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`„ A lot of it is complex, multifactorial disease

`„ Àowever, order chromosomes
`„ Àeart disease: leading cause of death (since 1900)
|„ 1 in every 2.5 deaths in USA: more lives than the next 4 leading causes combined

Development:

`„ cardiovascular system is first functioning organ system in th fetus

|„ 0lood circulation by end of third week; cardiac contractions
|„ urom linear heart tube to final structure (50 days)

cardiovascular disease categories

`„ Structural
|„ 25% of birth defects are cardiac (1 million Americans with some form of
congenital heart defect)
|„ O 1000 infants
|„ £ost lethal of all birth defects
|„ congenital heart defects result primarily from mutations in p
 

p
 p   

 p of heart development
|„ 0rickner, £.E. et al .N engl J £ed 2000;342:256-263
|„ [[: pat VSD is 2%, mat VSD: 6-10% Àowever this is if isolated! Look into
family history: these genes express with reduced penetrance and decreased
expressivity- can be up to 25% [[
|„ ·ranscription factors are the key to understand cÀD
|„ NKX2.5 gene: isolated and sporadic cases: one of the genes: should look into if a
range of heart defects in family
|„ Àolt-Oram: ·0X5-AD- completely penetrant-but difference in expressivity-can
have huge variability in phenotype- Àeart Àand syndrome: congential heart defect
and radial rays: thumb sign-some kind of skeletal involvement- triphallangeal
thumb (extra joint)-pseudo-thalidimide-
`„ cardiac (75%)
`„ Skeletal (100%)
`„ Order X-rays on mom and dad: may just see fused carpal bones
`„ £utation detection rate is not 100%: gene mutation could be somewhere
else upstream ec
`„ clinical criteria: radial ray (u l, b l a symet), cÀD (famhx or personal)
 `„ Exclusion criteria: ulnar, lower limb, renal, ocular, craniofacial, vertebral,
deafness
|„ Ulnar-£ammary Syndrome: ·0X 3 gene, Ulnar involvement: upper limb ulnar
ray defects, cÀD
`„ Electrophysical
|„ cardiac arrhythmias abnormalities in the electrical rhythm of the heart due to
altered impulse formation and or impulse condition
|„ Ventricular is the most lethal
X„ 1000 ScDs day
X„ £ost middle age elderly with cAD
X„ Some young (infant to young adult) in good health
|„ Long Q· syndrome: AD- though some cases with A[ but ALSO see deafness in
family history if A[- formally called [omano Ward Syndrome can be congenital
or acquired
X„ can be due to drugs: over 50 uDA approved meds have potential to alter
Q· interval; some recalled
X„ Q· prolongating drugs for people with LQ· syndrome: a lot of lifestyle
modifications that need to be made for these individuals
`„ Example: cardiac defib.
X„ Abnormality iin cardiac repolarization
`„ Ërolongation of Q· interval (reduced penetrance)
X„ Syncope, seizures, sudden death
X„ SIDs SUDS
X„ Six ion channel genes identified to date
`„ 0alance of K and Na in heart
`„ Kaufman (reference)
X„ Narrow down to · ËE of long Q·: ie: what was happening when you had
your event
`„ Àalmark triggers in long Q·1- exercise or stress: especially swimming
`„ Long Q·2: trigger: auditory stimuli: can¶t have alarm clock
`„ Long Q·3: prolongating drugs
`„ Jervell and Lange-Nielson syndrome: A[: congenital sensorineural
deafness
X„ £anagement of LQ·: beta blockers, avoidance of triggering events
(including certain [x. ·hat affect K+ chennels), assured availability of
external defibs, use of cardiac pacemakers ec
|„ 0rugada syndrome- common cause of cardiac death- ScN5A, ScNI0, GËDIL
`„ 4% of all sudden deaths and at least 20% of sudden death with structurally
normal hearts, mean age of sudden death of 41+ or ± 15 years
`„ £ost commonly occurs during sleep: during early morning hours
 `„ [egions of southeast asia is edemic in young men:
`„ Specificapattern in EKG that most cardiologists will pick up on
|„ cËV·: cASQ2
X„ Symptoms occur with excersise and strong emotions
X„ ounger age: 7 to 9 years
`„ cardiomyopathy
|„ Àeart muscle disease
|„ Àeterogenous group of disease of the myocardium
X„ £yocardium may become thickened, weakened and enlarged, rigid, or
replaced with scar tissue
|„ Ërimary cardiomyopathy: confined to the myocardium, underlying cause may be
genetic, acquired, or mixed
|„ Secondary: mycocardial involvement part of multisystem disease
X„ Àc£: noonan, LEOËard, friedrich¶s ataxia
X„ Dc£: D 0£D, emery, dreifuss, limb girdle, progeria
|„ Aquired causes of cardiomyopathy: factors you want to rule out: late
complications in pregnancy can be associated with cardiomyopathy
X„ Intensive athletic training
X„ Uncontrolled hypertension
X„ [ O coronary artery disease myocardial infarction (ischemia)
X„ ·oxins (EtOÀ, drugs, chemotherapy)
X„ Valvular disease
X„ ·hyroid disease
X„ cÀD structural defects
X„ Àemochromatosis, amyloidosis
X„ Sarcoidosis
|„ Seidman&Seidman, c. 2001
|„ Àc£: 1 500: unexplained ventricular wall thickness, myocyte enlargement and
disarray, increased myocardial fibrosis
X„ ueatures can vary widely (mild exertional dyspnea to heart failure); some
patients asymptomatic
X„ LV hypertrophy (LVÀ) is sign of established disease; usually manifests
during adolescence or young adulthood (during later life, infancy,
childhood possible)
X„ Sarcomere: basic unit of cardiac muscle; composed of thick and thin
filiments with contractile, structural or regulatory functions: clinical
course is more adverse in patients with an identified sarcomere mutation
than in patients with no mutation
X„ Seidman
X„ Sudden cardiac death (ScD) observed in subset of patients: 10-20%
 X„ [isk factors for ScD
`„ cardiac arrest spontaneous sustained tachycardia
`„ uamhx of premature sudden death
`„ Àigh-risk mutation
`„ Unexplained syncope
`„ Nonsustained tachycardia
`„ Ect
X„ Implantable cardioverterdefib (IcD) has been shown to prevent
ScD
|„ Seidman

Storage Àc£

`„ Danon disease
|„ Àistologic hallmark of danon disease: intracytoplasmicautophagic vacuoles with
undergraded cellular products
|„ [apid progression to heart failure leads to urgent need for cardiac transplant
|„ Seidman&Seidman, c. 2001

Screening family members

Echo + 12 lead EKG

If fam is <12, 12

|„ Dc£: 1 2500: most common cause for cardiac transplantation

X„ Very dilatated and impaired LV [V
X„ Lot of overlap between Àc£ and Dc£ due to sarcomere genes
implicated in both-overlap with Duchen¶s muscular dystrophy
X„ Genes: 5-O% of familial cases due to mutation in L£NA gene, L£NA-
associated Dc£ is allelic to Emery
|„ A[Vc (A[VD?): variable expressivity: can be very significant-tachacardia
X„ uibrofatty infiltration in A[Vc
X„ Non syndromic form: in families that may come to an adult cariology form
X„ Syndromic: Naxos syndrome: rare: palmoplantar, A[Vc and wooly hair
X„ Disorder of the desmeosome
|„ £ulticomplexes in cell membrane
X„ Anti-arhythmic [x, IcD, Ablation of pro-arhythmic areas of myocardium,
avoid stress (physical and emotional), avoid caffeine, cardiac
transplantation
|„ Vascular disease
X„ Aoric aneurysm dissection: up to 20% of aneurysms are inherted
 |„ Often asymptomatic, sometimes not detected until acute catastrophic
event
|„ Aneurysm: dilation of Ao, involving all layers of atrial wall, may
occur without dissection

|„ Dissection: disruption of medial layer with bleeding within and along

Ao wall; may occur with out aneurysm: a disruption or a tear of the
aortic wall: bleeding along the inside of the wall- blood flow in
channels that are not supposed to exist

|„
|„ Sporadic vs Inherited
X„ Sporadic:[isk factors: male sex, advancing age (60-70s), uncontrolled
hypertension, hypercholesterolemia, smoking, infection, cocaine or other
stimulant use, decleration or torsional injury (£VA or fall)
X„ Inherited: yonger age, extra-cardiac features (musculoskeletal, ocular,
craniofacial, GU GI, skin integument), bicuspid aortic valve, patent
ductusateriosus, famhx sudden death due etoAo dissection rupture: not
uncommon in marfan syndrome, loeys Dietz syndrome, ehlersDanlos,
vascular type, turner syndrome (10-15% have bicuspid aortic valve),
familial aortic aneurysm dissection (nonsyndromic, though £arfanoid
musculoskeletal features)
X„ Look at uvula: Loeys Dietz syndrome pearl: may not have severe
craniofacial: could be less severity: imaging of entire arterial tree is more
recommended in Loeys Dietz
 clinical management of uamilial Aoritic Aneurysm dissection

X„ Aoritic imaging for first degree relatives of affectives patients (absent

knowledge of familial mutation and uD[s true negative status)
X„ Affective invidivuals should have serial echocardiograms
X„ £edication to control heart rate and blood pressure
X„ Ëhysical activity guidelines
X„ Lifestyle to achieve healthy diet, weight
X„ Ërophylactic surgical intervention (Dacron graft-6„
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coronary Artery disease

X„ £ost of it is not familial

X„ Usually multifactorial
X„ If heart attack: lipid specialist to rule out familial hypercholesterolemia
X„ Valvular disease: a lot of people with mitrovalve prolapse:

X„ [efer to sheet regarding: eliciting family hx

X„ Sudden death in young atheltes: Àc£
X„ oung adults with cÀD are ambivilant about testing
X„ £aron, 0.J et al. circulation 2007; 115: 1643-1455
Electrocardiogram: electrical signals sent to the heart

Ërenatal: taking any teratogenic affects if person have heart disease:

X„ Àigher rate of pre term births

X„ Khairy et al., circulation 2006
X„
|„