Genome-wide analysis of genetic determinants of circulating factor VII-activating protease (FSAP) activity.

Essentials Knowledge of genetic regulators of plasma factor VII activating protease (FSAP) levels is limited. We performed a genome-wide analysis of variants influencing FSAP activity in Scandinavian cohorts. We replicated an association for Marburg-1 and identified an association for a HABP2 stop variant. We identified a novel locus near ADCY2 as a potential additional regulator of FSAP activity. SUMMARY: Background Factor VII-activating protease (FSAP) has roles in both coagulation and fibrinolysis. Recent data indicate its involvement in several other processes, such as vascular remodeling and inflammation. Plasma FSAP activity is highly variable among healthy individuals and, apart from the low-frequency missense variant Marburg-I (rs7080536) in the FSAP-encoding gene HABP2, determinants of this variation are unclear. Objectives To identify novel genetic variants within and outside of the HABP2 locus that influence circulating FSAP activity. Patients/Methods We performed an exploratory genome-wide association study (GWAS) on plasma FSAP activity amongst 3230 Swedish subjects. Directly genotyped rare variants were also analyzed with gene-based tests. Using GWAS, we confirmed the strong association between the Marburg-I variant and FSAP activity. HABP2 was also significant in the gene-based analysis, and remained significant after exclusion of Marburg-I carriers. This was attributable to a rare HABP2 stop variant (rs41292628). Carriers of this stop variant showed a similar reduction in FSAP activity as Marburg-I carriers, and this finding was replicated. A secondary genome-wide significant locus was identified at a 5p15 locus (rs35510613), and this finding requires future replication. This common variant is located upstream of ADCY2, which encodes a protein catalyzing the formation of cAMP. Results and Conclusions This study verified the Marburg-I variant to be a strong regulator of FSAP activity, and identified an HABP2 stop variant with a similar impact on FSAP activity. A novel locus near ADCY2 was identified as a potential additional regulator of FSAP activity.

Sex differences in coronary plaque composition evaluated by coronary computed tomography angiography in newly diagnosed Type 2 diabetes: association with low-grade inflammation.

AIM: To determine differences in coronary plaque composition and inflammatory biomarkers between men and women with newly diagnosed Type 2 diabetes without known cardiovascular disease. METHODS: A total of 88 people with newly diagnosed (<1 year) Type 2 diabetes underwent contrast-enhanced coronary computed tomography angiography. Advanced coronary plaque analysis was performed using semi-automated software. Plasma concentrations of inflammatory biomarkers were determined. RESULTS: There were no significant differences between men (n=60) and women (n=28) regarding age or cardiovascular risk factors (all P>0.05). The median (quartiles) serum levels of fibrinogen [10.9 (9.8-12.6) µmol/l vs 9.7 (8.8-10.9) µmol/l], fibrin d-dimer [0.3 (0.2-0.4) mg/l vs 0.27 (0.2-0.4) mg/l] and C-reactive protein [3.1 (1.1-5.2) mg/l vs (0.8-2.6) 1.6 mg/l] were significantly higher in women (all P<0.05). Overall, men more often had multi-vessel involvement [28 men (47%) vs 4 women (14%)], and higher total plaque burden [median (quartiles) 11.6 (2.3-36.0)% vs 2.0 (0.4-5.4)%; both P<0.05]. The median (quartiles) total plaque volume [269.9 (62.6-641.9) mm3 vs 61.1 (7.6-239.9) mm3 ] and absolute calcified plaque volume [33.5 (8.3-148.3) mm3 vs 4.7 (0.9-17.3) mm3 ] were higher in men (both P<0.05). Women had a lower relative proportion of the calcified plaque component [median (quartiles) 7.8 (4.7-15.4)% vs 23.7 (8.4-31.1)%] and a higher relative proportion (median [quartiles]) of the non-low-density non-calfied plaque component [77.6 (66.0-86.0)% vs 63.6 (54.0-72.9)%; both P<0.05]. CONCLUSIONS: In people with newly diagnosed Type 2 diabetes, women had lower absolute coronary plaque volumes but a more unfavourable plaque composition and enhanced systemic inflammation compared with men.

Uncontrolled hypertension is associated with coronary artery calcification and electrocardiographic left ventricular hypertrophy: a case-control study.

We conducted a 1:2 matched case-control study in order to evaluate whether the prevalence of coronary artery calcium (CAC) and electrocardiographic left ventricular hypertrophy (LVH) or strain was higher in patients with uncontrolled hypertension than in subjects from the general population, and evaluate the association between CAC and LVH in patients with uncontrolled hypertension. Cases were patients with uncontrolled hypertension, whereas the controls were random individuals from the general population without cardiovascular disease. CAC score was assessed using a non-contrast computed tomographic scan. LVH was evaluated using the Sokolow-Lyon voltage combination and Cornell voltage-duration product, respectively. Associations between CAC, LVH and traditional cardiovascular risk factors were tested by means of ordinal, conditional and classic binary logistic regression models. We found that uncontrolled hypertension was independently associated with both an ordinal CAC score category (odds ratio (OR) 3.9 (95% CI, 1.6-9.1), P = 0.002), the presence of CAC score>99 (OR 4.5 (95% CI, 1.4-14.7), P = 0.01) and electrocardiographic LVH (OR 10.1 (95% CI, 3.4-30.2), P < 0.001) on both univariate and multivariable analyses. There was, however, no correlation between CAC and LVH. The lack of an association between CAC and LVH suggests that they are markers of different complications of hypertension and may have independent predictive values. Patients with both CAC and LVH may be at higher risk than those in whom only one of these markers is present.

The relation between coronary artery calcification in asymptomatic subjects and both traditional risk factors and living in the city centre: a DanRisk substudy.

OBJECTIVE: To evaluate the association between the risk factor for living in the city centre as a surrogate for air pollution and the presence of coronary artery calcification (CAC) in a population of asymptomatic Danish subjects. DESIGN AND SUBJECTS: A random sample of 1825 men and women of either 50 or 60 years of age were invited to take part in a screening project designed to assess risk factors for cardiovascular disease (CVD). Noncontrast cardiac computed tomography was performed on all subjects, and their Agatston scores were calculated to evaluate the presence of subclinical coronary atherosclerosis. The relationship between CAC and several demographic and clinical parameters was evaluated using multivariate logistic regression. RESULTS: A total of 1225 individuals participated in the study, of whom 250 (20%) were living in the centres of major Danish cities. Gender and age showed the greatest association with the presence of CAC: the odds ratio (OR) for men compared with women was 3.2 [95% confidence interval (CI) 2.5-4.2; P < 0.0001], and the OR for subjects aged 60 versus those aged 50 years was 2.2 (95% CI 1.7-2.8; P < 0.0001). Other variables independently associated with the presence of CAC were diabetes and smoking with ORs of 2.0 (95% CI 1.1-3.5; P = 0.03) and 1.9 (95% CI 1.4-2.5, P < 0.0001), respectively. The adjusted OR for subjects living in city centres compared to those living outside was 1.8 (95% CI 1.3-2.4; P = 0.0003). CONCLUSION: Both conventional risk factors for CVD and living in a city centre are independently associated with the presence of CAC in asymptomatic middle-aged subjects.

R-wave changes in fatal air embolism during bone cementation.

Holter monitoring during cementation of a hip prosthesis showed sudden R-wave loss. At post mortem, demonstration of a large intracardiac air embolus may explain the ECG changes.

99mTc-Sestamibi SPECT is a useful technique for viability detection: results of a comparison with NH3/FDG PET.

OBJECTIVE: Assessment of myocardial viability by 99mTc-Sestamibi Single Photon Emission Computerized Tomography (SPECT) has been suggested as a more readily available and cheaper alternative to Positron Emission Tomography (PET) with 13N-ammonia (NH3) and 18F-fluoro-deoxy-glucose (FDG). We hypothesized that a semi-quantitative evaluation by SPECT could delineate myocardial viability with an acceptable concordance to PET. DESIGN: Fifty patients (age 57+/-7 years; ejection fraction 28 +/- 8%), with ischemic cardiomyopathy, underwent SPECT and PET imaging in random order. Viability by SPECT was defined as a defect size <50% of the segment area, or a defect representing > or =50% of the segment but with a mean activity > or =50% of peak activity. PET viability was defined as a perfusion score >2 and FDG score < or =2 (five-point scale, 0 = normal, 4 = absent activity). RESULTS: By segmental comparison to PET. SPECT yielded a sensitivity and specificity of 87% and 82% for detection of viable myocardium. The positive and negative predictive values were 96% and 58%, respectively. CONCLUSION: In patients with severe ischemic cardiomyopathy 99mTc-Sestamibi SPECT can delineate viable myocardium with an acceptable segmental concordance to NH3/FDG PET.

Myocardial perfusion imaging in breast cancer patients treated with or without post-mastectomy radiotherapy.

PURPOSE: To assess the occurrence and location of myocardial perfusion defects in left-sided mastectomized breast cancer patients, treated with or without postoperative radiotherapy according to the guidelines from the Danish Breast Cancer Cooperative Group (DBCG). PATIENTS AND METHODS: Seventeen left-sided breast cancer patients, with a median age of 59 years (range, 47-75 years), randomized to post-mastectomy irradiation plus systemic treatment, or systemic treatment alone, were examined after a median follow-up of 7.9 years (range, 6.0-12.2 years). The chest wall and the ipsilateral internal mammary nodes had been treated through two anterior-shaped electron fields, and the electron energy was chosen according to chest wall thickness, measured individually by ultrasound. The median absorbed dose was 50 Gy in 25 fractions, with 5 fractions/week. Information on clinical history was obtained and symptoms of ischemic heart disease (IHD), as well as major risk factors, were recorded. All patients had a physical examination, blood chemistry, electrocardiogram (ECG), chest X-ray and myocardial perfusion imaging by sestamibi-single photon emission computerized tomography (SPECT). SPECT-scanning was performed as a rest/dipyridamole 2-day protocol. The evaluation of regional myocardial perfusion was based on scintigrams using a 20-segment model. RESULTS: There was no significant difference between the scintigraphic findings in the two groups. Four of ten irradiated patients and four of seven non-irradiated patients showed scintigraphic defects. An anterior defect was found in one non-irradiated patient. CONCLUSIONS: This study does not indicate that the described radiotherapy technique induces detectable coronary artery disease. However, the small number of patients does not allow strong conclusions to be drawn.

Functional significance of recruitable collaterals during temporary coronary occlusion evaluated by 99mTc-sestamibi single-photon emission computerized tomography.

OBJECTIVES: The present study evaluated the impact of recruitable collaterals on regional myocardial perfusion measured by 99mtechnetium (Tc)-sestamibi single-photon emission computerized tomography (SPECT) during temporary coronary occlusion and related these estimates to the coronary wedge pressure and electrocardiographic (ECG) ST-segment changes. BACKGROUND: Clinical variables (angina and ECG changes) and intracoronary flow and pressure recordings have indicated a protective role of recruitable collaterals on myocardial perfusion during percutaneous transluminal coronary angioplasty (PTCA). METHODS: Thirty patients (mean age 55 years, SD 9; 20 men) with stable angina pectoris and proximal nonocluding single-vessel left anterior descending coronary artery (LAD)-stenosis scheduled for PTCA were included. Visualization of recruitable collaterals by ipsilateral and contralateral contrast injection, registration of coronary wedge pressure and injection of 99mTc-sestamibi during 90-s LAD occlusions were undertaken. A rest perfusion study was performed within four days before PTCA. As an estimate of the severity of regional hypoperfusion during occlusion, an occlusion/rest count ratio was calculated (mean defect pixel count during occlusion divided by mean pixel count in identical regions at rest). RESULTS: The scintigraphic occlusion/rest count ratio was higher in patients with recruitable collaterals (n = 16), 67 +/- 11%, compared to patients without collaterals (n = 14), 60 +/- 6% (p < 0.05). The occlusion/rest count ratio correlated with the coronary wedge pressure (R2 = 0.34; p < 0.001). The occlusion/rest count ratio was lower, 61 +/- 6%, in patients with ST-segment elevation (n = 23) versus 74 +/- 9% in patients without ST-segment elevation (n = 7) (p < 0.0001). CONCLUSIONS: Using 99mTc-sestamibi SPECT imaging during brief episodes of coronary occlusion, the severity of regional myocardial hypoperfusion was reduced by the presence of recruitable collaterals in a selected patient population with proximal LAD stenoses. Our results demonstrate a protective effect of recruitable collaterals on myocardial perfusion during temporary coronary occlusion.

Clinical assessment of indication for ACE-inhibitor treatment early after acute myocardial infarction.

An investigation was conducted to assess whether an algorithm based on simple clinical information would suffice to classify patients with acute myocardial infarction, with respect to indication for angiotensin-converting-enzyme inhibitor treatment. One hundred consecutive patients with myocardial infarction were prospectively studied. Based on clinical, radiological, electrocardiographic and biochemical information, the patients were classified as having (a) significantly depressed left ventricular function (ejection fraction < or = 40%) justifying treatment with angiotensin-converting-enzyme inhibitors (ACEI), (b) preserved ventricular function (ejection fraction > 40%) making ACEI unnecessary, or (c) indeterminate ventricular function, requiring further examination. Using a blinded design, ejection fraction was determined by echocardiography and radionuclide ventriculography. A clinical assumption of reduced left ventricular function had a predictive value of an echocardiographically determined ejection fraction < or = 40% of 83% (n = 23). Clinical criteria of good ventricular function had a predictive value of ejection fraction > 40% of 96% (n = 24). In these two groups clinical misclassification occurred in five patients with ejection fraction within the range of 39-45%. Left ventricular function was found to be clinically indeterminate in 53 of the 100 patients. Ejection fraction values assessed by radionuclide ventriculography (n = 44) were on average 9.3%-points lower than echocardiographic values. The indication for ACEI can apparently be determined on the basis of readily available clinical information in approximately 50% of patients with acute myocardial infarction.

Evaluation of regional myocardial perfusion in patients with severe left ventricular dysfunction: comparison of 13N-ammonia PET and 99mTc sestamibi SPECT.

OBJECTIVE: Positron emission tomography (PET) scanning with 13N-ammonia and 18FDG is well established for the detection of myocardial viability. Due to the limited availability of PET facilities, recent studies have combined technetium 99m sestamibi single photon emission computed tomography (SPECT) with 18FDG PET or 18FDG SPECT. This approach enables simultaneous assessment of regional myocardial blood flow and metabolism and substantially increases the capacity for viability detection. To validate whether 99mTc-Sestamibi SPECT can replace 13N-ammonia PET, we compared these two modalities in patients with severe left ventricular dysfunction due to coronary artery disease. MATERIALS AND METHODS: Thirty-one patients (mean age 57+/-8 years; mean ejection fraction 27%+/-8%) with angiographically verified coronary artery disease were included. In random order, ammonia-PET and sestamibi-SPECT scans were performed. In a 20-segment model of the left ventricle, two blinded observers scored a total of 610 segments on a five-point scale. In a subset of 20 patients, 400 segments were scored twice to evaluate the observer variations of the two techniques. Segmental score differences were used to compare the imaging modalities. The impact on viability detection was assessed by combining the two flow tracers with FDG PET. RESULTS: Segmental comparison of the PET and SPECT studies yielded similar (difference < or = 1) results in 74% of segments, reflecting regional concordance values in the lateral, apical, anterior, septal, and inferior myocardial walls of 86%, 82%, 71%, 66%, and 63%, respectively. The differences in the septal and inferior walls were primarily due to overestimation of perfusion defects by sestamibi SPECT, which yielded a higher proportion of mismatch patterns in those regions. The overall observer variations of the PET and SPECT studies were 7.5% and 5.8%. CONCLUSION: Myocardial perfusion imaging with 13N-ammonia PET and 99mTc-sestamibi SPECT yielded similar results in patients with severe left ventricular dysfunction, except for the septal and inferior regions. In these regions, SPECT tended to overestimate perfusion defects. Hence, attenuation correction should be considered when combining FDG PET and sestamibi SPECT for diagnosing myocardial viability to avoid overestimation of mismatch patterns in those regions.

Perioperative myocardial ischaemia in patients undergoing surgery for fractured hip randomized to incremental spinal, single-dose spinal or general anaesthesia.

Quantitative assessment of myocardial ischaemia during incremental spinal, single-dose spinal and general anaesthesia may provide guidelines for the choice of anaesthetic technique for osteosynthesis of hip fractures in the elderly atherosclerotic individual. Forty-three patients with coronary artery disease were allocated to receive either incremental spinal anaesthesia (bupivacaine 0.5% plain) (A), single-dose spinal anaesthesia (2.5 mL of bupivacaine 0.5% plain) (B) or general anaesthesia (fentanyl, thiopentone, atracurium, enflurane, N2O/O2) (C) for hip surgery. ST segment monitoring was performed from the induction of anaesthesia and for the following 48 h, and perioperative hypotension, blood loss and fluid therapy were recorded. ST depression developed in two out of 14 (A), seven out of 15 (B) and six out of 14 (C) patients (P = 0.14). In (A), a total of seven ST depressions occurred in the observation period as opposed to 125 in (B) and 16 in (C) (P < 0.05). Intra-operative ST depression only occurred in (B). Three (A), 33 (B) and 40 (C) hypotensive events were recorded (P < 0.002). Altogether, 56% of hypotensive patients developed ST depression compared with 10% of normotensive patients (P < 0.003). In (A), 1.6 mL of 0.5% bupivacaine were used as opposed to the fixed 2.5 mL dose in (B) (P < 0.001). In the first post-operative week, mortality was higher in (B) (P < 0.05) but, after 1 month, there was no significant difference in mortality between the three groups. The incidence of hypotension and myocardial ischaemia was lowest in the group receiving incremental spinal anaesthesia.

[Syndrome X. Somatic and social prognosis of patients with angina pectoris and normal coronary arteriography]. / Syndrom X. Somatisk og social prognose hos patienter med angina pectoris og normal koronararteriografi.

Over a seven year period, 8.6% of 990 patients subjected to coronary arteriography because of angina pectoris were found to have normal coronary arteries (NCA). The subsequent histories of these patients were compared to those of a group of patients (N = 112) with coronary atherosclerosis (CAD). On average 44 months after coronary arteriography, 2.4% (NCA) had died versus 20.5% (CAD) (p < 0.001). Myocardial infarction had occurred in 0% (NCA) versus 12.8% (CAD) of the survivors (p < 0.001). Chest pain was unchanged or had worsened in 58.2% (NCA) versus 21.1% (CAD) (p < 0.001). Of the NCA patients, 33.3% had ischaemia during exercise-ECG. Three patients developed ischaemia during hyperventilation test. Eighty % (NCA) versus 63.9% (CAD) gave up work due to chest pain (p < 0.05). Further, 55.7% (NCA) versus 34.6% (CAD) had reduced daily activities (p < 0.01); similarly, the frequency of divorce was higher in the NCA group (10.2%) than in the CAD group (1.3%) (p < 0.05).

Somatic and social prognosis of patients with angina pectoris and normal coronary arteriography: a follow-up study.

A follow-up over a 7-year period demonstrated that 8.6% of all patients subjected to coronary arteriography because of angina pectoris had normal coronary arteries (NCA). The somatic and social prognosis of these patients were evaluated and these were compared to that of an age- and sex-matched group of patients with arteriographically verified coronary atherosclerosis (CAD). On average 44 months after coronary arteriography, 2.4% with NCA had died versus 20.5% with CAD (P < 0.001). Myocardial infarction occurred in 0% (NCA) versus 12.8% (CAD) among survivors (P < 0.001). Coronary revascularization was carried out in 0% (NCA) versus 76.9% (CAD). Chest pain was unchanged or had worsened in 58.2% (NCA) versus 21.1% (CAD) (P < 0.001) and this in the NCA patients was correlated to the occurrence of minimal lesions of the coronary arteries. Of the NCA patients, 33.3% had ischaemia during exercise-ECG. Normalization was seen in 12 patients and newly developed ischaemia in seven patients. Three patients developed ischaemia during hyperventilation test. Eighty percent (NCA) versus 63.9% (CAD) gave up work due to chest pain (P < 0.001). Further, 55.7% (NCA) versus 34.6% (CAD) had reduced daily activities (P < 0.001); similarly, the frequency of divorce was higher in the NCA group (10.2%) than in the CAD group (1.3%) (P < 0.05).