Circulation Topic Review

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1 Circulation Topic Review Peripheral Vascular Disease in Circulation and the Circulation Subspecialty Journals The Editors The following articles are being highlighted as part of Circulation s Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in Circulation and the Circulation subspecialty journals. The studies included in this article represent the articles related to peripheral vascular disease that were published in Circulation and the Circulation subspecialty journals in 2010 and (Circulation. 2012;125:e600-e611.) Does Ginkgo biloba Reduce the Risk of Cardiovascular Events? Summary: Ginkgo biloba is a flavonoid that has previously been shown to improve walking in patients with peripheral vascular disease. In a secondary end point analysis of G biloba in the Ginkgo Evaluation of Memory Study, G biloba did not reduce incidence or mortality from coronary heart disease or stroke. There were fewer peripheral vascular disease events in participants taking G biloba (n 12, 8%) than placebo (n 23, 1.5%) (P 0.04). G biloba may reduce risk of peripheral vascular disease, especially among high-risk individuals with low ankle-brachial index. This positive effect on peripheral vascular disease is consistent with previous studies and requires further evaluation in larger trails before implementation in clinical practice. Conclusions: There was no evidence that G biloba reduced total or cardiovascular disease mortality or cardiovascular disease events. There were more peripheral vascular disease events in the placebo arm. G biloba cannot be recommended for preventing cardiovascular disease. Further clinical trials of peripheral vascular disease outcomes might be indicated. 1 Effects of Peripheral Arterial Disease on Outcomes in Advanced Chronic Systolic Heart Failure: A Propensity-Matched Study Summary: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis and is associated with poor outcomes. However, little is known about the effect of PAD in patients with heart failure (HF). In this study, we demonstrate that the prevalence and the burden of CAD were high among patients with advanced chronic systolic HF with a history of PAD and that a history of PAD was significantly associated with increased risk of mortality and hospitalization in these patients. To determine an independent effect of PAD, we used propensity scores methods to assemble a cohort of patients with HF in which those with and without PAD had similar baseline characteristics, so that any differences in outcomes could be attributed to the presence of PAD. Strong bivariate associations of PAD with major natural history end points suggest that the presence of PAD may be a useful as an inexpensive clinical tool to risk-stratify patients with HF who might be at an increased risk for poor outcomes. Strong independent associations of PAD with poor outcomes highlight the importance of prevention and timely detection of PAD, and aggressive treatment of atherosclerotic risk factors in patients with HF. Conclusions: In a well-balanced propensity-matched population of chronic systolic HF patients, a history of PAD was independently associated with increased mortality and hospitalization. 2 Efficacy and Safety of Varenicline for Smoking Cessation in Patients With Cardiovascular Disease: A Randomized Trial Summary: Smoking cessation is a key component of secondary cardiovascular disease (CVD) prevention because smokers who quit after the diagnosis of CVD have a rapid reduction in their risk of recurrence, disease progression, and cardiovascular mortality. Despite these facts, treating tobacco dependence often has a low priority in cardiology practice. The availability of more effective treatments for smoking cessation provides an opportunity to engage cardiovascular clinicians in treating tobacco use. Varenicline, a partial 4 2 nicotinic acetylcholine receptor agonist, is effective for smoking cessation in healthy smokers, but its efficacy and safety in smokers with CVD were untested. In this randomized, double-blind, placebo-controlled trial of 714 smokers with stable CVD, varenicline more than tripled the rate of continuous tobacco abstinence compared with placebo at the end of 12 weeks of treatment (47.0% versus 13.9%; odds ratio, 6.11; 95% confidence interval, ). The benefit of varenicline persisted even though many patients resumed smoking after treatment stopped. The rate of continuous tobacco abstinence to 1 year was 19.2% in the varenicline group versus 7.2% in the control subjects (odds ratio, 3.14; 95% confidence interval, ). Varenicline was well tolerated in smokers with CVD. It was not associated with increases in blood pressure, heart rate, new cardiovascular events, or cardiovascular or all-cause mortality, although the extent of drug exposure for safety assessment was limited. The rates of psychiatric adverse events, about which concern has been raised in postmarketing surveillance of varenicline, were low and comparable between the varenicline and placebo groups. These data provide a strong evidence base to support the use of varenicline for outpatient smokers with stable CVD. Conclusions: Varenicline is effective for smoking cessation in smokers with cardiovascular disease. It was well tolerated and did not increase cardiovascular events or mortality; however, trial size and duration limit definitive conclusions about safety. 3 Soluble CD40 Ligand Impairs the Function of Peripheral Blood Angiogenic Outgrowth Cells and Increases Neointimal Formation After Arterial Injury Summary: Previous work has revealed an essential involvement of soluble CD40 ligand (scd40l) in atherosclerosis. For instance, Correspondence to The Editors, Circulation Editorial Office, 560 Harrison Avenue, Suite 502, Boston, MA circ@circulationjournal.org 2012 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA e600

2 The Editors Peripheral Vascular Disease e601 interruption of CD40/sCD40L signaling was associated with a more stable plaque phenotype in atherosclerosis-prone mice. Furthermore, clinical trials have unveiled that scd40l plasma levels are elevated during diabetes mellitus and cardiovascular disease and can predict restenosis and acute ischemic events. Whereas interruption of CD40/ scd40l has mainly been examined with regard to primary atherosclerotic plaque formation and destabilization, systematic evidence as to whether the scd40l could also influence endothelial regeneration and neointimal growth after arterial injury has been elusive. Thus, we were prompted to investigate the effects of scd40l on the function of human peripheral blood derived angiogenic early outgrowth cells (EOCs) and during arterial remodeling after carotid wire injury in CD40-deficient mice, as well as in nude mice. Our data reveal that scd40l increased generation of intracellular superoxide anions and decreased homing capacity of EOCs. Moreover, CD40- deficient mice displayed reduced neointimal formation and improved re-endothelialization after carotid wire injury compared with wildtype mice, whereas therapeutic infusion of control EOCs but not EOCs pretreated with scd40l attenuated neointimal growth after wire injury in nude mice. Treatment with scd40l also attenuated luminal incorporation of EOCs and aggravated neointimal progression. Taken together, the endothelial dysfunction associated with elevated scd40l plasma levels can be additionally explained by dysfunction of angiogenic EOCs. In the context of secondary arterial healing during atherosclerosis, a therapeutic blockade of scd40l may provide a novel promising tool to prevent restenosis by attenuating inflammation and supporting endothelial regeneration. Conclusions: Endothelial dysfunction due to persistently elevated plasma levels of scd40l may be attributable to an impairment of EOC function. Hence, in the context of arterial injury, therapeutic blockade of scd40l may provide a novel strategy for accelerating endothelial regeneration and attenuating neointimal remodeling. 4 Incidence and Predictors of Plaque Rupture in the Peripheral Arteries Summary: This study investigated the incidence and clinical significance of the plaque rupture in the iliofemoral arteries detected by intravascular ultrasound in 101 patients with peripheral artery disease. Overall, plaque rupture of the iliofemoral arteries were detected in 42 of 101 arteries (42%), and a history of acute coronary syndrome and male gender were independent predictors of the plaque rupture. Importantly, major adverse cardiac or cerebrovascular events (death, myocardial infarction, and ischemic stroke) plus peripheral vascular event-free (unplanned vascular intervention and amputation) survival rate was significantly higher in patients with plaque rupture than in patients without plaque rupture (46% versus 21%, P 0.008). By multivariable analysis, plaque rupture and Fontaine stage IV were independent predictors of major adverse cardiac or cerebrovascular events plus peripheral vascular events. Therefore, even in the peripheral arterial territory, plaque rupture in the peripheral arteries is not a rare finding. Furthermore, the presence of plaque rupture in the peripheral arteries may suggest the presence of the coronary and peripheral vascular vulnerability. According to the results, clinicians should consider patients with peripheral arterial disease and plaque rupture as patients at a higher risk, and therefore, aggressive risk factor management may be indicated. Conclusions: Ruptured plaque of the iliofemoral arteries is a common finding. Patients with plaque rupture had a higher prevalence of history of acute coronary syndrome and lower major adverse cardiac or cerebrovascular events plus peripheral vascular event-free survival. 5 Th17 and Th1 T-Cell Responses in Giant Cell Arteritis Summary: Giant cell arteritis (GCA), an inflammatory vasculopathy of the aorta and its branches, causes blindness, stroke, and aortic arch syndrome combined with a syndrome of intense systemic inflammation. Pathognomic findings are granulomatous vessel wall infiltrates of activated T cells and macrophages in a temporal artery biopsy. Corticosteroids are highly effective in suppressing the systemic manifestations of disease. In the present study, patients with GCA were studied before and after corticosteroid treatment to identify which immunopathways mediate acute and chronic vasculitis and the manner in which therapy affects the immune-inflammatory abnormalities underlying GCA. In temporal artery biopsies and in the blood of untreated patients, 2 distinct types of effector T cells were expanded: interleukin-17-producing Th17 cells and interferon- producing Th1 cells. Corticosteroids effectively suppressed Th17 cells but left Th1 cells unaffected. Corticosteroids functioned by inhibiting macrophages that produce Th17-promoting cytokines, including interleukin-1, interleukin-6, and interleukin-23. Th1- promoting macrophages escaped from corticosteroid suppression, chronically sustaining one arm of vasculitic T-cell responses. In essence, the systemic and vascular inflammation of GCA involves abnormally activated innate and adaptive immune responses, with both Th17 and Th1 cells contributing to disease. Corticosteroids disrupt abnormal Th17 responses but fail to induce disease remission because Th1 cells are refractory and continue to support vascular inflammation. Thus, successful management of GCA requires combination therapy targeting several arms of the immune system. The identified immune abnormalities emerge as potential biomarkers to optimize monitoring of disease activity in large-vessel vasculitis. Conclusions: Two pathogenic pathways mediated by Th17 and Th1 cells contribute to the systemic and vascular manifestations of GCA. IL-17-producing Th17 cells are sensitive to glucocorticoid-mediated suppression, but interferon- producing Th1 responses persist in treated patients. Targeting steroid-resistant Th1 responses will be necessary to resolve chronic smoldering vasculitis. Monitoring Th17 and Th1 frequencies can aid in assessing disease activity in GCA. 6 Early Deaths in Patients With Heart Failure Discharged From the Emergency Department: A Population-Based Analysis Summary: Patients with acute heart failure (HF) often present to the emergency department (ED) for care, and approximately one third are discharged home without hospital admission. In this study of patients with HF, we found that death occurred in 1.3% within 7 days and 4.0% at 30 days after discharge from the ED. There was overlap in predicted probabilities of death among those who were discharged from the ED and those admitted to the hospital, suggesting that equipoise exists in the decision to admit or discharge the patients with HF from the ED. Among those with similar predicted probabilities of death, observed 90-day mortality was significantly higher among patients who were discharged from the ED compared with those who were admitted to the hospital (P and P for 7-day and 30-day predicted probability cohorts, respectively). Repeat ED visits or hospitalization for HF within 90 days occurred in 20.3% of those initially discharged and 16.6% of those initially hospitalized (P 0.001). Recurrent ED visits or hospitalizations after initial discharge conferred a 3.6-fold increase in risk of death. Older age, male sex, arrival by ambulance, 2 previous HF hospitalizations, valvular heart disease, peripheral vascular disease, respiratory disease, and longer length of ED stay were predictors of death after discharge from the ED. These early findings suggest that there is a need for further clinical evidence to guide risk stratification in the ED and to assist in decision making regarding the safety of direct discharge of patients with HF from the ED. Conclusions: Patients with HF who are discharged from the ED have substantial risks of early death, which, in some cases, may exceed that of hospitalized patients. 7 Functional Mesenchymal Stem Cells Derived From Human Induced Pluripotent Stem Cells Attenuate Limb Ischemia in Mice Summary: Despite the initial encouraging results of preclinical and clinical studies, mesenchymal stem cells (MSCs) derived from adult

3 e602 Circulation April 24, 2012 tissue such as bone marrow have a limited proliferation and differentiation potential for tissue repair in ischemic disease. More important, aging significantly impairs their survival and differentiation potential and thus limits their therapeutic efficacy. Recent breakthrough in the generation of induced pluripotent stem cells (ipscs) offers the possibility to obtain a high yield of patient-specific MSCs. In this study, we demonstrate that functional MSCs can be directly generated from ipscs (ipsc-mscs). Transplantation of ipsc-mscs into mice achieved a more beneficial effect than adult bone marrow derived MSCs in the attenuation of severe limb ischemia. This greater potential of ipsc-mscs may be attributable to their superior survival and engraftment via de novo vascular and muscle differentiation and paracrine mechanisms. Our study suggests that functional MSCs can be generated from human ipscs and have the potential to treat ischemic disease in a patient-specific, cost-effective, and batch-to-batch consistent manner. Conclusions: Functional MSCs can be clonally generated, beginning at a single-cell level, from human ipscs. Patient-specific ipsc- MSCs can be prepared as an off-the-shelf format for the treatment of tissue ischemia. 8 Targeting Lymphatic Vessel Activation and CCL21 Production by Vascular Endothelial Growth Factor Receptor-3 Inhibition Has Novel Immunomodulatory and Antiarteriosclerotic Effects in Cardiac Allografts Summary: Despite very good short-term results, the long-term survival of cardiac allograft recipients has not improved. Although the currently used immunosuppressive drugs efficiently inhibit the proliferation of alloreactive T cells, they have severe side effects such as infections, malignancies, and metabolic problems and do not prevent the development of cardiac allograft arteriosclerosis, a manifestation of chronic rejection. Here, we used rat and mouse heart transplantation models to investigate whether lymphatic vessel targeted therapies modulate the exit of antigen-presenting cells from the allograft to secondary lymphoid organs and the development of acute and chronic rejection. Chronic inflammation increased the expression of allograft lymphatic vessel growth factor (VEGF-C) and induced lymphangiogenesis in rat cardiac allografts. Lymphatic vessels were active and functional in that they contained antigenpresenting cells and expressed dendritic cell chemokine CCL21 and VEGF-C receptor VEGFR-3. Inhibition of VEGFR-3 with gene therapy or monoclonal antibodies decreased allograft CCL21 production, dendritic cell traffic to the secondary lymphoid organs, and the development of acute and chronic cardiac allograft rejection. These results suggest VEGFR-3 inhibition as a novel lymphatic vessel targeted immunomodulatory therapy for cardiac allograft rejection and indicate an active role for lymphatic vessels in inflammation-driven arteriosclerosis. Conclusions: These results show that VEGFR-3 participates in immune cell traffic from peripheral tissues to secondary lymphoid organs by regulating allograft lymphatic vessel CCL21 production and suggest VEGFR-3 inhibition as a novel lymphatic vessel targeted immunomodulatory therapy for cardiac allograft rejection and arteriosclerosis. 9 B Vitamins and the Risk of Total Mortality and Cardiovascular Disease in End-Stage Renal Disease: Results of a Randomized Controlled Trial Summary: We studied the effect of homocysteine-lowering treatment with B vitamins in patients with end-stage renal disease in a randomized controlled trial. After each dialysis session, patients received either a high-dose vitamin supplement (active treatment: 5 mg folic acid, 50 g vitamin B 12, and 20 mg vitamin B 6 )ora low-dose vitamin supplement to avoid vitamin deficiencies (control: 0.2 mg folic acid, 4 g vitamin B 12, and 1 mg vitamin B 6 ). Homocysteine concentrations were significantly lowered in the group receiving high amounts of vitamins. Patients were followed up for a median period of 25 months. The vitamin treatment did not affect total mortality (hazard ratio, 1.13; 95% confidence interval, ; P 0.51) or cardiovascular morbidity (hazard ratio, 0.80; 95% confidence interval, ; P 0.13). Adjustment for other risk factors did not change these results substantially. In this randomized clinical trial, a significant clinical benefit of additional amounts of B vitamins for lowering of homocysteine concentrations was not shown. The results are in accordance with other trials that used B vitamins in patients with renal disease. Conclusions: Increased intake of folic acid, vitamin B 12, and vitamin B 6 did not reduce total mortality and had no significant effect on the risk of cardiovascular events in patients with end-stage renal disease. 10 Erectile Dysfunction Predicts Cardiovascular Events in High-Risk Patients Receiving Telmisartan, Ramipril, or Both: The ONgoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial/Telmisartan Randomized AssessmeNt Study in ACE intolerant Subjects With Cardiovascular Disease (ONTARGET/TRANSCEND) Trials Summary: The prevalence of erectile dysfunction is 20% to 30% in the general population but increases to more than 50% in the cardiovascular high-risk population of the ONTARGET/TRANSCEND trials, who are commonly encountered in clinical practice. Moreover, erectile dysfunction is associated with cardiovascular risk factors owing to the physiology of penile erection, which is crucially dependent on endothelial function and nitric oxide synthesis. The prospective erectile dysfunction substudy of the ONTARGET/TRANSCEND trials shows for the first time that erectile function is a predictor of cardiovascular morbidity and mortality. These results remained after adjustment for possible confounders. Thus, erectile dysfunction represents an early symptom of endothelial dysfunction and atherosclerosis, and patients with erectile dysfunction are at a particularly high cardiovascular risk. The identification of these patients with erectile dysfunction offers the opportunity for early risk-adjusted treatment with the goal of further reducing cardiovascular events. Conclusions: Erectile dysfunction is a potent predictor of all-cause death and the composite of cardiovascular death, myocardial infarction, stroke, and heart failure in men with cardiovascular disease. Trial treatment did not significantly improve or worsen erectile dysfunction. 11 Periadventitial Rapamycin-Eluting Microbeads Promote Vein Graft Disease in Long-Term Pig Vein-Into-Artery Interposition Grafts Summary: The long-term success of vein bypass grafts to the coronary arteries is limited by accelerated atherosclerosis that leads to graft thrombosis in up to 50% of vein grafts within 10 to 12 years and can lead to recurrent angina, ischemic syndromes, and the need for repeat revascularization or death. There is no effective treatment, and vein graft disease remains a clinical problem that affects millions of patients worldwide. The recent clinical success of drug-eluting intracoronary stents that reduce neointima formation and restenosis rates and the prominent role of neointima formation in vein graft disease have led several investigators to assess whether a similar strategy might be effective in vein grafts. We and others have shown that locally applied antiproliferative drugs, including rapamycin, inhibit vein graft disease but only in the short term. In this study, we evaluated periadventitial rapamycin-eluting microspheres to assess

4 The Editors Peripheral Vascular Disease e603 whether prolonged exposure to rapamycin may have long-term benefits, and the results were not successful. Prolonged rapamycin exposure caused significant local toxicity with high rates of early graft rupture and late acceleration of vein graft disease in those grafts that remained viable. Altered drug-release characteristics may have produced a different outcome; however, the high level of local toxicity that we have shown means that clinical translation of this technique will be difficult. The effects of therapeutic agents on processes such as angiogenesis or vessel remodeling are additional considerations beyond the inhibition of neointimal formation for the long-term prevention of vein graft disease. Conclusions: Local toxicity and poor long-term efficacy limits the clinical applicability of locally applied, sustained rapamycin release in vein graft disease. 12 Nitinol Stent Implantation versus Balloon Angioplasty for Lesions in the Superficial Femoral Artery and Proximal Popliteal Artery: Twelve-Month Results From the RESILIENT Randomized Trial Summary: There is uncertainty regarding the optimal endovascular treatment strategy for patients with lifestyle-limiting claudication and disease in the superficial femoral artery. Previous clinical trials have demonstrated conflicting data regarding the benefits of stenting compared with balloon angioplasty for lesions in this location. There continue to be concerns about the potential for superficial femoral artery stent fracture. The RESILIENT (Randomized Study Comparing the Edwards Self-ExpandIng Lifestent versus Angioplasty Alone In LEsions INvolving The SFA and/or Proximal Popliteal Artery) trial compared the safety and efficacy of a self-expanding nitinol stent to balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery. In RESILIENT, 206 patients were randomly assigned to stent implantation versus balloon angioplasty (2:1 randomization). Stenoses or occlusions up to 15 cm in length could be treated. The acute angiographic results were better after stenting, and at 12-months, primary patency rate was significantly higher in the stent group. There was a reduced need for target lesion revascularization after stenting. The rate of stent fracture was low (3.1%), and none of these stent fractures were associated with adverse clinical consequences. In this multicenter, randomized trial, stenting with a self-expanding nitinol stent was superior to balloon angioplasty for moderate-length lesions in the superficial femoral artery and proximal popliteal artery. Conclusions: In this multicenter trial, primary implantation of a self-expanding nitinol stent for moderate-length lesions in the superficial femoral artery and proximal popliteal artery was associated with better acute angiographic results and improved patency compared with balloon angioplasty alone. 13 Relation of Platelet and Leukocyte Inflammatory Transcripts to Body Mass Index in the Framingham Heart Study Summary: There have been many genetic epidemiology and biomarker studies examining associations of common genetic variants (DNA) and circulating proteins with clinically apparent cardiovascular disease and associated risk factors; however, there has been relatively little study of gene expression or transcriptomics. Quantitative differences in the abundance of transcripts (messenger RNA) has been demonstrated in specific malignancies, but gene expression from a large community-based cohort examining cardiovascular disease or its risk factors has never been reported. In this study, we measured quantitative expression of 48 genes in 1846 participants of the Framingham Offspring cohort from RNA derived from isolated platelets and leukocytes. Specific inflammatory platelet-derived transcripts were significantly associated with higher body mass index. Compared with platelets, fewer leukocyte-derived transcripts were associated with body mass index or other cardiovascular risk factors. Select transcripts were found to be highly heritable. This study demonstrates that inflammatory transcripts derived from platelets, particularly those part inflammatory regulating pathways, are associated with BMI, whereas other distinct transcripts, many known to be related to platelet function, are heritable. This is the first study, using a large community-based cohort, to demonstrate that quantitative gene expression is associated with risk factors, most notably body mass index. Conclusions: Inflammatory transcripts derived from platelets, particularly those part of the nuclear factor B pathway, are associated with BMI, whereas others are heritable. This is the first study, using a large community-based cohort, to demonstrate clinical correlates of gene expression and is consistent with the hypothesis that specific peripheral-blood transcripts play a role in the pathogenesis of coronary heart disease and its risk factors. 14 Pulmonary and Systemic Vascular Dysfunction in Young Offspring of Mothers With Preeclampsia Summary: Epidemiological studies suggest that adverse events during early life predispose to cardiovascular disease in adulthood, but the underlying mechanisms are incompletely understood, and there is no information with regard to the pulmonary circulation. Here, we show for the first time in humans that a pathological event during the fetal period, namely preeclampsia, causes marked vascular dysfunction in the pulmonary and systemic circulation of the offspring. This vascular dysfunction was related to preeclampsia itself because siblings of offspring of mothers with preeclampsia who were born after normal pregnancy had normal vascular function. For the practicing physician, this study demonstrates that the pulmonary vascular defect predisposes offspring of mothers with preeclampsia to exaggerated hypoxic pulmonary hypertension already during childhood. When living at high altitude or suffering from disease states associated with chronic hypoxemia, offspring of preeclampsia may be at increased risk for developing right heart failure. Because exaggerated hypoxic pulmonary hypertension is an important underlying mechanism of high-altitude pulmonary edema, these children may also be at risk for this problem. Finally, endothelial dysfunction in the systemic circulation represents a very early step in the development of cardiovascular disease and may contribute to the increased risk of arterial hypertension and stroke in this population. Conclusions: Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life. 15 Periaortic Fat Deposition Is Associated With Peripheral Arterial Disease: The Framingham Heart Study Summary: Central obesity is associated with peripheral arterial disease, suggesting that ectopic fat depots may be associated with localized diseases of the aorta and lower-extremity arteries. We hypothesized that persons with greater amounts of periaortic fat are more likely to have clinical peripheral arterial disease and a low ankle-brachial index. We found that periaortic fat is associated with peripheral arterial disease and low ankle-brachial index, whereas no association with body mass index, waist circumference, or visceral abdominal fat was observed. Periaortic fat is associated with low ankle-brachial index and intermittent claudication. Conclusions: Periaortic fat is associated with low ankle-brachial index and intermittent claudication. 16

5 e604 Circulation April 24, 2012 Regulation of Circulating Progenitor Cells in Left Ventricular Dysfunction Summary: The development of left ventricular dysfunction has many important systemic manifestations. Neurohumoral activation is a key mediator of cardiac decompensation. This report describes a novel association between the development of left ventricular dysfunction and the regulation of circulating progenitor cells in the blood. The authors identified that circulating hematopoietic progenitor cells are decreased in a canine model of severe left ventricular dysfunction and that this decrease correlated with aldosterone levels. In additional models utilizing mineralocorticoid delivery, similar changes were seen. These decreases were associated with evidence of cellular senescence in these cells. As these circulating progenitors may be important mediators of multipotent cardiovascular and hematologic regeneration, these findings are significant. The potential clinical importance of these findings is evident from pathophysiologic and therapeutic perspectives. As neurohumoral mediators of oxidative stress, the effects of mineralocorticoid activation on progenitor cells may define a mechanism for the decreased numbers of cells identified in clinical studies of heart failure. Additionally, one of the beneficial effects of aldosterone inhibition may be manifested through effects on progenitor cells. The findings presented in these large animal studies may provide new concepts by which to consider the development and treatment of left ventricular dysfunction. Conclusions: This is the first study to demonstrate that mineralocorticoid excess, either endogenous or exogenous, results in reduction in hematopoietic precursor cells. These data suggest that mineralocorticoids may induce accelerated senescence of progenitor cells, leading to their reduced survival and decline in numbers. 17 Attained Educational Level and Incident Atherothrombotic Events in Low- and Middle-Income Compared With High-Income Countries Summary: Atherothrombotic diseases (coronary heart disease, cerebrovascular disease, and peripheral arterial disease) are the leading cause of death worldwide. Attained educational level is a socioeconomic indicator that strongly predicts cardiovascular outcomes. However, most studies reporting this association have been conducted in high-income countries (HICs), with very little representation from low- and middle-income countries (LMICs), which bear 80% of the world s cardiovascular deaths. In the global Reduction of Atherothrombosis for Continued Health (REACH) Registry, clinic outpatients with either established atherothrombotic disease or multiple atherothrombotic risk factors were recruited from 44 countries from both LMIC and HIC regions. Self-reported attained educational level (the number of years of formal education completed) and cardiovascular risk factors were documented at baseline, and patients were followed up longitudinally for 23 months for incident atherothrombotic events. Educational attainment was inversely associated with age and diabetes mellitus and directly associated with hypercholesterolemia in all subjects. However, for other risk factors such as obesity, smoking, hypertension, and baseline burden of vascular disease, attained educational level was protective (inversely associated) in HICs but not protective in LMICs. The protective association between higher attained educational level and incident cardiovascular events was strongest in men from HICs, more modest in men from LMICs and in women from HICs, and essentially absent in women from LMICs. These results indicate that studies that report a protective association between attained educational level and cardiovascular outcomes in HICs do not extrapolate to LMICs, especially in women. Further studies dedicated to LMIC settings are essential to investigate the association between socioeconomic indicators and cardiovascular outcomes in these regions. Conclusion: In contrast to HICs, higher attained educational level may not be protective against cardiovascular events in LMICs, particularly in women. 18 Volume Outcome Relationships and Abdominal Aortic Aneurysm Repair Summary: There is a well-established literature relating procedure volume to outcomes of care, but incorporating such information into clinical decision making is problematic when there is 1 treatment option for a particular condition. In the case of abdominal aortic aneurysm repair, surgeons may choose traditional open or endovascular repair. Because the approach is decided by the surgeon after referral, it is not clear whether the referring physician should consider overall abdominal aortic aneurysm repair volume or specific volumes for open and endovascular repair in their referral decisions. In this study, we used comprehensive data from the Medicare program over the years 2001 to 2006 to investigate the relationship between institutional volume and outcomes of abdominal aortic aneurysm repair. We found that whereas there is a relatively constant relationship between open repair and perioperative mortality, for endovascular repair there is a significant improvement in mortality from the lowest quintile of volume to the second lowest, but improvements beyond that volume are small. Because virtually all high-volume open repair facilities have at least modest endovascular volume, referral decisions should be made on the basis of open repair volume rather than total or endovascular repair volume. Our data also suggest the possibility that as endovascular repair increasingly replaces open repair, fewer hospitals will have adequate open repair volume to maintain the experience needed to achieve optimal outcomes. Conclusions: We found a steady increase in survival with increasing volume of open repair but relatively little improvement after reaching a relatively low threshold for endovascular repair. Because hospital experience with one repair method does not translate into improved outcomes for the alternative method, referring clinicians must consider both treatment options when making referral decisions. 19 Risk Score for In-Hospital Ischemic Stroke Mortality Derived and Validated Within the Get With the Guidelines Stroke Program Summary: Ischemic stroke is one of the top causes of mortality in the United States, and much of this mortality occurs during hospital admission. Determining an individual patient s risk of mortality at admission could aid clinical care by providing valuable prognostic information to patients and their family members. Third-party payers and regulatory agencies have shown increasing interest in tracking stroke mortality as a marker of care, so adjustment for baseline risk of mortality will be necessary to avoid penalizing hospitals that admit less healthy patient populations. Therefore, there is an increasingly important need to develop well-validated models that are useful in predicting patient risk of mortality from ischemic stroke. In this study, data from the US nationwide Get With The Guidelines Stroke Registry, sponsored by the American Heart Association, were used to develop a risk score for in-hospital ischemic stroke mortality using information routinely available at the time of admission. The model was developed in more than patients and then validated in another Ischemic stroke patients at low, intermediate, and high risk for in-hospital mortality can be identified with the validated model. A major finding was that the addition of a measure of stroke severity, the National Institutes of Health Stroke Scale score, greatly improved the ability to discriminate between patients who died and patients who survived. Reporting of the risk score has been implemented within Get With The Guidelines Stroke by use of computerized decision support via a World Wide Web based tool, so that hospitals can now access automated calculations of individual or aggregate mortality risk.

6 The Editors Peripheral Vascular Disease e605 Conclusions: The Get With the Guidelines Stroke risk model provides clinicians with a well-validated, practical bedside tool for mortality risk stratification. The National Institutes of Health Stroke Scale score provides substantial incremental information on a patient s short-term mortality risk and is the strongest predictor of mortality. 20 Enhanced External Counterpulsation Improves Peripheral Artery Flow-Mediated dilation in Patients With Chronic Angina: A Randomized Sham-Controlled Study Summary: Not all patients with symptomatic coronary artery disease are amenable to standard revascularization procedures because of unsuitable coronary anatomy, multiple previous revascularization attempts, age, additional comorbid conditions, or patient preference. Such difficult cases require physicians to entertain other options. In the United States alone, 2.5 million patients with coronary artery disease are not amenable to bypass or angioplasty. For those patients in whom repeat (or initial) revascularization procedures are not appropriate and in whom aggressive medical therapy fails to reduce anginal pain, the search for additional therapeutic options continues. New treatment modalities, which are at various stages of clinical evaluation, include minimally invasive bypass surgery, spinal cord stimulation, transcutaneous electric nerve stimulation, transmyocardial laser revascularization, and enhanced external counterpulsation (EECP). Of these modalities, EECP is the only truly noninvasive, atraumatic technique for which a reduction of angina symptoms and nitrate use, increased exercise tolerance, and an improvement in objective measures of myocardial ischemia have been shown. The present study was the first randomized shamcontrolled investigation to focus on peripheral vascular mechanisms that may contribute to the clinical benefits of EECP treatment. In a cohort of patients with symptomatic coronary artery disease (n 42), EECP reduced anginal episodes, nitrate usage, and Canadian Cardiovascular Society angina classification. EECP elicited commensurate improvements in peripheral artery vasodilatory capacity and increases in plasma levels of endothelial-derived vasoactive agents. These novel findings support the hypothesis that EECP improves peripheral endothelial function in patients with symptomatic function and may reduce myocardial oxygen demand. Conclusions: Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease. 21 Vascular Hospitalization Rates and Costs in Patients With Peripheral Artery Disease in the United States Summary: Patients with peripheral arterial disease (PAD) constitute a high-risk population with higher rates of polyvascular disease, higher annual cardiovascular event and hospitalization rates, and greater associated costs relative to coronary artery disease or cerebrovascular disease. This study provides an in-depth examination of long-term rates of vascular events, hospitalizations, and revascularization procedures in different PAD subgroups categorized according to symptomatic status and prior diagnostic/treatment history. This study documents the existence of an iterative pattern of cost accrual related to high rates of recurrent rehospitalizations and repeat revascularization procedures in patients with symptomatic PAD. The high rates of recurring rehospitalizations and revascularization procedures suggest that neither patients, physicians, nor healthcare systems should assume that an initial lower extremity PAD procedure serves as a permanent resolution of the underlying condition. Cost estimates provided by this study are potential inputs into health economic models aimed at examining the long-term cost implications and cost-effectiveness of different treatment options, including secondary cardiovascular risk prevention strategies. Conclusions: The economic burden of PAD is high. Recurring hospitalizations and repeat revascularization procedures suggest that neither patients, physicians, nor healthcare systems should assume that a first admission for a lower-extremity PAD procedure serves as a permanent resolution of this costly and debilitating condition. 22 Translesional Pressure Gradients to Predict Blood Pressure Response After Renal Artery Stenting in Patients With Renovascular Hypertension Summary: The clinical usefulness of renal artery stenting in improving blood pressure control in patients with hypertension and a renal artery stenosis has been questioned by recent studies. We evaluated whether translesional pressure gradients using a inch pressure guide wire, both at rest and during hyperemia, could help in selecting patients who will benefit from renal artery stenting. Dopamine-induced mean pressure gradient was found to be the strongest predictor of the actual blood pressure improvement at follow-up. Moreover, whereas angiographic parameters of stenosis severity were poor predictors of treatment success, a dopamineinduced mean gradient 20 mm Hg reliably predicted a favorable reduction in hypertension after renal stenting. Interestingly, in our study, more than half of the patients selected for renal stenting on the basis of a subjective angiographic evaluation had a hyperemic translesional gradient below the threshold we found to be predictive of hypertension improvement. Thus, a dopamine-induced mean pressure gradient of 20 mm Hg is highly predictive of arterial hypertension improvement after renal stenting, and therefore this measurement is useful for appropriate selection of patients with arterial hypertension. Conclusions: A dopamine-induced mean pressure gradient of 20 mm Hg is highly predictive of arterial hypertension improvement after renal stenting, and therefore this measurement is useful for appropriate selection of patients with arterial hypertension. 23 Defining the Optimal Degree of Heparin Anticoagulation for Peripheral Vascular Interventions: Insight From a Large, Regional, Multicenter Registry Summary: The optimal degree of heparin anticoagulation for peripheral vascular interventions (PVI) has not been defined. Current recommendations have been empirically based on data from the coronary literature. We sought to correlate heparin dose and peak procedural activated clotting time with postprocedural outcomes in patients undergoing PVI in a regional, multicenter registry. Total heparin dose 60 U/kg and peak activated clotting time 250 seconds were associated with significantly higher rates of post-pvi drop in hemoglobin 3 g/dl and/or transfusion, with no differences in technical or procedural success or thromboembolic complications. These findings suggest that weight-based heparin dosing (initially up to 60 U/kg) with a target activated clotting time of 250 seconds or less may improve outcomes in PVI, with the caveat that an acceptable lower activated clotting time threshold is unknown. Our study is important because it establishes an evidence base for the optimal degree of heparin anticoagulation for PVI. Conclusions: During PVI, higher total heparin dose ( 60 U/kg) and peak activated clotting time 250 seconds were predictors of postprocedural transfusion. The high technical and procedural success in all groups suggests that use of weight-based heparin dosing with a target activated clotting time 250 seconds in PVI may minimize the bleeding risk without compromising procedural success or increasing thromboembolic complications. 24

7 e606 Circulation April 24, 2012 Deregulation of microrna-503 Contributes to Diabetes Mellitus Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia Summary: MicroRNAs (mirnas) are post-transcriptional inhibitory regulators of gene expression that bind to complementary messenger RNA transcripts. After initial studies in developmental biology and cancer, mirnas have recently come into focus of cardiovascular diagnostics and therapeutics. Because each mirna can repress many target mrnas, it is possible that dysregulation of a single mirna might account, at least in part, for complex pathological situations. Here, we report for the first time the importance of mir-503 in diabetes mellitus associated ischemic disease, which currently represents a major cause of morbidity and mortality in diabetic patients. In vitro, the combination of high glucose and starvation remarkably enhances the expression of mir-503 in human endothelial cells, and so does diabetes mellitus in endothelial cells extracted from murine ischemic limb muscles. In vitro experiments showed that forced expression of mir-503 inhibits endothelial cell proliferation and endothelial network formation. Because mir-503 represses cell cycle associated genes, we investigated whether mir-503 activation may impinge on postischemic reparative angiogenesis. In a diabetic mouse model of limb ischemia, local inhibition of mir-503 activity accelerated vascular healing and blood flow recovery. Importantly, mir-503 was found up-regulated in muscular biopsies and peripheral blood derived plasma of diabetic patients with critical limb ischemia. From a therapeutic perspective, manipulation of mir-503 may represent a novel molecular means to foster reparative angiogenesis in diabetic patients. In the diagnostic context, more studies are necessary to determine if mir-503 could be exploited as a biomarker of progressive vascular disease. Conclusions: Our data suggest mir-503 as a possible therapeutic target in diabetic patients with critical limb ischemia. 25 Intraarterial Administration of Bone Marrow Mononuclear Cells in Patients With Critical Limb Ischemia: A Randomized-Start, Placebo-Controlled Pilot Trial (PROVASA) Summary: Injection of autologous bone marrow derived mononuclear cells (BM-MNC) is a promising therapeutic option in patients with critical limb ischemia, but double-blind, randomized trials are lacking. The present study is the first randomized, placebo controlled trial showing that intraarterial BM-MNC administration accelerates wound healing and induces pain reduction until 3 months in patients with critical limb ischemia with stable ulcers but not in patients with extensive gangrene. Ulcer healing induced by repeated BM-MNC administration significantly correlated with limb salvage. Successful ulcer healing required repeated applications of functionally competent BM-MNC. These exploratory findings of this pilot trial need to be confirmed in a larger randomized trial in patients with critical limb ischemia and stable ulcers. Conclusions: Intraarterial administration of BM-MNC is safe and feasible and accelerates wound healing in patients without extensive gangrene and impending amputation. These exploratory findings of this pilot trial need to be confirmed in a larger randomized trial in patients with critical limb ischemia and stable ulcers. 26 Lipoprotein(a) Genetic Variants Associated With Coronary and Peripheral Vascular Disease but Not With Stroke Risk in the Heart Protection Study Summary: Recent genetic studies have demonstrated strong support for a causal role of plasma levels of lipoprotein(a) [Lp(a)] in coronary disease. The current findings from the Heart Protection Study, which are based on prevalent disease cases and 3000 incident events, increase our understanding of the relevance of Lp(a) for vascular disease risk. The Heart Protection Study demonstrates comparable strength of associations of an LPA genotype score, previously shown to explain more than half of the genetic variation in Lp(a) levels with coronary disease and peripheral vascular disease but not with stroke. These results indicate that Lp(a) may have effects on atherosclerotic and thrombotic diseases that are only relevant at specific sites. Furthermore, as indicated by the paradoxical results from prospective and randomized evidence for cholesterol and ischemic stroke risk, the lack of evidence of an association of LPA and stroke in the present study does not exclude the possibility that lowering Lp(a) could have beneficial effects on the risk of stroke or stroke subtypes. The results of large-scale randomized trials of agents that reduce plasma levels of Lp(a), such as niacin and cholesterylester transfer protein inhibitors, will help to assess the safety and efficacy of lowering Lp(a) levels on a broad range of vascular outcomes. Conclusions: The comparable strength of associations of the LPA score with coronary disease and peripheral vascular disease but not with stroke suggest that lipoprotein(a) may have effects on atherothrombotic vascular disease that are only relevant at specific sites. 27 Efficacy of Quantified Home-Based Exercise and Supervised Exercise in Patients With Intermittent Claudication: A Randomized Controlled Trial Summary: A primary therapeutic goal for patients with peripheral artery disease and intermittent claudication is to regain lost ambulatory function through exercise rehabilitation. Medically supervised exercise programs are efficacious for improving claudication onset time and peak walking time, but more patients could benefit from an exercise program transported to the community setting (ie, homebased walking). However, home exercise has been poorly studied. This prospective, randomized, controlled clinical trial compared changes in claudication onset time, peak walking time, and daily ambulatory activity in peripheral artery disease patients with intermittent claudication after home-based exercise, supervised exercise, and usual-care control. Both exercise programs consisted of intermittent walking to near-maximal claudication pain for 12 weeks. We used a step activity monitor to address the primary flaw of previous home exercise programs by objectively measuring ambulatory cadence during home exercise sessions. Patients in home-based exercise completed 83% of their exercise sessions, averaging 42 minutes per session at a cadence of 37 strides per minute, and they increased claudication onset time, peak walking time, and daily ambulatory cadences apart from the exercise sessions. The changes in claudication onset time and peak walking time after home-based exercise were similar to those after supervised exercise, whereas the change in daily ambulatory cadences was greater. The clinical implication is that a home-based exercise program consisting of ambulatory monitoring, biweekly 15-minute meetings with staff, and feedback motivated patients to adhere to the program and may serve as a new model for improving claudication measures in more patients with less effort and fewer resources than a traditional supervised exercise program. Conclusions: A home-based exercise program, quantified with a step activity monitor, has high adherence and is efficacious in improving claudication measures similar to a standard supervised exercise program. Furthermore, home-based exercise appears more efficacious in increasing daily ambulatory activity in the community setting than supervised exercise. 28