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Cardiovascular Magnetic Resonance (CMR) is recognised as a valuable clinical tool which in a single scan setting can assess ventricular volumes and function, myocardial fibrosis, iron loading, flow quantification, tissue characterisation and myocardial perfusion imaging. The advent of CMR using extrinsic and intrinsic contrast-enhanced protocols for tissue characterisation have dramatically changed the non-invasive work-up of patients with suspected or known cardiomyopathy. Although the technique initially focused on the in vivo identification of myocardial necrosis through the late gadolinium enhancement (LGE) technique, recent work highlighted the ability of CMR to provide more detailed in vivo tissue characterisation to help establish a differential diagnosis of the underlying aetiology, to exclude an ischaemic substrate and to provide important prognostic markers. The potential application of CMR in the clinical approach of a patient with suspected non-ischaemic cardiomyopathy is discussed in this review.

Dilated cardiomyopathy (DCM) is an important cause of heart failure with a strong familial component. We performed an exome-wide array-based association study (EWAS) to assess the contribution of missense variants to sporadic DCM. 116,855 single nucleotide variants (SNVs) were analyzed in 2796 DCM patients and 6877 control subjects from 6 populations of European ancestry. We confirmed two previously identified associations with SNVs in BAG3 and ZBTB17 and discovered six novel DCM-associated loci (Q-value<0.01). The lead-SNVs at novel loci are common and located in TTN, SLC39A8, MLIP, FLNC, ALPK3 and FHOD3. In silico fine mapping identified HSPB7 as the most likely candidate at the ZBTB17 locus. Rare variant analysis (MAF<0.01) demonstrated significant association for TTN variants only (P = 0.0085). All candidate genes but one (SLC39A8) exhibit preferential expression in striated muscle tissues and mutations in TTN, BAG3, FLNC and FHOD3 are known to cause familial cardiomyopathy. We also investigated a panel of 48 known cardiomyopathy genes. Collectively, rare (n = 228, P = 0.0033) or common (n = 36, P = 0.019) variants with elevated in silico severity scores were associated with DCM, indicating that the spectrum of genes contributing to sporadic DCM extends beyond those identified here. We identified eight loci independently associated with sporadic DCM. The functions of the best candidate genes at these loci suggest that proteostasis regulation might play a role in DCM pathophysiology.

Background Left atrial (LA) size is related to cardiovascular morbidity and mortality. Cardiovascular magnetic resonance (CMR) provides high quality images of the left atrium with high temporal resolution steady state free precession (SSFP) cine sequences. We used SSFP cines to define normal ranges for LA volumes and dimensions relative to gender, age and body surface area (BSA), and examine the relative value of 2D atrial imaging techniques in patients. For definition of normal ranges of LA volume we studied 120 healthy subjects after careful exclusion of cardiovascular abnormality (60 men, 60 women; 20 subjects per age decile from 20 to 80 years). Data were generated from 3-dimensional modeling, including tracking of the atrioventricular ring motion and time-volume curves analysis. For definition of the best 2D images-derived predictors of LA enlargement, we studied 120 patients (60 men, 60 women; age range 20 to 80 years) with a clinical indication for CMR. Results In the healthy subjects, age was associated with LA 4-chamber transverse and 3-chamber anteroposterior diameters, but not with LA volume. Gender was an independent predictor of most absolute LA dimensions and volume, but following normalization to BSA, some associations became non-significant. CMR normal ranges were modeled and are tabled for clinical use with normalization, where appropriate, for BSA and gender and display of parameter variation with age. The best 2D predictors of LA volume were the 2-chamber area and 3-chamber area (both r = 0.90, p < 0.001). Conclusions These CMR data show that LA dimensions and volume in healthy, individuals vary significantly by BSA, with lesser effects of age and gender.

Diabetes increases the risk of cardiovascular disease (CVD) due to its multi-scale and diverse effects on cardiomyocyte metabolism and function, the circulation, and the kidneys. The complex relationship between organ systems affected by diabetes and associated comorbidities leads to challenges in estimating cardiovascular risk and stratifying optimal treatment strategies at the individual patient level. Most recently, sodium-glucose transport protein 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP1) receptor agonists have been shown to offer substantial cardiac benefits. However, the direct or indirect mechanisms through which these agents protect the heart remain unclear, posing a challenge to patient selection. Amidst a growing burden of diabetes and increased therapeutic armamentarium, there is an important unmet need to develop more precise methods and technologies to understand the effects of diabetes and anti-diabetic treatment on the heart with faster timelines than conventional randomised controlled trials. Cardiac computational models could be used to improve our understanding of the cardiac changes in diabetes and to predict how a patient’s heart will respond to anti-diabetic treatment. In this review, we provide an overview of current cardiac computational models to investigate the diabetic heart and the cardiac effects of anti-diabetic treatment. We discuss how multi-scale and multi-physics models could be applied in future to support the development of novel therapeutic approaches and further improve the treatment of diabetic patients with different CVD risk. Graphical abstract

Purpose Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs). Methods CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. Results We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher’s P  = 1.1  ×  10 −18 ), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. Conclusion CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.

Low concentrations of circulating 25-hydroxy-vitamin D are observationally associated with an increased risk of subclinical atherosclerosis and cardiovascular disease. However, randomized controlled trials have not reported the beneficial effects of vitamin D supplementation on atherosclerotic cardiovascular disease (ASCVD) outcomes. Whether genetically predicted vitamin D status confers protection against the development of carotid artery plaque, a powerful predictor of subclinical atherosclerosis, remains unknown. We conducted a two-sample Mendelian randomization (MR) study to explore the association of genetically predicted vitamin D status and deficiency with the risk of developing carotid artery plaque. We leveraged three genome-wide association studies (GWAS) of vitamin D status and one GWAS of vitamin D deficiency. We used the inverse-variance weighted (IVW) approach as our main method, and MR-Egger, weighted-median, and radialMR as MR sensitivity analyses. We also conducted sensitivity analyses using biologically plausible genetic instruments located within genes encoding for vitamin D metabolism ( GC , CYP2R1 , DHCR7 , CYP24A1 ). We did not find significant associations between genetically predicted vitamin D status (Odds ratio (OR) = 0.99, P  = 0.91) and deficiency (OR = 1.00, P  = 0.97) with the risk of carotid artery plaque. We additionally explored the potential causal effect of vitamin D status on coronary artery calcification (CAC) and carotid intima-media thickness (cIMT), two additional markers of subclinical atherosclerosis, and we did not find any significant association (β CAC  = − 0.14, P  = 0.23; β cIMT  = 0.005, P  = 0.19). These findings did not support the causal effects of vitamin D status and deficiency on the risk of developing subclinical atherosclerosis.

AbstractBackgroundSerial perfusion cardiovascular magnetic resonance (CMR) in symptomatic patients undergoing coronary artery bypass grafting (CABG) may provide mechanistic insight into dynamic abnormalities of the myocardium. ObjectivesTo assess how changes in cardiac reperfusion and remodelling associate with symptom improvement in patients undergoing CABG MethodsPatients awaiting elective CABG completed serial quality of life questionnaires and detailed CMR at baseline and at 6-12 months post CABG as per protocol. Automated fully quantitative stress and rest myocardial blood flow was calculated, alongside assessment of the visual ischaemic burden. Findings were correlated with changes in symptomatology. ResultsOf 40 patients who underwent serial evaluation with CMR (mean age 62.1±9.3, median LVEF 68% [IQR: 62-73%]), there was improvement in the median visual ischaemic burden (42% [IQR: 27-51] vs 18% [IQR: 11-21], P<0.001), mean global stress myocardial blood flow (1.34±0.5 ml/min/g vs 1.59±0.5 ml/min/g, P=0.002) and median global myocardial perfusion reserve (1.85±0.6 vs 2.4±0.9, P<0.001) following CABG. Greater improvement in the SAQ-7 summary score was associated with a greater decrease in the visual ischaemic burden following CABG (ρ=-0.38, P=0.02). Quantitative MBF metrics did not associate with baseline or change in SAQ-7 summary score. ConclusionSerial perfusion CMR identifies dynamic changes in markers of myocardial perfusion in patients following CABG. Greater reduction of visually assessed ischaemia associated with improvement in SAQ-7 score. Quantitative perfusion indices were not associated with symptom improvement in this study. The results also suggest residual inducible ischaemia post CABG requiring further studies to elucidate its clinical relevance.

Cardiovascular magnetic resonance (CMR) steady state free precession (SSFP) cine sequences with high temporal resolution and improved post-processing can accurately measure RA dimensions. We used this technique to define ranges for normal RA volumes and dimensions normalized, when necessary, to the influence of gender, body surface area (BSA) and age, and also to define the best 2D images-derived predictors of RA enlargement. For definition of normal ranges of RA volume we studied 120 healthy subjects (60 men, 60 women; 20 subjects per age decile from 20 to 80 years), after careful exclusion of cardiovascular abnormality. We also studied 120 patients (60 men, 60 women; age range 20 to 80 years) with a clinical indication for CMR in order to define the best 1D and 2D predictors of RA enlargement. Data were generated from SSFP cine CMR, with 3-dimensional modeling, including tracking of the atrioventricular ring motion and time-volume curves analysis. In the group of healthy individuals, age influenced RA 2-chamber area and transverse diameter. Gender influenced most absolute RA dimensions and volume. Interestingly, right atrial volumes did not change with age and gender when indexed to body surface area. New CMR normal ranges for RA dimensions were modeled and displayed for clinical use with normalization for BSA and gender and display of parameter variation with age. Finally, the best 2D images-derived independent predictors of RA enlargement were indexed area and indexed longitudinal diameter in the 2-chamber view. Reference RA dimensions and predictors of RA enlargement are provided using state-of-the-art CMR techniques.

Cardiovascular magnetic resonance (CMR) is the gold standard non-invasive method for determining left ventricular (LV) mass and volume but has not been used previously to characterise the LV remodeling response in aortic stenosis. We sought to investigate the degree and patterns of hypertrophy in aortic stenosis using CMR. Patients with moderate or severe aortic stenosis, normal coronary arteries and no other significant valve lesions or cardiomyopathy were scanned by CMR with valve severity assessed by planimetry and velocity mapping. The extent and patterns of hypertrophy were investigated using measurements of the LV mass index, indexed LV volumes and the LV mass/volume ratio. Asymmetric forms of remodeling and hypertrophy were defined by a regional wall thickening ≥ 13 mm and >1.5-fold the thickness of the opposing myocardial segment. Ninety-one patients (61±21 years; 57 male) with aortic stenosis (aortic valve area 0.93±0.32cm2) were recruited. The severity of aortic stenosis was unrelated to the degree (r2=0.012, P=0.43) and pattern (P=0.22) of hypertrophy. By univariate analysis, only male sex demonstrated an association with LV mass index (P=0.02). Six patterns of LV adaption were observed: normal ventricular geometry (n=11), concentric remodeling (n=11), asymmetric remodeling (n=11), concentric hypertrophy (n=34), asymmetric hypertrophy (n=14) and LV decompensation (n=10). Asymmetric patterns displayed considerable overlap in appearances (wall thickness 17±2mm) with hypertrophic cardiomyopathy. We have demonstrated that in patients with moderate and severe aortic stenosis, the pattern of LV adaption and degree of hypertrophy do not closely correlate with the severity of valve narrowing and that asymmetric patterns of wall thickening are common. ClinicalTrials.gov Reference Number: NCT00930735

Serial perfusion cardiovascular magnetic resonance (CMR) in symptomatic patients undergoing coronary artery bypass grafting (CABG) may provide mechanistic insight into dynamic abnormalities of the myocardium. To assess how changes in cardiac reperfusion and remodeling associate with symptom improvement in patients undergoing CABG Patients awaiting elective CABG completed serial quality of life questionnaires and detailed CMR at baseline and at 6–12 months post-CABG as per protocol. Automated fully quantitative stress and rest myocardial blood flow was calculated, alongside assessment of the visual ischemic burden. Findings were correlated with changes in symptomatology. Of 40 patients who underwent serial evaluation with CMR (mean age 62.1±9.3, median LVEF 68% [IQR: 62–73%]), there was improvement in the median visual ischemic burden (42% [IQR: 27–51] vs 18% [IQR: 11–21], P<0.001), mean global stress myocardial blood flow (1.34±0.5 mL/min/g vs 1.59±0.5 mL/min/g, P=0.002) and median global myocardial perfusion reserve (1.85±0.6 vs 2.4±0.9, P<0.001) following CABG. Greater improvement in the SAQ-7 summary score was associated with a greater decrease in the visual ischemic burden following CABG (ρ=−0.38, P=0.02). Quantitative MBF metrics did not associate with baseline or change in SAQ-7 summary score. Serial perfusion CMR identifies dynamic changes in markers of myocardial perfusion in patients following CABG. Greater reduction of visually assessed ischemia associated with improvement in SAQ-7 score. Quantitative perfusion indices were not associated with symptom improvement in this study. The results also suggest residual inducible ischemia post-CABG, requiring further studies to elucidate its clinical relevance. [Display omitted]