Therapeutic angiogenesis by stem cell transplantation

The prevalence of peripheral arterial disease(PAD) is increasing with reference to the life style related disease. Up to one third of patients are not susceptible to traditional revascularization. Therefore, new strategies are needed to offer these patients a viable therapeutic option. The discovery of endothelial progenitor cells (EPCs) in human peripheral blood advanced the field of cell-based therapeutics for many pathological conditions. Bone-marrow derived stem and progenitor cells have been identified as a potential new therapeutic option to induce angiogenesis. However, the mechanism by which cell therapy improves tissue ischemia remains obscure. The present study showed that angiogenic cytokines, especially IL-1beta, were associated with the response to treatment. It is likely that muscle cells but not implanted cells are a major source of angiogenic cytokines in ischemic limbs, thereby promoting neovascularization in ischemic tissues.     

The latest review of therapeutic angiogenesis using angiogenic growth factors to peripheral arterial diseases

Therapeutic angiogenesis using angiogenic growth factors is expected to be a new treatment of patients with severe ischemic diseases. Indeed, human gene therapy for peripheral arterial disease(PAD) using VEGF gene demonstrated the beneficial effects. In contrast, we have reported the potent angiogenic activity of hepatocyte growth factor (HGF) in animal study and we planned gene therapy for ASO and Buerger disease using HGF gene (TREAT-HGF). In a prospective, open-labeled clinical trial, we investigated the safety and biological efficiency of this gene therapy in patients with peripheral arterial disease(PAD) who had failed conventional therapy.     

Differential propensity for major hemorrhagic events in patients with different types of arterial disease

Summary. Aims: Atherosclerosis is the most frequent cause of coronary artery disease (CAD), cerebrovascular disease (CVD), and peripheral arterial obstructive disease (PAD). We previously found that patients with CVD or PAD had a two‐fold higher risk of major hemorrhagic complications than patients with CAD. We investigated whether this difference was attributable to baseline risk factors or genetic variants involved in hemostasis. Methods and results: We included 2622 consecutive patients from a single university hospital who presented with non‐disabling CAD, CVD, or PAD. All patients were followed for the occurrence of major hemorrhagic complications for a mean of 6.6 years. Major hemorrhagic events included intracranial hemorrhagic events, fatal hemorrhagic events, and any hemorrhagic complications requiring hospitalization, irrespective of interventions. Major hemorrhagic complications occurred in 122 patients (annual event rate of 0.77%). Patients with CVD or PAD had more hemorrhagic complications than patients with CAD (hazard ratio [HR] 2.05, 95% confidence interval [CI] 1.39–3.01). Hypertension, diabetes, renal failure and use of oral anticoagulants or antiplatelet therapy did not explain the difference (HR adjusted for all characteristics 1.74; 95% CI 1.14–2.61). Additional adjustment for genetic variants did not further change the HR. Conclusion: Patients with CVD or PAD are at higher risk for major hemorrhagic events than patients with CAD. This difference could not be explained by known risk factors, use of antithrombotic agents, or genetic variants involved in hemostasis. Further research to find the reason for this difference and possible differences in pathogenesis is warranted.     

Peripheral artery disease: therapeutic advances

Peripheral arterial disease (PAD), usually caused by atherosclerosis, is defined as an obstructive arterial disease of the lower extremities that reduces arterial flow during exercise or, in advanced stages, at rest. It affects more than 8.5 million people in the USA. PAD may appear as an asymptomatic arterial disease with abnormal noninvasive test results, or as a symptomatic disease presenting with atypical limb pain, classic intermittent claudication, or critical limb ischemia. The spectrum of PAD is not a continuum. Patients who present with critical limb ischemia may have experienced minimum symptoms. PAD results in limitation of exercise and walking ability, described as intermittent claudication. Patients with PAD are physically impaired and have a higher risk of cardiovascular events; therefore, the treatment goals are aimed at decreasing their cardiovascular risk, as well as improving exercise and daily functional performance. Apart from supervised exercise, which is a major treatment modality for patients with PAD, as of yet there have been very few significant pharmacological breakthroughs in the treatment of PAD that increases blood flow to the ischemic limb. Although percutaneous intervention has markedly improved the treatment of PAD, bypass surgery continues to play an important role. For the most part medical therapy for PAD is designed as a secondary prevention for cardiovascular risk. These include antiplatelet therapy, statins, ACE-inhibitors, smoking cessation and possibly antihypertensive therapy. Revascularization is most beneficial for patients with lifestyle limiting symptoms, acute or chronic limb ischemia with resting pain or nonhealing ulcers. In the following review article we will try to explore the clinical role of some of the latest developments in this field.     

Peripheral artery disease: therapeutic advances

Peripheral arterial disease (PAD), usually caused by atherosclerosis, is defined as an obstructive arterial disease of the lower extremities that reduces arterial flow during exercise or, in advanced stages, at rest. It affects more than 8.5 million people in the USA. PAD may appear as an asymptomatic arterial disease with abnormal noninvasive test results, or as a symptomatic disease presenting with atypical limb pain, classic intermittent claudication, or critical limb ischemia. The spectrum of PAD is not a continuum. Patients who present with critical limb ischemia may have experienced minimum symptoms. PAD results in limitation of exercise and walking ability, described as intermittent claudication. Patients with PAD are physically impaired and have a higher risk of cardiovascular events; therefore, the treatment goals are aimed at decreasing their cardiovascular risk, as well as improving exercise and daily functional performance. Apart from supervised exercise, which is a major treatment modality for patients with PAD, as of yet there have been very few significant pharmacological breakthroughs in the treatment of PAD that increases blood flow to the ischemic limb. Although percutaneous intervention has markedly improved the treatment of PAD, bypass surgery continues to play an important role. For the most part medical therapy for PAD is designed as a secondary prevention for cardiovascular risk. These include antiplatelet therapy, statins, ACE-inhibitors, smoking cessation and possibly antihypertensive therapy. Revascularization is most beneficial for patients with lifestyle limiting symptoms, acute or chronic limb ischemia with resting pain or nonhealing ulcers. In the following review article we will try to explore the clinical role of some of the latest developments in this field.     

Treatment of peripheral arterial disease

Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis strongly associated with cardiovascular (CV) morbidity and mortality. Approximately 12% of the US adult population is affected. Despite its prevalence, the disease has received little attention from clinicians. The primary causes of death in patients with PAD are myocardial infarction and stroke; thus, current treatment strategies for symptomatic PAD include aggressive modification of risk factors for CV disease such as cessation of smoking, treatment of hypertension and diabetes, and normalization of low-density lipoprotein cholesterol levels. All patients with PAD should be receiving antiplatelet therapy to prevent ischemic events. Medical treatment for patients with claudication includes exercise rehabilitation and drug therapy. Although many therapies for claudication have been thoroughly investigated, research continues on new treatments. In contrast, more prospective, randomized trials are needed to evaluate various therapies for treating patients with PAD.     

Diagnosis and treatment of peripheral arterial disease compared with other atherosclerotic vascular diseases in a university primary care clinic.

BACKGROUND: Despite the fact that peripheral arterial disease (PAD) significantly increases the risk of cardiovascular mortality, it is significantly underdiagnosed and undertreated. The purpose of this study was to evaluate the practice at a northeast Tennessee university primary care clinic regarding the diagnosis and treatment of PAD. METHODS: A retrospective medical record survey was conducted to evaluate practice patterns in diagnosing and treating PAD in a university primary care clinic. A clinic population of 711 patients was selected using International Classification of Diseases-9 codes for coronary artery disease (CAD), cerebovascular disease (CVD), and/or PAD. A sample of 180 patients (25.3%) was randomly selected using a systematic statistical method. Of these, 125 patients met the diagnostic criteria for CAD, CVD, and/or PAD. The study covered a 3-year period, from July 2001 until June 2004. Demographic and other data, including the use of antiplatelet therapy, were collected. RESULTS: One hundred ten patients met all of the inclusion and exclusion criteria. Thirty-nine percent were males, and 61% were females. Overall, 79% had CAD, 53% had CVD, and 25% had PAD. Almost half of the patients had some combination of these. Only about 2% had PAD only compared with 36% with CAD only and 17% with CVD only. Although the prevalence of CAD and CVD (among other atherosclerotic vascular diseases) in our clinic was comparable to national figures, the prevalence of PAD was significantly lower (p = .004). The overall use of any antiplatelet agent was 84.2% for patients with only CAD and 80% for only CVD. There was not an adequate number of patients with only PAD to evaluate the use of antiplatelet therapy in this group. CONCLUSION: The low prevalence of PAD only (most PAD patients had coexisting CAD and CVD) indicates that PAD is underdiagnosed at our clinic. There was suboptimal use of aspirin and other antiplatelet drugs among patients with atherosclerotic vascular disease.     

Imaging techniques to evaluate cell therapy in peripheral artery disease: state of the art and clinical trials

Cell‐based therapies, as potential approach to cure peripheral artery disease (PAD), have been clinically investigated after promising results in preclinical models. The so far published studies are very heterogeneous, as different cell sources, cell types, amounts of administered cells and delivering strategies have been used. Overall, cell therapies for PAD bring about a general improvement of patient's clinical condition, even though conclusions cannot be established due to the small size and non‐randomized design of these trials. In this context, non‐invasive imaging techniques, aimed to monitor angiogenesis and neovascularization after cell therapy, will help the follow‐up of clinical studies. However, still much work is needed to establish advanced imaging procedure to overcome the limitation of the current techniques and to accumulate more data in large populations of patients. Here, we report the main imaging techniques employed to evaluate the outcome of the different cell‐based therapies in PAD. Moreover, we focus on both published and ongoing clinical trials utilizing cell therapy in PAD.     

Risk factor profile, management and prognosis of patients with peripheral arterial disease with or without coronary artery disease: results of the prospective German REACH registry cohort

Aims  Peripheral arterial disease (PAD) and coronary artery disease (CAD) are manifestations of the same underlying condition, atherothrombosis. We compared patients with PAD only with those having PAD and concomitant documented CAD in terms of characteristics, risk factors, treatment and prognosis. Methods and results  This is a subgroup analysis of the German cohort of the Reduction of Atherothrombosis for Continued Health (REACH) Registry. It includes 483 patients with PAD only, and 479 patients with PAD plus CAD. Patients with concomitant cerebrovascular disease were excluded. Symptomatic PAD was defined as intermittent claudication (IC), confirmed by ankle brachial index <0.9, or PAD-related intervention. Patients in the total cohort were predominantly elderly (mean age 67.3 ± 8.9 years), males (72.3%), current or previous smokers (80.18%), and had often abdominal obesity (49.6%). Atherosclerotic risk factors and comorbidities were highly prevalent. Patients with PAD + CAD compared to those with PAD only were significantly more intensively treated with regards to antihrombotic agents (97.1% vs. 88.8%), statins (80.2% vs. 51.6%), or ACE inhibitors/ARB (75.6% vs. 61.1%). After two-year follow-up, no significant differences between subgroups were noted for total mortality (4.6% vs. 5.5%), cardiovascular mortality (3.7% vs. 3.9%), non-fatal myocardial infarction (1.9% vs. 2.7%) but for non-fatal stroke (4.4% vs. 2.0%, P < 0.05). Conclusion  Peripheral arterial disease patients carry a high burden of risk factors and co-morbidities, and are at high risk of death and cardiovascular events. If documented CAD is absent, PAD patients are undertreated. Thus, in PAD patients, secondary cardiovascular prevention with stringent treatment of risk factors to the same extent as in CAD patients is mandatory, in line with current guidelines.     

Contemporary management of peripheral arterial disease: III. Endovascular and surgical management

Traditional indications for invasive treatment in patients with peripheral arterial disease (PAD) have been salvage of a threatened limb or improvement of functional capacity in cases of disabling intermittent claudication, but advances in interventional therapy may be lowering the threshold for these therapies. Percutaneous transluminal angioplasty (PTA), with or without stent placement, is the most common endovascular intervention in patients with occlusive lower extremity PAD. In general, PTA is best suited to cases of short-segment stenosis or large-bore vessels, whereas surgery is best applied to multilevel occlusions involving smaller and more distant vessels. This article reviews endovascular therapy, catheter-based thrombolysis, and surgical revascularization procedures in patients with PAD, with special attention to recommendations from new American College of Cardiology/American Heart Association guidelines.     

Peripheral arterial disease assessment: wall, perfusion, and spectroscopy

INTRODUCTION: Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to atherosclerosis and is increasingly common. Presently used methods for diagnosis and follow-up as well as for assessment of novel therapies are limited. MATERIALS AND METHODS: Three distinct magnetic resonance examinations were developed. The first was high-resolution black-blood atherosclerotic plaque imaging of the superficial femoral artery using a surface coil and flow saturation. Second, first-pass contrast-enhanced dual-contrast perfusion imaging of the calf muscle was performed at peak exercise using a magnetic resonance (MR)-compatible pedal ergometer. Lastly, (31)P MR spectroscopy was also performed at peak exercise to measure phosphocreatine (PCr) recovery kinetics. RESULTS: Seventeen patients (age, 63 +/- 10 yrs) with mild to moderate PAD were studied with black-blood atherosclerotic plaque imaging. Mean atherosclerotic plaque volume measured was 7.27 +/- 3.73 cm(3). Eleven patients (age, 61 +/- 11 yrs) with mild to moderate symptomatic PAD and 22 normal control subjects were studied with first-pass contrast-enhanced perfusion imaging. Perfusion index was stepwise increased from patients to normal subjects with matched workload to normal subjects at maximal exercise. For PCr recovery kinetics, 20 patients with mild to moderate PAD and 14 controls were studied. The median recovery time constant of PCr was 34.7 seconds in the controls and 91.0 seconds in the PAD patients (P < 0.0001). CONCLUSIONS: Three distinct MR examinations of different aspects of peripheral arterial disease have been developed and tested and shown to differentiate patients with mild to moderate PAD from normal controls. Taken together, these tests are potential quantitative end points for clinical trials of novel therapies in PAD.     

Are elevated homocysteine plasma levels related to peripheral arterial disease? Results from a cross‐sectional study of 6880 primary care patients

BACKGROUND: It is still unclear whether the strength of the association between elevated plasma homocysteine (HC) levels and peripheral arterial disease (PAD), coronary artery disease (CAD) and cerebrovascular disease (CVD) is similar. METHODS: Fasting homocysteine plasma levels were measured in 6880 unselected primary care patients aged 65 years or older. Presence of PAD was determined with the ankle brachial index, and both CAD and CVD were recorded according to patient history. RESULTS: Median homocysteine levels in the total sample (58.0% females, mean age 72.5 years, mean body mass index 27.3 kg m-2) differed between patients with and without PAD: 15.2 micro mol L-1 (95% confidence interval [CI] 14.8; 15.7, vs. 13.9 micro mol L-1 (CI: 13.8; 14.1; P < 0.001). Peripheral arterial disease prevalence moderately increased from 13.0% in the lowest HC quintile to 24.3% in the highest quintile (crude odds ratio [OR], 2.1 [CI: 1.7; 2.6]). The frequency of atherothrombotic manifestations in the patients' history increased nearly linearly across the homocysteine quintiles in the univariate analysis. However, the association diminished substantially after adjusting for known interfering variables: the ORs between the HC highest fifth vs. lowest fifth (adjusted for age, gender, smoking status, diabetes, hypertension lipid disorders, and estimated glomerular filtration rate levels) for PAD decreased to 1.4, for CAD to 1.0 (NS), and for CVD to 1.1. (NS). CONCLUSIONS: Elevated HC is only slightly more related to PAD than to CAD and CVD. After adjustment for known risk factors, the effect size is small, and an association can no longer be observed between homocysteine and CAD and CVD.     

Prognostic value of coronary computed tomographic angiography in patients with arterial hypertension

Patients with arterial hypertension have a high risk of developing coronary artery disease (CAD), but noninvasive diagnosis of CAD remains difficult. We assessed the ability of coronary CT angiography (CCTA) to detect CAD and to predict subsequent cardiac events in hypertensive patients. We compared 906 hypertensive patients without known CAD undergoing CCTA with 906 matched normotensive patients. Besides calcium score and the degree of the most severe stenosis, the number of coronary segments with atherosclerotic changes was recorded. The primary endpoint was the occurrence of hard cardiac events defined as all cause death, nonfatal myocardial infarction or unstable angina requiring hospitalization. During a median follow-up of 29 months, there were 17 hard cardiac events in the hypertensive group and 13 events in the control group. The best predictor of events in hypertensive patients was the degree of the most severe stenosis (C-index 0.705, P < 0.001, both corrected for clinical risk). The annual event rate was 0.3% for patients without obstructive CAD and 1.5% for patients with obstructive CAD. In hypertensive patients without known CAD, coronary CT angiography allows for the identification of patients at high risk for incident cardiac events.     

Contemporary management of peripheral arterial disease: I. Cardiovascular risk-factor modification

Patients with peripheral arterial disease (PAD) are at increased risk of myocardial infarction or stroke, since multiple vascular beds, beyond the extremities, are likely to be affected by atherosclerosis. In addition to management of leg symptoms in patients with PAD, aggressive modification of cardiovascular risk factors is essential. Smoking cessation, antiplatelet medications, statin drugs, and blood pressure control are proven therapies and strategies for prolonging the lives of patients with PAD. Intensive glycemic control in diabetic patients with PAD lowers the risk of microvascular complications, such as nephropathy, and may reduce the risk of major cardiovascular events and lower extremity amputation. Although aggressive cardiovascular risk-factor modification for patients with PAD may be intuitive, these lifesaving medical therapies for PAD are greatly underprescribed.     

Medical management of peripheral arterial disease

Whether symptomatic or not, peripheral arterial disease (PAD), atherosclerosis in the arteries of the lower extremities, is a common disorder in the general population. The prevalence increases with age and under the influence of vascular risk factors. The most classic symptomatic expression of PAD is intermittent claudication. However, the majority of patients with PAD is asymptomatic or has leg symptoms other than classic intermittent claudication. Both symptomatic and asymptomatic subjects with PAD have increased mortality rates, mainly due to cardiovascular and cerebrovascular expressions of atherosclerotic disease. This review focuses on the current available medical therapies for PAD, including risk-factor modification and antiplatelet therapies, as well as strategies for symptomatic relief in both patients with intermittent claudication and patients with critical limb ischemia. In general, risk factor modification and antiplatelet therapy is essential in all patients with PAD to prevent systemic atherosclerotic complications. Furthermore, for symptomatic relief exercise therapy is the main intervention while pharmacological treatment should be only complementary. In patients with critical limb ischemia, when revascularization therapy is not possible, an attempt should be made to avoid amputation with conservative treatment using analgesics, vasodilators and/or anticoagulants. In case of an acute onset of critical limb ischemia, thrombolysis is indicated.     

Therapeutic angiogenesis for critical limb ischemia: invited commentary.

Lower extremity arterial occlusive disease results in tissue ischemia of the legs and is relatively common in the elderly. Clinically, it may be asymptomatic, cause muscle pain during exercise, or progress to a severe degree of ischemia that may result in limb loss. Although bypass surgery and angioplasty have increased the rate of limb salvage in these patients, amputation of the affected limb remains a common outcome for many patients. Therapeutic angiogenesis is the administration of angiogenic factors, or genes encoding these factors, to promote neovascularization and thereby increase blood flow to the ischemic leg. We have developed an animal model of hindlimb ischemia in which to study therapeutic angiogenesis. We chose nitric oxide as the angiogenic factor for our experiments because of its ability to induce angiogenesis, vasodilation, and inhibit inflammation. In this review, we will discuss our experience with our model of hindlimb ischemia, as well as discuss our results of gene therapy for therapeutic angiogenesis using nitric oxide.     

A cross-sectional study on coronary artery disease diagnosis in patients with peripheral artery disease

PurposeCompared with healthy individuals, patients with peripheral artery disease (PAD) generally have a very high risk of subclinical Coronary artery disease (CAD) and cardiovascular events. To determine the correlation between CAD in PAD patients, thereby promoting the lifetime of PAD patients and reducing the serious impacts of CAD.MethodsThis clinical-based cross-sectional study comprised 100 consecutive patients in India from 2014 to 2016. In this research, PAD patients were screened for CAD by treadmill stress test and cardiac colour Doppler examination. In addition, this study performed coronary angiography followed by peripheral angiography for patients who could not perform the treadmill test.ResultsWith the statistical results, the study observed a high prevalence of CAD in PAD patients that can be detected only with angiography. Further, 30.93% of asymptomatic CAD prevalence was observed in PAD patients. The study strengthens the need for coronary angiography in all symptomatic lower limb PAD cases to detect early CAD, particularly in patients with diabetes and dyslipidemia.ConclusionThere exists a strong correlation between PAD and CAD. Hence, precise diagnosis followed by supervision of PAD patients is significant for avoiding local progression of cardiovascular risk.     

Aspirin in the secondary prevention of cardiovascular disease: an update of the APTC meta‐analysis

We updated the 2002 Antiplatelet Trialists’ Collaboration meta‐analysis of antiplatelet therapy to assess the effects of aspirin alone in the secondary prevention of different types of thrombotic arterial disease. Results of randomized, placebo‐controlled trials of aspirin in patients with confirmed cardiovascular disease were abstracted and synthesized by the Mantel–Haenszel method. We defined three cardiovascular disease groups according to the qualifying disease at entry: coronary artery disease (CAD), cerebrovascular disease (CRVD), and peripheral arterial disease (PAD). Results are given as odds ratios (OR) and 95% confidence intervals (95% CI). Compared with placebo, aspirin decreased significantly the risk of all‐cause death in CAD and CRVD (OR = 0.80, 95% CI 0.75–0.86 and 0.91, 95% CI 0.85–0.98, respectively), and of vascular events in CAD, CRVD, and PAD (OR = 0.71, 95% CI 0.67–0.76, 0.87, 95% CI 0.82–0.93, and 0.50, 95% CI 0.29–0.88, respectively). The risk of non‐fatal stroke was decreased in the CAD, CRVD, and PAD (OR = 0.64, 95% CI 0.50–0.83, 0.81, 95% CI 0.74–0.89, and 0.26, 95% CI 0.07–0.94, respectively). The risk of non‐fatal myocardial infarction was decreased significantly in the CAD and CRVD (OR = 0.59, 95% CI 0.53–0.67, and 0.63, 95% CI 0.48–0.84, respectively), but not in the PAD (OR = 0.43, 95% CI 0.15–1.25). Aspirin nearly doubled the risk of major bleeds (OR = 1.87, 95% CI 1.51–2.32 for all clinical conditions). This meta‐analysis confirms that aspirin decreases the risk of thrombotic events in patients with confirmed disease of the coronary, cerebrovascular, or peripheral artery beds.     

Role of global vascular intervention on long-term prognosis in patients with coronary artery disease

Although recent advance of coronary intervention therapy for coronary artery disease (CAD) is remarkable, long-term clinical outcomes were similar with the past decade. Recent study demonstrated that poly-vascular disease was associated with a significant higher-risk of major adverse cardiovascular events in patients with CAD. The treatment of peripheral artery disease (PAD) reaches to improvement in exercise performance. Revascularization for atherosclerotic renal artery stenosis (ARAS) is associated with reduction in blood pressure and preservation of renal function. Revascularization for carotid artery stenosis (CAS) is associated with the prevention of stroke. Because systemic vascular diseases are related to cardiovascular events, the targeted screening by non-invasive testing for PAD, ARAS, and CAS would increase the frequency of diagnosis, the chance of revascularization therapies, and reach to the reduction in cardiovascular events.     

Targeting angiogenesis versus myogenesis with cardiac cell therapy

Considerable hope has been vested in cell therapy strategies designed to augment the endogenous neovascularization response to obstructive coronary artery disease, and to replace cardiomyocyte loss caused by myocardial infarction. Conceptually, the relative importance of targeting angiogenesis versus myogenesis in this scheme will vary depending on the clinical context (the predominance of ischemia versus ventricular dysfunction and scarring). Although the evidence so far is encouraging, whether these processes can be effectively targeted in a selective fashion with cell therapy is still unclear. Intriguingly, data are now emerging suggesting that the beneficial effects of cardiac cell therapies in a variety of clinical settings may be accounted for by a greater interaction of angiogenesis, myocardial salvage and myogenesis than heretofore appreciated, and through mechanisms that may include both cellular and paracrine effects. Greater understanding of these mechanisms should accelerate the development of effective cell therapies for the growing number of patients with advanced, and in many cases 'no-option', cardiovascular disease. Possible clinical targets for angiogenic and myogenic cardiac cell therapy, the scientific rationale for this therapeutic approach and future directions in this field are discussed here.