Siwan Choi, M.D. Chungnam National University

Vasomotor Regulation of Coronary Artery inNormal and Coronary Artery DiseaseSiwan Choi, M.D.Chungnam National University

Compartment of Coronary vesselsEpicrdialCoronary ArteryResistantArteriolesCapillariesVenulesCoronary sinusArterial systemepicardial artery,arteriole ≥ 200 µmMicrocirculationarteriole

Myocardial Blood Volume• 1/3 of total coronary corculation• 90 % of myocardial volume : Capillary blood volumediameter : 7 µm, length : 0.5 ~ 1 mm,intercapillary distance : 15 ~ 20 µmDensity : 3000 ~ 4000/mm 2 ( adult 8million capillaries )velocity of RBC in capillary : 1mm/secArteriolesubepicardiumVenulemidmyocardiumCapillarysubendocardium

Autoregulation of coronary blood flowCoronary Blood flow (Q) =Perfusion Pressure(δP) / Vascular Resistance(R)(Q)140120100806040200Autoregulation40 ~ 120 mmHg0 50 100 150 200Perfusion Pressure

Pressure in the Coronary CirculationEpicardial Coronary arteries1008090 mmHgArterioleCapillaryVenule6040200동맥계미세순환계45 mmHg30 mmHg15 mmHg정맥계400 200 200 400혈관직경 (um)

Distribution of Coronary Vascular resistance at rest90 45 30 15 5( mmHgmL -1 .min )21.510.50원위부관동맥저항성 세동맥(

Coronary Vascular resistance at hyperemia(stenosis)21.570 53 30 7 51( mmHgmL -1 .min )0.50원위부관동맥저항성세동맥(

Distribution of vascularresistance at rest & hyperemiaArteriolar vasodilation/vasoconstrictionCapillary (de)recruitment

Coronary Vasomotor RegulationInterplay of BP (myogenic response) and Blood Flow (FMD)Metabolic controlLuminal or myocardial hypoxia (Exercise or Ischemia)Neurohumoral controlSympathetic systemRenin angiotensin system

Mechanisms of metabolic regulation ofvessel toneEndothelial CellVascular smooth muscle cellCardiomyocytePO 2 ↓(lumen)Ca2+↑(releasefrom ER)HSPp20 ↑cAMPVessel tone ↓Contractile force ↓K ATpH+PO 2 ↓PG ↑ACATP[Ca2+]↓HyperpolarizationA 2ACO2AdenosineCa vg

Coronary Vasomotor RegulationInterplay of BP (myogenic response) and Blood Flow (FMD)Metabolic controlLuminal or myocardial hypoxia (Exercise or Ischemia)Neurohumoral controlSympathetic systemRenin angiotensin system

Determinants ofhuman coronary vascular tone• Myogenic vasoconstriction• Flow mediated dilation• Serotonin and thromboxane A2• TNF-α(PCI)• Substances released from myocardium• Alteration of NOS gene• Endothelial growth factors• Certain polymorphisms(eNOS gene)

Myogenic vasoconstriction(resistant arterioles)Vessel at 40mmHg Vessel at 80mmHgNormalized diameter0.90.80.70.60.50.420 40 60 80 100Intraluminal Pressure

Mechanisms of Myogenic constriction• Membrane depolarization• Molecular signaling cascades( 2° messenger )• Reactive oxygen species

Myogenic ConstrictionMembrane depolarization(VSMC)Pressure / Stretch??PLA 2PLCNSC Chan.AA(TRP)Cl Chan.20-HETE(-)EETsIP 3VGC Chan.depolarization(-)K ca Chan.(-)Calcium EntryKv Chan.Calcium StoresContraction

Myogenic ConstrictionMolecular signaling cascades•Protein kinase C(PKC)•Mitogen activatedProtein Kinase(MAPKs)ERK1/2PK(JNK)p38 kinase

Myogenic ConstrictionReactive oxygen Species

Myogenic ConstrictionReactive oxygen SpeciesPercent tone in mice mesenteric A

Complex components of vascular regulationin human coronary microcirculation

Flow Mediated dilation(FMD)Change in wall Flow through an artery or arteiolesChange in wall shear stress triggers complex signaling processFactors released and traverse basement membraneSmooth muscleVasodilation

Mediators of FMD :from Endothelium• Nitrix Oxide(NO) -- epicardial Ar• EDHF -- arterioles• PG

Mechanisms mediated by EDHF

Nature of EDHF• H 2 O 2Proximal coronary arteries• EETs( epoxyeicosatrienoic acid)• CNP• K +Resistant ar

Mechanisms mediated by EET

Complex components of vascular regulationin human coronary microcirculation

Microvascular dysfunctionEndothelial dysfunction• Coronary artery disease• CMP• Diabetes/ insulin resistance• Hypertension• Hyperlipidemia• Smoker

Enhanced ROS productionImpairments of NO bioavailability↓( K ATP channels, K Ca channels, K V channels )Microvascular dysfunctionEndothelial dysfunction

Microvascular alterationin chronic coronary artery diseaseIncreased levels of ET and increased sensitivity to ET -1Sustained vasoconstrictionDecreased Shear stress Mitogenic & fibrogenic growthIncreased AG II & catecholaminesVSMC hypertrophy & proliferationMicrovascular hypertrophic remodeling: Increased wall thickness and stifffnessAggravate myocardial ischemia

FMD in CAD

Mediators of FMD in CAD( Human coronary arterioles in patients with CAD & without CAD )Impaired NO mediated vasodilation Role of EDHF as compensatory mechanism

Contribution of EDHF,PG & NOin insulin resistance

How to restore normal vasomotorresponses in coronary artery disease• Reduction of oxidative stressNADPH inhibition, RAS inhibitionSOD mimetics• EDHF : EETsStatin, CCB, fibrates,Inhibitor of soluble eposide hydrolase• Endothelin receptor blocker• TNF-α & IL 6 antagonist

Complex components of vascular regulationin human coronary microcirculation

summary : Coronary Vasomotor regulationVasoconstrictionCoronaryVasomotorRegulationVasodilationAntioxidantEDHFET & RAS inhibitorPCI & CABGOxidative StressET & RASMicrocirculatoryremodelingOptimalMyocardial perfusionFor metabolic need