Coronary Physiology

Introduction to Nuclear Cardiology I:Principles of Coronary PhysiologyMatthew Schumaecker, MD

1ObjectivesTo understand:Determinants of myocardial oxygen consumptionDeterminants of coronary vascular resistanceRegulation of coronary blood flowCoronary flow reservePhysiologic consequences of ischemia

2 Pin - PoutRQ =Physical Principle #13Physical Principle #2When multiple resistors are connected in series, their combined resistance is equal to the individual resistances added together.R2R3R1Resistance total = R1 + R2 + R3

4Determinants of Myocardial Oxygen ConsumptionInotropyChronotropy

HR x BP is clinically referred to as double product and is used as a surrogate marker for myocardial oxygen demand5Coronary Vascular ResistanceR1Epicardial Arteries

Vascular tone of R1 vessels is controlled by:Nitric oxide causes vasodilation in response to shear stress.Endothelium-derived hyperpolarizing factor.Sympathetic -dilation (i.e., during exercise)Sympathetic 1-constriction

6Coronary Vascular ResistanceR1Epicardial Arteries

Due to their size, there is normally no pressure drop across epicardial arteries.Therefore, epicardial contribution to coronary vascular resistance is negligible in the normal heart.With hemodynamically significant lesions, fixed stenosis begins to contribute to total resistance.Severely narrowed arteries may reduce resting flow.

7Coronary Vascular ResistanceR2Coronary Microvasculature

Dynamic resistance occurs from arteriolar network (20 to 200m)Changes in response to multiple physical, metabolic, paracrine and neural effectors.Approximate contribution to resistance:25% - vessels > 200m20% - vessels 100-200m55% - vessels < 100 m

8Coronary Vascular ResistanceR3Compressive Resistance

Extravascular tissue pressure in the myocardium is determined by myocardial tension at that given point in the cardiac cycle.During systole, tissue pressure = SBP in the subendocardium while it falls to pleural pressure in the subepicardium. This decreases driving pressure for coronary blood flow.

9Coronary Vascular ResistanceR3Compressive Resistance

It is because of compressive resistance that there is no significant coronary blood flow during systole. i.e., Pin Pout

Increase in LV diastolic pressure increases compressive resistance and decreases flow during diastole.

10Physiologic Control of Coronary Blood FlowMyogenic RegulationFlow-Induced VasodilationDirect Metabolic Effectors11Myogenic RegulationVascular smooth muscle opposes change in arteriolar diameteri.e., vessels relax when distending pressure is decreased and constrict when it is elevated.Likely secondary to stretch-activated calcium channelsMost active in small vesselsPostulated to play a role in regulated precapillary tissue exchange

Am J Phys 273:H257 1997

12Flow-Induced VasodilationThree major affectors:Nitric oxide (mostly in vessels > 100 m)Endothelium-dependent hyperpolarizing factor.Prostacyclin PGI2

13Nitric OxideNO is a crucial signaling molecule in vascular biologyProduced in endothelial cellsIndirectly catalyzes intracellular cGMP formation from GTPcGMP acts a secondary messenger, ultimately causing the relaxation of endothelial smooth muscle by decreasing intracellular Ca2+ concentration and a decrease in the contractile sensitivity to extracellular Ca2+ .This causes a vasodilatory effect in vessels > 100 m (i.e., R1 and large R2 vessels)In patients with CAD, nitric oxide no longer plays a role in flow-mediated vasodilation.

Carvajal, et al. J. Cell. Physiol. 184:409-420, 2000.

14Endothelium-Derived Hyperpolarizing FactorUnidentified vasoactive substance Mediates flow-induced vasodilation, particular in CADEDHF activates K+ channels, leading to hyperpolarization and vasodilation.Strong evidence suggests that it is a metabolite of arachidonic acid derived from cytochrome P450Contribution of EDHF to vasodilation increases as vessel size decreases.Miura et al. Circulation 2001;103:1992-199815

Endothelium Independent VasodilationPlatelet factors:Thrombin ADPBradykininHistamineSubstance P

16Metabolic Affectors of Coronary ResistanceThese exert their actions almost exclusively on the R2 vessels (i.e., arterioles and microvasculature)

AdenosineTissue pO2Tissue pCO2Tissue pH

17Metabolic Affectors of Microvascular ResistanceAdenosineReleased by myocytes when ATP hydrolysis exceeds synthesis during ischemia.Powerful vasodilator which exerts action upon R2 vessels via A2A receptors agonism.A2A receptor activation increases cAMP levels, thereby activating calcium-activated KATP channels.Direct vasodilation occurs primarily in vessels 90% stenosis - compensatory mechanisms are exhausted28Coronary Flow ReserveRatio of blood flow in a maximally vasodilated vessel to that same vessel in a basal, autoregulated state.

Principle determinants of CFR are:Vessel stenosesInability to achieve optimal vasodilation (i.e., endothelial dysfunction)29Approximate Reduction in Maximum Vasodilated Flow (MVDF) for Vessel StenosisStenosisReduction in MVDF50%20%70%40%80%60%>90%Loss of flow reserveKlock FJ JACC 1990,16:763-76930Transmural Variations of Flow ReserveR2 vessels in the subendocardium are more vasodilated in the basal state than R2 vessels in the subepicardium.This is to account for the transmural gradient in the effect of compressive resistance (i.e., R3).Therefore, the subendocardium has less coronary reserve than the subepicardium.31Transmural Variations of Flow ReserveSubendocardium: R3>>>R2Epicardial VesselsLeft VentricleSubepicardium: R2>>>R3R3Decreasing Coronary Flow Reserve32Measuring Coronary Flow ReserveAbsolute Flow ReserveRelative Flow ReserveFractional Flow Reserve33Coronary Flow ReserveAbsolute Flow ReserveAmount of increase in flow with ischemic dilation (transient occlusion) or with pharmacologic dilation.Can be quantified using doppler, thermodilution or PETFlow-dependent as well as perfusion-dependent (i.e., anemia, increased VO2).Normal values are 4-5Clinically significant < 2

34Coronary Flow ReserveRelative Flow ReserveCornerstone physiologic concept behind nuclear perfusion imaging.Relative differences in regional perfusion are assessed in response to exercise or pharmacologic vasodilation and expressed as a fraction of flow to normal regions of the heart.

35Coronary Flow ReserveRelative Flow Reserve - Advantages

Compares perfusion differences under identical hemodynamic conditions (i.e., HR, BP, Hg, VO2).

Well suited to cardiac imaging.

36Coronary Flow ReserveRelative Flow Reserve - DisadvantagesRequires a normal reference segment. This may not be present in:States of impaired microcirculatory vasodilation.Diffuse multivessel CAD (balanced ischemia)

37SPECT Tracer LimitationsMyocardial uptake of nuclear tracers fail to increase proportionally to coronary flow beyond a certain threshold

TTracer UptakeMyocardial Blood FlowLow Normal Rest Exercise (2-3x) Pharmacologic Stress (4-5x)Ideal TracerThalliumTetrofosminSestamibi38SPECT Tracer Limitations (cont)Large differences in relative vasodilated flow are necessary to detect perfusion differences.

Differences in tracer deposition underestimate underlying differences in regional coronary flow.

TTracer UptakeMyocardial Blood FlowLow Normal Rest Exercise (2-3x) Pharmacologic Stress (4-5x)Ideal Tracer (O15)ThalliumTetrofosminSestamibi39Coronary Flow ReserveFractional Flow Reserve

Distal coronary pressure measured during vasodilation is directly proportional to maximum vasodilated flow.

TechniquePressure distal to a stenosis is measured with a transducer during infusion of adenosine. This is indexed to mean aortic pressure (Pd/Pao)Limited data show that values of > 0.75 are associated with good outcomes without intervention.

40Coronary Flow ReserveFractional Flow Reserve Clinical Limitations

Cannot assess abnormalities in microvascular flow reserve.Dependent upon inducing maximum vasodilation.Ignores back pressure to coronary flow and assumes that coronary venous pressure is zero.The wire itself can worsen the stenosis in small vessels

41ReferencesGerman G and Berman D Clinical Gated Cardiac SPECT Blackwell Futura, 2006

DiCarli M, et. al. (1997). "Effects of cardiac sympathetic innervation of coronary blood flow." New England Journal of Medicine 336: 1208-1215.Jorge A. Carvajal, e. a. (2000). "Molecular mechanism of cGMP-mediated smooth muscle relaxation." Journal of Cellular Physiology 184(3): 409-420. Miura H, W. R., Liu Y, et al. (2001). "Flow-induced diliation of human coronary arterioles: important role of Ca2+-activated K+ channels." Circulation 103: 1992-1998.Quyyumi AA, D. M., Andrews NP, Gilligan DM, Panz JA, Cannon RO III. (1995). "Contribution of nitric oxide to metabolic coronary vasodilation in the heart.

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