Structure determination and analysis of titin A-band fibronectin type III domains provides insights for disease-linked variants and protein oligomerisation.

Titin is the largest protein found in nature and spans half a sarcomere in vertebrate striated muscle. The protein has multiple functions, including in the organisation of the thick filament and acting as a molecular spring during the muscle contraction cycle. Missense variants in titin have been linked to both cardiac and skeletal myopathies. Titin is primarily composed of tandem repeats of immunoglobulin and fibronectin type III (Fn3) domains in a variety of repeat patterns; however, the vast majority of these domains have not had their high-resolution structure determined experimentally. Here, we present the crystal structures of seven wild type titin Fn3 domains and two harbouring rare missense variants reported in hypertrophic cardiomyopathy (HCM) patients. All domains present the typical Fn3 fold, with the domains harbouring variants reported in HCM patients retaining the wild-type conformation. The effect on domain folding and stability were assessed for five rare missense variants found in HCM patients: four caused thermal destabilization of between 7 and 13 °C and one prevented the folding of its domain. The structures also allowed us to locate the positions of residues whose mutations have been linked to congenital myopathies and rationalise how they convey their deleterious effects. We find no evidence of physiological homodimer formation, excluding one hypothesised mechanism as to how titin variants could exert pathological effects.

High-sensitive troponin is associated with subclinical imaging biosignature of inflammatory cardiovascular involvement in systemic lupus erythematosus.

BACKGROUND: Cardiovascular (CV) involvement in patients with systemic lupus erythematosus (SLE) is presumably subclinical for the major part of its evolution. We evaluated the associations between high-sensitive troponin T (hs-TropT), a sensitive marker of myocardial injury, and CV involvement using cardiac magnetic resonance (CMR). METHODS AND RESULTS: This is a two-centre (London and Frankfurt) CMR imaging study at 3.0 Tesla of consecutive 92 patients with SLE free of cardiac symptoms, undergoing screening for cardiac involvement. Venous samples were drawn and analysed post-hoc for cardiac biomarkers, including hs-TropT, high-sensitive C reactive protein and N-terminal pro brain natriuretic peptide. Compared with age-matched/gender-matched non-SLE controls (n=78), patients had significantly raised cardiac biomarker levels, native T1 and T2, aortic and ventricular stiffness, and reduced global longitudinal strain (p<0.01). In SLE, hs-TropT was significantly and independently associated with native T2, followed by the models including native T1 and aortic stiffness (Χ2 0.462, p<0.01). There were no relationships between hs-TropT and age, gender, CV risk factors, duration of systemic disease, cardiac structure or function, or late gadolinium enhancement. CONCLUSIONS: Patients with SLE have a high prevalence of subclinical myocardial injury as demonstrated by raised high-sensitive troponin levels. CMR with T2 mapping reveals myocardial oedema as the strongest predictor of hs-TropT release, underscoring the inflammatory interstitial remodelling as the main mechanism of injury. Patients without active myocardial inflammation demonstrate diffuse interstitial remodelling and increased vascular stiffness. These findings substantiate the role of CMR in screening of subclinical cardiac involvement. TRIAL REGISTRATION NUMER: NCT02407197; Results.

Focal But Not Diffuse Myocardial Fibrosis Burden Quantification Using Cardiac Magnetic Resonance Imaging Predicts Left Ventricular Reverse Modeling Following Cardiac Resynchronization Therapy.

INTRODUCTION: Many heart failure patients with dyssynchrony do not reverse remodel (RR) in response to cardiac resynchronization therapy (CRT). The presence of focal and diffuse interstitial myocardial fibrosis may explain this high nonresponse rate. T1 mapping is a new cardiac magnetic resonance imaging (CMR) technique that overcomes the limitations of conventional contrast CMR and provides reliable quantitative assessment of diffuse myocardial fibrosis. The study tested the hypothesis that focal and diffuse fibrosis quantification would correlate with a lack of left ventricular (LV) RR to CRT. METHODS AND RESULTS: In a prospective study of 48 consecutive patients (27 ischemic cardiomyopathy, 21 dilated cardiomyopathy) LV scar burdens were quantified (scar core and gray zone using late gadolinium enhancement LGE CMR; interstitial fibrosis using T1 mapping) before CRT implant. LV RR was defined by a ≥ 15% reduction in LV end-systolic volume 6 months postimplant. Twenty-seven (56%) patients were responders with RR. Association between scar quantification and LV RR was assessed using the Poisson regression model. Univariate analysis showed that QRS duration/morphology, scar core, and gray zone volumes expressed as % of LV mass and extracellular volume index (ECV) (a measure of interstitial fibrosis from T1 mapping) to be significant predictors of LV RR. Multivariable-adjusted analyses demonstrated scar core quantification (≥ 13.7% LV mass) to be the only independent predictor of LV RR (prevalence ratio 0.40, P = 0.038). CONCLUSIONS: Focal scar burden detected by LGE CMR is associated with a poor response to CRT. Diffuse interstitial fibrosis assessment by T1 mapping, however, is not independently predictive of CRT response.

Three-dimensional atrial wall thickness maps to inform catheter ablation procedures for atrial fibrillation.

AIMS: Transmural lesion formation is critical to success in atrial fibrillation ablation and is dependent on left atrial wall thickness (LAWT). Pre- and peri-procedural planning may benefit from LAWT measurements. METHODS AND RESULTS: To calculate the LAWT, the Laplace equation was solved over a finite element mesh of the left atrium derived from the segmented computed tomographic angiography (CTA) dataset. Local LAWT was then calculated from the length of field lines derived from the Laplace solution that spanned the wall from the endocardium or epicardium. The method was validated on an atrium phantom and retrospectively applied to 10 patients who underwent routine coronary CTA for standard clinical indications at our institute. The Laplace wall thickness algorithm was validated on the left atrium phantom. Wall thickness measurements had errors of <0.2 mm for thicknesses of 0.5-5.0 mm that are attributed to image resolution and segmentation artefacts. Left atrial wall thickness measurements were performed on 10 patients. Successful comprehensive LAWT maps were generated in all patients from the coronary CTA images. Mean LAWT measurements ranged from 0.6 to 1.0 mm and showed significant inter and intra patient variability. CONCLUSIONS: Left atrial wall thickness can be measured robustly and efficiently across the whole left atrium using a solution of the Laplace equation over a finite element mesh of the left atrium. Further studies are indicated to determine whether the integration of LAWT maps into pre-existing 3D anatomical mapping systems may provide important anatomical information for guiding radiofrequency ablation.

Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Feasibility of high-resolution quantitative perfusion analysis in patients with heart failure.

BACKGROUND: Cardiac magnetic resonance (CMR) is playing an expanding role in the assessment of patients with heart failure (HF). The assessment of myocardial perfusion status in HF can be challenging due to left ventricular (LV) remodelling and wall thinning, coexistent scar and respiratory artefacts. The aim of this study was to assess the feasibility of quantitative CMR myocardial perfusion analysis in patients with HF. METHODS: A group of 58 patients with heart failure (HF; left ventricular ejection fraction, LVEF ≤ 50%) and 33 patients with normal LVEF (LVEF >50%), referred for suspected coronary artery disease, were studied. All subjects underwent quantitative first-pass stress perfusion imaging using adenosine according to standard acquisition protocols. The feasibility of quantitative perfusion analysis was then assessed using high-resolution, 3 T kt perfusion and voxel-wise Fermi deconvolution. RESULTS: 30/58 (52%) subjects in the HF group had underlying ischaemic aetiology. Perfusion abnormalities were seen amongst patients with ischaemic HF and patients with normal LV function. No regional perfusion defect was observed in the non-ischaemic HF group. Good agreement was found between visual and quantitative analysis across all groups. Absolute stress perfusion rate, myocardial perfusion reserve (MPR) and endocardial-epicardial MPR ratio identified areas with abnormal perfusion in the ischaemic HF group (p = 0.02; p = 0.04; p = 0.02, respectively). In the Normal LV group, MPR and endocardial-epicardial MPR ratio were able to distinguish between normal and abnormal segments (p = 0.04; p = 0.02 respectively). No significant differences of absolute stress perfusion rate or MPR were observed comparing visually normal segments amongst groups. CONCLUSIONS: Our results demonstrate the feasibility of high-resolution voxel-wise perfusion assessment in patients with HF.

Prevalence of myocardial crypts in a large retrospective cohort study by cardiovascular magnetic resonance.

BACKGROUND: Myocardial crypts are discrete clefts or fissures in otherwise compacted myocardium of the left ventricle (LV). Recent reports suggest a higher prevalence of crypts in patients with hypertrophic cardiomyopathy (HCM) and also within small samples of genotype positive but phenotype negative relatives. The presence of a crypt has been suggested to be a predictor of gene carrier status. However, the prevalence and clinical significance of crypts in the general population is unclear. We aimed to determine the prevalence of myocardial crypts in a large cohort of subjects using clinical cardiovascular magnetic resonance (CMR). METHODS: Consecutive subjects referred for clinical CMR during a 12-month period (n = 1020, age 52.6 ± 17, males: 61%) were included. Crypts were defined as >50% invagination into normal myocardium and their overall prevalence, location and shape was investigated and compared between different patient groups. RESULTS: The overall prevalence of crypts was 64/1020 (6.3%). In a predefined 'normal' control group the prevalence was lower (11/306, 3.6%, p = 0.031), but were equally prevalent in ischemic heart disease (12/236, 5.1%, p = n/s) and the combined non-ischemic cardiomyopathy (NICM) groups (24/373; 6.4%, p = n/s). Within the NICM group, crypts were significantly more common in HCM (9/76, 11.7%, p = 0.04) and hypertensive CM subjects (3/11, 27%, p = 0.03). In patients referred for CMR for family screening of inherited forms of CM, crypts were significantly more prevalent (10/41, 23%, p < 0.001), including a smaller group with a first degree relative with HCM (3/9, 33%, p = 0.01). CONCLUSION: Myocardial crypts are relatively common in the normal population, and increasingly common in HCM and hypertensive cardiomyopathy. Crypts are also more frequently seen in normal phenotype subjects referred because of a family history of an inherited cardiomyopathy and HCM specifically. It is uncertain what the significance of crypts are in this group, and because of variability in the imaging protocols used and their relative frequency within the normal population, should not be used to clinically stratify these patients. Prospective studies are required to confirm the clinical significance of myocardial crypts, as their significance remains unclear.

A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study.

AIMS: Alternative forms of cardiac resynchronization therapy (CRT), including biventricular endocardial (BV-Endo) and multisite epicardial pacing (MSP), have been developed to improve response. It is unclear which form of stimulation is optimal. We aimed to compare the acute haemodynamic response (AHR) and electrophysiological effects of BV-Endo with MSP via two separate coronary sinus (CS) leads or a single-quadripolar CS lead. METHODS AND RESULTS: Fifteen patients with a previously implanted CRT system received a second temporary CS lead and left ventricular (LV) endocardial catheter. A pressure wire and non-contact mapping array were placed into the LV cavity to measure LVdP/dtmax and perform electroanatomical mapping. Conventional CRT, BV-Endo, and MSP were then performed (MSP-1 via two epicardial leads and MSP-2 via a single-quadripolar lead). The best overall AHR was found using BV-Endo pacing with a 19.6 ± 13.6% increase in AHR at the optimal endocardial site over baseline (P < 0.001). There was an increase in LVdP/dtmax with MSP-1 and MSP-2 compared with conventional CRT, but this was not statistically significant. Biventricular endocardial pacing from the optimal site was significantly superior to conventional CRT (P = 0.039). The AHR achieved when BV-Endo pacing was highly site specific. Within individuals, the best pacing modality varied and was affected by the underlying substrate. Left ventricular activation times did not predict the optimal haemodynamic configuration. CONCLUSION: Biventricular endocardial pacing and not MSP was superior to conventional CRT, but was highly site specific. Within individuals, however, different methods of stimulation are optimal and may need to be tailored to the underlying substrate.

Left ventricular anatomy in obstructive hypertrophic cardiomyopathy: beyond basal septal hypertrophy.

AIMS: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic obstruction of the left ventricular (LV) outflow tract (LVOT). Although this may be mediated by interplay between the hypertrophied septal wall, systolic anterior motion of the mitral valve, and papillary muscle abnormalities, the mechanistic role of LV shape is still not fully understood. This study sought to identify the LV end-diastolic morphology underpinning oHCM. METHODS AND RESULTS: Cardiovascular magnetic resonance images from 2398 HCM individuals were obtained as part of the NHLBI HCM Registry. Three-dimensional LV models were constructed and used, together with a principal component analysis, to build a statistical shape model capturing shape variations. A set of linear discriminant axes were built to define and quantify (Z-scores) the characteristic LV morphology associated with LVOT obstruction (LVOTO) under different physiological conditions and the relationship between LV phenotype and genotype. The LV remodelling pattern in oHCM consisted not only of basal septal hypertrophy but a combination with LV lengthening, apical dilatation, and LVOT inward remodelling. Salient differences were observed between obstructive cases at rest and stress. Genotype negative cases showed a tendency towards more obstructive phenotypes both at rest and stress. CONCLUSIONS: LV anatomy underpinning oHCM consists of basal septal hypertrophy, apical dilatation, LV lengthening, and LVOT inward remodelling. Differences between oHCM cases at rest and stress, as well as the relationship between LV phenotype and genotype, suggest different mechanisms for LVOTO. Proposed Z-scores render an opportunity of redefining management strategies based on the relationship between LV anatomy and LVOTO.

Relationship between endocardial activation sequences defined by high-density mapping to early septal contraction (septal flash) in patients with left bundle branch block undergoing cardiac resynchronization therapy.

AIMS: Early inward motion and thickening/thinning of the ventricular septum associated with left bundle branch block is known as the septal flash (SF). Correction of SF corresponds to response to cardiac resynchronization therapy (CRT). We hypothesized that SF was associated with a specific left ventricular (LV) activation pattern predicting a favourable response to CRT. We sought to characterize the spatio-temporal relationship between electrical and mechanical events by directly comparing non-contact mapping (NCM), acute haemodynamics, and echocardiography. METHODS AND RESULTS: Thirteen patients (63 ± 10 years, 10 men) with severe heart failure (ejection fraction 22.8 ± 5.8%) awaiting CRT underwent echocardiography and NCM pre-implant. Presence and extent of SF defined visually and with M-mode was fused with NCM bull's eye plots of endocardial activation patterns. LV-dP/dt(max) was measured during different pacing modes. Five patients had a large SF, four small SF, and four no SF. Large SF patients had areas of conduction block in non-infarcted regions, whereas those with small or no SF did not. Patients with large SF had greater acute response to LV and biventricular (BIV) pacing vs. those with small/no SF (% increase dP/dt 28 ± 14 vs. 11 ± 19% for LV pacing and 42 ± 28 vs. 22 ± 21% for BIV pacing) (P < 0.05). This translated into a more favourable chronic response to CRT. The lines of conduction block disappeared with LV/BIV pacing while remaining with right ventricle pacing. CONCLUSION: A strong association exists between electrical activation and mechanical deformation of the septum. Correction of both mechanical synchrony and the functional conduction block by CRT may explain the favourable response in patients with SF.

Healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy.

OBJECTIVES: Our primary aim was to evaluate the healthcare resource use associated with the diagnosis of transthyretin amyloidosis cardiomyopathy. Second, we aim to assess the effect of the number of diagnostic tests and clinical contact points on the total time and costs between symptom onset and diagnosis defining a quantitative hypothetical optimized diagnostic pathway. SETTING: Clinical and cost data were collected from patients presenting between 2010 and 2018 in a tertiary referral institution in South London involving two participating hospitals. PARTICIPANTS: Thirty-eight adult patients with a definite diagnosis of transthyretin amyloidosis cardiomyopathy were included, mostly male (n = 28, 74%) and of African-Caribbean descent (n = 23, 64%). We excluded patients without a confirmed transthyretin amyloidosis cardiomyopathy or those on inotersen, patisiran, or diflunisal at point of referral. PRIMARY AND SECONDARY OUTCOME MEASURES: The average time between first presentation and final diagnosis, and the cost per patient per month. By comparing to a more optimal clinical pathway towards diagnosis, we considered what could be the theoretical gain in terms of time to diagnosis and financial savings. RESULTS: The average time between first presentation and final diagnosis was 2.74 years. The average cost per patient per month was higher with progressive heart failure symptoms. A hypothetical optimal pathway reduces time to diagnosis of 1.65 to 1.74 years per patient. The potential financial savings are estimated within the range of £3000 to £4800 per patient. CONCLUSIONS: Patients diagnosed with transthyretin amyloidosis cardiomyopathy have substantial healthcare resource utilization and costs starting from symptom onset. Higher costs were observed with progression in symptoms and appear linked to a delayed diagnosis. The number of additional diagnostic tests and clinical contact points may contribute to this and could represent a path to explore further for important health and cost savings, with more efficient pathways for these patients to be managed.

Epidemiology of cardiomyopathies and incident heart failure in a population-based cohort study.

AIMS: The population prevalence of cardiomyopathies and the natural history of symptomatic heart failure (HF) and arrhythmia across cardiomyopathy phenotypes is poorly understood. Study aims were to estimate the population-diagnosed prevalence of cardiomyopathies and describe the temporal relationship between a diagnosis of cardiomyopathy with HF and arrhythmia. METHODS: People with cardiomyopathy (n=4116) were identified from linked electronic health records (~9 million individuals; 2000-2018) and categorised into hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), restrictive cardiomyopathy (RCM) and cardiac amyloidosis (CA). Cardiomyopathy point prevalence, rates of symptomatic HF and arrhythmia and timing relative to a diagnosis of cardiomyopathy were determined. RESULTS: In 2018, DCM was the most common cardiomyopathy. DCM and HCM were twice as common among men, with the reverse trend for ARVC. Between 2010 and 2018, prevalence increased for ARVC by 180% and HCM by 9%. At diagnosis, more patients with CA (66%), DCM (56%) and RCM (62%) had pre-existing HF compared with ARVC (29%) and HCM (27%). Among those free of HF at diagnosis of cardiomyopathy, annualised HF incidence was greatest in CA and DCM. Diagnoses of all cardiomyopathies clustered around the time of HF onset. CONCLUSIONS: The recorded prevalence of all cardiomyopathies increased over the past decade. Recognition of CA is generally preceded by HF, whereas individuals with ARVC or HCM more often developed HF after their cardiomyopathy diagnosis suggesting a more indolent course or better asymptomatic recognition. The clustering of HF and cardiomyopathy diagnoses suggests opportunities for presymptomatic or earlier diagnosis.

Real-world evidence in a national health service: results of the UK CardioMEMS HF System Post-Market Study.

AIMS: The CardioMEMS HF System Post-Market Study (COAST) was designed to evaluate the safety, effectiveness, and feasibility of haemodynamic-guided heart failure (HF) management using a small sensor implanted in the pulmonary artery of New York Heart Association (NYHA) Class III HF patients in the UK, Europe, and Australia. METHODS AND RESULTS: COAST is a prospective, international, multicentre, open-label clinical study (NCT02954341). The primary clinical endpoint compares annualized HF hospitalization rates after 1 year of haemodynamic-guided management vs. the year prior to sensor implantation in patients with NYHA Class III symptoms and a previous HF hospitalization. The primary safety endpoints assess freedom from device/system-related complications and pressure sensor failure after 2 years. Results from the first 100 patients implanted at 14 out of the 15 participating centres in the UK are reported here. At baseline, all patients were in NYHA Class III, 70% were male, mean age was 69 ± 12 years, and 39% had an aetiology of ischaemic cardiomyopathy. The annualized HF hospitalization rate after 12 months was 82% lower [95% confidence interval 72-88%] than the previous 12 months (0.27 vs. 1.52 events/patient-year, respectively, P < 0.0001). Freedom from device/system-related complications and pressure sensor failure at 2 years was 100% and 99%, respectively. CONCLUSIONS: Remote haemodynamic-guided HF management, using frequent assessment of pulmonary artery pressures, was successfully implemented at 14 specialist centres in the UK. Haemodynamic-guided HF management was safe and significantly reduced hospitalization in a group of high-risk patients. These results support implementation of this innovative remote management strategy to improve outcome for patients with symptomatic HF. Clinical registration number: ClinicalTrials.gov identifier: NCT02954341.

Association of Titin Variations With Late-Onset Dilated Cardiomyopathy.

IMPORTANCE: Dilated cardiomyopathy (DCM) is frequently caused by genetic factors. Studies identifying deleterious rare variants have predominantly focused on early-onset cases, and little is known about the genetic underpinnings of the growing numbers of patients with DCM who are diagnosed when they are older than 60 years (ie, late-onset DCM). OBJECTIVE: To investigate the prevalence, type, and prognostic impact of disease-associated rare variants in patients with late-onset DCM. DESIGN, SETTING, AND PARTICIPANTS: A population of patients with late-onset DCM who had undergone genetic testing in 7 international tertiary referral centers worldwide were enrolled from March 1990 to August 2020. A positive genotype was defined as the presence of pathogenic or likely pathogenic (P/LP) variants. MAIN OUTCOMES AND MEASURES: The study outcome was all-cause mortality. RESULTS: A total of 184 patients older than 60 years (103 female [56%]; mean [SD] age, 67 [6] years; mean [SD] left ventricular ejection fraction, 32% [10%]) were studied. Sixty-six patients (36%) were carriers of a P/LP variant. Titin-truncating variants were the most prevalent (present in 46 [25%] of the total population and accounting for 46 [69%] of all genotype-positive patients). During a median (interquartile range) follow-up of 42 (10-115) months, 23 patients (13%) died; 17 (25%) of these were carriers of P/LP variants, while 6 patients (5.1%) were genotype-negative. CONCLUSIONS AND RELEVANCE: Late-onset DCM might represent a distinct subgroup characterized by and a high genetic variation burden, largely due to titin-truncating variants. Patients with a positive genetic test had higher mortality than genotype-negative patients. These findings support the extended use of genetic testing also in older patients.

Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT).

OBJECTIVE: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration. METHODS: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown. RESULTS: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78). CONCLUSIONS: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients. TRIAL REGISTRATION NUMBER: NCT03583320.

Cardiac MRI to investigate myocardial scar and coronary venous anatomy using a slow infusion of dimeglumine gadobenate in patients undergoing assessment for cardiac resynchronization therapy.

PURPOSE: To evaluate a cardiac MR (CMR) examination with slow infusion of a high-relaxivity contrast agent to visualize coronary venous anatomy (CVA) and myocardial scar in heart failure patients awaiting cardiac resynchronization therapy (CRT). MATERIALS AND METHODS: Fourteen patients awaiting CRT (seven ischemic cardiomyopathy (ICM) and seven non-ICM) and two with normal LV function underwent CMR on a 1.5 Tesla (T) MR scanner. Dimeglumine-gadobenate was slowly infused. Bolus arrival in the LV was measured by a dynamic electrocardiogram (ECG) -triggered inversion recovery (IR) scan subsequent to starting an ECG-triggered respiratory-navigated three-dimensional (3D) SSFP MR scan with IR preparation to acquire systolic whole-heart anatomy for vein visualization. Delayed contrast-enhanced MR scan was performed to assess myocardial scar. CVA obtained by CMR was compared with X-ray venography in 11 patients. CVA and scar were segmented and registered for visual inspection. RESULTS: For all subjects, there was excellent visualization of the CVA. All ICM and one non-ICM patient showed scar. There was excellent correlation between veins seen by CMR and venography. CONCLUSION: We have demonstrated that slow infusion protocol of dimeglumine-gadobenate can be used to assess both CVA and myocardial scar in a single MR examination. Furthermore, an image overlay technique has been used to show the relationship of scar to the CVA.

Advanced image fusion to overlay coronary sinus anatomy with real-time fluoroscopy to facilitate left ventricular lead implantation in CRT.

BACKGROUND: Failure rate for left ventricular (LV) lead implantation in cardiac resynchronization therapy (CRT) is up to 12%. The use of segmentation tools, advanced image registration software, and high-fidelity images from computerized tomography (CT) and cardiac magnetic resonance (CMR) of the coronary sinus (CS) can guide LV lead implantation. We evaluated the feasibility of advanced image registration onto live fluoroscopic images to allow successful LV lead placement. METHODS: Twelve patients (11 male, 59 ± 16.8 years) undergoing CRT had three-dimensional (3D) whole-heart imaging (six CT, six CMR). Eight patients had at least one previously failed LV lead implant. Using segmentation software, anatomical models of the cardiac chambers, CS, and its branches were overlaid onto the live fluoroscopy using a prototype version of the Philips EP Navigator software to guide lead implantation. RESULTS: We achieved high-fidelity segmentations of cardiac chambers, coronary vein anatomy, and accurate registration between the 3D anatomical models and the live fluoroscopy in all 12 patients confirmed by balloon occlusion angiography. The CS was cannulated successfully in every patient and in 11, an LV lead was implanted successfully. (One patient had no acceptable lead values due to extensive myocardial scar). CONCLUSION: Using overlaid 3D segmentations of the CS and cardiac chambers, it is feasible to guide CRT implantation in real time by fusing advanced imaging and fluoroscopy. This enabled successful CRT in a group of patients with previously failed implants. This technology has the potential to facilitate CRT and improve implant success.

A case of mistaken arrhythmogenic identity during pregnancy.

Atypical LVOT ectopy can present with an RVOT morphology on ECG and differentiation to reveal this focus is in favor of benign idiopathic ventricular ectopy over an arrhythmogenic cardiomyopathy.

The Role of AI in Characterizing the DCM Phenotype.

Dilated Cardiomyopathy is conventionally defined by left ventricular dilatation and dysfunction in the absence of coronary disease. Emerging evidence suggests many patients remain vulnerable to major adverse outcomes despite clear therapeutic success of modern evidence-based heart failure therapy. In this era of personalized medical care, the conventional assessment of left ventricular ejection fraction falls short in fully predicting evolution and risk of outcomes in this heterogenous group of heart muscle disease, as such, a more refined means of phenotyping this disease appears essential. Cardiac MRI (CMR) is well-placed in this respect, not only for its diagnostic utility, but the wealth of information captured in global and regional function assessment with the addition of unique tissue characterization across different disease states and patient cohorts. Advanced tools are needed to leverage these sensitive metrics and integrate with clinical, genetic and biochemical information for personalized, and more clinically useful characterization of the dilated cardiomyopathy phenotype. Recent advances in artificial intelligence offers the unique opportunity to impact clinical decision making through enhanced precision image-analysis tasks, multi-source extraction of relevant features and seamless integration to enhance understanding, improve diagnosis, and subsequently clinical outcomes. Focusing particularly on deep learning, a subfield of artificial intelligence, that has garnered significant interest in the imaging community, this paper reviews the main developments that could offer more robust disease characterization and risk stratification in the Dilated Cardiomyopathy phenotype. Given its promising utility in the non-invasive assessment of cardiac diseases, we firstly highlight the key applications in CMR, set to enable comprehensive quantitative measures of function beyond the standard of care assessment. Concurrently, we revisit the added value of tissue characterization techniques for risk stratification, showcasing the deep learning platforms that overcome limitations in current clinical workflows and discuss how they could be utilized to better differentiate at-risk subgroups of this phenotype. The final section of this paper is dedicated to the allied clinical applications to imaging, that incorporate artificial intelligence and have harnessed the comprehensive abundance of data from genetics and relevant clinical variables to facilitate better classification and enable enhanced risk prediction for relevant outcomes.

The alcohol-induced cardiomyopathy: A cardiovascular magnetic resonance characterization.

BACKGROUND: Alcoholic cardiomyopathy(ACM) is part of the non-ischaemic dilated cardiomyopathy(NI-DCM) spectrum. Little is known about cardiovascular magnetic resonance(CMR) features in ACM patients. The aim of this study is to describe CMR findings and their prognostic impact in ACM patients. METHODS: Consecutive ACM patients evaluated in five referral CMR centres from January 2005 to December 2018 were enrolled. CMR findings and their prognostic value were compared to idiopathic NI-DCM(iNI-DCM) patients. The main outcome was a composite of death/heart transplantation/life-threatening arrhythmias. RESULTS: Overall 114 patients (52 with ACM and 62 with iNI-DCM) were included. ACM patients were more often males compared to iNI-DCM (90% vs 64%, respectively, p ≤ 0.001) and were characterized by a more pronounced biventricular adverse remodelling than iNI-DCM, i.e. lower LVEF (31 ± 12% vs 38 ± 11% respectively, p = 0.001) and larger left ventricular end-diastolic volume (116 ± 40 ml/m2 vs 67 ± 20 ml/m2 respectively, p < 0.001). Similarly to iNI-DCM, late gadolinium enhancement (LGE), mainly midwall, was present in more than 40% of ACM patients but, conversely, it was not associated with adverse outcome(p = 0.15). LGE localization was prevalently septal (87%) in ACM vs lateral in iNI-DCM(p < 0.05). Over a median follow-up of 42 months [Interquartile Range 24-68], adverse outcomes were similar in both groups(p = 0.67). CONCLUSIONS: ACM represents a specific phenotype of NI-DCM, with severe morpho-functional features at the onset, but similar long-term outcomes compared to iNI-DCM. Despite the presence and pattern of distribution of LGE was comparable, ACM and iNI-DCM showed a different LGE localization, mostly septal in ACM and lateral in iNI-DCM, with different prognostic impact.