Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis.

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Non-invasive assessment of endothelial activity in patients with coronary heart disease and cardiovascular risk factors.

BACKGROUND: The aim of this study was first to compare the widely used flow mediated dilation ( FMD ) method with the iontophoretically induced acetylcholine vasodilation (IAV ) procedure. The ultimate goal was to examine the endothelial activity ( EA ) in patients with various cardiovascular risk factors compared with control subjects. PATIENTS AND METHODS: In the upper extremities of 27 subjects, comparisons of EA by FMD and IAV measured with laser Doppler flux method (LDF) were conducted. IAV-EA was then measured using LDF in an additional 93 subjects with various cardiovascular ( CVD ) risk factors and/or a diagnosis of coronary heart disease (CHD). RESULTS: The mean age of the subjects was 56.2 years and 54% were male. There was a robust and significant correlation between FMD vs IAV endothelial activity (r = 0.87, p = 0.025). After adjustment for age, there were significant differences in LDF-measured, acetylcholine-induced EA by diagnosis of CHD (p = 0.02), hyperlipidemia (p = 0.03) and diabetes (p < 0.01), as well as by sex (p < 0.01). The difference by hypertension status was of borderline significance (p = 0.07). LDF EA was higher in non-smokers compared to smokers but this difference was not statistically significant (p = 0.3). After adjustment for age and gender, a 10-unit increase in LDF-measured EA was associated with a 12% lower odds for a diagnosis of CHD (p = 0.07). CONCLUSIONS: Measurement of IAV-EA by LDF is a simple, noninvasive methodology which is highly correlated with post-occlusive FMD EA and is also significantly associated with a diagnosis of CHD.

Noninvasive determination of venomuscular efficiency.

PURPOSE: The purpose of this study was to express quantitatively and noninvasively the efficiency of the venomuscular pump by using photoplethysmography (PPG). METHODS AND PATIENTS PPG was used to record volume changes induced by dorsiflexion resulting in exercise displacement volume (EDV) and subsequently by passive limb elevation resulting in tilt displacement volume (TDV). Dividing EDV by TDV yields efficiency of the venomuscular pump. Twenty-four control subjects, 21 patients with venous valvular insufficiency (VVI), and 10 additional patients with both VVI and deep venous thrombosis (DVT) were studied. Data for one leg in each subject are reported. Though calculation of efficiency does not require calibrated or quantitative PPG, in this case because we used calibrated PPG we recorded the respective values for EDV after dorsiflexion and TDV after passive leg elevation. RESULTS: EDV decreased from a normal value of 3.15% optical reflectance (% OR) to 1.68% OR in patients with VVI and 1.09% OR in patients with VVI plus DVT. TDV response was quite opposite, increasing from 6.55% OR in the control group to 10.30% OR in the VVI group and 16.66% OR in the VVI plus DVT group. Finally, efficiency decreased from the average normal value of 50.5% to 24.4% in the VVI group and 8.8% in the VVI plus DVT group. CONCLUSION: Dividing EDV by TDV, venomuscular efficiency can be determined and may be considered a useful index of venous hemodynamics.

Common femoral vein dimensions and hemodynamics including Valsalva response as a function of sex, age, and ethnicity in a population study.

PURPOSE: In this study we assessed the normal common femoral vein (CFV) dimensions and related hemodynamics in a cohort assembled to permit contrasts by means of sex, age, and ethnicity. METHODS: The CFV diameter and the flow velocity were analyzed by means of duplex ultrasonography at rest and with a standardized Valsalva maneuver, with the subject in a 15% reverse Trendelenberg position. Mean levels of each of the CFV measurements were analyzed with age category, sex, and ethnicity, each adjusted for the other two. Multiple linear regression was used as a means of assessing the independent associations of age, sex, ethnicity, body mass index (BMI), and height to the CFV measurements. RESULTS: The average CFV diameter at rest was 11.84 mm, increasing to 14.27 mm during the Valsalva maneuver. There was a significant (P <.0001) decline in both diameter measures beginning in patients 60 years old. The CFV diameter was larger in men (12.90 mm) than in women (11.22 mm; P <.0001). The average CFV diameter in Hispanics, Africian Americans, and Asians was significantly smaller (P <.001) than in the non-Hispanic whites in multivarate analysis. The independence of these associations was confirmed by means of multivariate analysis, and positive associations of CFV diameter with height and BMI were documented. The Valsalva response was higher in men than in women (2.67 mm vs 2.29 mm), but the percentage change was similar. CFV velocity at rest decreased significantly (P <.0001) in patients older than 50 years. The mean CFV velocity was 13.87 cm/s, and the values were significantly (P <.0001) higher in women (14.58 cm/s) than in men (12.67 cm/s). In multivariate analysis CFV velocity was higher in African Americans than in the other ethnic groups. We also documented an independent inverse association of CFV with BMI. The CFV velocity response (peak expiration post-Valsalva) increased significantly at all ages, from 52% to 83%. The percentage increase in women (68%) was slightly higher than that in men (58%). African American subjects had a somewhat higher percentage increase (74%) than the other three ethnic groups (63% to 64%). Because the flow rate is determined more by the diameter than the velocity, CFV flow associations were similar to those for diameter. Because an older age predicted both decreased diameter and velocity, the flow reduction with age was pronounced. CONCLUSION: Quantitative normative data that are age-, sex-, and ethnic group-specific are reported on CFV diameter, velocity, and total flow rate, both at rest and with the Valsalva maneuver. CFV diameter, velocity, and flow rate varied significantly as a function of age, sex, ethnicity, height, and BMI. The data also provide a baseline assessment for subsequent evaluations of changes with time in this cohort.

Venous outflow and inflow resistance in health and venous disease.

PURPOSE: The purpose of this study was to develop a physiologic method to measure outflow and inflow from the lower extremities and thus to quantify the degree of venous valvular insufficiency and venous obstructive disease. METHODS: Calibrated photoplethysmography was used in combination with passive changes in hydrostatic pressure, by leg elevation followed by repositioning of the leg to the original sitting position. With the principle of venous occlusion plethysmography, timed volume changes were then used to calculate the outflow and inflow. The inflow and outflow units were the percentage of optical reflectance (%OR) per minute. The respective resistances were calculated by identifying the hydrostatic pressure distance from the third intercostal space to the probe site that is inducing these site changes. The resistance units were millimeters of Mercury x minutes per %OR. RESULTS: Four groups of subjects were examined: normal individuals, patients with venous valvular insufficiency, deep venous thrombosis, and a combination of both. The most significant differences in outflow values were found between the control group (81.77% OR/min) and the deep venous thrombosis group (28.47% OR/min). In contrast, the most significant differences in inflow values were found between the control group (9. 67% OR/min) and the venous valvular insufficiency group (108.61% OR/min). The resistances changed correspondingly. CONCLUSION: The application of calibrated photoplethysmography in conjunction with induced changes in leg hydrostatic pressure proved to be an effective physiologic method to noninvasively quantify venous hemodynamics in normal control subjects, patients with venous valvular insufficiency, venous obstructive disease, or both.

Non-invasively determined ambulatory venous pressure.

In view of the resemblance of exercise-induced plethysmographic changes with those obtained by direct venous pressure measurement, we decided to use a combination of photoplethysmography (PPG) and hydrostatic pressure calibration to determine the PPG/pressure relationship. A standard foot dorsiflexion exercise involving stepwise position changing was performed which induced hydrostatic pressure changes that were recorded as the heart-probe distance. A logarithmic PPG/pressure relationship was identified and the resulting ambulatory venous pressure (AVP) was obtained from the PPG/pressure curve. Simultaneous direct AVP was recorded in 14 patients scheduled for venous surgery. 'Non-invasive AVP only' was determined in 24 normal control subjects with a mean value of 19.24 mmHg (+/-8.79 SD). In the patient group, the direct AVP values were 40.00 mmHg (+/-10.83 SD) compared with the PPG values of 33.07 mmHg (+/-12.94 SD). The resulting correlation was r = 0.8850. By utilizing stepwise leg elevation, a reliable PPG/pressure curve can be established which, in turn, permits AVP determination. It is suggested that this non-invasive AVP determination may serve as a screening test to evaluate non-invasively venous hemodynamics.

The correlation between the severity of peripheral arterial disease and carotid occlusive disease.

Peripheral arterial disease (PAD) and carotid occlusive disease (COD) are both known to be specific manifestations of atherosclerosis. Because they both have a common cause, it is reasonable to hypothesize that they should correlate with each other to a certain extent, and previous studies have shown that there is a correlation between the prevalence of PAD and COD. The purpose of this study was to determine whether a correlation exists between the severity of PAD and the severity of COD by retrospectively looking at a group of 203 patients who underwent non-invasive testing for suspicion of PAD at the San Diego VA Hospital or UCSD Medical Center, and who also had a non-invasive duplex carotid scan. The severity of PAD was assessed by segmental blood pressure ratios (leg segment/arm ratio) in each leg taken at the toe, ankle, and below the knee, as well as the peak flow velocity of the posterior tibial artery. The severity of COD was assessed by duplex ultrasound scans of six distinct segments of the carotid artery system: the right and left common, internal, and external carotid arteries. Correlation analysis showed r=0.23 (p=0.001) when comparing a PAD aggregate standard score with the number of diseased carotid arteries (>50% stenosis), and r=0.23 (p=0.001) when comparing a PAD aggregate standard score with an average COD score. Because about 50% of the patients had undergone surgical intervention on their leg or carotid arteries, another correlation analysis restricted to patients with no surgical interventions (n = 97) was performed. The above correlations were slightly attenuated in this analysis, r=0.21 (p=0.043) and r=0.17 (p= 0.092), respectively. The results indicate that there is a modest but significant correlation between the severity of PAD and the severity of COD in a population with a high prevalence of both.

Combination of pressure and velocity parameters in the non-invasive diagnosis of aorto-iliac disease.

Three different femoral artery flow velocity parameters in combination with segmental pressure measurements were evaluated for their respective diagnostic value in identifying the presence or absence of hemodynamically significant aorto-iliac disease. A total of 60 patients (119 legs) were examined both non-invasively and with arteriography. Doppler flow velocities were recorded using a 5-MHz CW Doppler velocity metering system. Of the three parameters used (peak velocity, decay time and deceleration), a decay time of 220 ms yielded the most practical discriminant value. The accuracy increases when in addition the upper thigh/arm pressure ratio values are considered. The results indicate that the combination of femoral artery decay time with the upper thigh/arm pressure index provides a simple and accurate non-invasive screening method to confirm or rule out aorto-iliac disease. This helps to determine whether the patient is a candidate for arteriography and for potential surgical intervention.

Quantitative and qualitative progression of peripheral arterial disease by non-invasive testing.

There is little information on the progression of peripheral arterial disease (PAD) over time. A series of 508 patients with a prior examination for PAD were contacted and brought in for follow-up to evaluate the natural history of PAD. A total of 85 patients were excluded because they had interventions in both limbs prior to their return visit. Progression was assessed in the remaining 423 patients for a total of 755 limbs, both quantitatively and qualitatively using six categories of PAD severity. There was a modest overall categorical progression of disease: 228 limbs (30.2%) displayed categorical progression, while 172 limbs (22.8%) improved over a 4.6-year average follow-up. Through analysis of quantitative change, it was determined that more quantitative progression occurred than was evident from categorical progression. Two of the three non-invasive tests employed, the ankle/brachial index (ABI) and posterior tibial peak forward flow velocity (peak PT), showed statistically significant progression during follow-up: mean ABI change = -0.019, 95% confidence interval (CI)= -0.031 to -0.007; mean peak PT change = -2.32 cm/s, 95% CI = -3.20 to -1.44. The toe/brachial index (TBI) also suggested progression: mean change= -0.013, but the 95% CI included no change. Standard scores (sum of the Z-scores for ABI, peak PT and TBI) were calculated. The standard score progressed approximately 0.34 units (standard deviations), p-value <0.001, over 4.6 years; or about 0.07 standard deviations per year. There were independent and statistically significant (p<0.05) associations between the rate of PAD progression (standard score change) and age, diabetes, classic ('Rose') intermittent claudication, moderate to severe PAD in the same limb, moderate to severe PAD in the contralateral limb and future therapeutic intervention. There were independent and suggestive associations (0.05

The epidemiology of peripheral arterial disease: importance of identifying the population at risk.

Data from the Framingham Study and other population studies indicate that intermittent claudication (IC) sharply increases in late middle age and is somewhat higher among men than women. Noninvasive testing in populations indicates that the true prevalence of peripheral arterial disease (PAD) is at least five times higher than would be expected based on the reported prevalence of IC. Peripheral arterial disease correlates most strongly with cigarette smoking and either diabetes or impaired glucose tolerance. Other risk factors for PAD include hypertension; low levels of high-density lipoprotein cholesterol; and high levels of triglycerides, apolipoprotein B, lipoprotein(a), homocysteine, fibrinogen and blood viscosity. Individuals with PAD are more likely to have coronary heart disease and cerebrovascular disease than those without PAD. Because of the high risk of both nonfatal and fatal cardiovascular disease (CVD) events in PAD patients, individuals with evidence of PAD should undergo both a careful examination of the entire cardiovascular system and aggressive modification of CVD risk factors.

The correlation between symptoms and non-invasive test results in patients referred for peripheral arterial disease testing.

The WHO/Rose questionnaire has served as the epidemiologic and clinical standard in the assessment of leg pain in patients with peripheral arterial disease (PAD) for over three decades. However, the structure of this questionnaire does not allow assessment of leg-specific (i.e. right versus left) symptoms. We studied 508 patients aged 39-95 years (mean 68 years), initially referred for PAD non-invasive testing. A revised questionnaire, the San Diego Claudication Questionnaire, was administered which allowed determination of leg-specific symptoms and evaluated thigh and buttock as well as calf pain. Leg-specific symptoms were categorized into no pain, pain at rest, non-calf claudication, non-Rose calf claudication, and Rose claudication. At the same visit, the ankle brachial index, the toe brachial index, and peak posterior tibial flow velocity were measured by Doppler ultrasound and five categories of non-invasive results by type and severity of PAD were defined. Legs with previous intervention (Rx), surgery or angioplasty, were evaluated separately. Claudication was reported in 42% of no Rx legs and 50% of Rx legs; 40% of claudication was atypical (not Rose); 64% of no Rx and 81% of Rx legs had PAD by non-invasive testing, and 27% of affected legs had severe PAD. The correlation between the severity of symptoms and the severity of ipsilateral PAD in no Rx legs was r = -0.40, p < 0.001. In Rx legs, this correlation was somewhat less (r = 0.27, p < 0.001) due to more symptomatology at lesser degrees of PAD, suggesting reporting bias and/or more residual disease than evident from non-invasive testing. To our knowledge, these results provide the first comparison between a standardized assessment of leg pain and the severity of ipsilateral PAD by non-invasive testing.

Photoplethysmography in the diagnosis of venous disease.

BACKGROUND: Photoplethysmography (PPG) has become a widely used method in the diagnosis of venous disease. OBJECTIVE: To describe briefly various aspects of PPG and its practical value. METHODS: Standard and quantitative PPG are described as well as various evaluation procedures. RESULTS: The refilling time is considered the most useful parameter; values higher than 22 seconds are considered normal. Quantitative PPG systems (calibrated or digital PPG) also permit evaluation of the drainage function. CONCLUSION: While refilling time is presently the only quantitative parameter, it is expected that by introducing calibrated or digital PPG in diagnostic practice, venous function will be evaluated in a more comprehensive and quantitative form.

Screening for peripheral arterial disease: the sensitivity, specificity, and predictive value of noninvasive tests in a defined population.

Large vessel peripheral arterial disease (LV-PAD) is a common condition that causes significant morbidity and disability. The authors evaluated the individual components of a comprehensive noninvasive vascular examination to identify the most sensitive and specific measurements for diagnosing LV-PAD. This cohort, initially screened between 1979 and 1981 in Rancho Bernardo, California, included 421 normal subjects and 63 subjects with LV-PAD. Segmental blood pressure ratios and flow velocities by Doppler ultrasound were used to define cases of LV-PAD. The sensitivity, specificity, positive predictive value, and negative predictive value of each individual component of the diagnostic algorithm were determined. Overall, measurements of posterior tibial flow showed the highest sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy. In addition, an absent or non-recordable posterior tibial peak forward flow, occurring in 96% of all limbs with isolated posterior tibial disease, or an ankle ratio < or = 0.8 considered in parallel yielded a test with sensitivity of 89%, specificity of 99%, positive predictive value of 90%, negative predictive value of 99%, and overall accuracy of 98%. These results indicate that the vast majority of LV-PAD cases can be detected with a single measurement using a handheld Doppler flowmeter employed at the ankle.

Toe pressure determination by audiophotoplethysmography.

PURPOSE: The purpose of this study was to evaluate the performance of audiophotoplethysmography as a modality to measure toe pressure without the requirement of a recorder. METHOD: A portable photoplethysmograph with an audio output was used to determine toe pressures, and the results were compared with those obtained by a commercial photoplethysmograph with a recorder. RESULTS: Thirty-one measurements in control subjects and 62 measurements in patients with arterial occlusive disease were performed. The average toe pressure recorded with oscillography with standard photoplethysmography was 103.5 mm Hg +/- 14.7 SD and 95.9 mm Hg +/- 13.4 SD with audio-photoplethysmography. In the patient group the pressure recorded with a commercial photoplethysmograph was 65.3 mm Hg +/- 34.9 SD compared with 61.6 mm Hg +/- 34.8 SD obtained with audio-photoplethysmography. The difference in both groups was insignificant, and the correlation between both methods was very good. CONCLUSION: A portable hand-held photoplethysmograph equipped with an audio output was used to measure toe pressure in control subjects and in patients with arterial occlusive disease. The results have been compared with the oscillometric method by a standard commercial photoplethysmograph connected to a recorder. The correlation was very good in the control and patient groups, and the difference between both methods was below the level of statistical significance. The fact that no recorder is needed may help in introducing toe pressure measurement into everyday office diagnostic practice.

Periodic hemodynamics (flow motion) in peripheral arterial occlusive disease.

PURPOSE: The occurrence of periodic blood flow variations (flow motion) in health and disease is controversially discussed. This is partly due to not reporting the incidence and to performing the analysis solely visually. We have therefore studied flow motion with computerized methods. METHODS: We used a computerized Prony spectral line estimator program to analyze the frequencies of resting skin blood flow variations, as determined by laser Doppler flowmetry on the thumb and great toe, in 50 male control subjects (group a), in 50 patients with mild peripheral arterial occlusive disease (PAOD stages I and II; group b), and in 25 patients with severe PAOD (stages III and IV; group c). RESULTS: The median ankle/arm pressure ratio was 1.10 in the control group, 0.72 in the mild PAOD group, and 0.66 in the severe PAOD group. Slow wave flow motion was detected in 19% of all thumbs from groups a and b (systolic arm pressures > 100 mm Hg) and in 12% of the toes in the control group. Patients with mild PAOD exhibited slow wave flow motion in 46% of the toes. Patients with severe PAOD showed slow waves in 77% of the toes. The median flow motion frequencies were about 1.6 cycles/min for groups a and b, when present. The median frequency in group c was significantly higher at 4.0 cycles/min, though still in the range of slow waves. The median peak-to-through amplitude was between 17% and 20% of mean flow for all groups. CONCLUSIONS: We conclude that evaluation of flow motion requires computerized frequency analysis and that slow wave flow motion is a perfusion pattern characteristic of PAOD rather than of normal perfusion states. This finding has potential implications for diagnostic and therapeutic approaches in arterial occlusive disease.

[Effect of transient therapeutic occlusion on some hemodynamic parameters and walking distance]. / Der Einfluss einer transienten therapeutischen Okklusion (TTO) auf einige hämodynamische Parameter und auf die Gehstrecke.

The effect of a one hour lasting occlusion was studied by recording the ankle/arm pressure ratios at rest and during post-occlusive reactive hyperemia 30 min, 1 day, 3 days and 7 days after the procedure. Both parameters improved, reaching a maximum on the 7th day at which time the changes became statistically significant. Finally, a standardized walking distance test yielded a highly significant improvement when determined on the 7th day (mean increase in walking distance: 69%). Although the underlying mechanism is yet unclear, the positive therapeutic results and absence of side effects warrant further investigations to be focused on the mechanism as well as on practical implications related to the procedure itself to optimize the results.

Mortality over a period of 10 years in patients with peripheral arterial disease.

BACKGROUND: Previous investigators have observed a doubling of the mortality rate among patients with intermittent claudication, and we have reported a fourfold increase in the overall mortality rate among subjects with large-vessel peripheral arterial disease, as diagnosed by noninvasive testing. In this study, we investigated the association of large-vessel peripheral arterial disease with rates of mortality from all cardiovascular diseases and from coronary heart disease. METHODS: We examined 565 men and women (average age, 66 years) for the presence of large-vessel peripheral arterial disease by means of two noninvasive techniques--measurement of segmental blood pressure and determination of flow velocity by Doppler ultrasound. We identified 67 subjects with the disease (11.9 percent), whom we followed prospectively for 10 years. RESULTS: Twenty-one of the 34 men (61.8 percent) and 11 of the 33 women (33.3 percent) with large-vessel peripheral arterial disease died during follow-up, as compared with 31 of the 183 men (16.9 percent) and 26 of the 225 women (11.6 percent) without evidence of peripheral arterial disease. After multivariate adjustment for age, sex, and other risk factors for cardiovascular disease, the relative risk of dying among subjects with large-vessel peripheral arterial disease as compared with those with no evidence of such disease was 3.1 (95 percent confidence interval, 1.9 to 4.9) for deaths from all causes, 5.9 (95 percent confidence interval, 3.0 to 11.4) for all deaths from cardiovascular disease, and 6.6 (95 percent confidence interval, 2.9 to 14.9) for deaths from coronary heart disease. The relative risk of death from causes other than cardiovascular disease was not significantly increased among the subjects with large-vessel peripheral arterial disease. After the exclusion of subjects who had a history of cardiovascular disease at base line, the relative risks among those with large-vessel peripheral arterial disease remained significantly elevated. Additional analyses revealed a 15-fold increase in rates of mortality due to cardiovascular disease and coronary heart disease among subjects with large-vessel peripheral arterial disease that was both severe and symptomatic. CONCLUSIONS: Patients with large-vessel peripheral arterial disease have a high risk of death from cardiovascular causes.