F. Faccenda

Premature carotid atherosclerosis: does it occur in both familial hypercholesterolemia and homocystinuria? Ultrasound assessment of arterial intima-media thickness and blood flow velocity.

Background and Purpose Homocystinuria due to cystathio-nine β-synthase deficiency and familial hypercholesterolemia are inherited disorders of metabolism that are associated with premature development of cardiovascular disease. This study addresses the possibility that different patterns of carotid wall damage and cerebral blood flow hemodynamics are present in these two metabolic diseases. Methods Twelve patients with homocystinuria due to cys-tathionine β-synthase deficiency (mean age, 24 years), 10 patients with homozygous familial hypercholesterolemia (mean age, 26 years), and 11 healthy control subjects (mean age, 26 years) underwent a vascular examination by noninvasive methods. B-mode ultrasound imaging was used to obtain measurements of intima-media thickness of common carotid, bifurcation, and internal carotid arteries as an index of atherosclerosis. Cerebral blood flow velocity was estimated from vascular examination of the middle cerebral artery by transcranial Doppler. Systolic, diastolic, and mean velocities were measured. Pulsatility index, a possible indicator of vascular resistance in the cerebral circulation, was also calculated. Results Mean maximum intima-media thickness was 1.4 mm in patients with familial hypercholesterolemia, 0.6 mm in patients with homocystinuria, and 0.6 mm in control subjects. The difference between hypercholesterolemic and homocystinuric patients or control subjects was statistically significant (p<.001). Diastolic blood flow velocities were significantly reduced in the middle cerebral arteries of hypercholesterolemic patients compared with homocystinuric patients or control subjects (P<.05), whereas systolic or mean velocities did not differ. The pulsatUity index, a possible indicator of vascular resistance in the cerebral circulation, was significantly higher in hypercholesterolemic patients compared with homocystinuric patients or healthy control subjects (P<.01). A direct relation was demonstrated between pulsatility index of the middle cerebral artery and mean maximum intima-media thickness of carotid arteries on the same side (P<.001). Conclusions Familial hypercholesterolemia is responsible for diffuse and focal thickening of carotid arteries and possibly also for hyperlipidemic endothelial dysfunction extending to small resistance arteries and leading to a disturbed cerebral blood flow. Patients with homocystinuria due to homozygosis for cystathionine β-synthase deficiency seldom have plaques in their carotid arteries. They are similar to healthy control subjects with regard to both intima-media thickness and blood flow velocity in the middle cerebral artery. Therefore, it is unlikely that typical atherosclerotic lesions precede thrombotic events in homocystinuria. However, it is possible that arterial dilatations caused by medial damage lead to thrombosis in homocystinuric patients.

Changes in middle cerebral artery blood velocity in uremic patients after hemodialysis.

Background and Purpose Strokes are a frequent complication in uremic patients on dialysis. We wanted to evaluate the effect of this treatment on cerebral hemodynamic parameters, particularly those of patients with carotid stenosis, who are at higher risk for atherothrombotic ischemic events. Methods We used transcranial Doppler ultrasonography to evaluate blood velocity of the middle cerebral artery in 18 uremic patients before and after hemodialysis. Carotid stenosis was evaluated by echo-Doppler investigation. Six patients were also studied before and after recombinant human erythropoietin treatment. Results Dialysis treatment decreased mean blood velocity in all patients (p<0.001). Eight of 18 patients (44%) with mild (16–50%), moderate (51–80%), or severe (>80%) carotid stenosis had lower velocity than patients with normal carotid arteries (p<0.01), and they experienced a further decrease to even lower levels after hemodialysis (p<0.05). In patients treated with recombinant human erythropoietin, hematocrit increased from 28±8% to 37±5% (p<0.001), and blood velocity had a further decrease by 11%. All changes were associated with modifications toward normality of pH, Paco2, and hematocrit. Conclusions Transcranial Doppler ultrasonography represents a useful method for monitoring cerebral circulation of uremic patients, especially of those at possible risk for ischemia.

Early signs of vascular disease in homocystinuria: A noninvasive study by ultrasound methods in eight families with cystathionine-β-synthase deficiency☆

Fourteen patients (six males, eight females; mean age, 20 years) with homocystinuria due to homozygous cystathionine-beta-synthase (CBS) deficiency, underwent a vascular examination. Fourteen heterozygotes (seven males, seven females; mean age, 46 years), including 12 parents and one daughter of homozygotes (obligate heterozygotes), and one sister of a homozygote (with low enzyme activity as evaluated in vitro), were also examined. Homozygotes and heterozygotes were compared with two separate control groups of different age (mean age, 20 and 43 years, respectively). Ankle/arm systolic pressure index (by continuous-wave Doppler) was, on average, lower in homozygotes (P less than .01) and heterozygotes (P less than .05) as compared with the controls. An ankle/arm index less than 0.97 and suggesting flow-reducing arterial lesions was found in six (21%) lower limbs of homozygotes versus zero in controls (P less than .05). Echo Doppler (Duplex Scanner) abnormalities, indicating early, non-flow-reducing lesions of iliac arteries were more frequent in homozygotes (seven wall abnormalities or stenoses less than 15%) than in young controls (P less than .05). The corresponding figures for heterozygotes were seven wall abnormalities or stenoses (1% to 15% and one stenosis 16% to 50%) (P less than .01 v middle-aged controls). Early lesions (three wall abnormalities or stenoses less than 15%, three stenoses 16% to 50%) were detected in six (23%) internal carotids of heterozygotes versus three (3%) of corresponding controls (P less than .05). Technical limitations precluded the accurate detection of early lesions in the internal carotid arteries of young homozygotes and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral blood flow velocity and systemic vascular resistance after acute reduction of low-density lipoprotein in familial hypercholesterolemia.

Background and Purpose Low-density lipoprotein apheresis is currently used for the treatment of familial hypercholesterolemia, an inherited disorder of metabolism associated with premature development of cardiovascular disease. We wanted to evaluate cerebral blood flow velocity, cardiac output, and systemic vascular resistance in patients with familial hypercholesterolemia before and after low-density lipoprotein apheresis. Methods Ten patients (age range, 14 to 46 years; 4 males, 6 females) with familial hypercholesterolemia (8 homozygotes, 2 heterozygotes) and 10 healthy control subjects of comparable age and sex distribution participated in the study. Low-density lipoprotein apheresis by dextran sulfate was performed in 8 patients (7 homozygotes, 1 heterozygote). Six patients (4 homozygotes, 2 heterozygotes) underwent a procedure of extracorporeal erythrocyte filtration with the same extracorporeal volume as for low-density lipoprotein apheresis, but with the exclusion of the passage of plasma through the dextran sulfate column. Cerebral blood flow velocity (transcranial Doppler), cardiac output, and systemic vascular resistance (electric bioimpedance cardiography) were determined by noninvasive techniques before and 1 day and 7 days after low-density lipoprotein apheresis or extracorporeal erythrocyte filtration. Plasma and blood viscosities were measured at the same time. Results Before apheresis, mean and diastolic cerebral flow velocities were abnormally low in hypercholesterolemic patients (P<01 and P<02 vs healthy control subjects, respectively). After apheresis, low-density lipoprotein cholesterol was lowered by 40% to 60% from baseline, and cerebral blood flow velocities (mean, systolic, and diastolic velocities) were increased (P<01). Cardiac output, systemic vascular resistance, and viscosity values were not significantly modified. Extracorporeal erythrocyte nitration (without passage of plasma through the dextran sulfate column) did not modify serum lipids, hemodynamic parameters, or viscosity values. Conclusions Low-density lipoprotein apheresis produces potentially useful hemodynamic effects. They are not adequately explained by changes in blood viscosity alone and might reflect a restoration of endothelium-mediated vasodilation, which is inhibited by high concentrations of low-density lipoprotein.

Small dense low-density lipoprotein in familial combined hyperlipidemia: Independent of metabolic syndrome and related to history of cardiovascular events

INTRODUCTION It is unclear whether small dense low-density lipoprotein (sdLDL) are associated with familial combined hyperlipidemia (FCHL), independently of the metabolic syndrome (MS). It is also unclear whether sdLDL are related to history of cardiovascular (CVD) events in FCHL patients, independently of MS. PATIENTS AND METHODS Serum levels of sdLDL, expressed as percentage of total LDL cholesterol (LDL score), were determined in 137 probands with FCHL and in 133 normolipidemic, normotensive, normoglycemic healthy subjects. RESULTS In binary logistic regression age- and gender-adjusted LDL score values above the 90th and 95th percentiles of the values in the control group (10.23 and 13.11%, respectively) were found to be significant predictors of FCHL status, independently of MS diagnosis (p=0.007 and p<0.0001, respectively). Values of the LDL score above the 90th and the 95th percentile of the control group resulted to be significantly related to FCHL status, even after adjustment for the components of MS (p=0.006 and p=0.001, respectively). Among FCHL patients, values of the LDL score above 95th percentile of the values in the control group were found to be significantly related to personal and/or family history of CVD events, independently of age, gender, total cholesterol, apolipoprotein (apo) B, and MS status (p=0.016). The same significant relationship was found adjusting for all components of MS (p=0.034). CONCLUSIONS High concentrations of sdLDL are highly specific markers of FCHL, independently of concomitant MS. In FCHL patients high levels of sdLDL are related to history of CVD events, independently of MS, total cholesterol and apo B.

Premature development of iliac artery stenosis in asymptomatic type II hyperlipoproteinemia.

There is conflicting evidence on the relationship between increased low density lipoprotein (LDL) concentration in Type II hyperlipoproteinemia and premature development of peripheral atherosclerosis of the lower limbs. We evaluated the early signs of iliac artery involvement in patients with asymptomatic Type II hyperlipoproteinemia. Of these, 23 were Type IIA, 12 were Type MB. Thirty-five consecutive patients, ages 40 to 60 years, with asymptomatic Type II hyperlipoproteinemia (LDL cholesterol ≥3.80 mmol/liter, 147 mg/dl) and 54 normocholesterolemic controls (plasma cholesterol <5.70 mmol/liter, 220.6 mg/dl) from a random sample of clinically healthy, 50-year-old men had a noninvasive examination to detect common and external iliac artery stenosis. Both Type II patients and the controls were examined by the echo-Doppler technique (Duplex Scanner Ill-ATL Mark V) with spectral analysis of the Doppler signals. This method is sensitive not only to severe stenosis or occlusion but also to non-flow-reducing stenosis (<50% narrowing of the lumen diameter) and to minor wall irregularities (1%—15% stenosis). In Type II patients, 19 of 70 limbs (27%) were abnormal as compared to 6 of 108 limbs (6%) in the controls (p < 0.001). The premature development of an obliterating disease of the iliac arteries was demonstrated in persons asymptomatic for Type II hyperlipoproteinemia.

Increased carotid artery intima-media thickness is associated with a novel mutation of low-density lipoprotein receptor independently of major cardiovascular risk factors

The current study sought to investigate the role of low-density lipoprotein receptor (LDLr) mutations in assessing the risk profile of familial hypercholesterolemia (FH) patients, independently of major cardiovascular risk factors. FH due to LDLr mutations is associated with premature atherosclerosis. The variable clinical severity of the disease in heterozygotes has been related to cholesterol levels and the coexistence of other cardiovascular risk factors, but the independent role of different LDLr mutations is still unclear. cDNA of LDL gene was sequenced in 102 patients with clinical features of heterozygous FH. Carotid artery intima-media thickness (IMT) was measured by B-mode ultrasound imaging in all patients. Sixteen different mutations (5 never described) were found in 82 patients (49 families; mean age, 39 years; 53% women). One of the newly described mutations, the 2312-3 C-->A, was found in 24 patients (13 families). The mean of maximum thicknesses was significantly higher in the 2312-3 C-->A group than in patients with other LDLr mutations (P=.004 after adjustment for major cardiovascular risk factors). Similar results (P=.001) were obtained in the adjusted comparisons of probands only, and of the patients with similar baseline cholesterol (P=.002). This study indicates that the identification of an LDLr mutation can help to assess the risk profile of FH patients independently of the major cardiovascular risk factors.

Doppler Measurement of the Pressure Drop Caused by Arterial Stenosis: An Experimental Study: A Case Report

A stenotic arterial lesion which reduces the cross-sectional area of the artery causes an increased velocity and, as a consequence, a loss in kinetic energy and a pressure drop. A simplified formula, derived from the Bernoulli principle, relates the pressure drop to the maximum velocity of the blood flow in the stenotic segment: ΔP (mmHg) =4 Vmax2 (m/sec). This formula has been validated for stenosis of cardiac valves. Aim of our study was to test the hypothesis that this formula applies in the major arteries using Doppler ultrasound with spectrum analysis. In our experiments we created artificial graded stenoses of varied geometry in the thoracic aorta of dogs. Invasive pressure measurements were obtained using intra-arterial needles on both sides of the stenosis. A Doppler signal was obtained with a 2.5 MHz CW probe, insonating the stenotic area from a distance, with an almost parallel approach. In these conditions the maximum Doppler frequency shift is an accurate estimate of the maximum flow velocity, according to the Doppler equation. We compared the Doppler derived (ΔP=0.36 Fmax2) and the invasive measurements of pressure drops. Our results show a highly significant correlation between the intra-arterial and the Doppler measurements of the pressure drops caused by arterial stenoses and encourage efforts in applying similar techniques in the noninvasive evaluation of vascular patients.

Tumor necrosis factor-α is a marker of familial combined hyperlipidemia, independently of metabolic syndrome

It is unclear whether an association between familial combined hyperlipidemia (FCHL) and inflammatory markers exists, independently of age, sex, body weight, insulin resistance, and metabolic syndrome. Serum concentrations of soluble vascular cell adhesion molecule-1 (sVCAM-1), monocyte chemoattractant protein 1, interleukin 6, tumor necrosis factor-alpha (TNF-alpha), and high-sensitive C-reactive protein were determined in 135 probands with FCHL and in 146 normolipidemic, normotensive, normoglycemic healthy subjects. Insulin resistance was evaluated using homeostasis model assessment (HOMA). All inflammatory parameters, except interleukin 6, were significantly higher in FCHL according to medians or mean comparisons. After adjustment for age, sex, body mass index, and HOMA, only TNF-alpha remained an independent predictor of FCHL status by binary logistic regression (odds ratio [OR], 1.19; 95% confidence interval [CI], 1.07-1.31; P = .001). In particular, elevated levels of TNF-alpha (above the 90th and 95th percentiles of the value observed in the control group, 9.6 and 9.8 pg/mL, respectively) were independent predictors of FCHL status: for TNF-alpha above the 90th percentile, OR was 7.91 (95% CI, 3.27-19.13; P < .001), and for TNF-alpha above 95th percentile, OR was 13.08 (95% CI, 4.60-37.15; P < .0001). The independent role of TNF-alpha as predictor of FCHL status was confirmed after adjustment for components of the metabolic syndrome (P = .007 and P = .003, for TNF-alpha values above 90th and 95th percentiles, respectively). In conclusion, among the inflammatory markers most commonly measured, only TNF-alpha was associated with FCHL independently of age, sex, body mass index, and HOMA. The association of TNF-alpha with FCHL was also independent of the metabolic syndrome.

Noninvasive ultrasound evaluation of pressure gradients in aortic root of homozygotes for familial hypercholesterolemia.

The aim of this study was to measure noninvasively by Doppler ultrasound the blood flow velocity at the level of the aortic root in patients with homozygous familial hypercholesterolemia (FH) to detect abnormal pressure gradients. Seven patients with homozygous FH and seven healthy controls matched for age and sex were included in the study. Continuous-wave Doppler (2 MHz) was used to measure the highest detectable velocity from the aortic root; the probe was positioned in the suprasternal notch. When an abnormal velocity was detected, the corresponding pressure drop was calculated from the formula: Delta P = 4Vmax2. Each FH patient had an abnormal aortic velocity consistent with a pressure gradient across the valvular area. All the controls had normal aortic velocities (p less than 0.01). The measurement of the pressure drop across the aortic valvular area in FH patients gives an estimate of the lesions produced by cholesterol deposition in a crucial area of the cardiovascular system near the origin of coronary arteries. The noninvasivity of this method makes it an excellent method for obtaining parameters for follow-up and clinical trials.