Cardio TBL Flashcards
Areteriosclerosis =
Hardening of Arteries
• Atherosclerosis: large and medium arteries;
INTIMAL CHANGES
—Lipid deposition, accumulation of macrophages + myointimal cells —>
plaque formation
• Arteriolosclerosis: Hypertension induced
hyperplasia/trophy of smooth muscle cells (Media)
• Endarteritis Obleterans:
Response to inflammation (syphilis); INTIMA
Arteritis:
• Arteritis: fibrinoid necrosis of arterial wall
Monkeberg’s:
Calcification of MEDIA
Areteriosclerosis Emphasis on Progression
• Intimal changes are persistent for decade(s), but then sclerosis can progress. Evidence shows lesions in same gross location, but different depth (in vessel wall) as individuals age.
Areteriosclerosis Presentation
• Presentation: 50 years of age
Arterial Structure Review Three Parts:
Intima:
Media:
Adventitia:
Arterial Intima:
Endothelium –> internal elastic lamella; contains myointimal cells in the sub-endothelial space
Arterial Media:
smooth muscle cells + Collagen I/III
Arterial Adventitia:
type I collagen + fibroblasts Vasa Vasorum not found in abdominal aorta –> more susceptible to athero.
CHRONIC ENDOTHELIAL DYSFUNCTION:
- Platelet Microthrombi
* Fatty Streaks
Platelet Microthrombi -
Proposed theory because aggregates of plat are found incommon sites of athero
Fatty Streaks -
Subendothelial lipid (cholesterol/esters) + foamy cells
- –No hemodynamic change
- –Reversible (Lactating babies +, 4-5 y/o)
Bottom Line: Endothelial injury
↑permeability for lipids + ↑adhesions
Endothelial Injury occurs from:
• Hyperlipidemia/hypercholesterolemia • HTN • Smoking • Diabetes/Metabolic Syndrome • Toxins/Viruses • Homocysteine Fatty streaks are reversible with lifestyle change. if not --> Fibrous (Fatty) Plaque
Areteriosclerosis Pathophysiology:
• Because Atherosclerosis = chronic endothelial dysfunction; any disease that causes endothelial injury can lead to it.
Three Consequence of endothelial injury:
- ↑Endothelial adhesion to leukocytes and platelets
- Passage of lipids (LDL) into subendothelial space (Fatty streak)
- DAMAGE –> endogenous activation macrophages–> ↑cytokines + ↑Macrophage presentation to T-Cells –> ↑T-Cell Inflammation
- ↑Endothelial adhesion to leukocytes and platelets leads to?
Adhesion Accumulation of macrophages, myointimal cells and monocytes (future foamy cells) in subendothleial space
- –Platelets on Fatty Streak –> ↑Cytokines –> ↑T Cell Activation
- **Cytokines–> Smooth muscle proliferation / ECM deposition (smooth muscle from tunica media –> tunica intima)
- Passage of lipids (LDL) into subendothelial space (Fatty streak) leads to?
- –LDL must be oxidized –> release inflammatory lipids
- –Can be modified by homocysteine (MI in Homocysteinuria)
- –Additional ↑Endothelial adhesion particles
- DAMAGE –> endogenous activation macrophages–> ↑cytokines +
↑Macrophage presentation to T-Cells –> ↑T-Cell Inflammation leads to?
—Inflammation –> ↑IL-6 –> ↑Acute Phase Proteins (SAA, CRP)
***CRP is best indicator of disrupted plaques; thus better than LDL for
predicting cardiovascular events
↑Endothelial adhesions leads to?
Macrophages and monocytes migrating: Lumen (L) to subendothelial space.
Once in subendothelial space,monocyte and macrophage ingests lipid –> Foamy Cell
Endothelial injury morphology?
• Fatty streaks: yellow streaks on
endothelium
• streaks occur at points of bifurcation
—Turbulent flow, likely place for injury
FATTY STREAK leads to?
FIBROUS PLAQUE
Proliferative lesion:
Monocyte, macrophage, myointimal cells proliferate===Intimal Thickening!
Fibrous Plaque =
• Amorpous central core: cholesterol + esters, acellular debris, foamy cells
• Fibrous cap: myointimal cells, collagen,
glycoproteins, PGs
—Provides stability
• Endothelium is intact (Continuous)
—But dysfunctional –> platelets!
Pathophysiology:
FATTY STREAK –> FIBROUS PLAQUE
- Untreated fatty streaks allow ↑Lipid deposition + ↑Leukocyte adherence to dysfunctional endothelium
- ↑Foamy Cells
- ↑Stress –> ↑Smooth muscles changes –> ↑Myointimal cells
Veins and Pulmonary Circulation
- VEINS ARE NOT AFFECTED
* Same with pulmonary circulation, EXCEPT IN PULMONARY ATHEROSCLEROSIS (DDx: Pulmonary Hypertension)
Morphology: “Fibrofatty Plaque”?
- Gross: elevated lesions at points of turbulent flow
- Micro: (image) see foamy cells (F) (in and out of core), fibrous cap, and central core (necrotic material and cholesterol crystals)
Complex Atheromatous Lesions
FIBROUS PLAQUE + SOMETHING ELSE
Complex Atheromatous Lesions Maintains Components of Fibrous Plaque
- Necrotic debris
- Cholesterol deposits
- Foamy cells/fibrous cap
Complex Atheromatous Lesions + New Process:
• Calcification (breaks off with pulse flow) • Hemorrhage (capillary ingrowth) • Ulceration/Fissure (abdominal aorta) • Ruptured Plaque (Coronary Syndrome) • Luminal Thrombosis (platelets) Progression from Fibrous Plaque --> Complex Lesions is NOT mandatory
Complex Atheromatous Lesions Pathophysiology:
- Again, lack of treatment/intervention allows fatty streak –> fibrous cap –> addition of new process
- Recall abdominal aorta is more susceptible to atherosclerosis because lack of vasa vasorum
Myocardial Infarction from CAD requires?
100% occlusion
Most patients with CAD have?
Multiple plaques along their entire coronaries
Because ATHEROsclerosis =
Intima of CA is thickened
Effect of Pre-Existing Collaterals:
• Men have ↑↑ collateral circulation
• Premenopausal women have ↓collaterals, but ↓atherosclerosis
• Immediately post-menopausal women CA occlusion = DEVESTATING
—Enter “accelerated atherosclerosis” and have ↓collateral circulation
Coronary Artery Disease Etiology:
• Coronary arteries especially at risk because intimal thickening naturally takes place at points of bifurcation (turbulent flow)
Coronary Artery Disease Areas at Risk
• LAD: anterior LV, IV-Septum, Apex
• Circumflex A: Wall of LV
• RCA: Posterior wall of LV, IV septum,
RV, and Right wall of Heart
Coronary Artery Disease Pathophysiology:
- 80% of lumen can be narrowed without myocardial necrosis
- Recall from acute coronary syndrome that endothelial dysfunction –> atherosclerosis, but damage does not occur until plaque ruptures
- Acute episode (plaque rupture, fissure, hemorrhage, thrombosis) —-> dislodge plaque + expose endothelium –> platelets aggregate (thrombus) —> TXA2 = VASOCONSTRICTION
Stary’s Classification of Coronary Artery Disease
- Type 1: Adaptive Thickening
- Type 2: Macrophageic Foam Cells
- Type 3: Extracellular Lipid = preatheroma
- Type 4: Necrotic Core = atheroma
- Type 5: Fibrous cap = fibroatheroma
- Type 6: Atheroma + addition = complicated lesion
Myocardial Infarction =
100% Occlusion of Coronary Artery
Myocardial Infarction Area of Risk vs. Area of Necrosis
• Area of risk: area irrigated by coronary
artery if occluded for long time
• Area of Necrosis: area of actual tissue
death
Big Point: quicker perfusion occurs –>
less area of necrosis
Myocardial Infarction: 10 hours:
no gross/micro change
Myocardial Infarction: 10-20 hrs:
Dead cells (white) cell surrounded by hypereosinophilic + some edema +/- PMN (Coagulative necrosis)
Myocardial Infarction:1-3 days:
↑eosinophilia, pyknosis, karyorrhexis, ↑edema + ↑PMNs
Myocardial Infarction: 4-7 days:
Macrophages + PMNS remove dead cells –> risk for rupture; granulation tissue begins to form around necrotic area
Myocardial Infarction: 7-10 days:
Gross yellowish color; ↑collagen + granulation tissue
Myocardial Infarction: 11-21 days:
Dead cells gone (macro w/ lipofuschin); granulation tissue
Myocardial Infarction: 4-10 weeks:
Granulation tissue —> non-contractile scar
Post-MI Complications Reperfusion Injury:
• Fibers at edge of MI are hypereosinophilic bands with distortion, pyknosis, and interstitial edema ===Contraction Bands • During MI, ↑Ca++ accumulation. • When reperfused --> massive sustained contraction • Also free radical damage
Post-MI Complications Pathophysiology:
During reperfusion post MI, lots going on:
- Mitochondria come back, but not quick enough to stop ROS
- pH is changing drastically (back up)
- Ca++ overload
- Inflammation
Myocardial Hypercontracture –>
↑Pores in Mito. Membrane = DAMAGE
Reperfusion ↓Infarction size, but do it after cardioprotection to prevent cardiac hypercontracture:
- Rx preventing mitochondrial membrane pore formation
* Rx activating reperfusion injury salvage kinase (RISK) pathway
Post-MI Complications Mural Thrombosis
Area over infarct thickens and is
abnormal –> attracts platelets
Post-MI Complications Consequences Mural Thrombosis
- Embolism
* Occupy LV volume —> ↓CO
Post-MI Complications Ventricular Aneurysms
Ventricular Aneurysms
• Common in transmural infarcts
Mechanism:
• While scarred area has ↑strength, during contraction it remains
stationary and healthy myocardium contracts, creating an anuerysm
Ventricular Aneurysms
Common in transmural infarcts
Ventricular Aneurysms Mechanism:
While scarred area has ↑ strength, during contraction it remains stationary and healthy myocardium contracts, creating an anuerysm
Myocardial Rupture Occurs
Days 4-7 (max removal of tissue)
—60% during this time period; 30% in 24 hr
Myocardial Rupture Risk Factors:
- Hypertension
- Diabetics
- Women in early menopause
- Psychiatric Patients
Myocardial Rupture Pathophysiology - Two Required Conditions
• Transmural infarct - full thickness of wall must be necrotic — Makes sense, or else blood would not seep out
• ↑↑ intraventricular pressure — Push blood out, dissecting through the wall
Rupture pushes blood into pericardial sac (TAMPONADE) or can rupture a papillary
Septal Rupture
Acquired A-V Defect Less common than rupture of the free wall.
Free wall > septal > papillary
Aneurysm =
Sac formed from dilation of vascular wall (cardiac, arterial, venous) —Call venous aneurysm “Varicose / Varices”
Thoracic aneurysms =
Dissecting unless proven otherwise.
Abdominal aneurysms =
Atherosclerotic unless proven otherwise.
Aneurysms Morphological Classification:
Fusiform, Saccular, Cylindrical, Fistula
Laplace’s Law :
Tension = (Pressure)(Radius)/(2xHeight)
• Dilation –> ↑Radius –> ↓Wall Thickens (↓H) –> –>
What causes symptoms of aneurysms?
- Compression of surrounding organs
- Ischemia distal to aneurysm
- Hemorrhage due to rupture
Dissecting (Thoracic) Aneurysm =
Intimal tear in Aorta –> Blood in MEDIA
• Intimal tear ~ 6cm from aortic valve.
Dissecting (Thoracic) Aneurysm Etiology:
• Poorly controlled hypertension*** • Marfan’s Syndrome (presents early) • Bicuspid Aortic Valve • Familial Thoracic Aortic Aneurysm Syn • Coarctation of Aorta (HTN proximal) • Ehlers Danlos Syndrome (Type IV) • Loey’s Dietz Syndrome (TGF B) • Iatrogenic (catheters, surgery) • Turnuer’s Syndrome (coarctation) Ascending/thoracic aorta has > 30 elastic lamella, it has vasa vasorum blood supply.
Dissecting (Thoracic) Aneurysm Presentation
Presentation
• Age: 50-70; males > females (2:1); >50% mortality
• Pain to back b/c adventitia is stretched (has pain receptors)
Dissecting (Thoracic) Aneurysm
Fate of Dissection
• Rupture —> hemorrhage OR false lumen (↑BP)
• Re-entry (best prognosis)
• No rupture —> thrombosis of false lumen (note normal BP)
• Collapse of Aorta
–hemocardium –> cardiac tamponade with retro-grade flow only
Dissecting (Thoracic) Aneurysm Morphology:
• Dissection occurs and blood flows to specific location
• 80% have Cystic Medial Necrosis
—No cysts; pools of PG (cystic) displacing smooth muscle and elastic
lamellae (necrosis) in media (medial) = Creates points of weakness
Vasa vasorum penetrates?
Adventitia and divides ~1/3 way into media; at this junction (inner 2/3 from outer 1/3 of media) is least resistance path for
blood being forced through intimal tear
Atherosclerotic (Abdominal) Aneurysm =
Weakening of Aortic Wall –> Leakage
Atherosclerotic (Abdominal) Aneurysm Etiology:
Atherosclerosis***
Atherosclerotic (Abdominal) Aneurysm Mechanism:
• Atherosclerosis ---> weakening of wall • ↑Dilation --> ↑Pressure (Laplace) • ↑Pressure --> Endo damage (↑ather) • Cycle continues; eventually endothelial damage ---> ↑Thrombus/Platelets • ↑Thrombus --> damage --> leakage
Atherosclerotic (Abdominal) Aneurysm Presentation:
• 33% die <10 years
• Usually asymptomatic until late
∝ size + diagnosis + rate
Leakage/Rupture most common COD
Atherosclerotic (Abdominal) Aneurysm
Consequence of Dissection
- Narrow/occlude renal and mesenteric arteries
- Pressure = ↑Bone Damage + ↑Viscera Damage + ↑Neuron Damage
- Rupture –> hemorrhage
Atherosclerotic (Abdominal) Aneurysm Morphology:
TONS of atherosclerosis and thrombi (mura/transmural)
Pseudoaneurysms (Thrombus)
Trauma induced bleed –> thrombus –>
dilation –> looks like aneurysm
Pseudoaneurysms (Thrombus) Presentation:
Knife, bullet wound, Carson Rider post-Wiz concert
Pseudoaneurysms (Thrombus) Morphology:
Hemorrhage –> clot –> dense fibrous tissue
Mycotic Aneurysm:
Bacterial Arteritis (Septic Emboli)
Vessel wall weakening from infection
Misnomer, caused more by bacterial
rather than from bacteria
Mycotic Aneurysm Presentation:
- Thrombosis +/- infarction
* Rupture
Most common cause of Sudden Cardiac Death?
Ventricle Fibrillation (1,000 Americans/day)
Ventricle Fibrillation most common in patients with?
MI + Heart Disease
Ventricle Fibrillation Treat with?
AICD (Automated Implantable
Cardioverter Defibrillator)
Ventricle Fibrillation Iatrogenic undetectable cause?
↑potassium
Most common cause of stroke?
Atrial Fibrillation (atrial stasis –> thrombus –> stroke)
Atrial Fibrillation Prophylaxis with?
Warfarin
Atrial Fibrillation interpret ECG?
• HR = 300 / (#Big boxes between peaks) = # total peaks x 6
• LV Hypertrophy: (V1 Depth of S-Wave) + (V5 Depth of R Wave) —If >35 mm = LV Hypertrophy
• Rhythm: look for normal P wave before each complex (normal~60)
• Axis: Determined by Lead I and aVF
+Lead 1 and +Lead aVF = normal
+Lead 1 and -Lead aVF = Left Axis Deviated (opposite is RAD)
-Lead 1 and -Lead aVF = Indeterminate Axis
Mechanisms Arrhythmia Types?
- Enhanced Automaticity
2. Re-Entry
Enhanced Automaticity Two things can change the slow depolarization?
Increasing rate of depolarization OR raising the threshold potential (less negative)
What causes ↑ In Phase 4 Slope?
↑SNS Tone / ↓PS Tone ↑CO2 / ↓O2 ↑Stretch ↑Digoxin ↓Potassium
Re-entry occurs requiring?
Slow conduction + re-excitable
cell
Re-entry causes?
Circular movement produces a rapid series of APs with ↑ Frequency
===TACHYCARDIA
===ARRHYTHMIA
Most common cause of SCD (Sudden Cardiac Death)?
Ventricular Fibrillation (1,000 Americans/day)
Ventricular Fibrillation ECG Features
- Complete erratic rhythm
* No Identifiable waves
AICD - Automated Implantable Cardioverter Defibrillator does what?
- Device is given preset HR
* Monitors rate and rhythm of heart and alters via shock delivery
Atrial Fibrillation ECG Features:
- Chaotic baseline = Irregularly irregular = not consistently weird
- NO DISCRETE P WAVES
Atrial Fibrillation Treatment:
- B-Blocker
- Ca++ Channel Blocker
- Digoxin
Atrial Flutter ECG Features:
- Rapid back-back atrial depolarization waves
* SAW TOOTH PATTERN
Ventricular Hypertrophy:
Ventricular Hypertrophy • ↑Mass of ventricle • ↑Mass --> Delayed Depolarization • Common with CHF • Common with valvular disease • LV Hypertrophy puts patient at ↑Risk for Coronary Heart disease • Equal risk factor for MI as smoking, etc
Ventricular Hypertrophy ECG Features:
- ↑QRS Complex Peak —> steep QRS Segment
- S in V1 + R in V5 or V6 (whichever is larger) ≥ 35 mm
- May see tall P-wave
- T-Wave Reversal
Bundle Branch Block:
- Conducting tissues is “blocked”
- Delayed activation of ventricle
- Always abnormal, but not specific
Bundle Branch Block ECG Features:
↑ QRS width –> prolonged QRS Segment
P waves –>
Look at for atrial / supraventricular origin
QRS –>
Widened in ventricular origin; can be narrowed in atrial
Tombstone ST =
STEMI
Depressed ST =
Ischemia
Automaticity Disease:
Sinus tachycardia, sinus arrest, VPB, etc.
*Both mechanisms can cause most arrhythmias; these are common groupings
Re-Entry Disease:
VTAC, PSVT, WPW, AFIB
*Both mechanisms can cause most arrhythmias; these are common groupings
Pathogenetic Mechanisms of Vasculitis
- Immune Complex Deposition in Vessel Wall
- ANCA-Mediated
- Ab Directed at Vessel Wall (endothelial, GBM)
- Cell Mediated Immune Reaction (Granuloma)
- Component of Other Immune Disorders
Vasculitis ANCA-Mediated:
- –Pathogenic from activating PMNs (↑adhesion via B2 integrin, Fcgamma)
- –Target Endothelia–> ANCA-PR3 + Endothelia –> lost thromboresistance
Vasculitis Ab Directed at Vessel Wall (endothelial, GBM):
- –In anti-endothelial, Ab levels == disease activity
- –Ab usually bind to cytoplasmic components, not surface
Immune Complex Pathogenicity Criteria
- Circulating immune complex
- Hypocomplementemia
- IgG (or other) deposition in vessel wall
- Complement deposition in vessel wall
Vasculitis has to be diagnosed with?
Biopsy
Vasculitis Infectious:
From pathogen directly invading wall.
Recognize that infectious can generate an immune-mediated inflammation.
Vasculitis Non-infectious
Non-infectious from immune-mediated inflammation.
Variability in Non-Infectious Vasculitis
Disease occurs from complexes; presentation is location-dependent
Vasculitis =
Vessel Wall Inflammation with necrosis of vessel walls, narrow/occlusion +/- aneurysms
Kawasaki’s Disease
Kawasaki’s Disease Vasculitis
• Exact etiology is uknown
• Most likely delayed hypersensitivity T
cell reaction
Kawasaki’s Disease Presentation:
- Asian children < 4 years old
- “strawberry tongue”
- Lymphadenitis, conjunctivitis
- High association with developing coronary aneurysms
Buerger’s Disease
Thromboangitis Obliterans
- SMOKING, SMOKING, SMOKING
* Treat: smoking cessation!
Buerger’s Disease
(Thromboangitis Obliterans)
Presentation:
- Heavy smokers
- Males < 40
- Intermittent claudication –> gangrene + autoamputation of digits
- Radial arteries often affected –> Raynaud’s Phenomenon
Temporal (Giant-Cell) Arteritis:
• Exact etiology unknown • Most likely T-cell mediated response against vessel antigen • Affects arteries neck and up • Most common vasculitis in elderly people (females)
Temporal (Giant-Cell) Arteritis Presentation:
- Female patients > 50 y/o
- Unilateral headache + jaw claudication
- Irreversible blindness (opthalmic artery occlusion)
- Associated with polymyalgia rheumatica
Temporal (Giant-Cell) Arteritis Morphology
- Affects branches of carotid artery
* Focal granulomatous inflammation
Temporal (Giant-Cell) Arteritis Labs
↑ ESR
Temporal (Giant-Cell) Arteritis Treatment
High Dose Steroids
Fats have two functions:
- P-lipids + cholesterol = structural part of all cell membranes
- Triglycerides (TG) and FFA = energy sources of body
General Flow of Transport Fats:
- TG in Liver/Gut —-> Muscle (energy) and Fat (storage)
- Cholesterol across tissue —> Liver
- –All cells make cholesterol; they have excess; rarely deficient
Lipoprotein Functions:
- Carry p-lipids, free cholesterol, cholesterol esters, TG, and apolipoproteins
- –Apo’s have structural, cofactor, and receptor roles - Allow easy circulation of fat throughout body
Lipoprotein Pathophysiology Disease Overview
- Genetic disease: think mutation in apo, apo-receptor, or enzymes
- Environmental disease: think overproduction of certain component
CM + VLDL =
TG Rich Lipoproteins
CM made in?
GI
VLDL made in?
Liver
CM has?
apoB-48 (no LDL receptor)
VLDL has?
apoB-100
• TG removed from and via?
CM or VLDL via LPL
LPL hydrolyses?
TG –> FFA + Monoglyc.
VLDL =
↑TG + ↑Cholesterol
Post LPL =
IDL/LDL w/↑Cholesterol
ApoE =
Liver, Macrophages, CNS
—Macrophages w/cholesterol secrete
apoE with the cholesterol; important b/
c macrophages are involved in athero
Hypobetalipoproteinemia =
trunc apoB ↓ApoB Production
• Truncated apoB secreted ↓, excreted ↑
by renal tubule
Hypobetalipoproteinemia Genetics Heterozygotes:
Heterozygotes: 25-50% of LDL; steatosis
Hypobetalipoproteinemia Genetics Homozygotes:
Homozygotes: ↓↓↓LDL and CM
- –Fat malabsorption –> ↓Vit A,D,E, K
- –Acanthocytosis
- –Neuromuscular Degeneration (↓VIt E)
Hypobetalipoproteinemia - Physiology
Intestine and liver REQUIRE apoB to export TG
• ApoB = hydrophobic; remains in membrane of ER and grabs p-lipids,
TG, esters and free cholesterol = forming lipoprotein
• Secreted; acquire additional apo-proteins from HDL in blood
Hypobetalipoproteinemia Pathophysiology:
• Partial (heterozygotes) or full (homozygote) truncation of apoB –>
inability to export TG from gut (48) or liver (100) in CM + VLDL
• Expect to see ↓CM and ↓LDL levels (↓Synthesis and ↓Secretion)
Abetalipoproteinemia =
Deficient MTP
↓CM + ↓VLDL production (RECESSIVE)
Abetalipoproteinemia Heterozygotes:
No abnormal values.
Abetalipoproteinemia Homozygotes:
↓CM + ↓LDL
- –Similar sympotoms as hypo-beta
- –↓ApoB containing lipoproteins (DDx)
Abetalipoproteinemia Physiology:
MTP = Manages Transport & Particle formation
• Shuttles TG and cholesterol esters: membranes lipoproteins
• Controls lipid particle / droplet formation for apoB to attach
Abetalipoproteinemia Pathophysiology
- If apoB does not accumulate lipoprotein components –> degrades
- ↓MTP –> ↓Shuttling of TG + ↓Lipoprotein Particle –> apoB degrade
Familial Combined Hyperlipidemia (FCHL) =
• Some patients have ↑ApoB Production ---B/c one gene cluster causing FCHL also involved in apoB/LDL metabolism • ↑Risk of CVD ---↑## of small dense particles --> ↑atherogenic risk of LDL • Family with varying lipid phenotypes, • Consistent ↑VLDL of NORMAL COMPOSITION
Familial Combined Hyperlipidemia (FCHL)
Physiology
apoB is key in forming lipoproteins CM and VLDL
Familial Combined Hyperlipidemia (FCHL)
Pathophysiology
- ↑ApoB synthesis —> ↑VLDL synthesis by liver (normal composition)
- ↑VLDL —> ↑LDL
Familial Combined Hyperlipidemia (FCHL)
Consequences of ↑LDL
- ↑VLDL Production + ↓LDL Clearance –> ↑Normal LDL –> ↑Cholesterol (b/c TG is removed via LPL)
- ↑VLDL Production + ↓Cholesterol Accumulation –> ↑LDL apoB (low TG and low cholesterol) –> HYPERAPOBETA
- ↑VLDL production + ↑LDL Clearance –> normal/↓LDL apoB and cholesterol
Familial Dysbetalipoproteinemia
Type III Hyperlipidemia
• ↑Beta-VLDL in plasma = ↑Risk Athero ---Cholesterol rich ---Labs: ↑TG + ↑Cholesterol • Called “Broad-Beta” Disease • E2/E2 genotype ---Normal VLDL, but... ---Post-delipidation, cannot bind to LDL-R ---Accumulates cholesterol via HDL CETP • Analysis will look like ↑VLDL, but these are composed of ↑cholesterol
Familial Dysbetalipoproteinemia
(Type III Hyperlipidemia)
Possible Genotypes
• E2/E2 = ↓+ charge in ApoE LDL-R binding domain • E2/E2 genotype is 1%, but frequency of this disease ~ 10,000 (rare) ---B/c mutation not inside AA 140-160 • 1-2 E2 alleles = ↓LDL + ↑TG ---Even without Type III HLP • 1-2 E4 alleles = ↑LDL + ↑TG ---↑LDL b/c better IDL--> IDL conversion
Familial Dysbetalipoproteinemia
(Type III Hyperlipidemia)
Alzheimer’s Risk
- ApoE4 best predictor for Alzheimer’s
* ApoE2 protects against Alzheimer’s
Familial Dysbetalipoproteinemia
(Type III Hyperlipidemia)
Physiology:
• AppE clears remnants of TG rich lipoproteins = CM/VLDL remnants
• ApoE gets into circulation via HDL or LDL, b/c these come from liver
—CM never has ApoE before plasma b/c ApoE not made in intestine
• Reservoir of ApoE is in HDL; new VLDL/CM particles get ApoE when they enter plasma from HDL transfer
• Post-lipolysis (TG removal via LPL), the ApoE donation to CM/VLDL allows them to bind to both B-E receptors on liver
—B-E receptors = LDL-R that bind both ApoB (LDL) and ApoE (IDL)
—Remnants are atherogenic; important to remove!
Familial Dysbetalipoproteinemia
(Type III Hyperlipidemia)
Pathophysiology
• AppE normally binds E-LDL-R via charge interaction (ApoE is ++++) • If + charge is lost --> binding is disrupted ---Note charge mutation has to exist AND it has to be in the LDLReceptor binding region (AA 140-160) • IEF Gel for ApoE Shows ---ApoE-3 = normal charges ---ApoE-2 = ↓+ or ↑- charge ---ApoE-4 = ↑+ or ↓- charge
Why is Beta-VLDL Bad?
Beta-VLDL, like LDL, is taken up by macrophages, but does not need to be oxidized first –> ↑foam cell formation
Changes in ApoA1 Production Cause:
• Mutated ApoA1 --> ↓HDL Levels • Most likely responsible for hypoalphalipoproteinemia (↓HDL) and hyperalphalipoproteinemia (↑HDL) • Most have ↑atherosclerosis Exception • ApoA1 Milano == Rapid RCT • Still have ↓HDL levels
LCAT Deficiency / Fish Eye Disease =
↓HDL Cholesterol • No LCAT = no FC --> CE in pre-HDL • HDL particles don’t acquire spherical shape b/c no hydrophobic ester • +/- Poor RCT; could be fine or terrible
LPL Deficiency Causes
↓ HDL Cholesterol • LPL genetic defect, ↓ApoC2, ↑ApoC3, ↓Insulin (DKA) • LPL delipidizes VLDL and gives extra superficial material to the growing HDL3 particle --> HDL2 • Ability to grow HDL3 w/CE is important for ccn-gradient transfer into liver via SR-B1
Abnormal ↑Hepatic Lipase Activity Causes:
↑HDL Clearance = ↓HDL Cholesterol • HL can ↑HDL uptake in liver, but does not recycle HDL/ApoA1 ↑HL From: • Hyperinsulinemia • Hyperthyroidism • Hyperandrogenism ↓HL From: • Estradiol • Adiponectin (cytokine in thin people)
Physiology - Reverse Cholesterol Transport (RCT)
- ApoA1 from liver/GI –> adds to disc-shaped nascent pre-beta HDL
- Cholesterol Efflux from Cells
- Free Cholesterol –> Cholesterol Esters (FC–>CE)
- HDL2 Uptake from Liver
- Cholesterol Ester Transfer Protein (CETP)
CETP levels don’t determine activity; CETP-Inhibitor levels do!
CETP Deficiency Yields:
↑CETP-I / ↑LTIP === (6-Fold)↑HDL2 Cholesterol
The real goal of cholesterol should be LDL
LDL<70 in those with other risk factors-not on test…
Stenosis:
Narrowing of orifice –> valve doesn’t open correctly
Regurgitation (=insufficiency):
Leakage in opposite direction –> valve doesn’t
close correctly
Cardiac Adaptation
Concentric Hypertrophy:
Pressure Overload = STENOSIS (+HTN)
—↑Thickness (thick walls) but normal volume - “LV Hypertrophy”
Cardiac Adaptation
Eccentric Hypertrophy:
Volume Overload = REGURGITATION
—↑Dilation of Chamber (more volume + thin walls) —> ↑Output (Starling’s Law)
Valvular Heart Disease Acute
In acute scenarios, there is no time to adapt; pt presents severely ill. Murmur heard, but no concentric/eccentric hypertrophy
• Thus, expect to see ↑↑ΔP in acute scenarios with ↓structural heart changes.
Valvular Heart Disease Chronic
↓↓ΔP with ↑structural heart changes in chronic
Diseased Aortic Valve Rheumatic:
Micro-vegetation (not as much as infective endocarditis) + FUSION of COMMISURES
Diseased Aortic Valve Calcification/Bicuspid:
Sinus of Valsalva calcification + NO FUSION
Symptoms of Stenosis
Syncope, Angina, Heart Failure, Arrhythmias
Types of Stenosis
Supravalvular Stenosis
Valvular Stenosis
Subvalvular
Supravalvular Stenosis:
Above the valve; congenital (ex: narrowing of aorta).
Valvular Stenosis:
At the valve; congenital or acquired.
Subvalvular:
Below the valve, congenital or acquired ex: IV septum pushing into one ventricle.
When is stenosis TOO severe?
Valve area depends on two things:
- Gradient - pressure drop across LV and Aorta in systole (normally 0)
- Flow Across Stenosed Valve approximated by CO
Stenosis Evaluation:
ECHO – view diseased valves, hypertrophy and blood flow.
Stenosis Pathology Basics:
Valves = AVASCULAR endothelial-lined (endocardium)
—Core of PG, GP, Collagen (Type 1) Fibers, and Fibroblasts
Post-Streptococcal Molecular Mimicry?
2-3 weeks post strept infection form Ab:
cross react with cytoskeletal proteins
What valve is affected?
Mitral > Aortic > Tricuspid > Pulmonary
—Mitral valve experiences the most pressure
in the entire heart.
Possible exam topic?
Fusion of commisures?
Occurs in RF, but not in calcified aortic stenosis.
Rheumatic Fever Presentation:
• 2-3 Weeks Post-Streptococcal Infection
• “Dog that licks the joint, but bites the heart” === TRANSIENT
(except long term pericarditis effects)
Mitral Valve Stenosis
Rheumatic Fever
↑P behind the mitral (stenosed) valve
—Concentric hypertrophy + dilation of the LA
—Pulmonary Hypertension-> Atherosclerosis
—Concentric hypertrophy of RV!
—Thrombi (stasis) from damaged + dilated
LA –> Ball/Valve + Emboli
Mitral Valve Stenosis
Rheumatic Fever
Presentation:
- SOB (pulmonary HTN –> ↑Pressure in Pulmonary Capillaries –> Capillary Congestion –> ↑fluid in alveolar space)
- Alveolar Fluid w/fibrinous material, RBC (+macrophages if chronic)
- Hemoptysis (if chronic)
- Right Heart Failure
- Atrial Fibrillation –> Brain emboli –> Stroke
- Dysphagia (atria compresses back on esophagus)
Mitral Valve Regurgitation Causes:
- MITRAL VALVE PROLAPSE
- Left Ventricular Dilation
- –Left sided heart failure dilates ring of MV - Rheumatic Fever
Mitral Prolapse Leaflets replaced by?
Myxomatous (spongy) tissue
Mitral Valve Regurgitation Presentation:
- Can be asymptomatic with murmur
- Sudden rise in Atrial pressure
- ↑Preload (from atrium) + ↓Afterload (from venting) = ↑↑SV
Mitral Valve Regurgitation
Acute vs. Chronic: EXAM QUESTION
• Acute =
No change in RA volume (adaptation), ↑Pulmonary Capillary Wedge Pressure (large pressure build up)
Murmur For MV Regurgitation
Systolic murmur= pansystolic: S1——S2
Aortic Valve Stenosis Causes:
- Age-Related Calcification
- –Calcified aortic stenosis from wear/tear
- –Calcification in Sinuses of Valsalvas
- –”Arthritis of the aortic valve” - Bicuspid Aortic Valve
- –Congenital Failure of Apoptosis
- –Prone to calcification –> stenosis
Aortic Valve Stenosis Pathophysiology:
In both, ↑P in LV —> LV Concentric
Hypertrophy –> HTN, Angina, Syncope
Aortic Valve Stenosis Presentation:
- Pt > 60 = Calcified
- Pt ~ 35-40 = Bicuspid Aortic Valve
- Delayed/Absent Arterial Pulse
- Heart Failure
- Angina = O2 demands from ↑work
- Syncope = ↓supply (fixed CO)
- Arrhythmia
- Sudden death
Aortic Valve Stenosis Murmur:
Systolic diamond shape murmur S1 –<>– S2
Mitral Valve Stenosis Murmur
Diastolic murmur: S1——S2 OS⤷S1
Aortic Valve Regurgitation Disease of?
Aorta/Aortic Cusps
Disease of Aorta/Aortic Cusps Pathophysiology:
- ↑LV Volume == ↑Preload + ↑Eccentric Hypertrophy (dilation) == ↑SV (Starling)
- ↑SV + aortic venting = ↑pulse pressure
Infective Endocarditis Two Requirements:
- BUGS in BLOOD
- –Any pathogen (virus, bacteria, fungi) - Abnormal Heart Valve
Infective Endocarditis Pathology:
• ↑Velocity blood across abnormal valve
• Platelets adhere –> thrombus formation
• Bacteria bind to injured endothelium
(direct contact / fibronectin mediated)
Infective Endocarditis Consequences
• Valve vegetation, regurge, destruction • Metastatic infection (Osteomyelitis) • Immune Reaction (Arthritis, nephritis) • Local spread (myocarditis, pericarditis) • Septic Embolus (Mycotic Aneurysm) ---Coronary vessels (MI), kidney, hand
Bacteremia =
Living bacteria in blood.
Septicemia =
↑invasion + replication in blood stream.
Infective Endocarditis Source of Infection
- –IVDU (polymicrobial); Prosthetic Valves (PVE)
- –Dental procedures involving gingiva/gums
- –Catheters/iatrogenic.
Infective Endocarditis Treatment:
- Recall –> VALVES = AVASCULAR
- Fibrin verruca forms colonies of bacteria; because avascular valves high dose of abx needed to kill bacteria via passive diffusion.
Infective Endocarditis Microbiology:
Gram + is most common EXAM* • Acute IE = Staph Aureus • Subactue = Strep Viridans • Non-enterococcal Group D (S.Bovis -- look for GI disease) Gram - in Key Patient Profiles • Pseudomonas Aeruginosa in IVDU and PVE Fungal • Also in IVDU and immuno-deficient Culture Negative? • Prior ABX most common cause
Infective Endocarditis Presentation:
- IV Drug abusers (polymicrobial)
- Immune compromised (Fungal)
- Age: 30 (pre-antibiotic, more women); 50% >50 (last decade, men)
- Subacute = nonspecific symptoms; ACute = ill + stroke/arthritis
- Splinter Hemorr – embolization ≠ 100% diagnostic septic emboli
- Roth Spots (eye)
- Janeway Lesions (septic emboli in palms of hands)
- Osler Nodes (immune complexes in fat pads)
Infective Endocarditis Morphology:
- Note large friable vurruca (vegetation) on mitral valve
- Valves often erode and perforate
- Fungal vegetations larger than bacterial, though less common
- Tricuspid valve commonly infected in Drug users.
Infective Endocarditis Tests:
- CULTURE, CULTURE, CULUTRE
* TEE - closer to the heart
Non-Infective Endocarditis (NBTE)
“Marantic”
Non-Infective Thrombotic Endocarditis • Aseptic vegetations = thrombotic deposits on endocardium • Often in Libman-Sacks Disease (SLE), DIC, Paraneoplastic
Non-Infective Endocarditis (NBTE)
“Marantic”
Morphology:
• Like infective, there are vegetations on valves, CT, and mural endocardium; unlike infective, there are vegetations on papillaries
(no septal defects here)
• NO INFLAMMATION = STERILE
Pericardial Disease is?
• Disease of fluid accum., inflammation, fibrous constriction of pericardium
• Disease of DIASTOLE
—Prevents heart from relaxing (expanding)
Pericardial Disease Characteristic Findings:
- Gets better when they lean forward
2. Friction rub from serous/parietal layers rubbing together.
Pericardial Response to Injury Acute:
Congestion, Transudate, Exudate (fibrin, inflammation).
Pericardial Response to Injury Chronic:
Exudate –> Fibrosis (adhesions + calcifications)
Pericarditis + Pericardial Effusion?
Go hand in hand.
Pericardial effusion:
Abnormal accum of serosal fluid in pericardial sac—If chronic accumulation (even though large) –> sac dilates –> asymptomatic
but w/↑Halo on Chest Xray
Cardiac Tamponade:
MEDICAL EMERGENCY (rapid accumulation) --> pulsus paradoxus ---Volume is less important than RATE (heart can accumulate 600 ml/mo without tamponade, but not 300 ml/min)
Pulsus Paradoxus
• Loss of heart beat on inspiration
• Inspiration –> ↓Intrathoracic Pressure –> ↑Blood to RA (but cannot expand b/c of pericardial disease/effusion) –> ↑Volume distorts IV septum into LV –> ↓Preload (↓LVEDV) –> ↓SV –> HYPOTENSION
• Starling Curve (Pressure/Volume) –> Results in ↑ΔP for small ΔLVEDV, but
overall ↓Pressure
Pericarditis Etiology (more often secondary than primary):
• Infectious: viral (primary), bacterial (lung infection), fungal, protozoal
• Immune Mediated: secondary to systemic inflammatory disease (SLE, RF, Scleroderma, PAN, RA) —Often see polyserositis (serosa attacked)
• Other: MI (Dresslers), Renal Failure
(Uremia - metabolites from urine damage pericardium), Trauma, Pancreatitis
Pericarditis Key to DDx:
Pericardial Fluid • Heart/Kidney Failure = Serous (clear/ straw colored) • Viral Infection = Sero-sanguinous • Bacterial Infection = Purulent + Serosanguinous • Mycoardial Rupture = Sanguinous • Trauma = sero-sanguinous • Drugs = serous
Pericarditis: Acute Pericarditis:
• Serous: mild inflammation + exudate
• Fibrinous: inflammation + fibrin strands in pericardial fluid
—”Shaggy” or “Bread and Butter” = PMN, Fibrin, RBC
—MOST COMMON
• Purulent: INFLAMMATION + PMNs
—Bacterial –> extension of nearby lung infection
—Often organizes –> granulation tissue w/capillaries and myofibro’s
—Gran tissue can lead to pericardial layer adhesion that may develop
into constrictive endocarditis
—Exudate –> Fibrosis = adhesions, restrictions
• Caseous: TB
• Hemorrhage: inflammatory exudate with RBC
Pericarditis: Chronic Pericarditis:
- Adhesions: chronic infections, repeated acute pericarditis (fibrosis)
- Constriction: fibrosis + calcification fuse the pericardial layers.
Pericarditis Labs/Tests:
- Silhouette/halo on CX-Ray
* Friction rub (fibrinous pericarditis especially)
Pericardial Effusion
Acute and Chronic Fluid Accumulation
• Acute vs. Chronic: recall that rate of
↑volume > amount of volume
• Mesothelial cells don’t offer passage to
fluid –> effusion during pericardial injury
Acute Pericardial Effusions
Ruptured MI, trauma, etc.
Chronic Pericardial Effusions
- Heart Failure, Myocarditis, RF
- Collagen Vascular Diseases
- Chronic Infections
- Chronic Renal Disease
- Neoplasms
- –Breast and lung seen the most (common)
- –Melanoma and lymphoma (preference) - Radiotherapy
Pericardial Effusions Presentation:
- If chronic, can be asymptomatic
* If acute (hemopericardium) –> pulses paradoxus –> EMERGENCY
Pericardial Effusions Types:
- Hydropericardium (Transudate)
- Hemopericardium (Blood)
- Chylopericardium (Lymph)
Chylopericardium (Lymph)
= Rare
—Lymph from thoracic duct
Hydropericardium (Transudate):
- –Associated with anasarca
- –NO INFLAMMATION
Hemopericardium (Blood):
—Blood accumulates over wks/months –> ↑intrapericardial P –> ↓SV
and ↓CO
—Ruptured MI (Req. transmural, ↑ventricular Pressure)
—Ruptured dissecting hematoma
—Aortic dissection
—Trauma
—Iatrogenic
Pericardial Effusions Labs/Tests
Silhouette/halo on CX-Ray
