Physiology of Coronary Blood Flow

1. Physiology of Coronary Blood Flow Dr Sandeep Mohanan, Department of Cardiology, Medical College, Calicut.

2. OUTLINE • Introduction • Coronary microcirculation, resistance beds & autoregulation • Endothelium dependent vasodilation • CBF during exercise • Physiology of CBF across a stenosis • Measurement of CBF • Physiologic assessment of CAD- noninvasively and invasively • Coronary collateral circulation • CBF abnormalities with ‘normal’ coronary vessels

3. INTRODUCTION • The resting coronary blood flow ~250ml/min (0.8ml/min/g myocardium=5% of COP) • Myocardial oxygen consumption --- balance between supply and demand • According to Fick’s principle, oxygen consumption in an organ is equal to the product of regional blood flow and oxygen extraction capacity. • The heart is unique in having a maximal resting O2 extraction (~70-80%) • So, MVO2 = CBF * CaO2 • Thus, when systemic oxygenation is stable, the oxygen supply is determined by the coronary blood flow

4. The coronary blood flow is unique: • Helps generate the systole (cardiac output) & simultaneously gets impeded by the systole it generates. • At systole – Arterial flow is minimum: directed from the subendocardium to the subepicardium; and the coronary venous outflow is maximum • Diastole – The coronary inflow is maximum

5. BASIC PHYSICS OF FLOW • Bernoulli’s principle • Daniel Bernoulli (Swiss scientist)studied fluid dynamics and postulated in his book,Hydrodynamica, that for an inviscid flow an increase in the speed of the fluid occurs simultaneously with a decrease in pressure or a decrease in the fluid's potential energy. • LAW OF CONSERVATION OF ENERGY {Total energy = Kinetic energy + Potential(Pressure) energy} - May explain in part the increase in flow during diastole

6. Hagen-Poisseuilles equation: -Gives the pressure drop for a viscous liquid( in laminar flow) as it flows through a long cylindrical pipe -Corresponds to the Ohms law for electrical circuits (V=IR) -Thus halving the radius of the tube increases the resistance by 16 times • Principles were also extended to turbulent flow and helped derived the Darcy-Weisbach equation and the Reynolds number

7. DETERMINANTS OF CORONARY RESISTANCE • Flow is determined by the segmental resistance and therefore an understanding of the resistance beds is necessary: • 3 resistance beds • R1 • R2 • R3

8. R2( Microcirculatory resistance) – 20- 200µm • Small arteries and arterioles • Capillaries: ~ 20% of R2 ( even if capillary density doubles, perfusion increases by only 10%) • R3( Compressive resistance) - time varying - Increased in heart failure In the subendocardium R3increases but R2 decreases. So, transmural flow is normally uniform.

9. Broadly 2 compartments of coronary resistance: 1) Epicardial conduit vessels – no pressure loss 2) Resistance vessels -- < 300μm -- gradually dissipating pressure till 20-30 mmHg Coronary driving pressure = Aortic root pressure – LVEDP The interactions of coronary driving pressure and the coronary resistance are coordinated so as to maintain a constant flow for a given workload. ---- CORONARY AUTOREGULATION

10. CORONARY AUTOREGULATION • Maintenance of a constant regional coronary blood flow over a wide range of coronary arterial pressures when determinants of myocardial oxygen consumption are kept constant. • Below the lower limit: flow becomes pressure dependent • Under optimal circumstances this lower threshold is a mean pressure of 40mmHg. • Sub-endocardial flow compromise: <40mmHg • Sub-epicardial flow compromise: <25mmHg -Due to higher resting blood flow in subendocardium and effects of systole on subendocardial coronary reserve

13. The threshold increases with increased determinants of oxygen consumption. • Even as constant flow is maintained at a constant work load; -- As the workload increases, the oxygen consumption proportionately increases. -- The increase in MvO2( Demand) needs a proportionate increase in coronary flow ( Supply). -- This increase in CBF is directed by endothelium related flow mediated dilatation as well as by various mediators that decrease coronary resistance.

14. CORONARY MICROCIRCULATION • A longitudinally distributed network with considerable spatial heterogeneity of control mechanisms. • Each resistance vessel needs to dilate in an orchestrated fashion.

15. Resistance As (100 -400μm) - shear stress + myogenic • Arterioles (<100 μm) –metabolic • Capillaries- 3500/mm2 • ΔP (Pressure drop) occurs b/w 50 - 200μm

16. Heterogeneity of microcirculatory auto-regulation: When driving pressure decreases, Autoregulation causes arterioles<100μm dilate where as larger resistance arteries tend to constrict due to a decrease in perfusion pressure. However metabolic vasodilation which is triggered shows a homogenous response.

17. Transmural penetrating arteries: • Not influenced by metabolic stimuli. • Blood flow driven by coronary driving pressure, flow mediated vasodilation and myogenic regulation. • Significantly influences the subendocardial blood flow

18. MEDIATORS OF CORONARY RESISTANCE • PHYSICAL FORCES • METABOLIC MEDIATORS • NEURALCONTROL • PARACRINE FACTORS

19. Physical forces • These are intraluminal forces: • Myogenic regulation: • Ability of the vascular smooth muscle to oppose changes in coronary arteriolar diameter • Probably due to stretch activated L-type Ca channels • Primarily in <100microm • Significant role in coronary autoregulation

20. 2) Flow mediated vasodilatation: • Coronary diameter regulation in response to changes in local shear stress. • Kuo et al • Endothelium mediated- NO, EDHF • Occurs in both conduit (?hyperpolarisation) as well as resistance arteries (NO mediated)

21. Metabolic mediators • Adenosine: - Cardiac myocytes during ischemia ( ATP hydrolysis) • T-half of 10sec • A2a receptors - cAMP : Ca2+ activated K-channels • Direct action on <100µm vessels • Indirectly on resistance arteries and conduit arteries : endothelium-dependent • Hypoxia • Exercise –induced myocardial ischemia

22. K+-ATP channels • - Contributes to resting coronary tone • - It is actually a common effector pathway of several other mediators • Hypoxia - However a direct vasodilatory mechanism is lacking • Acidosis and arterial hypercapnoea:

23. NEURAL CONTROL- Cholinergic innervation -Endothelium dependent and flow mediated vasodilatory effects also

24. NEURAL CONTROL- Sympathetic innervation - Sympathetic denervation does not affect resting flow

25. PARACRINE MEDIATORS Released from epicardial arterial thrombi following plaque rupture

26. ENDOTHELIUM DEPENDENT MODULATION OF CORONARY TONE A functional endothelium is the major determinant in the normal physiological effects of physical, metabolic, neural and paracrine factors on the coronary tone. • Nitric oxide (NO) • Endothelium dependent Hyperpolarising factor (EDHF) • Prostacyclins • Endothelins

27. Nitric Oxide • “Molecule of the year” in 1992 • Robert F. Furchgott, Louis J. Ignarro and FeridMurad received Nobel prize for Physiology/Medicine in 1998 • L-arginine + 3/2 NADPH + H+ + 2 O2 = citrulline + NITRIC OXIDE + 3/2 NADP+ • Action: It increases cGMP levels : Decreased i.c Ca levels -Its effects are enhanced by increased shear stress of flow • Exercise : Chronic upregulation of NO synthase • CVD risk factors – Increase oxidative stress(superoxide) – inactivates NO

28. EDHF • Shear stress induced vasodilation • Opens K+ channels – vasodilation • Probably metabolites of arachidonic acid by the CYP pathway • ? Epoxyeicosatrienoic acid • ? Endothelium derived hydrogen peroxide

29. PROSTACYCLIN: -Arachidonic acid metabolism via cycloxygenase pathway • Important in collateral vascular resistance • ENDOTHELINS: - prolonged vasoconstictor response • ETa and ETb receptors • Regulates blood flow only in pathophysiological states.

30. VARYING SENSITIVITIES OF THE MICROCIRCULATION TO STIMULI

31. Pharmacological Vasodilation • Nitroglycerin: • Vasodilation in conduit and resistance arteries • No effect in nomal coronary arteries due to autoregulatory mechanisms • Improves subendocardial perfusion: • Compensates for impaired endo-dependent mechanisms • Dilates collateral vessels • Reduces LV end-diastolic pressure

32. Calcium Channel blockers: • Vasodilation of conduit and submaximal action on resistance vessels ( Therefore rarely precipitate subendocardial ischemia ) • Adenosine & agonists : Regadenoson (A2) • Dipyridamole • Papaverine: • 1st agent used for coronary vasodilation • Increases cAMP by inhibiting phosphodiesterase

33. A newer mechanism for coronary blood flow • Davies et al (Circulation 2006) : “Pushing waves and Suction waves” • Pushing waves : Proximal to distal push- forward - pushes blood till the conduit vessels • Suction waves: Distal to proximal suction effect - backward - main determinant of diastolic flow

34. CBF DURING EXERCISE ACUTE EXERCISE: • Increases afterload, contractility, LV wall stress, tachycardia and oxygen demand • Proportional increase in myocardial blood flow (2 to 4 fold) mainly through a decrease in R2 and flow mediated dilation. • However in presence of a coronary stenosis the increase in R1 overruns the decrease in R2 above a threshold, causing stress induced ischemia.

35. PROLONGED EXERCISE TRAINED HEART: The CBF is maintained or increases

36. PHYSIOLOGY OF CBF ACROSS A CORONARY STENOSIS • Consequence of a coronary obstruction due to CAD: 1) Increased resistance in an epicardial artery due to stenosis 2) Abnormal microcirculatory control

38. The flow across a stenosis is determined by the P-Q relationship Perfusion of territory distal to a stenosis ------------ DISTAL CORONARY PRESSURE In normal coronaries : R2> R3>> R1 In CAD : R1 > R3 > R2 R1 increases with stenosis severity and impairs flow

40. Ideal stenosis P-Q relationship • According to Bernoullis principle and law of conservation of energy. The total energy = KE + PE; i.e E ∝ V2 + PE The flow across a stenosis (Flow= A * mean velocity) Thus V ∝ 1/D2 …. -Therefore in 50% stenosis, V- 4 times and KE- 16times. - The PE proportionately decreases and is lost as (ΔP) DISTAL PRESSURE LOSS Post stenosis: V comes back to normal …Therefore KE decreases to pre-stenosis values… PE thus becomes (prestenotic PE)- ΔP i.e =Pd

42. ΔP= Viscous losses + Separation losses + Turbulence Viscous losses = f1 Q , f1 (Viscous coefficient = 8πμL/ As2 ) (Hagen-Poiseuille equation) Separation losses= f2 Q2, f2 (Separation coefficient= ρ/2[1/As-1/An]2 ) μ - viscosity of blood ρ - density of blood L - length of stenosis As - CSA of stenotic segment An - CSA of normal segment Flow to distal territory = Pd- venous pressure

43. Thus the pressure drop across a stenosis varies directly with the length of the stenosis and inversely with fourth power of the diameter. • Therefore overall resistance and thus distal pressure is determined mainly by cross sectional area of the stenosis – increases exponentially • Resistance is also flow dependent ( α square of flow) • Abluminal outward remodelling : No effect on P-Q characteristics • Inward remodelling : Significant longitudinal pressure drop

45. MEASUREMENT OF CORONARY BLOOD FLOW • Earlier microsphere radionuclide techniques were considered gold standard. • Presently, regional myocardial blood flow can be quantitated non-invasively equally accurately using MRI, CT and PET. • Resting CBF – 0.7-1ml/min/g • However a resting CBF gives little information • This may be normal in HCM, CAD, DCMP etc due to inherent “adjusting mechanisms”. • It is the CBF in a “stressed” heart that brings out the true quality of the coronary vasculature. • “STRESS” – Pharmacological / Physiological

46. Noninvasive flow measurements • MRI, Doppler echo and Dynamic PET (Nuclear Perfusion studies) • Require measurements of the myocardial tissue tracer concentrations and its kinetics.

47. FUNCTIONAL ASSESSMENT OF CAD - Noninvasive • Vasodilator stress: - Adenosine 140µg/kg/min for 4 min( Dypiridamole 560µg/kg/min) • Induces hyperemia and makes CBF dependent on driving pressure and the residual resistance • 3 to 5 times flow (2-4ml/min/g) • Exposes the minimum coronary vascular resistance of the system • Noninvasive methods may measure either the relative flow (compared to normal regions)or the absolute flow • The concept of Coronary flow reserve pioneered by Lance Gould is central to the functional assessment of CBF across a stenosis.

48. Coronary reserve : Ability to increase CBF above resting value by maximum pharmacologic vasodilation (4 to 5 fold) Parameters that may affect CFR: - HR - preload - afterload - contractility - systemic oxygen supply • Flow in the maximally vasodilated heart is pressure dependent. • Thus CFR indirectly shows the consistency of the driving coronary pressure uptill the distal territory

49. Relative Flow Reserve = Regional perfusion of a segment/ Perfusion in normal segment during maximal pharmacological vasodilation/exercise • Compares under same hemodynamic conditions • Independent of HR and MAP • More lesion specific than the AFR --- correlates with FFR Limitations: - Requires a normal reference segment--- ? Diffuse CAD • Low sensitivity – requires relatively large differences in regional flow • The uptake of nuclear tracers may not be proportionate in both regions • Not much prognostic data available

50. Absolute Flow Reserve = Maximal vasodilated flow in a region of interest/ Resting flow of same region. - Normal AFR ~ 4-5 • Clinically significant impairment if <2 • AFR incorporates functional importance of a stenosis + microcirculatory dysfunction Limitations: - Altered by factors affecting resting flow also (Hb, HCM, Hemodynamics etc) • Instantaneous hemodynamic conditions of the values are different • Cannot specify the importance of the epicardial lesion alone • Correlation with stenosis severity decreases with more extensive CAD