Increased Aortic Valve Calcification in Familial Hypercholesterolemia: Prevalence, Extent, and Associated Risk Factors.

BACKGROUND: Familial hypercholesterolemia is typically caused by LDL receptor (LDLR) mutations that result in elevated levels of LDL cholesterol (LDL-C). In homozygous FH, the prevalence of aortic valve calcification (AoVC) reaches 100% and is often symptomatic. OBJECTIVES: The objective of this study was to investigate the prevalence, extent, and risk-modifiers of AoVC in heterozygous FH (he-FH) that are presently unknown. METHODS: Asymptomatic patients with he-FH and 131 non-familial hypercholesterolemia controls underwent CT computed tomography calcium scoring. AoVC was defined as the presence of calcium at the aortic valve leaflets. The extent of AoVC was expressed in Agatston units, as the AoVC-score. We compared the prevalence and extent of AoVC between cases and controls. In addition, we investigated risk modifiers of AoVC, including the presence of LDLR mutations without residual function (LDLR-negative mutations), maximum untreated LDL-cholesterol (maxLDL), LDL-C, blood pressure, and coronary artery calcification (CAC). RESULTS: We included 145 asymptomatic patients with he-FH (93 men; mean age 52 ± 8 years) and 131 non-familial hypercholesterolemia controls. The prevalence (%) and AoVC-score (median, IQR) were higher in he-FH patients than in controls: 41%, 51 (9-117); and 21%, 21 (3-49) (p < 0.001 and p = 0.007). Age, untreated maxLDL, CAC, and diastolic blood pressure were independently associated with AoVC. LDLR-negative mutational he-FH was the strongest predictor of the AoVC-score (OR: 4.81; 95% CI: 2.22 to 10.40; p = <0.001). CONCLUSIONS: Compared to controls, he-FH is associated with a high prevalence and a large extent of subclinical AoVC, especially in patients with LDLR-negative mutations, highlighting the critical role of LDL-C metabolism in AoVC etiology.

The effect of LDLR-negative genotype on CT coronary atherosclerosis in asymptomatic statin treated patients with heterozygous familial hypercholesterolemia.

OBJECTIVE: To evaluate the influence of LDL receptor (LDLR) -negative mutational status on CT coronary atherosclerosis in asymptomatic statin treated patients with heterozygous familial hypercholesterolemia (FH). METHODS: Coronary CT angiography (CCTA) was performed in 145 FH patients (93 men; mean age 52 ± 8) screened for LDLR and apolipoprotein B (APOB) mutations. The extent of coronary plaque was compared between two groups: 1) 59 patients (41%) heterozygous for LDLR-negative mutations (LDLR-negative) and 2) 86 patients (59%) with reduced or normal LDLR function (LDLR-positive) consisting of 32 LDLR-defective mutations, 8 APOB mutations and 46 patients in whom no mutation could be identified. The diseased segments score (DSS) was the primary study endpoint defined as the number of coronary artery segments (0-17) with >20% luminal diameter narrowing. We compared the DSS between LDLR-negative and LDLR-positive patients. Within the LDLR-positive group a secondary analysis was performed between identified (LDLR-defective, APOB) and unidentified mutational status. RESULTS: The median DSS was higher in LDLR-negative than in LDLR-positive patients (4 (1-7) and 2 (0-5); P = 0.017). After adjustment for risk factors, LDLR-negative mutational status remained an independent predictor of the DSS (B = 1.09; P = 0.047). The DSS in the LDLR-positive group was similar for patients with identified and patients with unidentified mutational status. CONCLUSION: In asymptomatic statin treated patients with a clinical diagnosis of FH, LDLR-negative mutational status is associated with a higher extent of subclinical CT coronary atherosclerosis.

Accelerated subclinical coronary atherosclerosis in patients with familial hypercholesterolemia.

OBJECTIVES: We determined the extent, severity, distribution and type of coronary plaques in cardiac asymptomatic patients with familial hypercholesterolemia (FH) using computed tomography (CT). BACKGROUND: FH patients have accelerated progression of coronary artery disease (CAD) with earlier major adverse cardiac events. Non-invasive CT coronary angiography (CTCA) allows assessing the coronary plaque burden in asymptomatic patients with FH. MATERIALS AND METHODS: A total of 140 asymptomatic statin treated FH patients (90 men; mean age 52 ± 8 years) underwent CT calcium scoring (Agatston) and CTCA using a Dual Source CT scanner with a clinical follow-up of 29 ± 8 months. The extent, severity (obstructive or non-obstructive plaque based on >50% or <50% lumen diameter reduction), distribution and type (calcified, non-calcified, or mixed) of coronary plaque were evaluated. RESULTS: The calcium score was 0 in 28 (21%) of the patients. In 16% of the patients there was no CT-evidence of any CAD while 24% had obstructive disease. In total 775 plaques were detected with CT coronary angiography, of which 11% were obstructive. Fifty four percent of all plaques were calcified, 25% non-calcified and 21% mixed. The CAD extent was related to gender, treated HDL-cholesterol and treated LDL-cholesterol levels. There was a low incidence of cardiac events and no cardiac death occurred during follow-up. CONCLUSION: Development of CAD is accelerated in intensively treated male and female FH patients. The extent of CAD is related to gender and cholesterol levels and ranges from absence of plaque in one out of 6 patients to extensive CAD with plaque causing >50% lumen obstruction in almost a quarter of patients with FH.

Image quality and radiation exposure using different low-dose scan protocols in dual-source CT coronary angiography: randomized study.

PURPOSE: To compare image quality, radiation dose, and their relationship with heart rate of computed tomographic (CT) coronary angiographic scan protocols by using a 128-section dual-source CT scanner. MATERIALS AND METHODS: Institutional review board approved the study; all patients gave informed consent. Two hundred seventy-two patients (175 men, 97 women; mean ages, 58 and 59 years, respectively) referred for CT coronary angiography were categorized according to heart rate: less than 65 beats per minute (group A) and 65 beats per minute or greater (group B). Patients were randomized to undergo prospective high-pitch spiral scanning and narrow-window prospective sequential scanning in group A (n = 160) or wide-window prospective sequential scanning and retrospective spiral scanning in group B (n = 112). Image quality was graded (1 = nondiagnostic; 2 = artifacts present, diagnostic; 3 = no artifacts) and compared (Mann-Whitney and Student t tests). RESULTS: In group A, mean image quality grade was significantly lower with high-pitch spiral versus sequential scanning (2.67 ± 0.38 [standard deviation] vs 2.86 ± 0.21; P < .001). In a subpopulation (heart rate, <55 beats per minute), mean image quality grade was similar (2.81 ± 0.30 vs 2.94 ± 0.08; P = .35). In group B, image quality grade was comparable between sequential and retrospective spiral scanning (2.81 ± 0.28 vs 2.80 ± 0.38; P = .54). Mean estimated radiation dose was significantly lower (high-pitch spiral vs sequential scanning) in group A (for 100 kV, 0.81 mSv ± 0.30 vs 2.74 mSv ± 1.14 [P < .001]; for 120 kV, 1.65 mSv ± 0.69 vs 4.21 mSv ± 1.20 [P < .001]) and in group B (sequential vs retrospective spiral scanning) (for 100 kV, 4.07 mSv ± 1.07 vs 5.54 mSv ± 1.76 [P = .02]; for 120 kV, 7.50 mSv ± 1.79 vs 9.83 mSv ± 3.49 [P = .1]). CONCLUSION: A high-pitch spiral CT coronary angiographic protocol should be applied in patients with regular and low (<55 beats per minute) heart rates; a sequential protocol is preferred in all others.

Detection and quantification of coronary atherosclerotic plaque by 64-slice multidetector CT: a systematic head-to-head comparison with intravascular ultrasound.

OBJECTIVE: We evaluated the ability of 64-slice multidetector computed tomography (MDCT)-derived plaque parameters to detect and quantify coronary atherosclerosis, using intravascular ultrasound (IVUS) as the reference standard. METHODS: In 32 patients, IVUS and 64-MDCT was performed. The MDCT and IVUS datasets of 44 coronary arteries were co-registered using a newly developed fusion technique and quantitative parameters were derived from both imaging modalities. The threshold of >0.5 mm of maximum wall thickness was used to establish plaque presence on MDCT and IVUS. RESULTS: We analyzed 1364 coregistered 1-mm coronary cross-sections and 255 segments of 5-mm length. Compared with IVUS, 64-MDCT enabled correct detection in 957 of 1109 cross-sections containing plaque (sensitivity 86%). In 180 of 255 cross-sections atherosclerosis was correctly excluded (specificity 71%). On the segmental level, MDCT detected 213 of 220 segments with any atherosclerotic plaque (sensitivity 96%), whereas the presence of any plaque was correctly ruled out in 28 of 32 segments (specificity 88%). Interobserver agreement for the detection of atherosclerotic cross-sections was moderate (Cohen's kappa coefficient K=0.51), but excellent for the atherosclerotic segments (K=1.0). Pearson's correlation coefficient for vessel plaque volumes measured by MDCT and IVUS was r=0.91 (p<0.001). Bland-Altman analysis showed a slight non-significant underestimation of any plaque volume by MDCT (p=0.5), with a trend to underestimate noncalcified and overestimate mixed/calcified plaque volumes (p=0.22 and p=0.87 respectively). CONCLUSION: MDCT is able to detect and quantify atherosclerotic plaque. Further improvement in CT resolution is necessary for more reliable assessment of very small and distal coronary plaques.

CT coronary plaque burden in asymptomatic patients with familial hypercholesterolaemia.

OBJECTIVE: To determine the calcium score and coronary plaque burden in asymptomatic statin-treated patients with heterozygous familial hypercholesterolaemia (FH) compared with a control group of patients with low probability of coronary artery disease, having non-anginal chest pain, using CT. DESIGN, SETTING AND PATIENTS: 101 asymptomatic patients with FH (mean age 53 ± 7 years; 62 men) and 126 patients with non-anginal chest pain (mean age 56 ± 7 years; 80 men) underwent CT calcium scoring and CT coronary angiography. All patients with FH were treated with statins during a period of 10 ± 8 years before CT. The coronary calcium score and plaque burden were determined and compared between the two patient groups. RESULTS: The median total calcium score was significantly higher in patients with FH (Agatston score = 87, IQR 5-367) than in patients with non-anginal chest pain (Agatston score = 7, IQR 0-125; p < 0.001). The overall coronary plaque burden was significantly higher in patients with FH (p < 0.01). Male patients with FH, whose low-density lipoprotein cholesterol levels were reduced by statins below 3.0 mmol/l, had significantly less coronary calcium (p < 0.01) and plaque burden (p = 0.02). CONCLUSION: The coronary plaque burden is high in asymptomatic middle-aged patients with FH despite intense statin treatment.

Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography.

Recently, small calcifications have been associated with unstable plaques. Plaque calcifications are both in intravascular ultrasound (IVUS) and multi-slice computed tomography (MSCT) easily recognized. However, smaller calcifications might be missed on MSCT due to its lower resolution. Because it is unknown to which extent calcifications can be detected with MSCT, we compared calcification detection on contrast enhanced MSCT with IVUS. The coronary arteries of patients with myocardial infarction or unstable angina were imaged by 64-slice MSCT angiography and IVUS. The IVUS and MSCT images were registered and the arteries were inspected on the presence of calcifications on both modalities independently. We measured the length and the maximum circumferential angle of each calcification on IVUS. In 31 arteries, we found 99 calcifications on IVUS, of which only 47 were also detected on MSCT. The calcifications missed on MSCT (n = 52) were significantly smaller in angle (27° ± 16° vs. 59° ± 31°) and length (1.4 ± 0.8 vs. 3.7 ± 2.2 mm) than those detected on MSCT. Calcifications could only be detected reliably on MSCT if they were larger than 2.1 mm in length or 36° in angle. Half of the calcifications seen on the IVUS images cannot be detected on contrast enhanced 64-slice MSCT angiography images because of their size. The limited resolution of MSCT is the main reason for missing small calcifications.

Comparison of the value of coronary calcium detection to computed tomographic angiography and exercise testing in patients with chest pain.

The aim of this study was to investigate the value of coronary calcium detection by computed tomography compared to computed tomographic angiography (CTA) and exercise testing to detect obstructive coronary artery disease (CAD) in patients with stable chest pain. A total of 471 consecutive patients with new stable chest complaints were scheduled to undergo dual-source multislice computed tomography (Siemens, Germany; coronary calcium score [CCS] and coronary CTA) and exercise electrocardiography (XECG). Clinically driven invasive quantitative angiography was performed in 98 patients. Only 3 of 175 patients (2%) with a negative CCS had significant CAD on CT angiogram, with only 1 confirmed by quantitative angiography. In patients with a high calcium score (Agatston score >400), CTA could exclude significant CAD in no more than 4 of 65 patients (6%). In patients with a low-intermediate CCS, CTA more often yielded diagnostic results compared to XECG and could rule out obstructive CAD in 56% of patients. For patients with CAD on CT angiogram, those with abnormal exercise electrocardiographic results more often showed severe CAD (p <0.034). In patients with diagnostic results for all tests, the sensitivity and specificity to detect >50% quantitative angiographic diameter stenosis were 100% and 15% for CCS >0, 82% and 64% for CCS >100, 97% and 36% for CTA, and 70% and 76% for XECG, respectively. In conclusion, nonenhanced computed tomography for calcium detection is a reliable means to exclude obstructive CAD in stable, symptomatic patients. Contrast-enhanced CTA can exclude significant CAD in patients with a low-intermediate CCS but is of limited value in patients with a high CCS.

Preserved diagnostic performance of dual-source CT coronary angiography with reduced radiation exposure and cancer risk.

PURPOSE: To evaluate the effects of standard and optimal electrocardiographic (ECG) pulsing on diagnostic performance, radiation dose, and cancer risk in symptomatic patients in a "real-world" clinical setting. MATERIALS AND METHODS: The institutional review board approved the study, and all patients gave informed consent. Dual-source computed tomographic (CT) coronary angiography was performed in 436 symptomatic patients (301 men, 135 women; mean age, 61.6 years +/- 10.6 [standard deviation]; age range, 23-89 years) referred for conventional coronary angiography. Standard and optimal ECG pulsing was performed in 327 and 109 patients, respectively. The diagnostic performance of dual-source CT coronary angiography for detection of significant stenosis (>or=50 luminal diameter reduction), with quantitative coronary angiography as the reference standard, was reported as sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. The mean effective radiation dose, additional fatal cancer risk, and age- and sex-specific cancer risks related to one CT coronary angiographic examination were determined from data averaged over the study population. RESULTS: Mean effective doses with standard and optimal ECG pulsing were 14.2 mSv +/- 3.2 and 10.7 mSv +/- 3.6, respectively. Optimal ECG pulsing resulted in a 43% overall reduction in mean effective radiation dose and cancer risk compared with a nonpulsing protocol (18.8 mSv +/- 3.5) and a 25% overall reduction in mean effective dose compared with the standard pulsing protocol. At patient-by-patient analysis, CT coronary angiography with standard ECG pulsing yielded sensitivity, specificity, and positive and negative predictive values of 100% (95% confidence interval [CI]: 99%, 100%), 85% (95% CI: 81%, 88%), 94% (95% CI: 91%, 96%), and 99% (95% CI: 98%, 100%), respectively, for detection of significant stenosis. Optimal ECG pulsing yielded similar results: Sensitivity, specificity, and positive and negative predictive values were 100% (95% CI: 100%, 100%), 88% (95% CI: 82%, 94%), 97% (95% CI: 93%, 100%), and 100%, respectively. CONCLUSION: Compared with a nonpulsing protocol, optimal ECG pulsing resulted in significant (P < .001) reductions in patient radiation dose and cancer risk (up to 55% reduction in patients with high heart rates) while preserving the diagnostic performance of dual-source CT coronary angiography.