Prior studies have assessed the prognostic value of a decrease, not an increase, of the post-exercise ankle–brachial index (ABI) among patients with normal resting results. Thus, we sought to evaluate the prognostic significance of an increase in post-exercise ABI among these patients. From a single center vascular laboratory database between September 2005 and January 2010, we retrospectively identified 1437 consecutive patients with a normal resting ABI (1.00–1.40) and available post-exercise results. We classified them into group 1 (normal subjects; post-exercise ABI drop <= 20%, 58%) and group 2 (post-exercise ABI increase, 42%) after excluding those with an ABI drop > 20% (peripheral artery disease) as they had known disease (n=192). The primary outcome was to assess the risk of ischemic events, defined as a composite of unadjudicated death, stroke, or myocardial infraction (MACE). Associations between groups and outcomes were examined using multivariable Cox proportional hazard and propensity analyses. Both groups had similar prevalence of cardiovascular comorbidities. In unadjusted analysis, group 2 was more likely to have MACE (p = 0.001). After adjusting for all baseline characteristics, an increase in post-exercise ABI compared to normal subjects was associated with a higher MACE (adjusted HR: 1.70, 95% CI: 1.14–2.53; p=0.009). This association stayed statistically significant after propensity matching (adjusted HR: 1.80, 95% CI: 1.17–2.76; p=0.007). This hypothesis-generating analysis showed that an increase in post-exercise ABI appears to identify a population with a higher risk for MACE. A prospective study of this association and mechanisms of risk should be conducted.
Both open surgery and endovascular peripheral interventions have been shown to effectively improve outcomes in patients with peripheral arterial disease, but minimal data exist comparing outcomes performed at and below the knee. The purpose of this study was to compare outcomes following infrageniculate lower extremity open bypass (LEB) versus peripheral vascular intervention (PVI) in patients with critical limb ischemia. Using data from the 2008–2014 Vascular Quality Initiative, 1-year primary patency, major amputation, and mortality were compared among all patients undergoing LEB versus PVI at or below the knee for rest pain or tissue loss. Overall, 2566 patients were included (LEB=500, PVI=2066). One-year primary patency was significantly worse following LEB (73% vs 81%; p<0.001). One-year major amputation (14% vs 12%; p=0.18) and mortality (4% vs 6%; p=0.15) were similar regardless of revascularization approach. Multivariable analysis adjusting for baseline differences between groups confirmed inferior primary patency following LEB versus PVI (HR 0.74; 95% CI, 0.60–0.90; p=0.004), but no significant differences in 1-year major amputation (HR 1.06; 95% CI, 0.80–1.40; p=0.67) or mortality (HR 0.71; 95% CI, 0.44–1.14; p=0.16). Based on these data, we conclude that endovascular revascularization is a viable treatment approach for critical limb ischemia resulting from infrageniculate arterial occlusive disease.
Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis minimizes the risk of intracranial bleeding compared with systemic full-dose fibrinolytic therapy for pulmonary embolism (PE). However, major bleeding is nevertheless a potential complication. We analyzed the 150-patient SEATTLE II trial of submassive and massive PE patients to describe those who suffered major bleeding events following ultrasound-facilitated, catheter-directed, low-dose fibrinolysis and to identify risk factors for bleeding. Major bleeding was defined as GUSTO severe/life-threatening or moderate bleeds within 72 hours of initiation of the procedure. Of the 15 patients with major bleeding, four (26.6%) developed access site-related bleeding. Multiple venous access attempts were more frequent in the major bleeding group (27.6% vs 3.6%; p<0.001). All patients with major bleeding had femoral vein access for device delivery. Patients who developed major bleeding had a longer intensive care stay (6.8 days vs 4.7 days; p=0.004) and longer hospital stay (12.9 days vs 8.4 days; p=0.004). The frequency of inferior vena cava filter placement was 40% in patients with major bleeding compared with 13% in those without major bleeding (p=0.02). Massive PE (adjusted odds ratio 3.6; 95% confidence interval 1.01–12.9; p=0.049) and multiple venous access attempts (adjusted odds ratio 10.09; 95% confidence interval 1.98–51.46; p=0.005) were independently associated with an increased risk of major bleeding. In conclusion, strategies for improving venous access should be implemented to reduce the risk of major bleeding associated with ultrasound-facilitated, catheter-directed, low-dose fibrinolysis. ClinicalTrials.gov Identifier: NCT01513759; EKOS Corporation 10.13039/100006522
Some believe that certain patients with intermittent claudication (IC) may be unsuitable for supervised exercise therapy (SET), based on the presence of comorbidities and the possibly increased risks. We conducted a systematic review (MEDLINE, EMBASE and CENTRAL) to summarize evidence on the potential influence of diabetes mellitus (DM) on the response to SET. Randomized and nonrandomized studies that investigated the effect of DM on walking distance after SET in patients with IC were included. Considered outcome measures were maximal, pain-free and functional walking distance (MWD, PFWD and FWD). Three articles met the inclusion criteria (n = 845). In one study, MWD was 111 meters (128%) longer in the non-DM group compared to the DM group after 3 months of follow-up (p = 0.056). In a second study, the non-DM group demonstrated a significant increase in PFWD (114 meters, p <= 0.05) after 3 months of follow-up, whereas there was no statistically significant increase for the DM group (54 meters). On the contrary, the largest study of this review did not demonstrate any adverse effect of DM on MWD and FWD after SET. In conclusion, the data evaluating the effects of DM on SET were inadequate to determine if DM impairs the exercise response. While trends in the data do not suggest an impairment, they are not conclusive. Practitioners should consider this limitation when making clinical decisions.
Stroke is a leading cause of death among women in the United States, and women are more affected by stroke than men. With women living longer than men, women experience not only a higher incidence of stroke but also more negative outcomes. Despite its lethal impact and high morbidity rate, the road from innovative bench research to improved clinical outcomes has been slow. This review explores the differential physiology, epidemiology, and clinical presentation of stroke between men and women, as well as the current status of laboratory and clinical data.
At some institutions, lower extremity ultrasound (LEUS) is performed routinely to screen for deep venous thrombosis (DVT) prior to sequential compression device (SCD) application. We set out to evaluate whether screening for DVT with LEUS is warranted prior to SCD application in critically ill adults with contraindications to anticoagulation. A total of 257 critically ill adults, who underwent LEUS screening prior to SCD application, were identified retrospectively using vascular laboratory records. Outcomes and delay in SCD application associated with screening for DVT were determined. Asymptomatic DVT risk factors were assessed using multivariable regression. Asymptomatic DVT prevalence was 7%. Significant predictors of DVT included prior DVT (OR=47.4, 95% CI: 3.91–575.4), thrombophilia (OR=20.2, 95% CI: 3.2–126.8) and recent surgery (OR=4.1, 95% CI: 1.1–14.9). SCDs were applied on average 4.4 days (SD=7.0) after ordering LEUS. Fourteen LEUS were needed to detect one asymptomatic DVT. The mortality rate was not significantly different between patients with and without asymptomatic DVT. Screening for asymptomatic DVT with LEUS prior to SCD application in critically ill patients with contraindications to anticoagulation is associated with a delay in applying SCDs, and no proven benefits. Better assessment of DVT predictors in this population could identify patients who may benefit from screening.
Published reports indicate low retrieval rates for retrievable inferior vena cava (IVC) filters. We performed a historic-controlled study of a 5-year intervention (March 2007 to February 2012) to improve IVC filter retrieval at a university medical center serving a rural area. All adults with a retrievable filter placed were included, except those with a life expectancy <6 months. The intervention included initial verbal counseling and printed educational materials, correspondence after discharge, and a hematology consultation. The control group included patients with retrievable filters placed in the 15 months preceding study initiation. In the control group, 116 filters were placed and 27 (23%) were removed, compared to 378 filters placed and 169 (45%) removed during the intervention. Adjusting for patient characteristics, the odds ratio of retrieval during the intervention was 3.03 (95% CI 1.85–4.27) compared to the control period. An intervention including patient education and hematology follow-up appeared to significantly improve IVC filter retrieval rates.
We sought to determine if symptomatic cardiogenic limb emboli have a random distribution or if there are demographic or echocardiographic factors that predict site of embolization, limb salvage and mortality. Upper (UE) and lower extremity (LE) emboli were evaluated over a 16-year period (1996–2012). Demographic (age, gender, smoking, medical comorbidities) and echocardiographic data were analyzed to determine predictors of embolic site. All symptomatic patients underwent surgical revascularization. Limb salvage and mortality were compared with Kaplan–Meier analysis. A total of 161 patients with symptomatic cardiogenic emboli were identified: 56 UE and 105 LE. The female-to-male ratio for UE emboli (70%:30%) was significantly higher than for LE emboli (47%:53%, p=0.008). No other demographic factors were statistically different. Upper extremity patients were more likely to have atrial fibrillation (50% vs 29.8%, p=0.028), while LE patients had a higher percentage of aortic or mitral valvular disease or intracardiac thrombus (71.4% vs 52.5%, p=0.038). The 30-day limb salvage was higher for UE compared to LE (100% vs 88%, p=0.008). There was a trend toward higher 30-day mortality in the LE group (14% vs 5%, p=0.11). Survival at 1, 3, and 5 years were similar (UE: 62.2%, 44.2%, 35.3%; LE: 69.1%, 47.5%, 30.3%; p=ns). Upper extremity emboli are more frequent in women and patients with atrial fibrillation. Lower extremity emboli are more frequent in the presence of valvular disease or intracardiac thrombus, and are associated with increased 30-day limb loss and mortality. These findings suggest gender- and cardiac-specific differences in patterns of blood flow leading to preferential sites of peripheral embolization.
It is unclear whether thrombophilia causes resistance to anticoagulant therapy. Post hoc analyses of data from RE-COVER®, RE-COVER™ II, and RE-MEDY™ were performed to compare dabigatran etexilate with warfarin for the treatment and prevention of venous thromboembolism (VTE) in patients with thrombophilia or antiphospholipid antibody syndrome (APS). There were no significant differences in symptomatic VTE/VTE-related deaths between dabigatran etexilate and warfarin in patients with or without thrombophilia. All bleeding event categories were less frequent with dabigatran etexilate than with warfarin, regardless of whether patients had thrombophilia, no thrombophilia, or were not tested. However, these differences did not reach significance in every group. In patients with APS, there was no significant difference in VTE/VTE-related deaths between the two treatment arms. Rates of bleeding events tended to be lower with dabigatran etexilate than with warfarin, reaching statistical significance for any bleeding event. In conclusion, the efficacy and safety of dabigatran etexilate were not significantly affected by the presence of thrombophilia or APS. ClinicalTrials.gov RECOVER Identifier: NCT00291330; RECOVER II Identifier: NCT00680186; RE-MEDY Identifier: NCT00329238
The purpose of the current study was to investigate the association between bone mineral density (BMD) scores and the prevalence of peripheral artery disease (PAD) in a large cohort of subjects who underwent arterial Doppler assessments and calcaneal bone densitometry. The study was performed using data obtained from Life Line Screening Inc. Subjects were self-selected and paid for screening tests. The prevalence of PAD was significantly higher in men with osteopenia (4.5%) and osteoporosis (10.9%) compared to men with normal BMD (3.0%) (p<0.001). Osteopenia (odds ratio (OR) 1.3) and osteoporosis (OR 2.3) were found to be independent risk factors for the presence of PAD in men. The prevalence of PAD was significantly higher in women with osteopenia (4.8%) and osteoporosis (11.8%) compared to women with normal BMD (3.3%) (p<0.001). Osteopenia (OR 1.15) and osteoporosis (OR 1.8) were found to be independent risk factors for the presence of PAD in women. The current study reports a strong association of abnormal BMD analysis with the prevalence of PAD, which persists even when controlling for age and associated atherosclerotic risk factors. Although the mechanism by which these two disease processes is related is not completely elucidated, the presence of osteoporosis should make clinicians aware of the possibility of occult PAD or associated atherosclerotic disease in appropriate patients.
Prospective studies supporting a relationship between elevated lipoprotein-associated phospholipase A2 (Lp-PLA2) and incident peripheral arterial disease (PAD) are limited. We evaluated the association of Lp-PLA2 with incident PAD in a multi-ethnic cohort without clinical cardiovascular disease. A total of 4622 participants with measurement of Lp-PLA2 mass and Lp-PLA2 activity and an ankle–brachial index (ABI) between 0.9 and 1.4 were followed for the development of PAD (median follow-up = 9.3 years), defined as an ABI <=0.9 and decline from baseline >=0.15. There were 158 incident PAD events during follow-up. In adjusted logistic regression models, each higher standard deviation of both Lp-PLA2 activity and mass did not confer an increased risk of developing PAD [odds ratios, (95% confidence intervals)]: 0.92 (0.66–1.27) for Lp-PLA2 activity and 1.06 (0.85–1.34) for mass. Additionally, no significant interaction was found according to ethnicity: p=0.43 for Lp-PLA2 activity and p=0.55 for Lp-PLA2 mass. We found no evidence of an association between Lp-PLA2 and incident PAD.
Fibromuscular dysplasia (FMD) is a vascular disorder about which little has been known until recently. Patients with FMD may suffer from hypertension, aneurysms, or strokes, as well as symptoms associated with local artery damage. As a result of advances in vascular medicine and growing outcomes registries, we now have a better understanding of the FMD disease process and epidemiology. Nevertheless, the consequences of FMD on patients’ day-to-day experiences and mental health status are not well understood. The purpose of this study was to begin to identify and characterize the experiences of living with FMD from the perspective of the patient using qualitative inquiry. Interviews with 19 FMD patients (18 female, 1 male) were conducted, audio-recorded, transcribed verbatim, and content analyzed. Individuals with FMD reported a complex array of psychological, physical, emotional, social, and health care concerns, which may be underdiagnosed. Findings suggest new opportunities for enhancing patient care.
Long-term right ventricular (RV) function, functional capacity, exercise capacity, and quality of life following pulmonary embolism (PE), and the impact of thrombolysis, are unclear. A systematic review of studies that evaluated these outcomes with >= 3-month mean follow-up after PE diagnosis was performed. For each outcome, random effects meta-analyses were performed. Twenty-six studies (3671 patients) with 18-month median follow-up were included. The pooled prevalence of RV dysfunction was 18.1%. Patients treated with thrombolysis had a lower, but not statistically significant, risk of RV dysfunction versus those treated with anticoagulation (odds ratio: 0.51, 95% CI: 0.24 to 1.13, p=0.10). Pooled prevalence of at least mild functional impairment (NYHA II–IV) was 33.2%, and at least moderate functional impairment (NYHA III–IV) was 11.3%. Patients treated with thrombolysis had a lower, but not statistically significant, risk of at least moderate functional impairment versus those treated with anticoagulation (odds ratio: 0.48, 95% CI: 0.15 to 1.49, p=0.20). Pooled 6-minute walk distance was 415 m (95% CI: 372 to 458 m), SF-36 Physical Component Score was 44.8 (95% CI: 43 to 46), and Pulmonary Embolism Quality of Life (QoL) Questionnaire total score was 9.1. Main limitations included heterogeneity among studies for many outcomes, variation in the completeness of data reported, and inclusion of data from non-randomized, non-controlled, and retrospective studies. Persistent RV dysfunction, impaired functional status, diminished exercise capacity, and reduced QoL are common in PE survivors. The effect of thrombolysis on RV function and functional status remains unclear.
Higher body mass index (BMI) is associated with greater cardiovascular disease (CVD) risk, in part due to aortic stiffening assessed by carotid-femoral pulse wave velocity (cfPWV). Importantly, greater cardiorespiratory fitness (CRF; VO2peak) decreases CVD risk, and is associated with reductions in aortic stiffness. We tested the hypothesis that young adult overweight (OW, n=17) compared with healthy-weight (HW, n=17) men will have greater resting aortic stiffness, reduced CRF and an impaired post-exercise hemodynamic response. Resting cfPWV was greater in OW versus HW individuals (5.81 ± 0.13 vs 4.81 ± 0.12 m/sec, p<0.05). Relative CRF (VO2peak; mL/kg/min) was lower in OW compared with HW individuals (49.4 ± 1.3 vs 57.6 ± 1.0 mL/kg/min, p<0.05), and was inversely related with cfPWV (p<0.05). However, CRF as absolute VO2peak (L/min) was not different between groups and there was no relation between cfPWV and absolute VO2peak (L/min), indicating reduced relative CRF in OW men is due to greater body mass. Following the maximal treadmill exercise test, cfPWV was greater in OW compared with HW subjects from rest to 60 minutes post-exercise (p<0.05). Compared with HW, OW individuals had higher systolic blood pressure (main effect, p<0.05) and diastolic blood pressure was selectively increased for up to 60 minutes following exercise (p<0.05). Overweight individuals had an attenuated post-exercise decrease in mean arterial pressure (p<0.05). Collectively, these results indicate that young, apparently healthy, OW men have greater resting aortic stiffening and an impaired post-exercise hemodynamic response.
Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease.
Although poor walking is the most common symptom of peripheral artery disease (PAD), reported results are inconsistent when comparing gait parameters between PAD patients and healthy controls. This inconsistency may be due to frailty, which is highly prevalent among PAD patients. To address this hypothesis, 41 participants, 17 PAD (74±8 years) and 24 aged-matched controls (76±7 years), were recruited. Gait was objectively assessed using validated wearable sensors. Analysis of covariate (ANCOVA) tests were used to compare gait parameters between PAD and non-PAD groups, considering age, gender, and body mass index as covariates, while stratified based on frailty status. According to the Fried frailty index, 47% of PAD and 50% of control participants were non-frail and the rest were classified as pre-frail. Within non-frail participants, gait speed, body sway during walking, stride length, gait cycle time, double-support, knee range of motion, speed variability, mid-swing speed, and gait initiation were significantly different between PAD and control groups (effect size d = 0.75±0.43). In the pre-frail group, however, most of the gait differences were diminished except for gait initiation and gait variability. Results suggest that gait initiation is the most sensitive parameter for detecting gait impairment in PAD participants when compared to controls, regardless of frailty status (d = 1.30–1.41; p<0.050). The observed interaction effect between frailty and PAD on gait parameters confirms the importance of assessing functionality in addition to age to provide more consistency in detecting motor performance impairments due to PAD.
A diet high in trans-fatty acids (TFAs) is associated with a higher risk of cardiovascular disease (CVD) than a diet high in saturated fatty acids (SFAs), but the mechanisms remain unclear. We hypothesized that a beverage high in TFAs would cause a larger reduction in postprandial endothelial function and an increase in arterial stiffness, in part from greater reductions in insulin sensitivity, compared with a beverage high in SFAs. Eleven healthy adults (aged 47±5 years) ingested a warm test beverage (520 kcal, 56 g total fat, 5 g carbohydrate, 1 g protein) high in either TFAs or SFAs in a randomized cross-over study. Ingestion of the beverage high in TFAs (p<0.01) but not high in SFAs (p=0.49) decreased endothelial function (brachial artery flow-mediated dilation, mm) at 3–4 hours (p<0.01 for time; p=0.034 for interaction), but did not alter aortic stiffness or carotid β-stiffness. The homeostasis model of insulin resistance (interaction p=0.062) tended to decrease after SFAs but not TFAs. A beverage high in TFAs but not SFAs results in a postprandial reduction in endothelial function and a trend for decreased insulin sensitivity, potentially explaining the higher risk of CVD with a diet high in TFAs.
Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS.
Ultrasound screening for abdominal aortic aneurysm (AAA) is recommended for male smokers >65 years of age, but screening rates remain low. If computed tomography (CT) performed for other indications could be considered adequate for screening, one-third of ultrasounds would potentially be unnecessary, and overall screening rates would be substantially higher. The objective of this study was to evaluate the sensitivity of CT imaging of the abdomen for the detection of AAA when performed for other clinical indications. We performed a retrospective study of patients eligible for AAA screening who had undergone an abdominal ultrasound as well as an abdominal CT scan for other indications within 3 years prior to that study. The primary outcome was identification of an AAA, recorded in the findings narrative or impression of the CT scan report. Of 142 patients with both a CT scan and an AAA on ultrasound, 127 (89.4%) were noted to have an AAA in the report of a CT scan performed within the 3 years prior to the ultrasound. An additional 10 films demonstrated an AAA that was not mentioned in the report. The sensitivity of pre-existing CT scans for AAA screening was 97.2% (137/141) [95% CI: 93.4–99.0%]; 123 (86.6%) of these positive findings were reported in the findings narrative and 120 (84.5%) were reported in the radiologist’s final impression. The sensitivity for AAA identification in the report of a pre-existing CT scan of the abdomen performed for alternate indications appears high enough to use as a screening test. When radiologists note an AAA, they should be sure to include it in the final impression.
Patients with abdominal aortic aneurysms (AAA) are more prone to develop popliteal artery aneurysms (PAA), but the prevalence is not well known. Our aim was to investigate the prevalence of PAA in patients with AAA, and to determine whether a certain risk factor profile is more commonly found in patients with concurrent aneurysms. All AAA patients (ICD code I71.3, I71.4) attending the outpatient clinic at the Karolinska University Hospital between 2011 and 2013 were included in the study cohort (n=465); 48% (225) had been subjected to an ultrasound or computed tomography scan of their popliteal arteries. In these patients, three definitions of PAA were considered (>= 10.5, >= 12, >= 15 mm), although the overall analysis is based on PAA >= 12 mm. The mean age was 70.7 years (SD 7.5), 89% were men, and the mean AAA diameter was 47 mm (SD 14). The prevalence of PAA was 19% (n=43) by definition >= 12 mm, and 11% (n=25) with 15 mm. Claudication was more frequently found in AAA patients with PAA than patients without PAA. Sensitivity between clinical examination and radiology was 26%, and the specificity for clinical examination was 90%. In conclusion, owing to the high prevalence of PAA in AAA patients, described by us and others, the low cost and risks associated with ultrasound and the poor sensitivity at clinical examination, all women and men with AAA should undergo one radiological examination of their popliteal arteries.
Traditional methods of intraoperative human saphenous vein preparation for use as bypass grafts can be deleterious to the conduit. The purpose of this study was to characterize acute graft preparation injury, and to mitigate this harm via an improved preparation technique. Porcine saphenous veins were surgically harvested (unprepared controls, UnP) and prepared using traditional (TraP) and improved preparations (ImP). The TraP used unregulated radial distension, marking with a surgical skin marker and preservation in heparinized normal saline. ImP used pressure-regulated distension, brilliant blue FCF-based pen marking and preservation in heparinized Plasma-Lyte A. Rings from each preparation were suspended in a muscle bath for characterization of physiologic responses to vasoactive agents and viscoelasticity. Cellular viability was assessed using the methyl thiazolyl tetrazolium (MTT) assay and the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay for apoptosis. Contractile responses to potassium chloride (110 mM) and phenylephrine (10 µM), and endothelial-dependent and -independent vasodilatory responses to carbachol (0.5 µM) and sodium nitroprusside (1 µM), respectively, were decreased in TraP tissues compared to both UnP and ImP tissues (p <= 0.05). TraP tissues demonstrated diminished viscoelasticity relative to UnP and ImP tissues (p <= 0.05), and reduced cellular viability relative to UnP control (p <= 0.01) by the MTT assay. On the TUNEL assay, TraP tissues demonstrated a greater degree of apoptosis relative to UnP and ImP tissues (p <= 0.01). In conclusion, an improved preparation technique prevents vascular graft smooth muscle and endothelial injury observed in tissues prepared using a traditional approach.
The aim of this study was to investigate the effect of cigarette smoking on peripheral and central blood pressure (BP) in a group of young stage I hypertensives. A total of 344 untreated subjects from the HARVEST study were examined (mean age 37±10 years). Patients were divided into three groups based on smoking status: non-smokers, light smokers (<=5 cigarettes/day) and moderate-to-heavy smokers (>5 cigarettes/day); and into three groups by age: 18–29, 30–39 and >=40 years. Central BP measurements and augmentation index (AIx) were calculated from brachial pressure waveform, with applanation tonometry, by means of the Specaway DAT System plus a Millar tonometer. The central waveform was derived from peripheral BP using the same software system of the SphygmoCor System pulse wave analysis. In addition, two indirect measurements of arterial stiffness were calculated: pulse pressure (PP) and systolic BP amplification. Central systolic BP and PP were higher in smokers than in non-smokers (systolic BP: 121.9±13.1 mmHg in non-smokers, 127.2±16.5 mmHg in light smokers, 126.7±15.3 mmHg in those who smoked >5 cigarettes/day, p=0.009; PP: 37.7±9.8 mmHg, 41.5±13.1 mmHg, 41.9±10.5 mmHg, respectively, p=0.005). Lower systolic BP amplification (p<0.001) and PP amplification (p=0.001) were observed in smokers compared to non-smokers. In a two-way ANCOVA analysis, systolic BP amplification markedly declined across the three age groups (p=0.0002) and from non-smokers to smokers (p=0.0001), with a significant interaction between smoking and age group (p=0.05). The AIx was higher in smokers compared to non-smokers (p=0.024). In young hypertensives, smoking has a detrimental effect on central BP, accelerating the age-related decline in BP amplification.
Patients with inferior vena cava (IVC) filter-associated deep venous thrombosis (DVT) are a challenging subset of patients for endovascular intervention. Given the lack of available data pertaining to this clinical scenario, the purpose of this study was to evaluate the authors’ experience with the use of endovascular treatment for DVT in patients with IVC filters. Primary aims included assessing the technical and clinical success, complications, and clinical patency in these patients. This was a retrospective single-center review of adult patients with IVC filters undergoing endovascular treatment of DVT between 1/2005 and 4/2014. Patient electronic medical records were reviewed for demographic data, anticoagulation status, symptoms, symptomatic extremities, extent of thrombosis, therapies received, technical and clinical success, and complications. Query yielded 82 patients (mean 53 years, range 18–96; 66% male), all of whom were included in our analysis. The majority of patients presented with lower extremity pain and swelling, with extensive clot burden despite the use of anticoagulant medication. Treatment elements utilized included pharmacologic lysis in 92%, mechanical thrombectomy in 77%, angioplasty in 63% and stent placement in 50% of patients. Interventions were technically successful in restoring flow in 87% of patients, and clinically successful in improving presenting symptoms in 79% of patients. By SIR criteria, 24% of patients experienced complications (categorized as 10% minor and 14% major). There were two deaths from intracranial hemorrhage. The probability of thrombosis-free survival at 1, 3, 6, 9 and 12 months was 0.85 (CI 0.74–0.93), 0.81 (CI 0.69–0.89), 0.74 (CI 0.62–0.83), 0.70 (CI 0.57–0.8) and 0.70 (CI 0.57–0.8), respectively. Endovascular interventions are usually effective in relieving symptoms in patients with DVT and pre-existing IVC filters. However, these outcomes are achieved with significant complication rates that may exceed those observed when endovascular therapy is provided for other DVT populations.
The feasibility of magnetic resonance venography (MRV) for measuring change in thrombus volume with a novel anticoagulation regimen versus standard anticoagulation in patients with symptomatic deep vein thrombosis (DVT) has not been assessed. Our aim was to study the feasibility of MRV to measure change in thrombus volume in patients with acute symptomatic objectively confirmed proximal DVT in an open-label multicenter trial (edoxaban Thrombus Reduction Imaging Study, eTRIS). We randomized patients in a 2:1 allocation ratio to edoxaban 90 mg/day for 10 days followed by 60 mg/day versus parenteral anticoagulation bridging to warfarin for 3 months. The primary efficacy outcome was a surrogate end point of the relative change in MRV-quantified thrombus volume from baseline to Day 14–21. A total of 85 eligible patients from 26 study sites were randomized to edoxaban monotherapy (n=56) versus parenteral anticoagulation as a ‘bridge’ to warfarin (n=29). The mean relative change in MRV-quantified thrombus volume from baseline to Day 14–21 was similar in patients treated with edoxaban and parenteral anticoagulation as a ‘bridge’ to warfarin (–50.1% vs –58.9%; 95% confidence interval of treatment difference, –12.7%, 30.2%). However, thrombus extension was observed in eight patients in the edoxaban monotherapy group and in none in the warfarin group. Rates of recurrent venous thromboembolism (3.6% vs 3.6%, p=0.45) and clinically relevant non-major bleeding (5.4% vs 7.1%, p=0.34) were also similar. No major bleeds occurred in either on-treatment group during the study period. In conclusion, MRV can assess change in thrombus volume in patients with acute DVT randomized to two different anticoagulant regimens. ClinicalTrials.gov Identifier: NCT01662908
Investigational New Drug (IND) Application: Edoxaban IND # 63266
The aim of this study was to determine if galectin-3 levels were different between participants with peripheral artery disease (PAD) and controls, and to describe its relationship with markers of early atherosclerosis. Sixty participants were recruited into two groups: a PAD group (n=31), ankle–brachial index (ABI) <=0.90 and a normal ABI group (n=29), ABI 1.0–1.4. PAD participants were older (68.6 vs 61.8 years, p=0.037), more commonly men (68% vs 38%, p=0.02), and with more cardiovascular risk factors (p<0.001). Galectin-3 was 22% higher in PAD participants (mean±SD: 17.6±4.7 vs 14.4±4.1 ng/mL, p<0.01). The odds ratio for galectin-3 in PAD to be 1 ng/mL higher than the participants with normal ABI was 1.19, after adjusting by age and gender (p=0.014). High-sensitivity C-reactive protein (hs-CRP) and homeostatic model assessment (HOMA) were positively associated with galectin-3 in the age- and gender-adjusted model, while arterial elasticity and microalbuminuria were not. In conclusion, galectin-3 levels were higher in participants with PAD.
We sought to evaluate whether case ascertainment using administrative health data would be a feasible way to identify peripheral artery disease (PAD) patients from the community. Subjects’ ankle–brachial index (ABI) scores from two previous prospective observational studies were linked with International Classification of Diseases (ICD) and Canadian Classification of Interventions (CCI) codes from three administrative databases from April 2002 to March 2012, including the Alberta Inpatient Hospital Database (ICD-10-CA/CCI), Ambulatory Care Database (ICD-10-CA/CCI), and the Practitioner Payments Database (ICD-9-CM). We calculated diagnostic statistics for putative case definitions of PAD consisting of individual code or sets of codes, using an ABI score <= 0.90 as the gold standard. Multivariate logistic regression was performed to investigate additional predictive factors for PAD. Different combinations of diagnostic codes and predictive factors were explored to find out the best algorithms for identifying a PAD study cohort. A total of 1459 patients were included in our analysis. The average age was 63.5 years, 66% were male, and the prevalence of PAD was 8.1%. The highest sensitivity of 34.7% was obtained using the algorithm of at least one ICD diagnostic or procedure code, with specificity 91.9%, positive predictive value (PPV) 27.5% and negative predictive value (NPV) 94.1%. The algorithm achieving the highest PPV of 65% was age >= 70 years and at least one code within 443.9 (ICD-9-CM), I73.9, I79.2 (ICD-10-CA/CCI), or all procedure codes, validated with ABI < 1.0 (sensitivity 5.56%, specificity 99.4% and NPV 84.6%). In conclusion, ascertaining PAD using administrative data scores was insensitive compared with the ABI, limiting the use of administrative data in the community setting.
This study was undertaken to determine the impact of shared decision-making when selecting a sedation option, from no sedation (local anesthetic), minimal sedation (anxiolysis with a benzodiazepine) or moderate sedation (benzodiazepine and opiate), for venous access device placement (port-a-cath and tunneled catheters) on patient choice, satisfaction and recovery time. This is an IRB-approved, HIPPA-compliant, retrospective study of 198 patients (18–85 years old, 60% female) presenting to an ambulatory vascular interventional radiology department for venous access device placement between 22 October 2014 and 7 October 2015. Patients were educated about sedation options and given the choice of undergoing the procedure with no sedation (local anesthetic only), or minimal or moderate sedation. Satisfaction was assessed through three survey questions. No sedation was selected by 53/198 (27%), minimal sedation by 71/198 (36%) and moderate sedation by 74/198 (37%). All subjects would recommend the option to another patient and valued the opportunity to select a sedation option. Post-procedure recovery time differences were statistically significant (p<0.0001) with median recovery times of 0 minutes for no sedation, 38 minutes for minimal sedation and 64 minutes for moderate sedation. In conclusion, patient sedation preference for venous access device placement is variable, signifying there is a role for shared decision-making as it empowers the patient to select the option most aligned with his or her goals. The procedure is well-tolerated, associated with high satisfaction, and the impact on departmental flow is notable because patients choosing no or minimal sedation results in a decreased post-procedure recovery time burden.
Patients with lower extremity peripheral artery disease (PAD) have a substantially increased risk for mortality as compared to healthy individuals. We aimed to evaluate the risk for all-cause mortality in PAD patients and in healthy controls during a 10-year follow-up period. Our hypothesis was that the mortality rates at 10 years would differ in diabetic and non-diabetic PAD patients. Our study group consisted of 331 consecutive patients with symptomatic PAD <75 years of age admitted to a tertiary care hospital, including 216 patients without diabetes and 115 with diabetes. Control subjects without atherosclerotic disease were matched to the patients in a 1:1 design by sex, age, and diabetes mellitus status. The outcome measure was all-cause mortality at 10 years. Mortality rates at 10 years were 29% in non-diabetic PAD patients versus 14% in age- and sex-matched non-diabetic controls (risk ratio (RR), 2.31; 95% confidence interval (CI), 1.54–3.47; p<0.001), and 58% in diabetic PAD patients versus 19% in age- and sex-matched diabetic controls (RR, 4.06; 95% CI, 2.67–6.18; p<0.001). Further, PAD patients with diabetes had a significantly increased risk for death within 10 years than did the non-diabetic PAD patients (RR, 2.51; 95% CI, 1.72–3.66; p<0.001). Diabetes was independently associated with outcome, and was the strongest predictor of death in multivariate Cox proportional hazards regression. We conclude that mortality rates at 10 years differ in PAD patients <75 years old with and without diabetes. Our findings suggest that future studies should apply distinct risk assessment strategies in the two PAD subgroups.
The object of this study was to utilize a novel feed-forward active contour (FFAC) algorithm to find a reproducible technique for analysis of brachial artery reactivity. Flow-mediated dilation (FMD) is an important marker of vascular endothelial function but has not been adopted for widespread clinical use given its technical limitations, including inter-observer variability and differences in technique across clinical sites. We developed a novel FFAC algorithm with the goal of validating a more reliable standard. Forty-six healthy volunteers underwent FMD measurement according to the standard technique. Ultrasound videos lasting 5–10 seconds each were obtained pre-cuff inflation and at minutes 1 through 5 post-cuff deflation in longitudinal and transverse views. Automated segmentation using the FFAC algorithm with initial boundary definition from three different observers was used to analyze the images to measure diameter/cross-sectional area over the cardiac cycle. The %FMD was calculated for average, minimum, and maximum diameters/areas. Using the FFAC algorithm, the population-specific coefficient of variation (CV) at end-diastole was 3.24% for transverse compared to 9.96% for longitudinal measurements; the subject-specific CV was 15.03% compared to 57.41%, respectively. For longitudinal measurements made via the conventional method, the population-specific CV was 4.77% and subject-specific CV was 117.79%. The intraclass correlation coefficient (ICC) for transverse measurements was 0.97 (95% CI: 0.95–0.98) compared to 0.90 (95% CI: 0.84–0.94) for longitudinal measurements with FFAC and 0.72 (95% CI: 0.51–0.84) for conventional measurements. In conclusion, transverse views using the novel FFAC method provide less inter-observer variability than traditional longitudinal views. Improved reproducibility may allow adoption of FMD testing in a clinical setting. The FFAC algorithm is a robust technique that should be evaluated further for its ability to replace the more limited conventional technique for measurement of FMD.
Current intra-arterial catheter-directed thrombolysis (CDT) protocols recommend treatment with small doses of a thrombolytic agent, which excludes patients in need of urgent revascularization. We evaluated the effects of accelerated thrombolysis utilizing increased recombinant tissue plasminogen activator (rt-PA) doses. Forty-one patients with acute, thrombotic limb ischemia (ALI) were treated using accelerated CDT. The treatment consisted of an initial dose of 10 mg rt-PA for 30 minutes followed by a 3-hour course of a continuous intra-arterial 10 mg/hour rt-PA infusion. Simultaneously, intravenous unfractionated heparin (500 IU/hour) was administered. No deaths occurred. Satisfactory lysis was achieved in 37 of the 41 patients (90.2%). All significant underlying lesions were corrected (89.2%). Complications developed in nine patients (22%); the most frequent complication (four patients, 9.8%) was puncture site hematoma. The reintervention rate was 2.6% and 15.4% at the 1 and 6-month follow-ups, respectively. The major amputation rate was 10.3% and 12.8% at the 1 and 6-month follow-ups, respectively. Outflow compromise was adversely related to successful outcome at the 6-month follow-up (p=0.01). In conclusion, this study confirms the effectiveness and safety of the accelerated CDT regimen for treatment of thrombotic ALI at a single center, but requires confirmation in further studies.
The purpose of this study is to characterize the plaque morphology of severe stenoses in the superficial femoral artery (SFA) employing combined near-infrared spectroscopy and intravascular ultrasound (NIRS-IVUS). Atherosclerosis is the most common cause of symptomatic peripheral arterial disease. Plaque composition of SFA stenoses has been characterized as primarily fibrous or fibrocalcific by non-invasive and autopsy studies. NIRS has been validated to detect lipid-core plaque (LCP) in the coronary circulation. We imaged severe SFA stenoses with NIRS-IVUS prior to revascularization in 31 patients (46 stenoses) with Rutherford claudication >= class 3. Angiographic parameters included lesion location and stenosis severity. IVUS parameters included plaque burden and presence of calcium. NIRS images were analyzed for LCP and maximum lipid-core burden index in a 4-mm length of artery (maxLCBI4mm). By angiography, 38 (82.6%) lesions were calcified and 9 (19.6%) were chronic total occlusions. Baseline stenosis severity and lesion length were 86.0 ± 11.0% and 36.5 ± 46.5 mm, respectively. NIRS-IVUS identified calcium in 45 (97.8%) lesions and LCP in 17 (37.0%) lesions. MaxLCBI4mm was 433 ± 244. All lesions with LCP also contained calcium; there were no non-calcified lesions with LCP. In conclusion, this is the first study of combined NIRS-IVUS in patients with PAD. NIRS-IVUS demonstrates that nearly all patients with symptomatic severe SFA disease have fibrocalcific plaque, and one-third of such lesions contain LCP. These findings contrast with those in patients with acute coronary syndromes, and may have implications regarding the pathophysiology of atherosclerosis in different vascular beds.
Although an association between serum ferritin and atherosclerosis has been suggested, limited epidemiologic data are available regarding the association between ferritin and arterial stiffness in healthy adults. A total of 2932 healthy subjects were enrolled in this study. Anthropometric and biochemical profiles including ferritin were measured. The arterial stiffness was measured using brachial–ankle pulse wave velocity (baPWV). Serum ferritin levels were classified into quartiles and baPWV values gradually increased with each ferritin quartile. Multiple regression analysis showed that ferritin levels were independently correlated with baPWV. After adjusting for multiple risk factors, as compared with the lowest quartile, the odds ratios for high baPWV (>75th percentile) were 1.15 (0.84–1.56), 1.37 (0.97–1.73), and 1.46 (1.29–2.17) among men (p for trend < 0.05) and 1.24 (0.87–1.79), 1.53 (1.09–2.16), and 1.80 (1.25–2.82) among women (p for trend < 0.05), for the second, third, and fourth quartiles of ferritin, respectively. In conclusion, serum ferritin levels are independently associated with arterial stiffness in healthy Korean adults.
We report recruitment strategies for an NIH-funded trial focused on African Americans with peripheral artery disease (PAD). We present complete recruitment efforts for this 1-year trial, 5-year study. Eligibility included the following: African American, a resting ankle–brachial index (ABI) <= 0.99, a short physical performance battery (SPPB) score of 10 or lower, English speaking, telephone access, and absence of coronary ischemia during a submaximal treadmill test. Recruitment included mailings of brochures to zip codes in which more than 50% of residents were African American, advertisements, community events, and physician/clinic referrals. We telephone-screened 3511 persons, of whom 792 did not recall the method by which they learned about the study. We randomized 174 participants. Mailings yielded the highest percentage of randomized participants (n=60, 34.4%), followed by television advertisements (n=42, 24.1%), followed by community events (n=24, 13.8%). In conclusion, to recruit African Americans with PAD for a clinical trial, investigators should consider mailings of brochures, television advertisements, and community events. ClinicalTrials.gov Identifier: NCT01321086
Arterial stiffness is associated with cardiovascular events and mortality. Lifestyle factors such as physical activity (PA) may reduce arterial stiffness. The purpose of this study is to determine the impact of change in PA on 1-year change in arterial stiffness in 274 overweight/obese sedentary young adults. The Slow Adverse Vascular Effects of excess weight (SAVE) trial was a study evaluating the relationships between weight loss, dietary sodium, and vascular health. PA was measured with the ActiGraph AM7164 accelerometer. Intensity of activity was determined using established cut-points. Arterial stiffness was assessed by brachial–ankle pulse wave velocity (baPWV) using an automated device. Analysis of covariance compared changes in total accelerometer counts, minutes/day in light-intensity PA (LPA), moderate-to-vigorous PA (MVPA), and sedentary time, by categories of change in baPWV. Models were adjusted for time since baseline visit, age, sex, race, homeostatis model of assessment of insulin resistance, mean arterial pressure, heart rate, and weight change. Total accelerometer counts and time spent in MVPA increased from baseline to 12 months while time spent in LPA significantly decreased. Mean baPWV was similar at each time point. Those who showed decreased baPWV also showed an increase in total accelerometer counts per day and time spent in MVPA in the fully adjusted models (p<0.001). Changes in sedentary time and time spent in LPA were not associated with changes in baPWV. These results indicate that even modest increases in MVPA can reduce arterial stiffness, a risk factor for future cardiovascular events.
Tirasemtiv (CK-2017357), a novel small-molecule activator of the fast skeletal muscle troponin complex, slows the rate of calcium release from troponin, thus sensitizing fast skeletal muscle fibers to calcium. In preclinical studies, tirasemtiv increased muscle force and delayed the onset and reduced the extent of muscle fatigue during hypoxia in vitro and muscle ischemia in situ. This study evaluated the effect of single doses of tirasemtiv on measures of skeletal muscle function and fatigability in patients with stable calf claudication due to peripheral artery disease (PAD). Sixty-one patients with an ankle–brachial index ≤0.90 in the leg with claudication received single double-blind doses of tirasemtiv 375 mg and 750 mg and matching placebo in random order about 1 week apart. After 33 patients were treated, the 750 mg dose was decreased to 500 mg due to adverse events and these dose groups were combined for analysis. On each study day, bilateral heel-raise testing was performed before and at 3 and 6 hours after dosing; a 6-minute walk test was performed at 4 hours after dosing. Claudicating calf muscle performance was increased at the highest dose and plasma concentration of tirasemtiv; however, the 6-minute walk distance decreased with both the dose and plasma concentration of tirasemtiv, possibly due to dose-related adverse events, particularly dizziness, that could impede walking ability. In conclusion, the mechanism of fast skeletal muscle troponin activation improved muscle function but not 6-minute walking distance in patients with claudication due to PAD. ClinicalTrials.gov Identifier: NCT01131013
Peripheral artery disease (PAD) is a highly prevalent condition that frequently goes undetected and untreated. Socioeconomic factors associated with unrecognized PAD are not known. The ankle–brachial index (ABI) was calculated in 1656 study participants undergoing non-emergent coronary angiography with PAD defined as an ABI <0.9. Subjects were followed for mortality and cardiovascular outcomes. Compared to those without PAD, those with unrecognized PAD at enrollment were older, had higher rates of cardiovascular comorbidities, and had higher major adverse cardiovascular events (MACE) (p<0.03 for all). Among those enrolling without a reported history of PAD, there was a higher prevalence of PAD with decreasing income (p=0.004), education level (p<0.001), social isolation (p=0.027) and depression (p=0.034); 50% of these individuals reported symptoms suggestive of claudication. In conclusion, the prevalence of unrecognized PAD is high amongst a cohort of high-risk individuals referred for coronary angiography. A profile of lower socioeconomic status is associated with unrecognized PAD. These subjects will report symptoms suggestive of claudication and impaired walking ability when directly queried.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. The breakdown of ADMA is mainly governed by the activity of dimethylarginine dimethylaminohydrolases (DDAHs). We investigated if genetic variation in the DDAH1 and DDAH2 genes were related to ADMA and
In 1016 70-year-old participants of the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study (50% women), we measured endothelium-dependent vasodilation (EDV) using the invasive forearm technique with acetylcholine given in the brachial artery and the brachial artery ultrasound technique with measurement of flow-mediated dilatation (FMD). Plasma
Several of the genotypes in the DDAH1 gene were highly significantly related to ADMA levels (p = 10–7 at best), but not to the
A close relationship was seen between SNPs in the DDAH1, but not DDAH2, gene and ADMA levels. However, variation in those genes was not related to measures of EDV in this elderly population.
Among patients with coronary artery disease (CAD), those with peripheral artery disease (PAD) have a greater vulnerability to cardiovascular (CV) events than those with CAD alone. In a prospective cohort study of patients with CAD, we evaluated potential mechanisms that might explain the adverse CV outcomes associated with PAD. We performed a prospective cohort study of 1018 patients with stable CAD who were recruited from 2000 to 2002. Incident symptomatic PAD events were adjudicated during a follow-up period of 7.2 ± 2.6 years. We used Cox proportional hazards models to evaluate the association between incident symptomatic PAD events and subsequent risk of CV events or death. Models were adjusted for demographics, traditional risk factors, inflammation, insulin resistance and health behaviors. Among the 1018 patients, 50 patients who did not report a history of PAD at baseline suffered incident symptomatic PAD events during the follow-up period. Those patients had a higher risk of subsequent CV events and death compared to those who did not develop PAD. After adjustment for traditional risk factors, symptomatic PAD events remained associated with a 70% increased risk of subsequent CV events (adjusted HR 1.7; 95% CI 1.0, 2.9; p = 0.04) and an 80% increased risk of death (adjusted HR 1.8; 95% CI 1.2, 2.7; p = 0.006). Inflammatory biomarkers were the strongest risk factor contributing to the excess risk. In a contemporary cohort of patients with CAD, incident symptomatic PAD events were associated with an increased risk for subsequent CV events. The increased vulnerability to CV events was partially explained by shared CV risk factors and inflammation.