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Background Cardiovascular magnetic resonance (CMR) derived ventricular volumes and function guide clinical decision-making for various cardiac pathologies. We aimed to evaluate the efficiency and clinical applicability of a commercially available artificial intelligence (AI) method for performing biventricular volumetric analysis. Methods Three-hundred CMR studies (100 with normal CMR findings, 50 dilated cardiomyopathy, 50 hypertrophic cardiomyopathy, 50 ischaemic heart disease and 50 congenital or valvular heart disease) were randomly selected from database. Manual biventricular volumetric analysis (CMRtools) results were derived from clinical reports and automated volumetric analyses were performed using short axis volumetry AI function of CircleCVI42v5.12 software. For 20 studies, a combined method of manually adjusted AI contours was tested and all three methods were timed. Clinicians` confidence in AI method was assessed using an online survey. Results Although agreement was better for left ventricle than right ventricle, AI analysis results were comparable to manual method. Manual adjustment of AI contours further improved agreement: within subject coefficient of variation decreased from 5.0–4.5% for left ventricular ejection fraction (EF) and from 9.9–7.1% for right ventricular EF. Twenty manual analyses were performed in 250min12s whereas same task took 5min48s using AI method. Clinicians were open to adopt AI but concerns about accuracy and validity were raised. Conclusions The AI method provides clinically valid outcomes and saves significant time. To address concerns raised by survey participants and overcome shortcomings of the automated myocardial segmentation, visual assessment of contours and performing manual corrections where necessary appears to be a practical approach.

BACKGROUND: Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction. OBJECTIVES: The purpose of this study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification. METHODS: Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years). RESULTS: In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005). CONCLUSIONS: Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine. ispartof: JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY vol:79 issue:22 pages:2219-2232 ispartof: location:United States status: published

Acute myocarditis is an inflammatory condition that may herald the onset of dilated cardiomyopathy (DCM) or arrhythmogenic cardiomyopathy (ACM). We investigated the frequency and clinical consequences of DCM and ACM genetic variants in a population-based cohort of patients with acute myocarditis. This was a population-based cohort of 336 consecutive patients with acute myocarditis enrolled in London and Maastricht. All participants underwent targeted DNA sequencing for well-characterized cardiomyopathy-associated genes with comparison to healthy controls (n=1053) sequenced on the same platform. Case ascertainment in England was assessed against national hospital admission data. The primary outcome was all-cause mortality. Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with

ObjectiveThe effect of moderate excess alcohol consumption is widely debated and has not been well defined in dilated cardiomyopathy (DCM). There is need for a greater evidence base to help advise patients. We sought to evaluate the effect of moderate excess alcohol consumption on cardiovascular structure, function and outcomes in DCM.MethodsProspective longitudinal observational cohort study. Patients with DCM (n=604) were evaluated for a history of moderate excess alcohol consumption (UK government guidelines; >14 units/week for women, >21 units/week for men) at cohort enrolment, had cardiovascular magnetic resonance and were followed up for the composite endpoint of cardiovascular death, heart failure and arrhythmic events. Patients meeting criteria for alcoholic cardiomyopathy were not recruited.ResultsDCM patients with a history of moderate excess alcohol consumption (n=98, 16%) had lower biventricular function and increased chamber dilatation of the left ventricle, right ventricle and left atrium, as well as increased left ventricular hypertrophy compared with patients without moderate alcohol consumption. They were more likely to be male (alcohol excess group: n=92, 94% vs n=306, 61%, p=ConclusionDCM patients with moderate excess alcohol consumption have adverse cardiac structure and function at presentation, but this is largely due to biological sex. Alcohol may contribute to sex-specific phenotypic differences in DCM. These findings help to inform lifestyle discussions for patients with DCM.

Purpose: To characterize the genetic architecture of left ventricular noncompaction (LVNC) and investigate the extent to which it may represent a distinct pathology or a secondary phenotype associated with other cardiac diseases. Methods: We performed rare variant association analysis with 840 LVNC cases and 125,748 gnomAD population controls, and compared results to similar analyses on dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Results: We observed substantial genetic overlap indicating that LVNC often represents a phenotypic variation of DCM or HCM. In contrast, truncating variants in MYH7, ACTN2, and PRDM16 were uniquely associated with LVNC and may reflect a distinct LVNC etiology. In particular, MYH7 truncating variants (MYH7tv), generally considered nonpathogenic for cardiomyopathies, were 20-fold enriched in LVNC cases over controls. MYH7tv heterozygotes identified in the UK Biobank and healthy volunteer cohorts also displayed significantly greater noncompaction compared with matched controls. RYR2 exon deletions and HCN4 transmembrane variants were also enriched in LVNC, supporting prior reports of association with arrhythmogenic LVNC phenotypes. Conclusion: LVNC is characterized by substantial genetic overlap with DCM/HCM but is also associated with distinct noncompaction and arrhythmia etiologies. These results will enable enhanced application of LVNC genetic testing and help to distinguish pathological from physiological noncompaction.

Cardiovascular magnetic resonance represents the imaging modality of choice for the investigation of patients with heritable cardiomyopathies. The combination of gold-standard volumetric analysis with tissue characterization can deliver precise phenotypic evaluation of both cardiac morphology and the underlying myocardial substrate. Cardiovascular magnetic resonance additionally has an established role in risk-stratifying patients with heritable cardiomyopathy and an emerging role in guiding therapies. This article explores the application and utility of cardiovascular magnetic resonance techniques with specific focus on the major heritable cardiomyopathies.

Background Quantitative cardiovascular magnetic resonance T1-mapping is increasingly used for myocardial tissue characterization. However, the lack of standardization limits direct comparability between centers and wider roll-out for clinical use or trials. Purpose To develop a quality assurance (QA) program assuring standardized T1 measurements for clinical use. Methods MR phantoms manufactured in 2013 were distributed, including ShMOLLI T1-mapping and reference T1 and T2 protocols. We first studied the T1 and T2 dependency on temperature and phantom aging using phantom datasets from a single site over 4 years. Based on this, we developed a multiparametric QA model, which was then applied to 78 scans from 28 other multi-national sites. Results T1 temperature sensitivity followed a second-order polynomial to baseline T1 values (R2 > 0.996). Some phantoms showed aging effects, where T1 drifted up to 49% over 40 months. The correlation model based on reference T1 and T2, developed on 1004 dedicated phantom scans, predicted ShMOLLI-T1 with high consistency (coefficient of variation 1.54%), and was robust to temperature variations and phantom aging. Using the 95% confidence interval of the correlation model residuals as the tolerance range, we analyzed 390 ShMOLLI T1-maps and confirmed accurate sequence deployment in 90%(70/78) of QA scans across 28 multiple centers, and categorized the rest with specific remedial actions. Conclusions The proposed phantom QA for T1-mapping can assure correct method implementation and protocol adherence, and is robust to temperature variation and phantom aging. This QA program circumvents the need of frequent phantom replacements, and can be readily deployed in multicenter trials., Highlights • CMR T1 correlated with reference T1 and T2; this derives the QA model for T1-map. • The proposed QA model is robust to temperature variations and phantom aging. • This QA method requires no frequent phantom replacements. • The T1-map QA program can be readily deployed in multicenter trials.

Atrial fibrillation (AF) in hypertrophic cardiomyopathy (HC) is associated with significant symptomatic deterioration, heart failure, and thromboembolic disease. There is a need for better mechanistic insight and improved identification of at risk patients. We used cardiovascular magnetic resonance (CMR) to assess predictors of AF in HC, in particular the role of myocardial fibrosis. Consecutive patients with HC referred for CMR 2003 to 2013 were prospectively enrolled. CMR parameters including left ventricular volumes, presence and percentage of late gadolinium enhancement in the left ventricle (%LGE) and left atrial volume index (LAVi) were measured. Overall, 377 patients were recruited (age 62 ± 14 years, 73% men). Sixty-two patients (16%) developed new-onset AF during a median follow up of 4.5 (interquartile range 2.9 to 6.0) years. Multivariable analysis revealed %LGE (hazard ratio [HR] 1.3 per 10% (confidence interval: 1.0 to 1.5; p = 0.02), LAVi (HR 1.4 per 10 mL/m 2[1.2 to 1.5; p < 0.001]), age at HC diagnosis, nonsustained ventricular tachycardia and diabetes to be independent predictors of AF. We constructed a simple risk prediction score for future AF based on the multivariable model with a Harrell's C-statistic of 0.73. In conclusion, the extent of ventricular fibrosis and LA volume independently predicted AF in patients with HC. This finding suggests a mechanistic relation between fibrosis and future AF in HC. CMR with quantification of fibrosis has incremental value over LV and LA measurements in risk stratification for AF. A risk prediction score may be used to identify patients at high risk of future AF who may benefit from more intensive rhythm monitoring and a lower threshold for oral anticoagulation.

IMPORTANCE: Low-flow severe aortic stenosis (AS) has higher mortality than severe AS with normal flow. The conventional definition of low-flow AS is an indexed stroke volume (SVi) by echocardiography less than 35 mL/m(2). Cardiovascular magnetic resonance (CMR) is the reference standard for quantifying left ventricular volumes and function from which SVi by CMR can be derived. OBJECTIVE: To determine the association of left ventricular SVi by CMR with myocardial remodeling and survival among patients with severe AS after valve replacement. DESIGN, SETTING, AND PARTICIPANTS: This multicenter longitudinal cohort study was conducted between January 2003 and May 2015 across 6 UK cardiothoracic centers. Patients with severe AS listed for either surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) were included. Patients underwent preprocedural echocardiography and CMR. Patients were stratified by echocardiography-derived aortic valve mean and/or peak gradient and SVi by CMR into 4 AS endotypes: low-flow, low-gradient AS; low-flow, high-gradient AS; normal-flow, low-gradient AS; and normal-flow, high-gradient AS. Patients were observed for a median of 3.6 years. Data were analyzed from September to November 2021. EXPOSURES: SAVR or TAVR. MAIN OUTCOMES AND MEASURES: All-cause and cardiovascular (CV) mortality after aortic valve intervention. RESULTS: Of 674 included patients, 425 (63.1%) were male, and the median (IQR) age was 75 (66-80) years. The median (IQR) aortic valve area index was 0.4 (0.3-0.4) cm(2)/m(2). Patients with low-flow AS endotypes (low gradient and high gradient) had lower left ventricular ejection fraction, mass, and wall thickness and increased all-cause and CV mortality than patients with normal-flow AS (all-cause mortality: hazard ratio [HR], 2.08; 95% CI, 1.37-3.14; P

Objective: Interstitial fibrosis is a pathological expansion of the heart's inter-cellular collagen matrix. It is a potential complication of nonischemic cardiomyopathy (NICM), a class of diseases involving electrical and or mechanical dysfunction of cardiac tissue not caused by atherosclerosis. Patients with NICM and interstitial fibrosis often suffer from life threatening arrhythmias, which we aim to simulate in this study. Methods: Our methodology builds on an efficient discrete finite element (DFE) method which allows for the representation of fibrosis as infinitesimal splits in a mesh. We update the DFE method with a local connectivity analysis which creates a consistent topology in the fibrosis network. This is particularly important in nonischemic disease due to the potential presence of large and contiguous fibrotic regions and therefore potentially complex fibrosis networks. Results: In experiments with an image-based model, we demonstrate that our methodology is able to simulate reentrant electrical events associated with cardiac arrhythmias. These reentries depended crucially upon sufficient fibrosis density, which was marked by conduction slowing at high pacing rates. We also created a 2D test-case which demonstrated that fibrosis topologies can modulate transient conduction block, and thereby reentrant activations. Conclusion: Ventricular arrhythmias due to interstitial fibrosis in NICM can be efficiently simulated using our methods in medical image based geometries. Furthermore, fibrosis topology modulates transient conduction block, and should be accounted for in electrophysiological simulations with interstitial fibrosis. Significance: Our study provides methodology which has the potential to predict arrhythmias and to optimize treatments non-invasively for nonischemic cardiomyopathies.

Aims:\ud There is an important need for better biomarkers to predict left ventricular (LV) remodelling in dilated cardiomyopathy (DCM). We undertook a comprehensive assessment of cardiac structure and myocardial composition to determine predictors of remodelling.\ud \ud Methods and results:\ud Prospective study of patients with recent‐onset DCM with cardiovascular magnetic resonance (CMR) assessment of ventricular structure and function, extracellular volume (T1 mapping), myocardial strain, myocardial scar (late gadolinium enhancement) and contractile reserve (dobutamine stress). Regression analyses were used to evaluate predictors of change in LV ejection fraction (LVEF) over 12 months. We evaluated 56 participants (34 DCM patients, median LVEF 43%; 22 controls). Absolute LV contractile reserve predicted change in LVEF (1% increase associated with 0.4% increase in LVEF at 12 months, P = 0.02). Baseline myocardial strain (P = 0.39 global longitudinal strain), interstitial myocardial fibrosis (P = 0.41), replacement myocardial fibrosis (P = 0.25), and right ventricular contractile reserve (P = 0.17) were not associated with LV reverse remodelling. There was a poor correlation between contractile reserve and either LV extracellular volume fraction (r = −0.22, P = 0.23) or baseline LVEF (r = 0.07, P = 0.62). Men were more likely to experience adverse LV remodelling (P = 0.01) but age (P = 0.88) and disease‐modifying heart failure medication (beta‐blocker, P = 0.28; angiotensin‐converting enzyme inhibitor, P = 0.92) did not predict follow‐up LVEF.\ud \ud Conclusions:\ud Substantial recovery of LV function occurs within 12 months in most patients with recent‐onset DCM. Women had the greatest improvement in LVEF. A low LV contractile reserve measured by dobutamine stress CMR appears to identify patients whose LVEF is less likely to recover.

Patients with non-ischemic systolic heart failure (HF) have increased risk of sudden cardiovascular death (SCD). The initiation and substrate for ventricular arrhythmias remains poorly understood. Our purpose was to describe the relationship between cardiac magnetic resonance (CMR) late gadolinium enhancement (LGE) and Holter recorded ventricular arrhythmic activity. Patients from the DANISH trial underwent a Holter-recording and a CMR-scan. The presence of non-sustained ventricular tachycardia (NSVT) and premature ventricular contractions (PVC) were examined in relation to presence and amount of LGE. Outcome measures were all-cause mortality and SCD. Overall, 180 patients were included. LGE was present in 86 (47%). NSVT occurred in 72 (40%), not different according to LGE status (p = 0.65). The amount of LGE was not correlated to the occurrence of NSVT (p = 0.40). The occurrence of couplet PVCs (p = 0.997), frequent PVCs (p = 0.12), PVCs in bigemini (p = 0.29), in trigemini (p = 0.26), or in quadrimini (p = 0.35) did not differ according to LGE status. LGE was significantly associated with risk of all-cause mortality (HR 2.14; 95% CI 1.05-4.37, p = 0.04). NSVT did not increase risk of all-cause mortality in either patients with LGE (HR 1.00; 95% CI 0.46-2.16, p = 0.996) or without LGE (HR 1.37; 95% CI 0.46-4.08, p = 0.57). There was no interaction between LGE and NSVT for the risk of all-cause mortality (p = 0.62). In patients with non-ischemic systolic HF there was no relationship between the presence of LGE and NSVT or any other Holter recorded ventricular tachyarrhythmia. LGE was associated with increased risk of mortality, independent of the presence of NSVT.

BACKGROUND: Empirical evidence suggests a strong link between exposure to air pollution and heart failure incidence, hospitalizations, and mortality, but the biological basis of this remains unclear. We sought to determine the relationship between differential air pollution levels and changes in cardiac structure and function in patients with dilated cardiomyopathy.METHODS AND RESULTS: We undertook a prospective longitudinal observational cohort study of patients in England with dilated cardiomyopathy (enrollment 2009-2015, n = 716, 66% male, 85% Caucasian) and conducted cross sectional analysis at the time of study enrollment. Annual average air pollution exposure estimates for nitrogen dioxide (NO 2) and particulate matter with diameter of 2.5 µm or less (PM 2.5) at enrolment were assigned to each residential postcode (on average 12 households). The relationship between air pollution and cardiac morphology was assessed using linear regression modelling. Greater ambient exposure to NO 2 was associated with higher indexed left ventricular (LV) mass (4.3 g/m 2 increase per interquartile range increase in NO 2, 95% confidence interval 1.9-7.0 g/m 2) and lower LV ejection fraction (-1.5% decrease per interquartile range increase in NO 2, 95% confidence interval -2.7% to -0.2%), independent of age, sex, socioeconomic status, and clinical covariates. The associations were robust to adjustment for smoking status and geographical clustering by postcode area. The effect of air pollution on LV mass was greatest in women. These effects were specific to NO 2 exposure. CONCLUSIONS: Exposure to air pollution is associated with raised LV mass and lower LV ejection fraction, with the strongest effect in women. Although epidemiological associations between air pollution and heart failure have been established and supported by preclinical studies, our findings provide novel empirical evidence of cardiac remodeling and exposure to air pollution with important clinical and public health implications.

Objectives(1) To evaluate the prevalence and hospitalisation rate of COVID-19 infections among patients with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) in the Royal Brompton and Harefield Hospital Cardiovascular Research Centre (RBHH CRC) Biobank. (2) To evaluate the indirect impact of the pandemic on patients with cardiomyopathy through the Heart Hive COVID-19 study. (3) To assess the impact of the pandemic on national cardiomyopathy-related hospital admissions.Methods(1) 1236 patients (703 DCM, 533 HCM) in the RBHH CRC Biobank were assessed for COVID-19 infections and hospitalisations; (2) 207 subjects (131 cardiomyopathy, 76 without heart disease) in the Heart Hive COVID-19 study completed online surveys evaluating physical health, psychological well-being, and behavioural adaptations during the pandemic and (3) 11 447 cardiomyopathy-related hospital admissions across National Health Service (NHS) England were studied from NHS Digital Hospital Episode Statistics over 2019–2020.ResultsA comparable proportion of patients with cardiomyopathy in the RBHH CRC Biobank had tested positive for COVID-19 compared with the UK population (1.1% vs 1.6%, p=0.14), but a higher proportion of those infected were hospitalised (53.8% vs 16.5%, p=0.002). In the Heart Hive COVID-19 study, more patients with cardiomyopathy felt their physical health had deteriorated due to the pandemic than subjects without heart disease (32.3% vs 13.2%, p=0.004) despite only 4.6% of the cardiomyopathy cohort reporting COVID-19 symptoms. A 17.9% year-on-year reduction in national cardiomyopathy-related hospital admissions was observed in 2020.ConclusionPatients with cardiomyopathy had similar reported rates of testing positive for COVID-19 to the background population, but those with test-proven infection were hospitalised more frequently. Deterioration in physical health amongst patients could not be explained by COVID-19 symptoms, inferring a significant contribution of the indirect consequences of the pandemic.Trial registration numberNCT04468256

Aims Remodelling of the left ventricular (LV) shape is one of the hallmarks of non-ischaemic dilated cardiomyopathy (DCM) and may contribute to ventricular arrhythmias and sudden cardiac death. We sought to investigate a novel three dimensional (3D) shape analysis approach to quantify LV remodelling for arrhythmia prediction in DCM. Methods and results We created 3D LV shape models from end-diastolic cardiac magnetic resonance images of 156 patients with DCM and late gadolinium enhancement (LGE). Using the shape models, principle component analysis, and Cox-Lasso regression, we derived a prognostic LV arrhythmic shape (LVAS) score which identified patients who reached a composite arrhythmic endpoint of sudden cardiac death, aborted sudden cardiac death, and sustained ventricular tachycardia. We also extracted geometrical metrics to look for potential prognostic markers. During a follow-up period of up to 16 years (median 7.7, interquartile range: 3.9), 25 patients met the arrhythmic endpoint. The optimally prognostic LV shape for predicting the time-to arrhythmic event was a paraboloidal longitudinal profile, with a relatively wide base. The corresponding LVAS was associated with arrhythmic events in univariate Cox regression (hazard ratio = 2.0 per quartile; 95% confidence interval: 1.3–2.9), in univariate Cox regression with propensity score adjustment, and in three multivariate models; with LV ejection fraction, New York Heart Association Class III/IV (Model 1), implantable cardioverter-defibrillator receipt (Model 2), and cardiac resynchronization therapy (Model 3). Conclusion Biomarkers of LV shape remodelling in DCM can help to identify the patients at greatest risk of lethal ventricular arrhythmias.

The increasing prevalence of patients with aortic stenosis worldwide highlights a clinical need for improved and accurate prediction of clinical outcomes following surgery. We investigated patient demographic and cardiovascular magnetic resonance (CMR) characteristics to formulate a dedicated risk score estimating long-term survival following surgery. We recruited consecutive patients undergoing CMR with gadolinium administration prior to surgical aortic valve replacement from 2003 to 2016 in two UK centres. The outcome was overall mortality. A total of 250 patients were included (68 ± 12 years, male 185 (60%), with pre-operative mean aortic valve area 0.93 ± 0.32cm2, LVEF 62 ± 17%) and followed for 6.0 ± 3.3 years. Sixty-one deaths occurred, with 10-year mortality of 23.6%. Multivariable analysis showed that increasing age (HR 1.04, P = 0.005), use of antiplatelet therapy (HR 0.54, P = 0.027), presence of infarction or midwall late gadolinium enhancement (HR 1.52 and HR 2.14 respectively, combined P = 0.12), higher indexed left ventricular stroke volume (HR 0.98, P = 0.043) and higher left atrial ejection fraction (HR 0.98, P = 0.083) associated with mortality and developed a risk score with good discrimination. This is the first dedicated risk prediction score for patients with aortic stenosis undergoing surgical aortic valve replacement providing an individualised estimate for overall mortality. This model can help clinicians individualising medical and surgical care.Trial Registration ClinicalTrials.gov Identifier: NCT00930735 and ClinicalTrials.gov Identifier: NCT01755936.

Background: Hypertrophic cardiomyopathy (HCM) is caused by rare variants in sarcomere-encoding genes, but little is known about the clinical significance of these variants in the general population. Objectives: The goal of this study was to compare lifetime outcomes and cardiovascular phenotypes according to the presence of rare variants in sarcomere-encoding genes among middle-aged adults. Methods: This study analyzed whole exome sequencing and cardiac magnetic resonance imaging in UK Biobank participants stratified according to sarcomere-encoding variant status. Results: The prevalence of rare variants (allele frequency

Background: Partial anomalous venous connections (PAPVC) are associated with left to right shunting and right heart dilatation. Identification of PAPVC has increased with widespread use of cross-sectional imaging modalities. However, management strategies are mostly based on expert opinion given the scarcity of data from large series. We aimed to define types and significance of isolated and atrial septal defect (ASD) associated PAPVC detected by cardiovascular magnetic resonance. Methods: We retrospectively reviewed our cardiovascular magnetic resonance database from 2002 to 2018 to identify isolated or ASD-associated PAPVC cases. Results: A total of 215 patients (median age 46 years; range, 6–83) with isolated or ASD-associated PAPVC were identified among 102 135 clinical cardiovascular magnetic resonance studies. Of these, 104 were isolated and 111 were associated with an ASD. Anomalous connection of right upper pulmonary vein was the most common single venous anomaly (99/215), but in the isolated PAPVC group there were more anomalous left than right upper pulmonary veins (39 versus 34). The Qp/Qs was significantly higher for isolated anomalous single right upper pulmonary vein than left upper pulmonary vein (1.6 versus 1.4 respectively; P =0.01) as were right ventricular end-diastolic volumes (113.7±30.9 versus 90 [57–157] mL/m 2 , P =0.004). In the PAPVC with an ASD group, sinus venosus ASDs (82%) were associated with right-sided PAPVCs while both right and left-sided venous anomalies were seen in secundum ASDs (18%). In a substantial number of patients (30 out of 91) with sinus venosus ASDs, PAPVCs were more complex and involved more than a single anomalous right upper pulmonary vein; and in 5 patients with ASD, PAPVC was identified only after the ASD closure. Conclusions: This large series provides descriptive and hemodynamic features for isolated and ASD-associated PAPVCs. Anomalous isolated right upper pulmonary vein may cause a significant shunt (Qp/Qs >1.5). PAPVC associated with sinus venosus and secundum ASDs might be more complex than a single anomalous pulmonary vein and missed before ASD correction.

Background Cardiovascular magnetic resonance (CMR) derived fractal analysis of the left ventricle (LV) has been shown in adults to be a useful quantitative measure of trabeculation with high reproducibility and accuracy for the diagnosis of LV non-compaction (LVNC). The aim of this study was to investigate the utility and feasibility of fractal analysis in children. Methods Eighty-four subjects underwent CMR: (1) 28 patients with LVNC (as defined by the Petersen criteria with NC/C ratio $$\ge$$ ≥ 2.3); (2) 28 patients referred by clinicians for assessment of hyper-trabeculation and found not to qualify as LVNC (NC/C $$\ge$$ ≥ 1.8 and Results Global fractal dimension (FD) was higher in the LVNC group than in the hyper-trabeculated group: 1.345 (SEM 0.053) vs 1.252 (SEM 0.034), p Conclusions It is technically feasible to perform fractal analysis in children using CMR and that it is quick, accurate and reproducible. Fractal scoring accurately distinguishes between LVNC, hyper-trabeculation and healthy controls as defined by the Petersen criteria.

Objectives The objective of this study was to determine the relationship between heart rate and relapse among patients in the TRED-HF (Therapy withdrawal in REcovered Dilated cardiomyopathy trial). Background Understanding markers and mechanisms of relapse among patients with recovered dilated cardiomyopathy (DCM) may enable personalized management. Methods The relationship between serial heart rate measurements and relapse was examined among patients in the TRED-HF trial, a randomized trial which examined the safety and feasibility of withdrawing heart failure therapy from 51 patients with recovered DCM over 6 months. In total, 25 patients were randomized to therapy withdrawal and 26 to continue therapy, of whom 25 subsequently began therapy withdrawal in a single arm crossover phase. Results The mean ± SD heart rate for those who had therapy withdrawn and did not relapse was 64.6 ± 10.7 beats/min at baseline and 74.7 ± 10.4 beats/min at follow-up, compared to 68.3 ± 11.3 beats/min at baseline and 86.1 ± 11.8 beats/min at follow-up for those who relapsed. After adjusting for differences in heart rate at baseline, patients who had therapy withdrawn and relapsed had a 10.4 beats/min (95% CI: 4.0–16.8) greater rise in heart rate than patients who had therapy withdrawn and did not relapse (P = 0.002). After data were adjusted for age, log N-terminal pro–B-type natriuretic peptide, and left ventricular ejection fraction (LVEF), heart rate (per 10 beats/min; hazard ratio [HR]: 1.65; 95% CI: 1.10-2.57; P = 0.01) and change in heart rate from baseline (per 10 beats/min; HR: 1.70; 95% CI: 1.12–2.57; p = 0.01) were associated with relapse. The results remained qualitatively the same after adjusting for beta-blocker dose. Conclusions For patients with DCM and improved LVEF, the rise in heart rate after treatment is withdrawn treatment identifies patients who are more likely to relapse. Whether the increase in heart rate is a marker or a mediator of relapse requires investigation. (Therapy withdrawal in REcovered Dilated cardiomyopathy trial [TRED]; NCT02859311), Central Illustration

There is increasing understanding of the genetic basis to dilated cardiomyopathy and in this review, we offer a practical primer for the practising clinician. We aim to help all clinicians involved in the care of patients with dilated cardiomyopathy to understand the clinical relevance of the genetic basis of dilated cardiomyopathy, introduce key genetic concepts, explain which patients and families may benefit from genetic testing, which genetic tests are commonly performed, how to interpret genetic results, and the clinical applications of results. We conclude by reviewing areas for future research in this dynamic field.

Pathological left ventricular hypertrophy is a common feature of many cardiac diseases. It results from both myocyte hypertrophy and interstitial expansion. Interstitial expansion is most commonly secondary to the accumulation of mature cross-linked collagen fibers due to dysregulated metabolism, known as interstitial fibrosis. This occurs secondary to a variety of stimuli including ischemic, toxic, metabolic, infective, genetic, and hemodynamic factors. Less commonly, interstitial expansion may occur because of the accumulation of misfolded amyloid protein or interstitial edema. It is now well recognized that the presence and extent of interstitial disease are associated with adverse outcomes. There is therefore interest in the development of novel therapies that target the pathways that drive these disease processes. With the emergence of such therapies, it is becoming increasingly important to be able to characterize the type and extent of interstitial disease to enable the use of such targeted therapies in a personalized manner.

Objective Develop an accelerated cine displacement encoding with stimulated echoes (DENSE) cardiovascular magnetic resonance (CMR) sequence to enable clinically feasible myocardial strain evaluation in patients with dilated cardiomyopathy (DCM). Materials and methods A spiral cine DENSE sequence was modified by limiting the field of view in two dimensions using in-plane slice-selective pulses in the stimulated echo. This reduced breath hold duration from 20RR to 14RR intervals. Following phantom and pilot studies, the feasibility of the sequence to assess peak radial, circumferential, and longitudinal strain was tested in control subjects (n = 18) and then applied in DCM patients (n = 29). Results DENSE acquisition was possible in all participants. Elements of the data were not analysable in 1 control (6%) and 4 DCM r(14%) subjects due to off-resonance or susceptibility artefacts and low signal-to-noise ratio. Peak radial, circumferential, short-axis contour strain and longitudinal strain was reduced in DCM patients (p 0.80), except peak radial strain. Discussion We demonstrate the feasibility of CMR strain assessment in healthy controls and DCM patients using an accelerated cine DENSE technique. This may facilitate integration of strain assessment into routine CMR studies. Electronic supplementary material The online version of this article (10.1007/s10334-019-00735-5) contains supplementary material, which is available to authorized users.

Aims Our objective was to better understand the genetic bases of dilated cardiomyopathy (DCM), a leading cause of systolic heart failure. Methods and results We conducted the largest genome-wide association study performed so far in DCM, with 2719 cases and 4440 controls in the discovery population. We identified and replicated two new DCM-associated loci on chromosome 3p25.1 [lead single-nucleotide polymorphism (SNP) rs62232870, P = 8.7 × 10−11 and 7.7 × 10−4 in the discovery and replication steps, respectively] and chromosome 22q11.23 (lead SNP rs7284877, P = 3.3 × 10−8 and 1.4 × 10−3 in the discovery and replication steps, respectively), while confirming two previously identified DCM loci on chromosomes 10 and 1, BAG3 and HSPB7. A genetic risk score constructed from the number of risk alleles at these four DCM loci revealed a 3-fold increased risk of DCM for individuals with 8 risk alleles compared to individuals with 5 risk alleles (median of the referral population). In silico annotation and functional 4C-sequencing analyses on iPSC-derived cardiomyocytes identify SLC6A6 as the most likely DCM gene at the 3p25.1 locus. This gene encodes a taurine transporter whose involvement in myocardial dysfunction and DCM is supported by numerous observations in humans and animals. At the 22q11.23 locus, in silico and data mining annotations, and to a lesser extent functional analysis, strongly suggest SMARCB1 as the candidate culprit gene. Conclusion This study provides a better understanding of the genetic architecture of DCM and sheds light on novel biological pathways underlying heart failure.

Aims We explored the experiences and motivations of participants and staff who took part in the TRED‐HF trial (Therapy withdrawal in REcovered Dilated cardiomyopathy). Methods and results We conducted a qualitative study, using semi‐structured interviews, with participants (n = 12) and the research team (n = 4) from the TRED‐HF trial. Interviews were carried out in 2019 and were audio‐recorded and transcribed. Data were managed using NVivo and analysed using framework analysis. A patient representative provided guidance on the interpretation of findings and presentation of themes to ensure these remained meaningful, and an accurate representation, to those living with dilated cardiomyopathy. Three key themes emerged from the data: (i) perception of health; (ii) experiences and relationships with healthcare services and researchers; and (iii) perception of risk. Study participants held differing perceptions of their health; some did not consider themselves to have a heart condition or disagreed with the medical term ‘heart failure’. Relationships between participants, research staff, and clinical management teams influenced participants' experiences and decision making during the trial, including following clinical advice. There were differences in participants' perceptions of risk and their decisions to take heart failure medication after the trial was completed. Although the original TRED‐HF trial did not provide the results many had hoped for, a strong motivator for taking part was the opportunity to withdraw medication in a safely monitored environment which had been previously considered by some participants before. Investigators acknowledged that the insights gained from the study can now be used to support evidence‐based conversations with patients. Conclusions For people whose dilated cardiomyopathy is in remission, decisions to continue, reduce, or stop their medication are influenced by perceptions of personal health, perceive risk and the important of work, employment, recreation, relationships, and long‐term plans. The unique relationship between patient and cardiologist provides opportunities to promote honest discussion about adherence to medication and personalized long‐term management.

The heart muscle diseases hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure in young, otherwise healthy, individuals. We conducted genome-wide association studies and multi-trait analyses in HCM (1,733 cases), DCM (5,521 cases) and nine left ventricular (LV) traits (19,260 UK Biobank participants with structurally normal hearts). We identified 16 loci associated with HCM, 13 with DCM and 23 with LV traits. We show strong genetic correlations between LV traits and cardiomyopathies, with opposing effects in HCM and DCM. Two-sample Mendelian randomization supports a causal association linking increased LV contractility with HCM risk. A polygenic risk score explains a significant portion of phenotypic variability in carriers of HCM-causing rare variants. Our findings thus provide evidence that polygenic risk score may account for variability in Mendelian diseases. More broadly, we provide insights into how genetic pathways may lead to distinct disorders through opposing genetic effects.

A prothrombotic state is reported with severe COVID-19 infection, which can manifest in venous and arterial thrombotic events. Coagulopathy is reflective of more severe disease and anticoagulant thromboprophylaxis is recommended in hospitalized patients. However, the prevalence of thrombosis on the intensive care unit (ICU) remains unclear, including whether this is sufficiently addressed by conventional anticoagulant thromboprophylaxis. We aimed to identify the rate of thrombotic complications in ICU-treated patients with COVID-19, to inform recommendations for diagnosis and management. A systematic review was conducted to assess the incidence of thrombotic complications in ICU-treated patients with COVID-19. Observational studies and registries reporting thrombotic complications in ICU-treated patients were included. Information extracted included patient demographics, use of thromboprophylaxis or anticoagulation, method of identifying thrombotic complications, and reported patient outcomes. In 28 studies including 2928 patients, thrombotic complications occurred in 34% of ICU-managed patients, with deep venous thrombosis reported in 16.1% and pulmonary embolism in 12.6% of patients, despite anticoagulant thromboprophylaxis, and were associated with high mortality. Studies adopting systematic screening for venous thrombosis with Duplex ultrasound reported a significantly higher incidence of venous thrombosis compared to those relying on clinical suspicion (56.3% vs. 11.0%, p

Myocardial inflammation in COVID-19 has been documented. Its pathogenesis is not fully elucidated, but the two main theories foresee a direct role of ACE2 receptor and a hyperimmune response, which may also lead to isolated presentation of COVID-19-mediated myocarditis. The frequency and prognostic impact of COVID-19-mediated myocarditis is unknown. This review aims to summarise current evidence on this topic. We performed a systematic review of MEDLINE and Cochrane Library (1/12/19–30/09/20). We also searched clinicaltrials.gov for unpublished studies testing therapies with potential implication for COVID-19-mediated cardiovascular complication. Eligible studies had laboratory confirmed COVID-19 and a clinical and/or histological diagnosis of myocarditis by ESC or WHO/ISFC criteria. Reports of 38 cases were included (26 male patients, 24 aged

Aims: To characterize adverse ventricular remodelling after withdrawing therapy in recovered dilated cardiomyopathy (DCM). Methods and results: TRED-HF was a randomized controlled trial with a follow-on single-arm cross-over phase that examined the safety and feasibility of therapy withdrawal in patients with recovered DCM over 6 months. The primary endpoint was relapse of heart failure defined by (i) a reduction in left ventricular (LV) ejection fraction >10% and to 10% increase in LV end-diastolic volume and to above the normal range, (iii) a twofold rise in N-terminal pro-B-type natriuretic peptide and to >400 ng/L, or (iv) evidence of heart failure. LV mass, LV and right ventricular (RV) global longitudinal strain (GLS) and extracellular volume were measured using cardiovascular magnetic resonance at baseline and follow-up (6 months or relapse) for 48 patients. LV cell and extracellular matrix masses were derived. The effect of withdrawing therapy, stratified by relapse and genotype, was investigated in the randomized and follow-on phases. In the randomized comparison, withdrawing therapy led to an increase in mean LV mass [5.4 g/m 2; 95% confidence interval (CI) 1.3–9.5] and cell mass (4.2 g/m 2; 95% CI 0.5–8.0) and a reduction in LV (3.5; 95% CI 1.6–5.5) and RV (2.4; 95% CI 0.1–4.7) GLS. In a non-randomized comparison of all patients (n = 47) who had therapy withdrawn in either phase, there was an increase in LV mass (6.2 g/m 2; 95% CI 3.6–8.9; P = 0.0001), cell mass (4.0 g/m 2; 95% CI 1.8–6.2; P = 0.0007) and matrix mass (1.7 g/m 2; 95% CI 0.7–2.6; P = 0.001) and a reduction in LV GLS (2.7; 95% CI 1.5–4.0; P = 0.0001). Amongst those who had therapy withdrawn and did not relapse, similar changes were observed (n = 28; LV mass: 5.1 g/m 2, 95% CI 1.5–8.8, P = 0.007; cell mass: 3.7 g/m 2, 95% CI 0.3–7.0, P = 0.03; matrix mass: 1.7 g/m 2, 95% CI 0.4–3.0, P = 0.02; LV GLS: 1.7, 95% CI 0.1–3.2, P = 0.04). Patients with TTN variants (n = 10) who had therapy withdrawn had a greater increase in LV matrix mass (mean effect of TTN: 2.6 g/m 2; 95% CI 0.4–4.8; P = 0.02). Conclusion: In TRED-HF, withdrawing therapy caused rapid remodelling, with early tissue and functional changes, even amongst patients who did not relapse.

ObjectivesThis study sought to investigate whether shape-based late gadolinium enhancement (LGE) metrics and simulations of re-entrant electrical activity are associated with arrhythmic events in patients with nonischemic dilated cardiomyopathy (NIDCM).BackgroundThe presence of LGE predicts life-threatening ventricular arrhythmias in NIDCM; however, risk stratification remains imprecise. LGE shape and simulations of electrical activity may be able to provide additional prognostic information.MethodsCardiac magnetic resonance (CMR)-LGE shape metrics were computed for a cohort of 156 patients with NIDCM and visible LGE and tested retrospectively for an association with an arrhythmic composite endpoint of sudden cardiac death and ventricular tachycardia. Computational models were created from images and used in conjunction with simulated stimulation protocols to assess the potential for re-entry induction in each patient’s scar morphology. A mechanistic analysis of the simulations was carried out to explain the associations.ResultsDuring a median follow-up of 1,611 (interquartile range: 881 to 2,341) days, 16 patients (10.3%) met the primary endpoint. In an inverse probability weighted Cox regression, the LGE–myocardial interface area (hazard ratio [HR]: 1.75; 95% confidence interval [CI]: 1.24 to 2.47; p = 0.001), number of simulated re-entries (HR: 1.40; 95% CI: 1.23 to 1.59; p ConclusionsThe area of interface between scar and surviving myocardium, as well as simulated re-entrant activity, are associated with an elevated risk of major arrhythmic events in patients with NIDCM and LGE and represent novel risk predictors.

Objectives This study aims to investigate the prognostic significance of late gadolinium enhancement (LGE) in patients without coronary artery disease and with normal range left ventricular (LV) volumes and ejection fraction. Background Nonischemic patterns of LGE with normal LV volumes and ejection fraction are increasingly detected on cardiovascular magnetic resonance, but their prognostic significance, and consequently management, is uncertain. Methods Patients with midwall/subepicardial LGE and normal LV volumes, wall thickness, and ejection fraction on cardiovascular magnetic resonance were enrolled and compared to a control group without LGE. The primary outcome was actual or aborted sudden cardiac death (SCD). Results Of 748 patients enrolled, 401 had LGE and 347 did not. The median age was 50 years (interquartile range: 38-61 years), LV ejection fraction 66% (interquartile range: 62%-70%), and 287 (38%) were women. Scan indications included chest pain (40%), palpitation (33%) and breathlessness (13%). No patient experienced SCD and only 1 LGE+ patient (0.13%) had an aborted SCD in the 11th follow-up year. Over a median of 4.3 years, 30 patients (4.0%) died. All-cause mortality was similar for LGE+/- patients (3.7% vs 4.3%; P = 0.71) and was associated with age (HR: 2.04 per 10 years; 95% CI: 1.46-2.79; P < 0.001). Twenty-one LGE+ and 4 LGE- patients had an unplanned cardiovascular hospital admission (HR: 7.22; 95% CI: 4.26-21.17; P < 0.0001). Conclusions There was a low SCD risk during long-term follow-up in patients with LGE but otherwise normal LV volumes and ejection fraction. Mortality was driven by age and not LGE presence, location, or extent, although the latter was associated with greater cardiovascular hospitalization for suspected myocarditis and symptomatic ventricular tachycardia., Central Illustration

The inner surfaces of the human heart are covered by a complex network of muscular strands that is thought to be a remnant of embryonic development1,2. The function of these trabeculae in adults and their genetic architecture are unknown. Here we performed a genome-wide association study to investigate image-derived phenotypes of trabeculae using the fractal analysis of trabecular morphology in 18,096 participants of the UK Biobank. We identified 16 significant loci that contain genes associated with haemodynamic phenotypes and regulation of cytoskeletal arborization3,4. Using biomechanical simulations and observational data from human participants, we demonstrate that trabecular morphology is an important determinant of cardiac performance. Through genetic association studies with cardiac disease phenotypes and Mendelian randomization, we find a causal relationship between trabecular morphology and risk of cardiovascular disease. These findings suggest a previously unknown role for myocardial trabeculae in the function of the adult heart, identify conserved pathways that regulate structural complexity and reveal the influence of the myocardial trabeculae on susceptibility to cardiovascular disease. A genome-wide association study shows that myocardial trabeculae are an important determinant of cardiac performance in the adult heart, identifies conserved pathways that regulate structural complexity and reveals the influence of trabeculae on the susceptibility to cardiovascular disease.

Background:\ud Fractional flow reserve (FFR) assessment of remote arteries, in the context of a bystander chronic total occlusion (CTO), can lead to false positive results. Adenosine stress cardiovascular magnetic resonance (CMR) evaluates perfusion defects across the entire myocardium and may therefore be a reliable tool in the work-up of remote lesions in CTO patients. The IMPACT-CTO study investigated donor artery invasive physiology before, immediately post, and at 4 months following right coronary artery (RCA) CTO percutaneous coronary intervention (PCI). The aim of this subanalysis was to assess the concordance between baseline perfusion CMR and serial FFR evaluation of left anterior descending artery (LAD) ischemia in patients from the IMPACT-CTO study.\ud \ud Methods:\ud Baseline adenosine stress CMR examinations from 26 patients were analyzed for qualitative evidence of LAD ischemia. The results were correlated with the serial LAD FFR measurements.\ud \ud Results:\ud The present findings demonstrated that before RCA CTO PCI, there was 62% agreement between perfusion CMR and FFR (ischemic threshold £ 0.8) in the assessment of LAD ischemia (k = 0.29; fair concordance). At 4 months after revascularization, there was 77% agreement (k = 0.52; moderate concordance) between the index CMR assessment of LAD ischemia and the follow-up LAD FFR. Concordance was improved at a LAD FFR ischemic threshold of £ 0.75.\ud \ud Conclusions:\ud In this hypothesis generating study, baseline CMR assessment of LAD ischemia correlated better with the 4 months LAD FFR data (threshold £ 0.8) as compared to the FFR measurements taken prior to RCA CTO revascularization.

Supplemental Digital Content is available in the text., Background: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. Methods: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. Results: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. Conclusions: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.

To evaluate the prognostic value of texture features based on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) images in hypertrophic cardiomyopathy (HCM) patients with systolic dysfunction. 67 HCM patients with systolic dysfunction (41 male and 26 female, mean age ± standard deviation, 46.20 years ± 13.38) were enrolled. All patients underwent 1.5 T CMR cine and LGE imaging. Texture features were extracted from LGE images. Cox proportional hazard analysis and Kaplan-Meier analysis were used to determine the association of texture features and traditional parameters with event free survival. Family history (hazard ratio [HR]=2.558, 95 % confidence interval [CI]=1.060–6.180), NYHA III-IV (HR=5.627, CI=1.652–19.173), left ventricular ejection fraction (HR=0.945, CI=0.902–0.991), left ventricular end-diastolic volume index (HR=1.006, CI=1.000–1.012), LGE extent (HR=1.911, CI=1.348–2.709) and three texture parameters [X0_H_skewness (HR=0.783, CI=0.691–0.889), X0_GLCM_cluster_tendency (HR=0.735, CI=0.616–0.877) and X0_GLRLM_energy (HR=1.344, CI=1.173–1.540)] were significantly associated with event free survival in univariate analysis (p

Background There is increasing evidence that the Brugada ECG pattern is a marker of subtle structural heart disease. Objective The purpose of this study was to characterize patients with Brugada syndrome (BrS) using cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE). Methods BrS was diagnosed according to international guidelines. Twenty-six percent of patients with BrS carried SCN5A mutations. CMR data from 78 patients with BrS were compared with 78 healthy controls (44 ± 15 vs 42 ± 14 years; P = .434; and 64% vs 64% male; P = 1). Results Right ventricular (RV) ejection fraction was slightly lower (61 ± 8% vs 64 ± 5%; P = .004) and RV end-systolic volume slightly greater (31 ± 10 mL/m2 vs 28 ± 6 mL/m2; P = .038) in BrS compared with controls. These values remained within the normal range. LGE was demonstrated in 8% of patients with BrS (left ventricular midwall LGE in 5%) but not in controls (P = .028). In patients with BrS with midwall LGE there were no other features of cardiomyopathy at the time of CMR, but genetic testing and follow-up revealed a desmoplakin mutation in 1 patient and evolution of T-wave inversion throughout all precordial ECG leads in another. Neither patient fulfils diagnostic criteria for arrhythmogenic right ventricular cardiomyopathy. Conclusion Some patients with BrS have left ventricular midwall LGE consistent with an underlying cardiomyopathic process. Even cases without LGE show greater RV volumes and reduced RV function. These findings lend further support to the presence of subtle structural abnormalities in BrS. The BrS pattern with LGE may serve as early markers for evolution of a cardiomyopathic phenotype over time. CMR is a potentially useful adjunct investigation in the clinical evaluation of BrS.

Dilated cardiomyopathy (DCM) is a common condition, which carries significant mortality from sudden cardiac death and pump failure. Left ventricular ejection fraction has conventionally been used as a risk marker for sudden cardiac death, but has performed poorly in trials. There have been significant advances in the areas of cardiac magnetic resonance imaging and genetics, which are able to provide useful rick prediction in DCM. Biomarkers and cardiopulmonary exercise testing are well validated in the prediction of risk in heart failure; however, they have been tested less specifically in the DCM setting. This review will discuss these methods with a view toward multiparametric risk assessment in DCM with the hope of creating parametric risk models to predict sudden cardiac death and pump failure in the DCM population.

This cohort study investigates the association of titin-truncating genetic variants with life-threatening ventricular arrhythmias in adult patients with dilated cardiomyopathy who have implanted cardiac defibrillators or cardiac resynchronization therapy defibrillators., Key Points Question Are titin-truncating variants in the TTN gene associated with life-threatening ventricular arrhythmias in patients with nonischemic dilated cardiomyopathy and an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator? Findings In this multicenter cohort study of 117 adult patients with dilated cardiomyopathy, 13 of 28 patients with titin-truncating variants (46%) received 1 or more appropriate implanted cardioverter defibrillator therapies compared with 13 of 89 patients without titin-truncating variants (16%), a significant difference. Meaning Having a titin-truncating variant may be an independent risk factor for arrhythmia in patients with dilated cardiomyopathy and an implanted cardioverter defibrillator or cardiac resynchronization therapy defibrillator., Importance There is a need for better arrhythmic risk stratification in nonischemic dilated cardiomyopathy (DCM). Titin-truncating variants (TTNtvs) in the TTN gene are the most common genetic cause of DCM and may be associated with higher risk of arrhythmias in patients with DCM. Objective To determine if TTNtv status is associated with the development of life-threatening ventricular arrhythmia and new persistent atrial fibrillation in patients with DCM and implanted cardioverter defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) devices. Design, Setting, and Participants This retrospective, multicenter cohort study recruited 148 patients with or without TTNtvs who had nonischemic DCM and ICD or CRT-D devices from secondary and tertiary cardiology clinics in the United Kingdom from February 1, 2011, to June 30, 2016, with a median (interquartile range) follow-up of 4.2 (2.1-6.5) years. Exclusion criteria were ischemic cardiomyopathy, primary valve disease, congenital heart disease, or a known or likely pathogenic variant in the lamin A/C gene. Analyses were performed February 1, 2017, to May 31, 2017. Main Outcome and Measures The primary outcome was time to first device-treated ventricular tachycardia of more than 200 beats/min or first device-treated ventricular fibrillation. Secondary outcome measures included time to first development of persistent atrial fibrillation. Results Of 148 patients recruited, 117 adult patients with nonischemic DCM and an ICD or CRT-D device (mean [SD] age, 56.9 [12.5] years; 76 [65.0%] men; 106 patients [90.6%] with primary prevention indications) were included. Having a TTNtv was associated with a higher risk of receiving appropriate ICD therapy (shock or antitachycardia pacing) for ventricular tachycardia or fibrillation (hazard ratio [HR], 4.9; 95% CI, 2.2-10.7; P

ispartof: JOURNAL OF THE AMERICAN HEART ASSOCIATION vol:8 issue:11 ispartof: location:England status: published

Background Exercise‐induced pulmonary hypertension is common in heart failure with preserved ejection fraction ( HF p EF ). We hypothesized that this could result in pericardial constraint and diastolic ventricular interaction in some patients during exercise. Methods and Results Contrast stress echocardiography was performed in 30 HF p EF patients, 17 hypertensive controls, and 17 normotensive controls (healthy). Cardiac volumes, and normalized radius of curvature ( NRC ) of the interventricular septum at end‐diastole and end‐systole, were measured at rest and peak‐exercise, and compared between the groups. The septum was circular at rest in all 3 groups at end‐diastole. At peak‐exercise, end‐systolic NRC increased to 1.47±0.05 ( P HF p EF patients, confirming development of pulmonary hypertension. End‐diastolic NRC also increased to 1.54±0.07 ( P HF p EF patients, indicating septal flattening, and this correlated significantly with end‐systolic NRC (ρ=0.51, P =0.007). In hypertensive controls and healthy controls, peak‐exercise end‐systolic NRC increased, but this was significantly less than observed in HF p EF patients ( HF p EF , P =0.02 versus hypertensive controls; P NRC in both groups (hypertensive controls, +0.17±0.05, P =0.38; healthy, +0.06±0.03, P =0.93). In HF p EF patients, peak‐exercise end‐diastolic NRC also negatively correlated ( r =−0.40, P r =−0.36, P =0.08). Conclusions Exercise pulmonary hypertension causes substantial diastolic ventricular interaction on exercise in some patients with HF p EF , and this restriction to left ventricular filling by the right ventricle exacerbates the pre‐existing impaired Frank‐Starling response in these patients.

Background Patients with nonischemic systolic heart failure are at an increased risk of sudden cardiac death, but more discriminating tools are needed to identify those patients likely to benefit from implantable cardioverter-defibrillator (ICD) implantation. Whether right ventricular (RV) ejection fraction (RVEF) can identify patients with nonischemic systolic heart failure more likely to benefit from ICD implantation is not yet known. Methods In this post hoc analysis of the DANISH trial (Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic Heart Failure on Mortality), patients with nonischemic systolic heart failure randomized to ICD or control underwent cardiovascular magnetic resonance. RV systolic dysfunction was defined as RVEF ≤45%. Cox regression assessed the effects of RV function and ICD implantation on all-cause mortality, sudden cardiac death, and cardiovascular death. Results Overall, 239 patients had interpretable images of RV volume. Median RVEF was 51%, RV systolic dysfunction was present in 75 (31%) patients, and 55 (23%) patients died. RVEF was an independent predictor of all-cause mortality, hazards ratio 1.34 per 10% absolute decrease in RVEF (95% CI, 1.05–1.70), P =0.02. There was a statistically significant interaction between RVEF and the effect of ICD implantation ( P =0.001). ICD implantation significantly reduced all-cause mortality in patients with RV systolic dysfunction, hazards ratio 0.41 (95% CI, 0.17–0.97), P =0.04 but not in patients without RV systolic dysfunction, hazards ratio 1.87 (95% CI, 0.85–3.92), P =0.12, ( P =0.01 for the difference in effect of ICD between RV groups). Conclusions In this post hoc analysis of the DANISH trial, ICD therapy was associated with survival benefit in patients with biventricular heart failure. These findings need confirmation in a prospective study. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00542945.

Background: Left ventricular noncompaction cardiomyopathy (LVNC) is associated with poor clinical outcome in childhood. Standard diagnostic criteria are still controversial, especially in young patients. Recent studies in adults demonstrated that left ventricular (LV) twist is abnormal in LVNC, but it has not been investigated in pediatric patients to date. Our aim was to assess LV cardiac mechanics, LV twist, and the prevalence of rigid body rotation, using 2-dimensional speckle tracking echocardiography, in young patients with LVNC and LV hypertrabeculation. Methods: Forty-seven children (age range: 0–18 years) were assessed for suspected LVNC. All patients underwent 2-dimensional speckle tracking echocardiography and cardiovascular magnetic resonance imaging at 1.5 Tesla (T). Twenty-three patients fulfilled the cardiovascular magnetic resonance imaging diagnostic criteria for LVNC (LVNC group), while the remaining 24 did not and were included in the LV hypertrabeculation group. Forty-seven age- and sex-matched healthy volunteers were used as controls. Results: The average LV twist was significantly reduced in LVNC compared with control and LV hypertrabeculation. Rigid body rotation was recognized in 13 (56%) children with LVNC and in 1 (4%) child with LV hypertrabeculation and a strong family history for LVNC. Multivariable analysis demonstrated that LV twist is an independent predictor of LVNC ( P =0.006; coefficient=0.462). The receiver operating characteristics curve showed that LV twist had optimal predictive value to discriminate patients with LVNC (cutoff value Conclusions: LV twist has good predictive value in diagnosing LVNC in young patients. Our findings strongly support the routine use of 2-dimensional speckle tracking echocardiography in the evaluation of young patients with suspected LVNC.

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:21 issue:3 pages:272-285 ispartof: location:England status: published

Aim Heart failure with preserved ejection fraction (HFpEF) is associated with increased sympathetic nervous system (SNS) tone. Attenuating the SNS with renal denervation (RDT) might be helpful and there are no data currently in humans with HFpEF. Methods and results In this single-centre, randomized, open-controlled study we included 25 patients with HFpEF [preserved left ventricular (LV) ejection fraction, left atrial (LA) dilatation or LV hypertrophy and raised B-type natriuretic peptide (BNP) or echocardiographic assessment of filling pressures]. Patients were randomized (2:1) to RDT with the Symplicity™ catheter or continuing medical therapy. The primary success criterion was not met in that there were no differences between groups at 12 months for Minnesota Living with Heart Failure Questionnaire score, peak oxygen uptake (VO2) on exercise, BNP, E/e′, LA volume index or LV mass index. A greater proportion of patients improved at 3 months in the RDT group with respect to VO2 peak (56% vs. 13%, P = 0.025) and E/e′ (31% vs. 13%, P = 0.04). Change in estimated glomerular filtration rate was comparable between groups. Two patients required plain balloon angioplasty during the RDT procedure to treat renal artery wall oedema. Conclusion This study was terminated early because of difficulties in recruitment and was underpowered to detect whether RD improved the endpoints of quality of life, exercise function, biomarkers, and left heart remodelling. The procedure was safe in patients with HFpEF, although two patients did require intraprocedure renal artery dilatation.

Dilated cardiomyopathy (DCM) has a population prevalence of ∼1 in 500 and is associated with prognostically adverse arrhythmias at initial disease presentation in up to one-third of patients [(1)][1]. While increasing age, male sex, and impaired ventricular function are established arrhythmic risk

Myocardial fibrosis, identified by late gadolinium enhancement cardiovascular magnetic resonance, predicts outcomes in chronic heart failure (HF). Its prognostic significance in new-onset HF and reduced left ventricular ejection fraction (LVEF) is unclear. We investigated whether the pattern and extent of fibrosis predict survival in new-onset HF and reduced LVEF of initially uncertain pathogenesis.Of 120 consecutive patients with new-onset (6 months) HF and reduced LVEF, 31 (26%) had infarct fibrosis, 25 (21%) had midwall fibrosis, and 64 (53%) had no fibrosis. During median follow-up of 8.9 years, 33 (28%) patients died. Patients with infarct fibrosis (hazard ratios [HR], 3.32; 95% CI, 1.46-7.58; P=0.004) or midwall fibrosis (HR, 2.99; 95% CI, 1.24-7.19; P=0.014) were more likely to die compared with those without fibrosis. On multivariable analysis, the pattern and extent of fibrosis were both associated with all-cause mortality (by fibrosis pattern: infarct: HR, 2.60; 95% CI, 1.08-6.27; P=0.033; midwall: HR, 2.64; 95% CI, 1.08-6.47; P=0.034; by fibrosis extent per 1%: HR, 1.07; 95% CI, 1.03-1.12; P0.001). Fibrosis pattern also predicted composites of cardiovascular mortality or aborted sudden cardiac death (infarct: HR, 3.45; 95% CI, 1.20-9.90; P=0.022; midwall: HR, 6.59; 95% CI, 2.26-19.22; P0.001), and all-cause mortality, HF hospitalization, or aborted sudden cardiac death (infarct: HR, 2.69; 95% CI, 1.26-5.76; P=0.011; midwall fibrosis: HR, 2.97; 95% CI, 1.37-6.45; P=0.006). Addition of fibrosis pattern to LVEF improved risk prediction for all-cause mortality (LVEF versus LVEF+fibrosis C statistic: 0.66 versus 0.71; P=0.033). Importantly, the absence of fibrosis heralded a favorable prognosis with an 85% survival rate over the duration of follow-up.The pattern and extent of myocardial fibrosis predict adverse outcomes in new-onset HF and reduced LVEF. In contrast, the absence of fibrosis portends a durable warranty period with a low incidence of adverse events. These findings support a role for late gadolinium enhancement cardiovascular magnetic resonance in the early risk stratification of patients with HF of uncertain pathogenesis.

Objective Segmented cardiac cine magnetic resonance imaging (MRI) is the gold standard for cardiac ventricular volumetric assessment. In patients with difficulty in breath-holding or arrhythmia, this technique may generate images with inadequate quality for diagnosis. Real-time cardiac cine MRI has been developed to address this limitation. We aimed to assess the performance of retrospective electrocardiography-gated real-time cine MRI at 3T for left ventricular (LV) volume and mass measurement. Materials and Methods Fifty-one patients were consecutively enrolled. A series of short-axis cine images covering the entire left ventricle using both segmented and real-time balanced steady-state free precession cardiac cine MRI were obtained. End-diastolic volume (EDV), end-systolic volume (ESV), stroke volume (SV), ejection fraction (EF), and LV mass were measured. The agreement and correlation of the parameters were assessed. Additionally, image quality was evaluated using European CMR Registry (Euro-CMR) score and structure visibility rating. Results In patients without difficulty in breath-holding or arrhythmia, no significant difference was found in Euro-CMR score between the two techniques (0.3 ± 0.7 vs. 0.3 ± 0.5, p > 0.05). Good agreements and correlations were found between the techniques for measuring EDV, ESV, EF, SV, and LV mass. In patients with difficulty in breath-holding or arrhythmia, segmented cine MRI had a significant higher Euro-CMR score (2.3 ± 1.2 vs. 0.4 ± 0.5, p < 0.001). Conclusion Real-time cine MRI at 3T allowed the assessment of LV volume with high accuracy and showed a significantly better image quality compared to that of segmented cine MRI in patients with difficulty in breath-holding and arrhythmia.