Noninvasive evaluation of endothelial activity in healthy and diseased individuals.

BACKGROUND: Diminished endothelial activity (EA) has been associated with an increased risk of incident cardiovascular disease (CAD) events. METHODS: Vasodilatory responses (EA and relative distensibility [RD]) were evaluated noninvasively using iontophoresis of acetylcholine (ACH) and sodium nitroprusside (SNP) and recorded by laser Doppler fluxmetry (LDF) and photoplethysmography (PPG) among 324 patients. RESULTS: The EA after ACH iontophoresis measured by LDF was significantly higher in the younger (<50 years) group than in the older (>50 years) group, 125.4 versus 103.3 integrated arbitrary unit (P < .005). Compared to the older patients, the EA values recorded by LDF were significantly lower in patients with diabetes mellitus (64.9), hypercholesterolemia (83.3), hypertension (88.7), CAD (61.0), and peripheral artery disease (67.4). The findings of RD were similar. CONCLUSIONS: The results indicate that measuring EA using the iontophoresis of ACH or SNP and combined with either LDF or PPG is a viable approach that can discriminate between different clinical groups.

Nonvisible insufficient subcutaneous reticular venous plexus can be observed through the skin using a new illumination method.

BACKGROUND: Insufficient subcutaneous reticular venous plexus (ISRVP) is an overlooked disease because the human eye cannot see many of the insufficient veins. OBJECTIVE: To present a total reticular vision (TRV) method that exposes nonvisible ISRVP to normal vision. METHOD & MATERIALS: TRV used visual-spectrum white and red light of 700 nm and infrared light of 15 to 850 nm from an ultradigital viewer camera. We studied 124 asymptomatic subjects from the general population without visible ISRVP. Another six patients with ISRVP without other venous pathology were compared with six healthy controls, Very low pressure was applied to the proximal thigh, and minimal volume increments on the medial malleolus were photoplethysmographically registered to validate subcutaneous venous reflux. RESULTS: Total reticular vision exposed ISRVP on the lower extremities in 72 of 124 subjects (58%), with observed damaged veins corresponding to more than 90% of nonvisible and 5% of visible portions of ISRVP. Subcutaneous reflux was registered only in patients with ISRVP. CONCLUSION: Total reticular vision exposed more than 90% of nonvisible ISRVP, a new pathology, allowing for the study of its relationship with other superficial venous insufficiencies. The authors have indicated no significant interest with commercial supporters.

Progression of peripheral arterial disease predicts cardiovascular disease morbidity and mortality.

OBJECTIVES: The purpose of this study was to examine the association of progressive versus stable peripheral arterial disease (PAD) with the risk of future cardiovascular disease (CVD) events. BACKGROUND: An independent association between PAD, defined by low values of the ankle-brachial index (ABI), and future CVD risk has been demonstrated. However, the prognostic significance of declining versus stable ABI has not been studied. METHODS: We recruited 508 subjects (59 women, 449 men) from 2 hospital vascular laboratories in San Diego, California. ABI and CVD risk factors were measured at Visit 2 (1990 to 1994). ABI values from each subject's earliest vascular laboratory examination (Visit 1) were abstracted from medical records. Mortality and morbidity were tracked for 6 years after Visit 2 using vital statistics and hospitalization data. RESULTS: In multivariate models adjusted for CVD risk factors, very low (<0.70) and, in some cases, low (0.70 < or = ABI <0.90) Visit 2 ABIs were associated with significantly elevated all-cause mortality, CVD mortality, and combined CVD morbidity/mortality at 3 and 6 years. Decreases in ABI of more than 0.15 between Visit 1 and Visit 2 were significantly associated with an increased risk of all-cause mortality (risk ratio [RR]: 2.4) and CVD mortality (RR: 2.8) at 3 years, and CVD morbidity/mortality (RR: 1.9) at 6 years, independent of Visit 2 ABI and other risk factors. CONCLUSIONS: Progressive PAD (ABI decline >0.15) was significantly and independently associated with increased CVD risk. Patients with decreasing ABI may be candidates for more intensive cardiovascular risk factor management.

Validation of a method for determination of the ankle-brachial index in the seated position.

OBJECTIVE: To validate a method for determination of the ankle-brachial index (ABI) in the seated position. BACKGROUND: Peripheral arterial disease (PAD) is a prevalent disorder that is associated with quality of life impairment and increased risk of a major cardiovascular event. The ABI is the initial test for screening and diagnosis of PAD. To prevent error due hydrostatic pressure, accurate measurement of the ABI requires supine patient positioning. Access to ABI measurement is limited for patients who are immobilized or unable to lie flat. METHODS: Patients presenting to a vascular laboratory for suspected arterial disease were enrolled. Arm and ankle blood pressures were measured in the supine and seated positions. Seated ankle pressures were corrected by the following physiology-based formula: Corrected ankle pressure = Measured ankle pressure - D*(.078), where D = the vertical distance between the arm and ankle cuffs (mm). This formula equates to a correction factor of 78 mm Hg per meter distance between the arm and ankle cuffs. Corrected ankle pressure measurements were used for seated ABI calculation. RESULTS: Complete data were available for 100 patients. Mean ABI was 0.97, and 31% of patients had an ABI < or =0.9. There was excellent correlation between supine and corrected seated ankle pressure measurements (r = 0.884-0.936, P < .001). The difference between measurements was negligible (<5 mm Hg). Similarly, there was excellent correlation between supine and seated ABI measures (r = 0.936, P < .001). There was no significant difference between the supine and seated ABI measures. CONCLUSION: We have developed and validated a method for determination of the ABI in the seated position which can be used to broaden availability of PAD testing. This method could also be incorporated into new technologies for ABI determination in the seated position.

Noninvasive determination of endothelial cell function in the microcirculation in Kawasaki syndrome.

The aim of the study was to noninvasively assess endothelial cell (EC) function in the microcirculation using laser Doppler fluximetry (LDF) in acute and convalescent Kawasaki syndrome (KS) patients and healthy controls. KS is an acute, self-limited vasculitis of childhood that affects the EC of medium-sized arteries. No studies have addressed EC function in the peripheral microcirculation. LDF preacetylcholine and postacetylcholine (ACh) iontophoresis estimates microcirculation EC nitric oxide production leading to smooth muscle relaxation and vasodilatation, which are blunted in EC dysfunction. We studied a total of 97 subjects: 36 acute and 27 convalescent KS patients and 34 normal children. Change in blood flow was measured by LDF for 10 min post-ACh iontophoresis. Acute KS patients had significantly lower average flux when compared to convalescent KS patients and controls in the first 5 min postiontophoresis. However, there was no difference in flux or area under the curve (AUC) between convalescent KS patients and healthy controls. Despite a reduced response of the microvascular EC to ACh in acute KS patients, convalescent patients with and without coronary aneurysms had microvascular EC function similar to normal controls. This suggests that the EC injury in KS is confined to the endothelium of medium-sized arteries and that microvascular EC function is normal after acute KS.

Noninvasive assessment of endothelial activity in patients with peripheral arterial disease and cardiovascular risk factors.

Microvascular endothelial activity (EA) after stimulation with iontophoretically administered acetylcholine was evaluated using laser Doppler fluxmetery (LDF) and calibrated photoplethysmography (c-PPG) in normal patients and patients with peripheral artery disease (PAD). The patients included 79 non-PAD subjects and 51 patients with PAD. Upper and lower extremity EA was examined using LDF and c-PPG after acetylcholine iontophoresis for 10 min. Sensitivity and specificity were assessed using integrated area under response curve. In non-PAD patients, the EA by LDF in the upper extremity was significantly lower in the older patients compared to the younger patients. Conversely, EA by LDF detected no significant difference between these groups in the lower extremity.With c-PPG, the EA was slightly reduced in the upper but not in the lower extremity in older patients. Comparing PAD patients to the older patients, there was a significantly lower EA response in the upper and lower extremities by LDF. Likewise, c-PPG detected a highly significantly reduced EA in the upper and lower extremities for PAD patients. These results indicated that using a noninvasive technique to determine EA, there were significant differences in the EA response to acetylcholine between those with PAD and normal patients over the age of 50. Importantly, the EA response was reduced in the upper and lower extremities, indicating systemic disease of the endothelium in PAD patients.

Risk factors for chronic venous disease: the San Diego Population Study.

BACKGROUND: The etiology of chronic venous disease in the lower limbs is unclear, and very limited data are available on potential risk factors from representative population studies. METHODS: Participants in the San Diego Population Study, a free-living adult population randomly selected from age, sex, and ethnic strata, were systematically assessed for risk factors for venous disease. Categorization of normal, moderate, and severe disease was determined hierarchically through clinical examination and ultrasonography imaging by trained vascular technologists, who also performed anthropometric measures. An interviewer administered a questionnaire and an examination assessed potential risk factors for venous disease suggested by previous reports. RESULTS: In multivariable models, moderate venous disease was independently related to age, a family history of venous disease, previous hernia surgery, and normotension in both sexes. In men, current walking, the absence of cardiovascular disease, and not moving after sitting were also predictive. Additional predictors in women were weight, number of births, oophorectomy, flat feet, and not sitting. For severe disease, age, family history of venous disease, waist circumference, and flat feet were predictive in both sexes. In men, occupation as a laborer, cigarette smoking, and normotension were also independently associated with severe venous disease. Additional significant and independent predictors in women were hours standing, history of leg injury, number of births, and cardiovascular disease, but African American ethnicity was protective. Multiple other postulated risk factors for venous disease were not significant in multivariable analysis in this population. CONCLUSIONS: Although some risk factors for venous disease such as age, family history of venous disease, and findings suggestive of ligamentous laxity (hernia surgery, flat feet) are immutable, others can be modified, such as weight, physical activity, and cigarette smoking. Overall, these data provide modest support for the potential of behavioral risk-factor modification to prevent chronic venous disease.

The vital prognosis of subclavian stenosis.

OBJECTIVES: This study sought to assess the prognosis of subclavian stenosis (SS) as a potential marker of total and cardiovascular disease (CVD) mortality. BACKGROUND: Subclavian stenosis, diagnosed by a brachial systolic pressure difference (BSPD) > or =15 mm Hg, is associated with an increased prevalence of CVD risk factors. However, the association between SS and mortality is unknown. We hypothesized that a BSPD > or =15 mm Hg would predict an increased risk of CVD events. METHODS: We analyzed baseline and longitudinal data from 3 cohorts. Two were recruited from noninvasive vascular laboratories, and the third was a community-dwelling cohort. Multivariate survival models were used to test for an independent association of SS with total and CVD mortality. RESULTS: Baseline and follow-up data (mean 9.8 years) were complete in 1,778 participants. Subclavian stenosis was found in 157 (8.8%) subjects. Adjusted for age, gender, ethnicity, and cohort of origin, the presence of SS was significantly associated with increased total and CVD mortality (respectively, hazard ratio [HR] 1.42, p < 0.005; and HR 1.50, p = 0.05). This association persisted after adjustments for CVD risk factors (smoking pack-years, hypertension, diabetes, total/high-density lipoprotein cholesterol ratio, and body mass index) as well as lipid-lowering and antiplatelet therapies (HR 1.40, p < 0.01; and HR 1.57, p < 0.05 for total and CVD mortality, respectively). When any history of CVD or an ankle-brachial index <0.90 were added to the model, SS remained an independent predictor for total mortality (HR 1.34, p = 0.02), with a similar trend for CVD mortality (HR 1.43, p = 0.09). CONCLUSIONS: The presence of SS, easily diagnosed by comparing systolic pressures in the left and right arm, predicts total and CVD mortality independent of both CVD risk factors and existent CVD at baseline.

Risk factors for progression of peripheral arterial disease in large and small vessels.

BACKGROUND: Data on the natural history of peripheral arterial disease (PAD) are scarce and are focused primarily on clinical symptoms. Using noninvasive tests, we assessed the role of traditional and novel risk factors on PAD progression. We hypothesized that the risk factors for large-vessel PAD (LV-PAD) progression might differ from small-vessel PAD (SV-PAD). METHODS AND RESULTS: Between 1990 and 1994, patients seen during the prior 10 years in our vascular laboratories were invited for a new vascular examination. The first assessment provided baseline data, with follow-up data obtained at this study. The highest decile of decline was considered major progression, which was a -0.30 ankle brachial index decrease for LV-PAD and a -0.27 toe brachial index decrease for SV-PAD progression. In addition to traditional risk factors, the roles of high-sensitivity C-reactive protein, serum amyloid-A, lipoprotein(a), and homocysteine were assessed. Over the average follow-up interval of 4.6+/-2.5 years, the 403 patients showed a significant ankle brachial index and toe brachial index deterioration. In multivariable analysis, current smoking, ratio of total to HDL cholesterol, lipoprotein(a), and high-sensitivity C-reactive protein were related to LV-PAD progression, whereas only diabetes was associated with SV-PAD progression. CONCLUSIONS: Risk factors contribute differentially to the progression of LV-PAD and SV-PAD. Cigarette smoking, lipids, and inflammation contribute to LV-PAD progression, whereas diabetes was the only significant predictor of SV-PAD progression.

Exertional leg pain in patients with and without peripheral arterial disease.

BACKGROUND: Although exertional leg pain is a hallmark of peripheral arterial disease (PAD) and can occur in persons without PAD, symptom variation has received inadequate attention. METHODS AND RESULTS: Three cohort studies were combined for cross-sectional analysis. The San Diego Claudication Questionnaire assessed exertional leg pain. PAD was defined as ankle brachial index (ABI) < or =0.90 or history of lower-extremity revascularization. Of 3658 subjects, 3629 were analyzed after exclusions. Of these, 24.1% had PAD in 1 or both legs. There was a stepwise decrease in average ABI, from no pain to pain on exertion and rest, noncalf pain, atypical calf pain, and classic claudication (P=0.002). When stratified by PAD, this trend was no longer significant. Legs with ABIs >0.90 and revascularization had pain distributions intermediate between that of normal legs (ABI, 1.00 to 1.39) and legs with ABIs < or =0.90. Compared with normal legs, legs with low-normal (0.91 to 0.99) and high-normal (> or =1.40) ABIs had higher pain rates, suggesting borderline disease and vascular stiffness, respectively. Multivariable logistic regression models showed that ABI was a strong correlate of pain category throughout the ABI range. Independently of ABI, age, male sex, diabetes, smoking history, high body mass index, myocardial infarction, and previous revascularization were all significant correlates of exertional leg pain. CONCLUSIONS: No category of exertional leg pain was sufficiently sensitive or specific for routine PAD diagnosis. Legs with low-normal and high-normal ABIs appeared to have ischemic leg pain; thus, a "normal ABI" is likely to range from 1.00 to 1.39. In addition to ABI, several risk variables were independent correlates of exertional leg pain.

Ethnicity and peripheral arterial disease: the San Diego Population Study.

BACKGROUND: Previous studies have indicated higher rates of peripheral arterial disease (PAD) in blacks than in non-Hispanic whites (NHWs), with limited information available for Hispanics and Asians. The reason for the PAD excess in blacks is unclear. METHODS AND RESULTS: Ethnic-specific PAD prevalence rates were determined in a randomly selected defined population that included 4 ethnic groups; NHWs, blacks, Hispanics, and Asians. A total of 2343 participants aged 29 to 91 years were evaluated. There were 104 cases of PAD (4.4%). In weighted logistic models with NHWs as the reference group and containing demographic factors only, blacks had a higher PAD prevalence than NHWs (OR=2.30, P<0.024), whereas PAD rates in Hispanics and Asians, although somewhat lower, were not significantly different from NHWs. Blacks had significantly more diabetes and hypertension than NHWs and a significantly higher body mass index. Inclusion of these variables and other PAD risk factors in the model did not change the effect size for black ethnicity (OR=2.34, P=0.048). A model containing interaction terms for black ethnicity and each of the other risk factors revealed no significant interaction terms, which indicates no evidence that blacks were more "susceptible" than NHWs to cardiovascular disease risk factors. CONCLUSIONS: Black ethnicity was a strong and independent risk factor for PAD, which was not explained by higher levels of diabetes, hypertension, and body mass index. There was no evidence of a greater susceptibility of blacks to cardiovascular disease risk factors as a reason for their higher PAD prevalence. Thus, the excess risk of PAD in blacks remains unexplained and requires further study.

Relationships between symptoms and venous disease: the San Diego population study.

BACKGROUND: The associations between symptoms and venous disease of the lower extremities are poorly characterized. METHODS: We conducted a cross-sectional study to evaluate relationships between symptoms associated with venous disease and prevalent disease in 2408 men and women aged 29 to 91 years who were employees, retirees, or spouses at a large state university. Index participants were randomly selected within strata by age, sex, and ethnicity. A structured interview assessed the prevalence of aching, itching, heaviness, tired legs, cramping, swelling, and nighttime restless legs. A comprehensive standardized examination determined the prevalence of visible disease (normal, telangiectasias, varicose veins, and trophic changes) and functional disease (normal, superficial, and deep disease). We related symptoms to disease with attention to modification by sex, ethnicity, and age. RESULTS: Aching, itching, heaviness, tired legs, cramping, and swelling were related to both superficial and deep functional disease. The same symptoms were related to varicose veins and trophic changes. Swelling and heaviness were related to telangiectatic disease. Except for restless legs and trophic changes, the prevalence of symptoms across each category was greater in women than men. Aching was the most common symptom but was relatively nonspecific. Swelling was the most specific marker for prevalent visible and functional disease. Heaviness and itching also helped to distinguish prevalent disease. CONCLUSIONS: Venous symptoms were more prevalent in study participants with both visible and functional disease and in women. Swelling was the most specific predictor; heaviness, itching, and aching also helped to distinguish cases.

Subclavian artery stenosis: prevalence, risk factors, and association with cardiovascular diseases.

OBJECTIVES: The objective was to assess the prevalence of subclavian artery stenosis (SS) in four cohorts (two free-living and two clinical populations) and determine both risk factors for this condition and the association with other cardiovascular conditions. BACKGROUND: The prevalence of SS in the general population is unknown, and its association with risk factors and other cardiovascular diseases is not well-established. METHODS: A total of 4,223 subjects (2,975 from two free-living cohorts and 1,248 from two clinical cohorts) were included in this cross-sectional analysis. Subclavian artery stenosis was defined as > or =15 mm Hg interarm pressure difference. RESULTS: The prevalence of SS was 1.9% in the free-living cohorts and 7.1% in the clinical cohorts; SS was significantly (p < 0.05) associated with past smoking (odds ratio [OR] = 1.80), current smoking (OR = 2.61), and higher levels of systolic blood pressure (OR = 1.90 per 20 mm Hg). Higher levels of high-density lipoprotein (HDL) cholesterol were inversely and significantly associated with SS (OR = 0.87 per 10 mg/dl). In regression analyses relating SS to other cardiovascular diseases, the only significant finding was with peripheral arterial disease (PAD) (OR = 5.11, p < 0.001). CONCLUSIONS: Significant SS is present in approximately 2% of the free-living population and 7% of the clinical population. Additionally, SS is correlated with current and past smoking histories, systolic blood pressure, HDL levels (inversely), and the presence of PAD. These findings suggest that bilateral brachial blood pressure measurements should routinely be performed in patients with an elevated risk profile, both to screen for SS, and to avoid missing a hypertension or PAD diagnosis because of unilateral pressure measurement in an obstructed arm.

Chronic venous disease in an ethnically diverse population: the San Diego Population Study.

In a 1994-1998 cross-sectional study of a multiethnic sample of 2,211 men and women in San Diego, California, the authors estimated prevalence of the major manifestations of chronic venous disease: spider veins, varicose veins, trophic changes, and edema by visual inspection; superficial and deep functional disease (reflux or obstruction) by duplex ultrasonography; and venous thrombotic events based on history. Venous disease increased with age, and, compared with Hispanics, African Americans, and Asians, non-Hispanic Whites had more disease. Spider veins, varicose veins, superficial functional disease, and superficial thrombotic events were more common in women than men (odds ratio (OR) = 5.4, OR = 2.2, OR = 1.9, and OR = 1.9, respectively; p < 0.05), but trophic changes and deep functional disease were less common in women (OR = 0.7 for both; p < 0.05). Visible (varicose veins or trophic changes) and functional (superficial or deep) disease were closely linked; 92.0% of legs were concordant and 8.0% discordant. For legs evidencing both trophic changes and deep functional disease, the age-adjusted prevalences of edema, superficial events, and deep events were 48.2%, 11.3%, and 24.6%, respectively, compared with 1.7%, 0.6%, and 1.3% for legs visibly and functionally normal. However, visible disease did not invariably predict functional disease, or vice versa, and venous thrombotic events occurred in the absence of either.

Quality of life in patients with chronic venous disease: San Diego population study.

BACKGROUND: Chronic venous disease in the lower extremities may have a substantial effect on functioning and quality of life. We report quality of life data for an ethnically diverse population that had been systematically evaluated for venous disease. SUBJECTS: Current and retired employees from a large public university were randomly selected within strata of age, sex, and ethnicity. The sample included 2404 men and women ages 40 to 79 years. MEASURES: Quality of life was measured with the Medical Outcomes Study 36-Item Short Form (SF-36). Venous disease of the lower extremities was evaluated with two methods. Visual inspection was used to place participants into four categories: normal, telangiectasias and spider veins, varicose veins, and trophic changes. Duplex ultrasound scanning was used to place participants into three categories: normal, superficial venous disease, and deep vein disease. RESULTS: There were significant associations between quality of life and venous disease severity as assessed with both visual and ultrasound methods. These differences were observed for both men and women for functional scales of the SF-36. The relationships were significant, and were graded with degree of disease severity. Differences categories were not statistically significant for the mental health scales of the SF-36. CONCLUSION: Chronic venous disease in the lower extremities has a substantial effect on physical health aspects of quality of life but not on mental health components.

Quantified duplex augmentation in healthy subjects and patients with venous disease: San Diego population study.

OBJECTIVE: This study was undertaken to determine the quantitative augmentation response in several veins examined in a cohort assembled to permit comparisons by sex, age, and ethnicity, under normal conditions and in the presence of obstruction, with and without trophic changes. METHOD: The common femoral vein, superficial femoral vein, sapheno-femoral junction, popliteal vein, sapheno-popliteal junction, and posterior tibial vein were studied with duplex ultrasonographic scanning. Augmentation response was elicited with use of an automated cuff inflator. Mean level of each response was analyzed according to patient sex, age, and ethnicity, each adjusted for the other two. Normal values were compared with those obtained from legs with venous obstructive disease, with or without signs of trophic changes. RESULTS: Decreased augmentation response was noted only in the sapheno-femoral junction and sapheno-popliteal junction, and was smaller in women. Augmentation response was slightly increased in the oldest age group (>70 years) in the common femoral vein, superficial femoral vein, popliteal vein, and posterior tibial vein. The highest augmentation response was found in Asian subjects, in the common and superficial femoral veins and the sapheno-femoral and sapheno-popliteal junctions; and the smallest augmentation response was found in African American subjects, in these same veins and junctions. Differences in vein diameters may explain these findings, ie, smaller diameters in Asians and larger diameters in African Americans. Most important, compared with normal values, augmentation response was decreased in legs with venous obstructive disease only when trophic changes were present. CONCLUSION: Like quantification of reflux, quantitative evaluation of the augmentation response may help in diagnosis of venous obstructive disease when trophic changes are present.