DCM Flashcards
How do LQTS, CPVT and HCM differ to Early Repolarization (ERS), Brugada (BrS) and DCM?
Former three are Mendelian
Latter three oligogenic
What are the three Inherited cardiomyopathies?
Hypertrophic cardiomyopathy (HCM): Sarcomeric Calcium handling Metabolic disorders Amyloid Restrictive Cardiomyopathy Left Ventricular non-compaction Mitochondrial
Dilated cardiomyopathy (DCM): Membrane-scaffolding TTN Sarcomeric Nuclear envelope Calcium-handling Transcription cofactors RNA splicing Cell energy-generating machinery Left Ventricular non-compaction
Arrhythmogenic right ventricular cardiomyopathy (ARVC):
Desmosome
Transcription factor
Calcium handling
Inherited cardiomyopathies present distinct pattens of what?
Fibrosis – can be seen using cardiac MRI
Myocardial fibrosis is due to accumulation of extracellular matrix proteins, most commonly collagen and accumulation of a collision within extracellular matrix is a substrate for arrhythmia and contractile dysfunction, thus assessment of scarring is important in cardiomyopathies
What is the diagnostic criteria (WHO/ISFC) for DCM?
- Enlarged left ventricular diameter
- Impaired contractility
- Excluding any known cause of myocardial disease.
Why is Cardiovascular magnetic resonance (CMR) useful in DCM?
CMR is useful in DCM as in fifteen to twenty percent of cases there is evidence of scar/myocardial fibrosis on scan, there is also increasing evidence from other cardiac conditions to suggest the more scar patient has, more severe the likely outcome
CMR allows measurement of chamber size and changes over time
Describe the pathogenesis in DCM?
Genetic heterogeneity
> 50 associated genes with DCM
Can involve problems with nuclear envelope e.g., lamin related DCM whereby mutations in lamin A and C lead to a particularly severe form of DCM associated with contractility problems and also conduction abnormalities and arrhythmias
Due to the severity of individuals with lamen related cardiomyopathy, ICD implantation is often recommended for these patients.
Lamin mutations’ cause arrythmias and conduction block independent of very several systolic dysfunction of the ventricle
Decreased myofilament activation is another pathway – Titan (TTN) mutations, in particular truncating mutations of TTN are most common in DCM. Ion channels and calcium also implicated.
Mutations in the SCM5A gene increase sodium channel and are associated with several inherited cardiac conditions such as Brugada and also cardiomyopathy. SCM5A is pleotropic
B. Fibrosis- pale scar interspersed amongst healthy cardiac tissue. Increase scar/collagen is one reason why arrhythmias are more prevalent and contraction is impaired. However, this is seen for any from of heart failure thus alone will not inform of what cause or condition is.
What is the sequelae of DCM?
Heart failure Valvular dysfunction Oedema Emboli Arrhythmias Sudden cardiac arrest
Leading cause for heart transplantation
DCM non genetic aetiology is possible
True or false
True
What are the characteristics of DCM?
Prevalence estimated 1:250
Penetrance incomplete and age related
Familial in 20-50% cases
Family screening needed
Over 50 genes involved
~30-50% cases genetic/familial
What are published variants in DCM?
TTN, LMNA, MYH7, TNNT2, MYH6 and SCN5A
ACTC1 causes what?
Rare DCM
What are X linked forms of DCM?
Duchenne and Becker muscular dystrophy are X-linked disorders caused by mutation of DMD. In males, features most commonly involve muscle weakness and increased serum CK levels with loss of ambulation in childhood or later in life. Heterozygous females may present with isolated DCM.
Barth syndrome, an X-linked disorder caused by mutation of TAZ, involves growth retardation, lactic acidosis, neutropenia, and elevated levels of 3-methylglutaconic acid.
What does DCM testing involve?
Ambiguous echocardiographic and/or ECG results in asymptomatic at-risk relatives
Testing of at-risk asymptomatic adult relatives – testing is not useful in predicting rate of progression etc
Molecular genetic testing of asymptomatic individuals younger than age 18 years
Genetic testing facilitates identification of at-risk children
What are the complexities of the Genotype–Phenotype Relationship in Inherited Cardiomyopathies?
1. Modifier genes In the locus- Common or rare in cis or in trans Additional coding variants Noncoding variants that alter level of expression
Outside of locus-
Common polymorphisms
or rare mutations affecting same system or down-stream pathways
2. Environmental effects HCM- Age Athletic training Hypertension Coronary disease
DCM- Age Pregnancy Cytotoxic drugs Viral infection Coronary disease
- Post-translational and epigenetic effects
DNA modification (e.g. methylation) Histone modification (acetylation) Translational control (e.g., microRNA) Post-translational modifications
What is the significance of segregation analysis and variant interpretation in DCM?
Clinical screening of relatives tested is an important consideration, as the chance that first-degree relatives will inherit the variant is 50%.
In contrast, the absence of the variant in a single affected individual provides strong evidence that the variant is not pathogenic.
It is appropriate to combine genetic testing with clinical evaluation in at-risk relatives to provide more comprehensive information about the disease and variant transmission in the family.
When pathogenicity of a variant is refuted by segregation analysis, this information should be communicated back to the genetic testing laboratory.
