1. Terapia chirurgica della cardiopatia ischemica
Anatomia e fisiopatologia del circolo coronarico

2. Anatomia Coronarica

7. Coronarografia

10. Electron-Beam CT Images of the Heart

11. 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

12. 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

13. 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

14. Perfusione coronarica “fasica”
150
Systole Diastole
Intramyocardial Pressure
(mmHg)
100
Arterial Blood
Pressure
120
100 50 80
Left Coronary
Blood Flow
150
Zone flow
100
Left Ventricular Pressure (mmHg)
Right Coronary
Blood Flow 50
Zero Flow
Perfusione coronarica “fasica”

15. HEART RATE AND CORONARY BLOOD FLOW
time in systole
vessel compression
Tachycardia: HR
metabolic activity
vasodilation
time in systole
vessel compression
Bradycardia: HR
metabolic activity
vasoconstriction

16. Oxygen Consumption (ml / 100 gm / min). 18 16 14 12
Oxygen Consumption (ml / 100 gm / min) 10 8 6 4 2 20 30 40 50 60 70 80 90
100
110
120
Coronary Flow (ml / 100 gm / min)

17. 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)

19. 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; up- regulation 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.

20. 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 smooth-muscle cells. The steps involved in this process include smooth-muscle migration, which is stimulated by platelet-derived 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 colony-stimulating factor; foamcell formation, which is mediated by oxidized low-density lipoprotein, macrophage colony-stimulating 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.

21. 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.

22. 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.

23. 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 ST-segment elevation occurs. Alternatively, if the process leads to severe stenosis but the artery nonetheless remains patent, then unstable angina occurs.

24. Atheroma morphology by intravascular ultrasound (IVUS)

27. Atherosclerosis Timeline
Foam
Cells
Fatty
Streak
Intermediate
Lesion
Atheroma
Fibrous
Plaque
Complicated
Lesion / Rupture
Atherosclerosis is a progressive disease involving the development of arterial wall lesions. As they grow, these lesions may narrow or occlude the arterial lumen. Complex lesions may also become unstable and rupture, leading to acute coronary events, such as unstable angina, myocardial infarction, and stroke.
Pepine CJ. The effects of angiotensin-converting enzyme inhibition on endothelial dysfunction: potential role in myocardial ischemia. Am J Cardiol. 1998; 82(suppl 10A):
Endothelial Dysfunction
From First
Decade
From Third
Decade
From Fourth
Decade
Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104). 9

30. CHD Narrowing of Coronary artery limits blood supply to heart muscle
If demand for blood supply cannot be met, muscle becomes ischaemic
Narrowing of Coronary artery limits blood supply to heart muscle

31. The Three Possible Outcomes of Myocardial Ischemia
3) Relief of ischemia
1) Myocardial
infarction
2) Chronic Ischemia
without infarction
Salvage of previously
ischemic myocardium
Hearts with elements
of both hibernating
and stunning:
Transient
postischemic
dysfunction:
Persistent Ischemia
dysfunction:
Stunned/
Hibernating
myocardium
Hibernating myocardium
Stunned myocardium ? ?
Relief of ischemia
No return of
contractile function
Return of
contractile function
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.

32. Schematic Diagram of Stunned Myocardium
Clamp
Wall motion
abnormality
Coronary occlusion
Wall motion
abnormality
during
occlusion
Coronary reperfusion
Persistent wall motion abnormality
(despite reperfusion
and viable myocytes)
Return of
function
Gradual return of
function (hours to days)
From Kloner, R.A., Am J Med 1986;86:14.

33. Hibernating Myocardium Atherosclerotic narrowing
Wall motion abnormality
Atherosclerotic narrowing
Wall motion abnormality
due to chronic ischemia
without infarction
From Kloner, R.A., Am J Med 1986;86:14.

34. Remodeling - Definition
Changes in interstitial, cellular, molecular,
and genome expression that results in
clinical changes in size, shape, and function
of the heart

35. 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:
White HD et al. Circulation 1987;76:44-51
Martin G. et al. Circulation 2000;101:

36. 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.

37. 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

38. 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

39. 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

40. Neurohormonal NA Noradrenaline - initially improves CO
Patients with decreasing levels of NA, ANP post MI had better prognosis.

41. 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.

42. 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.

43. 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.

44. 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.