Cardio TBL Flashcards
1
Q
Areteriosclerosis =
A
Hardening of Arteries
2
Q
• Atherosclerosis: large and medium arteries;
A
INTIMAL CHANGES
—Lipid deposition, accumulation of macrophages + myointimal cells —>
plaque formation
3
Q
• Arteriolosclerosis: Hypertension induced
A
hyperplasia/trophy of smooth muscle cells (Media)
4
Q
• Endarteritis Obleterans:
A
Response to inflammation (syphilis); INTIMA
5
Q
Arteritis:
A
• Arteritis: fibrinoid necrosis of arterial wall
6
Q
Monkeberg’s:
A
Calcification of MEDIA
7
Q
Areteriosclerosis Emphasis on Progression
A
• 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.
8
Q
Areteriosclerosis Presentation
A
• Presentation: 50 years of age
9
Q
Arterial Structure Review Three Parts:
A
Intima:
Media:
Adventitia:
10
Q
Arterial Intima:
A
Endothelium –> internal elastic lamella; contains myointimal cells in the sub-endothelial space
11
Q
Arterial Media:
A
smooth muscle cells + Collagen I/III
12
Q
Arterial Adventitia:
A
type I collagen + fibroblasts Vasa Vasorum not found in abdominal aorta –> more susceptible to athero.
13
Q
CHRONIC ENDOTHELIAL DYSFUNCTION:
A
- Platelet Microthrombi
* Fatty Streaks
14
Q
Platelet Microthrombi -
A
Proposed theory because aggregates of plat are found incommon sites of athero
15
Q
Fatty Streaks -
A
Subendothelial lipid (cholesterol/esters) + foamy cells
- –No hemodynamic change
- –Reversible (Lactating babies +, 4-5 y/o)
16
Q
Bottom Line: Endothelial injury
A
↑permeability for lipids + ↑adhesions
17
Q
Endothelial Injury occurs from:
A
• Hyperlipidemia/hypercholesterolemia • HTN • Smoking • Diabetes/Metabolic Syndrome • Toxins/Viruses • Homocysteine Fatty streaks are reversible with lifestyle change. if not --> Fibrous (Fatty) Plaque
18
Q
Areteriosclerosis Pathophysiology:
A
• Because Atherosclerosis = chronic endothelial dysfunction; any disease that causes endothelial injury can lead to it.
19
Q
Three Consequence of endothelial injury:
A
- ↑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
20
Q
- ↑Endothelial adhesion to leukocytes and platelets leads to?
A
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)
21
Q
- Passage of lipids (LDL) into subendothelial space (Fatty streak) leads to?
A
- –LDL must be oxidized –> release inflammatory lipids
- –Can be modified by homocysteine (MI in Homocysteinuria)
- –Additional ↑Endothelial adhesion particles
22
Q
- DAMAGE –> endogenous activation macrophages–> ↑cytokines +
↑Macrophage presentation to T-Cells –> ↑T-Cell Inflammation leads to?
A
—Inflammation –> ↑IL-6 –> ↑Acute Phase Proteins (SAA, CRP)
***CRP is best indicator of disrupted plaques; thus better than LDL for
predicting cardiovascular events
23
Q
↑Endothelial adhesions leads to?
A
Macrophages and monocytes migrating: Lumen (L) to subendothelial space.
Once in subendothelial space,monocyte and macrophage ingests lipid –> Foamy Cell
24
Q
Endothelial injury morphology?
A
• Fatty streaks: yellow streaks on
endothelium
• streaks occur at points of bifurcation
—Turbulent flow, likely place for injury
25
FATTY STREAK leads to?
FIBROUS PLAQUE
26
Proliferative lesion:
Monocyte, macrophage, myointimal cells proliferate===Intimal Thickening!
27
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!
28
Pathophysiology:
| FATTY STREAK --> FIBROUS PLAQUE
* Untreated fatty streaks allow ↑Lipid deposition + ↑Leukocyte adherence to dysfunctional endothelium
* ↑Foamy Cells
* ↑Stress --> ↑Smooth muscles changes --> ↑Myointimal cells
29
Veins and Pulmonary Circulation
* VEINS ARE NOT AFFECTED
| * Same with pulmonary circulation, EXCEPT IN PULMONARY ATHEROSCLEROSIS (DDx: Pulmonary Hypertension)
30
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)
31
Complex Atheromatous Lesions
FIBROUS PLAQUE + SOMETHING ELSE
32
Complex Atheromatous Lesions Maintains Components of Fibrous Plaque
* Necrotic debris
* Cholesterol deposits
* Foamy cells/fibrous cap
33
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
```
34
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
35
Myocardial Infarction from CAD requires?
100% occlusion
36
Most patients with CAD have?
Multiple plaques along their entire coronaries
37
Because ATHEROsclerosis =
Intima of CA is thickened
38
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
39
Coronary Artery Disease Etiology:
• Coronary arteries especially at risk because intimal thickening naturally takes place at points of bifurcation (turbulent flow)
40
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
41
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
42
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
43
Myocardial Infarction =
100% Occlusion of Coronary Artery
44
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
45
Myocardial Infarction: 10 hours:
no gross/micro change
46
Myocardial Infarction: 10-20 hrs:
Dead cells (white) cell surrounded by hypereosinophilic + some edema +/- PMN (Coagulative necrosis)
47
Myocardial Infarction:1-3 days:
↑eosinophilia, pyknosis, karyorrhexis, ↑edema + ↑PMNs
48
Myocardial Infarction: 4-7 days:
Macrophages + PMNS remove dead cells --> risk for rupture; granulation tissue begins to form around necrotic area
49
Myocardial Infarction: 7-10 days:
Gross yellowish color; ↑collagen + granulation tissue
50
Myocardial Infarction: 11-21 days:
Dead cells gone (macro w/ lipofuschin); granulation tissue
51
Myocardial Infarction: 4-10 weeks:
Granulation tissue ---> non-contractile scar
52
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
```
53
Post-MI Complications Pathophysiology:
During reperfusion post MI, lots going on:
1. Mitochondria come back, but not quick enough to stop ROS
2. pH is changing drastically (back up)
3. Ca++ overload
4. Inflammation
54
Myocardial Hypercontracture -->
↑Pores in Mito. Membrane = DAMAGE
55
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
56
Post-MI Complications Mural Thrombosis
Area over infarct thickens and is
| abnormal --> attracts platelets
57
Post-MI Complications Consequences Mural Thrombosis
* Embolism
| * Occupy LV volume ---> ↓CO
58
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
59
Ventricular Aneurysms
Common in transmural infarcts
60
Ventricular Aneurysms Mechanism:
While scarred area has ↑ strength, during contraction it remains stationary and healthy myocardium contracts, creating an anuerysm
61
Myocardial Rupture Occurs
Days 4-7 (max removal of tissue)
| ---60% during this time period; 30% in 24 hr
62
Myocardial Rupture Risk Factors:
* Hypertension
* Diabetics
* Women in early menopause
* Psychiatric Patients
63
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
64
Septal Rupture
Acquired A-V Defect Less common than rupture of the free wall.
Free wall > septal > papillary
65
Aneurysm =
Sac formed from dilation of vascular wall (cardiac, arterial, venous) ---Call venous aneurysm “Varicose / Varices”
66
Thoracic aneurysms =
Dissecting unless proven otherwise.
67
Abdominal aneurysms =
Atherosclerotic unless proven otherwise.
68
Aneurysms Morphological Classification:
Fusiform, Saccular, Cylindrical, Fistula
69
Laplace’s Law :
Tension = (Pressure)(Radius)/(2xHeight)
| • Dilation --> ↑Radius --> ↓Wall Thickens (↓H) --> -->
70
What causes symptoms of aneurysms?
* Compression of surrounding organs
* Ischemia distal to aneurysm
* Hemorrhage due to rupture
71
Dissecting (Thoracic) Aneurysm =
Intimal tear in Aorta --> Blood in MEDIA
| • Intimal tear ~ 6cm from aortic valve.
72
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.
```
73
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)
74
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
75
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
76
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
77
Atherosclerotic (Abdominal) Aneurysm =
Weakening of Aortic Wall --> Leakage
78
Atherosclerotic (Abdominal) Aneurysm Etiology:
Atherosclerosis***
79
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
```
80
Atherosclerotic (Abdominal) Aneurysm Presentation:
• 33% die <10 years
• Usually asymptomatic until late
∝ size + diagnosis + rate
Leakage/Rupture most common COD
81
Atherosclerotic (Abdominal) Aneurysm
| Consequence of Dissection
* Narrow/occlude renal and mesenteric arteries
* Pressure = ↑Bone Damage + ↑Viscera Damage + ↑Neuron Damage
* Rupture --> hemorrhage
82
Atherosclerotic (Abdominal) Aneurysm Morphology:
TONS of atherosclerosis and thrombi (mura/transmural)
83
Pseudoaneurysms (Thrombus)
Trauma induced bleed --> thrombus -->
| dilation --> looks like aneurysm
84
Pseudoaneurysms (Thrombus) Presentation:
Knife, bullet wound, Carson Rider post-Wiz concert
85
Pseudoaneurysms (Thrombus) Morphology:
Hemorrhage --> clot --> dense fibrous tissue
86
Mycotic Aneurysm:
Bacterial Arteritis (Septic Emboli)
Vessel wall weakening from infection
Misnomer, caused more by bacterial
rather than from bacteria
87
Mycotic Aneurysm Presentation:
* Thrombosis +/- infarction
| * Rupture
88
Most common cause of Sudden Cardiac Death?
Ventricle Fibrillation (1,000 Americans/day)
89
Ventricle Fibrillation most common in patients with?
MI + Heart Disease
90
Ventricle Fibrillation Treat with?
AICD (Automated Implantable
| Cardioverter Defibrillator)
91
Ventricle Fibrillation Iatrogenic undetectable cause?
↑potassium
92
Most common cause of stroke?
Atrial Fibrillation (atrial stasis --> thrombus --> stroke)
93
Atrial Fibrillation Prophylaxis with?
Warfarin
94
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
95
Mechanisms Arrhythmia Types?
1. Enhanced Automaticity
| 2. Re-Entry
96
Enhanced Automaticity Two things can change the slow depolarization?
Increasing rate of depolarization OR raising the threshold potential (less negative)
97
What causes ↑ In Phase 4 Slope?
```
↑SNS Tone / ↓PS Tone
↑CO2 / ↓O2
↑Stretch
↑Digoxin
↓Potassium
```
98
Re-entry occurs requiring?
Slow conduction + re-excitable
| cell
99
Re-entry causes?
Circular movement produces a rapid series of APs with ↑ Frequency
===TACHYCARDIA
===ARRHYTHMIA
100
Most common cause of SCD (Sudden Cardiac Death)?
Ventricular Fibrillation (1,000 Americans/day)
101
Ventricular Fibrillation ECG Features
* Complete erratic rhythm
| * No Identifiable waves
102
AICD - Automated Implantable Cardioverter Defibrillator does what?
* Device is given preset HR
| * Monitors rate and rhythm of heart and alters via shock delivery
103
Atrial Fibrillation ECG Features:
* Chaotic baseline = Irregularly irregular = not consistently weird
* NO DISCRETE P WAVES
104
Atrial Fibrillation Treatment:
* B-Blocker
* Ca++ Channel Blocker
* Digoxin
105
Atrial Flutter ECG Features:
* Rapid back-back atrial depolarization waves
| * SAW TOOTH PATTERN
106
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
```
107
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
108
Bundle Branch Block:
* Conducting tissues is “blocked”
* Delayed activation of ventricle
* Always abnormal, but not specific
109
Bundle Branch Block ECG Features:
↑ QRS width --> prolonged QRS Segment
110
P waves -->
Look at for atrial / supraventricular origin
111
QRS -->
Widened in ventricular origin; can be narrowed in atrial
112
Tombstone ST =
STEMI
113
Depressed ST =
Ischemia
114
Automaticity Disease:
Sinus tachycardia, sinus arrest, VPB, etc.
| *Both mechanisms can cause most arrhythmias; these are common groupings
115
Re-Entry Disease:
VTAC, PSVT, WPW, AFIB
| *Both mechanisms can cause most arrhythmias; these are common groupings
116
Pathogenetic Mechanisms of Vasculitis
1. Immune Complex Deposition in Vessel Wall
2. ANCA-Mediated
3. Ab Directed at Vessel Wall (endothelial, GBM)
4. Cell Mediated Immune Reaction (Granuloma)
5. Component of Other Immune Disorders
117
Vasculitis ANCA-Mediated:
- --Pathogenic from activating PMNs (↑adhesion via B2 integrin, Fcgamma)
- --Target Endothelia--> ANCA-PR3 + Endothelia --> lost thromboresistance
118
Vasculitis Ab Directed at Vessel Wall (endothelial, GBM):
- --In anti-endothelial, Ab levels == disease activity
| - --Ab usually bind to cytoplasmic components, not surface
119
Immune Complex Pathogenicity Criteria
* Circulating immune complex
* Hypocomplementemia
* IgG (or other) deposition in vessel wall
* Complement deposition in vessel wall
120
Vasculitis has to be diagnosed with?
Biopsy
121
Vasculitis Infectious:
From pathogen directly invading wall.
| Recognize that infectious can generate an immune-mediated inflammation.
122
Vasculitis Non-infectious
Non-infectious from immune-mediated inflammation.
123
Variability in Non-Infectious Vasculitis
Disease occurs from complexes; presentation is location-dependent
124
Vasculitis =
Vessel Wall Inflammation with necrosis of vessel walls, narrow/occlusion +/- aneurysms
125
Kawasaki’s Disease
Kawasaki’s Disease Vasculitis
• Exact etiology is uknown
• Most likely delayed hypersensitivity T
cell reaction
126
Kawasaki’s Disease Presentation:
* Asian children < 4 years old
* “strawberry tongue”
* Lymphadenitis, conjunctivitis
* High association with developing coronary aneurysms
127
Buerger’s Disease
| Thromboangitis Obliterans
* SMOKING, SMOKING, SMOKING
| * Treat: smoking cessation!
128
Buerger’s Disease
(Thromboangitis Obliterans)
Presentation:
* Heavy smokers
* Males < 40
* Intermittent claudication --> gangrene + autoamputation of digits
* Radial arteries often affected --> Raynaud’s Phenomenon
129
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)
```
130
Temporal (Giant-Cell) Arteritis Presentation:
* Female patients > 50 y/o
* Unilateral headache + jaw claudication
* Irreversible blindness (opthalmic artery occlusion)
* Associated with polymyalgia rheumatica
131
Temporal (Giant-Cell) Arteritis Morphology
* Affects branches of carotid artery
| * Focal granulomatous inflammation
132
Temporal (Giant-Cell) Arteritis Labs
↑ ESR
133
Temporal (Giant-Cell) Arteritis Treatment
High Dose Steroids
134
Fats have two functions:
1. P-lipids + cholesterol = structural part of all cell membranes
2. Triglycerides (TG) and FFA = energy sources of body
135
General Flow of Transport Fats:
1. TG in Liver/Gut ----> Muscle (energy) and Fat (storage)
2. Cholesterol across tissue ---> Liver
- --All cells make cholesterol; they have excess; rarely deficient
136
Lipoprotein Functions:
1. Carry p-lipids, free cholesterol, cholesterol esters, TG, and apolipoproteins
- --Apo’s have structural, cofactor, and receptor roles
2. Allow easy circulation of fat throughout body
137
Lipoprotein Pathophysiology Disease Overview
1. Genetic disease: think mutation in apo, apo-receptor, or enzymes
2. Environmental disease: think overproduction of certain component
138
CM + VLDL =
TG Rich Lipoproteins
139
CM made in?
GI
140
VLDL made in?
Liver
141
CM has?
apoB-48 (no LDL receptor)
142
VLDL has?
apoB-100
143
• TG removed from and via?
CM or VLDL via LPL
144
LPL hydrolyses?
TG --> FFA + Monoglyc.
145
VLDL =
↑TG + ↑Cholesterol
146
Post LPL =
IDL/LDL w/↑Cholesterol
147
ApoE =
Liver, Macrophages, CNS
---Macrophages w/cholesterol secrete
apoE with the cholesterol; important b/
c macrophages are involved in athero
148
Hypobetalipoproteinemia =
trunc apoB ↓ApoB Production
• Truncated apoB secreted ↓, excreted ↑
by renal tubule
149
Hypobetalipoproteinemia Genetics Heterozygotes:
Heterozygotes: 25-50% of LDL; steatosis
150
Hypobetalipoproteinemia Genetics Homozygotes:
Homozygotes: ↓↓↓LDL and CM
- --Fat malabsorption --> ↓Vit A,D,E, K
- --Acanthocytosis
- --Neuromuscular Degeneration (↓VIt E)
151
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
152
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)
153
Abetalipoproteinemia =
Deficient MTP
| ↓CM + ↓VLDL production (RECESSIVE)
154
Abetalipoproteinemia Heterozygotes:
No abnormal values.
155
Abetalipoproteinemia Homozygotes:
↓CM + ↓LDL
- --Similar sympotoms as hypo-beta
- --↓ApoB containing lipoproteins (DDx)
156
Abetalipoproteinemia Physiology:
MTP = Manages Transport & Particle formation
• Shuttles TG and cholesterol esters: membranes lipoproteins
• Controls lipid particle / droplet formation for apoB to attach
157
Abetalipoproteinemia Pathophysiology
* If apoB does not accumulate lipoprotein components --> degrades
* ↓MTP --> ↓Shuttling of TG + ↓Lipoprotein Particle --> apoB degrade
158
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
```
159
Familial Combined Hyperlipidemia (FCHL)
| Physiology
apoB is key in forming lipoproteins CM and VLDL
160
Familial Combined Hyperlipidemia (FCHL)
| Pathophysiology
* ↑ApoB synthesis ---> ↑VLDL synthesis by liver (normal composition)
* ↑VLDL ---> ↑LDL
161
Familial Combined Hyperlipidemia (FCHL)
| Consequences of ↑LDL
1. ↑VLDL Production + ↓LDL Clearance --> ↑Normal LDL --> ↑Cholesterol (b/c TG is removed via LPL)
2. ↑VLDL Production + ↓Cholesterol Accumulation --> ↑LDL apoB (low TG and low cholesterol) --> HYPERAPOBETA
3. ↑VLDL production + ↑LDL Clearance --> normal/↓LDL apoB and cholesterol
162
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
```
163
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
```
164
Familial Dysbetalipoproteinemia
(Type III Hyperlipidemia)
Alzheimer’s Risk
* ApoE4 best predictor for Alzheimer’s
| * ApoE2 protects against Alzheimer’s
165
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!
166
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
```
167
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
168
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
```
169
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
```
170
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
```
171
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)
```
172
Physiology - Reverse Cholesterol Transport (RCT)
0. ApoA1 from liver/GI --> adds to disc-shaped nascent pre-beta HDL
1. Cholesterol Efflux from Cells
2. Free Cholesterol --> Cholesterol Esters (FC-->CE)
3. HDL2 Uptake from Liver
4. Cholesterol Ester Transfer Protein (CETP)
CETP levels don’t determine activity; CETP-Inhibitor levels do!
173
CETP Deficiency Yields:
↑CETP-I / ↑LTIP === (6-Fold)↑HDL2 Cholesterol
174
The real goal of cholesterol should be LDL
LDL<70 in those with other risk factors-not on test…
175
Stenosis:
Narrowing of orifice --> valve doesn’t open correctly
176
Regurgitation (=insufficiency):
Leakage in opposite direction --> valve doesn’t
| close correctly
177
Cardiac Adaptation
| Concentric Hypertrophy:
Pressure Overload = STENOSIS (+HTN)
| ---↑Thickness (thick walls) but normal volume - “LV Hypertrophy”
178
Cardiac Adaptation
| Eccentric Hypertrophy:
Volume Overload = REGURGITATION
| ---↑Dilation of Chamber (more volume + thin walls) ---> ↑Output (Starling’s Law)
179
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.
180
Valvular Heart Disease Chronic
↓↓ΔP with ↑structural heart changes in chronic
181
Diseased Aortic Valve Rheumatic:
Micro-vegetation (not as much as infective endocarditis) + FUSION of COMMISURES
182
Diseased Aortic Valve Calcification/Bicuspid:
Sinus of Valsalva calcification + NO FUSION
183
Symptoms of Stenosis
Syncope, Angina, Heart Failure, Arrhythmias
184
Types of Stenosis
Supravalvular Stenosis
Valvular Stenosis
Subvalvular
185
Supravalvular Stenosis:
Above the valve; congenital (ex: narrowing of aorta).
186
Valvular Stenosis:
At the valve; congenital or acquired.
187
Subvalvular:
Below the valve, congenital or acquired ex: IV septum pushing into one ventricle.
188
When is stenosis TOO severe?
Valve area depends on two things:
1. Gradient - pressure drop across LV and Aorta in systole (normally 0)
2. Flow Across Stenosed Valve approximated by CO
189
Stenosis Evaluation:
ECHO -- view diseased valves, hypertrophy and blood flow.
190
Stenosis Pathology Basics:
Valves = AVASCULAR endothelial-lined (endocardium)
| ---Core of PG, GP, Collagen (Type 1) Fibers, and Fibroblasts
191
Post-Streptococcal Molecular Mimicry?
2-3 weeks post strept infection form Ab:
| cross react with cytoskeletal proteins
192
What valve is affected?
Mitral > Aortic > Tricuspid > Pulmonary
---Mitral valve experiences the most pressure
in the entire heart.
193
Possible exam topic?
| Fusion of commisures?
Occurs in RF, but not in calcified aortic stenosis.
194
Rheumatic Fever Presentation:
• 2-3 Weeks Post-Streptococcal Infection
• “Dog that licks the joint, but bites the heart” === TRANSIENT
(except long term pericarditis effects)
195
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
196
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)
197
Mitral Valve Regurgitation Causes:
1. MITRAL VALVE PROLAPSE
2. Left Ventricular Dilation
- --Left sided heart failure dilates ring of MV
3. Rheumatic Fever
198
Mitral Prolapse Leaflets replaced by?
Myxomatous (spongy) tissue
199
Mitral Valve Regurgitation Presentation:
* Can be asymptomatic with murmur
* Sudden rise in Atrial pressure
* ↑Preload (from atrium) + ↓Afterload (from venting) = ↑↑SV
200
Mitral Valve Regurgitation
Acute vs. Chronic: EXAM QUESTION
• Acute =
No change in RA volume (adaptation), ↑Pulmonary Capillary Wedge Pressure (large pressure build up)
201
Murmur For MV Regurgitation
Systolic murmur= pansystolic: S1------S2
202
Aortic Valve Stenosis Causes:
1. Age-Related Calcification
- --Calcified aortic stenosis from wear/tear
- --Calcification in Sinuses of Valsalvas
- --”Arthritis of the aortic valve”
2. Bicuspid Aortic Valve
- --Congenital Failure of Apoptosis
- --Prone to calcification --> stenosis
203
Aortic Valve Stenosis Pathophysiology:
In both, ↑P in LV ---> LV Concentric
| Hypertrophy --> HTN, Angina, Syncope
204
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
205
Aortic Valve Stenosis Murmur:
Systolic diamond shape murmur S1 --<>-- S2
206
Mitral Valve Stenosis Murmur
Diastolic murmur: S1------S2 OS⤷S1
207
Aortic Valve Regurgitation Disease of?
Aorta/Aortic Cusps
208
Disease of Aorta/Aortic Cusps Pathophysiology:
* ↑LV Volume == ↑Preload + ↑Eccentric Hypertrophy (dilation) == ↑SV (Starling)
* ↑SV + aortic venting = ↑pulse pressure
209
Infective Endocarditis Two Requirements:
1. BUGS in BLOOD
- --Any pathogen (virus, bacteria, fungi)
2. Abnormal Heart Valve
210
Infective Endocarditis Pathology:
• ↑Velocity blood across abnormal valve
• Platelets adhere --> thrombus formation
• Bacteria bind to injured endothelium
(direct contact / fibronectin mediated)
211
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
```
212
Bacteremia =
Living bacteria in blood.
213
Septicemia =
↑invasion + replication in blood stream.
214
Infective Endocarditis Source of Infection
- --IVDU (polymicrobial); Prosthetic Valves (PVE)
- --Dental procedures involving gingiva/gums
- --Catheters/iatrogenic.
215
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.
216
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
```
217
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)
218
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.
219
Infective Endocarditis Tests:
* CULTURE, CULTURE, CULUTRE
| * TEE - closer to the heart
220
Non-Infective Endocarditis (NBTE)
| “Marantic"
```
Non-Infective Thrombotic Endocarditis
• Aseptic vegetations = thrombotic
deposits on endocardium
• Often in Libman-Sacks Disease (SLE),
DIC, Paraneoplastic
```
221
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
222
Pericardial Disease is?
• Disease of fluid accum., inflammation, fibrous constriction of pericardium
• Disease of DIASTOLE
---Prevents heart from relaxing (expanding)
223
Pericardial Disease Characteristic Findings:
1. Gets better when they lean forward
| 2. Friction rub from serous/parietal layers rubbing together.
224
Pericardial Response to Injury Acute:
Congestion, Transudate, Exudate (fibrin, inflammation).
225
Pericardial Response to Injury Chronic:
Exudate --> Fibrosis (adhesions + calcifications)
226
Pericarditis + Pericardial Effusion?
Go hand in hand.
227
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
228
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)
```
229
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
230
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
231
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
```
232
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
233
Pericarditis: Chronic Pericarditis:
* Adhesions: chronic infections, repeated acute pericarditis (fibrosis)
* Constriction: fibrosis + calcification fuse the pericardial layers.
234
Pericarditis Labs/Tests:
* Silhouette/halo on CX-Ray
| * Friction rub (fibrinous pericarditis especially)
235
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
236
Acute Pericardial Effusions
Ruptured MI, trauma, etc.
237
Chronic Pericardial Effusions
1. Heart Failure, Myocarditis, RF
2. Collagen Vascular Diseases
3. Chronic Infections
4. Chronic Renal Disease
5. Neoplasms
- --Breast and lung seen the most (common)
- --Melanoma and lymphoma (preference)
6. Radiotherapy
238
Pericardial Effusions Presentation:
* If chronic, can be asymptomatic
| * If acute (hemopericardium) --> pulses paradoxus --> EMERGENCY
239
Pericardial Effusions Types:
1. Hydropericardium (Transudate)
2. Hemopericardium (Blood)
3. Chylopericardium (Lymph)
240
Chylopericardium (Lymph)
= Rare
| ---Lymph from thoracic duct
241
Hydropericardium (Transudate):
- --Associated with anasarca
| - --NO INFLAMMATION
242
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
243
Pericardial Effusions Labs/Tests
Silhouette/halo on CX-Ray
