Week 7, Lec 1

Question 1

what are cardiomyopathies

Answer 1

Disorders that target cardiac myocytes or the extracellular tissue in the myocardium

Question 2

what are the 3 major cardiomyopathies

Answer 2

1. dilated cardiomyopathies
2. hypertrophic cardiomyopathy
3. restrictive cardiomyopathy

Question 3

which 2 cardiomyopathies can be due to genetic deficits in sarcomere proteins?

Answer 3

dilated and hypertrophic

Question 4

dilated cardiomyopathy causes

Answer 4

Acquired – usually infectious, inflammatory, or toxic in etiology

Genetic deficits in sarcomere proteins

Question 5

hypertrophic cardiomyopathy cause

Answer 5

Genetic deficits in sarcomere proteins

Question 6

causes of restrictive cardiomyopathy

Answer 6

Numerous causes that are related to abnormal deposition of extracellular material

Question 7

what causes hypertrophic cardiomyotpathy? what part of the heart is effected?

Answer 7

septum overgrows–> resulting in outflow obstruction for the left ventricle
*
*
i.e. the entry to the aorta is blocked by the septum

Question 8

cause of hypertrophic cardiomyopathy

Answer 8

autosomal dominant

Question 9

pathogenesis in hypertrophic cardiomyopathy

Answer 9

-sarcomere proteins gain of function mutation

-myocytes are disorganized orientation

Question 10

symptoms of hypertrophic cardiomyopathy

Answer 10

often asymptomatic

-athletes heart- sudden cardiac death from dysrhythmias

As the patient ages, angina, dyspnea, and syncope become more predominant

Question 11

what is syncope

Answer 11

sudden loss of consciousness due to globally impaired cerebral hypoperfusion

Question 12

HFpEF or HFrEF in hypertrophic cardiomyopathy?

Answer 12

HFpEF that can turn into HFrEF

Question 13

what is the most common cardiomyopathy

Answer 13

dilated

Question 14

causes of dilated cardiomyopathy

Answer 14

toxicities (i.e. alcohol, catecholamine, cancer therapy)
-peripartum
-genetics
-inflammatory (infection, sarcoidosis)

Question 15

heart size in dilated cardiomyopathy

Answer 15

massive 2-3x

Question 16

HFpEF or HFrEF in dilated cardiomyopathy?

Answer 16

HFrEF

Question 17

cells in dilated cardiomyopathy

Answer 17

can alternate between hypertrophy and atrophic/fibrotic sections of myocardial cells

Question 18

symptoms of dilated cardiomyopathy

Answer 18

Asymptomatic –> heart failure symptoms (fatigue, exercise intolerance, dyspnea, dependent edema)
-mitral regurgitation
-palpitations/syncopal episodes from dysrhythmias

Question 19

characteristic of restrictive cardiomyopathy?

Answer 19

Characterized by restricted ventricular filling, reduced diastolic volume in one or both ventricles, and normal or near-normal ventricular systolic function and wall thickness

Question 20

least common cardiomyopathy

Answer 20

restrictive

Question 21

highest mortality rate for cardiomyopathy

Answer 21

restrictive

Question 22

HFpEF or HFrEF in restrictive cardiomyopathy?

Answer 22

HFpEF

isolated diastolic dysfunction, HFpEF picture – stroke volume is normal in most cases

Question 23

causes of restrictive cardiomyopathy?

Answer 23

Some are autosomal dominant mutations

Most secondary causes from outside the heart:
-amyloidosis (accumulate abnormal proteins in various tissues; i.e kidneys) –> form beta pleated sheets from liver or antibody fragments –> proteins deposit extracellularly
-hemochromatosis (accumulate iron in cardiomyocytes)
-sarcoidosis (granuloma disease infiltrate wall of ventricle)

Question 24

environmental and genetic factors in atherosclerosis

Answer 24

▪ Systemic and local inflammation
▪ Dyslipidemia
▪ Higher levels of lipoprotein A – Lp(a)
▪ Metabolic syndrome and diabetes
▪ Hypertension

Question 25

progression of atherosclerosis

Answer 25

Progression from fatty streak !–> deposition of oxidized
LDL –> migration and activation of macrophages –>

▪ Calcification, accumulation of cholesterol, foam cell development
▪ Increased deposition of extracellular matrix under the intima
▪ A variably-stable fibrous cap with underlying necrotic tissue and immune cells
▪ Stenosis of the lumen and impaired blood flow

Question 26

risk factors for atherosclerosis

Answer 26

• Smoking, high blood pressure, oxidative stress increase endothelial damage
• Lp(a)
• Diabetes and dyslipidemia (including metabolic syndrome)

Question 27

how does Lp(a) act as a risk factor for atherosclerosis

Answer 27

likely increases endothelial damage through increasing immune cell recruitment at a developing plaque
▪ May also inhibit breakdown of clots

Question 28

how is diabetes and dyslipidemia a risk factor for atherosclerosis

Answer 28

▪ Diabetes – LDL is more likely to be incorporated into the intima in the setting of AGEs in the endothelium – likely site of oxidation of LDL

▪ AGEs can also increase general inflammation, leading to increased oxidative stress

▪ Increased LDL–> increased oxidized LDL–> deposition in fatty streaks–> activation of macrophages (via the scavenger receptor)

Question 29

where is lp(a) produced? in response to what?

Answer 29

liver

elease can be increased by acute phase response (precipitated by elevated IL-6, other pro-inflammatory cytokines)

Question 30

female or male have more lpa

Answer 30

women

Question 31

if make higher level of lp(a) what does it increase risk of

Answer 31

increased risk of IHD, stroke, and calcific aortic stenosis

Tendency to produce higher Lp(a) is genetic, and antihyperlipidemics, exercise, do not seem to decrease it much

Thyroid hormone may decrease production

Question 32

what does lp(a) look like

Answer 32

LDL

▪ Apo(B) containing protein
▪ surface has a group of proteins that look like plasminogen, composed of units known as “kringle” units (KIV)
▪ Transports oxidized phospholipids (OxPL) – these are thought to be the major drivers of Lp(a) pathogenicity

Question 33

what does Lp(a) that LDL doesnt

Answer 33

KIV repeats (part that looks like plasminogen)

presence of oxidized phospholipids (OxPL) on Lp(a)

both have apoB

Question 34

how does Lp(a) increase atherogenesis

Answer 34

▪ Initiating coagulation
▪ Contributing to the development of unstable plaques
▪ Activation of monocytes in the arterial wall
▪ Eliciting secretion of pro-inflammatory cytokines and expression of adhesion molecules in the arterial wall

Question 35

what inflammatory marker increases lp(a) secretion

Answer 35

Lp(a) secretion is increased when IL-6 levels increase, and seems to do more harm when systemic inflammation is also present

Question 36

what part of the lp(a) particle is most bad

Answer 36

Thought that many of the effects are due to the OxPL that is carried by the Lp(a) particle, though not yet confirmed

Question 37

unstable plaques are prone to

Answer 37

rupture

a plaque with an unstable fibrous cap that is prone to rupture

▪ Rupture–> release of pro-coagulant molecules into the bloodstream

Question 38

how to increase stability in a plaque

Answer 38

amount of collagen in the fibrous cap

▪ Activated platelets can release growth factors that stimulate collagen production and deposition
*
▪ Activated macrophages produce metalloproteinases that degrade collage! weaker fibrous cap
▪ Therefore, inflammation tends to decrease stability of atherosclerotic plaque

Question 39

what can degrade collagen in a fibrous cap

Answer 39

activated macrophages producing metalloproteinases

Question 40

what can produce collagen for fibrous cap

Answer 40

activated platelets releasing growth factors

Question 41

metabolic syndrome and atherosclerosis

Answer 41

▪ Elevated VLDL–> increased circulating LDL
▪ Hypertension–> increased atherogenesis
▪ Visceral obesity–> insulin resistance, increased FFAs, and
increased release of pro-inflammatory cytokines
▪ Insulin resistance–> production of advanced glycation end- products (AGEs)