Sudden Cardiac death/Marfan's

Question 1

What is the natural progression of Sudden Cardiac Death (SCD)?

Answer 1

Progress:
Ventricular premature beat (VPB)
Ventricular tachycardia
Ventricular fibrillation**
Asystole (terminal rhythm)

** can treat with defibrillation or CPR, otherwise mortality is very high

Question 2

95% of SCD deaths are associated with…?

Answer 2

coronary artery disease

Question 3

What significantly decreases the risk of mortality and incidence of sudden death post-MI

Answer 3

b-blockers - decreases sympathetic tone, which blocks reentry circuits

Question 4

Patients with either one of these symptoms have the worst prognosis for sudden coronary death.

Answer 4

1) ventricular tachycardia

2) low ejection fraction

Question 5

What is the mechanism of tachyarrhythmias?

Answer 5

reentry circuits

• occur when there is a dense scar of myocardial cells interspersed with fibrous tissue
• this leads to heterogenous conduction due to differences in refractory periods and conduction speeds
• can result in retrograde reentry, which may ultimately lead to antegrade depolarization in adjacent tissues (ventricular pre-mature beats)

Question 6

How do you treat ventricular pre-mature beats?

Answer 6

if asymptomatic: no treatment

if symptomatic:

• drug therapies (antiarrhytmics) that minimize re-entry
• non-pharmacological therapies
  a) implantable cardioverter-defibrillator (ICD)
  b) cathether ablation of arrhythmic tissue
  c) cardiac surgery to remove ectopic foci

Question 7

Rundown of the differences of anti-arrhythmic:

Answer 7

I - blocks Na channels - slows conduction
II - b blockers - reduces sympathetic tone
III - blocks K channels - prolongs repolarization
IV - blocks Ca channels - decouples EC coupling

Question 8

What is serial drug testing?

Answer 8

used to determine which drugs is most effective for treating one’s arrhythmias. Process involves inducing artificial ventricular pre-mature beats (VPB) and then testing with various drugs to see which ones can prevent or modify the ventricular tachyarrhythmias

Question 9

What are some of the molecular causes of sudden cardiac death? (3)

Answer 9

1) heritable abnormalities (LQT, Brugada, ARVC)
2) drugs (“FAC”)
2) stress-induced abnormalities/electrical remodeling
3) myocardial Ca overload (b-blocker syndrome, ionotropic therapies)

Question 10

Mutations in ion channel associated genes result in channelopathies, one of which is called the Long QT syndrome. How does this cause SCD?

What are some genetic examples? What is the net effect of all of these gene mutations?

Answer 10

Long-QT syndrome: delayed repolarization following a heart beat (prolonged QT syndrome) increases risk of torsades de pointes.

TdeP results in increased palpitations

• > syncope
• > ventricular fibrillations
• > sudden death

Ex: LQT1, LQT2, LQT3 = delays repolarization, thereby prolonging the ventricular AP

Brugada = slows the rate of AP conduction

Question 11

SCN5A is a gene that encodes for an Na ion channel that is can be mutated to generate either a loss of function or a gain of function. What are the two disease process that ensue for either one?

Answer 11

loss of function: Brugada syndrome - shortens the depolarizing current, which slows the conduction velocity and reduces the amplitude of the AP, resulting in an increase in arrhythmias

gain of function: LQT3 - prolongs the depolarizing current (delays repolarization so that the ventricular AP is prolonged; prolonged QT); can ultimately lead to torsades de pointes

Question 12

What mutations does LQT1 and LQT2 have?

What is the net effect of these mutations

Answer 12

mutations in slow/rapid delayed rectifier K current channels.

net effect: delays repolarization, thereby prolonging the ventricular AP (prolonged QT), which can ultimately lead to torsades de pointes

Question 13

What is the etiology of Arrhythmic RV cardiomyopathy? What is the pathophysiology and pathology of ARVC?

Answer 13

cause: genetic defect in desmosomes, resulting in destabilized cell:cell linkages particularly in the right ventricular outflow tract (RVOT)

pathophysiology:
- nonischemic cardiomyopathy
- hypokinetic areas
- fibrofatty plaques replacing the RV myocardium
- arrhythmias originating in the RV

pathology:
- thinned RV
- abnormal trabeculations

Question 14

What is electrical remodeling/stressed induced abnormalities?

What are some examples?

Answer 14

syndrome caused by transient or chronic syndromes (MI, ischemia, post-tachycardia) that initiate molecular changes in cardiac myocytes that modify the cycling/coordination of several VG ion channels

Examples:

1) T wave inversion caused by reversible myocardial injury
2) Taku-Tsubo Syndrome
3) Ventricular hypertrophy

Question 15

What happens on an ECG following an acute MI that is indicative of electrical remodeling?

Answer 15

T wave evolution - T wave initially inverts in II/III, but gradually returns to abnormal, but upright T waves

Question 16

What is Taku-Tsubo syndrome?

Answer 16

transient apical ballooning of the LV apex w. a hyper-contractile base of the LV - weakens the myocardium; triggered by emotional stress

ECG changes suggestive of an anterior wall MI

Question 17

How can ventricular hypertrophy lead to SCD?

Answer 17

hypertrophy increases the time to repolarization, which results in a prolonged QT = poor prognosis

Question 18

How does electrical remodeling occur post-MI?

What can this lead to?

Answer 18

Stress on the cardiac myocyte causes it to release AII.

AII activates CREB, which results in a transient outward K current, this results in an inward Ca current, which results in a systolic Ca overload

This activates the Na/Ca exchanger (3Na in, 1Ca out), which results in a depolarizing current.

This can lead to after-depolarizations, TdeP, and V-fib

Question 19

What is the b-blocker withdrawal syndrome and how can it result in SCD?

how do you avoid this?

Answer 19

ABRUPT withdrawal of b-blockers in patients with heart disease increases mortality due to the REBOUND phenomenon.

This results because chronic blockade increases b-receptor #, density, and sensitivity, and abrupt withdrawal can lead to a POWERFUL CAMP-MEDIATED ADRENERGIC RESPONSE that activates ical (ultimately activates Na/Ca exchanger), which results in increased Ca levels in the cytosol; can lead to v-fib

avoid by gradually tapering the b-blocker dose.

Question 20

What is ionotropic therapy and how can it result in SCD?

Answer 20

ionotropes that increase ical activity and (ultimately activates Na/Ca exchanger), which results in increased Ca levels in the cytosol; can lead to v-fib.

examples:
b-agonists
phosphodiesterase inhibitors
dopaminergic agonists

Question 21

What is genetic pleiotropy vs genetic heterogeneity?

Which one is characteristic of Marfan’s Syndrome?

Answer 21

genetic pleiotropy: 1 gene –> many effects

genetic heterogeneity: >1 gene -> 1 syndrome/phenotype

Marfans: genetic pleiotropy

Question 22

What is the genetic defect in Marfan’s syndrome?

Answer 22

autosomal dominant mutation in FBN1, a gene that encodes for FIBRILLIN, which plays a structural role in connective tissue and is a negative regulator of TGFb signaling.

Question 23

What are some of the effects that a FBN1 mutation cause in Marfan’s syndrome?

cardiovascular:
skeletal:
ocular:
cutaneous:
pulmonary:

Answer 23

cardiovascular: aortic root aneurysm, dissection
skeletal: dolicostenomelia (long limbs), joint hypermobility, scoliosis with dural ectasia (widening of dural sac around spinal cord), flat feet
ocular: ectopia lentis (lens dislocation)
cutaneous: decreased elasticity of skin -> stretch marks without weight change
pulmonary: increased risk of asthma, bronchitis, pneumonia, emphysema
facial: hollow cheek bones, lugubrious facial expression, abnormal retrograde displacement of the mandible

Question 24

What are the effects of Marfan’s syndrome on:

aorta
valves
myocardium

Answer 24

aorta: aneurysm/dilation, aortic dissection
valves: mitral valve prolapse/regurgitation + aortic valve regurgitation = both increases the workload of the heart, which may cause dyspnea, fatigue, and palpitations (arrhythmias present on ECG)
myocardium: enlarges + weakens over time

Question 25

Cardiovascular treatments of Marfan’s syndrome:

Answer 25

goal: reduce stress on ascending aorta wall to prevent further dilation + decrease risk of aortic dissection

b-blockers - propranolol, atenolol

ARBs - blocks AII receptor (ie Losartan) reduces TFGb signaling

Surgery - replace dilated portion with a graft or valve replacement

Question 26

What is the dominant negative effect of Marfan’s Syndrome?

What are the two possible outcomes of this effect?

Answer 26

fibrillin is synthesized, secreted, and deposited into microfibrils in the ECM. DN effect occurs when the patient has one normal and one mutated FBN1 gene. This can lead to one of two phenotypes:

1) mutated fibrillin is not secreted or cannot interact with the normal fibrillin, results in a REDUCED # of microfibrils, but does not affect the normal functioning.
net: milder phenotype of Marfan’s syndrome

2) mutated fibrillin is secreted from the cell and can interact with the normal fibrillin, thus ALL of myofibrils formed are defective.
net: severe phenotype of Marfan’s syndrome