Week 7, Lec 1 Flashcards
what are cardiomyopathies
Disorders that target cardiac myocytes or the extracellular tissue in the myocardium
what are the 3 major cardiomyopathies
- dilated cardiomyopathies
- hypertrophic cardiomyopathy
- restrictive cardiomyopathy
which 2 cardiomyopathies can be due to genetic deficits in sarcomere proteins?
dilated and hypertrophic
dilated cardiomyopathy causes
Acquired – usually infectious, inflammatory, or toxic in etiology
Genetic deficits in sarcomere proteins
hypertrophic cardiomyopathy cause
Genetic deficits in sarcomere proteins
causes of restrictive cardiomyopathy
Numerous causes that are related to abnormal deposition of extracellular material
what causes hypertrophic cardiomyotpathy? what part of the heart is effected?
septum overgrows–> resulting in outflow obstruction for the left ventricle
*
*
i.e. the entry to the aorta is blocked by the septum
cause of hypertrophic cardiomyopathy
autosomal dominant
pathogenesis in hypertrophic cardiomyopathy
-sarcomere proteins gain of function mutation
-myocytes are disorganized orientation
symptoms of hypertrophic cardiomyopathy
often asymptomatic
-athletes heart- sudden cardiac death from dysrhythmias
As the patient ages, angina, dyspnea, and syncope become more predominant
what is syncope
sudden loss of consciousness due to globally impaired cerebral hypoperfusion
HFpEF or HFrEF in hypertrophic cardiomyopathy?
HFpEF that can turn into HFrEF
what is the most common cardiomyopathy
dilated
causes of dilated cardiomyopathy
toxicities (i.e. alcohol, catecholamine, cancer therapy)
-peripartum
-genetics
-inflammatory (infection, sarcoidosis)
heart size in dilated cardiomyopathy
massive 2-3x
HFpEF or HFrEF in dilated cardiomyopathy?
HFrEF
cells in dilated cardiomyopathy
can alternate between hypertrophy and atrophic/fibrotic sections of myocardial cells
symptoms of dilated cardiomyopathy
Asymptomatic –> heart failure symptoms (fatigue, exercise intolerance, dyspnea, dependent edema)
-mitral regurgitation
-palpitations/syncopal episodes from dysrhythmias
characteristic of restrictive cardiomyopathy?
Characterized by restricted ventricular filling, reduced diastolic volume in one or both ventricles, and normal or near-normal ventricular systolic function and wall thickness
least common cardiomyopathy
restrictive
highest mortality rate for cardiomyopathy
restrictive
HFpEF or HFrEF in restrictive cardiomyopathy?
HFpEF
isolated diastolic dysfunction, HFpEF picture – stroke volume is normal in most cases
causes of restrictive cardiomyopathy?
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)
environmental and genetic factors in atherosclerosis
▪ Systemic and local inflammation
▪ Dyslipidemia
▪ Higher levels of lipoprotein A – Lp(a)
▪ Metabolic syndrome and diabetes
▪ Hypertension
progression of atherosclerosis
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
risk factors for atherosclerosis
- Smoking, high blood pressure, oxidative stress increase endothelial damage
- Lp(a)
- Diabetes and dyslipidemia (including metabolic syndrome)
how does Lp(a) act as a risk factor for atherosclerosis
likely increases endothelial damage through increasing immune cell recruitment at a developing plaque
▪ May also inhibit breakdown of clots
how is diabetes and dyslipidemia a risk factor for atherosclerosis
▪ 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)
where is lp(a) produced? in response to what?
liver
elease can be increased by acute phase response (precipitated by elevated IL-6, other pro-inflammatory cytokines)
female or male have more lpa
women
if make higher level of lp(a) what does it increase risk of
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
what does lp(a) look like
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
what does Lp(a) that LDL doesnt
KIV repeats (part that looks like plasminogen)
presence of oxidized phospholipids (OxPL) on Lp(a)
both have apoB
how does Lp(a) increase atherogenesis
▪ 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
what inflammatory marker increases lp(a) secretion
Lp(a) secretion is increased when IL-6 levels increase, and seems to do more harm when systemic inflammation is also present
what part of the lp(a) particle is most bad
Thought that many of the effects are due to the OxPL that is carried by the Lp(a) particle, though not yet confirmed
unstable plaques are prone to
rupture
a plaque with an unstable fibrous cap that is prone to rupture
▪ Rupture–> release of pro-coagulant molecules into the bloodstream
how to increase stability in a plaque
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
what can degrade collagen in a fibrous cap
activated macrophages producing metalloproteinases
what can produce collagen for fibrous cap
activated platelets releasing growth factors
metabolic syndrome and atherosclerosis
▪ 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)
