Subtype Of Cardiomyopathy Research Articles

P3821Resting heart rate in late adolescence and long term risk of cardiomyopathy - A nationwide study of one million Swedish men

Abstract Background/Introduction Elevated resting heart rate (RHR) is a known risk factor for HF. Whether elevated RHR is also associated with cardiomyopathy (CM), a common cause of heart failure in the young, is unknown. Purpose To investigate the association of resting heart rate (RHR) measured in late adolescence with long term risk of various subtypes of CM with special attention to cardiorespiratory fitness (CRF), an important predictor of RHR and myocardial dysfunction. Methods We followed a cohort of Swedish men enrolled for conscription in 1968–2005 (n=1,008,485; mean age=18.3 years) until December 2014. Outcomes of CM were collected from the national inpatient- (IPR), outpatient- (OPR) and cause of death registries and were divided into categories: 1) dilated, 2) hypertrophic, 3) alcohol/drug-induced, and 4) other. Cox proportional hazard models were used to analyze the longitudinal association between RHR and outcomes while adjusting for potential confounders, including body mass index (BMI), arterial blood pressure and cardiorespiratory fitness (CRF). CRF was measured by maximum capacity ergometer testing as part of the enlistment protocol. Results During a mean follow up of 34 years, there were 3500 cases of a first hospitalization for CM (mean age at diagnosis, 50.1 years). Comparing the highest with the lowest quintile of the RHR distribution, we found a positive association between RHR and dilated CM (hazard ratio (HR) = 1.58 [confidence interval (CI) = 1.37–1.82]) after adjustment for BMI, age at conscription, conscription year, test center, and baseline comorbidities (diabetes, hypertension, congenital heart disease). There no significant association with alcohol/drug-induced (HR=1.32 [CI=0.94–1.85]) or other categories of CM. Conclusion Adolescent RHR is associated with future risk CM, independently of blood pressure, BMI and CRF. The association was driven by dilated CM. These findings are suggestive of a causal pathway between elevated heart rate and adverse cardiac remodeling that warrants further investigation. Acknowledgement/Funding The Swedish Heart and Lung Foundation, the Swedish Research Council, the Swedish Council for Health, Working Life and Welfare

Missed Opportunities in Identifying Cardiomyopathy Etiology Prior to Advanced Heart Failure Therapy

Purpose In October 2018, a new US adult heart allocation scheme was enacted in which the etiology of cardiomyopathy can play a significant role in the prioritization of patients listed for transplantation. Given this, we embarked on a review of the diagnoses of patients who underwent therapy for advanced heart failure at our center. Methods We retrospectively reviewed the etiology of cardiomyopathy of patients receiving either durable ventricular assist device (VAD) or orthotopic heart transplantation (OHT) at NYU Langone Medical Center in New York, NY between January 2011 and October 2018. We evaluated for discrepancies between the primary HF diagnosis at time of operation with the ultimate diagnosis, combining both clinical follow-up data and cardiac pathology. Results During the study period, a total of 110 patients were treated with advanced therapies, of which the majority (74.5%) were male. 40.9% were African American, 35.4% Caucasian, 4.5% Asian, and 23.6% Hispanic. 86.3% underwent VAD and 22.0% underwent OHT. The average age of those undergoing OHT and VAD were 58 and 61 respectively. The most common reported etiology of HF was dilated cardiomyopathy (57.3%), followed by ischemic (36.3%), familial DCM (1.8%), amyloidosis (1.8%), restrictive cardiomyopathy (1.8%), and sarcoidosis (0.9%). On final review of the diagnoses in these patients, 14 (12.7%) had a final diagnosis that was inconsistent with the prior reported one. 5 were clerical errors, but 9 were significant deviations from the prior diagnosis. The most common diagnoses that were misidentified prior to VAD or OHT were cardiac sarcoidosis (2), cardiac amyloidosis (2), and hypertrophic cardiomyopathy (2). Among those 9 patients, 7 patients received VAD with 5 eventually requiring OHT (median days to OHT = 248); 2 patients directly received OHT. All of those are alive except one patient who was lost to follow-up (transferred care to another center). Patients in whom the diagnosis was misidentified prior to VAD or OHT had smaller LV dimensions on transthoracic echocardiography on average than other LVAD or OHT patients with non-ischemic cardiomyopathy. Conclusions In this single-center review, we found that the majority of HF patients undergoing VAD and OHT had a correct diagnosis for their heart failure prior to treatment, although notably 8.1% had a missed diagnosis at time of intervention (VAD or OHT). Appropriately identifying the subtype of cardiomyopathy remains challenging especially in advanced HF patients but can significantly impact waiting list time in the current organ allocation scheme. A normal or minimally increased LV dimension on echocardiogram in a patient with advanced non-ischemic cardiomyopathy may warrant further workup for another diagnosis.

FLNC pathogenic variants in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations.

Pathogenic variants in FLNC encoding filamin C have been firstly reported to cause myopathies, and were recently linked to isolated cardiac phenotypes. Our aim was to estimate the prevalence of FLNC pathogenic variants in subtypes of cardiomyopathies and to study the relations between phenotype and genotype. DNAs from a cohort of 1150 unrelated index-patients with isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 51 cardiomyopathy disease-causing genes. An FLNC pathogenic variant was identified in 28 patients corresponding to a prevalence ranging from 1% to 8% depending on the cardiomyopathy subtype. Truncating variants were always identified in patients with dilated cardiomyopathy, while missense or in-frame indel variants were found in other phenotypes. A personal or family history of sudden cardiac death (SCD) was significantly higher in patients with truncating variants than in patients carrying missense variants (P = .01). This work reported the first observation of a left ventricular non-compaction associated with a unique probably causal variant in FLNC which highlights the role of FLNC in cardiomyopathies. A correlation between the nature of the variant and the cardiomyopathy subtype was observed as well as with SCD risk.

FLNC mutations in patients with cardiomyopathies: Prevalence and genotype-phenotype correlations

Mutations in FLNC encoding filamin C have been firstly reported to cause dominant myofibrillar and distal myopathy. More recently, dominant pathogenic variants in FLNC have also been linked to the development of isolated cardiac phenotypes. Only few publications on cohorts with FLNC pathogenic variants are published and the pathophysiology of FLNC-related cardiomyopathy is poorly understood. The aim of this retrospective study is to establish the prevalence of mutation in the FLNC gene in the different subtypes of cardiomyopathies and search for genotype-phenotype associations. DNAs from a cohort of 1150 unrelated index-patients with an isolated cardiomyopathy (700 hypertrophic, 300 dilated, 50 restrictive cardiomyopathies, and 100 left ventricle non-compactions) have been sequenced on a custom panel of 52 cardiomyopathy disease-causing genes. A FLNC pathogenic mutation was identified in 28 patients corresponding to a prevalence ranging from 1 to 8% depending on the cardiomyopathy subtypes. Truncating mutations were always identified in patients with dilated cardiomyopathy, while mis-sense or in-frame mutations were found in other phenotypes. In the cohort, nine patients (32%) were implanted with an automatic defibrillator. In 7 families (25%), history of sudden cardiac death (SCD) before 50 years was reported. A personal or family history of SCD was significantly higher in patients with truncating variants than in patients carrying missense variants ( P = 0.01). Acute heart failure was observed in 7 patients (25%). Four patients died of cardiac cause including 3 from SCD and 1 from heart failure. This work highlights the role of FLNCin studied cardiomyopathy subtypes. A correlation between the type of the mutation and the cardiomyopathy subtype was observed as well as with SCD risk. These new data should be taken into consideration for patient's management and primary prevention of sudden cardiac death.

Mid-ventricular obstructive hypertrophic cardiomyopathy with apical aneurysm: An important subtype of arrhythmogenic cardiomyopathy.

Mid-ventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is an uncommon type of HCM. LV apical aneurysms are present in more than 20% MVOHCM cases and has been identified as an independent predictor of potentially lethal arrhythmic events, including non-sustained or sustained ventricular tachycardia (VT), and ventricular fibrillation (VF), as well as SCD. Although the pathogenesis of LVA remains unknown, but it has been suggested that apical aneurysm may be secondary to the increased after-load and high apical pressure arising from significant pressure gradient of the midventricular obstruction. The scarred rim of the aneurysm and the adjacent areas of LV myocardial fibrosis and consequent apical oxygen-demand mismatch may be responsible for the formation of apical aneurysm. Recent electrophysiologic studies have demonstrated that the aneurysmal rim forms the primary culprit arrhythmogenic substrate for generation of monomorphic ventricular tachycardia leading to SCD, but the clinical significance of the size of aneurysm in relation to SCD remains unsettled. We summarized the clinical features of the patients with MVOHCM and apical aneurysms. Appropriate therapeutic interventions include ICD implantation, and early surgical intervention for gradient relief may be undertaken to relief the MVO.

Happy heart syndrome

A 62-year-old woman with a history of hypertension was brought to the emergency department presenting with acute chest pain for 3 hours. An immediate electrocardiogram showed ST-segment elevation in the...

Yamaguchi syndrome – A pseudoacute coronary syndrome of the young: A case report on apical hypertrophic cardiomyopathy

Yamaguchi syndrome, or apical hypertrophic cardiomyopathy (ApHCM), is a nonobstructive subtype of hypertrophic cardiomyopathy which predominantly affects the left ventricular apex. Due to the nature of its presentation that mimics acute coronary syndrome and also to the unfamiliarity of the condition by some physicians, the diagnosis of ApHCM is frequently missed or delayed. Here, we report a case of a young male who presented with chest pain and breathlessness. His cardiac enzyme was normal and electrocardiogram showed giant negative T-waves. He was treated as unstable angina and was then subjected to a line of diagnostic procedures including coronary angiogram before he subsequently underwent ventriculogram which reveal a characteristic “spade-like” configuration over the left ventricle, in keeping with the diagnosis of ApHCM. The purpose of this case report is to emphasize the importance of keeping ApHCM as one of the differential diagnoses in a young patient presented with chest pain.

Arrhythmogenic Isolated Left Atrial Cardiomyopathy

The atrial structure or substrate of patients with atrial arrhythmias can present very differently, and also, the “phenotype” of the arrhythmia cannot explain these differences. Idiopathic isolated atrial cardiomyopathy is a novel subtype of cardiomyopathy characterized possibly by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia and no systemic, inflammatory, or infiltrative disease. We report a 57-year-old female doctor who presented with recurrent palpitations of 2-week duration and was shown to have normal left ventricular size, function, longitudinal strain, and filling pressures as judged by E/e' ratio and mitral early diastolic Doppler tissue velocities. The study of atria revealed markedly enlarged left atrium (LA), significantly reduced left atrial reservoir strain, and increased LA stiffness index. Frequent atrial ectopy may be manifestation of a structural atrial disease which could be termed arrhythmogenic isolated LA cardiomyopathy.

Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy

BackgroundIdiopathic isolated fibrotic atrial cardiomyopathy (IIF-ACM) is a novel subtype of cardiomyopathy characterized by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia. The mechanisms underlying its pathogenesis are unknown. MethodsAtrium samples were obtained from 3 patients with IIF-ACM via surgical intervention. Control samples were consisted of 3 atrium biopsies from patients with congenital heart disease and normal sinus rhythm, matched for gender, age and basic clinical characteristics. Comparative histology, immunofluorescence staining, electron microscopy and proteomics analyses were carried out to explore the unique pathogenesis of IIF-ACM. ResultsIIF-ACM atria displayed disordered myofibrils, profound fibrosis and mitochondrial damages compared to the control atria. Proteomics profiling identified metabolic pathways as the most profound changes in IIF-ACM. ConclusionsOur study suggested that metabolic changes in the atrial myocardium caused mitochondrial oxidative stress and potential cell damage, which further led to atrial fibrosis and myofibril disorganization, the characteristic phenotype of IIF-ACM.

Prognosis of adult obstructive hypertrophic cardiomyopathy patients with different morphological types after surgical myectomy.

This study aims to assess the impact of morphological type on the prognosis of obstructive hypertrophic cardiomyopathy patients who underwent myectomy. We recruited 469 obstructive hypertrophic cardiomyopathy patients refractory to medicinal treatment who have undergone surgical myectomy at a nationwide referral centre. All patients were divided into 3 groups based on the morphological classification of left ventricular hypertrophy and were followed up by telephone every year. The primary end-points were sudden cardiac death, aborted sudden cardiac death and death due to heart failure or stroke. The secondary end-points were non-fatal cardiovascular events. Typical hypertrophy limited to the basal septum, hypertrophy of the whole ventricular septum and hypertrophy that involved the whole left ventricle were presented in 248 (52.9%), 141 (30.1%) and 80 (17.0%) patients, respectively. During the follow-up of 2.5 ± 1.4 years after myectomy, 10 (2.1%) and 43 (9.2%) patients met the primary end-point and secondary end-points, respectively. The maximal thickness of the ventricular septum, the left ventricular mass and the presence of extensive late gadolinium enhancement were lower in patients with hypertrophy limited to the basal septum than in other patients. Patients with the basal septum hypertrophy showed better survival after myectomy compared with other patients. For the secondary and composite end-points, there was no significant difference between the 3 groups. Patients with hypertrophy limited to the basal septum represented a special clinical subtype of obstructive hypertrophic cardiomyopathy showing better clinical outcomes, while diffuse hypertrophy of the ventricular septum and free wall indicated lower survival after surgical myectomy.

The Cardiomyopathy Registry of the EURObservational Research Programme of the European Society of Cardiology: baseline data and contemporary management of adult patients with cardiomyopathies.

The Cardiomyopathy Registry of the EURObservational Research Programme is a prospective, observational, and multinational registry of consecutive patients with four cardiomyopathy subtypes: hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmogenic right ventricular cardiomyopathy (ARVC), and restrictive cardiomyopathy (RCM). We report the baseline characteristics and management of adults enrolled in the registry. A total of 3208 patients were enrolled by 69 centres in 18 countries [HCM (n = 1739); DCM (n = 1260); ARVC (n = 143); and RCM (n = 66)]. Differences between cardiomyopathy subtypes (P < 0.001) were observed for age at diagnosis, history of familial disease, history of sustained ventricular arrhythmia, use of magnetic resonance imaging or genetic testing, and implantation of defibrillators. When compared with probands, relatives had a lower age at diagnosis (P < 0.001), but a similar rate of symptoms and defibrillators. When compared with the Long-Term phase, patients of the Pilot phase (enrolled in more expert centres) had a more frequent rate of familial disease (P < 0.001), were more frequently diagnosed with a rare underlying disease (P < 0.001), and more frequently implanted with a defibrillator (P = 0.023). Comparing four geographical areas, patients from Southern Europe had a familial disease more frequently (P < 0.001), were more frequently diagnosed in the context of a family screening (P < 0.001), and more frequently diagnosed with a rare underlying disease (P < 0.001). By providing contemporary observational data on characteristics and management of patients with cardiomyopathies, the registry provides a platform for the evaluation of guideline implementation. Potential gaps with existing recommendations are discussed as well as some suggestions for improvement of health care provision in Europe.

Plasma osteopontin levels in patients with dilated and hypertrophic cardiomyopathy.

Osteopontin (OPN) is an extracellular matrix glycoprotein that plays arole in avariety of cellular activities associated with inflammatory and fibrotic responses. Increased OPN levels in myocardium and plasma have been demonstrated in patients with dilated cardiomyopathy (DCM). However, nothing is known about OPN levels in patients with hypertrophic cardiomyopathy (HCM). Therefore, the aim of our study was to compare plasma OPN levels in patients with these two most common cardiomyopathies. We examined plasma OPN as well as creatinine, C‑reactive protein (CRP), brain-type natriuretic peptide (BNP), and troponinI levels in 64patients with DCM, 43patients with HCM, and 75control subjects. Transthoracic echocardiography was also performed on all cardiomyopathy patients. Plasma OPN levels were significantly elevated in patients with DCM compared with HCM patients (95± 43 vs. 57± 21 ng/ml; p< 0.001) and control subjects (54± 19 ng/ml; p< 0.001); however, there was no difference between HCM patients and control subjects. New York Heart Association (NYHA) classIII orIV disease was more frequently present in DCM patients than in HCM subjects (44 % vs. 2 %, p< 0.0001). In multivariate analysis, BNP and CRP levels together with NYHA class were found to be significant predictors of plasma OPN levels in DCM patients (p= 0.002, p= 0.029, and p< 0.001 for BNP, CRP, and NYHA, respectively). Plasma OPN levels were associated with overall heart failure severity rather than with specific cardiomyopathy subtype in patients suffering from DCM or HCM, respectively.

Differentially DNA methylation changes induced in vitro by traffic-derived nanoparticulate matter

The cytotoxicity, apoptosis, reactive oxygen species (ROS) and DNA damage induced by the commercial diesel exhaust particulate matter (PM) (SRM2975) with concentrations ranging from 0.1 μg mL−1 to 20 μg mL−1 were assessed in human umbilical vein endothelial cells (HUVECs) in vitro. An epigenetics-wide investigation of DNA methylation profiles was also performed using a new methylation beadchip (Illumina 850 K) to identify the health effects of traffic-derived nanoparticulate matter (nPM) with a concentration of 20 μg mL−1. By characterising its physical and chemical properties, we found that SRM2975 is a highly disordered graphitic structure material with a nanometer dimension and a large surface area. Low levels of traffic-derived nPM (≤10 μg mL−1) induced cell apoptosis and DNA damage as well as increased intracellular ROS levels (p < 0.001). The HUVECs showed a significantly decreased cell viability following their exposure to traffic-derived nPM with a concentration of 20 μg mL−1 (p < 0.001). A total of 149 significant differential methylated probes between the control and traffic-derived nPM treated-cells were identified, among which 86.6% were hypermethylated. A gene ontology (GO) enrichment analysis of differential methylated genes reported that the majority of the enriched GO terms were related to calcium ion and heart muscle, and further Kyoto encyclopaedia of genes and genomes (KEGG) pathway analysis indicated that the top three enriched pathways were involved in three common subtypes of cardiomyopathy. Overall, these results demonstrated that traffic-derived nPM could induce cytotoxic effects and demonstrate robust associations with cardiomyopathy though differential DNA methylation as well as the physiologic process of ROS, oxidative stress, inflammation, cell death and calcium ion channel.

Dilated Cardiomyopathy: Genetic Determinants and Mechanisms.

Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subtypes. Moreover, cascade genetic testing in family members can identify those who are at risk or with early stage disease, offering the opportunity for early intervention. This review will address diagnosis and management of DCM, including the role of genetic evaluation. We will also overview distinct genetic pathways linked to DCM and their pathogenetic mechanisms. Historically, cardiac morphology has been used to classify cardiomyopathy subtypes. Determining genetic variants is emerging as an additional adjunct to help further refine subtypes of DCM, especially where arrhythmia risk is increased, and ultimately contribute to clinical management.

Clinical genetic testing in pediatric cardiomyopathy: Is bigger better?

For clinical genetic testing of cardiomyopathy (CMP), current guidelines do not address which gene panels to use: targeted panels specific to a CMP phenotype or expanded (panCMP) panels that include genes associated with multiple phenotypic subtypes. Our objective was to assess the clinical utility of targeted versus panCMP panel testing in pediatric CMPs. 151 pediatric patients with primary hypertrophic (n = 66), dilated (n = 64), restrictive (n = 8), or left-ventricular non-compaction (n = 13) CMP who underwent clinical genetic panel testing at a single centre were included. PanCMP (n = 47) and targeted panel testing (n = 104) were compared for yield of pathogenic variants and variants of unknown significance (VUS). Pathogenic variants were identified in 26% of patients, 42% had indeterminate results (only VUS detected), and 32% had negative results. Yield was lower (15%) in panCMP vs. targeted panel testing (32%) (P = .03) in all CMP subtypes. VUS detection was higher with panCMP (87%) than targeted panel testing (30%) (P <.0001). PanCMP panel testing only identified pathogenic variants in genes that overlapped targeted panels. PanCMP testing did not increase diagnostic yield compared to targeted panel testing. Until accuracy of variant interpretation with panCMP panels improves, targeted panels may be suitable for clinical testing in pediatric CMP.

Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics

Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM.

Prognostic Significance of Non-Dilated Left Ventricular Size and Mitral Regurgitation in Patients With Dilated Phase of Hypertrophic Cardiomyopathy.

Although a subtype of hypertrophic cardiomyopathy (HCM), dilated phase of HCM (D-HCM) characterized by left ventricular (LV) systolic dysfunction, has been reported to have a poor prognosis, some patients with D-HCM survive for a relatively long period. The degree of LV dilatation and functional mitral regurgitation (MR) are generally thought to be important predictors of poor prognosis in patients with LV systolic dysfunction. However, there is little information available on the relations among LV size, presence of significant MR, and prognosis in D-HCM patients.We retrospectively studied 31 patients with D-HCM to determine whether echocardiographic assessment of LV size and MR provides incremental prognostic information.During a follow-up period of 5.6 ± 4.2 years, there were 13 cardiovascular deaths. When the patients were divided into two groups by LV size at diagnosis of D-HCM, a non-dilated LV group (LV end-diastolic diameter (LVEDD) < 50 mm, n = 9) and a dilated LV group (LVEDD ≥ 50 mm, n = 22), the clinical course in the non-dilated LV group was significantly worse. As for the clinical impact of MR, no patient in the non-dilated LV group showed significant MR and 7 of the patients with dilated LV size showed significant MR during follow-up. Once significant MR was reached, cardiovascular deaths were significantly more frequent in patients with MR.Patients with D-HCM, particularly those with less LV dilatation at diagnosis of dilated phase and with significant MR during follow-up, have a poor prognosis.

Insights into mildly dilated cardiomyopathy: temporal evolution and long-term prognosis.

Mildly dilated cardiomyopathy (MDCM) has been proposed as a subtype of dilated cardiomyopathy (DCM) characterized by systolic dysfunction in the absence of significant LV dilatation. Few data on the characteristics and outcomes of MDCM patients are available. We sought to assess the main features and the long-term natural history of MDCM. From 1988 to 2010 we analysed all DCM patients consecutively evaluated at our Institution. MDCM was defined as LVEF <45% and LV end-diastolic volume index (LVEDVI) ≤70 mL/m2 in women and ≤89 mL/m2 in men. Among a total population of 638 patients, 226 (35%) fulfilled the criteria for MDCM. Compared with the other patients, they presented features of a less advanced disease and an overall long-term lower rate of all-cause mortality/heart transplantation (D/HTx; total events = 209; 144 deaths, 65 HTx): D/HTx at 10 years 15% in MDCM vs. 30% in DCM (P < 0.001). However, throughout the follow-up, 55 MDCM patients (24%) evolved to DCM by increasing LVEDVI, consistently worsening their long-term prognosis. Among persistent MDCM patients, a restrictive filling pattern [hazard ratio (HR) 5.30; 95% confidence interval (CI) 2.34-12.01, P < 0.001] and non-sustained ventricular tachycardia (HR 2.21; 95% CI 1.003-5.11, P = 0.047), but not LVEF, were independently associated with D/HTx at multivariate analysis [time-dependent receiver operating characteristic (ROC) curve: area under the curve (AUC) 0.80, 95% CI 0.65-0.94, P = 0.003]. MDCM identifies a consistent subgroup of DCMs diagnosed in an earlier stage and presenting an apparent better evolution. However, some MDCMs evolve into DCM despite medical therapy, whereas persistent MDCMs with non-sustained ventricular arrhythmias and restrictive filling pattern are characterized by a very poor outcome.

Abstract 19585: Overestimation of Functional Cardiomyopathy Disease Variants in the Human Gene Mutation Database

Introduction: Dilated cardiomyopathy (DM), hypertrophic cardiomyopathy (HCM), and arryhmogenic right ventricular dysplasia (ARVD) have been associated with germline genetic variants. However, uncertainty exists regarding the functional impact of specific variants described in the literature. Hypothesis: We hypothesized that a substantial fraction of presumed casual variants would be identified as non-disease causing in a normal patient population. Methods: Missense variants associated with three main subtypes of cardiomyopathy were extracted from Human Gene Mutation Database Professional (HGMD). To assess the prevalence and pathogenicity of these potential disease-causing alleles, the population frequency of each variant was screened in a recently published large-scale exome database of over 60,000 whole exomes (ExAC). In addition, PolyPhen-2 was used to predict the functional impact of amino acid substitution for each missense variant. Results: In the HGMD, 1,405 missense variants were associated with cardiomyopathy, of which 25% were found in 2 or more samples in the ExAC database. Specifically 121 of 422 (28.7%) DM associated variants, 201 variants of 900 (22.3%) HCM associated variant, and 40 of 83 ARVD (48.2%) associated variants were observed in the ExAC database. Polyphen predicted 331 (23.9%) of variants as benign, 290 (20.6%) as possibly damaging, and 784 (55.8%) as probably damaging. Table 1 presents disease specific Polyphen results. Conclusions: We observed that a large proportion (25-45%) of cardiomyopathy-associated missense variants predicted as being damaging were indistinguishable from the background in ExAC. Using stringent cutoffs derived from these observations, we estimated more than 50% of previously associated cardiomyopathy variants may be non-functional or non-monogenic causes of cardiomyopathy.

Association of Cardiomyopathy With Adverse Cardiac Events in Pregnant Women at the Time of Delivery

ObjectivesThe aim of this study was to determine the predictors of adverse events in pregnant women with cardiomyopathy (CDM) and CDM subtypes at the time of delivery. BackgroundInvestigation of patients’ characteristics and outcomes in women with CDM at the time of delivery has been limited. MethodsThe Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with CDM from 2006 to 2010. Clinical characteristics and maternal outcomes were identified in women with and without CDM and in CDM subtypes. The primary outcome of interest was major adverse clinical events (MACE), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, or embolic event. ResultsOur study population comprised 2,078 patients with CDM and 4,438,439 patients without CDM. Of those with CDM, 52 (2.5%) were hypertrophic, 1,039 (50.0%) were peripartum, and 987 (47.5%) were classified as other. Women with CDM were older, white, and insured by Medicaid. MACE rates were significantly higher in women with peripartum CDM (46%), compared with hypertrophic CDM (23%) and all others (39%) (p < 0.001). In multivariable analysis, the presence of peripartum cardiomyopathy (odds ratio [OR]: 2.2; 95% confidence interval [CI]: 1.1 to 4.6), valvular disease (OR: 2.11; 95% CI: 1.6 to 2.9), and eclampsia (OR: 5.0; 95% CI: 1.6 to 1.9) was independently associated with MACE. ConclusionsPresence of CDM is independently predictive of MACE during hospitalization for delivery. Patients with peripartum CDM had the highest likelihood of MACE compared with other CDM subtypes.