemia involving the popliteal or distal arteries. Other recommendations indicated that new endovascular techniques and hybrid procedures be considered in patients with favourable anatomy and patient factors, and finally, the evidence for perioperative risk stratification for PAD patients who undergo surgery remains weak.     

Self-Reported Peripheral Arterial Disease Predicts Future Vascular Events in a Community-Based Cohort

Background  Lower extremity peripheral arterial disease (PAD) is highly prevalent and strongly associated with cardiovascular morbidity and mortality. The ankle-brachial index used to screen for PAD is not routinely performed in primary care settings. Objective  To determine if self-reported PAD is an independent predictor of combined vascular events (myocardial infarction, ischemic stroke, and vascular death). Design  Ongoing population-based prospective cohort (the Northern Manhattan Study). Subjects enrolled between July 1993 and June 2001 with a mean follow-up time of 7.1 years. Patients  Subjects (n = 2,977), aged 40 years or older and free of prior stroke or myocardial infarction, were classified as having self-reported PAD if they answered affirmatively to one of two questions regarding exercise-induced leg pain or a prior diagnosis of PAD. Main Outcome Measures  Combined vascular outcome defined as incident myocardial infarction, incident ischemic stroke, or vascular death. Results  The mean age of the cohort was 68.9 ± 10.4 years; 64% were women; 54% Hispanic, 25% African-American, 21% Caucasian; 15% reported having PAD. After a mean follow-up of 7.1 years, self-reported PAD was significantly predictive of combined events (n = 484) in the univariate model (HR 1.5, 95% CI, 1.2–1.9) and after adjustment for traditional cardiovascular risk factors (HR 1.3, 95% CI, 1.0–1.7). Conclusion  Self-reported PAD is an independent risk factor for future vascular events in this predominantly non-white cohort. The addition of two simple PAD questions to the routine medical history in general medicine settings could identify high-risk patients who would benefit from further vascular evaluation and risk factor modification.     

Antithrombotic Therapy in Peripheral Artery Disease: Risk Stratification and Clinical Decision Making

Patients with peripheral artery disease (PAD) are an underrecognised group with significant thrombotic risk. This risk is modifiable with the use of aggressive secondary preventative efforts, including optimisation of antithrombotic therapy. Appropriate antithrombotic selection for patients with PAD requires appropriate assessment of thrombotic and bleeding risk. Recent Canadian guidelines have recommended dual pathway therapy initiation for stable PAD and post-revascularisation patients. However, there is ongoing discussion about how to identify PAD patients who stand to benefit most from these therapies while trying to minimise harm from bleeding. Clinical equipoise also persists around questions such as the utility of dual antiplatelet therapy in conjunction with rivaroxaban after high-risk endovascular interventions and the optimal therapy for patients experiencing acute limb ischemia. In patients with chronic PAD and high-risk comorbidities or limb features, or in patients after revascularisation, dual pathway therapy with low-dose rivaroxaban and aspirin has emerged as the only regimen to reduce major adverse cardiovascular and limb events while maintaining an acceptable bleeding profile. After endovascular revascularisation, limited-duration (< 30 days) clopidogrel may be added to rivaroxaban and aspirin in selected high-risk patients at the provider’s discretion. After acute limb ischemia, the risk of another vascular event is exceptionally high, but there is no high-quality evidence to guide decision making for intensified antithrombotic therapy. Randomised investigations addressing this question are urgently needed to better serve this high-risk and vulnerable population.     

Vascular multimorbidity in patients with a documented coronary artery disease

Atherosclerotic artery disease is a systemic vascular disorder typically involving multiple vascular territories in the same patient. To assess the prevalence and the topographic distribution of non-coronary peripheral artery disease (PAD), cerebrovascular (CVD) and renal artery disease (RAD) in patients with an angiographically confirmed coronary artery disease (CAD) a cross-sectional survey among inpatients admitted for symptoms of CAD was performed. The relationship between CAD and multiterritory vascular disease, and the major risk factors were also assessed. A total of 1855 consecutive patients, mean age 65 +/- 10.6 years (18-92 years), 1184 (63.8%) men and 671 (36.2%) women with an angiographically confirmed CAD were studied. The patients were divided into four age groups: group A < 35 years of age, group B 35 to 54 years, group C 55 to 74 years and group D > or =75 years of age. While 1265 (68.2%) had no evidence of a relevant non-coronary artery disease, in 590 (31.8%) a significant non-coronary artery disease in at least one additional major vascular territory was documented. CAD was most frequently associated with PAD in n = 176 (9.5%) patients. In 22 (1.2%), all four studied vascular territories were significantly diseased. The prevalence of the multi-territory artery disease increased with age: lowest in group A and highest in the group D. However, the data analysis by gender revealed the highest prevalence of CAD associated with PAD and RAD, respectively, in women 35 to 54 years of age. Using the multivariant logistic regression model, type II diabetes was the only major risk factor for a multi-territory expression of atherosclerosis.