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CV Final Material > Inherited CV Disease > Flashcards

Inherited CV Disease Flashcards

1
Q

Central Dogma of genetics?

A

Cells have chromosomes which have genes on them which are made of DNA!!!! The DNA can be transcribed and translated into protein!

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2
Q

What is a proband?

A

person who is central to the family history/pedigree

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3
Q

What is autosomal dominant inheritance?

A
  • Gene is located on one of the non-sex chromosomes
  • Single copy of the gene mutation can cause disease
  • Affected parents have a 50% chance of having an affected child
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4
Q

What is autosomal recessive inheritance?

A
  • Gene is located on one of the non-sex chromosomes
  • Two copies of gene are mutated, causing disease
  • Parents with an affected child are carriers
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5
Q

What is x-link recessive inheritance?

A
  • Gene is located on the X chromosome

* Carrier mothers have a 50% chance of having an affected son and 50% chance of having a carrier daughter

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6
Q

What is genetic penetrance?

A

the proportion of individuals with a particular genetic variant who exhibit signs and symptoms of the genetic disorder

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7
Q

What happens in reduced genetic penetrance?

A

Less than 100% of individuals with a certain genotype actually express signs or symptoms

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8
Q

What is variable expressivity?

A

the signs and symptoms of a genetic condition differ among affected individuals

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9
Q

What is genetic heterogeneity?

A

a genetic disorder can be caused by more than one mutation in an allele

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10
Q

What is genetic pleiotrophy?

A

genetic variants in a particular allele can cause several signs or symptoms

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11
Q

What form of genetic inheritance do inherited CV diseases usually follow?

A

autosomal dominant

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12
Q

What are the 5 general categories of inherited CV disease?

A
  1. arrhythmia
  2. cardiomyopathy
  3. aneurysm syndromes
  4. familial hypercholesterolemia
  5. pulmonary arterial hypertension
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13
Q

What are some inherited arrhythmias?

A

– Long QT syndrome (LQTS)
– Brugada syndrome
– Catecholaminergic polymorphic ventricular tachycardia (CPVT)
– Familial atrial fibrillation

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14
Q

What are some inherited cardiomyopathies?

A 
– Hypertrophic cardiomyopathy (HCM)
– Dilated cardiomyopathy (DCM)
– Restrictive cardiomyopathy (RCM)
– Arrhythmogenic right ventricular dysplasia/cardiomyopathy(ARVD/C)
– Left ventricular noncompaction (LVNC)
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15
Q

What are some inherited aneurysm syndromes?

A

– Familial thoracic aortic aneurysm and dissection syndromes
– Marfan, Loeys-Dietz, and other connective tissue disorders
– Familial coronary artery disease and dyslipidemias
– Autosomal dominant polycystic kidney disease

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16
Q

What is the general cause on inherited arrhythmias?

A

channelopathies

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17
Q

What are clinical findings with arrhythmias?

A
  • Patients may be affected at any age
  • Syncope, sudden cardiac death (SCD) and sudden infant death syndrome (SIDS) are common findings
  • Distinct ECG patterns clarify disorders
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18
Q

What is the prevalence of long QT syndrome?

A

1:3,000 – 7,000

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19
Q

What do you see on an EKG for LQTS?

A

• Clinically identified by prolonged QT interval and T wave abnormalities on ECG and torsade de pointes (TdP)

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20
Q

How do LQTS pt present?

A

• Presents with syncope and SCD due to ventricular tachyarrhythmias, typically torsades de pointes (TdP)
– TdP also may cause seizures
– Syncopal episodes usually occur during exercise or high emotions, not as often during rest or sleep

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21
Q

What are two congenital causes of LQTS?

A

– Romano-Ward syndrome (RWS)

– Jervell and Lange-Nielson syndrome

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22
Q

What are some aquired causes of LQTS?

A

– Primary myocardial problems: myocardial infarction, myocarditis, cardiomyopathy
– Electrolyte abnormalities: hypokalemia, hypomagnesemia, hypocalcemia
– Autonomic influences
– Drug effects
– Hypothermia

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23
Q

How long does the QT interval have to be before you are sure it is LQTS?

A

> 470 msec in males

>480 msec in females

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24
Q

What is Romano-Ward syndrome (RWS)?

A
  • Primary electrophysiologic disorder due to ion channel abnormalities
  • Autosomal dominant disorder with Reduced penetrance: 50% of individuals with a disease-causing mutation will not show symptoms & heterogeneity: 10 genes known to be associated with RWS
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25
Q

Which channelopathy is most common in RWS?

A

K channel in >60%

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26
Q

What treatments are available to pt with LQTS?

A
  • Beta blockers
  • Pacemakers
  • Access to defibrillators
  • Implantable cardioverter-defibrilators (ICDs) for individuals resistant to medications
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27
Q

What is Jervell and Lange-Nielson syndrome?

A

Congenital, profound, bilateral sensorineural deafness and QT prolongation often >500 ms
– increased risk for SIDS & >50% of untreated children with JLNS die prior to age 15

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28
Q

How is Jervell and Lange-Nielson syndrome inherited?

A

Autosomal recessive inheritance – 2 genes known to be associated with JLNS (KCNQ1 causes 90%)

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29
Q

Why do you genetic test for LQTS?

A
  • Molecular confirmation of a clinical diagnosis in symptomatic individuals
  • Risk assessment of asymptomatic family members of a proband with arrhythmia
  • Differentiation of hereditary arrhythmia from acquired arrhythmia
  • Recurrence risk calculation
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30
Q

What is the current detection rate for RWS with genetic testing?

A

75%

31
Q

Does a negative genetic test rule out a genetic cause?

A

No!!! There could still be other unidentified genes

32
Q

What percentage of RWS pt will have two genetic mutations?

A

up to 10%

33
Q

What is brugada syndrome?

A
  • Cardiac conduction abnormalities ST-segment elevation in the right precordial leads (V1-V3), high risk for ventricular arrhythmias
  • Presents as syncope, SIDS or sudden unexpected nocturnal death syndrome (SUNDS)
34
Q

What is the prevalence of brugada syndrome?

A

1:2000

35
Q

What is the best way to diagnose brugada?

A

75% of cases are based on clinical history and ECG results

36
Q

What is the major genetic defect in brugada?

A

Majority occur in SCN5A (alpha subunit of cardiac sodium channel) and 25-30% of cases are found to have a gene mutation in 16 genes encoding ion channels

37
Q

What is Catecholaminergic polymorphic ventricular tachycardia (CPVT)?

A
  • Prevalence: 1 in 10,000
  • Distinct bidirectional or polymorphic ventricular tachycardia that can degenerate into ventricular fibrillation and cause sudden death
38
Q

How does CPVT present?

A

Syncope caused by exercise or acute emotion in an individual without structural heart disease

39
Q

What genes are important for CPVT?

A

55-65% of cases will have a gene mutation in the RYR2 (cardiac ryanodine receptor channel) or CASQ2 (calsequestrin, calcium buffering protein of the sarcoplasmic reticulum) genes

40
Q

How are RYR2 and CASQ2 genes of CPVT inherited?

A

– RYR2 are inherited in an autosomal dominant

– CASQ2 are inherited in an autosomal recessive

41
Q

Should we use single gene testing or genetic panels when looking for arrhythmia genes?

A

moving toward panels which have become more cost effective and allow for sequencing of multiple genes

42
Q

What are the 4 main proteins that can be mutated in cardiomyopathies?

A

cytoskeletal
desmosomes
sarcomeres
nuclear envelope proteins

43
Q

What is cardiomyopathy?

A

• Diseases of the myocardium
– Causes the heart to become enlarged and dilated, thickened, and/or stiffened
– Weakens the heart causing it to becomes inefficient and incapable of pumping blood and maintaining a normal rhythm
– This can lead to heart failure, arrhythmia or sudden death

44
Q

What is among the leading indications for heart transplant?

A

cardiomyopathy >26,000 deaths in the United States per year

45
Q

How is cardiomyopathy diagnosed?

A

Diagnosed based on echocardiogram and ECG

46
Q

What is the prevalence of hypertrophic cardiomyopathy (HCM)?

A

Prevalence: 1:500

47
Q

What is a major cause of sudden cardiac death (SCD) in the young (<30 years of age) and most common cause of SCD in young athletes?

A

HCM

48
Q

When do we diagnose HCM?

A

Unexplained left ventricular hypertrophy (LVH) in the absence of another cardiac or systemic disease (e.g. hypertension or aortic stenosis)

49
Q

How does HCM usually present?

A

Clinical spectrum is diverse with variable age of onset
– Typically includes chest pain, exertion-related dyspnea, or syncope
– Others experience progressive exercise intolerance, thromboembolic disease, heart failure or unexpected SCD
– Majority of individuals remain asymptomatic

50
Q

HCM is a disease of what structures in the heart?

A

sarcomeres
50-60% of individuals with a family history of HCM will have a sarcomere gene mutation & 20-30% of individuals without a family history of HCM will have a sarcomere gene mutation

51
Q

In HCM, there is some genotype-phenotype correlations what are they?

A

– MYH7: classic presentation
– MYBPC3: later age of onset
– TNNT2: mild or absent LVH, higher risk for arrhythmia, SCD

52
Q

What is the most common gene mutation for HCM?

A

beta myosine heavy chain (MYH7) and myosin binding protein C (MYBPC3) in about 70% of all HCM

53
Q

When does dilated cardiomyopathy (DCM) usually occur?

A

Clinical onset usually occurs
in the adult years (30s to 50s) but varies widely, occasionally even presenting in infants, small children, and the elderly

54
Q

What are the clinical features of DCM?

A 
congestive heart failure
reduced CO
arrhythmia/conduction system disease
thromboembolic disease
some pt have muscle weakness or dystrophy
55
Q

What are the general causes of DCM?

A
  • Acquired
  • Idiopathic DCM: after exclusion of all identifiable causes (except genetic)
  • Familial DCM: two or more closely related family members that meet the criteria for idiopathic DCM
56
Q

What are some aquired causes of DCM?

A 
– Ischemic injury from myocardial infarction (MI) or coronary artery disease (CAD)
– Congenital heart disease
– Toxins
– Thyroid disease
– Inflammatory conditions
– Myocarditis
– Severe chronic hypertension (HTN)
– Radiation
– Iron overload
57
Q

What kind of inheritance does DCM usually show?

A

Majority of cases show autosomal dominant inheritance – but can also have X-linked, autosomal recessive and mitochondrial inheritance

58
Q

Is DCM causes by a certain genetic mutation?

A

Extensive genetic heterogeneity with mutations in more than 20 genes involved in the sarcomere, Z-disc, nuclear lamina, intermediate filaments, sarcoplasmic reticulum, desmosome and dystrophin-associated glycoprotein complex

59
Q

LMNA mutation can lead to DCM how?

A

Prominent conduction disease, with or without supraventricular or ventricular arrhythmias, leading to DCM and heart failure

60
Q

LMNA has pleiotrophy what other diseases it involved in?

A 
– Muscular dystrophy: Skeletal muscle involvement indicated by elevated creatine kinase 
– Neuropathy
– Lipodystrophy
– Hutchinson-Gilford Progeria syndrome
– brachydactyly
61
Q

How do you manage/treat cardiomyopathy?

A
  • Pharmacologic therapy – ACE inhibitors & Diuretics
  • Lifestyle modifications– Avoiding competitive sports & Healthy lifestyle
  • Mechanical devices: pacemakers, ICD
  • Surgical intervention like Septal myectomy & Alcohol ablation
  • Cardiac transplantation
62
Q

How does familial hypercholesterolemia present?

A

• Significant elevationsin total serum cholesterol and LDL cholesterol early in life
– Xanthomas : yellowish cholesterol-rich material in tendons or other body parts
– Atheromas: accumulation of debris containing cholesterol in the artery walls (plaques)

63
Q

Is FH common?

A

yes! Prevalence 1:200-500

64
Q

What are cholesterol levels like in untreated pt with FH?

A
  • Untreated adults: LDL-C > 190 mg/dL or total cholesterol > 310
  • Untreated children/adolescents: LDL-C > 160 mg/dL or total cholesterol > 230
65
Q

How is total cholesterol in pt with homozygous FH?

A

really bad total cholesterol > 500 mg/dL

66
Q

What does FH predispose pt to?

A

Premature coronary heart disease (CHD) and CVD

67
Q

What is the inheritance pattern for FH?

A

Autosomal dominant (HeFH) and autosomal recessive (HoFH) inheritance – Homozygotes have earlier age of onset and more severe disease

68
Q

What gene is most commonly mutated in FH?

A

LDLr in 60-80% of cases

69
Q

How do you treat pt with FH?

A
  • Risk-factor modification before onset of disease – Diet/lifestyle changes
  • Pharmacotherapy: statin – HoFH not responsive to monotherapy; multiple medications and apheresis
  • Early screening and therapy for elevated cholesterol levels
70
Q

What are ethical, legal and societal implication of genetic testing?

A
  • Diagnostic testing vs predictive testing
  • Privacy of genetic information
  • Insurance discrimination – GINA 2008
  • Psychosocial impact
  • Genetic testing in children
  • Uncertainty in interpreting results and utility for clinical management
71
Q

When do you suspect hereditary component to a CV disease?

A

– Common diseases that present at younger ages with a more severe or progressive phenotype
– Family history: Non-traditional autosomal dominant inheritance, Incomplete penetrance, Variable expression

72
Q

What are benefits of genetic testing?

A

– Provides risk information for individuals and families
– Provides information useful for medical management
– Leads to early detection and minimize complications
– May relieve anxiety

73
Q

What are risks of genetic testing?

A

– Emotional (increased fear/anxiety)

– Insurance discrimination: State and Federal Laws

74
Q

What are the limitations of genetic testing?

A

– Genetic testing is not able to detect all causes of cardiovascular disease
– Continued risk for cardiovascular disease
– Some management strategies not proven effective

CV Final Material (16 decks)

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