Quantification of aortic valve calcification using multislice spiral computed tomography: comparison with atomic absorption spectroscopy.

OBJECTIVES: Multislice spiral computed tomography (MSCT) allows the in vivo detection of valvular calcification. The aim of this study was to validate the quantification of aortic valve calcification (AVC) by MSCT with in vitro measurements by atomic absorption spectroscopy. METHODS: In 18 patients with severe aortic stenosis, 16 detector row MSCT (SOMATOM Sensation 16, Siemens, Forchheim, Germany with scan parameters as follows: 420 milliseconds tube rotation time, 12 x 0.75 mm collimation, tube voltage 120 KV) was performed before aortic valve replacement. Images were reconstructed at 60% of the RR interval with an effective slice thickness of 3 mm and a reconstruction increment of 2 mm. AVC was assessed using Agatston AVC score, mass AVC score, and volumetric AVC score. After valve replacement, the calcium content of the excised human stenotic aortic valves was determined in vitro using atomic absorption spectroscopy. RESULTS: The mean Agatston AVC score was 3,842 +/- 1,790, the mean volumetric AVC score was 3,061 +/- 1,406, and mass AVC score was 888 +/- 492 as quantified by MSCT. Atomic absorption spectroscopy showed a mean true calcification mass (Ca5(PO4)3OH) of 19 +/- 8 mass%. There was a significant correlation between in vivo AVC scores determined by MSCT and in vitro mean true calcification mass (r = 0.74, P = 0.0004 for mass AVC score, r = 0.79, P = 0.0001 for volumetric AVC score and r = 0.80, P = 0.0001 for Agatston AVC score) determined by atomic absorption spectroscopy. Linear regression analysis showed a significant association between the degree of hydroxyapatite (given in mass%) in the aortic valve and the degree of AVC (R = 0.74, F = 19.6, P = 0.0004 for mass AVC score, R = 0.80, F = 29.3, P = 0.0001 for Agatston AVC score and R = 0.79, F = 27.3, P = 0.0001 for volumetric AVC score) assessed by MSCT. CONCLUSION: MSCT allows accurate in vivo quantification of aortic valve calcifications.

Lower serum calcium levels are associated with greater calcium hydroxyapatite deposition in native aortic valves of male patients with severe calcific aortic stenosis.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the relationship between serum calcium levels and the degree of calcification found in stenotic aortic valves. METHODS: Using atomic absorption spectroscopy, the hydroxyapatite content of 228 excised human stenotic aortic valves was determined and expressed as a percentage of valve mass. Left heart catheterization preceded valve replacement. In addition, serum levels of calcium and creatinine were determined before native calcific aortic valve excision. RESULTS: Valves from male patients contained more hydroxyapatite than those of female patients (26 +/- 9 versus 22 +/- 9 mass%; p < 0.001). Patients presenting with lower serum calcium levels showed a slight trend towards higher levels of valve calcification (r = -0.15, p = 0.026), but this association appeared only within the subgroup of male patients. Male patients with lowest serum calcium levels displayed greatest valvular hydroxyapatite deposition (1st calcium tertiary: 29.5 +/- 8.9 mass% versus 2nd calcium tertiary 26.4 +/- 7.8 mass% versus 3rd calcium tertiary 21.4 +/- 8.9 mass%; n = 122; p = 0.001; r = -0.25; p = 0.006). This association was even more distinct in male patients with normal serum creatinine levels. Furthermore, serum calcium was inversely and significantly associated with serum C-reactive protein in male patients (r = - 0.34; p < 0.001). CONCLUSION: Serum calcium levels appear to be inversely related to valve calcification in patients with severe calcific aortic stenosis (AS). This finding indicates the importance of systemic calcium metabolism in calcific AS, independent of manifest disorders of calcium metabolism or renal function. Interestingly, this association was evident only in male patients, suggesting a gender-dependent pathogenesis.

Additive effects of the chemokine receptor 2, vitamin D receptor, interleukin-6 polymorphisms and cardiovascular risk factors on the prevalence of myocardial infarction in patients below 65 years.

BACKGROUND: Cardiovascular risk factors (CRF) have been associated with myocardial infarction (MI), while the role of genetic risk factors (GRF) remains undetermined. METHODS: Cineventriculograms of 3436 were analyzed for presence of regional function impairment as sign of MI. Genotyping for genetic polymorphism (vitamin D receptor VDR BsmI, interleukin-6 IL6-174 G/C, chemokine receptor 2 CCR2 64 V/I) was performed. CRF were assessed (hypertension, hypercholesterolemia, smoking, and diabetes mellitus). RESULTS: In patients <65 years (n=1946) genotypes (VDR BB, IL6 GC/CC, CCR2 VI/II, defined as GRF) were significantly associated with the presence of MI (BB: OR 1.38, 95%CI 1.07-1.79, p=0.016 GC/CC: 1.28, 95%CI 1.03-1.60, p=0.028 VI/II: 1.49, 95%CI 1.17-1.88, p=0.001). Combining four CRF (14% vs. 21% vs. 27% vs. 31% vs. 38%, p<0.0001) and three GRF (21% vs. 25% vs. 32% vs. 44%, p<0.0001) revealed additive effects on the prevalence of MI. The more combined CRF and GRF were present (from 0 to 7) the higher was the prevalence of MI (11% vs. 12% vs. 21% vs. 27% vs. 30% vs. 34% vs. 59%, p< 0.0001). Age was not associated with MI. In patients > or =65 years (n=1490) the combination of CRF was only weakly associated with MI, while GRF were not. In these patients age was a predictor of MI. CONCLUSION: Certain GRF might have additive but small effects on the disposition for MI before the age of 65. In older patients the tested GRF had no effect, possibly indicating a mechanism of aging rather than a purely genetic determined entity. Given the small effect of the tested genetic polymorphisms the value of testing GRF remains uncertain.

Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age.

Inflammation is associated with atherosclerosis of coronary arteries. Chemokines have an important role in inflammation. The CCR2 chemokine receptor mediates leukocyte chemoattraction, which is involved in the pathogenesis of coronary heart disease. We prospectively studied 1960 consecutive patients aged under 65 years and referred for a first-time left ventricular catheter. Left heart catheters were analyzed by two independent cardiologists for the presence of myocardial infarction (regional wall motion abnormality) and moderate or severely reduced left ventricular function on cineventriculography and presence of coronary atherosclerosis on angiography. Genotyping for CCR2 V64I polymorphism was performed. The presence of the rare allele of the CCR2 gene was significantly associated with a higher prevalence of myocardial infarction on cinventriculography (32.0% vs. 24.2%, moderately or severely reduced left ventricular function (14.0% vs. 9.5%) and NYHA class III or IV (16.7% vs. 12.2%). The association of the CCR2 genotype with heart failure was not independent of the presence of myocardial infarction in multivariate analysis. There was no association of the CCR2 genotype with coronary atherosclerosis. The CCR2 genotype seems to predispose patients for myocardial infarction before the age of 65 years. The higher prevalence of heart failure in gene carriers with the rare alle might be a consequence of myocardial infarction. If the CCR2 genotype is associated with higher mortality in the general population must be investigated in further studies.

Relationship of five inflammatory gene polymorphisms with morbidity and mortality in 533 patients admitted to an ICU.

BACKGROUND: The aim of this study was to analyze the association of polymorphisms of five candidate genes with the outcome of consecutive patients admitted to a medical ICU. MATERIALS AND METHODS: The study population was prospectively recruited. Inclusion criteria were admission to the ICU and written informed consent by the patients or their relatives. A total of 533 patients were recruited. The morbidity was assessed by SAPS II Score. Outcome data of in hospital mortality and length of ICU and hospital stay were obtained. Genotyping for genetic polymorphisms (CRP 1059, IL1B -511, CTGF -477, CCR2 64VI, IL6 -174) were performed by allele-specific fluorogenic oligonucleotide probes (TaqMan analysis). RESULTS: All of the investigated polymorphisms were not associated with an altered outcome. There was no difference in morbidity and ICU or in-hospital mortality (neither in cross tabs analysis nor in Kaplan Meier or Cox regression analysis including age, gender and diagnosis as covariates) between the different genotypes. CONCLUSIONS: Genotyping of the investigated polymorphism for risk stratification of patients admitted to ICU does not seem to be appropriated.

Variants of the CYP11B2 gene predict response to therapy with candesartan.

In a prospective trial, patients with an elevated diastolic blood pressure (above 95 mm Hg) received high-dose (16 mg) or low-dose (8 mg) candesartan in addition to standardised medication. A positive response to treatment was defined as a diastolic blood pressure <85 mm Hg at follow-up. Genotyping for two candidate genes was performed in 116 patients. Genotypes of the CYP11B2 promotor polymorphism significantly predicted a positive response to treatment (CC: 67%; TC: 34%; TT: 21%; p=0.005).

Obesity is associated with a slower response to initial phenprocoumon therapy whereas CYP2C9 genotypes are not.

BACKGROUND: Initiation of phenprocoumon therapy is associated with a variable individual response. The CYP2C9 genotype has been shown to influence the response to warfarin therapy, but such an effect on phenprocoumon therapy remains uncertain. METHOD: Two hundred sixty hospital patients started on phenprocoumon were recruited for this study. Body mass index (BMI), waist and hip circumference, dietary habits, comorbidity, and comedication were initially assessed. A 5' exonuclease assay (TaqManR) was used to analyze the presence of five polymorphisms of the CYP2C9 gene in each of the study patients. Study endpoints included the time necessary to achieve the international normalized ratio (INR) target (INR >2) and the total drug amount required to attain target INR. For 250 of 260 patients, the subsequent required daily maintenance dose of phenprocoumon was also recorded. RESULTS: Both the necessary time and total dose required to attain target INR correlated significantly with BMI. The leaner the patient, the shorter the required time interval [BMI <22 (n=31), 5.48+/-2.49 days; BMI 22-25 (n=70), 6.09+/-2.40; BMI 25-30 (n=113), 6.76+/-3.61; BMI >30 (n=46), 8.50+/-5.75; p=0.001] and the lower the required dosage until the therapeutic range was achieved [BMI <22 (n=31), 23.8+/-12.1 mg; BMI 22-25 (n=70), 25.9+/-11.4 mg; BMI 25-30 (n=113), 29.6+/-25.2; BMI >30 (n=46), 35.8+/-19.7; p=0.027]. Overweight and waist circumference as a surrogate marker for abdominal fat were also associated significantly with these two parameters. Moreover, obesity was associated with a lower body-weight-adjusted maintenance dosage. All CYP2C9 genotypes that were tested failed to reveal an association with individual response variability. CONCLUSION: Patient obesity appears to directly correspond to the amount of phenprocoumon required during initiation of therapy. The CYP2C9 genotype was not shown to influence the necessary therapeutic dosage.

The amount of calcium-deficient hexagonal hydroxyapatite in aortic valves is influenced by gender and associated with genetic polymorphisms in patients with severe calcific aortic stenosis.

AIMS: The study evaluated the relationship between cardiovascular risk factors (CRF), gene polymorphism, calcification and fibrosis of stenotic aortic valves. METHODS AND RESULTS: The calcium content of 187 excised stenotic aortic valves was determined using atomic absorption spectroscopy. Hydroxyproline content was quantified. Left-heart catheterization was performed. CRF and genotypes of the interleukin 10, connective tissue growth factor (CTGF) and chemokine receptor 5 (CCR5) polymorphisms were assessed. Calcification consisted of Ca-deficient hexagonal hydroxyapatite, Ca(10 - x)(HPO4)x(PO4)(6 - x)(OH)(2 - x); with 0