Ellen V. Rouwet

Hypoxia Induces Aortic Hypertrophic Growth, Left Ventricular Dysfunction, and Sympathetic Hyperinnervation of Peripheral Arteries in the Chick Embryo

Background—Low birth weight is associated with an increased incidence of cardiovascular diseases, including hypertension, later in life. This suggests that antenatal insults program for fetal adaptations of the circulatory system. In the present study, we evaluated the effects of mild hypoxia on cardiac function, blood pressure control, and arterial structure and function in near-term chick embryos. Methods and Results—Chick embryos were incubated under normoxic (21% O2) or hypoxic (15% O2) conditions and evaluated at incubation day 19 by use of histological techniques, isolated heart preparations, and in vivo measurements of sympathetic arterial tone and systemic hemodynamics. Chronic hypoxia caused a 33% increase in mortality and an 11% reduction in body weight in surviving embryos. The lumen of the ascending aorta in hypoxic embryos was 23% smaller. Left ventricular systolic pressure was 22% lower, and heart weight/body weight ratio was 14% higher. In resistance arteries of hypoxic embryos, in vivo baseline tone was 23% higher, norepinephrine sensitivity was similar, and norepinephrine release from sympathetic nerves increased 2-fold, indicating sympathetic hyperinnervation. Mean arterial pressure and heart rate were similar under resting conditions, but chronically hypoxic embryos failed to maintain blood pressure during acute stress. Conclusions—This study indicates that mild hypoxia during embryonic development induces alterations in cardiac and vascular function and structure and affects hemodynamic regulation. These findings reveal that antenatal insults have profound effects on the control and design of the circulatory system that are already established at birth and may program for hypertension and heart failure at a later age.

Hypoxia induces dilated cardiomyopathy in the chick embryo: mechanism; intervention; and long-term consequences.

Background Intrauterine growth restriction is associated with an increased future risk for developing cardiovascular diseases. Hypoxia in utero is a common clinical cause of fetal growth restriction. We have previously shown that chronic hypoxia alters cardiovascular development in chick embryos. The aim of this study was to further characterize cardiac disease in hypoxic chick embryos. Methods Chick embryos were exposed to hypoxia and cardiac structure was examined by histological methods one day prior to hatching (E20) and at adulthood. Cardiac function was assessed in vivo by echocardiography and ex vivo by contractility measurements in isolated heart muscle bundles and isolated cardiomyocytes. Chick embryos were exposed to vascular endothelial growth factor (VEGF) and its scavenger soluble VEGF receptor-1 (sFlt-1) to investigate the potential role of this hypoxia-regulated cytokine. Principal Findings Growth restricted hypoxic chick embryos showed cardiomyopathy as evidenced by left ventricular (LV) dilatation, reduced ventricular wall mass and increased apoptosis. Hypoxic hearts displayed pump dysfunction with decreased LV ejection fractions, accompanied by signs of diastolic dysfunction. Cardiomyopathy caused by hypoxia persisted into adulthood. Hypoxic embryonic hearts showed increases in VEGF expression. Systemic administration of rhVEGF165 to normoxic chick embryos resulted in LV dilatation and a dose-dependent loss of LV wall mass. Lowering VEGF levels in hypoxic embryonic chick hearts by systemic administration of sFlt-1 yielded an almost complete normalization of the phenotype. Conclusions/Significance Our data show that hypoxia causes a decreased cardiac performance and cardiomyopathy in chick embryos, involving a significant VEGF-mediated component. This cardiomyopathy persists into adulthood.

The walking impairment questionnaire: An effective tool to assess the effect of treatment in patients with intermittent claudication

OBJECTIVE Assessment of walking distance by treadmill testing is the most commonly used method to evaluate the effect of treatment in patients with peripheral arterial disease. However, treadmill testing is time consuming, relatively expensive, and does not adequately reflect real life functional ability. We hypothesized that the Walking Impairment Questionnaire (WIQ) could be an alternative tool to assess objective improvement in functional walking ability of patients with intermittent claudication. METHODS This was a validation study. It was conducted through the outpatient clinic for vascular surgery. Patients with intermittent claudication were referred for supervised exercise therapy. Treadmill testing (absolute claudication distance [ACD]), WIQ, and quality of life questionnaires (RAND-36 and EuroQol) were administered at study onset and after 3 months of supervised exercise therapy. Responsiveness was determined by mean changes in and correlation coefficients of WIQ, ACD, and quality of life questionnaires. Patients were categorized into quartiles based on the increase in ACD, which were subsequently related to change in WIQ and quality of life. RESULTS The mean pre- and post-treatment total WIQ scores of 91 patients were 0.45 (0.22) and 0.58 (0.22), respectively. The correlation coefficient between the change in total WIQ score and ACD was 0.331 (P = .004). A 0.1 change in total WIQ score corresponded to a change of 345 meters in ACD. Analysis of the four quartiles compared to an increase in ACD showed that a greater increase in ACD corresponded with a greater increase in WIQ score, from 0.06 to 0.25 (P = .011). CONCLUSION These data indicate that the WIQ is a valid tool to detect improvement or deterioration in the daily walking ability of patients with intermittent claudication. Hence, the WIQ can be used as an alternative to treadmill testing for objective assessment of functional walking ability, both in daily practice and in clinical trials.

Endovascular Revascularization and Supervised Exercise for Peripheral Artery Disease and Intermittent Claudication: A Randomized Clinical Trial

IMPORTANCE Supervised exercise is recommended as a first-line treatment for intermittent claudication. Combination therapy of endovascular revascularization plus supervised exercise may be more promising but few data comparing the 2 therapies are available. OBJECTIVE To assess the effectiveness of endovascular revascularization plus supervised exercise for intermittent claudication compared with supervised exercise only. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial of 212 patients allocated to either endovascular revascularization plus supervised exercise or supervised exercise only. Data were collected between May 17, 2010, and February 16, 2013, in the Netherlands at 10 sites. Patients were followed up for 12 months and the data were analyzed according to the intention-to-treat principle. INTERVENTIONS A combination of endovascular revascularization (selective stenting) plus supervised exercise (n = 106) or supervised exercise only (n = 106). MAIN OUTCOMES AND MEASURES The primary end point was the difference in maximum treadmill walking distance at 12 months between the groups. Secondary end points included treadmill pain-free walking distance, vascular quality of life (VascuQol) score (1 [worst outcome] to 7 [best outcome]), and 36-item Short-Form Health Survey (SF-36) domain scores for physical functioning, physical role functioning, bodily pain, and general health perceptions (0 [severe limitation] to 100 [no limitation]). RESULTS Endovascular revascularization plus supervised exercise (combination therapy) was associated with significantly greater improvement in maximum walking distance (from 264 m to 1501 m for an improvement of 1237 m) compared with the supervised exercise only group (from 285 m to 1240 m for improvement of 955 m) (mean difference between groups, 282 m; 99% CI, 60-505 m) and in pain-free walking distance (from 117 m to 1237 m for an improvement of 1120 m vs from 135 m to 847 m for improvement of 712 m, respectively) (mean difference, 408 m; 99% CI, 195-622 m). Similarly, the combination therapy group demonstrated significantly greater improvement in the disease-specific VascuQol score (1.34 [99% CI, 1.04-1.64] in the combination therapy group vs 0.73 [99% CI, 0.43-1.03] in the exercise group; mean difference, 0.62 [99% CI, 0.20-1.03]) and in the score for the SF-36 physical functioning (22.4 [99% CI, 16.3-28.5] vs 12.6 [99% CI, 6.3-18.9], respectively; mean difference, 9.8 [99% CI, 1.4-18.2]). No significant differences were found for the SF-36 domains of physical role functioning, bodily pain, and general health perceptions. CONCLUSIONS AND RELEVANCE Among patients with intermittent claudication after 1 year of follow-up, a combination therapy of endovascular revascularization followed by supervised exercise resulted in significantly greater improvement in walking distances and health-related quality-of-life scores compared with supervised exercise only. TRIAL REGISTRATION Netherlands Trial Registry Identifier: NTR2249.

Magnetic Resonance Imaging in Peripheral Arterial Disease Reproducibility of the Assessment of Morphological and Functional Vascular Status

Objectives:The aim of the current study was to test the reproducibility of different quantitative magnetic resonance imaging (MRI) methods to assess the morphologic and functional peripheral vascular status and vascular adaptations over time in patients with peripheral arterial disease (PAD). Materials and methods:Ten patients with proven PAD (intermittent claudication) and arterial collateral formation within the upper leg and 10 healthy volunteers were included. All subjects underwent 2 identical MR examinations of the lower extremities on a clinical 1.5-T MR system, with a time interval of at least 3 days. The MR protocol consisted of 3D contrast-enhanced MR angiography to quantify the number of arteries and artery diameters of the upper leg, 2D cine MR phase contrast angiography flow measurements in the popliteal artery, dynamic contrast-enhanced (DCE) perfusion imaging to determine the influx constant and area under the curve, and dynamic blood oxygen level-dependent (BOLD) imaging in calf muscle to measure maximal relative T2* changes and time-to-peak. Data were analyzed by 2 independent MRI readers. Interscan and inter-reader reproducibility were determined as outcome measures and expressed as the coefficient of variation (CV). Results:Quantification of the number of arteries, artery diameter, and blood flow proved highly reproducible in patients (CV = 2.6%, 4.5%, and 15.8% at interscan level and 9.0%, 8.2%, and 7.0% at interreader level, respectively). Reproducibility of DCE and BOLD MRI was poor in patients with a CV up to 50.9%. Conclusions:Quantification of the morphologic vascular status by contrast-enhanced MR angiography, as well as phase contrast angiography MRI to assess macrovascular blood flow proved highly reproducible in both PAD patients and healthy volunteers and might therefore be helpful in studying the development of collateral arteries in PAD patients and in unraveling the mechanisms underlying this process. Functional assessment of the microvascular status using DCE and BOLD, MRI did not prove reproducible at 1.5 T and is therefore currently not suitable for (clinical) application in PAD.

Contrast-enhanced ultrasound versus computed tomographic angiography for surveillance of endovascular abdominal aortic aneurysm repair.

PURPOSE To compare diagnostic accuracy between contrast-enhanced ultrasound (US) and computed tomographic (CT) angiography to detect changes in abdominal aortic aneurysm (AAA) size and endoleaks during follow-up after endovascular aneurysm repair (EVAR). MATERIALS AND METHODS Between May 2006 and December 2008, 83 patients were consecutively enrolled for contrast-enhanced US and CT angiography imaging during surveillance after EVAR, yielding 127 paired examinations. Comparative analysis was performed for the anteroposterior and transverse maximal diameters of the aneurysm sac and for the presence or absence of endoleak, as determined by US and CT angiography. RESULTS Contrast-enhanced US demonstrated significantly more endoleaks, predominantly of type II, compared with CT angiography (53% vs 22% of cases). The number of observed agreements was 77 of 127 (61%), indicating a low level of agreement (kappa value of 0.237). US was as accurate as CT angiography in the assessment of maximal aneurysm sac diameters, as shown by Bland-Altman analyses and low coefficients of variation (8.0% and 8.6%, respectively). The interobserver variability for AAA size measurement by US was low, given the interclass correlation coefficients of 0.99 and 0.98 for anteroposterior and transverse maximal diameters, respectively. CONCLUSIONS Contrast-enhanced US may be an alternative to CT angiography in the follow-up of patients after EVAR. As US reduces exposure to the biologic hazards associated with lifelong annual CT angiography, including cumulative radiation dose and nephrotoxic contrast agent load, contrast-enhanced US might be considered as a substitute for CT angiography in the surveillance of patients after EVAR.

Vitamin D Deficiency may be an Independent Risk Factor for Arterial Disease

OBJECTIVES The aim of this study was to assess the vitamin D status in patients with occlusive or aneurysmatic arterial disease in relation to clinical cardiovascular risk profiles and markers of atherosclerotic disease. METHODS We included 490 patients with symptomatic peripheral arterial disease (PAD, n = 254) or aortic aneurysm (n = 236). Cardiovascular risk factors and comorbidities carotid intima-media thickness (CIMT), ankle-brachial index (ABI), serum high-sensitive C-reactive protein (hs-CRP) and vitamin D were assessed. Patients were categorised into severely (≤25 nmol l(-1)) or moderately (26-50 nmol l(-1)) vitamin D deficient, vitamin D insufficient (51-75 nmol l(-1)) or vitamin D sufficient (>75 nmol l(-1)). RESULTS Overall, 45% of patients suffered from moderate or severe vitamin D deficiency. The prevalence of vitamin D deficiency was similar in patients with PAD and those with an aortic aneurysm. Low levels of vitamin D were associated with congestive heart failure and cerebrovascular disease. Adjusting for clinical cardiovascular risk factors, multivariable regression analyses showed that low vitamin D status was associated with higher CIMT (P = 0.001), lower ABI (P < 0.001) and higher hs-CRP (P = 0.022). CONCLUSIONS The current study shows a strong association between low vitamin D status and arterial disease, independent of traditional cardiovascular risk factors and irrespective of the type of vascular disease, that is, occlusive or aneurysmatic disease.

In Treatment of Popliteal Artery Cystic Adventitial Disease, Primary Bypass Graft not Always First Choice: Two Case Reports and a Review of the Literature

Cystic adventitial disease (CAD) is a rare cause of unilateral intermittent claudication of unknown aetiology, which is characterized by the formation of multiple mucin-filled cysts in the adventitial layer of the arterial wall resulting in obstruction to blood flow. The disease predominantly presents in young otherwise healthy males and most commonly affects the popliteal artery. CAD can be diagnosed by magnetic resonance imaging, computed tomographic angiography, or duplex ultrasound. Surgery is the primary mode of treatment, including exarterectomy, or replacement of the affected vascular segment by venous or synthetic interposition graft. Alternatively, the cysts can be drained by percutaneous ultrasound-guided needle aspiration. We provide a literature update on the aetiology and treatment of this uncommon condition and present two cases supporting patient tailored treatment without primary bypass grafting.

Ankle brachial index measurement in primary care: are we doing it right?

BACKGROUND The reference standard for diagnosing peripheral arterial disease in primary care is the ankle brachial index (ABI). Various methods to measure ankle and brachial blood pressures and to calculate the index are described. AIM To compare the ABI measurements performed in primary care with those performed in the vascular laboratory. Furthermore, an inventory was made of methods used to determine the ABI in primary care. DESIGN OF STUDY Cross-sectional study. SETTING Primary care practice and outpatient clinic. METHOD Consecutive patients suspected of peripheral arterial disease based on ABI assessment in primary care practices were included. The ABI measurements were repeated in the vascular laboratory. Referring GPs were interviewed about method of measurement and calculation of the index. From each patient the leg with the lower ABI was used for analysis. RESULTS Ninety-nine patients of 45 primary care practices with a mean ABI of 0.80 (standard deviation [SD] = 0.27) were included. The mean ABI as measured in the vascular laboratory was 0.82 (SD = 0.26). A Bland-Altman plot demonstrated great variability between ABI measurements in primary care practice and the vascular laboratory. Both method of blood pressure measurements and method of calculating the ABI differed greatly between primary care practices. CONCLUSION This study demonstrates that the ABI is often not correctly determined in primary care practice. This phenomenon seems to be due to inaccurate methods for both blood pressure measurements and calculation of the index. A guideline for determining the ABI with a hand-held Doppler, and a training programme seem necessary.

Clinical outcome and morphologic analysis after endovascular aneurysm repair using the Excluder endograft

OBJECTIVE Long-term follow-up after endovascular aneurysm repair (EVAR) is very scarce, and doubt remains regarding the durability of these procedures. We designed a retrospective cohort study to assess long-term clinical outcome and morphologic changes in patients with abdominal aortic aneurysms (AAAs) treated by EVAR using the Excluder endoprosthesis (W. L. Gore and Associates, Flagstaff, Ariz). METHODS From 2000 to 2007, 179 patients underwent EVAR in a tertiary institution. Clinical data were retrieved from a prospective database. All patients treated with the Excluder endoprosthesis were included. Computed tomography angiography (CTA) scans were retrospectively analyzed preoperatively, at 30 days, and at the last follow-up using dedicated tridimensional reconstruction software. For patients with complications, all remaining CTAs were also analyzed. The primary end point was clinical success. Secondary end points were freedom from reintervention, sac growth, types I and III endoleak, migration, conversion to open repair, and AAA-related death or rupture. Neck dilatation, renal function, and overall survival were also analyzed. RESULTS Included were 144 patients (88.2% men; mean age, 71.6 years). Aneurysms were ruptured in 4.9%. American Society of Anesthesiologists classification was III/IV in 61.8%. No patients were lost during a median follow-up of 5.0 years (interquartile range, 3.1-6.4; maximum, 11.2 years). Two patients died of medical complications ≤ 30 days after EVAR. The estimated primary clinical success rates at 5 and 10 years were 63.5% and 41.1%, and secondary clinical success rates were 78.3% and 58.3%, respectively. Sac growth was observed in 37 of 142 patients (26.1%). Cox regression showed type I endoleak during follow-up (hazard ratio, 3.74; P = .008), original design model (hazard ratio, 3.85; P = .001), and preoperative neck diameter (1.27 per mm increase, P = .006) were determinants of sac growth. Secondary interventions were required in 32 patients (22.5%). The estimated 10-year rate of AAA-related death or rupture was 2.1%. Overall life expectancy after AAA repair was 6.8 years. CONCLUSIONS EVAR using the Excluder endoprosthesis provides a safe and lasting treatment for AAA, despite the need for maintained surveillance and secondary interventions. At up to 11 years, the risk of AAA-related death or postimplantation rupture is remarkably low. The incidences of postimplantation sac growth and secondary intervention were greatly reduced after the introduction of the low-permeability design in 2004.