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Introduction: Fibromuscular dysplasia (FMD) is a non-inflammatory vasculopathy associated with arterial stenosis, aneurysm, dissection, and tortuosity. We investigated racial differences in clinical manifestations and events of multifocal FMD. Methods: Demographics, medical history, presenting signs and symptoms, and major vascular events were queried from the US Registry for FMD and stratified into White or Black based on self-identified race. Results: Of the 1897 female patients (pts) with multifocal FMD and race reported from 14 sites as of 12/23/2020, there were 1697 (89.5 %) White, 123 (6.5 %) Black, 52 (2.7%) Hispanic, and 25 (1.3%) pts of other races. Given a small number of pts in other groups, analysis was only performed between White and Black pts. Age at diagnosis and at first sign/symptom was similar between the two groups. Black pts were more likely to have a history of hypertension (p=0.009), stroke (p=0.002), and subarachnoid hemorrhage (p Conclusion: We noted a low number of Black patients enrolled in the US Registry for FMD at FMD specialty centers. There were differences in clinical manifestations, events, and pattern of vascular involvement among Black and White patients enrolled in US Registry, the mechanisms for which require additional study.

Introduction: Pulmonary hypertension (PH) is a currently incurable disease with high morbidity and mortality. Treatment with extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) appeared to be effective and promising. Objective: We aimed at evaluating whether MSC-EVs could improve right ventricle (RV) and pulmonary artery (PA) functions in mice with PAH induced by monocrotaline (MCT). Methods: FVB mice (M/F – 6 weeks) received MCT injections 1x/week for 4 weeks (60mg/kg sc.) and were treated with MSCs-EVs 24 hours after each MCT injection (3x10 6 cells in 100μL PBS 1x, iv.). The experimental groups were: Control (vehicle-vehicle; n=9); MCT (MCT-vehicle; n=10); Control EVs (vehicle-EVs; n=8); MCT EVs (MCT-EVs; n=10); PA acceleration time (PAT), PA ejection time (PET) and tricuspid annular plane systolic excursion (TAPSE) were assessed by echocardiography 28 days after first MCT injection; Fulton index was used to calculate RV hypertrophy, and pulmonary vascular remodeling (WT/D) was assessed by histology. Results: PAT and PAT/PET were decreased by 22.6±5.7% and 15.6±4.9%, respectively, in MCT group compared to Control (p Conclusion: Treatment with MSC-EVs protects against the development of PH and improves PA and the RV function in MCT-treated mice.

Introduction: The pathogenesis of peripheral artery disease (PAD) and critical limb ischemia (CLI) are poorly understood. Hypothesis: We hypothesize that genetic factors related to abnormalities in coagulation or fibrinolysis, in addition to atherosclerosis, could play an important role in PAD patients and PAD with CLI patients. Methods: A genome-wide association study (GWAS) was performed testing for associations between single-nucleotide variants (SNVs) and PAD case-control (3,190 cases and 463,495 controls) and subgroup analysis of PAD with CLI case-control (142 cases and 3,048 controls) in the UK Biobank cohort. To further validate the results, we selected SNVs with the most significant Cochrane-Armitage trend p values without evidence of strong linkage disequilibrium (r2 > 0.8) for PAD with CLI case-control in the BioMe Biobank. We tested for association using BOLT-LMM with adjustment for age, sex, BMI, and the first ten principal components to control for population structure. The SNV association tests' significance level was set at P < 5x10–8 after Bonferroni correction. Results: 363 SNVs from 81 genetic loci reached the threshold for statistical significance based on a Bonferroni correction (p PLG and CDKN2B ) were independent for PAD with CLI. On pathway analyses, we identify several new loci that implicate thrombotic, inflammation, glycosaminoglycan synthesis, coagulation, and fibrinolytic pathways involved in PAD along with known atherosclerosis pathways (p Conclusions: We show that PLG gene related to coagulation pathways in PAD may play an important role in coagulation-related PAD pathogenesis.

Background: Observational studies suggest that symptomatic atherosclerosis may be associated with risk of venous thromboembolism (VTE). Prior randomized studies have demonstrated a significant reduction in recurrent VTE with aspirin monotherapy. Whether VTE risk is associated with more severe symptomatic atherosclerosis and more intensive antiplatelet therapy reduces VTE risk beyond aspirin monotherapy is unknown. Methods: TRA2P-TIMI 50 (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction) (vorapaxar) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54) (ticagrelor) were blinded, randomized placebo-controlled trials of antiplatelet therapy for the prevention of ischemic events in stable patients with symptomatic atherosclerosis. Two blinded vascular specialists systematically identified symptomatic venous thromboembolic events in both trials. Results: Of 47 611 patients with stable vascular disease followed for 3 years in both studies there were 343 VTE events in 301 patients (Kaplan-Meier rate at 3 years, 0.9% for placebo). The risk of VTE was independently associated with age, body mass index, polyvascular disease, chronic obstructive pulmonary disease, and malignancy. The burden of atherosclerosis manifested as an increasing number of symptomatic vascular territories was associated with a graded increase in the 3-year rates of VTE (0.76% for 1, 1.53% for 2, and 2.45% for 3 territories). More intensive antiplatelet therapy (vorapaxar and ticagrelor pooled) significantly reduced the risk of VTE by 29% compared with background antiplatelet therapy, from 0.93% to 0.64% at 3 years (hazard ratio, 0.71; 95% confidence interval, 0.56–0.89; P =0.003). Conclusions: The rate of VTE in patients with atherosclerosis is ≈0.3% per year while on treatment with ≥1 antiplatelet agent, with increased risk independently associated with the number of symptomatic vascular territories. More intensive antiplatelet therapy reduces the risk of VTE. These data suggest a relationship between atherosclerosis burden and VTE risk, and they support inclusion of VTE as a prospective end point in long-term secondary prevention trials evaluating the risks and benefits of antiplatelet therapies in patients with atherosclerosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01225562.

Background— Fibromuscular dysplasia (FMD), a noninflammatory disease of medium-size arteries, may lead to stenosis, occlusion, dissection, and/or aneurysm. There has been little progress in understanding the epidemiology, pathogenesis, and outcomes since its first description in 1938. Methods and Results— Clinical features, presenting symptoms, and vascular events are reviewed for the first 447 patients enrolled in a national FMD registry from 9 US sites. Vascular beds were imaged selectively based on clinical presentation and local practice. The majority of patients were female (91%) with a mean age at diagnosis of 51.9 (SD 13.4 years; range, 5–83 years). Hypertension, headache, and pulsatile tinnitus were the most common presenting symptoms of the disease. Self-reported family history of stroke (53.5%), aneurysm (23.5%), and sudden death (19.8%) were common, but FMD in first- or second-degree relatives was reported only in 7.3%. FMD was identified in the renal artery in 294 patients, extracranial carotid arteries in 251 patients, and vertebral arteries in 82 patients. A past or presenting history of vascular events were common: 19.2% of patients had a transient ischemic attack or stroke, 19.7% had experienced arterial dissection(s), and 17% of patients had an aneurysm(s). The most frequent indications for therapy were hypertension, aneurysm, and dissection. Conclusions— In this registry, FMD occurred primarily in middle-aged women, although it presents across the lifespan. Cerebrovascular FMD occurred as frequently as renal FMD. Although a significant proportion of FMD patients may present with a serious vascular event, many present with nonspecific symptoms and a subsequent delay in diagnosis.

Background— Lung inflammation precedes the development of hypoxia-induced pulmonary hypertension (HPH); however, its role in the pathogenesis of HPH is poorly understood. We sought to characterize the hypoxic inflammatory response and to elucidate its role in the development of HPH. We also aimed to investigate the mechanisms by which heme oxygenase-1, an anti-inflammatory enzyme, is protective in HPH. Methods and Results— We generated bitransgenic mice that overexpress human heme oxygenase-1 under doxycycline control in an inducible, lung-specific manner. Hypoxic exposure of mice in the absence of doxycycline resulted in early transient accumulation of monocytes/macrophages in the bronchoalveolar lavage. Alveolar macrophages acquired an alternatively activated phenotype (M2) in response to hypoxia, characterized by the expression of found in inflammatory zone-1, arginase-1, and chitinase-3-like-3. A brief 2-day pulse of doxycycline delayed, but did not prevent, the peak of hypoxic inflammation, and could not protect against HPH. In contrast, a 7-day doxycycline treatment sustained high heme oxygenase-1 levels during the entire period of hypoxic inflammation, inhibited macrophage accumulation and activation, induced macrophage interleukin-10 expression, and prevented the development of HPH. Supernatants from hypoxic M2 macrophages promoted the proliferation of pulmonary artery smooth muscle cells, whereas treatment with carbon monoxide, a heme oxygenase-1 enzymatic product, abrogated this effect. Conclusions— Early recruitment and alternative activation of macrophages in hypoxic lungs are critical for the later development of HPH. Heme oxygenase-1 may confer protection from HPH by effectively modifying the macrophage activation state in hypoxia.

It has been proposed that vascular screening programs should be widely established to provide earlier detection of peripheral artery disease, carotid artery disease, renal artery disease, and abdominal aortic aneurysms (AAAs) to diminish the societal burden of these illnesses. Early detection of these conditions could lead to treatments that offer the potential to reduce the incidence of fatal and nonfatal myocardial infarction (MI) and stroke, death due to AAA rupture, and renal failure, as well as to improve quality of life. These goals engender considerable enthusiasm. There are many reasons to propose a broad, populationbased approach to establishment of vascular screening programs. Each arterial disorder is asymptomatic for a prolonged length of time, during which detection might be effective, defining a proposed “detection gap”1; diagnostic tools are available that are accurate, safe, and relatively cost-effective; the database has improved overall such that these diagnostic methods could theoretically be applied selectively to targeted “at-risk” populations; and the publication of consensus-driven treatment guidelines now fosters use of effective treatments, while restraining the use of harmful or unproven treatments.2 Thus, it might be feasible to detect preclinical atherosclerosis and stenotic or aneurysmal disease in screening programs applied to specific at-risk populations with achievable benefits and minimal harm.

A pseudoaneurysm (PSA) is a contained rupture; there is a disruption in all 3 layers of the arterial wall (Figure 1). PSAs may occur under 4 circumstances: (1) after catheterization (Figure 2); (2) at the site of native artery and synthetic graft anastomosis (eg, aortofemoral bypass graft); (3) trauma; and (4) infection (eg, mycotic PSA) (Figure 3). This review will focus on PSAs that occur after cardiac and peripheral endovascular procedures. PSAs occur when an arterial puncture site does not adequately seal. Pulsatile blood tracks into the perivascular space and is contained by the perivascular structures, which then take on the appearance of a sac. Hematoma and the surrounding tissue form the wall of the PSA. Figure 1. Artist’s rendition of a postcatheterization PSA with proper placement of the needle for thrombin injection. There is a disruption in all 3 layers of the arterial wall. In essence, this represents a contained rupture. Figure 2. Arteriogram that demonstrates an axillary artery PSA after a diagnostic arteriographic procedure. Note the disruption in the vessel wall (white arrow) and the larger PSA sac (black arrow). Figure 3. Ultrasound of a spontaneous PSA in the left brachial artery. Note the absence of a tract. The PSA chamber is directly connected to the brachial artery. This type of PSA must be treated surgically. This patient had infective endocarditis. Postcatheterization PSA is one of the most common vascular complications of cardiac and peripheral angiographic procedures. The incidence of PSA after diagnostic catheterization ranges from 0.05% to 2%.1 When coronary or peripheral intervention is performed, the incidence increases to 2% to 6%. In 1 series where diagnostic ultrasound was performed on 536 consecutive patients who underwent catheterization, the incidence of PSA was 7.7%, with 83% of the PSAs associated with interventional procedures.2 Despite a low …

Fibromuscular dysplasia (FMD) is a nonatherosclerotic vascular disease leading to arterial stenosis, aneurysm and dissection, mainly in renal and carotid arteries. FMD has higher prevalence in females (80-90%) and is associated with hypertension and stroke. The pathophysiology of FMD is unclear and a genetic origin is suspected. We performed a genetic association study in European ancestry individuals. The discovery included 249 cases and 689 controls, in which we analyzed ∼26K common variants (MAF>0.05) using an exome-chip array. We followed up 13 loci (P The FMD risk variant is intronic to the phosphatase and actin regulator 1 gene (PHACTR1), involved in angiogenesis and cell migration. PHACTR1 is a risk locus for coronary artery disease, migraine, and cervical artery dissection, which may occur in FMD. We found a significant association between the risk allele and higher central pulse pressure (P=0.0009), increased intima media thickness (P=0.001) and wall cross-sectional area (P=0.003) of carotids assessed by echotracking in 3800 population-based individuals. The correlation of genotypes with the expression of PHACTR1 in primary cultured human fibroblasts showed higher expression in FMD risk allele carriers, compared to non carriers (N=57, P=0.02). Finally, Phactr1 knockdown of zebrafish showed significantly dilated vessels (P=0.003) indicating impaired vascular development. In conclusion, we report the first risk locus for FMD with the largest genetic association study conducted so far. Our data reveal a common genetic variant at PHACTR1 providing indices of shared pathophysiology between FMD and other cardiovascular and neurovascular diseases.

Background— Patients with peripheral artery disease (PAD) are at heightened risk of acute limb ischemia (ALI), a morbid event that may result in limb loss. We investigated the causes, sequelae, and predictors of ALI in a contemporary population with symptomatic PAD and whether protease-activated receptor 1 antagonism with vorapaxar reduced ALI overall and by type. Methods and Results— The Trial to Assess the Effects of Vorapaxar in Preventing Heart Attack and Stroke in Patients With Atherosclerosis–Thrombolysis in Myocardial Infarction 50 (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in stable patients, including 3787 with symptomatic PAD. ALI was a prespecified adjudicated end point using a formal definition. A total of 150 ALI events occurred in 108 patients during follow-up (placebo 3-year rate, 3.9%; 1.3% annualized). For patients with symptomatic PAD, previous peripheral revascularization, smoking, and the ankle-brachial index were predictive of ALI. The majority of ALI events occurred as a result of surgical graft thrombosis (56%), followed by native vessel in situ thrombosis (27%). Stent thrombosis and thromboembolism caused ALI in 13% and 5%, respectively. Amputation occurred in 17.6% presenting with ALI. Vorapaxar reduced first ALI events by 41% (hazard ratio, 0.58; 95% confidence interval, 0.39–0.86; P =0.006) and total ALI events by 41% (94 versus 56 events; risk ratio, 0.59; 95% confidence interval, 0.38–0.93; P =0.022). The efficacy of vorapaxar was consistent across types of ALI. Conclusions— In selected patients with symptomatic PAD and without atrial fibrillation, ALI occurs at a rate of 1.3%/y, is most frequently caused by acute bypass graft thrombosis or in situ thrombosis of a diseased vessel, and often results in limb loss. Vorapaxar reduces ALI in patients with symptomatic PAD with consistency across type, including PAD resulting from surgical graft thrombosis and in-situ thrombosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00526474.

Atherosclerotic renal artery stenosis is commonly present in patients with clinically manifest atherosclerosis in other vascular beds and is independently associated with increased cardiovascular morbidity and mortality. Screening tests such as renal angiography should be selectively applied to patients at high risk for renal artery stenosis who are potential candidates for revascularization. This multispecialty consensus document describes the rationale for patient selection for screening renal angiography at the time of cardiac catheterization.

Atherosclerosis is one of the most important and common causes of death and disability in the United States and throughout the world. More than 25 million persons in the United States have at least one clinical manifestation of atherosclerosis, and in many more, atherosclerosis remains an occult but important harbinger of significant cardiovascular events. Throughout the last half of the past century, coronary artery atherosclerosis has been a major focus for basic and clinical investigation. As a result, considerable strides have been made in the development of programs to prevent and treat the clinical manifestations of coronary artery disease. The development of lipid-lowering, antithrombotic, thrombolytic, and catheter-based therapies in particular has had considerable impact in reducing death and disability from coronary atherosclerosis. Yet atherosclerosis is a systemic disease with important sequelae in many other regional circulations, including those supplying the brain, kidneys, mesentery, and limbs. Persons with cerebral atherosclerosis are at increased risk for ischemic stroke. Those with renal artery atherosclerosis are at risk for severe and refractory hypertension as well as renal failure. Patients with atherosclerosis affecting the limb, ie, peripheral arterial disease (PAD), can develop disabling symptoms of claudication or critical limb ischemia and its associated threat to limb viability. Moreover, once disease is apparent in one vascular territory, there is increased risk for adverse events in other territories. For example, patients with PAD have a 4-fold greater risk of myocardial infarction and a 2- to 3-fold greater risk of stroke than patients without PAD.

There is a dearth of new information about fibromuscular dysplasia (FMD). Although the disease was first described in 1938 in a 5-year-old boy with malignant hypertension, it was nearly 25 years before the pathology and angiographic correlates were described in detail.1–6 From 1966 to the early 1980s there were multiple articles on the classification and treatment of patients with fibromuscular dysplasia.4–9 There is disparity and complexity among the 5 classification schemes, and thus no consensus as to the most accurate way to classify this disease exists.10,11 Article see p 3062 In the last 30 years there has been no new information regarding the cause and pathophysiology and little new information on the genetics and treatment of patients with FMD. The literature is inundated with single case reports and small case series, most adding little to the understanding of this uncommon disease. However, in the last 3 years there has been a resurgence of interest in FMD, leading to a better understanding of this condition.10,12,13 In 2012, the findings from the United States registry for Fibromuscular Dysplasia were reported on the first 447 patients entered into the registry.14 Additionally, a multidisciplinary State of the Science paper on FMD was commissioned by the American Heart Association, and those findings will be published in 2013. It is therefore timely that in this issue of Circulation , an experienced group of investigators in Paris published a provocative study that provides a plethora of important new information related to the classification and phenotypic expression of FMD.11 Because pathological specimens are rarely available as a result of technical advances in endovascular therapy, Savard and his associates11 investigated whether using a binary angiographic classification would accurately discriminate between 2 distinct …

Fibromuscular dysplasia (FMD) is nonatherosclerotic, noninflammatory vascular disease that may result in arterial stenosis, occlusion, aneurysm, or dissection.1–3 The cause of FMD and its prevalence in the general population are not known.4 FMD has been reported in virtually every arterial bed but most commonly affects the renal and extracranial carotid and vertebral arteries (in ≈65% of cases).5 The clinical manifestations of FMD are determined primarily by the vessels that are involved. When the renal artery is involved, the most frequent finding is hypertension, whereas carotid or vertebral artery FMD may lead to dizziness, pulsatile tinnitus, transient ischemic attack (TIA), or stroke. There is an average delay from the time of the first symptom or sign to diagnosis of FMD of 4 to 9 years.5,6 This is likely because of a multitude of factors: the perception that this is a rare disease and thus FMD is not considered in the differential diagnosis, the reality that FMD is poorly understood by many healthcare providers, and the fact that many of the signs and symptoms of FMD are nonspecific, thus leading the clinician down the wrong diagnostic pathway. A delay in diagnosis can lead to impaired quality of life and poor outcomes such as poorly controlled hypertension and its sequelae, TIA, stroke, dissection, or aneurysm rupture. It should also be noted that FMD may be discovered incidentally while imaging is performed for other reasons or when a bruit is heard in the neck or abdomen in an asymptomatic patient without the classic risk factors for atherosclerosis. The first description of FMD is attributed to Leadbetter and Burkland7 in a 5½-year-old boy with severe hypertension and a renal artery partially occluded by an intra-arterial mass of smooth muscle. He underwent a unilateral nephrectomy of an …

Background —This prospective study was designed to assess the safety and efficacy of using bovine thrombin injection to treat pseudoaneurysms. Methods and Results —From April 1998 through December 1999, 70 pseudoaneurysm were injected with bovine thrombin under the guidance of color duplex ultrasound. The most superficial pseudoaneurysm chamber was entered with a 1.5-inch, 19- to 22-gauge or spinal needle. Bovine thrombin, in a 1000 U/cc solution, was injected into the chamber. A total of 36 women and 34 men underwent ultrasound-guided thrombin injection (UGTI). Their mean age was 69.5 years. Most pseudoaneurysms were associated with diagnostic cardiac catheterization or percutaneous coronary intervention (80%). Two pseudoaneurysms arose from the brachial artery; the remainder were in the groin. Twenty-one patients were being treated with either heparin or warfarin, and the majority of the others were on antiplatelet therapy with aspirin or clopidogrel. UGTI was successful in 66 of the 70 patients (94%). The first patient in the series had 2 attempts at thrombin injection and refused further attempts. Two patients had undergone stent graft placement and had short, wide tracts. Both of these patients required surgical repair of their pseudoaneurysms. The fourth patient had a nearly complete pseudoaneurysm thrombosis and was lost to follow-up on discharge. No arterial thrombotic events occurred. One patient had a soleal vein thrombosis in the ipsilateral leg. Conclusions —UGTI was safe and effective in 94% of patients with postcatheterization pseudoaneurysms. Anticoagulant use did not hinder successful thrombosis. UGTI should be the initial treatment of choice for patients with postcatheterization pseudoaneurysms.

Background —Because the content of specific proteoglycans and apolipoproteins is increased in atherosclerotic plaques and in vitro studies have suggested a role for proteoglycans in mediating plaque apolipoprotein (apo) retention, immunohistochemistry was performed to systematically examine the relative locations of proteoglycans and apolipoproteins in human atherosclerosis. Methods and Results —The spatial relationships of versican, biglycan, and apoE were compared on 68 human coronary artery segments; apoA-I and apoB also were evaluated on an additional 20 segments. Nonatherosclerotic intima contained extensive deposits of versican, whereas deposits of apoE, apoB, and apoA-I were much less prevalent. In contrast, nearly all atherosclerotic segments contained substantial deposits of biglycan, apoE, apoA-I, and apoB. There was a high degree of colocalization of apoE and biglycan deposits. ApoA-I, the major apolipoprotein of HDL, and apoB also were detected in regions with apoE and biglycan deposition. Exceptions to the localization of biglycan with apolipoproteins were found in regions that lacked intact extracellular matrix because of necrosis or dense macrophage accumulation. In vitro studies demonstrated that biglycan binds apoE-containing but not apoE-free HDL and that biglycan also binds LDL. Conclusions —These results suggest that biglycan may bind apoE and apoB in atherosclerotic intima. They also raise the possibility that apoE may act as a “bridging” molecule that traps apoA-I–containing HDL in atherosclerotic intima. Taken together, these findings are consistent with the hypothesis that biglycan may contribute to the pathogenesis of atherosclerosis by trapping lipoproteins in the artery wall.

Background— Vorapaxar is a novel antagonist of protease-activated receptor-1, the primary receptor for thrombin on human platelets that is also present on vascular endothelium and smooth muscle. Patients with peripheral artery disease are at risk of systemic atherothrombotic events, as well as acute and chronic limb ischemia and the need for peripheral revascularization. Methods and Results— The Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Atherosclerosis (TRA2°P-TIMI 50) was a randomized, double-blind, placebo-controlled trial of vorapaxar in 26 449 patients with stable atherosclerotic vascular disease (myocardial infarction, stroke, or peripheral artery disease). Patients with qualifying peripheral artery disease (n=3787) had a history of claudication and an ankle-brachial index of P =0.53). However, rates of hospitalization for acute limb ischemia (2.3% versus 3.9%; hazard ratio, 0.58; 95% confidence interval, 0.39–0.86; P =0.006) and peripheral artery revascularization (18.4% versus 22.2%; hazard ratio, 0.84; 95% confidence interval, 0.73–0.97; P =0.017) were significantly lower in patients randomized to vorapaxar. Bleeding occurred more frequently with vorapaxar compared with placebo (7.4% versus 4.5%; hazard ratio, 1.62; 95% confidence interval, 1.21–2.18; P =0.001). Conclusions— Vorapaxar did not reduce the risk of cardiovascular death, myocardial infarction, or stroke in patients with peripheral artery disease; however, vorapaxar significantly reduced acute limb ischemia and peripheral revascularization. The beneficial effects of protease-activated receptor-1 antagonism on limb vascular events were accompanied by an increased risk of bleeding. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00526474.

Background— Hypoxia-inducible factor-1α (HIF-1α) is a transcriptional regulatory factor that orchestrates cellular responses to hypoxia. It increases collateral vessel growth and blood flow in models of hind-limb ischemia. This study tested whether intramuscular administration of Ad2/HIF-1α/VP16, an engineered recombinant type 2 adenovirus vector encoding constitutively active HIF-1α, improves walking time in patients with peripheral artery disease and intermittent claudication. Methods and Results— Two hundred eighty-nine patients with claudication were randomized in a double-blind manner to 1 of 3 doses of Ad2/HIF-1α/VP16 (2×10 9 , 2×10 10 , or 2×10 11 viral particles) or placebo, administered by 20 intramuscular injections to each leg. Graded treadmill tests were performed at baseline and then 3, 6, and 12 months after treatment. The primary end point was the change in peak walking time from baseline to 6 months. The secondary end point was change in claudication onset time, and tertiary end points included changes in ankle-brachial index and quality-of-life assessments. Median peak walking time increased by 0.82 minutes (interquartile range, −0.05–1.93 minutes) in the placebo group and by 0.82 minutes (interquartile range, −0.07–2.12 minutes), 0.28 minutes (interquartile range, −0.37–1.70 minutes), and 0.78 minutes (interquartile range, −0.02–2.10 minutes) in the HIF-1α 2×10 9 , 2×10 10 , and 2×10 11 viral particle groups, respectively ( P =NS between placebo and each HIF-1α treatment group). There were no significant differences in claudication onset time, ankle-brachial index, or quality-of-life measurements between the placebo and each HIF-1α group. Conclusions— Gene therapy with intramuscular administration of Ad2/HIF-1α/VP16 is not an effective treatment for patients with intermittent claudication. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00117650.

Schroecksnadel and collaborators seem a bit skeptical about our recent publication on β2 microglobulin (β2M)1 and about the laudatory editorial2 that accompanied it. Our article described the discovery that blood levels of β2M correlate with the severity of peripheral arterial disease (PAD) as assessed by the ankle-brachial index or treadmill testing. This novel finding arose from an agnostic high-throughput proteomic profiling effort using surface-enhanced laser desorption and ionization time-of-flight mass spectroscopy. This is a candidate-generating approach, in contrast to the more common candidate-based approach to proteomic profiling. The major advantage of the candidate-generating approach is that it provides for the discovery of new biomarkers for disease and potentially new insights into pathobiology. We hypothesized that repeated bouts of ischemia–reperfusion in the lower …

5Impaired renal function is an important emerging risk factor for atherosclerosis. Whether this is independent of other cardiovascular risk factors is not clearly known. We aimed to assess whether renal impairment was independently associated with the degree of coronary and peripheral atherosclerosis. Methods and Results One thousand and sixty seven subjects (mean ± standard deviation; age 66 ± 11 years, 63% male, 51% any history of smoking, 30% history of diabetes) undergoing elective coronary angiography for exertional chest pain and/or dyspnea were studied as part of the NHLBI funded Gene-PAD study. Angiograms were reviewed by an experienced angiographer, blinded to subject details. Significant CAD was defined as an epicardial stenosis of ≥70% in any vessel. PAD was defined as an ankle brachial index 2 and 16% if GFR was >60 mL/min/1.73 m 2 (p 2 . Reduced GFR was also predictive of a diagnosis of PAD [odds ratio (95%CI) =0.37 (0.17–0.83)}], independent of these other risk factors in logistic regression. Other predictors of PAD were increasing age, pack years smoking, fasting glucose and elevated triglycerides. Using ordinal regression, reduced GFR was an independent predictor of number of diseased coronary vessels (standardized coefficient −0.93, p =0.004). This was independent of age, gender, body mass index (BMI), lipids, blood pressure, pack years smoking and glucose. Other predictors in this model were age, male gender and lower high density lipoprotein cholesterol. Conclusion Reduced GFR is associated with PAD and extent of CAD in a high risk group of subjects, independent of other risk factors. The mechanism for this association is unknown but does not appear to be explained simply by an excess of risk factors. Estimating GFR may be of value evaluating patients at highest risk of PAD and multivessel CAD.

Background— Peripheral arterial disease (PAD) is common but commonly unrecognized. Improved recognition of PAD is needed. We used high-throughput proteomic profiling to find PAD-associated biomarkers. Methods and Results— Plasma was collected from PAD patients (ankle brachial index of Conclusions— In PAD patients, circulating B2M is elevated and correlates with the severity of disease independent of other risk factors. These findings might provide a needed biomarker for PAD and new insight into its pathophysiology. Further studies in other populations are needed to confirm the utility of measuring B2M in cardiovascular disease risk assessment.

Background— Critical limb ischemia, a manifestation of severe peripheral atherosclerosis and compromised lower-extremity blood flow, results in a high rate of limb loss. We hypothesized that adenoviral delivery of a constitutively active form of the transcription factor hypoxia-inducible factor-1α (ie, Ad2/HIF-1α/VP16 or HIF-1α) into the lower extremity of patients with critical limb ischemia would be safe and might result in a durable clinical response. Methods and Results— This phase I dose-escalation program included 2 studies: a randomized, double-blind, placebo-controlled study and an open-label extension study. In total, 34 no-option patients with critical limb ischemia received HIF-1α at doses of 1×10 8 to 2×10 11 viral particles. No serious adverse events were attributable to study treatment. Five deaths occurred: 3 in HIF-1α and 2 in placebo patients. In the first (randomized) study, 7 of 21 HIF-1α patients met treatment failure criteria and had major amputations. Three of the 7 placebo patients rolled over to receive HIF-1α in the extension study. No amputations occurred in the 2 highest-dose groups of Ad2/HIF-1α/VP16 (1×10 11 and 2×10 11 viral particles). The most common adverse events included peripheral edema, disease progression, and peripheral ischemia. At 1 year, limb status observations in HIF-1α patients included complete rest pain resolution in 14 of 32 patients and complete ulcer healing in 5 of 18 patients. Conclusions— HIF-1α therapy in patients with critical limb ischemia was well tolerated, supporting further, larger, randomized efficacy trials.

The goals of the imaging writing group were to define the role of imaging and to recommend important programmatic research and advocacy initiatives in atherosclerotic peripheral vascular disease for the American Heart Association. It should be noted that this is not a practice guideline initiative; therefore, the writing group purposely avoided recommending imaging modalities for specific circulatory beds. This report discusses the following imaging modalities: duplex ultrasound, MRI and MR angiography (MRA), CT imaging and angiography (CTA), and digital intra-arterial angiography. The requirements for proficiency in all of these modalities include physician oversight, quality assurance programs, and standardization for acquisition of images, interpretation of the study, postprocessing procedures, workstations, and reporting. The roles of imaging for each modality such as screening for subclinical disease, diagnosis, and treatment planning as an adjunct to invasive therapies (interventional MR and CT) and follow-up and monitoring are reviewed.