Family History Of Cardiomyopathy Research Articles

Genetic therapies for cardiomyopathy: survey of attitudes of the patient community for the CureHeart project.

Cardiomyopathies are a group of inherited heart muscle disorders. Expressivity is variable and while sometimes mild, complications can result in sudden cardiac death (SCD) at any age, heart failure and stroke. In around a third of patients a monogenic cause is identifiable, and development of genetic therapies that aim to correct the underlying genetic defect is underway. Here we describe results of a survey designed to understand preliminary views of the patient community about genetic therapies in the context of disease burden. The internet survey was publicized with a bespoke information video via patient support groups in the UK and USA; 634 people responded of whom 96% had a personal and/or family history of cardiomyopathy. Findings show that concern about cardiomyopathy-related issues with a future dimension, such as disease progression, is significantly greater than concern about current issues. A total of 93.6% thought that genetic therapies should be developed for cardiomyopathy. A majority would consider participation in a genetic therapy trial in six scenarios varying by age and clinical situation significantly more in the scenario of an adult with symptomatic disease and evident progression than an asymptomatic adult with SCD risk, or a child. In all scenarios, a majority said that the chance genetic therapy would stop or slow progression, and risk of serious adverse and unintended effects, were important considerations. Qualitative analysis of free-text responses found that concern was often informed by family experience. Patient consideration of genetic therapy is likely to require individualized assessment of the benefits and risks.

ECG of the month

In this issue's ECG of the month, Charles Bloe presents the case of a 19-year-old man with a family history of cardiomyopathy who noticed an irregular heart rhythm on his smartwatch.

Electrocardiographic predictors of left ventricular scar in athletes with right bundle branch block premature ventricular beats.

Right bundle branch block (RBBB) morphology non-sustained ventricular arrhythmias (VAs) have been associated with the presence of non-ischaemic left ventricular scar (NLVS) in athletes. The aim of this cross-sectional study was to identify clinical and electrocardiogram (ECG) predictors of the presence of NLVS in athletes with RBBB VAs. Sixty-four athletes [median age 39 (24-53) years, 79% males] with non-sustained RBBB VAs underwent cardiac magnetic resonance (CMR) with late gadolinium enhancement in order to exclude the presence of a concealed structural heart disease. Thirty-six athletes (56%) showed NLVS at CMR and were assigned to the NLVS positive group, whereas 28 athletes (44%) to the NLVS negative group. Family history of cardiomyopathy and seven different ECG variables were statistically more prevalent in the NLVS positive group. At univariate analysis, seven ECG variables (low QRS voltages in limb leads, negative T waves in inferior leads, negative T waves in limb leads I-aVL, negative T waves in precordial leads V4-V6, presence of left posterior fascicular block, presence of pathologic Q waves, and poor R-wave progression in right precordial leads) proved to be statistically associated with the finding of NLVS; these were grouped together in a score. A score ≥2 was proved to be the optimal cut-off point, identifying NLVS athletes in 92% of cases and showing the best accuracy (86% sensitivity and 100% specificity, respectively). However, a cut-off ≥1 correctly identified all patients with NLVS (absence of false negatives). In athletes with RBBB morphology non-sustained VAs, specific ECG abnormalities at 12-lead ECG can help in detecting subjects with NLVS at CMR.

Clinical predictors of right ventricular dysfunction and association with adverse outcomes in peripartum cardiomyopathy.

We sought to identify factors associated with right ventricular (RV) dysfunction and elevated pulmonary artery systolic pressure (PASP) and association with adverse outcomes in peripartum cardiomyopathy (PPCM). We conducted a multi-centre cohort study to identify subjects with PPCM with the following criteria: left ventricular ejection fraction (LVEF)<40%, development of heart failure within the last month of pregnancy or 5months of delivery, and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included a composite of (i) major adverse events (need for extracorporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation, or death) or (ii) recurrent heart failure hospitalization. RV function was obtained from echocardiogram reports. In total, 229 women (1993-2017) met criteria for PPCM. Mean age was 32.4±6.8years, 28% were of African descent, 50 (22%) had RV dysfunction, and 38 (17%) had PASP≥30mmHg. After a median follow-up of 3.4years (interquartile range 1.0-8.8), 58 (25%) experienced the composite outcome of adverse events. African descent, family history of cardiomyopathy, LVEF, and PASP were significant predictors of RV dysfunction. Using Cox proportional hazards models, we found that women with RV dysfunction were three times more likely to experience the adverse composite outcome: hazard ratio 3.21 (95% confidence interval: 1.11-9.28), P=0.03, in a multivariable model adjusting for age, race, body mass index, preeclampsia, hypertension, diabetes, kidney disease, and LVEF. Women with PASP≥30mmHg had a lower probability of survival free from adverse events (log-rank P=0.04). African descent and family history of cardiomyopathy were significant predictors of RV dysfunction. RV dysfunction and elevated PASP were significantly associated with a composite of major adverse cardiac events. This at-risk group may prompt closer monitoring or early referral for advanced therapies.

Clinical predictors of right ventricular dysfunction and association with adverse outcomes in peripartum cardiomyopathy

Abstract Background Peripartum cardiomyopathy (PPCM) is a type of pregnancy associated heart failure with reduced ejection of unknown etiology that is associated with significant morbidity and mortality in young women. It is a leading cause of peripartum maternal death in the United States, with mortality as high as 25% in some cohorts, and accounts for approximately 50% of cases of maternal cardiogenic shock. Purpose We sought to identify factors associated with right ventricular (RV) dysfunction and elevated RV systolic pressure (RVSP) and association with adverse outcomes in PPCM. Methods We conducted a multi-center cohort study to identify subjects with PPCM with the following criteria: LVEF &amp;lt; 40%, development of heart failure within the last month of pregnancy or 5 months of delivery and no other identifiable cause of heart failure with reduced ejection fraction. Outcomes included a composite of 1) major adverse events (need for extra-corporeal membrane oxygenation, ventricular assist device, orthotopic heart transplantation or death) or 2) recurrent heart failure hospitalization. Results In all, 229 women (1993 to 2017) met criteria. Mean age was 32.4 ± 6.8 years, 28% were of African descent, 50 (22%) had RV dysfunction, and 38 (17%) had RVSP &amp;gt; = 30mmHg. After a median follow-up of 3.4 years (IQR 1.0-8.8), 58 (25%) experienced the composite outcome of adverse events. African descent, family history of cardiomyopathy, LVEF, and RVSP were significant predictors of RV dysfunction (Table 1). Using Cox proportional hazards models, we found that women with RV dysfunction were three times more likely to experience the adverse composite outcome: HR 3.21 (95% CI: 1.11-9.28), p = 0.03 in a multivariable model adjusting for age, race, body mass index, preeclampsia, hypertension, diabetes, kidney disease and LVEF. Women with RVSP &amp;gt;= 30mmHg had a lower probability of survival free from adverse events (log rank p = 0.04) (Figure 1). Conclusion African descent and family history of cardiomyopathy were significant predictors of RV dysfunction. RV dysfunction and elevated RVSP were significantly associated with a composite of major adverse cardiac events. This at-risk group may prompt closer monitoring, genetic testing, or early referral for advanced therapies.Table of predictorsSurvival curves

Abstract 14343: Early Genetic Screening and Cardiac Intervention in Patients With Genetic Cardiomyopathies Within a Multidisciplinary Care Model

Introduction: Patients with genetic cardiomyopathies are a heterogeneous group of patients who experience significant morbidity and mortality. Early cardiac assessment and intervention coupled with access to genetic counselling and testing may improve clinical outcomes and prevent progression to end-stage heart failure. Methods: Our prospective cohort study was conducted at our multidisciplinary Cardiomyopathy Clinic and patients with suspected genetic cardiomyopathy (CM) or a family history of CM ( n =405) were recruited. Patients with genetic analysis completed ( n =228) were categorized into dilated cardiomyopathy (DCM) ( n= 118), hypertrophic cardiomyopathy (HCM) ( n= 55), infiltrative cardiomyopathy (CM) ( n= 18), and Stage A/at-risk for CM ( n= 37). Continuous variables were analyzed using Wilcoxon signed-rank test or paired t test, while categorical variables were compared using Pearson chi-square tests. Results: There was a median follow-up time of 13 months (IQR: 7 - 21 months) with an increase in genetic testing, cascade family screening, optimization of guideline-directed medical therapy, and usage of device therapies compared to prior to clinic enrolment. In patients with genetic testing, 29.4% ( n= 67) had positive genotypes (pathogenic or likely pathogenic variants), 11.8% ( n= 27) had variants of unknown significance (VUS), and 58.8% ( n= 134) had negative or inconclusive genotypes. Optimization of medical and device therapies resulted in improvements in left ventricular ejection fraction from 30.5% (20.8 - 42.5%) to 45.5% (34.0 - 48.5%, P&lt; 0.001), reduced left ventricular mass index from 121.2 g/m 2 (116.2 - 146.4 g/m 2 ) to 107.0 g/m 2 (88.9 - 134.7 g/m 2 , P&lt; 0.001), and reduced E/e’ ratio from 12.6 cm/s (9.2 - 15.3 cm/s) to 10.9 cm/s (9.0 - 14.2 cm/s, P= 0.015). These improvements were driven by patients with negative genotypes (no variants or VUS) relative to those with positive genotypes. Additionally, patients with normal blood pressure (SBP &lt; 120 mmHg and DBP &lt; 80 mmHg) at follow-up had improvement in LVEF ( P&lt; 0.001) and LVMI ( P= 0.005). Conclusion: Our findings demonstrate the efficacy of a combined cardiovascular genetics clinic in improving the clinical trajectories of patients with genetic cardiomyopathies.

Abstract 12588: A Hyperactive Heart: A Case of Adderall-Induced Cardiomyopathy

Introduction: Stimulants are commonly used in the treatment of attention deficit hyperactivity disorder (ADHD). Cardiomyopathy is a rare but serious potential side effect of long-term stimulant use, even when done so for therapeutic purposes. Case: We present a 56-year-old female with ADHD and long-term high dose Adderall use who presented for progressively worsening dyspnea over the course of 1 year. Labs were notable for peak hs-troponin 246ng/L and pro-BNP 6598pg/mL. On admission, echocardiogram was notable for reduced left ventricular (LV) ejection fraction (EF) of 20-25% with normal LV wall thickness and mild-moderate valvular disease. ECG showed sinus rhythm 97 bpm, bi-atrial enlargement, normal voltage and no evidence of conduction delay. A left heart catheterization demonstrated no evidence of coronary artery disease. Cardiac MRI at 1.5T was notable for LVEF 18%, severe LV dilation (EDV 189mL/m2), severe right ventricular (RV) dilation (EDV 131mL/m2) with RVEF 26%, native T1 1099 msec, ECV 41%, normal T2*, and a very thin circumferential subendocardial late gadolinium enhancement involving the apical and mid segments (6% of LV mass). TSH, Vitamin B1, and selenium levels were normal, and there was no evidence of tachyarrhythmia throughout her admission. She denied significant alcohol use, illicit substance use, or family history of cardiomyopathy. The absence of paraprotein gap and other stigmata lowered suspicion for amyloidosis. Due to the results of her workup, her Adderall was discontinued as this was thought to be the likely cause of her newly discovered cardiomyopathy. She was discharged home on GDMT with close follow up with advanced heart failure. Discussion: The association between long-term stimulant use and cardiomyopathy is known, but not well described. Common cardiac effects of stimulants include tachycardia, hypertension and increased risk of arrhythmias, all of which are associated with increased workload on the heart and therefore contribute to the development of cardiomyopathy. Although generally rare, long-term use of prescription stimulant medications can contribute to the development of cardiomyopathy and should therefore be used sparingly and for the shortest period possible when necessary for the treatment of ADHD.

Recurrent acute myocarditis: An under-recognized clinical entity associated with the later diagnosis of a genetic arrhythmogenic cardiomyopathy.

Myocardial inflammation has been consistently associated with genetic arrhythmogenic cardiomyopathy (ACM) and it has been hypothesized that episodes mimicking acute myocarditis (AM) could represent early inflammatory phases of the disease. We evaluated the temporal association between recurrent acute myocarditis (RAM) episodes and the later diagnosis of a genetic ACM. Between January 2012 and December 2021, patients with RAM and no previous cardiomyopathy were included (Recurrent Acute Myocarditis Registry, NCT04589156). A follow-up visit including clinical evaluation, resting and stress electrocardiogram, cardiac magnetic resonance imaging, and genetic testing was carried out. Endpoints of the study was the incidence of both ACM diagnosis criteria and ACM genetic mutation at the end of follow-up. Twenty-one patients with RAM were included and follow-up was completed in 19/21 patients (90%). At the end of follow-up, 3.3 ± 2.9 years after the last AM episode, 14/21 (67%) patients with an ACM phenotype (biventricular: 10/14, 71%; left ventricular: 4/14, 29%) underwent genetic testing. A pathogenic or likely pathogenic mutation was found in 8/14 patients (57%), 5/8 in the Desmoplakin gene, 2/8 in the Plakophillin-2 gene, and 1/8 in the Titin gene. Family history of cardiomyopathy or early sudden cardiac death had a positive predictive value of 88% for the presence of an underlying genetic mutation in patients with RAM. RAM is a rare entity associated with the latter diagnosis of an ACM genetic mutation in more than a third of the cases. In those patients, RAM episodes represent early inflammatory phases of the disease. Including RAM episodes in ACM diagnosis criteria might allow early diagnosis and potential therapeutic interventions.

Reproducibility of exercise-induced premature ventricular beats predicts concealed non-ischemic left ventricular scar on cardiac magnetic resonance in athletes

Abstract Background Non-ischemic left ventricular scar (NLVS) at cardiac magnetic resonance (CMR) is a common substrate of apparently idiopathic premature ventricular beats (PVBs) in athletes. PVBs morphology, complexity and exercise-behavior are known predictors of NLVS. It remains to be established whether reproducibility of PVBs at exercise testing correlates with CMR findings. Purpose We aimed to evaluate the possible role of PVBs reproducibility at repeated exercise testing in predicting the presence of an underlying NLVS in athletes who underwent CMR for apparently idiopathic ventricular arrhythmias. Methods We included all consecutive competitive athletes referred to our center for the evidence of PVBs during pre-participation screening, who underwent two maximal exercise testings within one month (the first at the time of pre-participation screening, the second at the time of outpatient evaluation at our sports cardiology clinic). Exclusion criteria were known heart disease, family history of cardiomyopathy or channelopathy, abnormal ECG and echocardiography. We also excluded athletes with “common/usually benign” PVBs (non-exercise-induced infundibular or fascicular PVBs) as well as those on ongoing antiarrhythmic therapy. Reproducibility was defined as the presence of PVBs with same morphology and exercise-behavior in two subsequent tests. LGE on CMR was quantified with 5-SD method, using a threshold of 5% to define the presence of pathological LVNS. Results A total of 64 apparently healthy competitive athletes (86% males, mean age of 33±14 years old) were included. On CMR, NLVS was identified in 26 (41%). PVBs reproducibility criteria was met in 32 athletes (50%). A statistically significant difference in PVBs reproducibility was found between patients with and without LVNS [26 (100%) versus 6 (16%), p&amp;lt;0,001], irrespective of other factors such as age, sex, biventricular volumes and function (Figure 1). Among the 26 patients with NLVS, 18 (69%) showed PVBs with right-bundle branch block (R-BBB) with superior axis configuration, alone or associated with other morphologies. These arrhythmic patterns were confirmed by a second test in all cases. Among the 38 patients with normal CMR, the first exercise test showed R-BBB/superior axis PVBs, alone or associated with other morphologies, in 22 (57%); the second test confirmed such pattern in only 6 (16%), showing instead different morphologies in 8 (21%) and no PVBs in 24 (63%). Figure 2 represents an example of two cases included in the study. Conclusion In apparently healthy athletes who underwent CMR for “uncommon” PVBs, the presence of underlying LVNS was predicted by ventricular arrhythmia reproducibility. Specifically, reproducibility of PVBs with RBBB/superior axis morphology was highly predictive of a positive CMR. This finding may be very relevant for appropriate prescription of CMR in athletes with apparently idiopathic ventricular arrhythmias. Funding Acknowledgement Type of funding sources: None.

Atrial fibrillation concerning worse prognosis in patients with left ventricular noncompaction

Abstract Purpose This study aims to investigate the relationship between atrial fibrillation (AF) and the prognosis of patients with left ventricular noncompaction (LVNC). Methods This retrospective study enrolled 302 patients (median age 46 years, 65.9% male) diagnosed as LVNC through echocardiography or cardiac nuclear magnetic according to Jenni criteria1 and Petersen criteria2, respectively. The primary endpoint is major cardiovascular adverse events (MACEs) which is a composite endpoint including heart transplantation, deaths in-hospital, stroke, system embolism, malignant ventricular arrhythmia, and rehospitalization for cardiovascular reasons. The second endpoints are thromboembolism events including system embolism and stroke. Results The patients with LVNC were divided into 2 groups: with AF group (n=56) and without AF group (n=246). In the group of patients combined with AF and LVNC, the proportion of CHA2DS2-VASc score≥2 was 66.07%. The rate of receiving oral anticoagulant therapy in LVNC patients with AF was significantly higher than without the AF group (69.64% vs. 19.51%, p&amp;lt;0.01). After a median follow-up of 4.3 years, a total of 69 MACEs (22.85%) and 19 thromboembolism events (6.3%) occurred. Among them, 49 MACEs in the non-AF group (19.92%) while 20 cases (35.71%) occurred MACEs in the AF group (p=0.01). Moreover, the rate of thromboembolism in the AF group was notably higher compared with the non-AF group (16.1% vs. 4.1%, p=0.01). The Kaplan-Meier curves (Figure 1) compared by the log-rank test showed that the AF group was associated with a higher risk of thromboembolism events than the non-AF group and the difference between the 2 groups was significant (p&amp;lt;0.05). Crude Logistic regression model results revealed that AF was associated with increased risk of MACEs in patients with LVNC [Crude odds ratio (OR) 2.23, 95% confidence interval (CI) 1.19–4.19, p=0.01]. Adjusted Logistic regression model indicated that AF was still an independent risk factor (adjusted OR 2.43, 95% CI 1.08–5.45, p=0.03) for MACEs after adjusting for other risk factors including age, heart rate, syncope, heart failure, NYHA class, cardio-pulmonary resuscitation history, hypertension, prior stroke, prior system embolism, family history of cardiomyopathy, levels of NT-pro-BNP, left atrial diameter, left ventricular ejection fraction, oral anticoagulant therapy and antiplatelet therapy. Conclusion This current study indicated that AF is associated with a worse prognosis in patients with LVNC. Extra attention is needed in clinical practice for LVNC patients with AF. Funding Acknowledgement Type of funding sources: None.

The predictive value of left atrial diameter for thrombotic risk in patients with left ventricular noncompaction

Abstract Purpose Patients with left ventricular noncompaction (LVNC) are associated with increased risk of thromboembolism including system embolism (SE) and stroke. Moreover, left atrial (LA) diameter was proved to be a strong predictor for stroke and SE [1]. This study aimed to evaluate the predictive value of left atrial diameter on the risk of thromboembolism in patients with LVNC. Methods This retrospective longitudinal study enrolled 302 patients (median age 46 years, 65.9% male) diagnosed as LVNC through echocardiography or cardiac nuclear magnetic according to Jenni criteria [2] and Petersen criteria [3], respectively. The primary endpoint was thromboembolism events including SE and stroke. Results The 302 patients with LVNC were divided into 2 groups: large LA group (LA diameter ≥43mm, n=155) and small LA group (LA diameter&amp;lt;43mm, n=147), according to the median of LA diameter. After a median follow-up of 4.3 years, 19 cases (6.3%) patients occurred thromboembolism events. In the large LA group, 16 patients (10.3%) occurred thromboembolism events while there were 3 cases (2.0%) suffering from SE/stroke in the small LA group (p&amp;lt;0.05). The Kaplan-Meier curves (Figure 1) compared by the log-rank test showed that the large LA group was associated with a higher risk of thromboembolism events and the difference between the 2 groups was significant (p&amp;lt;0.05). Crude Cox regression model results revealed that LA diameter was an independent risk factor for thromboembolism events in patients with LVNC (Crude HR 1.07, 95% CI 1.02–1.12, p=0.004). After adjusting for prior heart failure, NYHA class, atrial fibrillation, prior stroke, coronary artery disease, pulmonary arterial hypertension, family history of cardiomyopathy, LA diameter was still associated with increased thrombotic risk (Adjusted HR 4.98, 95% CI 1.07–23.04, p=0.04). Moreover, the ROC curves (Figure 2) showed that the AUC of LA diameter was 0.692 and even better than the CHA2DS2-VASc score (AUC=0.576). Conclusion The current study indicated that LA diameter is an effective predictor of thrombotic risk in patients with LVNC. Moreover, extra attention is needed in LVNC patients with larger LA diameters for the risk of thromboembolism. Funding Acknowledgement Type of funding sources: None.

Genetic Profile of Left Ventricular Noncompaction Cardiomyopathy in Children-A Single Reference Center Experience.

Background: Left ventricular noncompaction cardiomyopathy (LVNC) is a rare cardiac disorder characterised by the presence of a two-layer myocardium with prominent ventricular trabeculation, intertrabecular deep depressions and an increased risk of heart failure, atrial and ventricular arrhythmias and systemic thromboembolic events in affected patients. The heterogeneous molecular aetiology solved in 10%–50% of patients more frequently involves sarcomeric, cytoskeletal or ion channel protein dysfunction—mainly related to causative MYH7, TTN or MYBPC3 variants. The aim of the study was to determine the molecular spectrum of isolated LVNC in a group of children examined in a single paediatric reference centre. Methods: Thirty-one paediatric patients prospectively diagnosed with LVNC by echocardiography and cardiovascular magnetic resonance examination were recruited into the study group. The molecular analysis included next-generation sequencing (gene panel or whole exome) and classic Sanger sequencing. All selected variants with high priority were co-segregated in the available parents. Results: We identified 16 distinct variants in 11 genes in 16 patients (52%), including 10 novel alterations. The most frequent defects in our cohort were found in the genes HCN4 (n = 4), MYH7 (n = 2) and PRDM16 (n = 2). Other likely disease-causing variants were detected in ACTC1, ACTN2, HCCS, LAMA4, MYH6, RBM20, TAFFAZIN and TTN. Patients with established molecular defects more often presented with arrhythmia, thromboembolic events and death, whereas the predominant symptoms in patients with no identified molecular defects were heart failure and the presence of late gadolinium enhancement. Conclusion: This study expands the genetic and clinical spectrum of childhood LVNC. Although the molecular aetiology of LVNC varies widely, the comprehensive testing of a wide panel of cardiomyopathy-related genes helped to identify underlying molecular defects in more than half of the children in the study group. The molecular spectrum in our cohort correlated with the occurrence of arrhythmia, death and a family history of cardiomyopathy. We confirmed that genetic testing is an integral part of the work-up and management LVNC in children.

Adult-Onset Sandhoff Disease in a Filipino Patient: Asymmetric Weakness, Whole HEXB Gene Deletion, and Coexisting MYH7 Pathogenic Variant.

ObjectiveTo describe a Filipino patient with adult-onset Sandhoff disease manifesting with an atypical asymmetric lower motor neuron syndrome due to a novel whole HEXB deletion in trans with a pathogenic missense variant and with a coexisting MYH7 pathogenic variant.MethodsWe performed clinical, laboratory, myopathologic, and genetic evaluation with next-generation sequencing in the proband and targeted mutational analysis in an asymptomatic sibling.ResultsA 59-year-old Filipino woman presented with 15 years of slowly progressive, asymmetric, proximal-predominant, lower greater than upper extremity weakness, mildly elevated creatine kinase, and generalized cerebellar atrophy. Serum total β-hexosaminidase was significantly reduced, and hexosaminidase A percentage was increased. We identified a novel HEXB whole gene deletion in compound heterozygosity with a pathogenic missense variant (c.1513C>T, p.Arg505Trp) previously described in 1 patient with adult-onset Sandhoff disease. The patient, with a family history of cardiomyopathy, has a coexisting MYH7 pathogenic variant (c.3134G>A, p.Arg1045His), causative of cardiomyopathy but without cardiac involvement, likely due to variable penetrance. Myopathic features were absent from skeletal muscle biopsy.DiscussionThis patient expands the genotypic, phenotypic, and ethnic spectrum of Sandhoff disease and highlights challenges generated by low-penetrant pathogenic variants, especially when considering a potentially polygenic phenotype.

An Unusual Clinical Presentation of Danon Disease in a Female

<h3>Introduction</h3> Danon disease is a rare X-linked dominant skeletal and cardiac muscle disorder with multisystem clinical manifestations caused by mutations in the <i>LAMP2</i> gene. <i>LAMP2</i> mutations are identified in unselected cardiomyopathy cohorts in <0.3% of cases. We report a patient with Danon cardiomyopathy and no skeletal muscle involvement who underwent successful left ventricular assist device (LVAD) implantation. <h3>Case Report</h3> A 39-year-old patient with stage D heart failure (HF) and a LV ejection fraction of 20%, paroxysmal atrial fibrillation, Wolf-Parkinson-White (WPW) syndrome, and type 2 diabetes mellitus was admitted with decompensated HF. There was no family history of cardiomyopathy or sudden cardiac death. She was diagnosed with HF 4 years prior at that time she had concentric LV hypertrophy (interventricular septal thickness 1.4 mm) and LV end diastolic diameter of 5 cm. A cardiac PET did not identify any areas of ischemia and no FDG uptake to suggest active sarcoidosis. Left heart catheterization revealed angiographically normal coronary arteries. Genetic testing identified a heterozygous deletion in <i>LAMP2</i> (5'UTR_3'UTRdel), resulting in complete deletion of 1 allele. She was started on inotrope therapy due to low cardiac output but deteriorated due to incessant ventricular arrhythmias. She underwent HeartMate 3 (HM3) LVAD implantation as a bridge to heart transplant. The LV apical core biopsy revealed vacuolated and hypertrophic cardiomyocytes with endocardial fibrosis, consistent with Danon disease. In 6 months since surgery, she is doing well without LVAD-related complications. She was referred to genetic counseling and her now 10 years old daughter is being genetically tested. <h3>Summary</h3> This case reports an unusual clinical presentation of severe HF due to Danon disease in a female. She had primary myocardial involvement with WPW and mild learning disability but had no skeletal muscle or retinal involvement. Because of the X-linked nature of the disease, males are more severely affected, though progression to advanced HF has rarely been reported in females. This case highlights the importance of genetic testing for cardiomyopathies and subsequent genetic counseling of family members.

Clinical features and natural history of RASopathy-associated hypertrophic cardiomyopathy in children

Abstract Background The RASopathies are a group of genetic disorders caused by germline mutations in genes encoding components of the RAS/MAPK signalling pathway and frequently associated with hypertrophic cardiomyopathy (HCM). The clinical features and outcomes of RASopathy-related HCM are incompletely understood and most published studies are limited by relatively small numbers and incomplete clinical characterisation. Purpose To describe the clinical features outcomes in a large, single-centre cohort of patients with RASopathy-associated HCM diagnosed &amp;lt;18 years. Methods Data from 105 patients [68 (64.8%) males] diagnosed in childhood with RASopathy-associated HCM at a single specialist centre between 1985 and 2020 were retrospectively analysed. Results The RASopathy diagnosis was Noonan syndrome in 69 patients (65.7%); NSML in 10 (9.5%); CFC in 6 (5.7%); Costello in 5 (4.8%) and 15 patients (14.2%) had another Noonan-like variant. 72 patients (68.6%) had a pathogenic/likely pathogenic variant in a RAS-MAPK gene, most commonly PTPN11 [n=25 (34.7%)], followed by RAF 1 [n=13 (18.1%)]. 100 patients (95.2%) were probands, 9 (8.6%) had family history of cardiomyopathy and 2 (1.9%) family history of sudden cardiac death (SCD). 52 (49.5%) had concomitant congenital heart defects (CHD) [ASD 13 (25%), VSD 6 (11.5%), PDA 1 (1.9%), &amp;gt;1 CHD 32 (61.5%)]. 29 (27.6%) had symptoms at baseline assessment and 56 (53.3%) were on cardiac medication. The distribution of left ventricular hypertrophy (LVH) was concentric in 47 (44.7%); 32 (30.5%) had asymmetric septal hypertrophy (ASH), and undocumented in 25 patients (23.8%). 45 patients (42.9%) had biventricular hypertrophy (BVH). Resting left ventricular outflow tract obstruction (LVOTO) was present in 39 (37.1%) with haemodynamically significant LVOTO (≥50mmHg) in 23 (21.9%). Resting right ventricular outflow tract obstruction (RVOTO) was present in 21 (20%). Over a median follow up time of 6 years, 19 patients (18.1%) died [1 (5.3%) SCD; 2 (10.5%) due to Heart Failure-related death; 1 (5.3%) due to another CVS cause; 5 (26.3%) due to a non-CVS cause and for 10 (52.6%) cause of death was unknown]. Incidence rate of death was calculated at 2.7 deaths per 100 person-years. Surgical septal myectomy was performed in 9 patients (8.6%) and 3 (2.9%) underwent cardiac transplantation. 14 patients (13.3%) suffered arrhythmic events [atrial tachycardia 6 (42.9%), Non-Sustained Ventricular Tachycardia 4 (3.8%), and Ventricular Tachycardia/Ventricular Fibrillation 4 (3.8%)]. Conclusion To our knowledge, this is the largest cohort of RASopathy-associated HCM. The findings show a heterogeneous clinical presentation with a high prevalence of morbidity and mortality. Further work is needed to determine predictors of outcome in this population. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Onassis Foundation

Left ventricular noncompaction: the importance of identifying high-risk patients within the scope of left ventricular hypertrabeculation

Abstract Introduction Prominent left ventricular (LV) trabeculation is frequently encountered, however LV noncompaction (LVNC) criteria are not always fulfilled. The clinical and prognostic significance of these findings remains unclear. Objectives To characterize the patients (P) with echocardiographic suspicion of LVNC and to assess clinical outcomes. Methods Retrospective single-centre study that included all echocardiograms between January 2018 and June 2020 perceiving LV hypertrabeculation. The cohort underwent diagnostic assessment for LVNC by Chin and Jenni criteria. Baseline characteristics were evaluated. Composite endpoint of cardiovascular death, heart failure (HF) hospitalization, ventricular arrythmias (VA) and nonfatal stroke was considered. Results 51P, 75% male, mean age 50±18 years. 35P (69%) had associated heart conditions, of which 57% had other known cardiomyopathy (mainly dilated cardiomyopathy), 14% congenital, 26% ischemic and 3% valvular heart disease. 2P were in postpartum period and 1P was an athlete. Family history of cardiomyopathy was present in 8P (16%). 12P underwent genetic testing, with TTN and MYH7 mutations being the most frequently detected. Prior clinical HF was reported in 53%, previous stroke in 14%, and non-sustained and sustained VA in 24% and 4%, respectively. Mean NYHA classification was 1.8±0.7, with 31% being asymptomatic. The prevalence of LVNC by Chin criteria was 31% and by Jenni criteria was 55%. 32P (63%) met at least one LVNC criteria. This group was younger (45±18 vs 59±15, p=0.004), had higher NT-proBNP levels (3644±2819 vs 389±640, p=0.048) and QRS fragmentation (59% vs 21%, p=0.027). Significantly higher LV end-diastolic volume (84 (41) vs 64 (28)ml/m2, p=0.008) and end-systolic volume (51 (37) vs 35 (20)ml/m2, p=0.004), along with lower LV ejection fraction (39±12 vs 49±13%, p=0.009) and global longitudinal strain (−11±5 vs −17±4%, p=0.003) were noticed. P who met LVNC criteria also had higher number of affected LV segments (6.4±1.8 vs 4.2±1.6, p&amp;lt;0.001). Over a mean follow-up of 18±9 months, the incidence of composite endpoint was 35%. Univariate Cox analysis showed a significant association between the presence of LVNC criteria and adverse outcomes (HR: 5.108, 95% CI: 1.682–11.236, p=0.030) (Fig. 1). Conclusion LV hypertrabeculation can be encountered in a variety of clinical scenarios and often overlaps with other heart diseases. P satisfying criteria for LVNC had more impairment in LV performance and worse clinical outcomes. Funding Acknowledgement Type of funding sources: None. Figure 1

Peripartum cardiomyopathy: from genetics to management.

Peripartum cardiomyopathy (PPCM) is a disease that occurs globally in all ethnic groups and should be suspected in any peripartum women presenting with symptoms and signs of heart failure, towards the end of pregnancy or in the months following delivery, with confirmed left ventricular dysfunction. After good history taking, all women should be thoroughly assessed, and alternative causes should be excluded. Urgent cardiac investigations with electrocardiogram and natriuretic peptide measurement (if available) should be performed. Echocardiography follows as the next step in investigation. Patients with abnormal cardiac investigations should be urgently referred to a cardiology team for expert management. Referral for genetic work-up should be considered if there is a family history of cardiomyopathy or sudden death. PPCM is a disease with substantial maternal and neonatal morbidity and mortality. Maternal mortality rates range widely, from 0% to 30%, depending on the ethnic background and geographic region. Just under half of women experience myocardial recovery. Remarkable advances in the comprehension of the pathogenesis and in patient management and therapy have been achieved, largely due to team efforts and close collaboration between basic scientists, cardiologists, intensive care specialists, and obstetricians. This review summarizes current knowledge of PPCM genetics, pathophysiology, diagnostic approach, management, and outcome.

A novel risk model for predicting potentially life-threatening arrhythmias in non-ischemic dilated cardiomyopathy (DCM-SVA risk)

BackgroundNon-ischemic dilated cardiomyopathy (DCM) can be complicated by sustained ventricular arrhythmias (SVA) and sudden cardiac death (SCD). By now, left-ventricular ejection fraction (LV-EF) is the main guideline criterion for primary prophylactic ICD implantation, potentially leading either to overtreatment or failed detection of patients at risk without severely impaired LV-EF. The aim of the European multi-center study DETECTIN-HF was to establish a clinical risk calculator for individualized risk stratification of DCM patients. Methods1393 patients (68% male, mean age 50.7 ± 14.3y) from four European countries were included. The outcome was occurrence of first potentially life-threatening ventricular arrhythmia. The model was developed using Cox proportional hazards, and internally validated using cross validation. The model included seven independent and easily accessible clinical parameters sex, history of non-sustained ventricular tachycardia, history of syncope, family history of cardiomyopathy, QRS duration, LV-EF, and history of atrial fibrillation. The model was also expanded to account for presence of LGE as the eight8h parameter for cases with available cMRI and scar information. ResultsDuring a mean follow-up period of 57.0 months, 193 (13.8%) patients experienced an arrhythmic event. The calibration slope of the developed model was 00.97 (95% CI 0.90–1.03) and the C-index was 0.72 (95% CI 0.71–0.73). Compared to current guidelines, the model was able to protect the same number of patients (5-year risk ≥8.5%) with 15% fewer ICD implantations. ConclusionsThis DCM-SVA risk model could improve decision making in primary prevention of SCD in non-ischemic DCM using easily accessible clinical information and will likely reduce overtreatment.

Rajaie Cardiomyopathy and Myocarditis Registry: Protocol for an Observational Study

Most of the information on the natural history and management of cardiomyopathies and myocarditis in Iran has been obtained from cohort studies in a small number of patients. The prevalence of patients with cardiomyopathies referred to Rajaei Cardiovascular medical and research centers from all over the country is remarkable. Rajaie Cardiomyopathy and myocarditis Registry (RCMR) study is an observational registry of patients with four subtype of cardiomyopathy include: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM) as well as myocarditis designed to determine clinical characteristics, natural history, current therapeutic approaches, response to treatment and long-term outcomes of patients with cardiomyopathy and myocarditis. Prediction of mortality and response to different treatments in these patients using artificial intelligence is another aim of this Registry. COVID 19 Myocarditis and its sequence as cardiomyopathy seem a new challenge in forthcoming years. At the baseline visit, past medical history, clinical signs/symptoms, risk factors, physical examination and family history of cardiomyopathy, current standards for diagnostic workup and clinical follow-up, and relevant electrocardiogram echocardiography, cardiac magnetic resonance, Holter monitoring, or biomarker analyses will be checked. The outcome and results of various therapeutic approaches currently employed for patients, including implantable cardioverter defibrillator, cardiac resynchronization therapy, septal myomectomy, ablation, cardiac transplantation, and medications, will be assessed. Long-term outcomes, including the benefits and complications of therapeutic interventions, will be collected. A follow-up visit will be scheduled after 12 months for all patients, and survival status, hospitalizations, co-morbidities, medications will be assessed.

Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study.

BackgroundPediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices.Methods and ResultsChildren with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes.ConclusionsA definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first‐degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.