Transcript Cardiochirurgia universitaria

Terapia chirurgica della cardiopatia
ischemica
Anatomia e fisiopatologia del
circolo coronarico
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Anatomia Coronarica
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Coronarografia
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Electron-Beam CT Images of the Heart
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CORONARY CIRCULATION
• Blood flow
left ventricle = 80/ml/min/100g
right ventricle = 40 ml/min/100g
atria = 20 ml/min/100g
*Flow can increase 4-fold
• Capillary density - all capillaries open
• Very high O2 extraction: (A-V)02 = 14 ml
02/dl
• VO2 = 12 ml/min/100g ----> very high
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MYOCARDIAL OXYGEN
CONSUMPTION
• a to cardiac work
– influenced by
• a) contractility
• b) heart rate
• c) after-load
– increases achieved primarily by hyperemia
– 40% due to oxidation of carbohydrates, 60%
fatty acids
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TRANSMURAL DISTRIBUTION
OF BLOOD FLOW
• contraction (systole) leads to compression of intramural
vessels and reduction in flow
• pressure inside left ventricle can exceed aortic pressure
during systole
• vessel compression greatest in endocardium, decreases
toward epicardium
• O2 demand and flow/g is greatest in endocardium
• LV coronary flow decreases as HR increases since
diastole shorter
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Intramyocardial Pressure
(mmHg)
150
Systole
100
Arterial Blood
Pressure
50
10
0
80
Left Coronary
Blood Flow
0
Left Ventricular Pressure (mmHg)
120
150
Zone flow
100
Right Coronary
Blood Flow
50
Zero Flow
0
Perfusione coronarica “fasica”
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Diastole
HEART RATE AND
CORONARY BLOOD FLOW
Tachycardia:
Bradycardia:
HR
time in systole
vessel compression
metabolic activity
vasodilation
time in systole
vessel compression
HR
metabolic activity
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vasoconstriction
Oxygen Consumption (ml / 100 gm / min)
.
18
16
14
12
10
8
6
4
2
20
30
40
50
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60
70
80
90
100
110
120
Coronary Flow (ml / 100 gm / min)
LOCAL CONTROL OF
CORONARY BLOOD FLOW
• Tissue oxygenation is major regulator of
vascular tone (adenosine, tiss pO2)
• Essentially all capillaries are open to flow
(O2 diffusion distance)
• Flow regulation occurs at arterioles
• VO2 limited by blood flow (max O2
extraction)
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Endothelial Dysfunction in Atherosclerosis
The earliest changes that precede the formation of
lesions of atherosclerosis take place in the
endothelium. These changes include increased
endothelial permeability to lipoproteins and
other plasma constituents, which is mediated by
nitric oxide, prostacyclin, platelet-derived growth
factor, angiotensin II, and endothelin; upregulation of leukocyte adhesion molecules,
including L-selectin, integrins, and platelet–
endothelial-cell adhesion molecule 1, and the
up-regulation of endothelial adhesion molecules,
which include E-selectin, P-selectin, intercellular
adhesion molecule 1, and vascular-cell adhesion
molecule 1; and migration of leukocytes into
the artery wall, which is mediated by oxidized
low-density lipoprotein, monocyte chemotactic
protein 1, interleukin-8, platelet-derived growth
factor, macrophage colony-stimulating factor, and
osteopontin.
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Fatty-Streak Formation in Atherosclerosis
Fatty streaks initially consist of lipid-laden
monocytes and macrophages (foam cells)
together with T lymphocytes. Later they
are joined by various numbers of smoothmuscle cells. The steps involved in this
process include smooth-muscle
migration, which is stimulated by plateletderived growth factor, fibroblast growth
factor 2, and transforming growth factor b;
T-cell activation, which is mediated by
tumor necrosis factor a, interleukin-2, and
granulocyte–macrophage colonystimulating factor; foamcell formation,
which is mediated by oxidized low-density
lipoprotein, macrophage colonystimulating factor, tumor necrosis factor a,
and interleukin-1; and platelet adherence
and aggregation, which are stimulated by
integrins, P-selectin, fibrin, thromboxane
A2, tissue factor, and the factors described
as responsible for the adherence and
migration of leukocytes.
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Formation of an Advanced, Complicated Lesion of Atherosclerosis
As fatty streaks progress to intermediate and advanced
lesions, they tend to form a fibrous cap that
walls off the lesion from the lumen. This represents a type
of healing or fibrous response to the injury.
The fibrous cap covers a mixture of leukocytes, lipid, and
debris, which may form a necrotic core.
These lesions expand at their shoulders by means of
continued leukocyte adhesion and entry The principal
factors associated with macrophage
accumulation include macrophage colony-stimulating
factor, monocyte chemotactic protein 1,
and oxidized low-density lipoprotein. The necrotic core
represents the results of apoptosis and necrosis,
increased proteolytic activity, and lipid accumulation. The
fibrous cap forms as a result of increased activity of
platelet-derived growth factor, transforming growth factor
b, interleukin-1, tumor necrosis factor a , and osteopontin
and of decreased connective-tissue degradation.
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Unstable Fibrous Plaques in Atherosclerosis
Rupture of the fibrous cap or ulceration of the
fibrous plaque can rapidly lead to thrombosis
and usually occurs at sites of thinning of the
fibrous cap that covers the advanced lesion.
Thinning of the fibrous cap is apparently due
to the continuing influx and activation of
macrophages, which release
metalloproteinases and other proteolytic
enzymes at these sites. These enzymes cause
degradation of the matrix, which can lead to
hemorrhage from the vasa vasorum or from
the lumen of the artery and can result in
thrombus formation and occlusion of the
artery.
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Pathophysiologic Events Culminating in
the Clinical Syndrome of Unstable Angina
Numerous physiologic triggers probably initiate the
rupture of a vulnerable plaque. Rupture leads to the
activation, adhesion, and aggregation of platelets
and the activation of the clotting cascade, resulting
in the formation of an occlusive thrombus.
If this process leads to complete occlusion of the
artery, then acute myocardial infarction with STsegment elevation occurs. Alternatively, if the
process leads to severe stenosis but the artery
nonetheless remains patent, then unstable angina
occurs.
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Atheroma morphology by intravascular ultrasound
(IVUS)
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Atherosclerosis Timeline
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion / Rupture
Endothelial Dysfunction
From First
Decade
From Third
Decade
From Fourth
Decade
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).
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CHD
Narrowing of Coronary artery
limits blood supply to heart
muscle
If demand for blood supply
cannot be met, muscle
becomes ischaemic
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The Three Possible Outcomes of
Myocardial Ischemia
Myocardial Ischemia
3) Relief of ischemia
1) Myocardial
infarction
2) Chronic Ischemia
without infarction
Hearts with elements
of both hibernating
and stunning:
Persistent Ischemia
dysfunction:
Stunned/
Hibernating
myocardium
Hibernating myocardium
?
Salvage of previously
ischemic myocardium
Transient
postischemic
dysfunction:
Stunned myocardium
?
Relief of ischemia
No return of
contractile function
Return of
contractile function
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Adapted from Kloner, R., et al., Myocardial stunning and hibernation:
Mechanisms and clinical implications. In Braunwald, E. (ed.): Heart Disease:
A textbook of Cardiovascular Medicine, 3rd ed. Philadelphia, W.B., Aaunders
Company. Update No. 11, p. 253, 1990.
Schematic Diagram of Stunned
Myocardium
Clamp
Wall motion
abnormality
Wall motion
abnormality
during
occlusion
Coronary occlusion
Coronary reperfusion
Return of
function
Persistent wall motion
abnormality
(despite reperfusion
and viable myocytes)
Gradual return of
function (hours to days)
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From Kloner, R.A., Am J Med 1986;86:14.
Hibernating Myocardium
Wall motion abnormality
Atherosclerotic narrowing
Wall motion abnormality
due to chronic ischemia
without infarction
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From Kloner, R.A., Am J Med 1986;86:14.
Remodeling - Definition
Changes in interstitial, cellular, molecular,
and genome expression that results in
clinical changes in size, shape, and function
of the heart
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Remodeling Post-IMA
• Early Remodeling (within 72 hours)
¤
involves expansion of the infarct zone
• Late Remodeling (beyond 72 hours)
¤
involves the left ventricle globally and is involves the left ventricle
globally and is associated with time-dependent dilatation, and the
distortion of ventricular shape, and mural hypertrophy.
Pfeffer MA et al. Circulation 1990;81:1161-1172
White HD et al. Circulation 1987;76:44-51
Martin G. et al. Circulation 2000;101:2981-2988
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Post infarction remodeling (PIR)
• (PIR) Most studied model of remodeling
• Begins rapidly within hours of infarction
• There is variation in post infarction remodeling
depending on the time of ischaemia, duration, amount of
preconditioning, collaterals, genotype, neuroendocrine
status, treatment and response.
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Left ventricular remodeling after myocardial infarction
During the critical initial hours of MI when acute ischemia progresses to true necrosis, regional systolic
dysfunction is already present. However, in this particularly crucial period, measures to restore the balance
between O2 demand and delivery can lead to salvage of contractile tissue. Once cell death has occurred, and
particularly if there is a transmural infarction involving the ventricular apex, there is a high likelihood that this
initially functional distortion of ventricular contour will become structural for infarct expansion. The distorted
ventricle undergoes further remodeling as a consequence of heightened wall stress on the remaining viable
myocardium, which leads to further cavity enlargement and shape distortion. The latter insidious process is
associated with a greater likelihood of cardiovascular morbidity and mortality
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Processes of PIR
• Infarct expansion - thinning & regional expansion (in
animals occurs within 1 day)
• Global function impairment - occurs on day 2
• Myocyte lengthening
• Ventricular wall thinning
• Inflammation and resorption of necrotic tissue
• Dilatation and reshaping of LV
late expansion
• Myocyte hypertrophy
• Late myocyte loss
• Fibrosis and collagen accumulation in interstitium
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Haemodynamics
• Thinning of the infarct area
• Compensatory hypertrophy of remaining
LV
• The balance of thinning and hypertrophy
determines the wall stress and thus the
further dilatation of the heart.
• Therapy can alter these factors
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Neurohormonal NA
• Noradrenaline - initially improves CO
• Patients with decreasing levels of NA,
ANP post MI had better prognosis.
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Neurohormonal Angiotensin
• AII - increases DNA synthesis in
fibroblast and increases cell growth
and hypertrophy in response to stretch.
• Also increase permeability and has
cytotoxic effects on myocardium.
• Aldosterone stimulates fibroblasts in
collagen synthesis.
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Cytokines
• Interleukins, TNF, endothelins PKC, all mediate
the remodeling process
• Increased levels associated with poorer
prognosis
• Blockage of endothelin in animal models
improves remodeling
• Stimulation of TNF alpha can lead to LV
remodeling in animals.
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Oxidative stress
• Incomplete understanding of oxidative
stress and its role in remodeling beyond that
of apoptosis.
• Seems to alter viability of myocytes in the
presence of cytokines.
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Myocytes
• Myocytes Decreased numbers - residual myocytes
lengthen and hypertrophies.
• This compensates for the loss of other myocytes.
• Wall stress leading to cell membrane stretching and
local neurohormonal and cytokine environment leads
to altered expression of hypertrophy associated genes
and increased synthesis of contractile proteins.
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