Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Cardiovascular > Arrhythmogenic Cardiomyopathies > Flashcards

Arrhythmogenic Cardiomyopathies Flashcards

1
Q

What is Sudden Cardiac Death (SCD) ?

A

Death due to a cardiovascular cause that occurs within one hour of the onset of symptoms.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is Sudden Cardiac Death (SCD) caused by?

A
  1. SUDDEN ARRHYTHMIC DEATH SYNDROME (SADS)
  2. Structural substrate: CARDIOMYOPATHIES
Hypertrophic cardiomyopathy (HCM)
Dilated cardiomyopathy (DCM)
Restrictive cardiomyopathy (RCM)
Arrhythmogenic cardiomyopathy (ACM)
  1. Electrical substrate: CHANNELOPATHIES

Brugada syndrome
LQT syndrome
Short QT syndrome
Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What features define Arrhythmogenic Cardiomyopathy (ACM)?

A

● Primary myocardial disease: ventricular arrhythmias, SCD, fibrofatty replacement of the myocardium

● In certain regions of the world: No 1 cause of SCD in the young, particularly athletes

● Nomenclature: ARVD (1982), ARVC (1994), ACM (2010)

● Disease progression: 1) concealed, 2) overt electric, 3) RV failure, 4) biventricular pump

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Arrhythmogenic Cardiomyopathy (ACM) IS the Most Arrhythmogenic Disease Known to Man.

What features define it

A

Arrhythmias arise even in the concealed phase without any structural remodelling

Unique among the primary cardiomyopathies

More reminiscent of electrical diseases/ cardiac channelopathies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Why is diagnosis of Arrhythmogenic Cardiomyopathy (ACM) difficult?

A

Overlapping entities:
BrS, Myocarditis, DCM, Sarcoidosis, Uhl’s anomaly…

No ‘gold standard’ for diagnosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What does diagnosis of Arrhythmogenic Cardiomyopathy (ACM) rely upon?

A 
Diagnosis relies on Task Force Criteria
Relatively specific but not highly sensitive 
Diagnosis requires: 
2 major
1 major & 2 minor or
4 minor criteria
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What was the breakthrough in genetic studies?

A

Naxos disease: a triad of ACM, palmoplantar keratoderma and woolly hair

Palmoplantar keratoderma and woolly hair – those with these conditions found to have 100 % penetrance of their disease and also very evident who will develop cardiomyopathy, because they are born with woolly hair within first year of life and begin to manifest lesions in feet and hands

Linkage analysis pursued and this revealed that the first mutations- 2157del2 in the gene coding for Plakoglobin

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What was another breakthrough found?

A

Another recessive disease

Carvajal syndrome: a triad of DCM, palmoplantar keratoderma and woolly hair

7901delG in gene DESMOPLAKIN found

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Plakoglobin and desmoplakin are both diseases of what?

A

The desmosome

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is a desmosome?

A

A mechanical bridge, in the heart resides in areas that connect the cells with each other, known as the intercalated disks

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is desmosome composed of?

What percentage of ACM patients harbour one or more mutations in these 5 genes?

A

5 proteins

The cadherins DSG2 and DSC2 span the membrane connecting adjacent cells
The armadillo proteins plakoglobin, PKP2 and the plakin protein DSP link the cadherins to the cytoskeleton

60%

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What do Desmosomes provide the myocardium with?

A

Mechanical strength

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What is the the mechanical hypothesis of ‘defective cell-cell adhesion’ of the desmosome?

A

Essentially hypothesis that if one of the 5 genes is mutated, the bridge will collapse and therefore cells cannot adhere to each other and separate, and the cell that is loose and will become apoptotic, because the heart is a terminally differentiated organ, the cell cannot be replaced by another viable, healthy cell and instead the area will be covered by fat and scar.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Why do the remaining 40% of ACM patients develop the disease?

A
  1. Most common founder mutation in the Netherlands: Phospholamban (PLN): R14del
  2. Most common founder mutation in Newfoundland: TMEM43: S358L
  3. Mutations in Filamin C (FLNC); an actin-cytoskeleton binding protein
  4. Rare; Mutations in SCN5A (Nav1.5)
  5. Rare; Mutations in N-cadherin
  6. Rare; Mutations in Lamin A/C
  7. Rare; Mutations in Desmin
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

ACM is not a single disease but an umbrella term used to encompass a number of different diseases

True or false

A

True

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Despite genetic knowledge, why does diagnosis of ACM remain a challenge?

A

● Vast range of phenotypic manifestations
● Age-related progression
● Incomplete genetic penetrance

● Endomyocardial biopsy not always helpful because:

● Typical histological changes tend to spare the sub-endocardium and the septum

● They are mostly present in patients with advanced/severe disease

17
Q

What was found in an experiment that used immunostaining to investigate Carvajal syndrome?

A

Desmoplakin lacking

Also lacked plakoglobin even if this was not mutated

Thus if one protein is mutated, this may affect localisation of another protein even if it is not itself mutated

18
Q

One experiment found plakoglobin not localised in every form of ACM regardless of which gene carried the pathogenic variant.

It was absent only in areas that are morphologically and histologically affected, but also gone in areas that appeared normal.

What does this mean?

A

Thus if need to attain a biopsy sample, do no need to biopsy thin vulnerable and risky right ventricle free wall but can safety attain region of septum which in terms of histology is normal, yet plakoglobin will absent. This was found to be specific for the ACM because when checked heart from patients with other cardiomyopathy the plakoglobin present.

19
Q

Why does plakoglobin distribution track with the phenotype, not the genotype?

A

PLN R14del in ACM, DCM and control measured

Plakoglobin absent in those with ACM, but present/ normal at bridges with those with DCM

Thus this change seems to track with actual disease phenotype, if have ACM plakoglobin will be absent

20
Q

Once strong mechanical junctions formed, the heart will form what?

A

Electrical junctions known as gap junctions to allow electricity to move smoothly from one cell to another in heart

21
Q

Major protein in electrical bridges is Cx43

Cx43 is absent from every heart from every patient with any cardiomyopathy

However in other cardiomyopathies, cx43 leaves junction towards end of the disease progression, once heart has been significantly remodelled.

How does ACM differ?

A

In ACM, cx43 leaves early when heart is histologically normal

22
Q

In ACM Nav1.5 is absent from where?

Where do proteins that fail to reach bridges go?

A

Bridges

If use western blot (essentially allows examination of expression levels of a given protein) the proteins are present, less expression is seen, however proteins are not degraded, but it is hypothesised that proteins fail to reach junction and perhaps diffusely localised within cell so microscope cannot identify them

Thus hypothesises that this is disease of defective protein trafficking of protein to the bridges

SAP97- role is to transfer the sodium channel and the protein plakoglobin to the membrane, thus in essence, it is like the bus that brings two passengers to their destination.

Since passengers never reach their destination, what happens to the actual bus?

In ACM significant drop of intensity of the signal, in every other form of heart disease, can examine parallel lines in sarcomeres but no signal at bridges.

Thus lack of signalling both from sarcomeres and the bridges appears to be characteristic feature of ACM

23
Q

What effect does SB2 have upon zebrafish with a plakoblobin mutation?

A

SB2 can prevent and reverse the ACM phenotype in fish

● It can prevent the disease in 2 different ACM mouse models

24
Q

SB2 is toxic however focuses attention upon what?

A

Marker GSK36 as this is inhabited by the drug

This enzyme forms a complex, role is to phosphorylate substrate proteins, these proteins will be ubiquitinated meaning they will be degraded by proteosome

In normal heart GSK36 is in cytoplasm and it searches for proteins that needs to be degraded and flags them, so that the proteosome can perform its function

25
Q

What proteins that reach the bridge in ACM?

A

APC

26
Q

Each one of the markers discussed (PLAKOGLOBIN, Cx43
NAV1.5, SAP97, GSK3β and APC) may not be specific for ACM together give a molecular signature of ACM

True or false

A

True

27
Q

Can attain biopsy of skin and immunostaining for the 6 proteins –in previous slide

It is not as invasive or risky as it is to attain piece of heart but it is also not so pleasant.

What can be used instead?

A

Inside of mouth swabbed and smeared on glass microscope to see if expresses proteins

28
Q

Desmosomes present in tissues subjected to increased what?

A

mechanical stress: heart, ski

29
Q

ACM caused recessive or >1 dominant desmosomal mutations associated with skin changes

True or false

A

True

30
Q

What happened when cells were swabbed from the cheek of patients with plakoglobin mutations and SB216763 was added?

A

proteins start to grow back

31
Q

What are current management options in ACM?

A

● Anti-arrhythmic drugs

Not always effective
Side effects

● Implantable defibrillator (ICD)

Sensitivity and performance problems
Requires invasive surgery at frequent intervals
Risk of infection, lead displacement, technical failure
Psychological burden
Changes in lifestyle

Neither does anything to prevent/delay disease progression

32
Q

Why is GSK3β problematic?

A

Causes cancer thus this drug was problematic, but knowing the pathway we need to attack to stop this disease, can focus on a a pathway immediately downstream of this degradation complex

33
Q

What was found downstream of GSK3β?

A

Inflammation pathway

P50 and -65 under normal conditions are blocked, however if have an infection or chemical injection or matter that is considered an inflammatory stimulus, then this protein (GSK3B) will be degraded, meaning now proteins can reach nucleus and drive expression inflammation genes

34
Q

Inflammatory infiltrates in >80% of ACM hearts in autopsy series

Biopsy samples during ‘hot phases’ reminiscent of myocarditis

Does the disease progress through ‘bouts of inflammation’?

A

Mouse with desmoglein 2 mutation

Ejection fraction of mice very lowered meaning function of heart severally compromised

NF-κB (inflammatory pathway) blocker drug BAY11-7082; 8 weeks added

This reversed disease phenotype and restored key protein re-distribution and reduced cytokine secretion by cardiac myocytes!

Now examining if defibrillator can be replaced with anti-inflammatory agents such as aspirin

Cardiovascular (19 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions