cattedra di cardiochirurgia universita degli studi di firenze terapia chirurgica della cardiopatia...

Cattedra di CardiochirurgiaUNIVERSITA’ DEGLI STUDI DI FIRENZE

Terapia chirurgica della Terapia chirurgica della cardiopatia ischemicacardiopatia ischemica

Anatomia e fisiopatologia del circolo coronarico


Anatomia Coronarica


Coronarografia


Electron-Beam CT Images of the Heart


CORONARY CIRCULATIONCORONARY CIRCULATION• Blood flowBlood 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 Capillary density - all capillaries open

• Very high OVery high O2 2 extraction: (A-V)0extraction: (A-V)022 = = 14 ml 14 ml

0022/dl /dl

• VOVO22 = = 12 ml/min/100g12 ml/min/100g ----> very high ----> very high


MYOCARDIAL OXYGEN MYOCARDIAL OXYGEN CONSUMPTIONCONSUMPTION

• to cardiac workto cardiac work– influenced byinfluenced by

• a) contractility

• b) heart rate

• c) after-load

– increases achieved primarily by hyperemiaincreases achieved primarily by hyperemia– 40% due to oxidation of carbohydrates, 60% 40% due to oxidation of carbohydrates, 60%

fatty acidsfatty acids


TRANSMURAL TRANSMURAL DISTRIBUTION OF BLOOD DISTRIBUTION OF BLOOD

FLOWFLOW• contraction (systole) leads to compression of intramural contraction (systole) leads to compression of intramural vessels and reduction in flowvessels and reduction in flow

• pressure inside left ventricle can exceed aortic pressure pressure inside left ventricle can exceed aortic pressure during systoleduring systole

• vessel compression greatest in endocardium, decreases vessel compression greatest in endocardium, decreases toward epicardiumtoward epicardium

• OO22 demand and flow/g is greatest in endocardium demand and flow/g is greatest in endocardium

• LV coronary flow decreases as HR increases since LV coronary flow decreases as HR increases since diastole shorterdiastole shorter


120

100

80

150

100

50

0

150

100

50

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Systole Diastole

Arterial Blood Pressure

Left Coronary Blood Flow

Zone flow

Right Coronary Blood Flow

Zero Flow

Intr

amyo

card

ial P

ress

ure

(m

mH

g)L

eft

Ven

tric

ula

r P

ress

ure

(m

mH

g)

Perfusione coronarica “fasica”


HEART RATE AND HEART RATE AND CORONARY BLOOD FLOWCORONARY BLOOD FLOW

Tachycardia: HRtime in systole

metabolic activity

vessel compression

vasodilation

Bradycardia: HRtime in systole vessel compression

metabolic activity vasoconstriction


.

20 30 40 50 60 70 80 90 100 110 1202

4

6

8

10

12

14

16

18

Oxy

gen

Con

sum

pti

on (

ml /

100

gm

/ m

in)

Coronary Flow (ml / 100 gm / min)


LOCAL CONTROL OF LOCAL CONTROL OF CORONARY BLOOD FLOWCORONARY BLOOD FLOW• Tissue oxygenation is major regulator of Tissue oxygenation is major regulator of

vascular tone vascular tone (adenosine, tiss pO2)(adenosine, tiss pO2)

• Essentially all capillaries are open to flow Essentially all capillaries are open to flow (O2 diffusion distance)(O2 diffusion distance)

• Flow regulation occurs at arteriolesFlow regulation occurs at arterioles

• VOVO22 limited by blood flow limited by blood flow (max O2 (max O2

extraction)extraction)


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.

Endothelial Dysfunction in Atherosclerosis


Fatty-Streak Formation in AtherosclerosisFatty 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.


As fatty streaks progress to intermediate and advanced lesions, they tend to form a fibrous cap thatwalls 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 macrophageaccumulation 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.

Formation of an Advanced, Complicated Lesion of 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.

Unstable Fibrous Plaques in Atherosclerosis


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.


Atheroma morphology by intravascular ultrasound (IVUS)


Atherosclerosis TimelineAtherosclerosis TimelineFoamFoamCells Cells

FattyFattyStreak Streak

IntermediateIntermediateLesion Lesion AtheromaAtheroma

FibrousFibrousPlaquePlaque

ComplicatedComplicatedLesion / RuptureLesion / Rupture

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

From FirstDecade

From ThirdDecade

From FourthDecade

Endothelial DysfunctionEndothelial Dysfunction


CHDCHD

Narrowing of Coronary artery limits blood supply to heart muscle

If demand for blood supply cannot be met, muscle becomes ischaemic


The Three Possible Outcomes The Three Possible Outcomes of Myocardial Ischemiaof Myocardial Ischemia

1) Myocardialinfarction

3) Relief of ischemiaMyocardial Ischemia

2) Chronic Ischemiawithout infarction

Salvage of previouslyischemic myocardium

Transientpostischemicdysfunction:

Hearts with elementsof both hibernating

and stunning:

Stunned/Hibernatingmyocardium Stunned myocardiumHibernating myocardium

? ?

No return ofcontractile function

Return ofcontractile function

Persistent Ischemiadysfunction:

Relief of ischemia

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 Schematic Diagram of Stunned MyocardiumStunned Myocardium

Wall motion abnormalityduringocclusion

Wall motionabnormality

From Kloner, R.A., Am J Med 1986;86:14.

Gradual return offunction (hours to days)

Persistent wall motion abnormality(despite reperfusionand viable myocytes)

Coronary occlusion

Coronary reperfusion

Return offunction

Clamp


Hibernating Hibernating MyocardiumMyocardium

Atherosclerotic narrowing

Wall motion abnormalitydue to chronic ischemiawithout infarction

Wall motion abnormality

From Kloner, R.A., Am J Med 1986;86:14.


Remodeling - Remodeling - DefinitionDefinition

Changes in interstitial, cellular, molecular,and genome expression that results inclinical changes in size, shape, and functionof the heart


Remodeling Post-IMARemodeling 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;81:1161-1172White HD et al. Circulation 1987;76:44-51Martin G. et al. Circulation 2000;101:2981-2988


• (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.

Post infarction remodeling (PIR)


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

Left ventricular remodeling after myocardial infarction


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


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


Neurohormonal NA

• Noradrenaline - initially improves CO

• Patients with decreasing levels of NA, ANP post MI had better prognosis.


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.


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.


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.


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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