Soluble LR11 associates with aortic root calcification in asymptomatic treated male patients with familial hypercholesterolemia.

BACKGROUND AND AIMS: Despite statin treatment, a high prevalence of severe vascular calcification is found in patients with familial hypercholesterolemia (FH). We assessed the relation between the circulating soluble form of low-density lipoprotein receptor relative with 11 ligand-binding repeats (sLR11), a risk factor for cardiovascular disease, and vascular calcification in asymptomatic statin-treated heterozygous FH patients. METHODS: In 123 asymptomatic heterozygous FH patients (age 40-69 years), aortic root (ARC), aortic valve (AVC) and coronary artery calcification (CAC) were determined with CT-based calcium scoring expressed in Agatston units. Plasma sLR11 levels were measured by sandwich ELISA. RESULTS: Seventy-three patients displayed ARC, 48 had AVC and 96 CAC. Plasma sLR11 levels were positively correlated with the presence of ARC (r = 0.2, p = 0.03), but not with AVC or CAC. The correlation between sLR11 levels and ARC was restricted to male FH patients (r = 0.31, p = 0.006). Multivariate logistic analyses showed that the association of plasma sLR11 with the presence of ARC was independent of other determinants (Adjusted Odds Ratio, 2.01 (95% CI = 1.28-3.16) p = 0.002). CONCLUSIONS: Plasma sLR11 is associated with ARC in male FH patients and may be mechanistically involved in the differential distribution of atherosclerotic lesions in the vasculature.

Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study.

BACKGROUND AND AIMS: Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH). However, some FH patients still develop ASCVD despite statin therapy. We compared subclinical atherosclerosis assessed by carotid plaque presence and intima media thickness (C-IMT), in long-term statin-treated FH patients and healthy controls. Furthermore, we analysed whether carotid ultrasonography findings associated with subclinical coronary atherosclerosis. METHODS: We assessed the presence of carotid plaques and C-IMT in 221 asymptomatic heterozygous FH patients (48% men; 46 ± 15 years) on long-term (10.0 ± 7.8 years) statin treatment and 103 controls (32% men, 47 ± 16 years). RESULTS: The frequency of carotid plaques and C-IMT did not differ significantly between the FH patients and controls (69 (31%) versus 24 (23%), p = 0.1 and 0.58 ± 0.13 versus 0.58 ± 0.12 mm, p = 0.9, respectively). In a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence (R = 0.47; p = 0.001), but not with C-IMT (R = 0.20; p = 0.2). CONCLUSIONS: Carotid plaques and C-IMT did not differ between long-term statin-treated heterozygous FH patients and healthy controls. This shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree of a healthy population. These findings strongly suggests that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value.

Prognostic Value of Coronary Computed Tomography Imaging in Patients at High Risk Without Symptoms of Coronary Artery Disease.

At present, traditional risk factors are used to guide cardiovascular management of asymptomatic subjects. Intensified surveillance may be warranted in those identified as high risk of developing cardiovascular disease (CVD). This study aims to determine the prognostic value of coronary computed tomography (CT) angiography (CCTA) next to the coronary artery calcium score (CACS) in patients at high CVD risk without symptoms suspect for coronary artery disease (CAD). A total of 665 patients at high risk (mean age 56 ± 9 years, 417 men), having at least one important CVD risk factor (diabetes mellitus, familial hypercholesterolemia, peripheral artery disease, or severe hypertension) or a calculated European systematic coronary risk evaluation of >10% were included from outpatient clinics at 2 academic centers. Follow-up was performed for the occurrence of adverse events including all-cause mortality, nonfatal myocardial infarction, unstable angina, or coronary revascularization. During a median follow-up of 3.0 (interquartile range 1.3 to 4.1) years, adverse events occurred in 40 subjects (6.0%). By multivariate analysis, adjusted for age, gender, and CACS, obstructive CAD on CCTA (≥50% luminal stenosis) was a significant predictor of adverse events (hazard ratio 5.9 [CI 1.3 to 26.1]). Addition of CCTA to age, gender, plus CACS, increased the C statistic from 0.81 to 0.84 and resulted in a total net reclassification index of 0.19 (p <0.01). In conclusion, CCTA has incremental prognostic value and risk reclassification benefit beyond CACS in patients without CAD symptoms but with high risk of developing CVD.

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.

Computed tomography coronary imaging as a gatekeeper for invasive coronary angiography in patients with newly diagnosed heart failure of unknown aetiology.

AIMS: To evaluate the accuracy of cardiac computed tomography (CT) in distinguishing CAD and non-CAD heart failure (HF) and its effectiveness as a gatekeeper for invasive coronary angiography (ICA). METHODS AND RESULTS: We prospectively included 93 symptomatic patients with newly diagnosed HF of unknown aetiology (59 men; mean age 53 ± 13) and EF <45%, and/or fractional shortening <25%, and/or end-diastolic LV diameter >60 mm (men) or >55 mm (women). In all patients, the CT calcium score (CTCS) was determined. CTCS = 0 excluded CAD HF. Additional CT coronary angiography (CTCA) was performed if CTCS >0. ICA was used as the gold standard for distinguishing between CAD and non-CAD HF in patients with >20% luminal diameter narrowing on CTCA. CAD HF was defined as >50% luminal diameter narrowing in either (i) the left main coronary artery or proximal left anterior descending coronary artery or (ii) in multiple coronary arteries. Diagnostic accuracy and follow-up data (20 ± 16 months) were collected for all patients. CTCS = 0 ruled out CAD HF in 43 patients (46%). The CT algorithm had 100% sensitivity, 95% specificity, 67% positive predictive value, and 100% negative predictive value for detecting CAD HF. Patients with CTCS = 0 or non-CAD HF on CTCA had no coronary events during follow-up, and ICA could have been safely avoided in 76 out of 93 patients (82%). CONCLUSION: In patients with HF of unknown aetiology, cardiac CT combining CTCS and CTCA has high accuracy for detecting CAD HF and can be used effectively as a gatekeeper for ICA.

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.

Carotid plaque burden as a measure of subclinical coronary artery disease in patients with heterozygous familial hypercholesterolemia.

Patients with familial hypercholesterolemia (FH) are at markedly increased risk of developing premature coronary artery disease. The objective of the present study was to evaluate the role of carotid ultrasonography as a measure of subclinical coronary artery disease in patients with FH. The present prospective study compared the presence of subclinical carotid and coronary artery disease in 67 patients with FH (mean age 55 ± 8 years, 52% men) to that in 30 controls with nonanginal chest pain (mean age 56 ± 9 years, 57% men). The carotid intima-media thickness and carotid plaque burden were assessed using B-mode ultrasonography, according to the Mannheim consensus. Coronary artery disease was assessed using computed tomographic coronary angiography. A lumen reduction >50% was considered indicative of obstructive coronary artery disease. The patients with FH and the controls had a comparable carotid intima-media thickness (0.64 vs 0.66 mm, p = 0.490), prevalence of carotid plaque (93% vs 83%, p = 0.361), and median carotid plaque score (3 vs 2, p = 0.216). Patients with FH had a significantly greater median coronary calcium score than did the controls (62 vs 5, p = 0.015). However, the prevalence of obstructive coronary artery disease was comparable (27% vs 31%, p = 0.677). No association was found between the carotid intima-media thickness and coronary artery disease. An association was found between the presence of carotid plaque and coronary artery disease in the patients with FH and the controls. The absence of carotid plaque, observed in 5 patients (7%) with FH, excluded the presence of obstructive coronary artery disease. In conclusion, the patients with FH had a high prevalence of carotid plaque and a significantly greater median coronary calcium score than did the controls. A correlation was found between carotid plaque and coronary artery disease in patients with FH; however, the presence of carotid plaque and carotid plaque burden are not reliable indicators of obstructive coronary artery disease.

Diagnostic accuracy of 128-slice dual-source CT coronary angiography: a randomized comparison of different acquisition protocols.

OBJECTIVES: To compare the diagnostic performance and radiation exposure of 128-slice dual-source CT coronary angiography (CTCA) protocols to detect coronary stenosis with more than 50 % lumen obstruction. METHODS: We prospectively included 459 symptomatic patients referred for CTCA. Patients were randomized between high-pitch spiral vs. narrow-window sequential CTCA protocols (heart rate below 65 bpm, group A), or between wide-window sequential vs. retrospective spiral protocols (heart rate above 65 bpm, group B). Diagnostic performance of CTCA was compared with quantitative coronary angiography in 267 patients. RESULTS: In group A (231 patients, 146 men, mean heart rate 58 ± 7 bpm), high-pitch spiral CTCA yielded a lower per-segment sensitivity compared to sequential CTCA (89 % vs. 97 %, P = 0.01). Specificity, PPV and NPV were comparable (95 %, 62 %, 99 % vs. 96 %, 73 %, 100 %, P > 0.05) but radiation dose was lower (1.16 ± 0.60 vs. 3.82 ± 1.65 mSv, P < 0.001). In group B (228 patients, 132 men, mean heart rate 75 ± 11 bpm), per-segment sensitivity, specificity, PPV and NPV were comparable (94 %, 95 %, 67 %, 99 % vs. 92 %, 95 %, 66 %, 99 %, P > 0.05). Radiation dose of sequential CTCA was lower compared to retrospective CTCA (6.12 ± 2.58 vs. 8.13 ± 4.52 mSv, P < 0.001). Diagnostic performance was comparable in both groups. CONCLUSION: Sequential CTCA should be used in patients with regular heart rates using 128-slice dual-source CT, providing optimal diagnostic accuracy with as low as reasonably achievable (ALARA) radiation dose.

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.

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.