PeripheralArteryDisease (PAD) is one of the leading causes of disability and mortality in developed countries. The atherosclerotic blockage and stenosis of peripheral arteries is among the main causes of PAD which mostly occurs in the feeding arteries into the lower extremities (1). PAD has a prevalence of 12%, mainly affecting older individuals; it is a strong predictor of cardiovascular events, often accompanied by atherosclerosis in the coronary and cranial arteries. Furthermore, PAD and coronary atherosclerosis share their risk factors. At the same time, PAD presents with no symptoms in most patients (2-5). The most common symptom is intermittent claudication, presenting as cramping, pain, fatigue, or discomfort in the muscles of the calves, thighs, or buttocks. The pain starts by walking and is alleviated through rest. More severe symptoms include rest pain, necrosis, and gangrene (6,7). Since the most important finding in patients with cardiovascular problems is atherosclerosis, and its existence in peripheral arteries is closely related to cardiovascular disease, therefore early diagnosis of PAD can be an important factor in predicting cardiovascular events (8-11).
Peripheralarterydisease (PAD) is a broad term encompassing a range of atherosclerotic and aneurysmal conditions of the extra-coronary arteries . PAD is estimated to affect up to 15% of the population aged over 65 years, and is predicted to become increasingly common in parallel with an ageing population . Indeed, recent data suggest that global abdominal aortic aneurysm (AAA) related mortality increased by ~10% between 1990 and 2010 . Similarly, the world-wide prevalence of lower limb atherothrombosis increased by ~20% in the 10 years between 2000 and 2010 . There are significant shortfalls in current PAD management, including a need for better ways to diagnose PAD early and a requirement for new treatment options. PAD is recognized to present a cardiovascular risk equivalent to coronary heart disease, although risk factor management appears to be less intensive in PAD patients, possibly due to a primary treatment focus on the presenting complaint [5–9]. Thus, there is a clear need to improve PAD patient care through directed research. We are delighted to present a Special Issue of the International Journal of Molecular Sciences  which includes 11 articles focused on PAD. Collectively these articles cover aspects of AAA and lower limb atherothrombosis and discuss findings of current research using human tissues and animal models. We are extremely grateful to all contributing authors and peer-reviewers for their excellent work and support in making this Special Issue possible.
Figure 2. Circulating biomarkers in peripheralarterydisease. A schematic depiction of the stages at which circulating biomarkers could be informative in the peripheralarterydisease (PAD) course. Since PAD is multifactorial it is likely that a single biomarker may not be sufficient to predict diagnosis or prognosis. Since PAD development and progression is due to the interaction of multiple factors, it is possible that the combination of a number of biomarkers may be preferable to a single maker. Abbreviations: ABI, Ankle brachial index; Ang-2, Angiopoetin-2; ApoA1, Apolipoprotein A1; B2M, β-2-microglobulin; EPC, Endothelial progenitor cell; HCgp, Human cartilage glycoprotein; Hcy, Homocysteine; hsCRP, high sensitivity C-reactive protein; IL, Interleukin; Lp-a, Lipoprotein-1; MMP, Matrix mettalloprotenase; MPO, Myeloperoxidase; NO, Nitric oxide; NOX, NADPH Oxidase; NT-pro-BNP, N-terminal pro-B-type natriuretic peptide; OxPL/ApoB, Oxidised phospholipids on ApoB100 containing lipoproteins; PAD, Peripheralarterydisease; PAR, Protease activated receptor; PON, Paraoxonase; sICAM-1, soluble Intercellular adhesion molecule-1; sRAGE, soluble receptor for advanced glycation end product; sTie-2, soluble Tyrosine kinase with immunoglobulin-like and EGF-like domains 2; sVCAM-1, soluble Vascular cell adhesion molecule-1; TBARS, Thiobarbituric acid-reactive substrates; TGF, Transforming growth factor; TWEAK, Tumour necrosis factor like weak inducer of apoptosis; TSP, Thrombospondin; TIMP, Tissue inhibitor of matrix metalloproteinase; VEGF, Vascular endothelial growth factor.
Peripheralarterydisease (PAD) is a major cardiovascular disease that affected 202 million people worldwide in 2010. PAD is characterized by pathological distal vasoconstriction and is a serious cardiovascular disease with high mortality . Factors increasing the risk of PAD include obesity (BMI> 30), smoking, hypercholesterolaemia, diabetes, hypertension and renal failure . Peripheral arterial disease manifests itself by various symptoms depending on its localization. The most common include: intermittent claudication, atypical lower limb pain, acute limb ischemia, and critical limb ischemia caused by arterial lumen occlusion [1, 3]. Peripheralarterydisease is the third most common clinical manifestation of atherosclerosis after coronary arterydisease and stroke . Peripheralarterydisease is the third most common clinical manifestation of atherosclerosis after coronary arterydisease and stroke . Ankle-brachial index (ABI) - the ratio of blood pressure at the ankle level to the highest blood pressure in the brachial artery - is a cheap and effective method used to diagnose PAD in primary care settings. It is very sensitive (90%) and specific (98%) . Values below 0.9 suggest a diagnosis of peripheral arterial disease. Along with the longer duration of the disease, the risk of complications such as severe limb ischemia requiring amputation and heart attack increases . Treatment of PAD includes both pharmacological therapy and interventions such as intravascular lithotripsy (IVL) [7, 8].
Background: Asymptomatic peripheralarterydisease (PAD) increases the risk of mortality in non-hemodialysis patients. However, the association between asymptomatic PAD and mortality rate remains unclear in patients on hemodialysis. Methods: This retrospective cohort study aimed to assess the prognostic significance of asymptomatic PAD in a population of 310 hemodialysis patients. Patients with an ankle – brachial index of < 1.00, or > 1.40 with a toe – brachial index of < 0.70, were diagnosed as having PAD. The San Diego Claudication Questionnaire was used to characterize leg symptoms in patients with PAD, and asymptomatic PAD was defined as the absence of symptoms in the legs or buttocks while walking. The mortality risk of asymptomatic PAD was assessed using the Cox proportional hazard model. Results: The rate of PAD was 28.1%. Among 87 patients, those with PAD, 66.7% were asymptomatic. Fifty-eight patients died during a mean follow-up of 38.9 months. Multivariate analysis revealed hazard ratios of 1.963 (95% confidence interval (CI), 1.012 to 3.740; P = 0.046) and 3.237 (95% CI, 1.402 to 7.020; P = 0.007) in patients with asymptomatic PAD and symptomatic PAD, respectively, compared to patients without PAD. No significant difference was observed between patients with asymptomatic PAD and symptomatic PAD in terms of survival.
Abstract: Peripheralarterydisease (PAD) is a significant cause of morbidity and mortality in the USA. Not only is it a major cause of functional impairment and limb loss, but it is also strongly associated with an increased risk of myocardial infarction, stroke, and death. Large population studies have demonstrated high rates of PAD in women, but this is not widely recognized by the public or by clinicians. One potential reason for this is that women with PAD are more likely than men to be asymptomatic or have atypical symptoms. In addition, women with PAD experi- ence higher rates of functional decline and may have poorer outcomes after surgical treatment for PAD compared with men. Currently, it is not known if there are sex-specific differences in risk factors for the onset, progression, and surgical outcomes of PAD. This review will focus on the diagnosis and management of PAD in women and examine sex-specific differences in the prevalence, risk factors, presentation, and outcomes of this disease.
Peripheralarterydisease (PAD) is caused by stenosis of the arteries in the lower limbs, leading to a reduction in blood flow to the legs . It affects approximately 8-12 million people within the United States alone, one-third of whom suffer from intermittent claudication (IC), defined as ischemic leg pain that occurs with walking and improves with rest . Patients with IC suffer a markedly impaired quality of life and a high perception of disability . Consequently, improving pain-free walking time is an important clinical goal for these patients . Thus far, interventions aimed at improving clinical outcomes in patients with PAD have been either surgical, pharmacological, or exercise based, with supervised exercise training identified as the current best intervention for improving functional outcomes such as peak walking time and pain-free walking time [5-7]. Exercise training has proven efficacy in improving vascular health and function for atherosclerosis-associated comorbidities such as obesity, hypertension, dyslipidemia, and type 2 diabetes mellitus [8-14]. Patients with PAD have marked impairments in the oxygen delivery and uptake pathway due to deficiencies in both vascular function—increased arterial stiffness, endothelial dysfunction, and decreased peripheral blood flow—and skeletal muscle composition and architecture—capillary density rarefaction, mitochondrial dysfunction, and a loss of oxidative (ie, slow-twitch) fibers [15-18]. As they result in a more glycolytic phenotype leading to earlier onset of fatigue and exhaustion, the skeletal muscle abnormalities have a detrimental effect on the delivery, uptake, and utilization of oxygen. While supervised exercise training can improve both the skeletal abnormalities  and vascular function  in these patients, improving the patient’s ability to acutely tolerate an exercise bout could lead to even greater efficacy in the exercise training intervention by allowing them to exercise at a greater intensity at each session. Thus, to identify the next best treatment for patients with PAD, there is a continued need to advance our current understanding of both the disease and optimal interventional therapies.
As with Australian data, previously published re- search in other countries focused on Indigenous pop- ulations has mainly looked at lower limb amputations secondary to diabetes-associated foot disease and cardiovascular events in patients that have diabetes [21–23]. It is therefore difficult to compare our findings to those reported regarding other Indigenous populations. In a retrospective ana- lysis of Canadian Aboriginal and non-Aboriginal sub- jects with PAD, Aboriginal patients had a significantly higher prevalence of risk factors for PAD such as diabetes, hypertension, and renal failure, al- though Aboriginal ethnicity did not have an inde- pendent association with mortality . A more comprehensive understanding of the epidemiology and outcome of PAD amongst different populations is warranted, given the high morbidity and mortality associated with this condition. In addition to differ- ences in cardiovascular risk factors between Indigen- ous and non-Indigenous populations, previous studies have suggested that specific populations may have a predisposition to develop a particular anatomical dis- tribution of arterial disease, which may contribute to poor clinical outcomes . For example, in a retro- spective analysis of 1215 PAD patients, the preva- lence of aorto-iliac and infra-geniculate disease was higher in African-American and Asian populations compared to the Caucasian population [26 – 28]. In the current study, Indigenous Australians had more frequent lower limb presentations (intermittent clau- dication and critical limb ischemia) compared to non-Indigenous Australians, although differences were not significant. It is not yet clear whether these differences are related to ethnicity or rather clinical risk factors associated with distal PAD, such as dia- betes .
The laboratory findings, clinical presentations, ECG changes and procedural characteristics during hospi- talisation for MI patients with and without PAD are outlined in table 2. The laboratory findings showed that patients with MI and PAD had higher levels of C reactive protein and creatinine and lower levels of haemoglobin. Patients with PAD were more likely to present with dyspnoea compared with patients without PAD. They also had slightly lower blood pressure and higher heart rate compared with the non-PAD group at presentation. Moreover, the PAD group experienced more NSTEMI than STEMI, and their presenting ECG showed more atrial fibrillation or flutter and more bundle branch block. PAD patients had more severe CAD with more multivessel and left main disease on the angiogram and they had lower left ventricular function. The PAD group were less often revascularised with PCI or CABG compared with the non-PAD group. All differ- ences presented have a p value of <0.05.
2 dedicated lines. The removed, potentially embolic, material is aspirated at the treatment site, via ports in the fluted tip, into the catheter lumen, and transported to a collection bag located on the device console . The fluted tip rotates at approximately 55,000 rpm with a delivery system that is 8 F compatible and uses a 0.014- inch guidewire. The device is designed to treat the wide spectrum of disease found in patients with LE-PAD, including hard and soft plaque, calcium, thrombus, and fibrotic lesions. Based on limited data set, the Pathway system appears to be effective in treating SFA athero- sclerotic disease, including cases with the presence of sig- nificant calcification. In a multicenter registry using the first-generation Pathway device, 172 patients with 210 lesions in nine European centers were treated; the mean lesion length was 35 mm with moderate to high calcium. The primary endpoint was freedom from device-related serious adverse events (SAEs) at 6 months. TLR at 6 and 12 months was 13% and 26%, respectively. The ABI (Ankle- Brachial Index) increased from 0.59 ± 0.21 at baseline to 0.77 ± 0.26 and 0.82 ± 0.26 (P < .05) at 6 and 12 months, respectively . TRUE (Tissue Removal by Ultrasound Evaluation) study evaluated the debulking properties of this device by analyzing changes in the pla- que volume and composition and vessel size using intra- vascular ultrasound (IVUS) and virtual histology (VH).
socioeconomic group. Males have higher predilection than females. Prevalence increases with age. The most common level of arterial occlusion is femoro- popliteal segment followed by tibial segment. PAD influences the outcome of diabetic foot ulcers significantly with higher rate of amputations in these patients. Coronary arterydisease & Cerebrovascular disease are significantly increased in diabetics with PAD and hence PAD is a marker of systemic vascular disease involving coronary & cerebral vessels, like myocardial infarction (MI), stroke and death.
step length was shorter in patients with PAD, which cor- roborates the results of our study. Moreover, compared to the control group, the speed and cadence of gait in PAD patients were lower by 27% and 11%, respectively, while the stance phase and double support phase were longer. As for the stance phase, the appearance of ischemic pain in the lower limbs shortened the propulsion phase by 14% and extended the flat foot phase by 17% in patients with PAD. What the two studies have in common is the fact that they included patients with symptoms in one and both lower limbs and that the patients walked on the treadmill with their preferred speed. The preferred gait speed in the study by Gommans et al. was found to be almost twice as high as that observed in our study (3.3 km/h vs. 1.8 km/h). The patients’ ability to walk faster might have stemmed from the shorter disease duration (16 months vs. 72 months). What is more, in the study by Gommans et al., the gait pattern analysis was performed when the ischemic pain reached the intensity described by the patients as “between moderate and intense” . It might be assumed that these methodological differences explain why adaptive changes in the gait of patients with PAD were more intense than those observed in our study.
One reported that patients with DM develop more symptomatic forms of PAD such as intermittent claudica- tion, foot ulcers and critical limb ischaemia symptoms . But in the follow-up, we found that patients who received infrapopliteal artery balloon expansion surgery have high restenosis rate, but the limb ulcer have healed, and the clinical symptoms have disappeared. Thus, the endovascular treatment for diabetic peripheral arterial dis- ease could rapidly improve the blood supply and provide time for the foot ulcer and sectional toe wound to heal. With the gradual formation of restenosis, the collateral compensatory circulation was also gradually established, thereby greatly increasing the limb-salvage rate. These are the clinical significance and value of the endovascular treatment for diabetic peripheral arterial disease.
Cardiovascular disease is the most common cause of death and disability among people with diabetes. The cardiovascular disease that accompany diabetes include angina, myocardial infarction (heart attack), stroke, peripheralarterydisease and congestive heart failure. CVD is increased in individual with type1 or type 2 DM. The Framingham Heart Study revealed a marked increase in PAD, CAD, MI and CHF (risk increase from one -to fivefold) in diabetic population. In addition, the prognosis for individuals with diabetes who have coronary arterydisease or MI is worse than for nondiabetics. 5
Abstract Diabetes mellitus (DM) is recognised as a major health problem. Ninety-nine percent of diabetics suffer from type 2 DM and 10% from type 1 and other types of DM. The number of diabetic patients worldwide is expected to reach 380 millions over the next 15 years. The duration of diabetes is an important factor in the pathogenesis of complications, but other factors frequently coexisting with type 2 DM, such as hypertension, obesity and dyslipidaemia, also contribute to the development of diabetic angiopathy. Microvascular compli- cations include retinopathy, nephropathy and neuropathy. Macroangiopathy mainly affects coronary arteries, carotid arteries and arteries of the lower extremities. Eighty percent of deaths in the diabetic population result from cardiovascular incidents. DM is considered an equivalent of coronary heart disease (CHD). Stroke and peripheralarterydisease (PAD) are other main manifestations of diabetic macroangiopathy. Diabetic cardiomyopathy (DC) represents another chronic complication that occurs independently of CHD and hyper- tension. The greater susceptibility of diabetic patients to infections completes the spectrum of the main consequences of DM. The serious complications of DM make it essential for physicians to be aware of the screening guidelines, allowing for earlier patient diagnosis and treatment.
CLI is the end stage of peripheralarterydisease PAD disease and a slow process over years that leads to rest pain, tissue loss and necrosis . The mechanisms of PGE1 in CLI are not only based on active vasodilation, but are considered to be due to inhibition of expression of adhesion molecules, release of inflammatory cytokines and generation and release of growth factors, amongst others, which might be missing in RAO . The expla- nation for the missing therapeutic effect might be due to the not entirely identical pathophysiology of CLI treated with vasoactive medicine and the “missing” critical Fig. 2 Probability of patency recovery after radial artery occlusion
The ankle blood pressure is usually measured in conjunction with the arm blood pressure and the ankle brachial pressure index (ABI) is calculated. Decreased ABI is strongly associated with cardiovascular diseases 71-80 . Also an elevated ABI value seems to be a significant risk factor of CVD 81,82 . The ankle brachial index (ABI) is widely accepted as a diagnostic test used to evaluate the presence of lower extremity peripheralarterydisease (PAD) in patients with symptoms of intermittent claudication or rest ischemia 83-85 . However, the majority of patients with PAD are asymptomatic and therefore, measurement of the ABI only when prompted by symptoms will result in most cases of PAD going unrecognized 86 .
airflow obstruction-related parameters measured by body plethysmography compared with the non-COPD group: FEV 1 % predicted: 66.4% ± 20.3% vs 97.5% ± 19.6%, FEV 1 /VC: 57.2.% ± 12.6% vs 82.3% ± 7.9%, RV% predicted: 162.9% ± 55.9% vs 124.5% ± 37.0%, Rtot% pre- dicted: 149.9% ± 87.8% vs 79.6% ± 28.0%, TLC% predicted: 110.7% ± 20.6% vs 102.0% ± 17.1% and DLCO% predicted: 55.1% ± 19.5% vs 75.3% ± 18.6%, p,0.05 for each (Figure 2). In the capillary blood gas analysis of COPD patients, pO 2 and pCO 2 were, respectively, significantly lower and higher in comparison with the non-COPD group: 70.9 ± 11.5 vs 75.2 ± 11.0 mmHg and 36.8 ± 7.5 vs 34.4 ± 4.4 mmHg, p,0.05 for each (Figure 3). There were no significant differences in age, sex and BMI between COPD and non-COPD group (Table 2). Based on the inclusion criterion, atherosclerotic arterydisease was present in all patients from both groups. Peripheralarterydisease was predominant and detected Table 2 Baseline characteristics of COPD and non-COPD
Persons with poorly controlled diabetes often heal slowly, even from small cuts, abrasions, blisters, or separated callus (corns). In such cases, the damage, if unnoticed, left untreated, or failing to heal, can result in an infection. The resulting infection, in extreme cases, can lead to amputation. About 15 % of patient with diabetes with have serious foot problem. They are the leading cause of hospitalizations for these patients. Diabetes is responsible for more than half of all lower limb amputation performed in the U.S. Each year there are abount 88,000 non-injury amputations, 50-75 % of them due to diabetes. Abount 85 % of amputations start with foot ulcers, which develop on about 12 % of people with diabetes. Those most at risk are people with a long history of diabetes, and people with diabetes who are overweight or who smoke. People who have the disease for more than 20 years and are insulin-dependent are at the highest risk. Related conditions that put prople at risk include peripheral neuropathy, peripheralarterydisease, foot ulcers develop from infections, such as those resulting from blood vesseal injury(Fig. 9). Foot infections often develop from injuries. Even minor infections can develop into severe complications. Numbness from nerve damage, which is common in diabetes, compounds the danger since the patient may not be aware of injuries. About one-third of foot ulcers occur on the big toe.
A Cox proportional hazards model was used to identify baseline prognostic factors associated with 28-day and 1 year mortality. Univariate analysis initially tested all base- line variables: age, gender, history of diabetes, hypertension, heart failure, peripheralarterydisease, coronary arterydisease, COPD, statin use, baseline eGFR, CKD status (baseline eGFR < 60ml/min/1.73m 2 ; yes or no), creatinine on admission, hemoglobin (Hb) on admission and SAPS II. The same variables were then tested in a backward multi- variate Cox Regression analysis including baseline eGFR or CKD status to predict 28-day or 1-year mortality.