Etiology Of Dilated Cardiomyopathy Research Articles

Diverse Concepts in Definitions of Dilated Cardiomyopathy: Theory and Practice.

Our understanding of dilated cardiomyopathy (DCM) is evolving as new insights into the underlying pathophysiology become available. Professional organizations and clinical experts are improving definitions of DCM, allowing for more accurate treatment recommendations. This review summarized key published literature describing definitions and/or diagnostic criteria for DCM. Embase was searched from database inception to September 19, 2022 for 1) publications reporting definitions of DCM by major professional organizations and related opinion papers, and 2) clinical studies in DCM and heart failure with reduced ejection fraction. Sixty-eight records were included in this review. Definitions of DCM provided by two major professional organizations (American Heart Association (AHA) and European Society of Cardiology (ESC)) agreed on the clinical presentation of DCM; however, they differed in the classification of DCM within the larger context of cardiomyopathy taxonomies. Both organizations agreed that DCM could be clinically defined by the presence of left ventricular dilation and contractile dysfunction in the absence of abnormal loading conditions and severe coronary artery disease. AHA guidelines divided cardiomyopathies into two major groups (primary and secondary) based on predominant organ involvement. DCM was classified as primary cardiomyopathy with mixed (genetic and/or acquired) etiology. Conversely, ESC published a clinically oriented taxonomy in which cardiomyopathies were grouped into specific morphological and functional phenotypes; each was subclassified into familial or non-familial forms. Opinion papers further elaborated on the complex interplay between genetics and environment in the etiology of DCM. Several articles summarized the importance of the new and updated diagnostic tools, such as cardiac magnetic resonance imaging, electrocardiogram, and other biomarkers, in correctly identifying the etiology of DCM. Within clinical studies, most inclusion criteria used standard definitions proposed by leading professional associations (AHA and ESC). Clinical study investigators sometimes used a narrower definition of DCM using additional criteria for the left ventricular ejection fraction threshold value and left ventricular dilatation. Current efforts in cardiology research are focused on a more granular understanding of DCM etiology and the natural history of the disease. Definitions of DCM found in clinical studies mainly rely on published guidelines, with some studies adding idiosyncratic inclusion criteria refining the broad definitions of DCM.

Long-Term Outcomes in ICD: All-Causes Mortality and First Appropriate Intervention in Ischemic and Nonischemic Etiologies

Real-life data comparing the long-term outcome in patients with different heart diseases carrying an implantable cardioverter defibrillator (ICD) are scarce. This study aimed to compare the long-term risk of the first appropriate ICD intervention and overall survival in patients with ICD and heart disease of different etiologies. Patients with an ICD implanted between January 1, 2010, and December 31, 2022, followed in our center were included. Study outcomes were all-cause mortality and first appropriate ICD intervention. A comparison between ischemic heart disease (IHD) and non-IHD (NIHD) was performed. In NIHD different etiologies of dilated cardiomyopathy (DCM) were analyzed. Overall, 1184 patients (592 IDH; 592 NIHD) were included. During a median follow-up of 53 months all-cause death occurred in 399 patients (34%) whereas first appropriate ICD intervention occurred in 320 (27%). All-cause mortality was significantly higher in IHD vs NIHD patients (60% vs 43%; p <0.0001) but no differences in appropriate ICD intervention rate at 10 years (34% vs 40%; p = 0.125) were observed. In patients with NIHD, a higher 10-year mortality rate was found in valvular heart disease, post-radio/chemotherapy DCM (rctDCM), and hypertensive DCM. Hypertrophic cardiomyopathy, alcoholic DCM, and rctDCM were the least arrhythmic phenotypes in NIHD. Of note, inappropriate interventions in alcoholic DCM and rctDCM were higher than appropriate ones. In conclusion, the rate of ICD-appropriate interventions and mortality is different according to the etiology of heart disease and cardiovascular risk profile; this should be taken into consideration in the prognostic stratification of these patients at the time of implantation.

Exploring the etiology of dilated cardiomyopathy using Mendelian randomization.

Observational clinical studies suggest an association between dilated cardiomyopathy (DCM) and various factors including titin, cardiac troponin I (CTnI), desmocollin-2, the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency. The causal nature of these associations remains uncertain. This study aims to explore these correlations using the Mendelian randomization (MR) approach. To investigate the etiology of DCM through Mendelian randomization analysis. Data mining was conducted in genome-wide association study databases, focusing on variant target proteins (titin, CTnI, desmocollin-2), the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, and renal insufficiency, with DCM as the outcome. The analysis employed various regression models, namely, the inverse-variance weighted (IVW), MR-Egger, simple mode, weighted median, and weighted mode methods. The IVW results showed a correlation between titin protein and DCM, identifying titin as a protective factor [OR = 0.856, 95% CI (0.744-0.985), P = 0.030]. CTnI protein correlated with DCM, marking it as a risk factor [OR = 1.204, 95% CI (1.010-1.436), P = 0.040]. Desmocollin-2 also correlated with DCM and was recognized as a risk factor [OR = 1.309, 95% CI (1.085-1.579), P = 0.005]. However, no causal relationship was found between the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, renal insufficiency, and DCM (P > 0.05). The MR-Egger intercept test indicated no pleiotropy (P > 0.05), affirming the effectiveness of Mendelian randomization in causal inference. Titin, CTnI, and desmocollin-2 proteins were identified as independent risk factors for DCM. Contrasting with previous observational studies, no causal relationship was observed between DCM and the perinatal period, alcoholism, Behçet's disease, systemic lupus erythematosus, hyperthyroidism and thyrotoxicosis, hypothyroidism, carnitine metabolic disorder, or renal insufficiency.

Familial Profile of Pediatric and Adult Patients With Congenital Heart Disease in Heart Transplantation

Congenital heart disease represents the most common birth defect and heart transplantation is the main treatment of choice. As genetic causes can be identified in a considerable proportion of cases, investigation of possible family cardiac history is essential. The objective of this work is to analyze the profile of transplant patients in terms of family history of heart disease.This is a single-center retrospective study with the inclusion of pediatric heart transplant patients from 2013 to 2023 at a tertiary hospital. Out of the 170 patients, 13 patients were identified with a family history relevant to congenital heart disease. The presence of pediatric transplant patients with a family history of cardiology was observed, with emphasis on the etiology of dilated cardiomyopathy and the occurrence of the same heart disease in siblings. Thus, the results can impact the management of cases of congenital heart disease.

Abstract P160: Prevalence of Genetic Dilated Cardiomyopathy: A Systematic Literature Review

Background: Dilated cardiomyopathy (DCM) is a leading cause of heart failure and cardiac transplantation worldwide. Many cases of DCM are due to genetic or idiopathic etiology. Two prominent contributors to genetic DCM (gDCM) are the TTN and MYH7 genes, which encode proteins associated with DCM etiology. Purpose: This study aimed to synthesize the published literature on the global prevalence of adult and pediatric gDCM within the clinical DCM population and the general population. Methods: A systematic review was conducted by searching MEDLINE® and Embase from database inception to 09/19/2022. We included observational studies reporting the prevalence of gDCM within any population; prevalence of TTN and MYH7 mutations were also extracted. Excluded were studies using family history as a proxy for gDCM. Median with interquartile range (IQR) or mean with standard deviation (SD) weighted by sample size (in cases of calculations with &lt;10 studies) were used to summarize the data. Results: Of 2,720 identified abstracts, 57 studies were included in the review. Among the adult or mixed (adults and children) DCM population in any country, median prevalence was 21.0% for overall DCM-related genetic mutations, 11.4% for TTN mutations, and 3.2% for MYH7 mutations ( Table ). The prevalence of pediatric gDCM within the DCM population was similar (weighted mean: 21.3%). Data on prevalence of gDCM within the general population were scarce. Conclusion: This study highlights the variable prevalence of gDCM reported across different populations and settings. The current evidence may underestimate the genetic causes due to technical limitations in genetic testing and limited screening. Accurately determining the prevalence of gDCM is critical for identifying high-risk populations, developing targeted prevention strategies for disease complications, and improving outcomes; epidemiological studies using long-read sequencing techniques and large cohort datasets with genotype-phenotype correlation analyses are needed.

DILATED CARDIOMYOPATHY IN SLENDER-TAILED MEERKATS (SURICATA SURICATTA) UNDER HUMAN CARE.

Meerkats (Suricata suricatta) housed at two accredited zoological institutions in the United States were evaluated via echocardiography, thoracic radiography, and blood biomarkers-taurine and feline N-terminal pro-B-type natriuretic peptide-to determine the prevalence and severity of dilated cardiomyopathy (DCM) in both populations. In total, 24 meerkats were evaluated and 7 were diagnosed with DCM based on the following parameters: left ventricular internal diameter at end diastole > 1.30 cm, left ventricular internal diameter at end systole > 1.10 cm, and a fractional shortening of <18%. Echocardiographic parameters were identified and reported for normal and affected meerkats, whereas thoracic radiographs were not useful for screening for DCM. Meerkats with DCM were treated with pimobendan and/or benazepril and furosemide if indicated. Seven meerkats died during the study period, with the majority exhibiting myocardial fibrosis. Of the blood parameters tested, elevated taurine levels were associated with DCM. Further research is necessary to characterize the etiology of DCM in meerkats.

Genetic Characterization of Dilated Cardiomyopathy in Romanian Adult Patients.

Dilated cardiomyopathy (DCM) represents a group of disorders affecting the structure and function of the heart muscle, leading to a high risk of heart failure and sudden cardiac death (SCD). DCM frequently involves an underlying genetic etiology. Genetic testing is valuable for risk stratification, treatment decisions, and family screening. Romanian population data on the genetic etiology of DCM are lacking. We aimed to investigate the genetic causes for DCM among Romanian adult patients at tertiary referral centers across the country. Clinical and genetic investigations were performed on adult patients presenting to tertiary hospitals in Romania. The genetic investigations used next-generation sequencing panels of disease-associated DCM genes. A total of 122 patients with DCM underwent genetic testing. The mean age at DCM diagnosis was 41.6 ± 12.4 years. The genetic investigations identified pathogenic or likely pathogenic variants in 50.8% of participants, while 25.4% had variants of unknown significance. Disease-causing variants in 15 genes were identified in people with DCM, with 31 previously unreported variants. Variants in TTN, LMNA, and DSP explained 75% of genetic causes for DCM. In total, 52.4% of patients had a family history of DCM/SCD. Left ventricular ejection fraction of <35% was observed in 41.9% of patients with disease-causing variants and 55% with negative or uncertain findings. Further genotype-phenotype correlations were explored in this study population. The substantial percentage (50.8%) of disease-causing variants identified in patients with DCM acknowledges the importance of genetic investigations. This study highlights the genetic landscape in genes associated with DCM in the Romanian population.

Abstract 18860: Molecular Pathways Altered in Pediatric Dilated Cardiomyopathy Hearts Are Dependent on Disease Etiology

Introduction: Dilated cardiomyopathy presents a significant clinical burden in pediatric patients due to limited effective treatment options. This study hypothesizes molecular alterations in the heart of pediatric dilated cardiomyopathy (DCM) patients are dependent on specific etiologies. By understanding the molecular mechanisms underlying different etiologies, we aim to enhance diagnostics and guide future targeted therapies. An advanced understanding of the molecular mechanisms of DCM holds potential to transform pediatric cardiovascular care. Methods: RNA was extracted from the IRB approved University of Colorado's pediatric cardiac tissue bank. Samples included non-failing (NF), idiopathic dilated cardiomyopathy (IDCM), myocarditis, and left-ventricle non-compaction (LVNC) hearts. RNA-seq was performed using the Illumina HiSeq 4000 platform, and aligned using the TOPmed RNA-seq pipeline. Statistical analysis between NF and each etiology was performed to identify fold changes and q-values. Gene expression analysis was further examined using Ingenuity Pathway Analysis (Qiagen). Results: Demographics of patient samples were as follows: NF (N=23, % male=61%, Median age=13.65 years, Interquartile range (IQR)=8.6), IDCM (N=20, % male=55%, Median age=9.83 years, IQR=8.98), myocarditis (N=4, % male=75%, Median age=0.35 years, IQR=0.1), LVNC (N=3, % male=33.3%, Median age=0.27 years, IQR= Undetermined). Comparisons between NF versus IDCM, NF versus myocarditis, and NF versus LVNC hearts revealed noteworthy differences in gene expression patterns. Pathways associated with IDCM related to inflammation and immune response trends, whereas DNA repair and cellular damage were strongly associated with myocarditis. Lastly, analysis of LVNC hearts suggest pathways associated with ischemic remodeling. Conclusions: In conclusion, our study provides insights into gene expression patterns associated with different etiologies of DCM in pediatric patients. Distinct patterns were observed between non-failing and IDCM, myocarditis, or LVNC hearts. These findings have implications for improving diagnostics and guiding targeted therapies in pediatric DCM management.

Investigating the role of NPR1 in dilated cardiomyopathy and its potential as a therapeutic target for glucocorticoid therapy.

Background: Dilated cardiomyopathy (DCM), a specific form of cardiomyopathy, frequently presents clinically with either left ventricular or biventricular enlargement, often leading to progressive heart failure. In recent years, the application of bioinformatics technology to scrutinize the onset, progression, and prognosis of DCM has emerged as a fervent area of interest among scholars globally. Methods: In this study, core genes closely related to DCM were identified through bioinformatics analysis, including weighted gene co expression network analysis (WGCNA) and single sample gene set enrichment analysis (ssGSEA) and so on. The correlation was verified through experiments on DCM patients, DCM rat models, and core gene knockout mice. Subsequently, the effects of glucocorticoids on DCM and the regulation of core genes were observed. Result: In the present study, natriuretic peptide receptor 1 (NPR1) was identified as a core gene associated with DCM through WGCNA and ssGSEA. Significant impairment of cardiac and renal function was observed in both DCM patients and rats, concomitant with a notable reduction in NPR1 expression. NPR1 KO mice displayed symptomatic manifestations of DCM, underscoring the pivotal role of NPR1 in its pathogenesis. Notably, glucocorticoid treatment led to substantial improvements in cardiac and renal function, accompanied by an upregulation of NPR1 expression. Discussion: These findings highlight the critical involvement of NPR1 in the pathophysiology of DCM and its potential as a key target for glucocorticoid-based DCM therapy. The study provides a robust theoretical and experimental foundation for further investigations into DCM etiology and therapeutic strategies.

Obesity Paradox in Heart Failure Revisited: Etiology as Effect Modifier

The prognostic value of overweight/obesity in heart failure (HF) may vary according to HF etiologies. We aim to determine whether body mass index has differential impacts on survival among hospitalized HF patients with varying etiologies. Consecutive hospitalized HF patients between December 2006 and December 2017 were included. Multivariable analyses, including Cox proportional hazard models and restricted cubic splines, were used to investigate the impact of body mass index on mortality by HF etiology. Among the 3,836 patients included (mean age 57.1years, 28.4% women), 1,475 (38.5%) were identified as having ischemic etiology. Of the remaining 2,361 patients with non-ischemic etiologies, dilated cardiomyopathy (DCM) accounted for 45.6% (n=1,077). The rest of the patients were uniformly classified as having non-ischemic-non-DCM HF. The unadjusted data demonstrated an adiposity-related survival paradox in HF across all etiologies. However, the paradox holds only among non-ischemic-non-DCM HF patients after multivariate adjustment, wherein overweight patients exhibit the lowest mortality compared with their normal-weight counterparts (adjusted hazard ratio [aHR] 0.69, 95% confidence interval [CI] 0.52 to 0.91), with a nadir in mortality risk at 28.18kg/m2. Similar survival benefits of overweight were not demonstrated in ischemic or DCM HF patients (ischemic etiology: aHR 1.07, 95% CI 0.84 to 1.36; DCM etiology: aHR 0.97, 95% CI 0.74 to 1.28). In conclusion, being overweight or obese does not confer better survival in HF patients of ischemic or DCM etiology, and the prognostic benefit of being overweight is maintained only in non-ischemic-non-DCM HF patients. Pathophysiologic interpretations are warranted, and whether patients of certain etiologies would benefit from weight reduction needs to be explored.

Causes and ways of detection of dilated cardiomyopathy and hypertrophic cardiomyopathy

Inherited cardiomyopathy has a wide variety and complex symptoms, which can cause a severe burden on the patient's family. Researchers have done a lot of research on inherited cardiomyopathy. Among the five inherited cardiomyopathy under the current classification standard, hypertrophic cardiomyopathy and dilated cardiomyopathy are two of the more in-depth studies. Researchers have now identified many of the genes responsible for the two most familiar forms of cardiomyopathy. The pathogenic factors of hypertrophic cardiomyopathy mainly concentrate on the two gene mutations of MYBPC3 and MYH7, and others are fairly rare. The etiology of dilated cardiomyopathy is more complex. LMNA gene variants are relatively common in familial dilated cardiomyopathy. Also, MYH7 and TNNT2 variants are more common causes of this condition. In addition, the researchers discovered part of the pathogenic mechanism of the two diseases and achieved different results of the clinical detection methods and etiological detection methods of the diseases. In clinical testing, myocardial biopsy is still the gold standard, and electrocardiography and echocardiography are widely utilized as clear indicators. In terms of etiology detection, two generations of genetic testing methods with their advantages and disadvantages, but with an accuracy rate higher than 95% have been put into use. This article summarizes information about the two diseases the authors read, including basic information on cardiomyopathy, the gene-level etiology of hypertrophic and dilated cardiomyopathy, and the role of gene sequencing in disease detection, as well as several commonly available methods for the detection of both types of cardiomyopathy.

Genome-wide fetalization of enhancer architecture in heart disease.

SUMMARYHeart disease is associated with re-expression of key transcription factors normally active only during prenatal development of the heart. However, the impact of this reactivation on the regulatory landscape in heart disease is unclear. Here, we use RNA-seq and ChIP-seq targeting a histone modification associated with active transcriptional enhancers to generate genome-wide enhancer maps from left ventricle tissue from up to 26 healthy controls, 18 individuals with idiopathic dilated cardiomyopathy (DCM), and five fetal hearts. Healthy individuals have a highly reproducible epigenomic landscape, consisting of more than 33,000 predicted heart enhancers. In contrast, we observe reproducible disease-associated changes in activity at 6,850 predicted heart enhancers. Combined analysis of adult and fetal samples reveals that the heart disease epigenome and transcriptome both acquire fetal-like characteristics, with 3,400 individual enhancers sharing fetal regulatory properties. We also provide a comprehensive data resource (http://heart.lbl.gov) for the mechanistic exploration of DCM etiology.

Gene module regulation in dilated cardiomyopathy and the role of Na/K-ATPase.

Dilated cardiomyopathy (DCM) is a major cause of cardiac death and heart transplantation. It has been known that black people have a higher incidence of heart failure and related diseases compared to white people. To identify the relationship between gene expression and cardiac function in DCM patients, we performed pathway analysis and weighted gene co-expression network analysis (WGCNA) using RNA-sequencing data (GSE141910) from the NCBI Gene Expression Omnibus (GEO) database and identified several gene modules that were significantly associated with the left ventricle ejection fraction (LVEF) and DCM phenotype. Genes included in these modules are enriched in three major categories of signaling pathways: fibrosis-related, small molecule transporting-related, and immune response-related. Through consensus analysis, we found that gene modules associated with LVEF in African Americans are almost identical as in Caucasians, suggesting that the two groups may have more common rather than disparate genetic regulations in the etiology of DCM. In addition to the identified modules, we found that the gene expression level of Na/K-ATPase, an important membrane ion transporter, has a strong correlation with the LVEF. These clinical results are consistent with our previous findings and suggest the clinical significance of Na/K-ATPase regulation in DCM.

Ultrastructural Changes in Mitochondria in Patients with Dilated Cardiomyopathy and Parvovirus B19 Detected in Heart Tissue without Myocarditis.

Understanding the meaning of parvovirus B19 (PB19V) in an etiology of dilated cardiomyopathy (DCM) is difficult. Viruses change the dynamics of the mitochondria by interfering with the mitochondrial process/function, causing the alteration of mitochondrial morphology. In this study, the ultrastructural changes in the mitochondria in endomyocardial biopsy (EMB) samples from patients with DCM and PB19V were determined. Methods: The PB19V evaluation was performed in EMB specimens by real-time PCR in 20 patients (age: 28 ± 6 years). The biopsy specimens were examined by histo- and immunohistochemistry to detect the inflammatory response. The ultrastructural features of the mitochondria were evaluated by electron microscopy. Results: The presence of PB19V in the heart tissue without the presence of inflammatory process, defined according to Dallas and immunohistochemical criteria, was associated with ultrastructural changes in the mitochondria. Distinctive ultrastructural pathologies were indicated, such as the presence of mitochondria in the vicinity of the expanded sarcoplasmic reticulum with amorphous material, blurred structure of mitochondria, interrupted outer mitochondrial membrane and mitophagy. Conclusions: Extending diagnostics with ultrastructural analysis of biopsy samples provides new knowledge of the changes associated with the presence of PB19V in the heart tissue. The observed changes can be a basis for searching for the damage mechanisms, as well as for new therapeutic solutions.

The benefit of genetic testing using next-generation sequencing in patients with dilated cardiomyopathies: A multicentric international study

Over the past several years, genetic testing has emerged as an essential tool in the etiological study of dilated cardiomyopathy (DCM). Being able to pinpoint the etiology of DCM may lead to a specific individualized treatment, besides the prognostic and family implications, if a genetic cause is identified. Discovery of new genes, alongside improvements in genetic sequencing, implies a higher benefit than previously reported. Determining and quantifying the current yield of genetic studies in an international cohort of patients with DCM. Observational study of retrospective cohorts in two university hospitals (France and Spain). All genetic panels indicated in the study of DCM, carried out between December 2018 and December 2020, have been reviewed. Both centers have used the next-generation sequencing technique, involving panels of 80 and 83 genes, depending on the availability in each center. The encountered variants were classified by each center as: benign, of uncertain significance or disease-causing (DCV). 79 patients have undergone genetic testing. Mean age was of 52 years, with 29% of females. One quarter of the patients had family history of DCM. A cardiac magnetic resonance imaging (CMRI) was performed in 72%. In 54% of the cases ( n = 43), a mutation was found, giving rise to 64 variants, of which 51% were described as DCV ( n = 33, 42% of the total cohort– Fig. 1 ). More than half (54%) of the DCV concerned genes encoding the titin, myosin binding protein C, and filamin C. We identified a DCV in 8/14 (57%) of patients with family history of DCM and in 15/18 (83%) of patients with late gadolinium enhancement in the CMRI. Our results reflect the current practice of genetic testing, suggesting a higher yield (42%) compared with what is described in literature.

Abstract 13550: Genotype-Phenotype Mismatch of Val122Ile Transthyretin Mutation in Dilated Cardiomyopathy

Introduction: An estimated 3.4% of African Americans carry the Valine 122 Isoleucine (Val122Ile) mutation associated with hereditary transthyretin (TTR) amyloidosis cardiomyopathy (hATTR-CM). Val122Ile is inherited in an autosomal dominant pattern, but penetrance of the clinical disease is variable and incompletely understood. Asymptomatic carriers therefore require screening for phenotypic manifestations of hATTR-CM before initiation of TTR-targeted therapies. Case Description: A 57-year-old African American male with non-ischemic dilated cardiomyopathy (DCM) presented in cardiogenic shock for advanced therapy evaluation. DCM was diagnosed 20 years prior, and family history was pertinent for cardiomyopathy in both parents. Echocardiography on admission revealed severely reduced left ventricular systolic function (EF 10%) with moderate cavitary dilation but no evidence of concentric or septal hypertrophy (LVeDd 6.1 cm, IVSd 0.9 cm, LVPWd 1.0 cm &amp; LVMI 103 g/m 2 ). His family history prompted genetic testing to evaluate hereditary etiologies of DCM. However, his genetic test only revealed a heterozygous Val122Ile mutation. He underwent left ventricular assist device (LVAD) implantation, after which LV apical core biopsy was negative for Congo red staining. Discussion: This case illustrates a clear genotype (Val122Ile) - phenotype (DCM) mismatch. Although positive for the Val122Ile mutation, the lack of Congo red staining on his LV core biopsy rules out cardiac infiltration of mutated TTR amyloid fibrils and instead suggests an entirely independent, idiopathic DCM. The increasing ease and availability of genetic testing, combined with the known high prevalence of the Val122Ile mutation in the African American population will inevitably lead to more cases of genotype-phenotype mismatch. The variable penetrance of this pathogenic mutation (Val122Ile) may lead to inappropriate treatment with TTR-targeted therapies in patients without clear disease, potentially increasing patient and healthcare costs unnecessarily. Further research is needed to understand the variable penetrance of Val122Ile and factors that may predict development of clinical disease in the future.

Abstract 11176: Family Screening in Dilated Cardiomyopathy; Long-Term Incidence and Potential for Limiting Follow-Up

Introduction: Guidelines recommend family screening in dilated cardiomyopathy (DCM) to uncover pre-symptomatic familial DCM (FDC). So far, no guidelines provide specific recommendations on the intensity and frequency of follow-up screening. This study sought to provide the first detailed estimates of the incidence of FDC during follow-up and identify baseline markers which could inform future follow-up of relatives. Methods: The study was a retrospective, observational, longitudinal cohort study of relatives to DCM probands screened at a regional assembly of family screening clinics in Copenhagen, Denmark, from 2006 to 2020. Results: In total, 563 relatives (50% women) from 211 families were included. At baseline, 124 relatives (22%) were diagnosed with FDC: 97 (18%) as a result of screening and 27 (5%) with symptom-onset prior to screening. Genetic sequencing identified the etiology of DCM in 35% of families and classified 90 relatives (17%) as unaffected carriers (n=44) or relatives not at risk of FDC (n=46). As such, the combined clinical and genetic baseline-yield was 31%. In 439 relatives considered unaffected at baseline, 45 (10%) were diagnosed with FDC during follow-up (median 5.0 years). The age-standardized incidence rate of FDC was 2.0% per person-year [CI: 1.4-2.8%] with higher rates in men vs women (3.0% vs 1.4% per person-year). In relatives without predictive genetic findings (n=349), non-diagnostic abnormal baseline-findings on ECG or echocardiography was associated with a higher incidence rate of FDC (figure A), while the risk was low in relatives with normal findings (0.4% vs 4.7% per person-year; figure B). Conclusion: Systematic family screening identified FDC or genetic predisposition to FDC in 1 out of 3 relatives at baseline. Relatives without predictive genetic findings and with normal findings on ECG and echocardiography at baseline had a low risk of developing FDC. Follow-up can be limited and may not be warranted in these relatives.

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing — involving genetics, imaging, or cardiovascular techniques — makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case–control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker.Key messagesThe limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM).The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies.Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters.We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

Echocardiographic assessment of dilated cardiomyopathy in dogs

Dilated cardiomyopathy (DCM) is a frequent cause of cardiac disability, congestive heart failure (CHF), and arrhythmic death in dogs. The etiology of DCM is usually idiopathic/genetic, but some causes of a DCM phenotype are reversible. The disease is classified into preclinical (occult) and clinical (overt) stages; the latter stems from heart failure with reduced ejection fraction. DCM is further characterized by clinical, electrocardiographic, circulating biomarker, and imaging abnormalities. The diagnosis of clinical DCM with CHF is straightforward; however, identification of the preclinical stage can be challenging. Echocardiography is central to the diagnosis of both stages and characterized by left ventricular (LV) systolic dysfunction with progressive chamber dilation and variable enlargements of the left atrium and right-sided chambers. Left ventricular dilation is defined by increased LV end-diastolic volumes, areas, and internal dimensions normalized to body size or indexed to the aorta. Systolic dysfunction is characterized by decreased LV ejection fraction, increased end-systolic volume, and reduced shortening across minor and longitudinal LV axes. Dyssynchrony can confound the interpretation of linear indices of systolic function. A comprehensive echocardiogram in DCM includes two-dimensional and M-mode studies, spectral and tissue Doppler imaging, and potentially three-dimensional echocardiography and myocardial strain imaging. Echocardiographic findings should be interpreted within the context of identifiable risks and comorbidities, physical diagnosis, complementary diagnostic testing, and limitations of current reference intervals. Ambiguous examinations should be repeated. Specific echocardiographic criteria for the diagnosis of DCM are proposed to encourage discussion and additional outcome and breed-specific echocardiographic studies of canine DCM.

Phenotype and progression among patients with dilated cardiomyopathy and RBM20 mutations

BackgroundOver 70 genes that encode different cell components have been involved in the aetiology of dilated cardiomyopathy. Genotype-phenotype interactions are an unsolved problem, and to a large extent the effects of mutations in the expression mechanisms involved in the disease remain unknown, although associations are increasingly being established which have clinical and prognostic implications. Methods and resultsThe objective of our work was to describe our population that has cardiomyopathy associated with mutations in the gene RBM20, and study the genotype-phenotype relationship. We studied 8 cases undergoing follow-up at our Unit, and collected data for demographic, clinical and diagnostic testing variables. The mean age on diagnosis was 55 years [52–59], with a median follow-up of 31.5 months [26.0–67.3]. It is worth noting that 62.5% of the patients in our group had a history of cardiomyopathy in first degree relatives, and 37.5% of them had a family history of sudden death. One of the genetic variations of the sample was shared by three subjects who had no apparent family relationship with each other, and this variation had not been described in controls. It is also interesting that arrhythmic events were found in 37.5% of the sample, and 50% of patients had an indication for implantable cardiac defibrillator. ConclusionThis is the first analysis of patients with RBM20 mutations conducted in our country, and it indicates a profile with prominent arrhythmogenesis, a high penetrance of familial cardiomyopathy, and sudden death.