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Basic Physiology / Determinants of MVO2 Autoregulatory Mechanisms / Coronary Flow Reserve Pathophysiology of Coronary Ischemia and Atherosclerosis Clinical Syndromes
Basic Principles
myocardial cells have to do only 2 things: contract and relax; both are aerobic, O2 requiring processes oxygen extraction in the coronary bed is maximal in the baseline state; therefore to increase O2 delivery, flow must increase large visible epicardial arteries are conduit vessels not responsible for resistance to flow (when normal)
Basic Principles
small, distal arterioles make up the major resistance to flow in the normal state atherosclerosis (an abnormal state) affects the proximal, large epicardial arteries once arteries are stenotic (narrowed) resistance to flow increases unless distal, small arterioles are able to dilate to compensate
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
Heart Rate
10 8 MVO2 cc/min /100g
6
4 2 100 150 Heart Rate (BPM) 200
Contractility
10
Norepinephrine
Control
Wall Tension
Is related to
Defined as: Force per unit area generated in the LV throughout the cardiac cycle
Afterload - LV systolic pressure Preload - LV end-diastolic pressure or volume
Myocardial Ischemia:
Occurs when myocardial oxygen demand exceeds myocardial oxygen supply
&
O2 Carrying Capacity
Oxygen saturation of the blood Hemoglobin content of the blood
Local metabolites Endothelial factors Neural factors (esp. sympathetic nervous system)
Diastole
Systole
Endocardium vs Epicardium
Greater shortening / thickening, higher wall tension: increased MVO2 Greater compressive resistance ? Decreased Perfusion Pressure Less collateral circulation Net Result is more compensatory arteriolar vasodilatation at baseline and therefore decreased CFR
Autoregulatory Resistance
Major component of resistance to flow Locus at arteriolar level Adjusts flow to MVO2 Metabolic control
Oxygen Adenosine
Autoregulatory Resistance
Involves 3 different cells
Myocardial muscle cell - produces byproducts of aerobic metabolism (lactate,adenosine, etc) Vascular endothelial cell (arteriole) - reacts to metabolic byproducts Vascular smooth muscle cell (arteriole) signaled by endothelial cell to contract (vessel constriction) or relax (vessel dilation)
Oxygen
Adenosine
Acts as vasoconstrictor As O2 levels drop during ischemia: precapillary vasodilation and increased myocardial blood supply
Potent vasodilator Prime mediator of coronary vascular tone Binds to receptors on vascular smooth muscle, decreasing calcium entry into cell
Adenosine
During hypoxemia, aerobic metabolism in mitochondria is inhibited Accumulation of ADP and AMP Production of adenosine Adenosine vasodilates arterioles Increased coronary blood flow
Autoregulatory Resistance
200 Flow cc/100g /min 100
Adenosine
Control
60
80
100
115
130
Autoregulators
Dilators include:
EDRF (NO) Prostacyclin
Constrictors include:
Endothelin-1
Arteriolar autoregulatory vasodilatory capacity in response to increased MVO2 or pharmacologic agents Expressed as a ratio of Maximum flow / Baseline flow ~ 4-5 / 1 (experimentally) ~ 2.25 - 2.5 (when measured clinically)
Stenosis in large epicardial (capacitance) vessel decreased perfusion pressure arterioles downstream dilate to maintain normal resting flow As stenosis progresses, arteriolar dilation becomes chronic, decreasing potential to augment flow and thus decreasing CFR Endocardial CFR < Epicardial CFR As CFR approaches 1.0 (vasodilatory capacity maxxed out), any further decrease in PP or increase in MVO2 ischemia
Maximum Flow
1
0
Resting Flow
25
50
75
100
Epicardium Endocardium
Coronary Steal
A
Sub-epicardium
B
Sub-endocardium
Vasodilator Rx (Ado) R2 decreases Flow increases to A R3 - no reserve Increased flow across R1 GRT P1-2 No change in P1 P2 Flow to B is dependant on P2 and
Age(years)
70%
50%
% Donors
40 30 20 10 0
25%
Risk Factors
family History cigarette smoking diabetes mellitus hypertension hyperlipidemia sedentary life-style obesity elevated homocysteine, LP-a ?
Fatty streaks present in young adults Soft atherosclerotic plaques most vulnerable to fissuring/hemorrhage Complex interaction of substrate with circulating cells (platelets, macrophages) and neurohumoral factors
Plaque progression.
Fibrous cap develops when smooth muscle cells migrate to intima, producing a tough fibrous matrix which glues cells together
Atherosclerotic Plaque
Physiologic Remodeling
Coronary atherosclerosis
mid-substernal chest pain squeezing, pressure-like in quality (closed fist = Levines sign) builds to a peak and lasts 2-20 minutes radiation to left arm, neck, jaw or back associated with shortness of breath, sweating, or nausea exacerbated by exertion, cold, meals or stress relieved by rest, NTG
Risk factor modification (HMG Co-A Reductase inhibitors = Statins) Aspirin Decrease MVO2 nitrates beta-blockers calcium channel blockers ACE-inhibitors Anti-oxidants (E, C, Folate, B6)?
Unstable Plaque:
More Detail.
Pathophysiology of all 3 is the same Unstable Angina (UA) ST depression, T Wave inversion or normal No enzyme release Non-Transmural Myocardial Infarction (NTMI or SEMI) ST depression, T Wave inversion or normal No Q waves CPK, LDH + Troponin release Transmural Myocardial Infarction (AMI) ST elevation + Q waves CPK, LDH + Troponin release
Vulnerable Plaque
% Stenosis
68%
14% 18%
new onset angina increase in frequency, duration or severity decrease in exertion required to provoke any prolonged episode (>10-15min) failure to abate with >2-3 S.L. NTG onset at rest or awakening from sleep
prolonged rest pain dynamic EKG changes (ST depression) age > 65 diabetes mellitus left ventricular systolic dysfunction angina associated with congestive heart failure, new murmur, arrhythmias or hypotension elevated Troponin i or t
Anti-Platelet Therapy
Three principle pathways of platelet activation with >100 agonists: ( TXA2, ADP, Thrombin ) Final common pathway for platelet activation / aggregation involves membrane GP II b / III A receptor Fibrinogen molecules cross-bridge receptor on adjacent platelets to form a scaffold for the hemostatic plug
( Death,Re- MI at 30days )
Placebo (% ) Rx ( % )
PURSUIT
15.7
14.2
PRISM
(vs Heparin)
7.1
5.8
PRISM PLUS
(+ Heparin)
11.9
8.7
PARAGON
(high dose)
11.7
12.0
0.2
Rx better
Placebo better
UH / Placebo (%)
Rx (%)
FRISC
10.3
5.4
FRIC
7.6
9.3
ESSENCE
19.8
16.6
16.6
14.2
LMWH Better
UH Better
total thrombotic occlusion of epicardial coronary artery onset of ischemic cascade prolonged ischemia altered myocardial cell structure and eventual cell death (release of enzymes - CPK, LDH, Troponin) altered structure altered function (relaxation and contraction) consequences of altered function often include exacerbation of ischemia (ischemia begets ischemia)
Non-transmural / sub-endocardial
Transmural
Non-occlusive thrombus or spontaneous reperfusion EKG ST depression Some enzymatic release troponin i most sensitive
total, prolonged occlusion EKG - ST elevation Rx - Thrombolytic Therapy or Cath Lab / PTCA
Legend: A. Early CPK-MB isoforms after acute MI B. Cardiac troponin after acute MI C. CPK-MB after acute MI D. Cardiac troponin after unstable angina
Troponin I is highly sensitive Troponin I may be elevated after prolonged subendocardial ischemia See examples below
angina pectoris Prolonged tachycardia in setting of CAD Congestive heart failure (elevated LVEDP causing decreased subendocardial perfusion) Hypoxia, coupled with CAD aborted MI (lytic therapy or spontaneous clot lysis)
EKG diagnosis of MI
chest pain systolic dysfunction (loss of contraction) decrease cardiac output decrease coronary perfusion pressure diastolic dysfunction (loss of relaxation) higher pressure (PCWP) for any given volume dyspnea, decrease pO2, decrease O2 delivery increased wall tension (increased MVO2)
All 3 give rise to stimulation of sympathetic nervous system with subsequent catecholamine release- increased heart rate and blood pressure (increased MVO2)
Ischemic Cycle
Ischemia / infarction Diastolic Dysfunction Systolic Dysfunction
chest pain
LV diastolic pressure
cardiac output
wall tension
aspirin, heparin, analgesia, oxygen reperfusion therapy thrombolytic therapy (t-PA, SK, n-PA, r- PA) new combinations ( t-PA, r-PA + 2b / 3a inhib) cath lab (PTCA, stent) decrease MVO2 nitrates, beta blockers and ACE inhibitors for high PCWP - diuretics for low Cardiac Output - pressors (dopamine, levophed, dobutamine; IABP; early catheterization
GUSTO
30 Day Mortality
p-values
10 8 6 4 2 0 SK + SQ H e p a r in S K + IV H epera n A c c e l. t-P A t-P A + S K 7 .2 7 .4 6 .3 7 .0
t-PA vs. t-PA + SK t-PA vs. SK (IV) t-PA vs. SK (SQ) t-PA vs. Combo SK
N:
9,796
10,376
10,344
10,327
GUSTO
% of Patients
100 80 60 40 20 0 SK + SQ H epa rin
90 min Patency
TIM I 3 TIM I 2
81 % * 73 % 56 % 61 %
p < 0.001
SK + IV H epa rin
p < 0.001
t-P A + SK
A ccel. t-P A
N:
295
282
291
297
9 6
p=0.05
7.9
3 4.3 0 TIMI 0 TIMI 1 TIMI 2 TIMI 3
259
81
342
447
Adenosine
Flow
Assumptions Collateral resistance P1 drops with vasodil P2 bed with no vaso dilator reserve
P2
collateral
P1
P2
collateral
P1