Gianni Belcaro

Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women : The British Regional Heart Study

BACKGROUND AND PURPOSE B-mode ultrasound is a noninvasive method of examining the walls of peripheral arteries and provides measures of the intima-media thickness (IMT) at various sites (common carotid artery, bifurcation, internal carotid artery) and of plaques that may indicate early presymptomatic disease. The reported associations between cardiovascular risk factors, clinical disease, IMT, and plaques are inconsistent. We sought to clarify these relationships in a large, representative sample of men and women living in 2 British towns. METHODS The study was performed during 1996 in 2 towns (Dewsbury and Maidstone) of the British Regional Heart Study that have an approximately 2-fold difference in coronary heart disease risk. The male participants were drawn from the British Regional Heart Study and were recruited in 1978-1980 and form part of a national cohort study of 7735 men. A random sample of women of similar age to the men (55 to 77 years) was also selected from the age-sex register of the general practices used in the original survey. A wide range of data on social, lifestyle, and physiological factors, cardiovascular disease symptoms, and diagnoses was collected. Measures of right and left common carotid IMT (IMTcca) and bifurcation IMT (IMTbif) were made, and the arteries were examined for plaques 1.5 cm above and below the flow divider. RESULTS Totals of 425 men and 375 women were surveyed (mean age, 66 years; range, 56 to 77 years). The mean (SD) IMTcca observed were 0. 84 (0.21) and 0.75 (0.16) mm for men and women, respectively. The mean (SD) IMTbif were 1.69 (0.61) and 1.50 (0.77) mm for men and women, respectively. The correlation between IMTcca and IMTbif was similar in men (r=0.36) and women (r=0.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very common, affecting 57% (n=239) of men and 58% (n=211) of women. Severe carotid plaques with flow disturbance were rare, affecting 9 men (2%) and 6 women (1.6%). Plaques increased in prevalence with age, affecting 49% men and 39% of women aged <60 years and 65% and 75% of men and women, respectively, aged >70 years. Plaques were most common among men in Dewsbury (79% affected) and least common among men in Maidstone (34% affected). IMTcca showed a different pattern of association with cardiovascular risk factors from IMTbif and was associated with age, SBP, and FEV1 but not with social, lifestyle, or other physiological risk factors. IMTbif and carotid plaques were associated with smoking, manual social class, and plasma fibrinogen. IMTbif and carotid plaques were associated with symptoms and diagnoses of cardiovascular diseases. IMTbif associations with cardiovascular risk factors and prevalent cardiovascular disease appeared to be explained by the presence of plaques in regression models and in analyses stratified by plaque status. CONCLUSIONS IMTcca, IMTbif, and plaque are correlated with each other but show differing patterns of association with risk factors and prevalent disease. IMTcca is strongly associated with risk factors for stroke and with prevalent stroke, whereas IMTbif and plaque are more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Our analyses suggest that presence of plaque, rather than the thickness of IMTbif, appears to be the major criterion of high risk of disease, but confirmation of these findings in other populations and in prospective studies is required. The association of fibrinogen with plaque appears to be similar to its association with incident cardiovascular disease. Further work elucidating the composition of plaques using ultrasound imaging would be helpful, and more data, analyzed to distinguish plaque from IMTbif and IMTcca, are required to understand the significance of thicker IMT in the absence of plaque.

Venous thrombosis from air travel: the LONFLIT3 study--prevention with aspirin vs low-molecular-weight heparin (LMWH) in high-risk subjects: a randomized trial.

The LONFLIT1 and 2 studies established that in high-risk subjects after long (> 10 hours) flights, the incidence of deep venous thrombosis (DVT) may be between 4% and 6%. The LONFLIT3 study aimed to evaluate methods of prevention in high-risk subjects. Of 467 subjects contacted for the study, 300 were included. These 300 subjects at high risk for DVT were randomized, after informed consent, into three groups: 1) a control group that had no prophylaxis; 2) an aspirin treatment group, in which patients were treated with 400 mg , (tablets of oral, soluble aspirin; one dose daily for 3 days, starting 12 hours before the beginning of the flight); and 3) a low-molecular-weight heparin (LMWH) group, in which one dose of enoxaparine was injected between 2 and 4 hours before the flight. The dose was weight-adjusted (1000 IU [equivalent to 0.1 mL] per 10 kg of body weight). Subjects with potential problems due to prophylaxis with aspirin or LMWH or at risk of drug interactions were excluded. Of the 100 included subjects in each group, a total of 249 subjects completed the study (dropouts due to low compliance or traveling/connections problems were 17%). Age and sex distribution were comparable in the three groups as well as risk distributions. Mean age was 47 (range, 28-75; SD, 11; 65% males). Of the 82 subjects in the control group, there were 4.82% of subjects with DVT with two superficial thromboses. In total 4.8% of limbs suffered a thrombotic event. Of 84 subjects in the aspirin treatment group, there were 3.6% of patients with DVT and three superficial thrombosis. In total 3.6% of limbs had a throm botic event. In the LMWH group (82 subjects), there were no cases of DVT. One superficial thrombosis was documented. In total only 0.6% of limbs had a thrombotic event (p < 0.002 in comparison with the other two groups). DVT was asymptomatic in 60% of subjects; 85% of DVTs were observed in passengers in non-aisle seats. Mild gastrointestinal symptoms were reported in 13% of patients taking aspirin. One dose of LMWH is an important option to consider in high-risk subjects during long-haul flights.

Measurement of the ultrasonic intima-media complex thickness in normal subjects

PURPOSE The evolution of atherosclerosis can be studied before development of symptomatic plaque by evaluating morphologic changes of the intima-media (I-M) complex, seen on high-resolution ultrasonography of the arterial wall. These qualitative changes require large alterations in vessel wall appearance to recognize progression of atherosclerosis. It has been suggested that measurement of the thickness of the I-M complex may be a quantitative and more sensitive method of assessing these early atherosclerotic changes. METHODS High-resolution ultrasonography has been used to measure the thickness of the I-M complex in 140 symptom-free subjects. RESULTS The mean thickness of the I-M complex of the common carotid arteries was linearly related to the age (r = 0.77; p < 0.001), pack-years of smoking (r = 0.39; p < 0.05), the systolic blood pressure (r = 0.51, p < 0.01), and to the arterial ultrasound score (r = 0.85). The arterial ultrasound score has previously been shown to correlate with the presence of asymptomatic myocardial ischemia and with the development of cardiovascular symptoms. The mean thickness of the I-M complex in subjects without plaque (in the common carotid or common femoral artery bifurcations) was significantly thinner than in subjects with plaque (p < 0.001). CONCLUSION The thickness of the I-M complex of the common carotid arteries is a measure of the risk for the development of cardiovascular symptoms in symptom-free individuals.

Angiographic and Duplex Grading of Internal Carotid Stenosis: Can We Overcome the Confusion?

The stroke risk reduction benefit of surgical intervention in carotid occlusive disease has been validated in multicenter trials for various angiographically defined lesion severity categories. The two divergent angiographic grading methods used for internal carotid artery stenosis in these trials have caused confusion in the clinical application of their recommendations. Moreover, while todays highly accurate carotid duplex scanning can obviate the need for preoperative angiography in many cases, the duplex criteria must be tailored to achieve sufficiently reliable results on which therapeutic decisions can be made. This review offers a clarification of the discrepancies between the angiographic grading techniques and how their measurements of percent stenosis correlate to the duplex criteria needed to support the treatment decision-making process for carotid obliterative disease.

Ultrasound Morphology Classification of the Arterial Wall and Cardiovascular Events in a 6-Year Follow-up Study

A 6-year follow-up based on an arterial morphology classification defined with an ultrasound assessment of carotid and femoral artery bifurcations was conducted on 2322 asymptomatic subjects. Four morphology classes were considered. When 2000 subjects (86% of total subjects; 1124 males, 876 females) completed a 6-year follow-up, the study was terminated. At 6 years, no cardiovascular events were observed in subjects who were in class I (80.05% of the population sample) at inclusion; there were 69 events in classes II, III, and IV (19.95% of the population; incidence, 17.3%); 59 events, including the five deaths, occurred in classes III and IV (10.85% of the population), producing an event incidence of 27.2%. The increased event rate in classes II, III, and IV was significant (log-rank test; P < .05, P < .025, and P < .025, respectively). Thus, the arterial morphology classification identified 19.95% of the population (subjects in classes II, III, and IV) in which all events occurred. There was a higher (P < .05) rate of progression of altered arterial morphology in 6 years in classes III (26.5% of subjects progressed) and IV (41.9% progressed) than in classes I and II. The total number of cigarette-years was higher (P < .05) in classes II, III, and IV than in class I. In conclusion, the ultrasound-based arterial classification was useful in selecting from the population sample 80.05% of subjects (class I) who remained event-free for 6 years. All events occurred in class II, III, and IV subjects (19.95%), and all five deaths (0.25% of the population) occurred in classes III and IV (10.85% of the sample).

Venous Thromboembolism from Air Travel The LONFLIT Study

The LONFLIT study was planned to evaluate the incidence of deep venous thrombosis (DVT) occurring as a consequence of long flights. In the Lonflit 1 study 355 subjects at low-risk for DVT and 389 at high-risk were studied. Low-risk subjects had no cardiovascular disease and used no drugs. All flights were in economy class. The average flight duration was 12.4 hours (range, 10-15 hr). The mean age of the studied subjects was 46 years (range 20-80 yr, SD 11; 56% males). DVT diagnosis was made by ultrasound scans after the flights (within 24 hours). In low-risk subjects no events were recorded while in high-risk subjects 11 had DVT (2.8%) with 13 thromboses in 11 subjects and 6 superficial thromboses (total of 19 thrombotic events in 389 patients [4.9%]). In the Lonflit2 study the authors studied 833 subjects (randomized into 422 control subjects and 411 using below-knee stockings). Mean age was 44.8 years (range, 20-80 yr, SD 12; 57% males). The average flight duration was 12.4 hours. Scans were made before and after the flights. In the control group there were 4.5% of subjects with DVT while only 0.24% of subjects had DVT in the stockings group. The difference was significant. The incidence of DVT observed when subjects were wearing stockings was 18.75 times lower than in controls. Long-haul flights are associated to DVT in some 4-5% of high-risk subjects. Below-knee stockings are beneficial in reducing the incidence of DVT.

Hemispheric symptoms and carotid plaque echomorphology.

PURPOSE In patients with carotid bifurcation disease, the risk of stroke mainly depends on the severity of the stenosis, the presenting hemispheric symptom, and, as recently suggested, on plaque echodensity. We tested the hypothesis that asymptomatic carotid plaques and plaques of patients who present with different hemispheric symptoms are related to different plaque structure in terms of echodensity and the degree of stenosis. METHODS Two hundred sixty-four patients with 295 carotid bifurcation plaques (146 symptomatic, 149 asymptomatic) causing more than 50% stenosis were examined with duplex scanning. Thirty-six plaques were associated with amaurosis fugax (AF), 68 plaques were associated with transient ischemic attacks (TIAs), and 42 plaques were associated with stroke. B-mode images were digitized and normalized using linear scaling and two reference points, blood and adventitia. The gray scale median (GSM) of blood was set to 0, and the GSM of the adventitia was set to 190 (gray scale range, black = 0; white = 255). The GSM of the plaque in the normalized image was used as the objective measurement of echodensity. RESULTS The mean GSM and the mean degree of stenosis, with 95% confidence intervals, for plaques associated with hemispheric symptoms were 13.3 (10.6 to 16) and 80.5 (78.3 to 82.7), respectively; and for asymptomatic plaques, the mean GSM and the mean degree of stenosis were 30.5 (26.2 to 34.7) and 72. 2 (69.8 to 74.5), respectively. Furthermore, in plaques related to AF, the mean GSM and the mean degree of stenosis were 7.4 (1.9 to 12. 9) and 85.6 (82 to 89.2), respectively; in those related to TIA, the mean GSM and the mean degree of stenosis were 14.9 (11.2 to 18.6) and 79.3 (76.1 to 82.4), respectively; and in those related to stroke, the mean GSM and the mean degree of stenosis were 15.8 (10.2 to 21.3) and 78.1 (73.4 to 82.8), respectively. CONCLUSION Plaques associated with hemispheric symptoms are more hypoechoic and more stenotic than those associated with no symptoms. Plaques associated with AF are more hypoechoic and more stenotic than those associated with TIA or stroke or those without symptoms. Plaques causing TIA and stroke have the same echodensity and the same degree of stenosis. These findings confirm previous suggestions that hypoechoic plaques are more likely to be symptomatic than hyperechoic ones. They support the hypothesis that the pathophysiologic mechanism for AF is different from that for TIA and stroke.

Ultrasonic carotid artery plaque structure and the risk of cerebral infarction on computed tomography

PURPOSE The North American and the European Symptomatic Carotid Endarterectomy Trial investigators reported a conclusive benefit of carotid endarterectomy for patients with symptomatic 70% to 99% internal carotid artery (ICA) stenosis. However, it has been suggested that plaque structure may be an even more important factor in producing stroke than the degree of stenosis. The aim of this study was to test the hypothesis that the ultrasonic characteristics of carotid artery plaques were closely related to symptoms and to the prevalence of cerebral infarcts on computed tomography (CT). METHODS One hundred five carotid artery plaques causing greater than 70% stenosis in the ICA in 83 consecutive patients who underwent brain CT were characterized into four ultrasonic types: echolucent plaques, predominantly echolucent plaques, predominantly echogenic plaques, and echogenic plaques. Patients with permanent neurologic deficit were excluded. RESULTS There was a significant ipsilateral association between type 1 plaques and symptomatic hemispheres (p < 0.002). Twenty-six of the 105 cerebral hemispheres assessed by CT had infarcts. There was an increased incidence of brain infarcts in type I plaques (37%) compared with 18% in types II, III, and IV combined (p < 0.02). CONCLUSION Our results support the hypothesis that echolucent plaques are more frequently associated with symptoms and cerebral infarctions and provide further evidence that these plaques are unstable and tend to embolize. Studies on the natural history of asymptomatic carotid artery stenosis should investigate whether plaque characterization could identify a high-risk group.

Endovascular sclerotherapy, surgery, and surgery plus sclerotherapy in superficial venous incompetence: a randomized, 10-year follow-up trial--final results.

The study was planned to evaluate efficacy and costs of endovascular sclerotherapy (ES) in comparison with surgery and surgery associated with sclerotherapy in a prospective (10-year follow-up), good-clinical-practice study. Patients with varicose veins and pure, superficial venous incompetence were included. Of the patients randomized into the three groups 39 (group A) were treated with ES, 40 (B) with surgery + sclerotherapy, and 42 with surgery only (C). Surgery consisted of ligation of the SFJ (saphenofemoral junction) and of incompetent veins detected with color duplex. Of the preselected 150 patients, 121 subjects entered the study; 96 completed the 10-year follow-up (mean age 52.6 ±6 years; 51 men, 45 women). Dropouts were due to nonmedical problems. At 10 years no incompetence was observed in subjects treated with SPJ ligation (B and C). In the ES group 18.8% of the SFJs were patent and incompetent and in 43.8% of limbs the distal (below-knee) venous system was still incompetent [16.1% in the surgery + scle rotherapy group (p < 0.05) and 36% in the group treated with surgery only (p < 0.05 vs B and 0.05 vs A)]. Color duplex of the long saphenous vein indicated atrophy or obstruc tion of a segment (average 6.7 cm) after SFJ ligation (4.2 cm after ES). The cost of ES was 68% of surgery while the cost of surgery and sclerotherapy was 122% of surgery only. Endovascular sclerotherapy is an effective, cheaper treatment option, but surgery after 10 years is superior.

Femoral atherosclerosis in an older British population: prevalence and risk factors.

Most estimates of the prevalence of peripheral atherosclerosis have been based on intermittent claudication or lower limb blood flow. The aim of this study was therefore to determine the prevalence of underlying femoral plaque, and to determine its association with other cardiovascular disease and risk factors. Presence of plaque was identified using ultrasound in a random sample of men (n=417) and women (n=367) aged 56-77 years. Coexistent cardiovascular disease, exercise and smoking were determined by questionnaire, blood pressure was recorded, and serum cholesterol and plasma fibrinogen were determined. Of the 784 subjects that were scanned, 502 (64%) demonstrated atherosclerotic plaque. Disease prevalence increased significantly with age (P<0.0001), and was more common in men (67.1 vs. 59.4%, P<0.05). Subjects with femoral plaque had a significantly greater odds of previous ischaemic heart disease (OR 2. 2, 95% CI 1.3, 3.7) and angina (OR 1.7, 95% CI 1.03, 2.7), but not of stroke or leg pain on exercise. Current and ex-smoking, raised serum total cholesterol and plasma fibrinogen levels, but not blood pressure, were associated with an increased risk of femoral plaque, independent of age and sex. Frequent exercise and a high HDL cholesterol were significantly associated with lower risk. In conclusion, therefore, atherosclerotic disease of the femoral artery affects almost two-thirds of the population in late middle age. It is associated with an increased prevalence of ischaemic heart disease and angina, but whether detecting at risk individuals using ultrasound offers advantages over simpler and less expensive risk factor scoring requires evaluation in trials.