Continuous Spinal Anesthesia for Labor Analgesia and Cesarean Delivery in a Parturient With Familial Dilated Cardiomyopathy: A Case Report.

We report a case of successful continuous spinal anesthesia (CSA) for labor analgesia and cesarean delivery in a patient with familial dilated cardiomyopathy (DCM). A 33-year-old pregnant woman diagnosed with DCM was scheduled for a vaginal delivery under labor analgesia. An accidental intrathecal catheter was placed, and labor analgesia was provided by CSA. The vaginal delivery was converted to a cesarean delivery, and an intrathecal catheter was used for transition, which avoided hemodynamic changes and allowed the patient to safely undergo cesarean delivery. CSA is a reliable and rapidly titratable technique that provides excellent analgesia without hemodynamic changes in patients with DCM undergoing labor analgesia and subsequent cesarean delivery.

Cardiac MRI after Sudden Cardiac Arrest in a Young Woman Prompts Diagnosis of Familial Dilated Cardiomyopathy.

Teaching Point: Familial dilated cardiomyopathy (DCM) predisposes to malignant ventricular arrhythmias and sudden cardiac death, and magnetic resonance imaging (MRI) has important diagnostic value in demonstrating non-ischemic patterns of late gadolinium enhancement (LGE).

Cardiovascular Magnetic Resonance Imaging in Familial Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is a common cause of non-ischaemic heart failure, conferring high morbidity and mortality, including sudden cardiac death due to systolic dysfunction or arrhythmic sudden death. Within the DCM cohort exists a group of patients with familial disease. In this article we review the pathophysiology and cardiac imaging findings of familial DCM, with specific attention to known disease subtypes. The role of advanced cardiac imaging cardiovascular magnetic resonance is still accumulating, and there remains much to be elucidated. We discuss its potential clinical roles as currently known, with respect to diagnostic utility and risk stratification. Advances in such risk stratification may help target pharmacological and device therapies to those at highest risk.

The genetic basis for adult-onset idiopathic dilated cardiomyopathy in people of African descent.

Cardiomyopathies are a heterogeneous group of cardiac muscle disorders that result in dilated, hypertrophic, or restrictive pathophysiological entities. Dilated cardiomyopathy (DCM) is the most common form in sub-Saharan Africa (SSA). However, population-specific research studies reporting the actual burden of DCM in this region are still lacking. Also, little is known about the genetic basis of DCM in this population, and genetic testing is still not readily accessible. This review describes the common pathogenic genes implicated in DCM globally and discusses the evidence-based management of patients with DCM. We also present a summary of studies describing genes implicated or associated with DCM in patients residing in SSA.

Compound Heterozygous Missense Variants in RPL3L Genes Associated with Severe Forms of Dilated Cardiomyopathy: A Case Report and Literature Review.

Whole exome sequencing has identified an infant girl with fulminant dilated cardiomyopathy (DCM), leading to severe acute heart failure associated with ribosomal protein large 3-like (RPL3L) gene pathologic variants. Other genetic tests for mitochondrial disorders by sequence analysis and deletion testing of the mitochondrial genome were negative. Secondary causes for DCM due to metabolic and infectious etiologies were ruled out. She required a Berlin-Excor left ventricular assist device due to worsening of her heart failure as a bridge to orthotopic heart transplantation. At three months follow-up after heart transplantation, she has been doing well. We reviewed the literature on published RPL3L-related DCM cases and their outcomes. Bi-allelic variants in RPL3L have been reported in only seven patients from four unrelated families in the literature. RPL3L is a newer and likely pathogenic gene associated with a severe form of early-onset dilated cardiomyopathy with poor prognosis necessitating heart transplantation.

Case Report: A novel desmoplakin mutation in a taiwanese woman with familial dilated cardiomyopathy that necessitated heart transplantation.

Around one-third of patients diagnosed with idiopathic dilated cardiomyopathy (DCM) turn out to be familial cases, in only a few of which the identification of a pathogenic/likely pathogenic variant could be achieved. Cardiomyopathy caused by desmoplakin gene mutations represents a distinct form with a high prevalence of left ventricle involvement. We report a novel desmoplakin mutation carried by two individuals in a Taiwanese family, in which the proband recovered well after heart transplantation and under medical control, while her son had received an implantable cardioverter defibrillator and has been under guideline-directed medical therapy. The present study broadens the genetic spectrum of this disease entity and strengthens the notion that a detailed family history with genetic study contributes to the early detection and treatment of inherited diseases.

Genetic Testing as a Guide for Treatment in Dilated Cardiomyopathies.

PURPOSE OF REVIEW: Dilated cardiomyopathy (DCM) is one of the most prevalent primary cardiomyopathies and may be caused by genetic and non-genetic etiologies. DCM may also be the final common pathway of other cardiomyopathies such as hypertrophic, arrhythmogenic, or non-compaction cardiomyopathy. We review the main DCM genetic substrates, specific genotype-phenotype aspects, the role of genetic testing in risk stratification, and advances regarding genotype-based precision medicine. RECENT FINDINGS: Performing a comprehensive genetic study could have a diagnostic yield up to 40% in DCM, and it is considered a cost-effective approach nowadays. The detection of a specific underlying genetic substrate explaining the disease can have important consequences for clinical management, especially for familial cascade screening, optimizing medical treatment, and improving the arrhythmic risk stratification. The identification of the genetic substrate underlying dilated cardiomyopathy makes possible the genotype-phenotype correlation analysis and a better understanding of the natural history of this disease. Nowadays, there are many promising targeting-gene therapies in different developing phases.

Molecular studies in familial dilated cardiomyopathy - A pilot study.

Aim: To study genetic variants in patients of familial dilated cardiomyopathy. Methodology: Patients with reduced ejection fraction of less than 45% and dilated left ventricle are considered to have dilated cardiomyopathy. Clinical history was taken and possible secondary causes of dilated cardiomyopathy were excluded. Family history of ≥2 affected relatives or sudden cardiac death in a relative with age less than 35 years were included. Such patients blood sample were sent for next generation sequencing and analysed for presence of genetic variants. Results: As part of pilot study 20 patients (44% were female and 66% were male) were included. There was presence of 16 different pathogenic variants in 14 patients. Two patients had more than one variants in them. Most common of which were sarcomeric mutations constituting 32%. Titin followed by Filamin, Lamin and Desmosomal where the most commonly repeated mutations. Discussion: In our patients of familial dilated cardiomyopathy, 70% were detected to have pathogenic variants in them. Most common variations were seen on Titin gene. Thus those with familial dilated cardiomyopathy should be considered for next generation sequencing. First degree relatives of those with pathogenic variants should be screened using cascade testing for earlier detection and disease monitoring in them.

Further Evidence of Autosomal Recessive Inheritance of RPL3L Pathogenic Variants with Rapidly Progressive Neonatal Dilated Cardiomyopathy.

Neonatal dilated cardiomyopathy (DCM) is rare with high etiologic heterogeneity. Recently, biallelic, autosomal recessive, pathogenic variants in RPL3L (ribosomal protein L3-like) have been reported in the literature with severe early-onset DCM. In the present brief report, we identified two pathogenic RPL3L variants, each harbored in unaffected heterozygous parents: mother (RPL3L c.1076_1080delCCGTG (p.Ala359Glyfs*4)) and father (RPL3L c.80G > A (p.Gly27Asp)). Pathogenic variants were segregated as autosomal recessive to two offspring born with compound heterozygous RPL3L variants and affected by neonatal DCM. This is the second report in the literature to the best of our knowledge and our findings support the pathogenicity of biallelic RPL3L pathologic variants associated with rapidly progressive neonatal DCM and heart failure with a poor prognosis.

Teen pregnancy in the setting of familial dilated cardiomyopathy: a case report.

BACKGROUND: Women with pre-existing forms of familial cardiomyopathy are at increased risk for morbidity and mortality due to hemodynamic changes of pregnancy. There is a lack of consensus about the management and care for these patients given the rarity of this condition. This case represents possibly the youngest pregnant familial dilated cardiomyopathy patient to deliver and the youngest patient to be fitted for a wearable cardiac defibrillator in the postpartum period. CASE PRESENTATION: A 14-year-old gravida 1 with familial dilated cardiomyopathy presented late for prenatal care at 38 weeks, which precluded typical care plans including baseline and serial echocardiograms, medication management, and routine prenatal care. An echocardiogram showed severely decreased left ventricular systolic function compared to studies from one year prior. Three days later the patient presented in labor and had a spontaneous vaginal delivery complicated by postpartum hemorrhage. Her postpartum course was notable for persistence of decreased cardiac function testing and placement of a wearable cardiac defibrillator for prevention against life threatening arrhythmias. CONCLUSION: This case report adds to the literature on pregnancy complicated by familial dilated cardiomyopathy and describes management best practices and considerations during the antepartum, intrapartum, and postpartum periods.

Familial Dilated Cardiomyopathy and Sudden Cardiac Arrest: New Association with a SCN5A Mutation.

Dilated cardiomyopathy (DCM) has significant morbidity and mortality. Familial transmission is reported in 20-35% of cases, highlighting the role of genetics in this disorder. We present an interesting family in which the index case is a 64-year-old woman who survived a sudden cardiac arrest. She presented left ventricular dilatation and dysfunction, which indicated the presence of DCM, as well as a history of DCM and sudden arrest in her family (mother and sister). Genetic testing identified a heterozygous mutation c.74A > G missense change that causes an amino acid, p.Glu25Gly, change in the N-terminal domain of the SCN5A protein. After performing an exhaustive family medical history, we found that this previously not described mutation segregated within the family. All relatives with the DCM phenotype were carriers, whereas none of the noncarriers showed signs of heart disease, so this mutation is the most likely cause of the disease. This is the first time that a variant in the N-terminal domain of SCN5A has been associated with DCM.

[Second-degree AV block type Mobitz I (Wenckebach) in a 49-year-old man with dilative cardiomyopathy]. / AV-Block 2. Grades Typ Wenckebach bei einem 49-jährigen Patienten mit dilatativer Kardiomyopathie.

A 49-year-old man with dilated cardiomyopathy (left ventricular ejection fraction 50%, unremarkable left ventricular biopsy) developed atrioventricular conduction abnormalities (AV block II type Wenckebach) during exercise testing.

Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20-50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in TTN (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.

Heterozygous desmin gene (DES) mutation contributes to familial dilated cardiomyopathy.

Familial dilated cardiomyopathy (FDCM) is characterized by high genetic heterogeneity and an increased risk of heart failure or sudden cardiac death in adults. We report the case of a 62-year-old man with a 2-month history of shortness of breath during activity, without paroxysmal nocturnal dyspnea. The patient underwent a series of examinations including transthoracic echocardiography, coronary arteriography, transesophageal echocardiography, and myocardial perfusion imaging. After excluding secondary cardiac enlargement, he was diagnosed with dilated cardiomyopathy (DCM). His sister had also been diagnosed with DCM several years before. Genetic sequencing analysis revealed that the patient, his sister, and his son all had the same mutation in the desmin gene (DES) (chr2-220785662, c.1010C>T). Genetic testing confirmed a heterozygous DES mutation contributing to FDCM. In this case, the etiology of the patient's whole-heart enlargement was determined as FDCM with DES gene mutation. This is the first report to describe DES c.1010C>T as a cause of FDCM.

Retrospective Analysis of Clinical Genetic Testing in Pediatric Primary Dilated Cardiomyopathy: Testing Outcomes and the Effects of Variant Reclassification.

Background Genetic testing in pediatric primary dilated cardiomyopathy (DCM) patients has identified numerous disease-causing variants, but few studies have evaluated genetic testing outcomes in this population in the context of patient and familial clinical data or assessed the clinical implications of temporal changes in genetic testing results. Methods and Results We performed a retrospective analysis of all patients with primary DCM who presented to our institution between 2008 and 2018. Variants identified by genetic testing were reevaluated for pathogenicity on the basis of current guidelines for variant classification. A total of 73 patients with primary DCM presented to our institution and 63 (86%) were probands that underwent cardiomyopathy-specific gene testing. A disease-causing variant was identified in 19 of 63 (30%) of cases, with at least 9/19 (47%) variants occurring de novo. Positive family history was not associated with identification of a causal variant. Reclassification of variants resulted in the downgrading of a large proportion of variants of uncertain significance and did not identify any new disease-causing variants. Conclusions Clinical genetic testing identifies a causal variant in one third of pediatric patients with primary DCM. Variant reevaluation significantly decreased the number of variants of uncertain significance, but a large burden of variants of uncertain significance remain. These results highlight the need for periodic reanalysis of genetic testing results, additional investigation of genotype-phenotype correlations in DCM through large, multicenter genetic studies, and development of improved tools for functional characterization of variants of uncertain significance.

Familial Dilated Cardiomyopathy.

Advances in human genome sequencing have re-invigorated genetics studies of dilated cardiomyopathy (DCM), facilitating genetic testing and clinical applications. With a range of genetic testing options now available, new challenges arise for data interpretation and identifying single pathogenic variants from the many thousands of rare variants present in every individual. There is accumulating evidence that genetic factors have an important role in the pathogenesis of DCM. However, although more than 100 genes have been implicated to date, the sensitivity of genetic testing, even in familial disease, is only ∼25-40%. As more patients are genotyped, nuanced information about disease phenotypes is emerging including variability in age of onset and penetrance of DCM, as well as additional cardiac and extra-cardiac features. Genotype-phenotype correlations have also identified a subset of genes that can be highly arrhythmogenic or show frequent progression to heart failure. Recognition of variants in these genes is important as this may impact on the timing of implantable cardioverter-defibrillators or heart transplantation. Finding a causative variant in a patient with DCM allows predictive testing of family members and provides an opportunity for preventative intervention. Diagnostic imaging modalities such as speckle-tracking echocardiography and cardiac magnetic resonance imaging are increasingly being used to detect and monitor pre-clinical ventricular dysfunction in asymptomatic variant carriers. Although there are several examples of successful genotype-based therapy, optimal strategies for implementation of precision medicine in familial DCM remain to be determined. Identification of modifiable co-morbidities and lifestyle factors that exacerbate or protect against DCM development in genetically-predisposed individuals remains a key component of family management.

Familial cardiomyopathy caused by a novel heterozygous mutation in the gene LMNA (c.1434dupG): a cardiac MRI-augmented segregation study.

In a five-generation family carrying a novel frameshift LMNA variant (c.1434dupG, p.Leu479AlafsX72), imaging-augmented segregation analysis supports its association with lamin heart disease. Affected members exhibit conduction abnormalities, supraventricular and ventricular arrythmias, dilated cardiomyopathy with non-infarct pattern midwall septal fibrosis, heart failure and thromboembolic complications.

Differential expression of circulating miRNAs as a novel tool to assess BAG3-associated familial dilated cardiomyopathy.

A new familial dilated cardiomyopathy (FDCM) was found related to mutations in BAG3 gene. MicroRNAs (miRNAs) represent new targets of FDCM, although no studies have assessed clinical association between Bcl2-associated athanogene 3 (BAG3)-related DCM and miRNAs. Here, we studied whether a clinical association between BAG3-related FDCM and circulating miRNAs may have diagnostic and prognostic value in a small cohort of familial related individuals carrying a BAG3 mutation (BAG3+) and/or diagnosed of dilated cardiomyopathy (DCM) (DCM+). The analysis of 1759 circulating miRNAs showed significant differences between BAG3+ and BAG3- individuals for miRNAs mir-3191-3p, 6769b-3p, 1249-ep, 154-5p, 6855-5p, and 182-5p, while comparisons between BAG3+/DCM+ versus BAG3+/DCM- were restricted to miRNAs mir-154-5p, 6885-5p, and 182-5p, showing significant correlation with systolic and diastolic blood pressure, A wave, left atrium length, and left atrium area. Additionally, when stratified by gender and age, miRNAs were statistically correlated with critical parameters, including left ventricle ejection fraction (LVEF) and ventricular diameter, in women and young men. Likewise, 56% of BAG3+/DCM+, significantly co-expressed mir-154-5p and mir-182-5p, and a slight 4% did not express such combination, suggesting that co-expression of mir-154-5p and mir-182-5p may potentially show diagnostic value. Further studies will require long-term follow-up, and validation in larger populations.

Contemporary characteristics and outcomes of adults with familial dilated cardiomyopathy listed for heart transplantation.

BACKGROUND: Familial dilated cardiomyopathy (FDCM) account for 20%-30% of non-ischemic cardiomyopathies (NICM). Previous published data showed that some patients with FDCM tend to have rapidly progressive disease; however, five-year mortality was not significantly different in the familial and non-familial forms of NICM with optimal medical therapy. AIM: To better define the characteristics and clinical outcomes of FDCM patients listed for heart transplantation (HT). METHODS: We queried the United Network for Organ Sharing Registry to identify FDCM patients listed for HT between January 2008 and September 2015 and compared them to NICM and ischemic cardiomyopathy (ICM) patients. We included all patients ≥ 18 years old and we separated patients to three groups: FDCM, NICM and ICM. Chi-square test was used to compare between categorical variables, the t-test was used to compare between continues variables, and Cox-proportional hazards model was used to perform time-dependent survival analyses. RESULTS: Of the 24809 adults listed for HT, we identified 677 patients (2.7%) with the diagnosis of FDCM. Compared to patients with NICM and ICM, FDCM patients were younger (FDCM 43.9 ± 13.5 vs NICM 50.9 ± 12.3, P < 0.001, vs ICM 58.5 ± 8.1, P < 0.001), more frequently listed as status 2 (FDCM 35.2% vs NICM 26.5%, P < 0.001), with significantly lower left ventricular assist device (LVAD) utilization (FDCM 18.4% vs NICM 25.1%, P < 0.001; vs ICM 25.6%, P < 0.001), but higher use of total artificial heart (FDCM 1.3% vs NICM 0.6%, P = 0.039; vs ICM 0.4%, P = 0.002). Additionally, patients with FDCM were less frequently delisted for clinical deterioration or death and more likely to be transplanted compared to those with NICM [hazard ratio (HR): 0.617, 95% confidence interval (CI): 0.47-0.81; HR: 1.25, 95%CI: 1.14-1.37, respectively], and ICM (HR: 0.5, 95%CI: 0.38-0.66; HR: 1.18, 95%CI: 1.08-1.3, respectively). There was more frequent rejection among patients with FDCM (FDCM 11.4% vs NICM 9.8%, P = 0.28; vs ICM 8.4%, P = 0.034). One, three, and five post-transplant survival of patients with FDCM (91%, 88% and 80%) was similar to those with NICM (91%, 84%, 79%, P = 0.225), but superior to those with ICM (89%, 82%, 75%, P = 0.008), respectively. CONCLUSION: End-stage FDCM patients are more likely to be transplanted, more likely to have early rejection, and have similar or higher survival than patients with other cardiomyopathies.