regulation of coronary blood flow - heart

British Heart Journal, I97I, 33, Supplement, 9-I4.

Regulation of coronary blood flow

Richard GorlinlFrom the Cardiovascular Division, Department of Medicine, Peter Bent Brigham Hospitaland Harvard Medical School, Boston, Massachusetts, U.S.A.

Coronary bloodflow is dependent upon arterial pressure, diastolic time, and small vessel resistance.The system is regulated to achieve a low flow high oxygen extraction and low myocardial Po2.This setting is sensitive to change in oxygen needs. Regulation of blood flow occurs primartilythrough local intrinsic regulation, most likely through production of vasodilating metabolites inresponse to minimal degrees of ischaemia. Local regulation appears to dominate over remoteregulation in most circumstances. Blood flow distribution to the myocardium is depth dependentas well as regional in variation. Both types of distribution of bloodflow are profoundly disturbedin the presence of obstructive coronary atherosclerosis. This results in either concentric myocardialshells or patchy transmural zones of selective ischaemia with clear-cut but local abnormalities inmetabolism and performance.

Experimental studies during the last decadehave provided a better understanding of theoperation of the coronary circulation than waspossible before. The types of vascular effectorreceptors, the relative importance of localversus remote control of blood flow, the differ-ence between deep and superficial myocardialblood flow, and the relationship between localblood flow, metabolism, and contractile stateall deserve discussion. The purposes of thispaper are to describe the unique characteris-tics of the normal coronary circulation; toelucidate the above mentioned areas of newknowledge; and to describe the mechanism ofblood flow delivery when there is intrinsicobstructive disease of the large coronaryarteries - that is, atherosclerosis.

Normal coronary circulationCoronary blood flow as in any other vascularbed is a direct function of blood pressure andan inverse function of the degree of small ves-sel resistance (Fig. i). Blood pressure is aprimary variable, but because coronary flowoccurs mainly in diastole the diastolic level ofpressure and the duration of diastole (heartrate effect) become important modifying fac-tors. Similarly, as will be discussed below,

I Supported by USPHS and Heart Research Foun-lation, Boston, Massachusetts. Dr. Gorlin is an in-7estigator of the Howard Hughes Medical Institute.

intramyocardial resistance will add to or sub-tract from resistance forces intrinsic to thesmall vessels per se. Small vessel resistance isa function of a variety of neurogenic andchemical effects on its smooth muscle cells.Small changes in the diameter of resistancevessels result in profound changes in bloodflow for any given pressure.The energy requirement ofthe human heart

in relation to its size is the greatest of anytissue in the body. The heart consumesapproximately oxI ml. of oxygen per grammeof muscle per minute. Under normal con-ditions high energy phosphate is derived al-most exclusively via aerobic pathways. Energyrequirements may double or triple withapplied cardiovascular stress.The oxygen delivery system is essentially a

high extraction low flow system. The myo-cardium removes approximately 120 ml. oxy-gen per litre of coronary blood flow (Fig. 2).As a result, coronary venous oxygen contentis about 50 to 60 ml. per litre and venous Po2is in the range of 20 mm. Hg. Thus myocar-dial fluid Po2 must be lower, a conditionunique to the heart and to exercising skeletalmuscle. Basal myocardial flow is less than iml. per gramme of muscle or about 250 ml.per minute. This is in sharp contrast to otherorgans such as liver, kidney, or brain, inwhich tissue Po2 is much higher, arterio-venous oxygen extraction less, and blood flowper unit mass the same or even greater.

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Io Richard Gorlin

Local versus remote control of coronaryflowIt is necessary at this point to consider therelative importance of local versus remotemechanisms in the regulation of myocardialflow. The pattern of blood flow and energyneed described above provides the first insightinto local control within the myocardiumitself.

Chemical regulation The 'set' of thecoronary system is one of relative under-perfusion as a result of high basal vasculartone. This forces the myocardial cells tooperate at a low Po2. It has been suggestedthat this marginally 'hypoxic' state providesa mechanism for sensitive local auto regulationof blood flow. Even the slightest decrease intissue Po2 from 20 mm. Hg may be enoughto render the cell hypoxic. The cell may re-lease chemical byproducts as a result. Sheaand co-workers (I962), for example, haveshown that glycolysis with profuse lactateproduction occurs in the dog heart whencoronary venous Po2 drops to I0 mm. Hg orless. Berne (I963) has promulgated the theorythat intracellular high energy phosphate com-pounds are exquisitely sensitive to intra-cellular oxygen conditions. These moietiesreadily break down to adenosine which dif-fuses out of the cell into the surroundingextracellular fluid. Most members of this classof compounds are potent vasodilators. Afterbiochemical analysis of recovery productsduring induced hypoxia in various prepara-tions, Rubio and Berne (I969) believe thatadenosine, in particular, acts on the smoothmuscle in the walls of arterioles adjacent tothe cardiac muscle cells. This causes vaso-dilatation (Fig. 3). Thus, a feedback mechan-ism directly related to intracellular oxygenavailability would exist which could regulateflow either to general or to regional myocardialneeds. Whether or not adenosine is the trueeffector, this autoregulation occurs both withand without cardiac nerves and in both intactand isolated preparations.

Physical control The blood flow distribu-tion to cardiac muscle is governed in part byanatomical and physical factors. It has beenknown for many years that the subendocar-dium of the left ventricle is uniquely prone todevelop ischaemia. Intramural blood supplyparticularly of the thick-walled left ventricletakes place through two separate types ofblood vessels (Fig. 4). Estes and co-workers(I966) have termed these 'A' and 'B' vessels.The A vessels leave the epicardial arteries at

MECHANISMS CHANGING CORONARY FLOW

Arteriolar

Intramyocardial

BPd ResistI I

Collateral

rterial

I

tonce

Rate Systole

Diastolic time-I

C.F.

FIG. i Hydraulic factors affecting coronaryflow (C.F.). Diastolic blood pressure (BPd) andtime act in concert with resistance factors todeliver coronary flow. There are multiplepoints of resistance to blood flow.

a shallow angle, and branch within and supplythe outer one-half of the myocardium.1 Theinner aspects of the myocardium (except forthe endocardium), however, are supplied bythe B vessel, a 'perforator' arising at rightangles and plunging directly through themyocardial substance to ramify in the sub-endocardial plexus.The B vessel by its very anatomical course

is susceptible to change in the balance betweenintramyocardial compressive forces and coron-ary perfusion pressure. As a result, change inblood pressure or myocardial contractile state

OVERALLSYSTEMIC BRAIN

SK EL.LIVER KIDNEY MUSCLE HEART

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FIG. 2 Systemic and regional arteriovenousoxygen extraction. qO2 = oxygen conswnptionper minute. Exercising skeletal muscle extractsan increasing but varying amount of 02during effort (arrow). Cardiac muscle extrac-tion remains relatively constant and exceedsthat of other organs.

1 The right ventricular myocardium has only A vessels.

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Regulation of coronary blood flow II

per se can selectively alter deep as opposed tosuperficial myocardial blood flow. Thus thereemerges the concept of 'shells' of blood flowcapacity, all depth-dependent in nature (Kirkand Honig, I964). Some investigators haveattributed certain differences in biochemicalcomposition of the deep and superficial myo-cardial layers to the differences in blood flow(Griggs, Tchokoev, and De Clue, I969).

Topographic as distinct from transmuraldifferences in regional perfusion will be dis-cussed later.

Remote regulation Thus far mechanismsfor autoregulation of blood supply have beendescribed. The coronary system like othervascular beds is under central nervous andcirculating humoral control as well.

Adrenergic mechanisms Evolution of thepharmacological concept of alpha and betareceptors within the vascular bed has givennewinsights into circulatory regulation. Selectivereceptor stimulators and inhibitors havehelped to define the characteristics of thecoronary small vessels. Both alpha and betareceptors are present. In the normal basalstate there is a mild alpha or vasoconstrictor'set' to the system with no apparent betaactivity (Brachfeld, Monroe, and Gorlin,I960; Wolfson and Gorlin, I969). In the pres-ence of chronic recurrent ischaemia, however,the system generally exhibits an overall beta-stimulated or vasodilated state (Wolfson andGorlin, I969).

Infused catecholamines have characteristicprimary effects on the coronary circulation.Methoxamine, an alpha stimulator, constrictswhile isoproterenol, a beta stimulator, dilates.The naturally occurring catecholaniine nor-epinephrine is a primary coronary constrictor(Yurchak et al., I964).

Cholinergic stimulators appear to causecoronary vasodilatation. There are certainother humoral substances which influence thecoronary vessels, in particular vasopressin,which leads to vasoconstriction.

Integration of control mechanismsThe primacy of local over remote regulationseems to be established in most circumstances.For example, certain catecholamines whichstimulate myocardial activity and thereforecreate a need for increased coronary bloodflow, at the same time also stimulate alphareceptors in the coronary arterioles whichpromote vasoconstriction. The pattern seen isan initial coronary constriction followed bycoronary vasodilatation, suggestng that localbiochemical or other influences are more

My0c cA ER LD LIAL

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FIG. 3 Schematic diagram to illustrate pro-posed pathways for synthesis degradation andsite of action of adenosine arising from break-down of intracellular adenosine triphosphate.(Reprinted with permission from Rubio andBerne, I969).

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FIG. 4 Intramyocardial vascular supply. The'A' and 'B' vessels are shown in cross section.(Reprinted with permission from Estes et al.,1966.)



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I2 Richard Gorlin

powerful than adrenergic receptor stimulation(Berne, I958). This tends to ensure regulationof blood flow to need in the face of a varietyof competing influences.

There have been certain clinical physio-logical examples in which coronary vasocon-striction has occurred as part of a generalizedvasoconstrictor response. This has been in-tense enough to cause myocardial ischaemia(Gorlin, I965). These situations have beendifficult to document, however, and in generalit seems that for the most part the local con-trols supersede remote control of coronaryblood flow.

Factors influencing coronary flowFig. 5 represents a schema of factors knownto influence coronary blood flow. These areexclusive of factors which are mechanicallyresponsible for the actual delivery of coronaryflow (Fig. i).

Basal coronary flow will depend in part onthe available oxygen per litre of blood flow.Therefore, arterial anoxaemia or anaemia willresult in increased coronary flow to keepvenous Po2 and corresponding tissue P02 con-stant. There may be minor effects of pH onthe haemoglobin oxygen dissociation curve.

Coronary flow will also depend on myo-cardial oxygen requirements, both acute andchronic. Energy needs are dependent in turnon mechanical activity of the heart. Thus in-creases or decreases in systemic arterial pres-sure, heart rate, heart size, and in intrinsiccontractile state (speed of muscle shortening)all profoundly influence the need for or createa deficiency of coronary flow. Neurogenic in-fluences are usually superseded by changes inlocal metabolic factors if the two occur simul-taneously as with adrenergic stimulation.

Effect of coronary atherosclerosis onmyocardial blood flowThe prevalence and importance of coronaryartery disease justify a separate analysis of itseffect on regulation of blood flow. Coronaryatherosclerosis is a heterogeneous disease inall respects: distribution and severity ofobstruction and the extent and uniformity ofcollateral compensation exhibit major andunpredictable variation.Two heterogeneities in blood flow distribu-

tion have resulted from coronary atherosclero-sis: deep versus superficial myocardial bloodflow differences, and topographic or regionalblood flow differences.

Deep versus superficial blood flow Owingto the peculiar architecture of the B ves-

FACTORS REGULATING CORONARY FLOW

Volume Pressure

Force Heart ContractionRote Velocity

|MECHANICS OF MYOCARDIAL CONTRACTIO

MYOCARDIAL 02 DEMAND

pH- PCO2

CHEMICAL

Drugs

IBLOOD ,°2 AVAILABILITYL

Arterial

Capacity Content

FIG . 5 Factors regulating coronary flow(C.F.). These factors can be subdivided intothose affecting myocardial 02 requirements(above), 02 availability per unitflow (below),and those acting directly on the arteriole. Neuro-humoral factors can affect coronary flow notonly through primary vasomotion but alsothrough altered 02 demand. Likewise pH canaffect both arteriolar resistance and 02 avail-ability.

sels only minor reductions in epicardialperfusion pressure can lead to profoundchanges in deep blood supply. Downey andKirk (I970, unpublished observations) haveshown that, given even a 'noncritical' arterialstenosis, tachycardia can induce subendo-cardial ischaemia. Furthermore, this type ofischaemia leads to a subendocardial 'shell' ofpoor contractility at a time when epicardialcontractility remains normal (Kirk et al., 1970).Thus, even mild degrees of coronary obstruc-tion may under appropriate mechanical cir-cumstances lead to deep myocardial ischae-mia. This, of course, is recognized clinicallyin ST segnent depression in the electro-cardiogram recorded during an attack ofangina pectoris.

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Regulation of coronary blood flow 13

Regional differences in blood flow It hasbeen demonstrated in man with coronaryatherosclerosis that myocardial flow is region-ally non-uniform (Sullivan et al., I967;Liedtke et al., I970) (Fig. 6). The degreeof non-uniformity is dependent not only onthe degree of local arterial obstruction butalso on the extent of compensating collateralvessels. The region of low flow is suppliedalmost invariably at a greatly reduced arterialperfusion pressure (Fig. 7). It is probable thatlocal blood supply is maintained through con-stant generation of local metabolites whicheffect local vasodilatation. This in no way,however, assures participation of the sur-rounding normal coronary vascular tree in thehighly localized chemical feedback response.Evidence that local blood supply may yet beimproved, presumably by effects on the sur-rounding vascular tissue, has been derivedfrom studies with nitroglycerin, a powerfuldilator of smooth muscle. This agent givensublingually causes little or no effect on over-all coronary blood flow in patients with coron-ary disease. Yet it does increase localmyocardial flow in zones of potential ischae-mia (Horwitz et al., I970) (Fig. 8). Thisselective action is not well understood, butmay represent recruitment and dilatation ofresistance vessels or collaterals lying outsidethe local area of production of vasodilatingmetabolites.How much flow can occur via collateral

pathways is unknown. This depends in parton the type, size, route, and site of origin ofthe collateral. A collateral arising from theproximal part of an artery which runs epi-cardially to another epicardial artery will de-liver more flow than a distally arising vesselwhich runs via an intramyocardial course to anadjacent artery. Regulation of all these vesselsis believed to occur via local mechanisms.The level of blood pressure becomes all

important when there are obstructions in thelarge coronary arteries. The pressure dropacross the stenosis can be as great as 50 to 70mm. Hg (Fig. 7). Even a minor decrease inarterial pressure can so lower postobstructivepressure that flow reaches intolerably lowlevels. The resulting flow per mm. Hg pres-sure is a function of degree of small vessel(arteriole and collateral) dilatation in responseto hypoxia. Again, it would appear that localregulation dominates in redistribution ofblood supply in coronary artery disease. It iscurrently unknown whether systemic mechan-isms of control play a significant part in theadjustment to this disease, except that thereappears to be a mild chronic beta adrenergicstimulation (Wolfson and Gorlin, I969).

MYOCARDIAL TRANSIT TIMES

NORMALAppeorance time 1l5 set

Buld-up time 41Disoppworance timn 9A4Pasoae tiam 1T'.Peok tcon. 1 mm

lnd#cyonain

CADAppeersc tith .8 secw"p time 90o

Wsopperanve time 16.0.... :e s#. 1.* .,..s16mm

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FIG. 6 Coronary arterial indicator dilutioncurves in a normal subject (above) and a

patient with coronary artery disease (CAD)(below). Indocyanine green was injected selec-tively into each of the right coronary arteriesshown and the curve sampledfrom coronarysinus. The wide spread of the lower curve isindicative of the heterogeneous blood flowpattern in coronary artery disease. (Liedthe etal., 1970.)

FIG. 7 Arterial pressures recorded duringdirect coronary artery surgery. The panel tothe left indicates pressures in radial artery (RA)and postobstructive right coronary artery(RCA). Note the mean pressure difference ofabout 50 mm. Hg. This was restored to normalafter vein bypass surgery. (S. Smith, W. J.

Taylor, and R. Gorlin, I970, unpublishedobservations.)

RCA VENOUS BY-PASS

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14 Richard Gorlin

Similar to the relationship between shellsof ischaemia causing shells of subnormal con-tractility, regional zones of ischaemic myo-cardium exhibit disordered or absent con-traction during systole. The result is thatpatients with coronary artery disease oftendevelop cardiac failure based solely onasynergy of contraction (Herman et al., I967).This is accentuated by any state which induceslocal ischaemia. This can be through increasedlocal stimulation, such as tachycardia oradrenergic activity, or through reduction inperfusion pressure so that the local supply ofblood cannot match the cellular demand forenergy. The ease with which the local myo-cardium ceases to contract against the loadshows how close to the threshold of hypoxiais the state ofotherwise normal cardiac muscle.Anaerobic glycolysis can in no way supplyenergy in sufficient amount for the mammalianheart under normal operating conditions(Krasnow et al., I962).Thus it can be appreciated that 'normal'

blood supply in coronary artery disease is inpart relative to and dependent on the appliedload. For example, cardiac load can be mini-mized or check-reined by the use of betaadrenergic blocking agents. These drugs arecapable of inhibiting adrenergic increases inheart rate, blood pressure, and contractilestate. Under these conditions coronary bloodflow is reduced. Evidence of myocardialischaemia, if formerly present, is eliminated,and myocardial flow may be autoregulated toachieve nearly normal values despite wide-spread disparities in the pathways of bloodflow in the diseased myocardium.

ReferencesBerne, R. M. (I958). Effect of epinephrine and nor-

epinephrine on coronary circulation. CirculationResearch, 6, 644.

- (I963). Cardiac nucleotides in hypoxia: possiblerole in regulation of coronary blood flow. AmericanJ'ournal of Physiology, 204, 317.

Brachfeld, N., Monroe, R. G., and Gorlin, R. (I960).Effect of pericoronary denervation on coronaryhemodynamics. American Jrournal of Physiology,199, 174.

Downey, J. M., and Kirk, E. S. (I970). The effect ofheart rate on the distribution of blood flow in themaximally dilated coronary circulation. In prepara-tion.

Estes, E. H., Jr., Entman, M. L., Dixon, H. B., II,and Hackel, D. B. (I966). The vascular supply ofthe left ventricular wall. American Heart Journal,71, 58.

Gorlin, R. (I965). Pathophysiology of cardiac pain.Circulation, 32, I38.

Griggs, D. M., Jr., Tchokoev, V. V., and De Clue,J. W. (I969). Non-uniform anaerobic myocardialmetabolism (abstr.). Circulation, 39-40, Suppl. 3,96.

Herman, M. V., Heinle, R. A., Klein, M. D., andGorlin, R. (1967). Localized disorders in myocar-

CONTROL

B.

SECONDS

FIG. 8 Intramyocardial 133Xe clearancecurves before and after sublingual nitroglycerin(o03 mg.). Studies were done during revascu-larization surgery at a myocardial site distal toa known severe obstruction in the left anteriordescending artery. Praecordial gamma scintilla-tion counting revealed an increase in both fastand slow components of myocardial flow afternitroglycerin administration (CPM= countsper minute). (Horwitz et al., 1970.)

dial contraction. New England J'ournal of Medicine,277, 222.

Horwitz, L. D., Gorlin, R., Taylor, W. J., and Kemp,H. G. (1970). Effects of nitroglycerin on regionalmyocardial blood flow in coronary artery disease.Clinical Research, I8, 31I2.

Kirk, E. S., and Honig, C. R. (I964). Nonuniform dis-tribution of blood flow and gradients of oxygentension within the heart. American Journal ofPhysiology, 207, 66I.

-, Turbow, M. E., Urschel, C. W., and Sonnen-blick, E. H. (1970). Non-uniform contractilityacross the heart wall caused by redistribution ofcoronary flow. American Society for Clinical In-vestigation, 62nd Annual Meeting, 5Ia (No. I63).

Krasnow, N., Neill, W. A., Messer, J. V., and Gorlin,R. (I962). Myocardial lactate and pyruvate meta-

bolism. Journal of Clinical Investigation, 41, 2075.Liedtke, A. J., LaRaia, P. J., Borkenhagen, D., Kemp,

H. G., and Gorlin, R. (1970). Selective right coron-

ary artery indicator-dilution curves in normal andcoronary artery disease patients. Clinical Research,I8, 3I8.

Rubio, R., and Berne, R. M. (1969). Release of adeno-sine by the normal myocardium in dogs and itsrelationship to the regulation of coronary resist-ance. Circulation Research, 25, 407.

Shea, T. M., Watson, R. M., Piotrowski, S. F.,Dermksian, G., and Case, R. B. (I962). Anaerobicmyocardial metabolism. American Journal of Physi-ology, 203, 463.

Sullivan, J. M., Taylor, W. J., Elliott, W. C., andGorlin, R. (1967). Regional myocardial blood flow.Journal of Clinical Investigation, 46, I402.

Wolfson, S., and Gorlin, R. (I969). Cardiovascularpharmacology of propranolol in man. Circulation,40, 501.

Yurchak, P. M., Rolett, E. L., Cohen, L. S., and Gor-lin, R. (I964). Effects of norepinephrine on thecoronary circulation in man. Circulation, 30, i8o.

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