Mitral Annulus Disjunction: A Comprehensive Cardiovascular Magnetic Resonance Phenotype and Clinical Outcomes Study.

BACKGROUND: Clinical importance of mitral annulus disjunction (MAD) is not well established. PURPOSE: Characterize a population of MAD all-comers diagnosed by cardiac magnetic resonance imaging (MRI). STUDY TYPE: Retrospective. POPULATION: MAD confirmed in 222 patients, age of 49.2 ± 19.3 years, 126 (56.8%) males. FIELD STRENGTH/SEQUENCE: 1.5 T and 3 T/steady-state free precession and inversion recovery. ASSESSMENT: Clinical history, outcomes, imaging, and arrhythmia data. MAD defined as a separation ≥2 mm between left ventricular myocardium and mitral annulus. Presence and pattern of late gadolinium enhancement (LGE) were analyzed. LGE in the papillary muscles and adjacent to MAD were identified as MAD related. Ventricular arrhythmias (VA) were grouped into non-sustained ventricular arrhythmias (NSVA) or sustained. Cardiovascular death assessed. STATISTICAL TESTS: Differences between baseline characteristics were compared. Univariate regression was used to investigate possible associations between ventricular arrhythmia and cardiovascular death with characteristics associated with the severity of MAD. A multivariable logistic regression included significant variables from the univariate analysis and was performed for MAD-related and global LGE. RESULTS: MAD extent 5.0 ± 2.6 mm. MV annulus expanded during systole for MAD ≥6 mm. Systolic expansion associated with prolapse, billowing, and curling. LGE present in 82 patients (36.9%). Twenty-three patients (10.4%) showed MAD-related LGE by three different observers. No association of LGE with MAD extent (P = 0.545) noted. Follow-up 4.1 ± 2.4 years. No sustained VA observed. In univariable analysis, NSVA was more prevalent in patients with MAD ≥6 mm (33.3% vs. 9.9%), but this was attenuated on multivariate analysis (P = 0.054). The presence of NSVA was associated with global LGE but not MAD-related LGE in isolation (P = 0.750). Three patients died of cardiovascular causes (1.4%) and none had MAD-related LGE. None died of sudden cardiac arrest. CONCLUSION: In patients referred for cardiac MRI, mitral valve dysfunction was associated with MAD severity. Scar was not related to the extent of MAD, but associated with NSVA. The risk of sustained arrhythmias and cardiovascular death was low in this population. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Novel Multiplexed Plasma Biomarker Panel Has Diagnostic and Prognostic Potential in Children With Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is defined clinically by pathological left ventricular hypertrophy. We have previously developed a plasma proteomics biomarker panel that correlates with clinical markers of disease severity and sudden cardiac death risk in adult patients with HCM. The aim of this study was to investigate the utility of adult biomarkers and perform new discoveries in proteomics for childhood-onset HCM. METHODS: Fifty-nine protein biomarkers were identified from an exploratory plasma proteomics screen in children with HCM and augmented into our existing multiplexed targeted liquid chromatography-tandem/mass spectrometry-based assay. The association of these biomarkers with clinical phenotypes and outcomes was prospectively tested in plasma collected from 148 children with HCM and 50 healthy controls. Machine learning techniques were used to develop novel pediatric plasma proteomic biomarker panels. RESULTS: Four previously identified adult HCM markers (aldolase fructose-bisphosphate A, complement C3a, talin-1, and thrombospondin 1) and 3 new markers (glycogen phosphorylase B, lipoprotein a and profilin 1) were elevated in pediatric HCM. Using supervised machine learning applied to training (n=137) and validation cohorts (n=61), this 7-biomarker panel differentiated HCM from healthy controls with an area under the curve of 1.0 in the training data set (sensitivity 100% [95% CI, 95-100]; specificity 100% [95% CI, 96-100]) and 0.82 in the validation data set (sensitivity 75% [95% CI, 59-86]; specificity 88% [95% CI, 75-94]). Reduced circulating levels of 4 other peptides (apolipoprotein L1, complement 5b, immunoglobulin heavy constant epsilon, and serum amyloid A4) found in children with high sudden cardiac death risk provided complete separation from the low and intermediate risk groups and predicted mortality and adverse arrhythmic outcomes (hazard ratio, 2.04 [95% CI, 1.0-4.2]; P=0.044). CONCLUSIONS: In children, a 7-biomarker proteomics panel can distinguish HCM from controls with high sensitivity and specificity, and another 4-biomarker panel identifies those at high risk of adverse arrhythmic outcomes, including sudden cardiac death.

Phenotypic Spectrum of Subclinical Sarcomere-Related Hypertrophic Cardiomyopathy and Transition to Overt Disease.

Genetic hypertrophic cardiomyopathy (HCM) is classically caused by pathogenic/likely pathogenic variants in sarcomere genes (G+). Currently, HCM is diagnosed if there is unexplained left ventricular (LV) hypertrophy with LV wall thickness ≥15 mm in probands or ≥13 mm in at-risk relatives. Although LV hypertrophy is a key feature, this binary metric does not encompass the full constellation of phenotypic features, particularly in the subclinical stage of the disease. Subtle phenotypic manifestations can be identified in sarcomere variant carriers with normal LV wall thickness, before diagnosis with HCM (G+/LV hypertrophy-; subclinical HCM). We conducted a systematic review to summarize current knowledge about the phenotypic spectrum of subclinical HCM and factors influencing penetrance and expressivity. Although the mechanisms driving the development of LV hypertrophy are yet to be elucidated, activation of profibrotic pathways, impaired relaxation, abnormal Ca2+ signaling, altered myocardial energetics, and microvascular dysfunction have all been identified in subclinical HCM. Progression from subclinical to clinically overt HCM may be more likely if early phenotypic manifestations are present, including abnormal ECG, longer mitral valve leaflets, lower global E' velocities on Doppler echocardiography, and higher serum N-terminal propeptide of B-type natriuretic peptide. Longitudinal studies of variant carriers are critically needed to improve our understanding of penetrance, characterize the transition to disease, identify risk predictors of phenotypic evolution, and guide the development of novel treatment strategies aimed at influencing disease trajectory.

Inflammation in Fabry disease: stages, molecular pathways, and therapeutic implications.

Fabry disease, a multisystem X-linked disorder caused by mutations in the alpha-galactosidase gene. This leads to the accumulation of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3), culminating in various clinical signs and symptoms that significantly impact quality of life. Although treatments such as enzyme replacement, oral chaperone, and emerging therapies like gene therapy exist; delayed diagnosis often curtails their effectiveness. Our review highlights the importance of delineating the stages of inflammation in Fabry disease to enhance the timing and efficacy of diagnosis and interventions, particularly before the progression to fibrosis, where treatment options are less effective. Inflammation is emerging as an important aspect of the pathogenesis of Fabry disease. This is thought to be predominantly mediated by the innate immune response, with growing evidence pointing towards the potential involvement of adaptive immune mechanisms that remain poorly understood. Highlighted by the fact that Fabry disease shares immune profiles with systemic autoinflammatory diseases, blurring the distinctions between these disorders and highlighting the need for a nuanced understanding of immune dynamics. This insight is crucial for developing targeted therapies and improving the administration of current treatments like enzyme replacement. Moreover, our review discusses the complex interplay between these inflammatory processes and current treatments, such as the challenges posed by anti-drug antibodies. These antibodies can attenuate the effectiveness of therapies, necessitating more refined approaches to mitigate their impact. By advancing our understanding of the molecular changes, inflammatory mediators and causative factors that drive inflammation in Fabry disease, we aim to clarify their role in the disease's progression. This improved understanding will help us see how these processes fit into the current landscape of Fabry disease. Additionally, it will guide the development of more effective diagnostic and therapeutic approaches, ultimately improving patient care.

Regional Distribution of Extracellular Volume Quantified by Cardiac CT in Aortic Stenosis: Insights Into Disease Mechanisms and Impact on Outcomes.

BACKGROUND: Extracellular volume fraction (ECV) is a marker for myocardial fibrosis and infiltration, can be quantified using cardiac computed tomography (ECVCT), and has prognostic utility in several diseases. This study aims to map out regional differences in ECVCT to obtain greater insights into the pathophysiological mechanisms of ECV expansion and its clinical implications. METHODS: Three prospective cohorts were included: patients with aortic stenosis (AS) and coexisting AS and transthyretin cardiac amyloidosis were referred for a transcatheter aortic valve replacement and had ECG-gated CT angiography and Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy to differentiate between the 2 cohorts. Controls had CT angiography and cardiac magnetic resonance demonstrating no significant coronary artery disease or infarction. Global and regional ECVCT was analyzed, and its association with mortality was assessed for patients with AS. RESULTS: In 199 patients, controls (n=65; 66% male), AS (n=115), and coexisting AS and transthyretin cardiac amyloidosis (n=19) had a global ECVCT of 26.1 (25.0-27.8%) versus 29.1 (27.5-31.1%) versus 37.4 (32.5-46.6%), respectively; P<0.001. Across cohorts, ECVCT was higher at the base (versus apex), the inferoseptum (versus anterolateral wall), and the subendocardium (versus subepicardium); P<0.05 for all. Among patients with AS, epicardial ECVCT, rather than any other regional value or global ECVCT, was the strongest predictor of mortality at a median of 3.9 (max 6.3) years (adjusted hazard ratio, 1.21 [95% CI, 1.08-1.36]; P=0.002). CONCLUSIONS: Regional differences in ECVCT suggest a predilection for fibrosis and amyloid infiltration at the base, subendocardium, inferior wall, and septum more than the anterior and lateral myocardium. ECVCT can predict long-term mortality with the subepicardium demonstrating the strongest discriminatory power. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03029026 and NCT03094143.

Accurate diagnosis of apical hypertrophic cardiomyopathy using explainable advanced electrocardiogram analysis.

AIMS: Typical electrocardiogram (ECG) features of apical hypertrophic cardiomyopathy (ApHCM) include tall R waves and deep or giant T-wave inversion in the precordial leads, but these features are not always present. The ECG is used as the gatekeeper to cardiac imaging for diagnosis. We tested whether explainable advanced ECG (A-ECG) could accurately diagnose ApHCM. METHODS AND RESULTS: Advanced ECG analysis was performed on standard resting 12-lead ECGs in patients with ApHCM [n = 75 overt, n = 32 relative (<15 mm hypertrophy); a subgroup of which underwent cardiovascular magnetic resonance (n = 92)], and comparator subjects (n = 2449), including healthy volunteers (n = 1672), patients with coronary artery disease (n = 372), left ventricular electrical remodelling (n = 108), ischaemic (n = 114) or non-ischaemic cardiomyopathy (n = 57), and asymmetrical septal hypertrophy HCM (n = 126). Multivariable logistic regression identified four A-ECG measures that together discriminated ApHCM from other diseases with high accuracy [area under the receiver operating characteristic (AUC) curve (bootstrapped 95% confidence interval) 0.982 (0.965-0.993)]. Linear discriminant analysis also diagnosed ApHCM with high accuracy [AUC 0.989 (0.986-0.991)]. CONCLUSION: Explainable A-ECG has excellent diagnostic accuracy for ApHCM, even when the hypertrophy is relative, with A-ECG analysis providing incremental diagnostic value over imaging alone. The electrical (ECG) and anatomical (wall thickness) disease features do not completely align, suggesting that future diagnostic and management strategies may incorporate both features.

APOE ε4 carriage associates with improved myocardial performance from adolescence to older age.

BACKGROUND: Although APOE ε4 allele carriage confers a risk for coronary artery disease, its persistence in humans might be explained by certain survival advantages (antagonistic pleiotropy). METHODS: Combining data from ~ 37,000 persons from three older age British cohorts (1946 National Survey of Health and Development [NSHD], Southall and Brent Revised [SABRE], and UK Biobank) and one younger age cohort (Avon Longitudinal Study of Parents and Children [ALSPAC]), we explored whether APOE ε4 carriage associates with beneficial or unfavorable left ventricular (LV) structural and functional metrics by echocardiography and cardiovascular magnetic resonance (CMR). RESULTS: Compared to the non-APOE ε4 group, APOE ε4 carriers had similar cardiac phenotypes in terms of LV ejection fraction, E/e', posterior wall and interventricular septal thickness, and LV mass. However, they had improved myocardial performance resulting in greater LV stroke volume generation per 1 mL of myocardium (higher myocardial contraction fraction). In NSHD (n = 1467) and SABRE (n = 1187), ε4 carriers had a 4% higher MCF (95% CI 1-7%, p = 0.016) using echocardiography. Using CMR data, in UK Biobank (n = 32,972), ε4 carriers had a 1% higher MCF 95% (CI 0-1%, p = 0.020) with a dose-response relationship based on the number of ε4 alleles. In addition, UK Biobank ε4 carriers also had more favorable radial and longitudinal strain rates compared to non APOE ε4 carriers. In ALSPAC (n = 1397), APOE ε4 carriers aged < 24 years had a 2% higher MCF (95% CI 0-5%, p = 0.059). CONCLUSIONS: By triangulating results in four independent cohorts, across imaging modalities (echocardiography and CMR), and in ~ 37,000 individuals, our results point towards an association between ε4 carriage and improved cardiac performance in terms of LV MCF. This potentially favorable cardiac phenotype adds to the growing number of reported survival advantages attributed to the pleiotropic effects APOE ε4 carriage that might collectively explain its persistence in human populations.

Quality assurance of late gadolinium enhancement cardiac magnetic resonance images: a deep learning classifier for confidence in the presence or absence of abnormality with potential to prompt real-time image optimization.

BACKGROUND: Late gadolinium enhancement (LGE) of the myocardium has significant diagnostic and prognostic implications, with even small areas of enhancement being important. Distinguishing between definitely normal and definitely abnormal LGE images is usually straightforward, but diagnostic uncertainty arises when reporters are not sure whether the observed LGE is genuine or not. This uncertainty might be resolved by repetition (to remove artifact) or further acquisition of intersecting images, but this must take place before the scan finishes. Real-time quality assurance by humans is a complex task requiring training and experience, so being able to identify which images have an intermediate likelihood of LGE while the scan is ongoing, without the presence of an expert is of high value. This decision-support could prompt immediate image optimization or acquisition of supplementary images to confirm or refute the presence of genuine LGE. This could reduce ambiguity in reports. METHODS: Short-axis, phase-sensitive inversion recovery late gadolinium images were extracted from our clinical cardiac magnetic resonance (CMR) database and shuffled. Two, independent, blinded experts scored each individual slice for "LGE likelihood" on a visual analog scale, from 0 (absolute certainty of no LGE) to 100 (absolute certainty of LGE), with 50 representing clinical equipoise. The scored images were split into two classes-either "high certainty" of whether LGE was present or not, or "low certainty." The dataset was split into training, validation, and test sets (70:15:15). A deep learning binary classifier based on the EfficientNetV2 convolutional neural network architecture was trained to distinguish between these categories. Classifier performance on the test set was evaluated by calculating the accuracy, precision, recall, F1-score, and area under the receiver operating characteristics curve (ROC AUC). Performance was also evaluated on an external test set of images from a different center. RESULTS: One thousand six hundred and forty-five images (from 272 patients) were labeled and split at the patient level into training (1151 images), validation (247 images), and test (247 images) sets for the deep learning binary classifier. Of these, 1208 images were "high certainty" (255 for LGE, 953 for no LGE), and 437 were "low certainty". An external test comprising 247 images from 41 patients from another center was also employed. After 100 epochs, the performance on the internal test set was accuracy = 0.94, recall = 0.80, precision = 0.97, F1-score = 0.87, and ROC AUC = 0.94. The classifier also performed robustly on the external test set (accuracy = 0.91, recall = 0.73, precision = 0.93, F1-score = 0.82, and ROC AUC = 0.91). These results were benchmarked against a reference inter-expert accuracy of 0.86. CONCLUSION: Deep learning shows potential to automate quality control of late gadolinium imaging in CMR. The ability to identify short-axis images with intermediate LGE likelihood in real-time may serve as a useful decision-support tool. This approach has the potential to guide immediate further imaging while the patient is still in the scanner, thereby reducing the frequency of recalls and inconclusive reports due to diagnostic indecision.

The effect of CTCA guided selective invasive graft assessment on coronary angiographic parameters and outcomes: Insights from the BYPASS-CTCA trial.

BACKGROUND: Computed tomography cardiac angiography (CTCA) is recommended for the evaluation of patients with prior coronary artery bypass graft (CABG) surgery. The BYPASS-CTCA study demonstrated that CTCA prior to invasive coronary angiography (ICA) in CABG patients leads to significant reductions in procedure time and contrast-induced nephropathy (CIN), alongside improved patient satisfaction. However, whether CTCA information was used to facilitate selective graft cannulation at ICA was not protocol mandated. In this post-hoc analysis we investigated the influence of CTCA facilitated selective graft assessment on angiographic parameters and study endpoints. METHODS: BYPASS-CTCA was a randomized controlled trial in which patients with previous CABG referred for ICA were randomized to undergo CTCA prior to ICA, or ICA alone. In this post-hoc analysis we assessed the impact of selective ICA (grafts not invasively cannulated based on the CTCA result) following CTCA versus non-selective ICA (imaging all grafts irrespective of CTCA findings). The primary endpoints were ICA procedural duration, incidence of CIN, and patient satisfaction post-ICA. Secondary endpoints included the incidence of procedural complications and 1-year major adverse cardiac events. RESULTS: In the CTCA cohort (n â€‹= â€‹343), 214 (62.4%) patients had selective coronary angiography performed, whereas 129 (37.6%) patients had non-selective ICA. Procedure times were significantly reduced in the selective CTCA â€‹+ â€‹ICA group compared to the non-selective CTCA â€‹+ â€‹ICA group (-5.82min, 95% CI -7.99 to -3.65, p â€‹< â€‹0.001) along with reduction of CIN (1.5% vs 5.8%, OR 0.26, 95% CI 0.10 to 0.98). No difference was seen in patient satisfaction with the ICA, however procedural complications (0.9% vs 4.7%, OR 0.21, 95% CI 0.09-0.87) and 1-year major adverse cardiac events (13.1% vs 20.9%, HR 0.55, 95% CI 0.32-0.96) were significantly lower in the selective group. CONCLUSIONS: In patients with prior CABG, CTCA guided selective angiographic assessment of bypass grafts is associated with improved procedural parameters, lower complication rates and better 12-month outcomes. Taken in addition to the main findings of the BYPASS-CTCA trial, these results suggest a synergistic approach between CTCA and ICA should be considered in this patient group. REGISTRATION: ClinicalTrials.gov, NCT03736018.

Electrophysiological Characterization of Subclinical and Overt Hypertrophic Cardiomyopathy by Magnetic Resonance Imaging-Guided Electrocardiography.

BACKGROUND: Ventricular arrhythmia in hypertrophic cardiomyopathy (HCM) relates to adverse structural change and genetic status. Cardiovascular magnetic resonance (CMR)-guided electrocardiographic imaging (ECGI) noninvasively maps cardiac structural and electrophysiological (EP) properties. OBJECTIVES: The purpose of this study was to establish whether in subclinical HCM (genotype [G]+ left ventricular hypertrophy [LVH]-), ECGI detects early EP abnormality, and in overt HCM, whether the EP substrate relates to genetic status (G+/G-LVH+) and structural phenotype. METHODS: This was a prospective 211-participant CMR-ECGI multicenter study of 70 G+LVH-, 104 LVH+ (51 G+/53 G-), and 37 healthy volunteers (HVs). Local activation time (AT), corrected repolarization time, corrected activation-recovery interval, spatial gradients (GAT/GRTc), and signal fractionation were derived from 1,000 epicardial sites per participant. Maximal wall thickness and scar burden were derived from CMR. A support vector machine was built to discriminate G+LVH- from HV and low-risk HCM from those with intermediate/high-risk score or nonsustained ventricular tachycardia. RESULTS: Compared with HV, subclinical HCM showed mean AT prolongation (P = 0.008) even with normal 12-lead electrocardiograms (ECGs) (P = 0.009), and repolarization was more spatially heterogenous (GRTc: P = 0.005) (23% had normal ECGs). Corrected activation-recovery interval was prolonged in overt vs subclinical HCM (P < 0.001). Mean AT was associated with maximal wall thickness; spatial conduction heterogeneity (GAT) and fractionation were associated with scar (all P < 0.05), and G+LVH+ had more fractionation than G-LVH+ (P = 0.002). The support vector machine discriminated subclinical HCM from HV (10-fold cross-validation accuracy 80% [95% CI: 73%-85%]) and identified patients at higher risk of sudden cardiac death (accuracy 82% [95% CI: 78%-86%]). CONCLUSIONS: In the absence of LVH or 12-lead ECG abnormalities, HCM sarcomere gene mutation carriers express an aberrant EP phenotype detected by ECGI. In overt HCM, abnormalities occur more severely with adverse structural change and positive genetic status.

Meta-Analysis of Penetrance and Systematic Review on Transition to Disease in Genetic Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy and is classically caused by pathogenic or likely pathogenic variants (P/LP) in genes encoding sarcomere proteins. Not all subclinical variant carriers will manifest clinically overt disease because penetrance (proportion of sarcomere or sarcomere-related P/LP variant carriers who develop disease) is variable, age dependent, and not reliably predicted. METHODS: A systematic search of the literature was performed. We used random-effects generalized linear mixed model meta-analyses to contrast the cross-sectional prevalence and penetrance of sarcomere or sarcomere-related genes in 2 different contexts: clinically-based studies on patients and families with HCM versus population or community-based studies. Longitudinal family/clinical studies were additionally analyzed to investigate the rate of phenotypic conversion from subclinical to overt HCM during follow-up. RESULTS: In total, 455 full-text manuscripts and articles were assessed. In family/clinical studies, the prevalence of sarcomere variants in patients diagnosed with HCM was 34%. The penetrance across all genes in nonproband relatives carrying P/LP variants identified during cascade screening was 57% (95% CI, 52%-63%), and the mean age at HCM diagnosis was 38 years (95% CI, 36%-40%). Penetrance varied from ≈32% for MYL3 (myosin light chain 3) to ≈55% for MYBPC3 (myosin-binding protein C3), ≈60% for TNNT2 (troponin T2) and TNNI3 (troponin I3), and ≈65% for MYH7 (myosin heavy chain 7). Population-based genetic studies demonstrate that P/LP sarcomere variants are present in the background population but at a low prevalence of <1%. The penetrance of HCM in incidentally identified P/LP variant carriers was also substantially lower at ≈11%, ranging from 0% in Atherosclerosis Risk in Communities to 18% in UK Biobank. In longitudinal family studies, the pooled phenotypic conversion across all genes was 15% over an average of ≈8 years of follow-up, starting from a mean of ≈16 years of age. However, short-term gene-specific phenotypic conversion varied between ≈12% for MYBPC3 and ≈23% for MYH7. CONCLUSIONS: The penetrance of P/LP variants is highly variable and influenced by currently undefined and context-dependent genetic and environmental factors. Additional longitudinal studies are needed to improve our understanding of true lifetime penetrance in families and in the community and to identify drivers of the transition from subclinical to overt HCM.

Efficacy of human experts and an automated segmentation algorithm in quantifying disease pathology in coronary computed tomography angiography: A head-to-head comparison with intravascular ultrasound imaging.

BACKGROUND: Coronary computed tomography angiography (CCTA) analysis is currently performed by experts and is a laborious process. Fully automated edge-detection methods have been developed to expedite CCTA segmentation however their use is limited as there are concerns about their accuracy. This study aims to compare the performance of an automated CCTA analysis software and the experts using near-infrared spectroscopy-intravascular ultrasound imaging (NIRS-IVUS) as a reference standard. METHODS: Fifty-one participants (150 vessels) with chronic coronary syndrome who underwent CCTA and 3-vessel NIRS-IVUS were included. CCTA analysis was performed by an expert and an automated edge detection method and their estimations were compared to NIRS-IVUS at a segment-, lesion-, and frame-level. RESULTS: Segment-level analysis demonstrated a similar performance of the two CCTA analyses (conventional and automatic) with large biases and limits of agreement compared to NIRS-IVUS estimations for the total atheroma (ICC: 0.55 vs 0.25, mean difference:192 (-102-487) vs 243 (-132-617) and percent atheroma volume (ICC: 0.30 vs 0.12, mean difference: 12.8 (-5.91-31.6) vs 20.0 (0.79-39.2). Lesion-level analysis showed that the experts were able to detect more accurately lesions than the automated method (68.2 â€‹% and 60.7 â€‹%) however both analyses had poor reliability in assessing the minimal lumen area (ICC 0.44 vs 0.36) and the maximum plaque burden (ICC 0.33 vs 0.33) when NIRS-IVUS was used as the reference standard. CONCLUSIONS: Conventional and automated CCTA analyses had similar performance in assessing coronary artery pathology using NIRS-IVUS as a reference standard. Therefore, automated segmentation can be used to expedite CCTA analysis and enhance its applications in clinical practice.

The atrial and ventricular myocardial proteome of end-stage lamin heart disease.

Lamins A/C (encoded by LMNA gene) can lead to dilated cardiomyopathy (DCM). This pilot study sought to explore the postgenomic phenotype of end-stage lamin heart disease. Consecutive patients with end-stage lamin heart disease (LMNA-group, n = 7) and ischaemic DCM (ICM-group, n = 7) undergoing heart transplantation were prospectively enrolled. Samples were obtained from left atrium (LA), left ventricle (LV), right atrium (RA), right ventricle (RV) and interventricular septum (IVS), avoiding the infarcted myocardial segments in the ICM-group. Samples were analysed using a discovery 'shotgun' proteomics approach. We found that 990 proteins were differentially abundant between LMNA and ICM samples with the LA being most perturbed (16-fold more than the LV). Abundance of lamin A/C protein was reduced, but lamin B increased in LMNA LA/RA tissue compared to ICM, but not in LV/RV. Carbonic anhydrase 3 (CA3) was over-abundant across all LMNA tissue samples (LA, LV, RA, RV, and IVS) when compared to ICM. Transthyretin was more abundant in the LV/RV of LMNA compared to ICM, while sarcomeric proteins such as titin and cardiac alpha-cardiac myosin heavy chain were generally less abundant in RA/LA of LMNA. Protein expression profiling and enrichment analysis pointed towards sarcopenia, extracellular matrix remodeling, deficient myocardial energetics, redox imbalances, and abnormal calcium handling in LMNA samples. Compared to ICM, end-stage lamin heart disease is a biventricular but especially a biatrial disease appearing to have an abundance of lamin B, CA3 and transthyretin, potentially hinting to compensatory responses.

Technical development and feasibility of a reusable vest to integrate cardiovascular magnetic resonance with electrocardiographic imaging.

BACKGROUND: Electrocardiographic imaging (ECGI) generates electrophysiological (EP) biomarkers while cardiovascular magnetic resonance (CMR) imaging provides data about myocardial structure, function and tissue substrate. Combining this information in one examination is desirable but requires an affordable, reusable, and high-throughput solution. We therefore developed the CMR-ECGI vest and carried out this technical development study to assess its feasibility and repeatability in vivo. METHODS: CMR was prospectively performed at 3T on participants after collecting surface potentials using the locally designed and fabricated 256-lead ECGI vest. Epicardial maps were reconstructed to generate local EP parameters such as activation time (AT), repolarization time (RT) and activation recovery intervals (ARI). 20 intra- and inter-observer and 8 scan re-scan repeatability tests. RESULTS: 77 participants were recruited: 27 young healthy volunteers (HV, 38.9 ± 8.5 years, 35% male) and 50 older persons (77.0 ± 0.1 years, 52% male). CMR-ECGI was achieved in all participants using the same reusable, washable vest without complications. Intra- and inter-observer variability was low (correlation coefficients [rs] across unipolar electrograms = 0.99 and 0.98 respectively) and scan re-scan repeatability was high (rs between 0.81 and 0.93). Compared to young HV, older persons had significantly longer RT (296.8 vs 289.3 ms, p = 0.002), ARI (249.8 vs 235.1 ms, p = 0.002) and local gradients of AT, RT and ARI (0.40 vs 0.34 ms/mm, p = 0,01; 0.92 vs 0.77 ms/mm, p = 0.03; and 1.12 vs 0.92 ms/mm, p = 0.01 respectively). CONCLUSION: Our high-throughput CMR-ECGI solution is feasible and shows good reproducibility in younger and older participants. This new technology is now scalable for high throughput research to provide novel insights into arrhythmogenesis and potentially pave the way for more personalised risk stratification. CLINICAL TRIAL REGISTRATION: Title: Multimorbidity Life-Course Approach to Myocardial Health-A Cardiac Sub-Study of the MRC National Survey of Health and Development (NSHD) (MyoFit46). National Clinical Trials (NCT) number: NCT05455125. URL: https://clinicaltrials.gov/ct2/show/NCT05455125?term=MyoFit&draw=2&rank=1.

Prognostic utility and characterization of left ventricular hypertrophy using global thickness.

Cardiovascular magnetic resonance (CMR) can accurately measure left ventricular (LV) mass, and several measures related to LV wall thickness exist. We hypothesized that prognosis can be used to select an optimal measure of wall thickness for characterizing LV hypertrophy. Subjects having undergone CMR were studied (cardiac patients, n = 2543; healthy volunteers, n = 100). A new measure, global wall thickness (GT, GTI if indexed to body surface area) was accurately calculated from LV mass and end-diastolic volume. Among patients with follow-up (n = 1575, median follow-up 5.4 years), the most predictive measure of death or hospitalization for heart failure was LV mass index (LVMI) (hazard ratio (HR)[95% confidence interval] 1.16[1.12-1.20], p < 0.001), followed by GTI (HR 1.14[1.09-1.19], p < 0.001). Among patients with normal findings (n = 326, median follow-up 5.8 years), the most predictive measure was GT (HR 1.62[1.35-1.94], p < 0.001). GT and LVMI could characterize patients as having a normal LV mass and wall thickness, concentric remodeling, concentric hypertrophy, or eccentric hypertrophy, and the three abnormal groups had worse prognosis than the normal group (p < 0.05 for all). LV mass is highly prognostic when mass is elevated, but GT is easily and accurately calculated, and adds value and discrimination amongst those with normal LV mass (early disease).

Clinical utilisation of implantable loop recorders in adults with Fabry disease-a multi-centre snapshot study.

Fabry disease (FD) is an X-linked deficiency of alpha-galactosidase-A, leading to lysosomal storage of sphingolipids in multiple organs. Myocardial accumulation contributes to arrhythmia and sudden death, the most common cause of FD mortality. Therefore, there is a need for risk stratification and prediction to target device therapy. Implantable loop recorders (ILRs) allow for continual rhythm monitoring for up to 3 years. Here, we performed a retrospective study to evaluate current ILR utilisation in FD and quantify the burden of arrhythmia that was detected, which resulted in a modification of therapy. This was a snapshot assessment of 915 patients with FD across three specialist centres in England during the period between 1 January 2000 and 1 September 2022. In total, 22 (2.4%) patients underwent clinically indicated ILR implantation. The mean implantation age was 50 years and 13 (59%) patients were female. Following implantation, nine (41%) patients underwent arrhythmia detection, requiring intervention (six on ILR and three post-ILR battery depletion). Three patients experienced sustained atrial high-rate episodes and were started on anticoagulation. Three had non-sustained tachyarrhythmia and were started on beta blockers. Post-ILR battery depletion, one suffered complete heart block and two had sustained ventricular tachycardia, all requiring device therapy. Those with arrhythmia had a shorter PR interval on electrocardiography. This study demonstrates that ILR implantation in FD uncovers a high burden of arrhythmia. ILRs are likely to be underutilised in this pro-arrhythmic cohort, perhaps restricted to those with advanced FD cardiomyopathy. Following battery depletion in three patients as mentioned above, greater vigilance and arrhythmia surveillance are advised for those experiencing major arrhythmic events post-ILR monitoring. Further work is required to establish who would benefit most from implantation.

Novel near-infrared spectroscopy-intravascular ultrasound-based deep-learning methodology for accurate coronary computed tomography plaque quantification and characterization.

Aims: Coronary computed tomography angiography (CCTA) is inferior to intravascular imaging in detecting plaque morphology and quantifying plaque burden. We aim to, for the first time, train a deep-learning (DL) methodology for accurate plaque quantification and characterization in CCTA using near-infrared spectroscopy-intravascular ultrasound (NIRS-IVUS). Methods and results: Seventy patients were prospectively recruited who underwent CCTA and NIRS-IVUS imaging. Corresponding cross sections were matched using an in-house developed software, and the estimations of NIRS-IVUS for the lumen, vessel wall borders, and plaque composition were used to train a convolutional neural network in 138 vessels. The performance was evaluated in 48 vessels and compared against the estimations of NIRS-IVUS and the conventional CCTA expert analysis. Sixty-four patients (186 vessels, 22 012 matched cross sections) were included. Deep-learning methodology provided estimations that were closer to NIRS-IVUS compared with the conventional approach for the total atheroma volume (ΔDL-NIRS-IVUS: -37.8 ± 89.0 vs. ΔConv-NIRS-IVUS: 243.3 ± 183.7 mm3, variance ratio: 4.262, P < 0.001) and percentage atheroma volume (-3.34 ± 5.77 vs. 17.20 ± 7.20%, variance ratio: 1.578, P < 0.001). The DL methodology detected lesions more accurately than the conventional approach (Area under the curve (AUC): 0.77 vs. 0.67, P < 0.001) and quantified minimum lumen area (ΔDL-NIRS-IVUS: -0.35 ± 1.81 vs. ΔConv-NIRS-IVUS: 1.37 ± 2.32 mm2, variance ratio: 1.634, P < 0.001), maximum plaque burden (4.33 ± 11.83% vs. 5.77 ± 16.58%, variance ratio: 2.071, P = 0.004), and calcific burden (-51.2 ± 115.1 vs. -54.3 ± 144.4, variance ratio: 2.308, P < 0.001) more accurately than conventional approach. The DL methodology was able to segment a vessel on CCTA in 0.3 s. Conclusions: The DL methodology developed for CCTA analysis from co-registered NIRS-IVUS and CCTA data enables rapid and accurate assessment of lesion morphology and is superior to expert analysts (Clinicaltrials.gov: NCT03556644).

Improved Diagnostic Criteria for Apical Hypertrophic Cardiomyopathy.

BACKGROUND: There is no acceptable maximum wall thickness (MWT) threshold for diagnosing apical hypertrophic cardiomyopathy (ApHCM), with guidelines referring to ≥15 mm MWT for all hypertrophic cardiomyopathy subtypes. A normal myocardium naturally tapers apically; a fixed diagnostic threshold fails to account for this. Using cardiac magnetic resonance, "relative" ApHCM has been described with typical electrocardiographic features, loss of apical tapering, and cavity obliteration but also with MWT <15 mm. OBJECTIVES: The authors aimed to define normal apical wall thickness thresholds in healthy subjects and use these to accurately identify ApHCM. METHODS: The following healthy subjects were recruited: healthy UK Biobank imaging substudy subjects (n = 4,112) and an independent healthy volunteer group (n = 489). A clinically defined disease population of 104 ApHCM subjects was enrolled, with 72 overt (MWT ≥15 mm) and 32 relative (MWT <15 mm but typical electrocardiographic/imaging findings) ApHCM subjects. Cardiac magnetic resonance-derived MWT was measured in 16 segments using a published clinically validated machine learning algorithm. Segmental normal reference ranges were created and indexed (for age, sex, and body surface area), and diagnostic performance was assessed. RESULTS: In healthy cohorts, there was no clinically significant age-related difference for apical wall thickness. There were sex-related differences, but these were not clinically significant after indexing to body surface area. Therefore, segmental reference ranges for apical hypertrophy required indexing to body surface area only (not age or sex). The upper limit of normal (the largest of the 4 apical segments measured) corresponded to a maximum apical MWT in healthy subjects of 5.2 to 5.6 mm/m2 with an accuracy of 0.94 (the unindexed equivalent being 11 mm). This threshold was categorized as abnormal in 99% (71/72) of overt ApHCM patients, 78% (25/32) of relative ApHCM patients, 3% (122/4,112) of UK Biobank subjects, and 3% (13/489) of healthy volunteers. CONCLUSIONS: Per-segment indexed apical wall thickness thresholds are highly accurate for detecting apical hypertrophy, providing confidence to the reader to diagnose ApHCM in those not reaching current internationally recognized criteria.