Download CV Pathophysiology

Atherosclerosis
1. Layers Intima, media and Adventitia. Elastic boundaries in arteries Internal and
External are also fenestrated.
2. Large arteries are more elastic so that they are stretched during systole and they
rebound during diastole to propel blood forward
3. Small arteries are more muscular (have thicker muscularis layer) to actually literally
squeeze blood through them
4. Vaso vasorum are the arteries that feed the arterial layers (in adventitia)
5. Endothelial Vasodilatory substances
a. Thrombomodulin binds thrombin and inactivates it…this is the natural state of
endothelium (inactive thrombi)
b. Heparin sulfate (Heparin) binds Antithrombin III and activates it
6. Smooth muscle of Arteries has 2 fxns:
a. Contractile
b. Synthetic – forms connective tissue, collagen, elastin, IL-6 etc.
7. Normal Laminar flow depends on endothelial production of NO and superoxide
dismutase to prevent endothelial injury
8. Lipoproteins:
a. Free cholesterol core surrounded by coating of phospholipids
b. Apolipoproteins on surface target the lipoproteins to various receptors/target
organs
9. Steps in Atherosclerosis:
a. Endothelial Injury due to Toxins or Shear stress, whatever
b. Increase in endothelial production of reactive O2 species which causes
impairment of endothelium’s role as permeability barrier, release of
cytokines Increase in Endo Permeability AND Increase expression of
VCAM etc.
c. Endo permeability allows entry of LDL into intima  Increase in LDL
receptor expression in intima ECM so LDL binds and is drawn into subintimal space where it binds to ECM components and is “trapped”
d. LDL in sub-intimal space is then modified by one of two methods:
i. Oxidation of LDL to mLDL which increases VCAM expression,
leukocytes attraction and leukocyte ingestion of mLDL (Macrophages
can phagocytose mLDL and uptake of LDL is not down-regulated so
they do so uncontrollably)
ii. Glycation of LDL which renders LDL antigenic and pro-inflammatory
e. Macrophages w/ phagocytosed LDL become lipid-laden – foam cells, fatty
streak
f. Foam cells release PDGF, TNF-a, IL-1, FGF, TGF-B which recruit smooth
muscle cells into intima which causes monoclonal smooth muscle cell
proliferation and the formation of a “Fibrous Plaque”
g. Calcification/ Embolization/ Rupture/ Aneurysm of Fibrous Plaque
h. Leukocytes meanwhile have been releasing metalloproteinases and block the
synthetic fxns of proliferating smooth muscle cells which are laying down
connective tissue to stabilize the fibrous plaque…this combination ultimately
causes breakdown of shoulder regions…
i. RUPTURE OF PLAQUE  exposes underlying Tissue Factor  Extrinsic
arm of Coag cascade to Intrinsic arm of coag cascade to  THROMBUS.
10. Risk factors for atherosclerosis: Metabolic syndrome: DM, HTN, Dyslipidemia (high
LDL, low HDL), Smoking, Abdominal girth/obesity. High homocysteine & Creactive protein
11. Familial hypercholesterolemia: Defective for LDL-Receptor which causes high levels
of circulating cholesterol (not removed by liver). Heterozygotes are familial
hypercholesterolemic. Homozygotes totally lack LDL-Rs and have MIs when they
are 10
12. Statins are HMG CoA reductase inhibitors which lower LDL levels and raise HDL
levels. Also act as anti-inflammatories by lowering cytokines and C-reactive protein.
13. DM: 1) glycation of endothelium (Increase immune rxn to LDL), 2) Prothrombotic
and anti-fibrinolytic state, 3) Impaired endothelial fxn decreased NO and increased
adhesion molecules
14. HTN: direct effects by causing endothelial damage due to increased hemodynamic
stress
15. Smoking: oxidative modification of LDL to mLDL; decreases HDL levels;
endothelial dysfxn due to hypoxia etc; prothrombotic
16. Exercise enhances insulin sensitivity and endothelial NO production
17. Estrogen: decreases LDL, antioxidant and antiplatelet
18. Homocysteine: promote thrombosis…genetic defects in methionine metabolism
or B12 deficiencies are common causes of hyperhomocysteinemia
Unstable Angina/MI
1. Classification:
a. UA – Partial obstruction of CBF, Negative cardiac enzymes (some necrosis,
not much)
b. NSTEMI – Partial obstruction, Positive enzymes (necrosis present) non Qwave MI
c. STEMI – Complete occlusion of coronary artery, Q-wave MI (Q-waves show
up later and are unpredictable so they are no longer used, but just so we know
about them)
2. Hemostasis
a. Primary hemostasis = Platelets plug up exposed collagen
b. Secondary hemostasis = Coag. Cascade/extrinsic triggers intrinsicFibrin
clot strengthens platelet plug
3. Endogenous anti-thrombotics
a. AntiThrombin III
b. Thrombomodulin binds Thrombin → activates protein C & S which inactivate
Factors 5 & 8
c. TF inhibitors block TF activity
d. tPA cleaves plaminogen → plasmin (degrades fibrin into split products)
e. Prostacyclin → ↑cAMP in platelets which block platelet
activation/aggregation; also vasodilates
f. NO → vasodilation
4. Rupture of plaque due to:
a. Mфs make metalloproteases
b. Lфs make IFN-y which disrupt collagen synth by smooth musc. Cells
c. ↑ BP – shear stress
d. Torsion
e. Early morning → ↑viscosity of blood, ↑BP, ↑epinephrine levels
5. Other causes of Acute coronary syndromes
a. Septic emboli from valves
b. Acute vasculitis (type III hypersensitivity)
c. Cocaine use → SNS stimulant and vasospasm
6. Infarct types
a. Transmural infarct spans entire thickness of wall, prolonged occlusion
b. Subendocardial infarct is particularly susceptible since it has few collaterals,
its vessels have to travel through layers of contracting myocardium and its
subjected to the highest ventricular pressures.
7. Histology
a. 4-12hrs: Edema which looks like wavy lines + contraction bands near infarct
borders, eosinophilic belts (consolidated sarcomeres due to ↑ Ca++)
b. 18-24hrs: PMNs + chromatin + pyknosis or coagulative necrosis
c. 5-7 days: Mфs remove necrotic myocytes → yellow-softening
d. 7-10days: Granulation tissue → collagen, capillaries
e. 10+days: Fibrosis & scar tissue
8. Function changes:
a. Impaired contractility & compliance
i. Systolic dysfxn: impaired contraction & dykinesis (bulges outwards)
ii. Diastolic dysfxn: impaired ventricular filling, decreased diastolic
relaxation and loss of compliance
b. Stunned myocardium – Prolonged systolic dysfxn despite reperfusion.
Gradual recovery ensues to recover full contractile force
c. Ischemic preconditioning – Ischemia might make myocardium more ischemia
resistant in the future. Possibly due to ↑ in adenosine (vasodilator)
d. Infarct expansion post-MI – Myocyte slippage resulting in decreased volume
of myocytes in region of infarct→↑ventricle size → ↑wall stress (↑ R),
decreases contractile force and ↑ likelihood of developing aneurysm
9. UA Clinical presentation
a. Crescendo pattern with increasing frequency of sx
b. Angina @ rest
c. New onset angina
10. MI Clinical
a. Pain in C7-T4 region – adenosine released from infracted cells irritate free
nerve endings
b. Pain @ rest
c. Asymptomatic among diabetics (neuropathy)
d. MI + Pericarditis – acute, pleuritic pain
e. SNS response – sweating, cold clammy skin, tachycardia
f.
g.
11. Dx:
a.
b.
Shallow breathing/dyspnea / edema in lungs
S4, S3 and ↑WBC
UA or NSTEMI: ST depression, T-wave inversions (may be transient)
STEMI: ST elevation, T-wave inversions + pathologic Q-wave. Also
Troponin I&T 3-4 hrs and peak at 18-36 hrs for 2 wks after. CK-MB
increased 308 hrs and peaks @ 24 hrs, normal after 48hrs use proportion of
CKMB/CK total. Myoglobin 1-4 hrs, cleared rapidly, low specificity. LDH
increases 3-5 days after MI
12. Tx:
a. UA or NSTEMI:
i. Antithrombotics: aspirin, clopidogrel (ADP blocker, фplatelet
aggregation), heparin, GpIIbIIIa antagonists (eptifibatide, abcixamib
etc.)
ii. Anti-ischemics: nitrates, beta-blockers, CCBlockers
iii. Invasive (PCI) which is better than more conservative mgmt.
b. STEMI:
i. Thrombolytics: streptokinase and tPA (targets fibrin in new clots
which is better)
ii. PCI – better than thrombolysis, no bleeding complications
iii. Anti-ischemics and antithrombosis as above
c. Prevention
i. Aspirin, B-blockers, ACE inhibitors, Statins (ABCs)
13. Complications
a. Arrythmias due to: 1) ischemia of nodal tissue, 2) Toxins/metabolites ion
leaks, 3) Stimulation of SNS, 4) Drug toxicity…Types: Vfib, Vectopic with
re-entrant circuits ↑ectopic beats (lidocaine works on these).
Supraventricular arrythmias→bradycardia, tachycardia, APCs
b. CHF: decrease in ventricular contractility
c. Cardiogenic shock: decrease in CO/hypotension→decrease in peripheral
perfusion, decrease in coronary perfusion both cause ischemia→Decrease
LVEDV → decrease SV → decrease CO. Dobutamine or + inotrope to
increase SV.
d. Papillary muscle rupture: Mitral regurg, flash pulm edema
e. Free wall rupture: Cardiac tamponade
14. Extent of LV dysfxn predicts post-MI morbidity and outcome closely.
Heart Failure
1. HF is defined as the inability of the heart to pump blood forward to meet the
metabolic demands of the body. Incidence of HF is increasing
2. Physio
a. Tension generated by myocardial fibers is proportional to the stretch of the
fibers at the time of stimulation…more stretch = greater force of contraction
b. Preload = ventricular wall stress at the end of diastole…in other words the
stretch of the wall after diastolic filling
3.
4.
5.
6.
7.
c. Afterload = ventricular wall stress that develops during systolic ejection
d. Contractility = Force generated by the myocardium for a given preload and
afterload, ↑ contractility actually shifts the Frank-Starling curve up
LEFT HEART FAILURE
a. Systolic Heart Failure = diminished capacity of the affected ventricle to eject
blood because of impaired contractility or pressure overload
i. Impaired contractility
ii. Increased Afterload
iii. Increasing preload (Frank-Starling) increases stroke volume but
impaired contractility means that less is ejected, backs up and causes
pulmonary edema
b. Diastolic Heart Failure =
i. Impaired ventricular filling, impaired diastolic relaxation, increased
stiffness of the ventricle wall (S4)
RIGHT HEART FAILURE
a. RV is thin and highly compliant chamber
b. Most common cause of failure is LHF and secondly cor pulmonale
Compensatory mechanisms:
a. Frank-Starling mechanism or ↑ preload/ ventricle filling → problem is that
since ejection fraction is low, less blood is ejected and pressure builds up →
pulm edema
b. Neurohumoral (RAA, AT II, aldosterone, ADH, SNS) all of these combine to
increase stroke volume and cardiac output to maintain BP
c. Hypertrophy:
i. Volume load (mitral, aortic regurg) – Eccentric hypertrophy (series)
ii. Pressure load (stenosis, HTN) – Concentric hypertrophy (parallel)
Decompensation
a. Unknown what triggers this but you basically lose contractility
b. Increasing metabolic demand during fever, infection, tachyarrythmia, salt
ingestion, renal dysfxn, HTN, PE, etc. etc. might tip the precarious balance
towards decompensating
Tx
a. Diuretics, Nitrates, ACE Inhibitors, Dig/Dob (inotropes), B-blockers?
Congenital Defects
1. Acyanotic lesions
a. Atrial Septal Defect
i. Most common site is at the foramen ovale in the ostium secundum
ii. Also in the ostium primum → associated w/ bad mitral/tricuspid
iii. Different from patent foramen ovale because higher LA pressure
usually closes the foramen ovale during systole so no mixing occurs.
iv. Systemic embolism may result
v. L to R shunt in ASD may cause Eisenmenger’s and reversal to R to L
shunt (cyanosis!)
vi. S2 splitting and systolic murmur, RVH
b. VSD
i. Membranous rather than muscular most of the time
ii. L to R shunt develops
iii. Harsh holosystolic murmur
c. Patent Ductus Arteriosus
i. Usually closes due to rise in blood oxygen tension and a fall in
prostaglandins (can keep it open by administering prostaglandins)
ii. Usually asymptomatic
d. Congenital Aortic Stenosis
i. More common in males than females, bicuspid valves are common
cause
ii. LVH, tachycardia, harsh AS type murmur split of S2 is reverse so that
A comes after P instead of A then P.
e. Coarctation of Aorta
i. Narrowing of aortic lumen, occurs in pats w/ Turner’s syndrome
ii. LV increased pressure load, usually obstruction occurs after head and
UE artery branches so these are preserved…LE circulation diminished
iii. LVH, Dilation of intercostals bypass arteries
iv. Preductal coarctation = cyanosis, Postductal = HTN at birth
v. Weak femoral pulses, variable pressures in UE vs LE
2. Cyanotic Lesions
a. Tetralogy of Fallot
i. VSD, Subvalvular Pulm Stenosis, Overriding aorta that gets blood
from both ventricles, RVH
ii. Most common cyanotic defect, R to L shunt!
iii. Spells of irritability, cyanosis, hyperventilation, syncope….clubbing,
hypoxia, ‘boot-shaped’ heart,
iv. Alleviate symptoms by squatting which increases systemic vasc
resistance by kinking the femorals which decreases R to L shunting
b. Transposition of Great Arteries
i. Aorta connected to RV, Pulm Art to LV → cyanosis
ii. Pulm and systemic circulations are complete separate from one
another so cyanosis in systemic circulation
iii. Compatible w/ life in utero since the pulm circulation is normally
bypassed…umbilical vein feeds into RA w/ oxygenated blood →LA
via foramen ovale → LV to pulm artery → blood moves across patent
ductus arteriosis to body or goes directly via RV.
iv. After birth, umbilical supply removed, ductus closes so this doesn’t
work anymore.
v. Maintain patent ductus arteriosis using prostaglandins (which allows
some oxygenated blood into the aorta and then SURGERY w/
transposition of coronaries as well.
Aortic Aneurysm
1. Aneurysm is an abnormal localized dilation of an artery. Applied when aorta
diameter is more than 50% > than normal or approximately 3.5-4cm in diameter
2. True aneurysm – Dilation of all three layers of artery creating a bulge in vessel wall.
Either fusiform (entire circumference) or saccular (outpouching)
3. Pseudoaneurysm or False Aneurysm – Contained rupture through the intima and
media blood leaks out through a hole and is contained merely by layer of
adventitia…often caused by surgery or catheter insertion
4. Etiology
a. Descending aortic aneurysm: Atherosclerosis
b. Ascending aortic aneurysms: some kind of degenerative change, cystic medial
degeneration (due to greatest shear stress), connective tissue disorder
(marfan’s, ehler-danos)
5. Clinical
a. Asymptomatic to a point → then back pain or dysphagia, hoarseness if
compresses recurrent laryngeal nerve, in ascending aneurysms (aortic regurg)
b. Pulsatile abdominal mass
c. Rupture often fatal
6. Tx: Prosthetic graft or percutaneous endovascular graft
Aortic Dissection
1. Life-threatening blood-filled channel dividing (within) the medial layer of aorta.
2. Tear in intima that allows blood into media under systemic pressure → propagates
along the muscular plane of artery
3. Commonly involves ascending aorta > descending aorta
4. Type A = ascending aorta; Type B = descending aorta
5. Clincal
a. Sudden, severe pain, ripping, tearing in anterior chest (type A) or btw scapula
(type B)
b. Rupture into pericardium (tamponade)
c. Stroke, visceral ischemia, renal failure, loss of pulse in extremity
d. HTN, different BP in either arm, aortic regurg
6. Tx:
a. Type A: surgery with graft
b. Type B: medical mgmt over surgery with B-blockers, nitrates
Vasculitic Syndromes
1. General
a. Immune complex deposition (type III hypersensitivity) with complement
activation (c5a) which attracts neutrophils → release lysosomal contents →
produces free radicals
b. T-cell mediated (type IV hypersensitivity) – Mфs and Lфs with vessel
inflammation and necrosis etc.
2. Polyarteritis nodosa
a. Systemic vasculitis of small and medium sized vessels.
b. Nodules found along course of these vessels
c. PMNs in all three layers with intimal proliferation, fibrinoid necrosis and
lumen occlusion
d. Idiopathic but may be secondary to Hep B infecdtion
e. Tx with prednisone
3. Takayasu’s arteritis
a. Targets the aorta & causes cerebrovascular ischemia, arm claudication,
pulselessness (branches of aorta)
b. Malaise and fever
c. Infiltration of plasma cells and Lфs
d. Tx: steroids
4. Temporal arteritis
a. Medium to large-sized arteries
b. Cranial vessels
c. Lф infiltration w/ fibrosis, necrosis and granulomas containing multinucleated
giant cells
d. Decreased temporal pulses, prominent headache, visual impairment due to
ophthalmic artery arteritis
5. Raynaud’s Syndrome (NOT A VASCULITIS, JUST ADDED HERE FOR
CONVENIENCE SAKE)
a. Vasospasm of peripheral (digital) arteries occurs in indivudals in cold
temperatures.
b. Pattern is white as blood flow is interrupted, cyanotic as Hgb saturation falls
and then ruddy as blood flow returns.
c. Clinical: pain, numbness, paresthesias.