Imputation strategies for genomic prediction using nanopore sequencing.

BACKGROUND: Genomic prediction describes the use of SNP genotypes to predict complex traits and has been widely applied in humans and agricultural species. Genotyping-by-sequencing, a method which uses low-coverage sequence data paired with genotype imputation, is becoming an increasingly popular SNP genotyping method for genomic prediction. The development of Oxford Nanopore Technologies' (ONT) MinION sequencer has now made genotyping-by-sequencing portable and rapid. Here we evaluate the speed and accuracy of genomic predictions using low-coverage ONT sequence data in a population of cattle using four imputation approaches. We also investigate the effect of SNP reference panel size on imputation performance. RESULTS: SNP array genotypes and ONT sequence data for 62 beef heifers were used to calculate genomic estimated breeding values (GEBVs) from 641 k SNP for four traits. GEBV accuracy was much higher when genome-wide flanking SNP from sequence data were used to help impute the 641 k panel used for genomic predictions. Using the imputation package QUILT, correlations between ONT and low-density SNP array genomic breeding values were greater than 0.91 and up to 0.97 for sequencing coverages as low as 0.1 × using a reference panel of 48 million SNP. Imputation time was significantly reduced by decreasing the number of flanking sequence SNP used in imputation for all methods. When compared to high-density SNP arrays, genotyping accuracy and genomic breeding value correlations at 0.5 × coverage were also found to be higher than those imputed from low-density arrays. CONCLUSIONS: Here we demonstrated accurate genomic prediction is possible with ONT sequence data from sequencing coverages as low as 0.1 × , and imputation time can be as short as 10 min per sample. We also demonstrate that in this population, genotyping-by-sequencing at 0.1 × coverage can be more accurate than imputation from low-density SNP arrays.

Determining the optimal interval for imaging surveillance of ascending aortic aneurysms.

BACKGROUND: Cardiovascular guidelines recommend (bi-)annual computed tomography (CT) or magnetic resonance imaging (MRI) for surveillance of the diameter of thoracic aortic aneurysms (TAAs). However, no previous study has demonstrated the necessity for this approach. The current study aims to provide patient-specific intervals for imaging follow-up of non-syndromic TAAs. METHODS: A total of 332 patients with non-syndromic ascending aortic aneurysms were followed over a median period of 6.7 years. Diameters were assessed using all available imaging techniques (echocardiography, CT and MRI). Growth rates were calculated from the differences between the first and last examinations. The diagnostic accuracy of follow-up protocols was calculated as the percentage of subjects requiring pre-emptive surgery in whom timely identification would have occurred. RESULTS: The mean growth rate in our population was 0.2 ± 0.4 mm/year. The highest recorded growth rate was 2.0 mm/year, while 40.6% of patients showed no diameter expansion during follow-up. Females exhibited significantly higher growth rates than men (0.3 ± 0.5 vs 0.2 ± 0.4 mm/year, p = 0.007). Conversely, a bicuspid aortic valve was not associated with more rapid aortic growth. The optimal imaging protocol comprises triennial imaging of aneurysms 40-49 mm in diameter and yearly imaging of those measuring 50-54 mm. This strategy is as accurate as annual follow-up, but reduces the number of imaging examinations by 29.9%. CONCLUSIONS: In our population of patients with non-syndromic TAAs, we found aneurysm growth rates to be lower than those previously reported. Yearly imaging does not lead to changes in the management of small aneurysms. Thus, lower imaging frequencies might be a good alternative approach.

The role of inflammation in the association between overall and visceral adiposity and subclinical atherosclerosis.

BACKGROUND AND AIMS: Inflammation may underlie the association between obesity, atherosclerosis and cardiovascular disease. We investigated to what extent markers of inflammation mediate associations between overall and visceral body fat and subclinical atherosclerosis. METHODS AND RESULTS: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study we estimated total body fat (TBF) by bio-impedance analysis, carotid artery intima media thickness (cIMT) by ultrasound, C-reactive protein (hs-CRP) and glycoprotein acetyls (GlycA) concentrations in fasting blood samples (n = 5627), and visceral adipose tissue (VAT) by magnetic resonance imaging (n = 2247). We examined associations between TBF and VAT, and cIMT using linear regression, adjusted for potential confounding factors, and for mediators: cardiometabolic risk factors (blood pressure, glucose and low-density lipoprotein cholesterol), and inflammation using CRP and GlycA as proxies. Mean (SD) cIMT was 615 (90) µm. Per SD of TBF (8%), cIMT was 19 µm larger (95% confidence interval, CI: 10, 28). This association was 17 µm (95% CI: 8, 27) after adjustment for cardiometabolic risk factors, and did not change after adjustment for markers of inflammation. Per SD (56 cm2) VAT, cIMT was 9 µm larger (95% CI: 2, 16) which changed to 5 µm (95% CI: -3, 12) after adjustment for cardiometabolic risk factors, and did not change after adjustment for inflammatory markers. CONCLUSION: Our results suggest that associations between measures of overall and visceral body fat and subclinical atherosclerosis are not mediated by inflammation as measured by CRP and GlycA. Obesity may exert cardiovascular risk via other markers of systemic inflammation.

Intramyocardial bone marrow cell injection does not lead to functional improvement in patients with chronic ischaemic heart failure without considerable ischaemia.

BACKGROUND: It has been suggested that bone marrow cell injection may have beneficial effects in patients with chronic ischaemic heart disease. However, previous trials have led to discrepant results of cell-based therapy in patients with chronic heart failure. The aim of this study was to evaluate the efficacy of intramyocardial injection of mononuclear bone marrow cells in patients with chronic ischaemic heart failure with limited stress-inducible myocardial ischaemia. METHODS AND RESULTS: This multicentre, randomised, placebo-controlled trial included 39 patients with no-option chronic ischaemic heart failure with a follow-up of 12 months. A total of 19 patients were randomised to autologous intramyocardial bone marrow cell injection (cell group) and 20 patients received a placebo injection (placebo group). The primary endpoint was the group difference in change of left ventricular ejection fraction, as determined by single-photon emission tomography. On follow-up at 3 and 12 months, change of left ventricular ejection fraction in the cell group was comparable with change in the placebo group (P = 0.47 and P = 0.08, respectively). Also secondary endpoints, including left ventricle volumes, myocardial perfusion, functional and clinical parameters did not significantly change in the cell group as compared to placebo. Neither improvement was demonstrated in a subgroup of patients with stress-inducible ischaemia (P = 0.54 at 3­month and P = 0.15 at 12-month follow-up). CONCLUSION: Intramyocardial bone marrow cell injection does not improve cardiac function, nor functional and clinical parameters in patients with severe chronic ischaemic heart failure with limited stress-inducible ischaemia. CLINICAL TRIAL REGISTRATION: NTR2516.

Assessing genetic and environmental influences on epicardial and abdominal adipose tissue quantities: a classical twin study.

BACKGROUND/OBJECTIVES: Various adipose tissue compartments play an important role in the development of cardiometabolic diseases. The quantity of different fat compartments is influenced by genetic and environmental factors. The aim of our study was to evaluate the magnitude of genetic and environmental effects on epicardial, subcutaneous and visceral adipose tissue (EAT, SAT and VAT) quantities in a cohort of adult twin pairs. SUBJECTS/METHODS: In this cross-sectional study we investigated adult twins (57 monozygotic (MZ) and 33 dizygotic (DZ) same-gender twin pairs; 180 twin subjects). We measured EAT volume using electrocardiogram-gated native computed tomography (CT) scan of the heart, and abdominal SAT and VAT areas were quantified between the third and fourth lumbar vertebra on native CT images. We calculated genetic and environmental impact on the size of various adipose tissue compartments by analyzing co-twin correlations in MZ and DZ pairs separately, and furthermore by using genetic structural equation models. RESULTS: In co-twin analysis, MZ twins had stronger correlations than DZ twins for EAT (rMZ=0.81, rDZ=0.32), similar to SAT and VAT quantities (rMZ=0.80, rDZ=0.68 and rMZ=0.79, rDZ=0.48, respectively). In multi-trait model fitting analysis, the overall contribution of genetic factors to EAT, SAT and VAT volumes were 80%, 78% and 70%, whereas environmental factors were 20%, 22% and 30%, respectively. Common pathway model analyses indicated that none of the EAT, SAT and VAT phenotypes was independent of the other two. CONCLUSIONS: Genetic factors have substantial influence, while environmental factors have only a modest impact on EAT volume, abdominal SAT and VAT quantities. There is a considerable amount of common genetic background influencing the quantities of all three adipose tissue compartments.

Interrelationship of the rs7903146 TCF7L2 gene variant with measures of glucose metabolism and adiposity: The NEO study.

BACKGROUND AND AIMS: We investigated the interrelationship of rs7903146-T in TCF7L2 with measures of glucose metabolism and measures of adiposity. METHODS AND RESULTS: This cross-sectional analysis was conducted in 5744 middle-aged participants (mean (standard deviation [SD]) age is 55.9 (6.0) years) from the Netherlands Epidemiology of Obesity (NEO) Study. Associations between rs7903146-T and Type 2 diabetes mellitus (T2D) were assessed with logistic regression. Additive (per-allele) associations with measures of glucose metabolism (e.g., fasting insulin) and adiposity (e.g., body mass index [BMI]) were examined with multivariable linear regression. In the total study population, rs7903146-T was associated with a higher risk of T2D (additive odds ratio: 1.42; 95% confidence interval: 1.17; 1.72), and specifically with T2D treated with insulin analogs (2.31 [1.19; 4.46]). After exclusion of participants treated with glucose-lowering medication, rs7903146-T was associated with lower mean insulin concentration (additive mean difference: -0.07 SD [-0.14; 0.00]), but not with higher mean glucose concentration (0.03 SD [-0.01; 0.07]). Furthermore, rs7903146-T was associated with, among other measures of adiposity, a lower mean BMI (-0.04 SD [-0.09; -0.00]), and a lower mean total body fat (-0.04 SD [-0.08; -0.00]). The association between rs7903146-T and T2D increased after adjustment for BMI (odds ratio: 1.51 [1.24; 1.86]); the association between rs7903146-T and fasting insulin diminished after adjustment (-0.05 SD [-0.11; 0.02]). CONCLUSION: rs7903146-T is associated with a decreased insulin concentration and increased risk of T2D with opposing effects of adjustment for adiposity.

Cardiovascular flexibility in middle-aged overweight South Asians vs. white Caucasians: response to short-term caloric restriction.

BACKGROUND AND AIMS: South Asians have a higher risk of developing cardiovascular disease than white Caucasians. The underlying cause is unknown, but might be related to higher cardiac susceptibility to metabolic disorders. Short-term caloric restriction (CR) can be used as a metabolic stress test to study cardiac flexibility. We assessed whether metabolic and functional cardiovascular flexibility to CR differs between South Asians and white Caucasians. METHODS AND RESULTS: Cardiovascular function and myocardial triglycerides were assessed using a 1.5T-MRI/S-scanner in 12 middle-aged overweight male South Asians and 12 matched white Caucasians before and after an 8-day very low calorie diet (VLCD). At baseline South Asians were more insulin resistant than Caucasians. Cardiac dimensions were smaller, despite correction for body surface area, and pulse wave velocity (PWV) in the distal aorta was higher in South Asians. Systolic and diastolic function, myocardial triglycerides and pericardial fat did not differ significantly between groups. After the VLCD body weight reduced on average by 4.0 ± 0.2 kg. Myocardial triglycerides increased in both ethnicities by 69 ± 18%, and diastolic function decreased although this was not significant in South Asians. However, pericardial fat and PWV in the proximal and total aorta were reduced in Caucasians only. CONCLUSION: Myocardial triglyceride stores in middle-aged overweight and insulin resistant South Asians are as flexible and amenable to therapeutic intervention by CR as age-, sex- and BMI-matched but less insulin resistant white Caucasians. However, paracardial fat volume and PWV showed a differential effect in response to an 8-day VLCD in favor of Caucasians. CLINICAL TRIAL REGISTRATION: NTR 2473 (URL: http://www.trialregister.nl/trialreg/admin/rctsearch.asp?Term=2473).

Morphological and functional carotid vessel wall properties in relation to cerebral white matter lesions in myocardial infarction patients.

OBJECTIVE: Atherosclerotic large vessel disease is potentially involved in the pathogenesis of cerebral small vessel disease related to occurrence of white matter lesions (WMLs) in the brain. We aimed to assess morphological and functional carotid vessel wall properties in relation to WML using magnetic resonance imaging (MRI) in myocardial infarction (MI) patients. MATERIALS AND METHODS: A total of 20 MI patients (90 % male, 61 ± 11 years) underwent carotid artery and brain MRI. Carotid vessel wall thickness (VWT) was assessed, by detecting lumen and outer wall contours. Carotid pulse wave velocity (PWV), a measure of elasticity, was determined using the transit-time method. Patients were divided according to the median VWT into two groups. Brain MRI allowed for the WML score. RESULTS: Mean VWT was 1.41 ± 0.29 mm and mean carotid PWV was 7.0 ± 2.2 m/s. A significant correlation (Pearson r = 0.45, p = 0.046) between VWT and PWV was observed. Furthermore, in the group of high VWT, the median WML score was higher as compared with the group with lower VWT (4.0 vs 3.0, p = 0.035). CONCLUSIONS: Carotid artery morphological and functional alterations are correlated in MI patients. Patients with high VWT showed a higher amount of periventricular WMLs. These findings support the hypothesis that atherosclerotic large vessel disease is potentially involved in the pathogenesis of cerebral small vessel disease.

Prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in a middle-aged population with overweight and normal liver enzymes, and diagnostic accuracy of noninvasive proxies.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing at an alarming rate. Elevated liver enzymes are a primary reason to refer patients for further testing. However, liver enzymes within the normal range do not exclude the presence of MASLD. We examined the prevalence of MASLD in a middle-aged population with overweight and normal liver enzymes. In addition, we examined the accuracy of 4 sets of noninvasive proxies for MASLD. We included 1017 participants from the Netherlands epidemiology of obesity cohort study with body mass index ≥25 kg/m2 and liver enzymes (asparate aminotransferase, alanine aminotransferase, gamma-glutamyltranspeptidase) within normal range. The diagnostic accuracy of biomarker scores (fatty liver index, liver fat score [LFS], STEATO-ELSA, and hepatic steatosis index) was determined against elevated hepatic triglyceride content measured by 1proton magnetic resonance spectroscopy. Participants (mean age 56 years, 49% women), had a median body mass index of 29.6 kg/m2 and a median hepatic triglyceride content of 4.4%. MASLD was present in 42% of participants and was more common in men than women, with respectively 47% and 36% being affected. The LFS showed the highest accuracy with an area under the curve of 0.72. We identified metabolic syndrome as the prime predictor for MASLD with an odds ratio of 2.95 (95% confidence interval 2.20-3.98). The prevalence of MASLD in middle-aged men and women with overweight and liver enzymes within the normal range is over 40%. LFS showed the highest accuracy to detect MASLD, but, overall, biomarker scores performed relatively poor. The presence of metabolic syndrome was the prime predictor of MASLD.

Flow patterns in ascending aortic aneurysms: Determining the role of hypertension using phase contrast magnetic resonance and computational fluid dynamics.

Thoracic aortic aneurysm (TAA) is a local dilation of the thoracic aorta. Although universally used, aneurysm diameter alone is a poor predictor of major complications such as rupture. There is a need for better biomarkers for risk assessment that also reflect the aberrant flow patterns found in TAAs. Furthermore, hypertension is often present in TAA patients and may play a role in progression of aneurysm. The exact relation between TAAs and hypertension is poorly understood. This study aims to create a numerical model of hypertension in the aorta by using computational fluid dynamics. First, a normotensive state was simulated in which flow and resistance were kept unaltered. Second, a hypertensive state was modeled in which blood inflow was increased by 30%. Third, a hypertensive state was modeled in which the proximal and peripheral resistances and capacitance parameters from the three-element Windkessel boundary condition were adjusted to mimic an increase in resistance of the rest of the cardiovascular system. One patient with degenerative TAA and one healthy control were successfully simulated at hypertensive states and were extensively analyzed. Furthermore, three additional TAA patients and controls were simulated to validate our method. Hemodynamic variables such as wall shear stress, oscillatory shear index, endothelial cell activation potential (ECAP), vorticity and helicity were studied to gain more insight on the effects of hypertension on flow patterns in TAAs. By comparing a TAA patient and a control at normotensive state at peak-systole, helicity and vorticity were found to be lower in the TAA patient throughout the entire domain. No major changes in flow and flow derived quantities were observed for the TAA patient and control when resistance was increased. When flow rate was increased, regions with high ECAP values were found to reduce in TAA patients in the aneurysm region which could reduce the risk of thrombogenesis. Thus, it may be important to assess cardiac output in patients with TAA.

Chemotherapy for testicular cancer induces acute alterations in diastolic heart function.

BACKGROUND: After treatment with cisplatin-based chemotherapy for testicular cancer (TC), patients have higher prevalence of cardiovascular complications after long-term follow up. Little is known about acute cardiovascular effects of cisplatin-based chemotherapy. The aim of this study was to explore acute effects of chemotherapy on cardiac function in patients treated for TC. METHODS: Fourteen TC patients (age 34.6 ± 12.3 years) were studied before and 3 months after start with cisplatin-based chemotherapy. Cardiac function was assessed with magnetic resonance imaging. Fasting glucose and insulin levels were measured and insulin sensitivity, reflected by the quantitative insulin sensitivity index (Quicki index), was calculated. RESULTS: Left ventricular (LV) end-diastolic volume and LV stroke volume (SV) significantly decreased from 192 ± 27 to 175 ± 26 ml (P<0.05) and 109 ± 18 to 95 ± 16 ml (P<0.05), respectively. The ratio of early and atrial filling velocities across the mitral valve, a parameter of diastolic heart function, decreased after chemotherapy from 1.87 ± 0.43 to 1.64 ± 0.45 (P<0.01). Metabolic parameters were unfavourably changed, reflected by a decreased Quicki index, which reduced from 0.39 ± 0.05 to 0.36 ± 0.05 (P<0.05). CONCLUSION: Chemotherapy for TC induces acute alterations in diastolic heart function, paralleled by unfavourable metabolic changes. Therefore, early after chemotherapy, metabolic treatment may be indicated to possibly reduce long-term cardiovascular complications.

Ascending aorta curvature and flow displacement are associated with accelerated aortic growth at long-term follow-up: A MRI study in Marfan and thoracic aortic aneurysm patients.

BACKGROUND: Aortic aneurysm formation is associated with increased risk of aortic dissection. Current diagnostic strategies are focused on diameter growth, the predictive value of aortic morphology and function remains underinvestigated. We aimed to assess the long-term prognostic value of ascending aorta (AA) curvature radius, regional pulse wave velocity (PWV) and flow displacement (FD) on aortic dilatation/elongation and evaluated adverse outcomes (proximal aortic surgery, dissection/rupture, death) in Marfan and non-syndromic thoracic aortic aneurysm (NTAA) patients. METHODS: Long-term magnetic resonance imaging (MRI) and clinical follow-up of two previous studies consisting of 21 Marfan and 40 NTAA patients were collected. Baseline regional PWV, AA curvature radius and normalized FD were assessed as well as diameter and length growth rate at follow-up. Multivariate linear regression was performed to evaluate whether baseline predictors were associated with aortic growth.=. RESULTS: Of the 61 patients, 49 patients were included with MRI follow-up (n = 44) and/or adverse aortic events (n = 7). Six had undergone aortic surgery, no dissection/rupture occurred and one patient died during follow-up. During 8.0 [7.3-10.7] years of follow-up, AA growth rate was 0.40 ± 0.31 mm/year. After correction for confounders, AA curvature radius (p = 0.01), but not FD or PWV, was a predictor of AA dilatation. Only FD was associated with AA elongation (p = 0.01). CONCLUSION: In Marfan and non-syndromic thoracic aortic aneurysm patients, ascending aorta curvature radius and flow displacement are associated with accelerated aortic growth at long-term follow-up. These markers may aid in the risk stratification of ascending aorta elongation and aneurysm formation.

Exercise-induced modulation of cardiac lipid content in healthy lean young men.

Cardiac lipid accumulation is associated with decreased cardiac function and energy status (PCr/ATP). It has been suggested that elevated plasma fatty acid (FA) concentrations are responsible for the cardiac lipid accumulation. Therefore, the aim of the present study was to investigate if elevating plasma FA concentrations by exercise results in an increased cardiac lipid content, and if this influences cardiac function and energy status. Eleven male subjects (age 25.4 ± 1.1 years, BMI 23.6 ± 0.8 kg/m²) performed a 2-h cycling protocol, once while staying fasted and once while ingesting glucose, to create a state of high versus low plasma FA concentrations, respectively. Cardiac lipid content was measured by proton magnetic resonance spectroscopy (¹H-MRS) at baseline, directly after exercise and again 4 h post-exercise, together with systolic function (by multi-slice cine-MRI) and cardiac energy status (by ³¹P-MRS). Plasma FA concentrations were increased threefold during exercise and ninefold during recovery in the fasted state compared with the glucose-fed state (p < 0.01). Cardiac lipid content was elevated at the end of the fasted test day (from 0.26 ± 0.04 to 0.44 ± 0.04%, p = 0.003), while it did not change with glucose supplementation (from 0.32 ± 0.03 to 0.26 ± 0.05%, p = 0.272). Furthermore, PCr/ATP was decreased by 32% in the high plasma FA state compared with the low FA state (n = 6, p = 0.014). However, in the high FA state, the ejection fraction 4 h post-exercise was higher compared with the low FA state (63 ± 2 vs. 59 ± 2%, p = 0.018). Elevated plasma FA concentrations, induced by exercise in the fasted state, lead to increased cardiac lipid content, but do not acutely hamper systolic function. Although the lower cardiac energy status is in line with a lipotoxic action of cardiac lipid content, a causal relationship cannot be proven.

The impact and challenges of implementing CTCA according to the 2019 ESC guidelines on chronic coronary syndromes: a survey and projection of CTCA services in the Netherlands.

BACKGROUND: The 2019 ESC-guidelines on chronic coronary syndromes (ESC-CCS) recommend computed tomographic coronary angiography (CTCA) or non-invasive functional imaging instead of exercise ECG as initial test to diagnose obstructive coronary artery disease. Since impact and challenges of these guidelines are unknown, we studied the current utilisation of CTCA-services, status of CTCA-protocols and modeled the expected impact of these guidelines in the Netherlands. METHODS AND RESULTS: A survey on current practice and CTCA utilisation was disseminated to every Dutch hospital organisation providing outpatient cardiology care and modeled the required CTCA capacity for implementation of the ESC guideline, based on these national figures and expert consensus. Survey response rate was 100% (68/68 hospital organisations). In 2019, 63 hospital organisations provided CTCA-services (93%), CTCA was performed on 99 CTCA-capable CT-scanners, and 37,283 CTCA-examinations were performed. Between the hospital organisations, we found substantial variation considering CTCA indications, CTCA equipment and acquisition and reporting standards. To fully implement the new ESC guideline, our model suggests that 70,000 additional CTCA-examinations would have to be performed in the Netherlands. CONCLUSIONS: Despite high national CTCA-services coverage in the Netherlands, a substantial increase in CTCA capacity is expected to be able to implement the 2019 ESC-CCS recommendations on the use of CTCA. Furthermore, the results of this survey highlight the importance to address variations in image acquisition and to standardise the interpretation and reporting of CTCA, as well as to establish interdisciplinary collaboration and organisational alignment.

Relation between regional and global systolic function in patients with ischemic cardiomyopathy after beta-blocker therapy or revascularization.

BACKGROUND: To assess the relationship between improved regional and global myocardial function in patients with ischemic cardiomyopathy in response to beta-blocker therapy or revascularization. MATERIALS AND METHODS: Cardiovascular magnetic resonance (CMR) was performed in 32 patients with ischemic cardiomyopathy before and 8 +/- 2 months after therapy. Patients were assigned clinically to beta-blocker therapy (n = 20) or revascularization (n = 12). CMR at baseline was performed to assess regional and global LV function at rest and under low-dose dobutamine. Wall thickening was analyzed in dysfunctional, adjacent, and remote segments. Follow-up CMR included rest function evaluation. RESULTS: Augmentation of wall thickening during dobutamine at baseline was similar in dysfunctional, adjacent and remote segments in both patient groups. Therefore, baseline characteristics were similar for both patient groups. In both patient groups resting LV ejection fraction and end-systolic volume improved significantly (p < 0.05) at follow-up. Stepwise multivariate analysis revealed that improvement in global LV ejection fraction in the beta-blocker treated patients was significantly related to improved function of remote myocardium (p < 0.05), whereas in the revascularized patients improved function in dysfunctional and adjacent segments was more pronounced (p < 0.05). CONCLUSION: In patients with chronic ischemic LV dysfunction, beta-Blocker therapy or revascularization resulted in a similar improvement of global systolic LV function. However, after beta-blocker therapy, improved global systolic function was mainly related to improved contraction of remote myocardium, whereas after revascularization the dysfunctional and adjacent regions contributed predominantly to the improved global systolic function.

Borderline Q-waves in individuals without overt cardiovascular disease: Relations with adiposity, subclinical atherosclerosis and vascular stiffness.

BACKGROUND: Characteristics and risk factors associated with electrocardiographic borderline Q-waves are not fully elucidated, especially in individuals without overt cardiovascular disease (CVD). Also, the relation of isolated and non-isolated borderline Q-waves with subclinical atherosclerosis and vascular stiffness is unknown. METHODS AND RESULTS: We included 5746 Netherlands Epidemiology of Obesity study participants without overt CVD. Participants were divided in three groups: no Q-waves (93.7%), isolated (4.6%) and non-isolated borderline Q-waves (1.7%). Borderline Q-waves were defined as Minnesota Codes 1.2.x and 1.3.x and non-isolated as ≥1 of abnormal QRS axis, left ventricular hypertrophy or ST/T abnormalities. Several characteristics and measures of body fat were assessed. Vascular stiffness was assessed by pulse wave velocity (PWV) and subclinical atherosclerosis by carotid intima-media thickness (cIMT). Percentage of men, alcohol intake, blood pressure and fasting glucose concentrations were, compared with no Q-waves, higher in the isolated and highest in the non-isolated borderline Q-wave group. Isolated borderline Q-waves were associated with higher body mass index (difference compared with no Q-waves: 1.0 kg/m2; 95%CI: 0.3-1.7; p-value: 0.006), waist circumference (3.4 cm; 1.0-5.8; 0.005), and visceral adipose tissue (21.9 cm2; 7.4-36.3; 0.003) and differences were even larger for non-isolated borderline Q-waves. Compared with no Q-waves, non-isolated borderline Q-waves were associated with higher PWV (1.2 m/s; 0.4-2.0; 0.004) and cIMT (23.4 µm; 3.0-43.8; 0.024), whereas isolated borderline Q-waves were not. CONCLUSION: Cardiovascular risk factors and measures of body fat, especially abdominal adiposity, were higher in participants with isolated borderline Q-waves, compared with no Q-waves, and highest in the non-isolated borderline Q-wave group. Non-isolated borderline Q-waves were associated with subclinical atherosclerosis and vascular stiffness. Future studies should investigate potential added value of borderline Q-waves in CVD prediction.

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population.

Essentials Why venous thrombosis is more prevalent in chronic kidney disease is unclear. We investigated whether renal and vascular function are associated with hypercoagulability. Coagulation factors showed a procoagulant shift with impaired renal and vascular function. This suggests that renal and vascular function play a role in the etiology of thrombosis. SUMMARY: Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n = 6536), and PWV was assessed in a random subset (n = 2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (> 50th [reference] to < 1st) and UACR (< 50th [reference] to > 99th), and per four categories (< 50th [reference] to > 95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6 years, mean eGFR 86.0 (12SD) mL 1.73 m- ² and median UACR 0.4 mg mmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22 IU dL-1 (95% CI, 13-32) higher in the eGFR < 1st percentile compared with the > 50th percentile, and FVIII was 12 IU dL-1 (95% CI, 3-22) higher in the UACR > 99th percentile compared with the < 50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0 IU dL-1 (95% CI, 0.70-3.2) higher. Conclusions Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

Serum microRNA-1 and microRNA-133a levels reflect myocardial steatosis in uncomplicated type 2 diabetes.

Using in vitro, in vivo and patient-based approaches, we investigated the potential of circulating microRNAs (miRNAs) as surrogate biomarkers of myocardial steatosis, a hallmark of diabetic cardiomyopathy. We analysed the cardiomyocyte-enriched miRNA signature in serum from patients with well-controlled type 2 diabetes and with verified absence of structural heart disease or inducible ischemia, and control volunteers of the same age range and BMI (N = 86), in serum from a high-fat diet-fed murine model, and in exosomes from lipid-loaded HL-1 cardiomyocytes. Circulating miR-1 and miR-133a levels were robustly associated with myocardial steatosis in type 2 diabetes patients, independently of confounding factors in both linear and logistic regression analyses (P < 0.050 for all models). Similar to myocardial steatosis, miR-133a levels were increased in type 2 diabetes patients as compared with healthy subjects (P < 0.050). Circulating miR-1 and miR-133a levels were significantly elevated in high-fat diet-fed mice (P < 0.050), which showed higher myocardial steatosis, as compared with control animals. miR-1 and miR-133a levels were higher in exosomes released from lipid-loaded HL-1 cardiomyocytes (P < 0.050). Circulating miR-1 and miR-133a are independent predictors of myocardial steatosis. Our results highlight the value of circulating miRNAs as diagnostic tools for subclinical diabetic cardiomyopathy.