11CORONARY CIRCULATION Blood flow left ventricle = 80/ml/min/100gright ventricle = 40 ml/min/100gatria = 20 ml/min/100g*Flow can increase 4-foldCapillary density - all capillaries openVery high O2 extraction: (A-V)02 = 14 ml 02/dlVO2 = 12 ml/min/100g ----> very high
12MYOCARDIAL OXYGEN CONSUMPTION a to cardiac workinfluenced bya) contractilityb) heart ratec) after-loadincreases achieved primarily by hyperemia40% due to oxidation of carbohydrates, 60% fatty acids
13TRANSMURAL DISTRIBUTION OF BLOOD FLOW contraction (systole) leads to compression of intramural vessels and reduction in flowpressure inside left ventricle can exceed aortic pressure during systolevessel compression greatest in endocardium, decreases toward epicardiumO2 demand and flow/g is greatest in endocardiumLV coronary flow decreases as HR increases since diastole shorter
17LOCAL 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 arteriolesVO2 limited by blood flow (max O2 extraction)
19Endothelial 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.
20Fatty-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.
21Formation of an Advanced, Complicated Lesion of Atherosclerosis 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.
22Unstable 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.
23Pathophysiologic 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.
24Atheroma morphology by intravascular ultrasound (IVUS)
27Atherosclerosis Timeline FoamCellsFattyStreakIntermediateLesionAtheromaFibrousPlaqueComplicatedLesion / RuptureAtherosclerosis 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 DysfunctionFrom FirstDecadeFrom ThirdDecadeFrom FourthDecadeAdapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).9
30CHD Narrowing of Coronary artery limits blood supply to heart muscle If demand for blood supply cannot be met, muscle becomes ischaemicNarrowing of Coronary artery limits blood supply to heart muscle
31The Three Possible Outcomes of Myocardial Ischemia 3) Relief of ischemia1) Myocardialinfarction2) Chronic Ischemiawithout infarctionSalvage of previouslyischemic myocardiumHearts with elementsof both hibernatingand stunning:Transientpostischemicdysfunction:Persistent Ischemiadysfunction:Stunned/HibernatingmyocardiumHibernating myocardiumStunned myocardium??Relief of ischemiaNo return ofcontractile functionReturn ofcontractile functionAdapted 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.
32Schematic Diagram of Stunned Myocardium ClampWall motionabnormalityCoronary occlusionWall motionabnormalityduringocclusionCoronary reperfusionPersistent wall motion abnormality(despite reperfusionand viable myocytes)Return offunctionGradual return offunction (hours to days)From Kloner, R.A., Am J Med 1986;86:14.
33Hibernating Myocardium Atherosclerotic narrowing Wall motion abnormalityAtherosclerotic narrowingWall motion abnormalitydue to chronic ischemiawithout infarctionFrom Kloner, R.A., Am J Med 1986;86:14.
34Remodeling - Definition Changes in interstitial, cellular, molecular,and genome expression that results inclinical changes in size, shape, and functionof the heart
35Remodeling Post-IMA Early Remodeling (within 72 hours) ¤ involves expansion of the infarct zoneLate 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;76:44-51Martin G. et al. Circulation 2000;101:
36Post infarction remodeling (PIR) (PIR) Most studied model of remodelingBegins rapidly within hours of infarctionThere is variation in post infarction remodeling depending on the time of ischaemia, duration, amount of preconditioning, collaterals, genotype, neuroendocrine status, treatment and response.
37Left 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
38Processes of PIR Infarct expansion - thinning & regional expansion (in animals occurs within 1 day)Global function impairment - occurs on day 2Myocyte lengtheningVentricular wall thinningInflammation and resorption of necrotic tissueDilatation and reshaping of LVlate expansionMyocyte hypertrophyLate myocyte lossFibrosis and collagen accumulation in interstitium
39Haemodynamics Thinning of the infarct area Compensatory hypertrophy of remaining LVThe balance of thinning and hypertrophydetermines the wall stress and thus thefurther dilatation of the heart.Therapy can alter these factors
40Neurohormonal NA Noradrenaline - initially improves CO Patients with decreasing levels of NA, ANP post MI had better prognosis.
41Neurohormonal 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.
42CytokinesInterleukins, TNF, endothelins PKC, all mediate the remodeling processIncreased levels associated with poorer prognosisBlockage of endothelin in animal models improves remodelingStimulation of TNF alpha can lead to LV remodeling in animals.
43Oxidative stressIncomplete understanding of oxidative stress and its role in remodeling beyond that of apoptosis.Seems to alter viability of myocytes in the presence of cytokines.
44MyocytesMyocytes 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.