Circulating endothelial cell markers in peripheral vascular disease: relationship to the location and extent of atherosclerotic disease

We examined the relationship between specific endothelial cell markers soluble E-selectin, von Willebrand factor and soluble thrombomodulin and the location or extent of atherosclerosis by analysing plasma samples from 200 patients with symptomatic peripheral vascular disease and 213 age- and sex-matched asymptomatic control subjects. Using ELISAS, we found increased von Willebrand factor and thrombomodulin (both P < 0.0001) in the patients relative to the control subjects, but no significant change in soluble E-selectin. Soluble thrombomodulin was increased in patients with disease at one locus (i.e. of the carotid or iliac/femoral arteries), with an additional significant increase in patients with disease at multiple loci (i.e. any combination of carotid, coronary or iliac/femoral artery disease). No marker differentiated carotid artery disease from iliac/femoral artery disease. We conclude that von Willebrand factor is a marker of generalized atherosclerosis, but that soluble thrombomodulin is related to the extent of disease. Further research into these endothelial cell products are warranted to explore their diagnostic and/or prognostic potential.     

Lipoprotein(a) and general risk factors in patients with angiographically assessed peripheral arterial disease

High lipoprotein(a) [Lp(a)] has been observed in patients with ischemic heart disease and cerebrovascular disease. Lp(a) is actually thought to be an independent risk factor for coronary disease. We therefore carried out a case-control study, evaluating plasma Lp(a) in 61 patients with angiographically documented peripheral arterial disease (PAD) and in 61 age- and sex-matched patients with no cardiovascular disease. General risk factors for vascular disease were also taken into account. Lp(a) was significantly higher in patients than controls (257.0 +/- 34.8 vs 146.5 +/- 23.5 mg/l p < 0.05), as were cigarette smoking, diabetes, cholesterolemia, fibrinogenemia and the waist-to-hip circumference ratio. Stepwise logistic regression analysis showed that, in addition to cigarette smoking, diabetes, cholesterol and fibrinogen, Lp(a) is a significant independent risk indicator for PAD. This result suggests that high plasma Lp(a) is associated with enhanced risk of PAD and must therefore be evaluated alongside traditional risk factors.     

The role of angioplasty in the treatment of cerebrovascular disease

Percutaneous transluminal angioplasty (PTA), an established treatment of arterial stenosis in coronary, renal, and other peripheral sites, is being applied to the cerebrovascular territory with greater frequency. Early results suggest that PTA may be safe and efficacious in the treatment of extracranial arterial stenosis secondary to atherosclerosis and fibromuscular dysplasia. PTA is also being used with promising results in treating symptomatic intracranial arterial stenosis from atherosclerosis. This review examines PTA in the treatment of cerebrovascular disease, current indications, and results.     

Soluble adhesion molecules reflect endothelial cell activation in ischemic stroke and in carotid atherosclerosis

BACKGROUND AND PURPOSE: Activation of endothelial cells and platelets plays an important role in the development of atherosclerosis and thrombotic disorders. Soluble adhesion molecules originating from these cells can be demonstrated in plasma. We hypothesized that elevated plasma concentrations of soluble P-selectin (sP-selectin), soluble intercellular adhesion mole-cule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), and soluble E-selectin (sE-selectin) can reflect activation of endothelial cells and/or platelets in acute ischemic stroke and in previously symptomatic internal carotid artery stenosis. METHODS: Plasma was sampled from patients within 2 days of acute ischemic stroke (n = 28), from patients with a previous (> 1 week) transient or persistent ischemic neurological deficit associated with stenosis of the internal carotid artery (n = 34), and from control patients without a history of vascular disease (n = 34). Concentrations of sP-selectin, sICAM-1, sVCAM-1, and sE-selectin were measured by means of an enzyme-linked immunosorbent assay. RESULTS: Compared with control subjects, sP-selectin and sE-selectin were significantly elevated in the acute stage of ischemic stroke (P < .0001 and P = .001, respectively) as well as in previously symptomatic carotid stenosis (P < .0001 and P = .0007). sICAM-1 and sVCAM-1 were not increased. CONCLUSIONS: The elevated levels of sE-selectin indicate that endothelial cell activation occurs both in the acute stage of ischemic stroke and in previously symptomatic carotid atherosclerosis. Increased sP-selectin concentrations reflect endothelial cell activation as well but may also be caused by platelet activation.     

George Lyman Duff Memorial Lecture. Arterial imaging and atherosclerosis reversal

This review explores evidence for the reversibility of atherosclerosis and augmentation of angiography with non-invasive arterial wall imaging. Meta-analysis from coronary angiographic trials demonstrates that regression and stabilization are 1.5 to 2 times more common in treated than placebo subjects, and progression is reduced by half in treated subjects. Odds ratios for clinical coronary events are significantly reduced with treatment. Lesion improvement occurs more readily in women than men and more so in women receiving concomitant estrogen replacement therapy. Lesions with > or = 50% diameter stenosis (%S) at baseline respond more readily to lipid lowering than those < 50% S, whereas reduction in coronary events is related to stabilization of lesions < 50% S. Lipoproteins have a differential effect on lesion progression according to lesion size, and triglyceride-rich lipoproteins play an important role in the progression of coronary artery lesions < 50% S. Improved therapeutic regimens to alter progression of atherosclerosis may require adjunctive therapy, such as with antioxidants or hormone replacement therapy, in concert with low-density lipoprotein cholesterol reduction to prevent new lesion formation or early lesion progression. Sequential coronary angiographic determination of progression evaluated by both quantitative coronary angiography and global change score, a visual assessment of overall lesion change, predicts clinical coronary events. Only inferences about the state of the arterial wall can be made from angiography, because it delineates only the lumen. Therapy testing and study of atherosclerosis progression can be improved with noninvasive B-mode ultrasonographic imaging of the distal common carotid artery far-wall intima-media thickness (IMT), a reliable measure of early preintrusive atherosclerosis. Measurement of common carotid IMT is useful for the study of coronary artery risk factors and can augment studies of coronary artery intrusive lesions, because it is associated with coronary artery disease. B-mode measurement of common carotid IMT has the potential of serving as a noninvasive surrogate end point for clinical coronary events. Screening for peripheral vessel changes indicative of high risk for coronary artery disease is possible and cost-effective with the noninvasive procedures now available.     

Secondary prevention of arteriosclerosis

Secondary prevention of arteriosclerosis tries to inhibit progression of the atherosclerotic process. Therapeutic measures focus on modification of cardiovascular risk factors and antithrombotic treatment. Hypercholesterolemia is the main risk factor for coronary artery disease. The risk of a coronary event is correlated to the plasma cholesterol level. Lowering plasma cholesterol results in reduction of vascular morbidity and mortality. Cigarette smoking is the predominant risk factor for peripheral arterial occlusive disease (PAOD). Smoking cessation reduces progression of PAOD and lowers cardiovascular morbidity and mortality. The preventive effect of antihypertensive therapy in hypertensive patients is most pronounced for cerebrovascular events. Antihypertensive measures improve prognosis after stroke and myocardial infarction. The increased cardiovascular risk in diabetics is in part explained by hyperglycemia and hyperinsulinemia, but also depends on coexisting dyslipidemia and hypertension. Intensive treatment of elevated blood glucose levels, dyslipidemia and hypertension are important preventive measures. Aspirin is highly effective in secondary prevention of vascular events. For the coronary arteries, low-dose aspirin is well established. Whether low-dose aspirin is equally effective for reducing progression of arteriosclerosis in the cerebrovascular and in the peripheral vessels is questionable. Ticlopidine serves as an alternative to aspirin; however, neutropenia may occur, which requires supervision of the patient.     

Ultrasound and lipoproteins as predictors of lipid-rich, rupture-prone plaques in the carotid artery

The aim of this review is to summarize present knowledge of the ultrasonic detection and determinants of carotid atherosclerosis with lipid-rich cores and to review the evidence that these measures of plaque type may predict cerebral events. With the use of high-resolution ultrasound B-mode imaging, carotid plaques evaluated as only weakly reflecting the ultrasound beam (echolucent) have been associated with a higher risk of neurological events than are plaques reflecting the ultrasound signal strongly (echorich). Histologically, these echolucent plaques have a higher content of lipid and hemorrhage than do echorich plaques, which contain more calcification and fibrous tissue. Findings in the coronary arteries indicate that a lipid-rich plaque with a thin, fibrous cap is more vulnerable, is more prone to rupture, and cause symptoms compared with fibrous plaques. A search for determinants in the blood for these vulnerable plaques suggests that low density lipoprotein (LDL) cholesterol is the best lipid predictor for the extent of atherosclerosis, whereas triglyceride-rich lipoproteins in particular seem to predict an echolucent plaque. Lowering of LDL cholesterol and triglyceride-rich lipoproteins in plasma is associated with reduced progression of coronary atherosclerosis and coronary events. LDL cholesterol reduction is also associated with a reduced stroke rate. These improvements in the prognosis are thought to be the result of a reduction in the lipid content of the plaques, making them more stable and resistant to rupture rather than an actual reduction in plaque volume and degree of stenosis. In conclusion, it appears that ultrasound B-mode imaging as well as lipoproteins presumably may predict dangerous and rupture-prone, lipid-rich plaques in the carotid arteries, thereby being potential diagnostic tools in the prevention of neurological events.     

Insulin resistance as an independent risk factor for carotid wall thickening

It has been reported that insulin resistance is associated with essential hypertension and that an aggregation of risk factors-hypertension, dyslipidemia, and glucose intolerance-together with insulin resistance leads to the more frequent appearance of coronary artery disease. We examined the relation between early asymptomatic atherosclerosis and these risk factors in 72 nondiabetic subjects with essential hypertension (41 men, 31 women) aged 50 to 59 years. Intima-media thickness and plaque formation of the carotid artery were assessed by B-mode ultrasonography, and insulin sensitivity was measured by the steady-state plasma glucose method. Lipoprotein profile was analyzed by ultracentrifugation. The intima-media thickness of the common carotid artery significantly correlated with systolic pressure; mean blood pressure; steady-state plasma glucose, indicating insulin resistance; fasting insulin; area under the curve of plasma insulin and glucose; body mass index; apolipoprotein B; apolipoprotein B in low-density lipoprotein; lower ratio of cholesterol to apolipoprotein B of low-density lipoprotein; and decreased high-density lipoprotein cholesterol. By multiple regression analysis, steady-state plasma glucose was the strongest risk, followed by lower high-density lipoprotein and systolic pressure. These three factors accounted for 54.9% of all the risk for increased intima-media thickness of the common carotid artery. In conclusion, insulin resistance was the strongest risk factor for carotid intima-media thickness, followed by lower high-density lipoprotein cholesterol and hypertension. An effort to maintain normal insulin sensitivity is essential for the prevention of early atheromatous lesions in essential hypertension.     

Relation of exercise-induced myocardial ischemia to cardiac and carotid structure

There is a strong relation of carotid atherosclerosis to coronary artery disease and left ventricular hypertrophy. In addition, abnormalities of carotid structure are strongly associated with abnormal left ventricular geometry and structure. However, little is known regarding the relation of exercise-induced ST depression to carotid atherosclerosis, carotid, or left ventricular structure in the absence of apparent coronary disease. The relationship of exercise ECG myocardial ischemia to the presence of carotid atherosclerosis and to carotid and left ventricular structure was assessed in 204 asymptomatic subjects free of clinical evidence of cardiovascular disease. Myocardial ischemia on the exercise ECG, defined by a chronotropically adjusted ST/HR slope of >3.47 microV/bpm, was associated with a nearly threefold greater likelihood of discrete carotid atherosclerosis (50% [6 of 12] versus 17% [29 of 192], P=.007) and with older age, male sex, higher systolic and diastolic blood pressures, greater left ventricular mass and mass index, and greater common carotid artery intimal-medial thickness and cross-sectional area index. Stepwise logistic regression analyses, including standard risk factors, revealed that only carotid artery cross-sectional area index (P=.0007) and systolic blood pressure (P=.005) independently predicted an abnormal chronotropically adjusted ST/heart rate slope. Moreover, among 132 subjects with > or = 10 microV of ST-segment depression, only left ventricular mass index and carotid artery cross-sectional area index were significant predictors of the chronotropically adjusted ST/heart rate slope response. Subendocardial ischemia on the exercise ECG is strongly associated with the presence of carotid atherosclerosis and is related to systolic blood pressure, carotid artery cross-sectional area index, and left ventricular mass index, independent of age, sex, and other cardiac risk factors. These findings provide additional insights into the relation between coronary and carotid atherosclerosis and suggest that an association among ischemia and left ventricular and carotid structural abnormalities may contribute to the pathogenesis of coronary events.     

Association of chronic infection of Chlamydia pneumoniae and coronary heart disease in the Japanese

The association of Chlamydia pneumoniae with atherosclerosis of coronary and carotid arteries and the aorta has been demonstrated by seroepidemiology and by detection of the organism in atheromata. We investigated the frequency of C. pneumoniae seropositivity in patients with acute myocardial infarction (AMI). C. pneumoniae-specific antibodies were measured by the microimmunofluorescence test in 160 AMI patients and 160 control subjects matched for age and gender. The odds ratios (ORs) were 2.2 (95% confidence interval (CI), 1.2 to 3.9) for immunoglobulin (Ig)G and 2.7 (95% CI, 1.7 to 4.3) for IgA. After adjustment for other cardiovascular risk factors of age, gender, hypertension, diabetes, cigarette smoking and serum cholesterol, the ORs were essentially unchanged. This study confirmed that the observations of an association between antibody against C. pneumoniae and coronary heart disease in Western nations is also present in Japan. Our results are comparable to the previous seroepidemiological studies reporting ORs of 2.0 or greater.     

Angioplasty and stenting of the carotid artery

Percutaneous endovascular techniques are well established procedures in the management of peripheral vascular disease and visceral arterial stenosis. They are now being adapted for use in the carotid artery as well. 8 patients with 9 extracranial carotid artery stenoses were successfully treated by percutaneous angioplasty, following which in 4 of them 5 stents were inserted. The stenotic lesions were situated in the proximal internal carotid artery and in its bifurcation and also in the common carotid artery. The indications for angioplasty in these patients were the same as for surgery. There were no major complications. 1 patient had transient hemiparesis lasting a few hours, and another had bradycardia following balloon dilation in the region of the carotid body. Percutaneous endovascular treatment of carotid artery stenosis is becoming a safe, feasible alternative to surgery.     

Asymptomatic occlusive lesions of carotid and intracranial arteries in Japanese patients with ischemic heart disease: evaluation by brain magnetic resonance angiography

BACKGROUND AND PURPOSE: The purpose of this study was to elucidate the prevalence and degree of asymptomatic occlusive lesions in the carotid and intracranial arteries in Japanese patients with ischemic heart disease (IHD). METHODS: We performed carotid and intracranial MR angiography (MRA) on 67 patients (49 men, 18 women; age range, 40 to 78 years; mean age, 60.1 years) who had received selective coronary angiography for the clinical diagnosis of IHD. On the basis of these images, degree of stenosis in the regions of the bilateral carotid artery bifurcation and five regions of the intracranial arteries, ie, bilateral intracranial portions of the internal carotid arteries and the middle cerebral arteries and the basilar artery were estimated. RESULTS: Stenosis of more than 25% narrowing of the diameter of the target arteries was found in 15 patients (22.4%) in the extracranial carotid arteries and in 11 patients (16.4%) in the intracranial arteries. Most of the stenotic lesions were mild. The incidence of extracranial carotid stenosis and the severity of coronary atherosclerosis showed a significant correlation. The mean age of the patients with intracranial arterial lesions was statistically higher than those without intracranial lesions. CONCLUSIONS: Our data suggest that asymptomatic occlusive lesions in the carotid and intracranial arteries are fairly common in Japanese patients with IHD, although the degree of stenosis is relatively mild. Coexistence of carotid atherosclerosis should be suspected in IHD patients with severe coronary atherosclerosis, and the possibility of atherosclerosis in the intracranial arteries should be considered in aged IHD patients.     

Effect of pravastatin (10 mg/day) on progression of coronary atherosclerosis in patients with serum total cholesterol levels from 160 to 220 mg/dl and angiographically documented coronary artery disease. Coronary Artery Regression Study (CARS) Group

To evaluate the effect of pravastatin on progression of coronary atherosclerosis in normocholesterolemic patients with coronary artery disease (CAD), 90 patients with CAD and serum cholesterol levels of 160 to 220 mg/dl were randomized into a pravastatin (10 mg/day) group (n = 45) and control group (n = 45) in a 2-year study. The proportions of patients with progression (an increase of > or = 15% in percent stenosis) and regression (a decrease of > or = 15% in percent stenosis) of coronary atherosclerosis were compared between the 2 groups. Of 90 patients, 80 (89%) had a final angiogram: the pravastatin (n = 39) and control group (n = 41). Percent changes in total cholesterol, low-density lipoprotein cholesterol, and apoprotein B levels were significantly greater in the pravastatin group than in the control group (total cholesterol -11 +/- 12% vs 3 +/- 15%, p < 0.01; low-density lipoprotein cholesterol -18 +/- 16% vs 4 +/- 21%, p < 0.01; apoprotein B -5 +/- 20% vs 6 +/- 20%, p < 0.05). The proportion of patients with progression of coronary atherosclerosis was significantly smaller in the pravastatin group than in the control group (21% vs 49%, p < 0.05). The proportion of patients with disease regression did not differ in the 2 groups (3% vs 2%, p = NS). In conclusion, this study indicates that cholesterol-lowering therapy with pravastatin can prevent the progression of coronary atherosclerosis even in normocholesterolemic patients with established CAD.     

Homocysteine, a risk factor of atherosclerosis

Homocysteine is a sulphurated amino acid which, at high plasma concentrations, predisposes to thrombosis and induces focal arteriosclerosis. These characteristics have been established both in patients with homocystinuria, a genetic disease in which homocysteine accumulates in the blood, and in animals submitted to intravenous infusions of this amino acid. Many recent publications have addressed the problem of whether mild increases in plasma homocysteine predisposed to the development of the usual forms of atherosclerosis. Transverse epidemiological studies have established a correlation between homocysteine levels and atherosclerosis at all its vascular localisations, coronary, carotid and lower limb. Multivariate analysis in several prospective studies have shown plasma homocysteine to be an independent risk factor for cerebrovascular accidents and myocardial infarction. Causes of mild increases in plasma homocysteine are usually dietetic deficiencies in folic acid, vitamin B6 or B12, or genetic by mutation of the methylene-tetrahydrofolate reductase. Renal failure is also associated with a high risk in plasma homocysteine levels. However, the toxicity of homocysteine to the arterial wall at slightly elevated concentration remains speculative.     

Comparison of isradipine and enalapril effects on regional carotid circulation in patients with hypertension with unilateral internal carotid artery stenosis

This randomized, double-blind, placebo-controlled study was aimed at detecting cerebrovascular effects of isradipine and enalapril in patients with moderate hypertension depending on the presence and grade on unilateral stenosis of internal carotid artery (ICA). We evaluated carotid vascular resistance by using Doppler analysis and regional cerebral blood flow (rCBF) by using 133Xe-clearance technique before and after a single 5-mg oral dose of isradipine, enalapril, or placebo. Their effects were randomly and consecutively tested in 73 patients with essential hypertension subdivided into three groups: without carotid occlusive lesions, with moderate (50-75%), and with severe (76-99%) unilateral asymptomatic ICA stenosis. There were no differences in age, gender, and antihypertensive effects of the drugs between these three subgroups. Three major variants of cerebrovascular drug effects were observed: absence of changes (variant I), decrease in carotid vascular resistance with increase in rCBF and elimination of side-to-side asymmetry (variant II), and increase in carotid vascular resistance with further reduction of rCBF ipsilaterally ICA stenosis, and increased side-to-side asymmetry (variant III). Frequency of variant III was significantly higher in patients with severe ICA stenosis. Enalapril produced variant I of cerebrovascular effects in most patients examined; variant III was observed only in 13% of patients with severe ICA stenosis. Isradipine produced variant I of cerebrovascular effects much less frequently than did enalapril. For this drug, variant II was most typical in patients without ICA stenosis and with moderate ICA stenosis. In 43.5% of patients with severe ICA stenosis, however, isradipine produced reduction of cerebral perfusion. Presumably the presence of ICA stenosis, especially >75%, increases the risk of cerebrovascular disorders in antihypertensive therapy. In patients with severe ICA stenosis, treatment with enalapril appears to be safer than that with isradipine.     

Whole blood viscosity and haematocrit are associated with internal carotid atherosclerosis in men

BACKGROUND: Alterations in blood viscosity and haematocrit have been described in patients with coronary and cerebrovascular diseases. The results have not been conclusive, as modifications of these parameters are often associated with the presence of coronary heart disease (CHD) risk factors. The aim of this study was to verify whether blood viscosity and haematocrit are increased in patients with carotid atherosclerosis, independently of the presence of CHD risk factors. METHODS: Male patients with internal carotid atherosclerosis (ICA+, n = 28) were selected from participants in a cardiovascular disease prevention campaign. Controls (ICA-, n = 28), also participating in the prevention campaign, were matched for age and all the classical CHD risk factors. Plasma lipids, glucose and fibrinogen were determined by routine methods. Cigarette smoking and current drug therapy was established by questionnaire. Whole blood viscosity was measured at shear rates of 450 and 225/s, using a cone-plate viscometer. Echo-Doppler of carotid arteries was performed with an ATL Ultramark 9 HDI using a 5-10 MHz multifrequency probe. RESULTS: Blood pressure, plasma lipids, glucose, body mass index, fibrinogen and plasma viscosity were similar in the two groups. ICA+ patients, compared with the ICA- group, had significantly greater values of blood viscosity (4.52 +/- 0.37 cP compared with 4.18 +/- 0.45 cP, P < 0.005 respectively; shear rate 450/s) and haematocrit (48.57 +/- 3.19% compared with 45.57 +/- 4.81%, P < 0.008 respectively). CONCLUSIONS: Our findings demonstrate that blood viscosity and haematocrit are increased in men with internal carotid atherosclerosis, independently of the presence of risk factors for atherosclerosis.     

Cardiovascular risk factors associated with clinically isolated and diffuse atherosclerosis in Spanish patients with coronary artery disease

BACKGROUND: Patients with coronary artery disease (CAD) associated with peripheral (PAD) or cerebrovascular disease (CVD), a condition called diffuse atherosclerosis, have a higher risk of death than patients with isolated CAD. The prevalence of diffuse atherosclerosis and the atherogenic risk factors associated with this condition in our geographic area have not been described previously. METHODS: A cohort of 2597 patients (62 +/- 10.8 years, 665 women) consecutively admitted at Bellvitge Hospital because of acute coronary syndromes were studied. CAD patients were divided in two groups with diffuse and located atherosclerosis according to whether they had or they had not an associated PAD or CVD. Baseline history, physical data and lipid profile were recorded in each patient according to a standardized questionnaire. RESULTS: A total of 370 patients (14.2%) had diffuse atherosclerosis. Among them, there were more men and women older than 55 years than among those with isolated CAD. Patients with diffuse atherosclerosis were more frequently hypertensive, diabetic and former smokers than those with isolated CAD (60.5% vs. 49.4%, P < 0.01; 37.4% vs. 24.5%, P < 0.01; and 47% vs. 35.7%, P < 0.01, respectively). There were no significant differences in the mean values of total cholesterol (TC), low-density cholesterol (LDL-C), high-density cholesterol (HDL-C) and triglycerides between both groups of patients, but patients with diffuse atherosclerosis had a lower HDL-C/TC ratio, with borderline statistical significance (0.18 +/- 0.06 vs. 0.19 +/- 0.06, P = 0.06). Using multiple logistic regression analysis, the variables associated with diffuse atherosclerosis in men were age greater than 55 years (OR 1.97, CI 1.33-2.93), hypertension (OR 1.50, CI 1.14-2.20), diabetes (OR 1.78, CI 1.20-2.70), smoking (former smokers) (OR 2.09, CI 1.36-3.24) and HDL-C/TC < 0.20 (OR 1.60, CI 1.18-2.17); and in women hypertension (OR 3.43, CI 1.48-7.94) and diabetes (OR 2.58, CI 1.55-4.80). CONCLUSIONS: Clinically overt diffuse atherosclerosis is a relatively common disease. Older patients and those with hypertension, diabetes or low HDL-C/TC ratio are more likely to have diffuse atherosclerosis than those without these conditions.     

Reduced coronary flow reserve in familial hypercholesterolemia

Familial hypercholesterolemia (FH) presents the highest risk for coronary artery disease (CAD) among patients with hyperlipidemia. Therefore, early detection of coronary arterial atherosclerosis is important for the treatment of FH patients. The aim of this study was to detect early coronary arterial abnormalities that may relate to future atherosclerosis in asymptomatic FH patients by measuring coronary flow reserve (CFR) using PET and 13N-ammonia. METHODS: Twenty-five patients with FH (14 men, 11 women) without a history of myocardial ischemia and 14 control subjects (9 men, 5 women) were studied. Total serum cholesterol (mmole/liter) was 5.33 +/- 0.66 in control subjects and 7.90 +/- 0.77 in FH patients (p < 0.01 versus control subjects). RESULTS: Myocardial blood flow (MBF) at rest and during dipyridamole loading was measured using PET, and CFR was calculated. MBF (ml/min/100 g weight heart) at rest in the FH group (79.0 +/- 20.0) was comparable to that in control subjects (70.0 +/- 17.0). However, MBF during dipyridamole loading was significantly lower in FH patients (163.0 +/- 67.0) than in control subjects (286.0 +/- 120.0, p < 0.01). CFR in FH patients (2.09 +/- 0.62) was also significantly lower than that in control subjects (4.13 +/- 1.38, p < 0.01). CFR showed a gender-specific variance in FH patients (1.85 +/- 0.40 in men versus 2.55 +/- 0.74 in women p < 0.05) but not in control subjects. Significant inverse correlations between CFR and the total plasma cholesterol level as well as plasma LDL cholesterol were observed. CONCLUSION: The CFR was reduced in patients with FH. This abnormality was more prominent in men than in women patients. Noninvasive assessment of CFR by 13N-ammonia PET was useful to detect early abnormalities of the coronary arteries in asymptomatic patients with FH.