Cardiomyopathies Flashcards
what are the main types of genetic primary cardiomyopathy?
- hypertrophic cardiomyopathy (HCM)
- arrhythmogenis right ventricular cardiomyopathy (ARVC)
- isolated ventricular non-compaction
- mitochondrial cardiomyopathy
Also: restrictive cardioomyopahties
the genetic pathological basis for each of the four cardiomyopathies?
HCM caused by mutations in genes encoding SARCOMERES
ARVC caused by mutation encoding DESMOSOMES
NCC caused by mutation in genes associated with CARDIOMYOCYTE DEVELOPMENT
Mitochondrial myopathy associated iwth mitochondrial disease
how to find a suspected causative mutation in cardiomyopathy:
- co-segregates with HCM phenotype in family memebers
- previously reported or identified as a cause of HCM
- absent from ethnic-matched normal controls
- protein structure and function is altered
- amino acid change in conserved region of protein
what is a primary cardiomyopathy?
affects the heart alone rather than resulting from an illness that affects other parts of the body too
describe HCM:
genetics, features, prevalence
an autosomal dominant condition, with about 60% of cases having mutations in sarcomere genes
characterised by an UNEXPLAINED cardiac hypertrophy and increased risk of sudden cardiac death.
Histologically, characterised by myocyte dissaray
affects 1 in 500, has a varied clinical course and outcome
is myocyte disarray specific to autosomal dominant HCM?
no, it arises in other syndromic causes of LV hypertrophy: noonan’s syndrome, Friedreich’s ataxia.
what may be the final common pathophysiological pathway in HCM and what is the evidence?
Abnormal myocardial bioenergetics:
Phosphorus-31 magnetic resonance spectroscopy has shown that the ratio of cardiac phosphocreatine to ATP (an index of cellular energy status) is 30% lower in patients positive for Troponin T, beta-myosin heavy chain, and cardiac myosin binding protein C with HCM than in controls. However, abnormal ATP use is also seen in HF, IHD, thus whether it is a primary or a secondaaary event is unknown.
what is the relation between sarcomere mutations and clinical outcome in patients with HCM?
the relation between sarcomere mutations and clinical outcome in patients with HCM is unreliable, attributable largely to genetic and phenotypic heterogeneity, thus a sspecific single mutation does not determine the prognosis.
what are the reasons for genetic testing in clinical practice? HCM
to identify a patient’s family members who may be at risk of developing LV hypertrophy even if they are not showing any signs yet. this is true if a pathogenic mutation is identified in a relative expressing the phenotype, otherwise it genetic testing is unlikely to be useful.
genetic testing ccan also make a distinction between metabolic storage disorders that have similar clinical presentatio to HCM: Fabry’s disease, PRKAG2, LAMP2
what imaging modalities are used for HCM
echo
and
tomographic high resolution cardiovascular MRI: often superior to echo for characterisation of the phenotype, eg presence and magnitude of LV hypertrophy in the anterolateral free wall, apaec, posterior septum.
what does the presence of gene-positive, phenotype-apparently-negative individuals? HCM
gene-positive phenotype-negative individuals expand the spectrum of HCM and show that any LV thickness can be consistent with inherited cardiac disease.
Nevertheless, non-hypertrophies LV myocardium may still show a variety of abnormalities: myocardial fibrosis by gadollinium-enhanced MRI, collagen biomarkers, mitral leaflet elongation, subclinical diastolic dysfunction, blood filled myocardial crypts and ECG abnormalities.
what does the fact that HCM disease expression is variable may suggest?
disease expression varies not only between unrelated individuals but also within the same family, which suggests that HCM is a complex inherited trait determined by other genetic and environmental factors.
describe the HCM histology
myocyte dissaray in which indicidual myocytes vary in size and shape, and form abnormal intracellular connection, usually with expansion of the interstitial compartment and areas of replacement fibrosis.
Also: small vessel disease in which intramural coronary vesseuls are apparently narrowed by emdial hypertrophy. clinical signifiance unclear.
common diagnositc dilemmas in HCM
coexistent hypertension: in whites is unlikely to cause significant LVH but does so in black.
Phaeochromocytoma: a rare ccause of apparently unexplained hypertrophy
Athletic heart: generally limited to national/international standard athletes in sporting disciplines that combine isometric and isotonic activity such as cycling and rowing.
obstruction in HCM
at least a third of HCM patients have non-obstructive form of the disase both at rest and with exercise/
may still have dyspnoea and chest pain, usually due to diastolic dysfunction and myocardial ischaemia.
1/4 have aresting LV outflow tract gradient. Usually dynamic with onset during mid-systole.
