Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Screening for cardiovascular risk using ultrasound: a practical approach

As indicated in previous chapters, cardiovascular disease (CVD) is one of the most common causes of death in the western world, and stroke, the most common cause of disability in women. Treatment is a major financial burden to health services, and effective prevention has now become a priority. The official aim in the UK is to reduce mortality from heart disease among men under 75 by 40%

Comparison between insulin resistance indices and carotid and femoral atherosclerosis: a cross-sectional population study

Objectives: To investigate the association between commonly used insulin resistance indices and presence and extent of carotid and femoral atherosclerosis in a general population setting. Methods: Cross-­sectional analysis of 762 volunteers from the ongoing epidemiological Cyprus Study (46.6% male; mean age=60.5±10.2). (a) Carotid intima-­media thickness (IMTcc), (b) carotid and femoral atherosclerotic plaque presence, (c) total plaque area in the carotid/femoral bifurcations (sum of the largest plaques in each carotid/femoral bifurcation-­SPAcar/fem) and (d) total plaque area in both carotid and femoral bifurcations (sum of the areas of the largest plaques present in each of the four bifurcations-­SPA) were measured using ultrasound at baseline. The HOMA-­IR, QUICKI and McAuley indices as well as fasting insulin levels were estimated and their quartiles were used in linear and logistic regression analysis. Results: All insulin resistance indices studied were strongly associated with IMTcc (p<0.01for all) even after adjustment for age and sex and exclusion of diabetic subjects. However, when looking at plaque presence and size (i.e.area) only the HOMA-­IR and especially the McAuley indexwere associated with both carotid plaque presence (OR adj = 1.17; 95%CI=1.01 to 1.36; p=0.03 and OR adj = 0.86; 95%CI=0.74 to 0.99; p=0.04 respectively) and area(OR adj = 0.10; 95%CI=0.008 to 0.20; p=0.03 and OR adj = -­0.11; 95%CI=-­0.20 to -­0.009; p=0.03 respectively), after adjustment.The McAuley index remained a significant predictor of both carotid plaque presence and area even after exclusion of diabetic subjects (p=0.04). CONCLUSIONS: Our results show that while all indices were associated with carotid IMT, supporting a strong role for insulin resistance in intimal-­medial thickening, only the HOMA-­IR and especially the McAuley indexwere associated with both carotid plaque presence and area, after adjustment. This highlights the importance of including triglyceride levels in estimating the risk for atherosclerotic plaque in the carotids as well as the possible differences in determinants for atherosclerosis between arterial sites

Evidence for contribution of the y chromosome in atherosclerotic plaque occurrence in men

Diseases such as atherosclerosis and coronary artery disease demonstrate disparate population prevalence or present with variable severity in men and women. While the usual explanation points to hormonal status, the role of the Y chromosome has been implicated, but not sufficiently studied. We genotyped six markers of the male-specific region of the Y chromosome, representing the major haplogroups (YAP, G, I, J, K, and R) in 373 male participants of the “Cyprus Study” with ultrasonic data on subclinical atherosclerosis. Of the five major haplogroups identified, two (J and K) accounted for roughly 67% of the Y-chromosome variance among these Greek Cypriot men. Carriers of haplogroup K had a 2.5-fold higher age-adjusted risk for having an atherosclerotic plaque present in any of the four bifurcations scanned, compared to men with other Y-chromosome lineages (OR=2.51; 95% CI=1.18 to 5.33; p=0.017). Carriers of the YAP haplogroup had about 50% less risk for having a plaque in the femoral bifurcation versus the rest (OR=0.46; 95% CI=0.27 to 0.77; p<0.001). We show a possible contribution of the Y chromosome in atherosclerotic phenotypes in men adding to the previous findings for coronary artery disease. Additional studies are warranted as evidence suggests that the Y chromosome could serve as a biomarker for the health status of men

A comparison of ultrasound intima media thickness measurements of the left and right common carotid artery

The intima-media thickness (IMT) of the common carotid artery (CCA) is an established indicator of cardiovascular disease (CVD). There have been reports about the difference between the left and the right sides of the CCA IMT and its importance when evaluated with various risk factors as well as their association with the risk of stroke. In this study, we use an automated system based on snakes, for segmenting the CCA and perform measurements of the IMT of the carotid artery and provide their differences between the left and right sides. The study was performed on 205 longitudinal-section ultrasound images acquired from 87 men and 118 women at a mean±SD age of 63±10.47 years, out of which 51 had cardiovascular symptoms. A cardiovascular expert manually measured the IMT on the left CCA side (mean±standard deviation = 0.79±0.21 mm) and the right CCA side (0.76±0.33 mm). The left and right IMT automated measurements were 0.70±0.15 mm and 0.66±0.15 mm, respectively. We found no statistical significant differences: 1) between the left and right IMT measurements, for both the manual and automated measurements, and 2) between the manual and automated measurements for both sides. These findings suggest that the measurement of the CCA IMT on one side only is enough (and this is in agreement with other studies), as well as automated measurements can be used

Association of Intima-Media Texture With Prevalence of Clinical Cardiovascular Disease

Recent studies have suggested that textural characteristics of the intima-media complex (IMC) may be more useful than the intima-media thickness (IMT) in evaluating cardiovascular risk. The primary aim of our study was to investigate the association between texture features of the common carotid IMC and prevalent clinical cardiovascular disease (CVD). The secondary aim was to determine whether IMT and IMC texture features vary between the left and right carotid arteries. The study was performed on 2208 longitudinal-section ultrasound images of the left (L) and right (R) common carotid artery (CCA), acquired from 569 men and 535 women out of which 125 had clinical CVD. L and R sides of the IMC were intensity normalized and despeckled. The IMC was semiautomatically delineated for all images using a semiautomated segmentation system, and 61 different texture features were extracted. The corresponding IMT semiautomated measurements (mean±SD) of the L and R sides were 0.73±0.21 mm/0.69±0.19 mm for the normal population and 0.83±0.17 mm/0.79±0.18 mm for those with CVD. IMC texture features did not differ between the right- and left-hand sides. Several texture features were independent predictors of the presence of CVD. The multivariate logistic regression analysis combining age, IMT, and texture features produced a receiver operating characteristic curve with an area under the curve of 89%. A correct classification rate of 77% for separating the normal subject (NOR) versus CVD subjects was achieved using the support vector machine classifier with a combination of clinical features, IMT, and extracted texture features. Texture features provide additional information on the presence of clinical CVD, which is over and above that provided by conventional risk factors or IMT alone. The value of IMC texture features in the prediction of future cardiovascular events should be tested in prospective studies

A Comparison of Ultrasound Intima-Media Thickness Measurements of the Left and Right Common Carotid Artery

The intima-media thickness (IMT) of the common carotid artery (CCA) is an established indicator of cardiovascular disease (CVD). There have been reports about the difference between the left and the right sides of the CCA IMT and their relation with CVD. In this paper, we propose an automated system based on image normalization, speckle reduction filtering, and snakes segmentation, for segmenting the CCA, perform IMT measurements, and provide the differences between the left and the right sides. The study was performed on 1104 longitudinal-section ultrasound images acquired from 568 men and 536 women out of which 125 had cardiovascular symptoms (CVD). A cardiovascular expert manually delineated the IMT for the normal and the CVD groups. The corresponding (normal versus CVD) IMT mean ± standard deviation values for the left and the right sides were 0.74 ± 0.24 versus 0.87 ± 0.24 mm and 0.70 ± 0.17 versus 0.80 ± 0.18 mm, respectively. The main findings of this paper can be summarized as follows: 1) there was no significant difference between the CCA left side IMT and the right side IMT. These findings suggest that the measurement of the CCA IMT on one side only is needed for the normal group (and this is in agreement with other studies); 2) there were statistical significant differences for the IMT measurements between the normal group and the CVD group for both the left and the right sides; 3) there was an increasing linear relationship of the left and the right IMT measurements with age for the normal group; and to a lesser extend for the CVD group; 4) no statistical significant differences were found between the manual and the automated IMT measurements for both sides; and 5) the best result for classification disease modeling, using support vector machines, to discriminate between the normal and the CVD groups was a 64%±3.5% correct classifications score when using both the left and the right IMT automated measurements. Further research is required for estimating differences and similarities between left and right intima media complex structure and morphology and their variability with texture features for differentiating between the normal and the CVD group

Texture analysis of the media-layer of the left and right common carotid artery

The intima-media thickness (IMT) of the common carotid artery (CCA) is a well-known indicator of cardiovascular disease (CVD). The objective of this study was to investigate the application of texture analysis of the medial layer (ML) of the CCA, and how texture features vary between the left and right carotid sides, as well as how these are affected by CVD. The study was performed on 200 longitudinal-section ultrasound images from 150 normal subjects, and 50 symptomatic subjects suffering with CVD. The ML was segmented automatically by a snakes segmentation system and 61 different texture features were extracted. This study showed that only the gray level difference statistics (GLDS) correlation measure of the ML component could be used to differentiate between normal subjects, and subjects suffering with CVD for either the left or the right CCA sides. We furthermore found that a number of texture features were significantly different between the left and the right CCA sides. We have found no other studies in the literature where these findings could be compared to. These findings should be further validated on a larger number of subjects as well as combined with additional risk factors