Week 6, Lec 3 Flashcards
normal ventricles should be (2)
compliant and strong
compliant ventricles
diastolic filling occurs at low atrial pressures, and the atria do not have to undergo hypertrophy to fill the ventricle at the end of diastole
- The ventricle should be able to relax quickly and most filling should take place in early diastole
strong ventricles
a ventricle should generate enough force at rest with low diastolic pressures/preload to meet the needs of the body
- Calcium should be quickly released and re- sequestered each cycle
- There should be a significant reserve of function for when activity increases
reasons for heart failure
- increased afterload
- reduced compliance
- impaired oxygen supply
- disorders that damage myocardial and effect contractility - cardiomyopathies
why does increased afterload of the ventricles over long period of time cause heart failure
Ventricles become hypertrophic, increasing wall thickness and eventually chamber size
- Molecular changes→decreased contractility
why does impaired oxygen supply cause heart failure
in a setting of chronic ischemic
heart disease
- May or may not involve sites of infarcted tissue
reduced compliance/ impaired ability to relax due to?
fibrosis or poorly-characterized molecular changes
cardiomyopathies
Disorders that damage the myocardium and impair compliance or contractility
biggest risk factors for heart failure
hypertension (like 40-60%)
myocardial infarction, diabetes, valvular disease etc.
2 major phenotypes of heart failure
systolic dysfunction
diastolic dysfunction
THERE ARE NEW NAMES
what is systolic dysfunction heart failure
impaired force of contraction/contractility→reliance on elevated preload for adequate cardiac output
what is diastolic dysfunction heart failure
elevated diastolic pressures are evident, but force of contraction/contractility is maintained
- Despite elevated diastolic pressures, there maybe impaired EDV
what are systolic and diastolic dysfunction now known as
systolic dysfunction= HFrEF (heart failure with reduced ejection fraction)
diastolic= HFpEF (heart failure with preserved ejection fraction)
2 major problems in heart failure progressuon
- forward flow problems
- backward problems
forward flow problems in heart failure
impaired cardiac output to a range of tissues impairs function
▪ Major tissues that experience decreased perfusion include the brain, the heart, the kidneys, and the extremities
* Sometimes reduced flow to the viscera can lead to abdominal pain, but uncommon
▪ Impaired venous return from the pulmonary veins→LV
which important tissues have decreased perfusion from heart failure
brain, heart, kidneys
backwards problems/ congestion in heart failure
left ventricle cardiac output and right ventricle cardiac output decline
what happens when left ventricle cardiac output declines
As LV CO declines, blood congests in the pulmonary venous circulation→elevated pressures in pulmonary capillaries → development of pulmonary edema and thickening of arterioles/arteries in the lung
as right ventricle cardiac output declines what happens
blood congests in the systemic venous circulation→elevated pressures in systemic capillaries→edema
* Hepatic congestion & splenomegaly
* Dependent edema
RV vs LV come from
RV comes from systemic circulation
LV comes from pulmonary circulation
what part of the heart is usually the first to fail in heart failure and why
left ventricle bc has greatest afterload
▪ As pulmonary congestion increases, the afterload of the RV also increases→ development of RV failure
what is the situation in which the right ventricle will fail first in heart failure
▪ Lung disease → areas that are hypoxic/poorly ventilated→ pulmonary vasoconstriction
▪ Known as cor pulmonale – common causes include COPD and obstructive sleep apnea
what is cor pulmonale
right ventricle fails first
bc of COPD or obstructive sleep apnea
pulmonary microcirculation is controlled by
oxygen concentrations
the pulmonary microcirculation ____ in reseponse to decreased oxygen levels
constricts
helps redirect blood flow to regions with higher oxygen levels. This optimizes gas exchange, allowing for more efficient oxygen uptake and carbon dioxide removal.
in heart failure what happens to diastolic and systolic dysfunction
some reduction in both compliance (diastolic dysfunction) and force of contraction (systolic dysfunction)
▪ However, most cases of heart failure can be clearly dichotomized into HFrEF and HFpEF
two common patterns of heart hypertrophy (that is not the normal physiologic hypertrophy seen in athletes)
▪ Concentric hypertrophy ▪ Eccentric hypertropy
concentric hypertrophy vs eccentric hypertrohy
concentric- increase ventricular wall thickness
eccentric- myocytes increase in length and narrow
concentric hypertrophy
▪ Thought to be earlier in the
development of HF
▪ Thickened ventricular wall, no increase in chamber size
▪ Increased thickness is thought to minimize wall stress
eccentric hypertrophy
▪ Ongoing remodeling → eccentric hypertrophy as myocytes increase in length
▪ Usually associated with a decrease in ejection fraction and increased symptoms
ventricular remodelling (mycotyes structure altered to adapt to failing heart)
▪ Increased expression of fetal forms of myosin that use ATP more effectively but generate less force
▪ Increased expression of TGF-beta leads to deposition of extracellular matrix in the extracellular spaces
▪ Myocytes themselves enlarge, but the capillary network in the hypertrophic heart tends to be less extensive than in physiologic hypertrophy
which singling pathway for heart failure
angiotensin ii
beta adrenergic
endothelia 1
inflammatory cytokines
angiotensin ii pathway in heart failure
- Angiotensin II – as cardiac output to the kidneys decreases→ increased AT II
▪ AT II can also be released by “stressed” cardiac cells - AT II can directly bind to myocyte and myofibroblast receptors→ hypertrophy, proliferation of myofibroblasts, and increased deposition of connective tissue
- Increased AT II also increases volume and vasoconstriction→ worsened edema and afterload
beta adrenergic signaling increased in heart failure
Beta-adrenergic signaling is increased in early heart failure→ receptor downregulation
- Long-term beta-adrenergic signaling also results in hypertrophy and fibrosis, and even eventually apoptosis of myocytes
▪ long-term activation of the SNS in the heart is maladaptive, even though short-term activation improves cardiac function
▪ Exact signaling mechanisms are currently being studied
other detreminetal pathways in heart failure
▪ Endothelin-1: potent vasoconstrictor that is also a growth factor for cardiomyocytes
▪ Inflammatory cytokines: activate JNK and MAPK pathways that seem to be linked to maladaptive remodeling and apoptosis
how does calcium homeostasis change in heart failure
▪ Ryanodine receptors release less calcium per AP
▪ SERCA calcium uptake is inhibited
▪ The net effect seems to be elevated diastolic calcium levels and impaired calcium spikes during contraction
what is a beneficial pathway in heart failure
Activation of IGF-1 and PI3K pathways seem to be the major routes that drive physiologic (healthy) hypertrophy
what does activation of SNS and RAAS lead to initially and then over time
initial: increase HR, BP, contractility, retention of water and sodium (increases preload and cardiac output)
overtime:
-excessive vasoconstriction and volume retention
-baroreceptor dysfunction —> elevated pressures and decrease PNS tone
▪ Increased ADH release → increased volume
▪ Excessive SNS activation → decreased renal perfusion… which leads to chronically elevated release of renin + AT2 to maintain blood flow to the kidney
what can renin release be casued by
decreased perfusion to kidneys and SNS activation
if decreased perfusion to kidney then what
release renin; have AT1 into AT2 which has many effects
-vasoconstrict, increase BP, h20 and Na+ reabsorption (via aldosterone and ADH)
what do atrial (ANP) and b type natriuretic peptide (BNP) do?
vasodilator, decrease angiotensin 2 and renin
natriuresis diuresisi
what happens to BNP and ANP in heart failure
patients become resistant
no longer leads to sodium and water loss
symtpoms of heart failure
fatigue
▪ “Left-sided” symptoms: orthopnea, dyspnea, angina, impaired cognitive function
* Can cause chronic kidney disease (CKD) and exacerbate ischemic heart disease
▪ “Right-sided” symptoms: dependent edema, RUQ pain
signs of heart failure
▪ Pitting edema, hepatosplenomegaly
▪ Elevated JVP, displacement of the apical impulse, S3 or S4
▪ Crackles, wheezing, and sometimes pleural effusions depending on the extent of pulmonary edema
what are the classes for heart failure
class 1- Ordinary physical activity does not cause undue fatigue, dyspnea, palpitations, or angina
class 2- Comfortable at rest. Ordinary physical activity (e.g., carrying heavy packages) may result in fatigue, dyspnea, palpitations, or angina
class 4- Symptoms of heart failure or angina are present at rest and worsened with any activity
how to diagnose heart failure
echocardiography (cardiac ultrasound)
BNP
chest x ray
what is found in echocardiography for heart failure
HFrEF- decreased ejection fraction; <40%
HFpEF is normal (>50%) but can see:
* Left ventricular hypertrophy
* Atrial enlargement, abnormal ventricular wall movement
* More challenging diagnosis than HFrEF
what is normal echocardiography
HFpEF >50 %
BNP is
a natriuretic factor that is released by the ventricle in response to increased strain
chest x ray to identify
cardiomegaly and pulmonary edema
what is the most common cause of heart failure (60%)
- Chronic IHD (coronary artery disease)
the majority of the rest of the cases are due to hypertension (2nd most common), valvular abnormalities, or patients with congenital heart disease
what are the clinic features of heart failure due to ischemic heart disease IHD
myocardial hypertrophy and fibrosis
HFrEF; left ventricle involved first
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 athersolsceorsi
- Smoking, high blood pressure, oxidative stress increase endothelial damage
- Lp(a) – (immune cell recruitment, plaque, endothelial damage)
- Diabetes and dyslipidemia (including metabolic syndrome): LDL and AGEs into endothelium, oxidative stress
chronic hypertesnion is the second most common cause of heart failure… which ventricle effected first? concentric or eccentric?
oncentric LV hypertrophy – wall thickens, but the chamber size does not tend to increase
- Over time can proceed to eccentric hypertrophy
medication for angina and CHF (congestive heart failure)
beta blockers
medications for CHF (congestive heart failure)
cardiac glycoside (digoxin)
diuretics
beta blockers for angina and CHF; what receptor? what effect?
beta-1 epi/norepinephrine receptor
▪ IHD: Reduce cardiac oxygen demand – thus effective prophylactic for angina, other complications of IHD
▪ CHF: reduces and even reverses cardiac remodeling (less fibrosis, hypertrophy, cell death)
beta blocker effcet
block SNS, NE and E –> lower HR and contractions and oxygen demans
cardiac glycosides (digoxin) inhibit what
sodium potassium pump
cardiac glycoside (digoxin) increases what
Increase contractility by increasing intracellular calcium, but also increase vagal tone (resulting in a slower heart rate)
- Increasing vagal tone helps decrease oxygen demand
digoxin inhibits Na+/K+ pump why is this good?
bc calcium extrusion from cytosol is partially determined by sodium gradient (sodium calcium exchanged)
digoxin decreases this gradient so increases cytosolic calcium during systole
duretics in CHF
diuretics reduce blood volume, usually by
increasing water and sodium loss at the kidney tubule
types of diuretics
- Loop and thiazide diuretics – inhibit sodium reabsorption by inhibiting particular sodium transporters earlier in the nephron
- Spironolactone – blocks the aldosterone receptor→ loss of sodium and water in the distal nephron
- ACE inhibitors (ACE-i) block angiotensin-converting enzyme that converts AT1 to AT2
▪ They likely also have beneficial impacts on heart remodeling, just like beta-blockers
medications for angina
calcium channel blockers (nondihydropryridine and dihyrdorpyridine)
nitrates
what do dihydropyridine calcium channel blocker do
Can cause vasodilation with limited impact cardiac conduction or contractility
what do nondihydropyridine calcium channel blocker do
Can cause slowing of AV conduction (slows heart rate) and decreased contractility, but with variable effects on vasodilation
dihydropyrdiine vs nondihydropyridine calcium channel blockers
dihydro= vasodilate
non= slow AV conduction (HR) and decrease contractility
nitrates effect on angina
converted to nitric oxide= vasodilate
- Decreased preload (through vasodilation of veins, decreased venous
return)→decreased oxygen demand - Decreased afterload (through vasodilation of arterioles) → decreased
oxygen demand - Coronary vasodilation → increased blood supply
4 meds for dyslipidemia
- HMG CoA reductase inhibitors (statins)
- PCSK9 inhibitors
3.ezetimibe
- niacin
what do HMG coa reductase inhibitors (statins) do? organ they act on?
reduce the hepatocyte’s ability to produce cholesterol→depletion of the hepatocyte’s “intracellular supply” of cholesterol→upregulation of the LDL receptor on the hepatocyte cell membrane
▪ This increases clearance of LDL from the circulation
▪ These medications also:
* Decrease circulating triglyceride levels
* Improve endothelial function
* Seem to also reduce oxidative stress and inflammation at the plaque
PCSK9 inhibitors do what?
block a protease known as PCSK9 on the hepatocyte membrane
▪ This protease degrades the LDL receptor – if it is blocked, then there are more LDL receptors available to clear LDL
ezetimibe does what in dyslipidemia
reduces the absorption of dietary and biliary cholesterol in the small intestine
▪ This leads to a decrease in cholesterol stores in the hepatocyte→increased LDL receptor expression
what does niacin do in dyslipidemia
inhibits lipolysis in adipose tissue
▪ Therefore less release of FFAs → less production of VLDL by the liver
▪ This in turn leads to decreased circulating LDL, but main effect is decreased in TG (VLDL) synthesis
▪ Also increases HDL… however importance of this is not known
what pathological processes damage valves
-congenital disorders
-wear and tear from chronic infalmmation/ calfcification
-infalmmatory; infection or autoimmune
-ischemia or aortic dissection
-idiopathic
what is stenosis
the valve has a more narrow than normal orifice, and/or it is difficult to open
▪ Either way → increased strain across the wall of the heart proximal to the stenosis→hypertrophy and complications
▪ Can also initially result in impaired outflow to structures after the stenosis→physiologic adaptations to poor outflow
what is regurgitation
backflow of blood across a valve
▪ Backflow of blood to chamber proximal to the regurgitation→BOTH increased EDV/preload + impaired outflow distal to the regurgitation→ eventual chamber enlargement
what is incompetence (insufficiency) in a valve
causes regurgitation
the valve does not close completely
what is prolapse in a valve
causes regurgitation
excessive (backwards) valve movement into the proximal chamber
4 valvular pathologies
- Aortic regurgitation
- Bicuspidandcalcific
aortic stenosis - Mitral valve prolapse and mitral regurgitation
- Rheumatic heart disease
how does aortic sclerosis progress to heart failure
aortic sclerosis→asymptomatic aortic stenosis→aortic stenosis with heart failure
congenital cause of aortic stenosis
congenital bicuspid aortic valves account for about 5% of all congenital heart disease, and is one of the most common congenital valvular defects
calcific aortic stenosis
Damage to the valvular endothelium→oxidized LDL and migration of chronic inflammatory cells→ calcification and sclerosis of tissue
▪ Some myofibroblasts actually differentiate into cells that are “bone-like”
(osteoblast-like)
▪ This process is accelerated in the presence of a bicuspid aortic valve
- As the valve calcifies→ increased afterload→ concentric hypertrophy of the heart
3 ethologies of aortic regurgiation
- related to aortic stenosis (most common) (valvular malformation)
- inflammatory disorders (ankylosing spondylitis and rheumatic heart disease)
- acute damage of the valve (thoracic aortic dissection, infective endocarditive)
most common valvular abnormality
mitral valve prolapse
pathologic findings in mitral valve prolapse
▪ Enlarged valve leaflets that are redundant and often “billow”
into the left atrium during systole
▪ The annulus and chordae tendinae can also be enlarged, and sometimes the chordae break
▪ Microscopy – lots of myxomatous connective tissue that massively increases the thickness leaflet – full of proteoglycans with a deficit in collagen
* Primary causes – not well-understood, some show a deficit in the cadherins
* Secondary causes – associated with disorders of connective tissue that impact other organs (Marfan’s syndrome, Ehlers-Danlos Syndrome)
mitral valve regurgitation is usually do to? what is less common?
longer term mitral valve prolpase
less common:
▪Ischemia→dysfunction or actual rupture of papillary muscles
* Rupture can be acutely life-threatening
▪Infective endocarditis
▪ Rheumatic heart disease
▪ Enlargement of the left atrium or left ventricle
acute mitral regurgitation causes left atrial pressures to ___ and pulmonary pressures to ____
increase
mitral regurgitation caused by
chordae tendinae rupture, impaired papillary function, or papillary rupture
rheumatic fever
auto-immune reaction to infection with Group A streptococcus
▪ Can occur with strep throat OR with strep skin infection (i.e. impetigo)
what happens in rheumatic fever
The “M-protein” of streptococcal antigens stimulates an immune response→antibodies & T also recognize epitopes
c
on cardiac cells (particularly valves)
who is rheumatic fever most common in
kids /teens
rheumatic heart disease causes by rheumatic fever affects which part of heart wall
- Canaffecteverylayeroftheheartwall–endocarditis(valves), myocarditis, pericarditis
pathogenesis of rheumatic heart disease
- GAS (group A strep) introduces streptococcal antigens into the body→antibodies and activated cytotoxic T cells
- Immune responses can cross-react with cardiac antigens, including those from myocyte sarcolemma and valvular glycoproteins.
- inflammation of the heart in acute rheumatic fever may involve all cardiac layers (endocarditis, myocarditis, pericarditis). Occurs 2-3 weeks after infection
- Active inflammation of the valves may lead to chronic valvular stenosis or insufficiency
▪ These lesions involve mitral, aortic, and tricuspid valves, in that order of frequency.
which valves are most effected in rheumatic heart disease
mitral and aortic valve (mitral and aortic stenosis)
mitral stenosis and aortic stenosis in rheumatic heart disease
▪ RHD is the most common cause of mitral stenosis
▪ Often the scarring along the valve and the shortening of the chordae tendinae cause the valve to be incompetent as well
aortic stenosis;
▪ Often the aortic commissures are fused, making them resemble a bicuspid aortic valve
▪ The aortic valve can also become incompetent as well as stenotic
SLIDE 52- 54 on lec 6 week 3 very important ****
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