The development of inherited cardiac conditions services: current position and future perspectives.

BACKGROUND: Over the last two decades, inherited cardiac conditions (ICC) centres have emerged with the aim of improving outcomes for patients and their families, through early diagnosis, genetic testing, risk assessment and specialist treatment. SOURCES OF DATA: A literature search was performed using PubMed (https://pubmed.ncbi.nlm.nih.gov/). Commissioned ICC service reviews from NHS England, NHS Improvement and PHG Foundation were evaluated. AREAS OF AGREEMENT: ICC patient management requires a multi-disciplinary approach. ICC services are predominantly based within tertiary centres. Despite expansion, provision of care remains inadequate to meet rising demands. Access to services is inconsistent, partly due to geographic variation and lack of standardized pathways. AREAS OF CONTROVERSY: The optimal ICC care model remains undecided, although there is growing interest in 'hub-and-spoke' networks, which could aid secondary and tertiary service integration and repatriation of care. GROWING POINTS: Genetic mainstreaming is a priority for the Genomic Medicine Service Alliance. The benefits of telehealth and virtual clinics have been validated by their use during the COVID-19 pandemic. Other innovations to improve resource efficiency, such as clinical scientist-led and nurse-led clinics, show promise. AREAS TIMELY FOR DEVELOPING RESEARCH: An update for the NHS ICC service specifications is planned that appears well timed given the rapid evolution of the ICC landscape in the decade since last review. This has the potential to address needs including national audit, standardized pathways and ICC networks to improve governance and equity of care. Delegation of commissioning for specialist services to integrated care systems may also provide opportunity for increased regional direction.

Genetic Architecture of Acute Myocarditis and the Overlap With Inherited Cardiomyopathy.

BACKGROUND: 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. METHODS: 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. RESULTS: Variants that would be considered pathogenic if found in a patient with DCM or ACM were identified in 8% of myocarditis cases compared with <1% of healthy controls (P=0.0097). In the London cohort (n=230; median age, 33 years; 84% men), patients were representative of national myocarditis admissions (median age, 32 years; 71% men; 66% case ascertainment), and there was enrichment of rare truncating variants (tv) in ACM-associated genes (3.1% of cases versus 0.4% of controls; odds ratio, 8.2; P=0.001). This was driven predominantly by DSP-tv in patients with normal LV ejection fraction and ventricular arrhythmia. In Maastricht (n=106; median age, 54 years; 61% men), there was enrichment of rare truncating variants in DCM-associated genes, particularly TTN-tv, found in 7% (all with left ventricular ejection fraction <50%) compared with 1% in controls (odds ratio, 3.6; P=0.0116). Across both cohorts over a median of 5.0 years (interquartile range, 3.9-7.8 years), all-cause mortality was 5.4%. Two-thirds of deaths were cardiovascular, attributable to worsening heart failure (92%) or sudden cardiac death (8%). The 5-year mortality risk was 3.3% in genotype-negative patients versus 11.1% for genotype-positive patients (Padjusted=0.08). CONCLUSIONS: We identified DCM- or ACM-associated genetic variants in 8% of patients with acute myocarditis. This was dominated by the identification of DSP-tv in those with normal left ventricular ejection fraction and TTN-tv in those with reduced left ventricular ejection fraction. Despite differences between cohorts, these variants have clinical implications for treatment, risk stratification, and family screening. Genetic counseling and testing should be considered in patients with acute myocarditis to help reassure the majority while improving the management of those with an underlying genetic variant.

Interpretation and actionability of genetic variants in cardiomyopathies: a position statement from the European Society of Cardiology Council on cardiovascular genomics.

This document describes the contribution of clinical criteria to the interpretation of genetic variants using heritable Mendelian cardiomyopathies as an example. The aim is to assist cardiologists in defining the clinical contribution to a genetic diagnosis and the interpretation of molecular genetic reports. The identification of a genetic variant of unknown or uncertain significance is a limitation of genetic testing, but current guidelines for the interpretation of genetic variants include essential contributions from clinical family screening that can establish a de novo assignment of the variant or its segregation with the phenotype in the family. A partnership between clinicians and patients helps to solve major uncertainties and provides reliable and clinically actionable information.

Sudden cardiac death in cardiomyopathies: acting upon "acceptable" risk in the personalized medicine era.

Patients with cardiomyopathies are confronted with the risk of sudden cardiac death (SCD) throughout their lifetime. Despite the fact that SCD is relatively rare, prognostic stratification is an integral part of physician-patient discussion, with the goal of risk modification and prevention. The current approach is based on a concept of "acceptable risk." However, there are intrinsic problems with an algorithm-based approach to risk management, magnified by the absence of robust evidence underlying clinical decision support tools, which can make high- versus low-risk classifications arbitrary. Strategies aimed at risk reduction range from selecting patients for an implantable cardioverter defibrillator (ICD) to disqualification from competitive sports. These clinical options, especially when implying the use of finite financial resources, are often delivered from the physician's perspective citing decision-making algorithms. When the burden of intervention-related risks or financial costs is deemed higher than an "acceptable risk" of SCD, the patient's perspective may not be appropriately considered. Designating a numeric threshold of "acceptable risk" has ethical implications. One could reasonably ask "acceptable to whom?" In an era when individual choice and autonomy are pillars of the physician-patient relationship, the subjective aspects of perceived risk should be acknowledged and be part of shared decision-making. This is particularly true when the lack of a strong scientific evidence base makes a dichotomous algorithm-driven approach suboptimal for unmitigated translation to clinical practice.

The Electrocardiogram in the Diagnosis and Management of Patients With Left Ventricular Non-Compaction.

PURPOSE OF THE REVIEW: Left ventricular non-compaction (LVNC) is characterised by prominent left ventricular trabeculae and deep inter-trabecular recesses. Although considered a distinct cardiomyopathy, prominent trabeculations may also be found in other cardiomyopathies, in athletes or during pregnancy. Clinical presentation includes heart failure symptoms, systemic embolic events, arrhythmias and sudden cardiac death. Currently, LVNC diagnosis relies on imaging criteria, and clinicians face several challenges in the assessment of patients with prominent trabeculations. In this review, we summarise the available information on the role of the ECG in the diagnosis and management of LVNC. RECENT FINDINGS: ECG abnormalities have been reported in 75-94% of adults and children with LVNC. The lack of specificity of these ECG abnormalities does not allow (in isolation) to diagnose the condition. However, when considered in a set of diagnostic criteria including family history, clinical information, and imaging features, the ECG may differentiate between physiological and pathological findings or may provide clues raising the possibility of specific underlying conditions. Finally, some ECG features in LVNC constitute ominous signs that require a stricter patient surveillance or specific therapeutic measures. The ECG remains a cornerstone in the diagnosis and management of patients with cardiomyopathies, including LVNC.

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

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.

Systematic large-scale assessment of the genetic architecture of left ventricular noncompaction reveals diverse etiologies.

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.

Arrhythmogenic potential of myocardial disarray in hypertrophic cardiomyopathy: genetic basis, functional consequences and relation to sudden cardiac death.

Myocardial disarray is defined as disorganized cardiomyocyte spatial distribution, with loss of physiological fibre alignment and orientation. Since the first pathological descriptions of hypertrophic cardiomyopathy (HCM), disarray appeared as a typical feature of this condition and sparked vivid debate regarding its specificity to the disease and clinical significance as a diagnostic marker and a risk factor for sudden death. Although much of the controversy surrounding its diagnostic value in HCM persists, it is increasingly recognized that myocardial disarray may be found in physiological contexts and in cardiac conditions different from HCM, raising the possibility that central focus should be placed on its quantity and distribution, rather than a mere presence. While further studies are needed to establish what amount of disarray should be considered as a hallmark of the disease, novel experimental approaches and emerging imaging techniques for the first time allow ex vivo and in vivo characterization of the myocardium to a molecular level. Such advances hold the promise of filling major gaps in our understanding of the functional consequences of myocardial disarray in HCM and specifically on arrhythmogenic propensity and as a risk factor for sudden death. Ultimately, these studies will clarify whether disarray represents a major determinant of the HCM clinical profile, and a potential therapeutic target, as opposed to an intriguing but largely innocent bystander.

Genetic Variants Associated With Cancer Therapy-Induced Cardiomyopathy.

BACKGROUND: Cancer therapy-induced cardiomyopathy (CCM) is associated with cumulative drug exposures and preexisting cardiovascular disorders. These parameters incompletely account for substantial interindividual susceptibility to CCM. We hypothesized that rare variants in cardiomyopathy genes contribute to CCM. METHODS: We studied 213 patients with CCM from 3 cohorts: retrospectively recruited adults with diverse cancers (n=99), prospectively phenotyped adults with breast cancer (n=73), and prospectively phenotyped children with acute myeloid leukemia (n=41). Cardiomyopathy genes, including 9 prespecified genes, were sequenced. The prevalence of rare variants was compared between CCM cohorts and The Cancer Genome Atlas participants (n=2053), healthy volunteers (n=445), and an ancestry-matched reference population. Clinical characteristics and outcomes were assessed and stratified by genotypes. A prevalent CCM genotype was modeled in anthracycline-treated mice. RESULTS: CCM was diagnosed 0.4 to 9 years after chemotherapy; 90% of these patients received anthracyclines. Adult patients with CCM had cardiovascular risk factors similar to the US population. Among 9 prioritized genes, patients with CCM had more rare protein-altering variants than comparative cohorts ( P≤1.98e-04). Titin-truncating variants (TTNtvs) predominated, occurring in 7.5% of patients with CCM versus 1.1% of The Cancer Genome Atlas participants ( P=7.36e-08), 0.7% of healthy volunteers ( P=3.42e-06), and 0.6% of the reference population ( P=5.87e-14). Adult patients who had CCM with TTNtvs experienced more heart failure and atrial fibrillation ( P=0.003) and impaired myocardial recovery ( P=0.03) than those without. Consistent with human data, anthracycline-treated TTNtv mice and isolated TTNtv cardiomyocytes showed sustained contractile dysfunction unlike wild-type ( P=0.0004 and P<0.002, respectively). CONCLUSIONS: Unrecognized rare variants in cardiomyopathy-associated genes, particularly TTNtvs, increased the risk for CCM in children and adults, and adverse cardiac events in adults. Genotype, along with cumulative chemotherapy dosage and traditional cardiovascular risk factors, improves the identification of patients who have cancer at highest risk for CCM. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifiers: NCT01173341; AAML1031; NCT01371981.

Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial.

BACKGROUND: Patients with dilated cardiomyopathy whose symptoms and cardiac function have recovered often ask whether their medications can be stopped. The safety of withdrawing treatment in this situation is unknown. METHODS: We did an open-label, pilot, randomised trial to examine the effect of phased withdrawal of heart failure medications in patients with previous dilated cardiomyopathy who were now asymptomatic, whose left ventricular ejection fraction (LVEF) had improved from less than 40% to 50% or greater, whose left ventricular end-diastolic volume (LVEDV) had normalised, and who had an N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) concentration less than 250 ng/L. Patients were recruited from a network of hospitals in the UK, assessed at one centre (Royal Brompton and Harefield NHS Foundation Trust, London, UK), and randomly assigned (1:1) to phased withdrawal or continuation of treatment. After 6 months, patients in the continued treatment group had treatment withdrawn by the same method. The primary endpoint was a relapse of dilated cardiomyopathy within 6 months, defined by a reduction in LVEF of more than 10% and to less than 50%, an increase in LVEDV by more than 10% and to higher than the normal range, a two-fold rise in NT-pro-BNP concentration and to more than 400 ng/L, or clinical evidence of heart failure, at which point treatments were re-established. The primary analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02859311. FINDINGS: Between April 21, 2016, and Aug 22, 2017, 51 patients were enrolled. 25 were randomly assigned to the treatment withdrawal group and 26 to continue treatment. Over the first 6 months, 11 (44%) patients randomly assigned to treatment withdrawal met the primary endpoint of relapse compared with none of those assigned to continue treatment (Kaplan-Meier estimate of event rate 45·7% [95% CI 28·5-67·2]; p=0·0001). After 6 months, 25 (96%) of 26 patients assigned initially to continue treatment attempted its withdrawal. During the following 6 months, nine patients met the primary endpoint of relapse (Kaplan-Meier estimate of event rate 36·0% [95% CI 20·6-57·8]). No deaths were reported in either group and three serious adverse events were reported in the treatment withdrawal group: hospital admissions for non-cardiac chest pain, sepsis, and an elective procedure. INTERPRETATION: Many patients deemed to have recovered from dilated cardiomyopathy will relapse following treatment withdrawal. Until robust predictors of relapse are defined, treatment should continue indefinitely. FUNDING: British Heart Foundation, Alexander Jansons Foundation, Royal Brompton Hospital and Imperial College London, Imperial College Biomedical Research Centre, Wellcome Trust, and Rosetrees Trust.

Early and medium-term outcomes of Alfieri mitral valve repair in the management of systolic anterior motion during septal myectomy.

BACKGROUND: This report studies the early and medium-term clinical and echocardiographic outcomes of the Alfieri edge-to-edge mitral valve repair, as adjunctive therapy, to prevent and treat systolic anterior motion (SAM) at the time of septal myectomy (SM) for left ventricular outflow tract obstruction in hypertrophic cardiomyopathy. METHODS: From 2009-2015, 11 consecutive patients had a trans-atrial Alfieri repair, to prevent (n = 7) or treat (n = 4) SAM at the time of SM. RESULTS: No patients were lost to follow-up. There were no perioperative or late deaths. Pre-bypass, the mean left ventricular outflow tract gradient, measured directly by simultaneous needle insertion, was 40.7 ± 19.9 mmHg at rest and 115.8 ± 30.4 mmHg on provocation with Isoproterenol, which reduced after SM and Alfieri repair and discontinuation of bypass, to a mean gradient of 8.3 ± 9.8 mmHg at rest and 25.8 ± 9.2 mmHg on provocation. One patient who required mitral valve replacement on day 4, was hospitalized at 2.7 years with heart failure requiring diuresis and remains well at 6 years. One patient developed postoperative atrial fibrillation. There were no other early or late complications. At a median follow-up of 6.6 years (international quartile range 1.2-7.4), clinical and echocardiographic data demonstrated maintained improvement in mean New York Heart Association class from 2.6 ± 0.9 preoperatively to 1.7 ± 0.4 and reduction in mean grade of mitral regurgitation from 2.7 ± 0.8 preoperatively to 0.7 ± 0.6. CONCLUSIONS: The Alfieri repair, as adjunctive therapy, for the prevention or treatment of SAM at the time of SM demonstrates satisfactory early and medium-term clinical and echocardiographic outcomes supporting the ongoing utility of this approach.

'Paradoxical' low-flow, low-gradient severe aortic valve stenosis: an entity with limited improvement following transcatheter aortic valve implantation.

BACKGROUND AND AIM OF THE STUDY: The aim of this single-center observational study was to determine the outcome of patients with 'paradoxical' low-flow, low-gradient aortic valve stenosis (PLF-LG-AS) after transcatheter aortic valve implantation (TAVI). METHODS: Based on pre-procedural echocardiographic data, a total of 150 patients with severe aortic valve stenosis (AS) (indexed aortic valve area (AVA) ≤ 0.6 cm2/m2) who underwent TAVI at the authors' institution were allocated retrospectively to three groups: Group 1: PLF-LG-AS (ejection fraction (EF) ≥ 50%, indexed stroke volume (SV) ≤ 35 ml/m2, mean AV gradient < 40 mmHg; n = 30); Group 2: Classical low-flow, low-gradient AS (CLF-LG-AS: EF < 50%, SV ≤ 35 ml/m2, mean AV gradient < 40 mmHg; n = 21); and Group 3: High-gradient AS (HG-AS: EF < or ≥ 50%, mean AV gradient ≥ 40 mmHg; n = 99). RESULTS: PLF-LG-AS was associated with an increased relative wall thickness (RWT) and a higher post-procedural systolic blood pressure (sBP) and pulse pressure (PP) (RWT 60.6 ± 15.3%, sBP 144 ± 14 mmHg, PP 79 ± 15 mmHg) compared to patients with HG-AS or CLF-LG-AS: (RWT 52 ± 13% and 40 ± 9%, p < 0.001; sBP 138 ± 15 mmHg and 125 ± 25 mmHg, p = 0.006; PP 68 ± 16 mmHg and 60 ± 21 mmHg, p = 0.01). These patients experienced less improvement in a 6-min walk test (improvement for PLF-LG-AS 14 ± 84 m, for CLF-LG-AS 86 ± 83 m, for HG-AS 87 ± 66 m; intergroup p < 0.007). PLF-LG-AS and CLF-LG-AS were also associated with significantly increased one-year overall mortality (PLF-LG-AS 31%, CLF-LG-AS 19%, HG-AS 6%; p = 0.001) and cardiovascular mortality (PLF-LG-AS 20%, CLF-LG-AS 19%, HG-AS 3%; p = 0.002). CONCLUSION: Patients with PLF-LG-AS may represent a subgroup with a worse clinical outcome after TAVI.

Atrial Fibrillation in Hypertrophic Cardiomyopathy.

Atrial fibrillation (AF) is common among patients with hypertrophic cardiomyopathy (HCM) with a prevalence greater than 25%. AF in HCM is associated with a high risk of stroke and can be a marker of more advanced cardiomyopathy. Although, it frequently results in cardiac hemodynamic changes which are poorly tolerated, it can be subclinical. Thus, prompt diagnosis and adequate management of AF are essential to minimizing AF-related adverse outcomes in HCM. All HCM patients should be screened for AF regularly, and those with high-risk features should be screened more frequently preferably with extended ambulatory monitoring. Once AF is detected, oral anticoagulation should be initiated. Both general and HCM-specific modifiable risk factors should be addressed and assessment for cardiomyopathy progression should be performed. Although no randomized controlled studies have compared rate versus rhythm control in HCM, early rhythm control could be considered to prevent further LA remodeling.

Long-term follow-up of the TRED-HF trial: Implications for therapy in patients with dilated cardiomyopathy and heart failure remission.

AIMS: In TRED-HF, 40% of patients with recovered dilated cardiomyopathy (DCM) relapsed in the short term after therapy withdrawal. This follow-up investigates the longer-term effects of therapy withdrawal. METHODS AND RESULTS: TRED-HF was a randomized trial investigating heart failure therapy withdrawal in patients with recovered DCM over 6 months. Those randomized to continue therapy subsequently withdrew treatment between 6 and 12 months. Participants were recommended to restart therapy post-trial and were followed until May 2023. Clinical outcomes are reported in a non-randomized fashion from enrolment and from the end of the trial. The primary outcome was relapse defined as ≥10% reduction in left ventricular ejection fraction to <50%, doubling in N-terminal pro-B-type natriuretic peptide to >400 ng/L, or clinical features of heart failure. From enrolment to the last follow-up (median 6 years, interquartile range 6-7), 33 of 51 patients (65%) relapsed. The 5-year relapse rate from enrolment was 61% (95% confidence interval [CI] 45-73) and from the end of the trial was 39% (95% CI 19-54). Of 20 patients who relapsed during the trial, nine had a recurrent relapse during follow-up. Thirteen relapsed for the first time after the trial; seven had restarted low intensity therapy, four had not restarted therapy and two did not have therapy withdrawn. The mean intensity of therapy was lower after the trial compared to enrolment (mean difference -6 [-8 to -4]; p < 0.001). One third of relapses during follow-up had identifiable triggers (arrhythmia [n = 4], pregnancy [n = 1], hypertension [n = 1], infection [n = 1]). Corrected atrial fibrillation was associated with reduced risk of relapse (hazard ratio 0.33, 95% CI 0.12-0.96; p = 0.042). CONCLUSIONS: The risk of relapse in the 5 years following the TRED-HF trial remained high. Restarting lower doses of heart failure medications at the end of the trial, external triggers and disease progression are likely to have contributed to relapse.

Proposed diagnostic criteria for arrhythmogenic cardiomyopathy: European Task Force consensus report.

Arrhythmogenic cardiomyopathy (ACM) is a heart muscle disease characterized by prominent "non-ischemic" myocardial scarring predisposing to ventricular electrical instability. Diagnostic criteria for the original phenotype, arrhythmogenic right ventricular cardiomyopathy (ARVC), were first proposed in 1994 and revised in 2010 by an international Task Force (TF). A 2019 International Expert report appraised these previous criteria, finding good accuracy for diagnosis of ARVC but a lack of sensitivity for identification of the expanding phenotypic disease spectrum, which includes left-sided variants, i.e., biventricular (ABVC) and arrhythmogenic left ventricular cardiomyopathy (ALVC). The ARVC phenotype together with these left-sided variants are now more appropriately named ACM. The lack of diagnostic criteria for the left ventricular (LV) phenotype has resulted in clinical under-recognition of ACM patients over the 4 decades since the disease discovery. In 2020, the "Padua criteria" were proposed for both right- and left-sided ACM phenotypes. The presently proposed criteria represent a refinement of the 2020 Padua criteria and have been developed by an expert European TF to improve the diagnosis of ACM with upgraded and internationally recognized criteria. The growing recognition of the diagnostic role of CMR has led to the incorporation of myocardial tissue characterization findings for detection of myocardial scar using the late­gadolinium enhancement (LGE) technique to more fully characterize right, biventricular and left disease variants, whether genetic or acquired (phenocopies), and to exclude other "non-scarring" myocardial disease. The "ring-like' pattern of myocardial LGE/scar is now a recognized diagnostic hallmark of ALVC. Additional diagnostic criteria regarding LV depolarization and repolarization ECG abnormalities and ventricular arrhythmias of LV origin are also provided. These proposed upgrading of diagnostic criteria represents a working framework to improve management of ACM patients.

Myocardial strain analysis by cardiac magnetic resonance 3D feature-tracking identifies subclinical abnormalities in patients with neuromuscular disease and no overt cardiac involvement.

AIMS: Cardiovascular magnetic resonance (CMR) is valuable for the detection of cardiac involvement in neuromuscular diseases (NMDs). We explored the value of 2D- and 3D-left ventricular (LV) myocardial strain analysis using feature-tracking (FT)-CMR to detect subclinical cardiac involvement in NMD. METHODS AND RESULTS: The study included retrospective analysis of 111 patients with NMD; mitochondrial cytopathies (n = 14), Friedreich's ataxia (FA, n = 27), myotonic dystrophy (n = 27), Becker/Duchenne's muscular dystrophy (BMD/DMD, n = 15), Duchenne's carriers (n = 6), or other (n = 22) and 57 age- and sex-matched healthy volunteers. Biventricular volumes, myocardial late gadolinium enhancement (LGE), and LV myocardial deformation were assessed by FT-CMR, including 2D and 3D global circumferential strain (GCS), global radial strain (GRS), global longitudinal strain (GLS), and torsion. Compared with the healthy volunteers, patients with NMD had impaired 2D-GCS (P < 0.001) and 2D-GRS (in the short-axis, P < 0.001), but no significant differences in 2D-GRS long-axis (P = 0.101), 2D-GLS (P = 0.069), or torsion (P = 0.122). 3D-GRS, 3D-GCS, and 3D-GLS values were all significantly different to the control group (P < 0.0001 for all). Especially, even NMD patients without overt cardiac involvement (i.e. LV dilation/hypertrophy, reduced LVEF, or LGE presence) had significantly impaired 3D-GRS, GCS, and GLS vs. the control group (P < 0.0001). 3D-GRS and GCS values were significantly associated with the LGE presence and pattern, being most impaired in patients with transmural LGE. CONCLUSIONS: 3D-FT CMR detects subclinical cardiac muscle disease in patients with NMD even before the development of replacement fibrosis or ventricular remodelling which may be a useful imaging biomarker for early detection of cardiac involvement.