Regulation of Coronary Blood Flow in Health and Ischemic ......Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease Dirk J. Dunckera,⁎, Akos Kollerb,c, Daphne Merkusa,

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Regulation of Coronary Blood Flow

in Health and Ischemic Heart Disease

Dirk J. Dunckera,⁎, Akos Kollerb, c, Daphne Merkusa, John M. Canty Jr. d

aDivision of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus MC,University Medical School, Rotterdam, The NetherlandsbDepartment of Pathophysiology and Gerontology, Medical School, University of Pécs, HungarycDepartment of Physiology, New York Medical College, Valhalla, NY, USAdDivision of Cardiovascular Medicine, University at Buffalo and theWestern New York Department of Veterans Affairs Health System, Buffalo,NY, USA

A R T I C L E I N F O

Statement of Conflict of Interest: There aFinancial support: DJD: European Commis

Programme grant 606998. Hungarian NationaMEDIA-261409). JMC: National Heart Lung an⁎ Address reprint requests to Dirk J. Dunck

Cardiovascular Research Institute COEUR,The Netherlands.

E-mail address: [email protected]

http://dx.doi.org/10.1016/j.pcad.2014.12.0020033-0620/© 2014 Elsevier Inc. All rights rese

A B S T R A C T

Keywords:
The major factors determining myocardial perfusion and oxygen delivery have beenelucidated over the past several decades, and this knowledge has been incorporated intothe management of patients with ischemic heart disease (IHD). The basic understanding ofthe fluid mechanical behavior of coronary stenoses has also been translated to the cardiaccatheterization laboratory where measurements of coronary pressure distal to a stenosisand coronary flow are routinely obtained. However, the role of perturbations in coronarymicrovascular structure and function, due to myocardial hypertrophy or coronarymicrovascular dysfunction, in IHD is becoming increasingly recognized. Future studiesshould therefore be aimed at further improving our understanding of the integratedcoronary microvascular mechanisms that control coronary blood flow, and of theunderlying causes and mechanisms of coronary microvascular dysfunction. This knowledgewill be essential to further improve the treatment of patients with IHD.
© 2014 Elsevier Inc. All rights reserved.

Coronary blood flowIschemic heart diseaseMicrovascular dysfunctionHypertrophyCoronary artery disease

The left ventricle (LV) is responsible for generating the arterialblood pressure, which is required to sustain blood flow in thesystemic circulation. Among the regional vascular beds withinthe systemic circulation, the coronary circulation is unique inthat its perfusion is impeded during the systolic phase of thecardiac cycle by the contracting muscle that surrounds it.Because the LV utilizes most of the oxygen (O2) deliveredthrough the coronary vasculature to sustain its function,

re no conflicts of interestsion (FP7-Health-2010; MEl Scientific Research Foud Blood Institute (HL 553er, MD PhD, Division of ExErasmus MC, University

l (D.J. Duncker).

rved.

myocardial contraction is closely connected to coronary bloodflow (CBF). As a result, O2 delivery, and the balance between O2supply and demand are critical determinants of normal LVfunction. Knowledge of the regulation of CBF in health anddisease is therefore essential for proper understanding ofthe pathophysiological basis and management of many car-diovascular (CV) disorders,1–3 including obstructive coronaryartery disease (CAD),4–6 metabolic dysfunction,7–9 and cardiac

to declare for any of the authors.DIA-261409). AK: SMARTER, European Union's Seventh Frameworknd (OTKA) K-108444. DM: European Commission (FP7-Health-2010;24; HL 61610) and the Albert and Elizabeth Rekate fund.perimental Cardiology, Department of Cardiology, Thoraxcenter,Medical School, Rotterdam, PO Box 2040, 3000 CA, Rotterdam,

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Abbreviations and Acronyms

CAD = coronary arterydisease

CBF = coronary blood flow

CFR = coronary flow reserve

cGMP = cyclic guanylyl-monophosphate

CMR = cardiac magneticresonance

CVD = cardiovascular disease

CVR = coronary vascularresistance

EDHF = endothelium-derivedhyperpolarizing factor

FFR = fractional flow reserve

H2O2 = hydrogen peroxide

HF = heart failure

IHD = ischemic heart disease

KATP = ATP-sensitive potassi-um channel

LV = left ventricle

LVH = left ventricularhypertrophy

NO = nitric oxide

O2 = oxygen

PCI = percutaneous coronaryintervention

PET = positron emissiontomography

SPECT = single photon emis-sion computed tomography

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hypertrophy.10–12 In thisreview we discuss thecontrol of CBF in the nor-mal healthy heart and inCV disease (CVD) statesthat are associated withchronic ischemicheart dis-ease (IHD). We will brieflydiscuss the impact of thesedisease states on clinicalmeasurements of flow ca-pacity and stenosis severi-ty in the setting of CAD.

Regulation of CBF inthe healthy heart

CBF is characterized bymarked phasic variationsduring the cardiac cyclewith coronary arterial in-flow out of phase with ve-nous outflow.13 Systoliccontraction increases LVwall tension and com-presses the intramyocardialmicrovessels, thereby im-peding coronary arterialinflow and increasingcoronary venous out-flow. Systolic compres-sion is not uniformlydistributed across the LVwall, resulting in a redis-tribution of blood flowfrom the subendocardialto the subepicardial layersof the LV.14 Conversely,during diastole, coronaryarterial inflow increaseswith a transmural gradient

that favors perfusion to the subendocardial layers, at which timethe coronary venous outflow falls.13

Myocardial oxygen extraction in the LV at rest averages 60–80% of arterially delivered O2,15,16 implying that the ability toincrease O2 extraction to increase O2 consumption is limited.Consequently, increases in myocardial O2 consumption, forexample during physical activity, are principally met throughproportional increases in CBF and hence O2 supply,15,16 thatis also dependent on arterial O2 content, which is the productof hemoglobin concentration and arterial O2 saturation plus asmall amount of O2 dissolved in plasma that is directly relatedto arterial O2 tension. This implies that for any given flowlevel, anemia results in proportional reductions in O2 deliverywhereas hypoxia, due to the nonlinear O2 dissociation curve,results in relatively small reductions in O2 content untilarterial O2 tension falls to the steep portion of the O2dissociation curve, i.e. below 50 mm Hg.

Autoregulation of CBF

CBF remains relatively constant over a wide range ofperfusion pressures, provided that the determinants ofmyocardial O2 consumption are kept constant (Fig 1A).17

This is accomplished by changes in diameter of the coronarymicrovasculature, which involves both myogenic and meta-bolic mechanisms.3 This autoregulation of blood flow isespecially important to maintain myocardial perfusion whencoronary pressure is reduced distal to a coronary arterystenosis. The pressure at which the resistance vessels becomemaximally dilated is the lowest pressure at which normalmyocardial perfusion can be sustained and is referred to asthe lower limit of autoregulation. Below this pressure, flowdecreases in a pressure-dependent way, resulting in the onsetof myocardial ischemia.

Under normal hemodynamic conditions, resting LV-CBFaverages 0.7–1.0 ml/min per g of myocardium and canincrease 4–5 fold during vasodilation in the absence ofmicrocirculatory dysfunction.15,16,18 The ability to increaseCBF above resting values in response to pharmacologicalvasodilation is termed coronary flow reserve (CFR).6 Maximumperfusion and CFR are reduced when the diastolic timeavailable for (subendocardial) perfusion is decreased (e.g.during an increase in heart rate) or the compressivedeterminants of diastolic perfusion (preload and hence,radial wall stress) are increased (Fig 1B).15,16,18 Coronaryreserve is also reduced when resting flow is increased, forexample in response to increases in the hemodynamicdeterminants of O2 consumption (systolic pressure, heartrate, and contractility) or with reductions in arterial O2supply (anemia and hypoxia). Hence, conditions can developthat favor the development of subendocardial ischemia inthe presence of normal coronary arteries.1 Studies inconscious dogs in the basal resting state have shown thatautoregulation of coronary flow can maintain resting flow inthepresence ofmean coronary pressures as lowas 40 mmHg.17

These coronary pressure levels are similar to those recordedin humans without symptoms of ischemia during balloonocclusions, using pressure wiremicromanometers.19 The lowerpressure range of autoregulation increases to higher pressurevalues during tachycardia due to an increase in flow require-ments in conjunction with a decrease in diastolic perfusiontime (Fig 1B).20

Mechanical and hemodynamic determinants of CBF

CBF is dependent upon the effective perfusion pressureand the resistive properties of the coronary vascular bed.The effective perfusion pressure of the coronary bed is thepressure-drop (ΔP) across the coronary vascular bed, with theinput pressure being arotic pressure. However, becauseextravascular forces are exerted on the compressible intra-mural coronary vasculature by the surrounding myocardi-um, the effective output- or backpressure, i.e. the pressure atwhich flow becomes zero (termed zero flow pressure or Pf = 0),cannot simply be equated to right atrial pressure (Fig 1A).In LV hypertrophy (LVH), compressive effects from elevatedLV diastolic pressure also impede perfusion via passive

Fig 1 – Autoregulatory relation under basal conditions and following metabolic stress (e.g., tachycardia). The normal heartmaintains CBF constant (left panel) as regional coronary pressure is varied over a wide range when the global determinants ofoxygen consumption are kept constant (red lines). Below the lower autoregulatory pressure limit (approximately 40 mm Hg),subendocardial vessels are maximally vasodilated and myocardial ischemia develops. During vasodilation (blue lines), flowincreases four to five times above resting values at a normal arterial pressure. Coronary flow ceases at a pressure higher thanright atrial pressure (PRA), called zero flow pressure (Pf = 0), which is the effective back pressure to flow in the absence ofcoronary collaterals. Following stress (right panel), tachycardia increases the compressive determinants of coronary resistanceby decreasing the time available for diastolic perfusion and thus, reduces maximum vasodilated flow. Increases in myocardialoxygen demand or reductions in arterial oxygen content (e.g. from anemia or hypoxemia) increase resting flow. These changesreduce coronary flow reserve, the ratio between dilated and resting coronary flow, and cause ischemia to develop at highercoronary pressures. Abbreviations: LV, left ventricular; HR, heart rate; SBP, systolic blood pressure; Hb, hemoglobin. Reprintedfrom Canty and Duncker6 with permission.

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compression of microcirculatory vessels by elevated extra-vascular tissue pressure during diastole.

Extravascular compressive forcesDuring systole, cardiac contraction raises myocardial tissuepressure to values equal to LV pressure at the subendocardium.This declines to values near pleural pressure at thesubepicardium.15 The increased extravascular pressure istransmitted across the vessel wall and provides an effectivebackpressure to flow, which produces a time-varying reductionin the driving pressure for coronary flow that impedesperfusion particularly to the subendocardium. Although thisparadigmcan explain variations in systolic coronary inflow, it isnot able to account for the increase in coronary venous systolicoutflow. To explain both impaired inflow and acceleratedvenous outflow, some investigators have proposed theconcept of the intramyocardial pump.14 In this model, micro-circulatory vessels are compressed during systole and producea capacitive discharge of blood that accelerates flow from themicrocirculation to the coronary venous system. At the sametime, the upstream capacitive discharge impedes systoliccoronary arterial inflow. Although this explains the phasic

variations in coronary arterial inflow and venous outflow, aswell as its transmural distribution in systole, vascular capaci-tance cannot explain compressive effects related to elevatedtissue pressure during diastole. This concept is supported byobservations that increases in preload effectively raise thenormal backpressure to coronary flow above coronary venouspressure levels.14 Thus, intramyocardial capacitance, compres-sive forces changing effective coronary backpressure as well ascoronary resistance, and a time-varying driving pressure allcontribute to the mechanical compressive determinants ofphasic CBF.

Coronary vascular resistanceCoronary vascular resistance (CVR) can be divided into severalcomponents.18 Under normal circumstances, there is nomeasurable pressure drop in the epicardial arteries, indicatingnegligible conduit resistance. With the development of hemo-dynamically significant epicardial artery narrowing (more than50% diameter reduction), the fixed conduit artery resistancebegins to contribute significantly to total CVR and, when thevessel is severely narrowed (more than 90% diameter reduc-tion), may reduce basal resting flow. The major component of


CVR under normal conditions primarily arises from smallarteries and arterioles, so called resistance vessels.21 Thisresistance is dynamic and distributed throughout the myocar-dium across a broad range of vessel sizes (20–400 μm indiameter). Because the diameter of these vessels, and hencetheir resistance can be changed substantially both by passiveand active mechanisms they play a pivotal role in theregulation of CBF. Interestingly, there is normally little resis-tance contributed by capillaries and coronary venules, and theirresistance remains fairly constant during changes invasomotortone.21 Thus,minimal CVR of themicrocirculation is principallydetermined by the size and density of arterial resistancevessels, while changes in vasomotor tone enable substantialvariations in CBF in the healthy heart.

Transmural variations in minimum CVR and diastolicdriving pressureThe vulnerability of the LV subendocardium to compressiveforces1 is partially compensated for by a lower minimalvascular resistance in the innermost LV layer, which is theresult of increased densities of arterioles and capillaries ascompared to the subepicardium. Because of this vasculargradient, subendocardial flow during maximal pharmacologi-cal vasodilation of the non-beating heart is greater thansubepicardial perfusion14; CVR in the maximally vasodilatedheart is also pressure-dependent, reflecting passive distentionof arterial resistance vessels.14 Thus,minimal CVRobtained at anormal coronary distending pressure will increase when

Fig 2 – Transmural variations in coronary autoregulation and mysubendocardium (ENDO; red) versus subepicardium (EPI; gold) to ihigher coronary pressure (40 versus 25 mm Hg). This is the resusubendocardium and an increased sensitivity to systolic comprediastole. Subendocardial vessels become maximally vasodilatedpressure is reduced. These transmural differences can be increaelevated preload, which reduce maximum subendocardial perfu

coronary pressure is reduced.19 The precise determinants ofthe effective driving pressure for diastolic perfusion continue tobe controversial.14 Most experimental studies demonstrate thatthe effective backpressure Pf = 0 to LV-CBF is higher than rightatrial pressure, and its minimum value is approximately10 mm Hg in the maximally vasodilated heart. This increasesto values close to LV diastolic filling pressure when preload iselevated above 20 mmHg.22 Elevated preload reduces coronarydriving pressure and diminishes subendocardial perfusion. It isparticularly important in determining flow when coronarypressure is reduced by a stenosis, as well as in the severelyhypertrophied or failing heart.16,23

Transmural variations in autoregulationFigure 2 shows transmural variations in the lower autoregulatorypressure limit, which are responsible for the increased vulnera-bility of the subendocardium to ischemia.1 Subendocardialflow primarily occurs in diastole and resistance vessels aremaximally vasodilated below a mean coronary pressure of40 mm Hg.17 In contrast, subepicardial flow occurs through-out the cardiac cycle and is maintained until coronarypressure falls below 25 mm Hg. This difference arises fromthe more pronounced effects of systolic contraction onsubendocardial vasodilator reserve,1 as well as the highersubendocardial oxygen consumption, requiring a higherresting flow level (Fig 2). The transmural difference in theminimal autoregulatory pressure translates into vulnerabilityof the subendocardium to ischemia in the presence of a

ocardial metabolism. Increased vulnerability of theschemia reflects the fact that autoregulation is exhausted at alt of increased resting flow and oxygen consumption in thessive effects because subendocardial flow only occurs duringbefore those in the subepicardium as coronary arterysed further during tachycardia or during conditions withsion. Modified from Canty and Duncker6 with permission.


coronary stenosis. Although there is no pharmacologicallyrecruitable flow reserveduring ischemia in thenormal coronarycirculation under resting conditions with low sympatheticactivity,24 reductions in coronary flow below the lower limit ofautoregulation can occur in the presence of pharmacologicallyrecruitable coronary flow reserve during exercise.4,16

Structure and function of the coronary microcirculation

Individual coronary resistance arteries are a longitudinallydistributed network and experimental studies of the coronarymicrocirculation have demonstrated considerable spatial hete-rogeneity of specific resistance vessel control mechanisms.4,25

To meet the metabolic requirements of the myocardiumsupplied by the downstream vascular bed, all resistance vesselsegments need to dilate in an orchestrated manner, with asignificant part of the resistance vessels being upstream of thesite of metabolic control of coronary resistance. This is achievedindependently of “metabolic signals” by sensing hemodynamicforces, suchas intraluminal flow (shear stress–mediated control)or intraluminal pressure changes (myogenic control). Epicardialarteries (>400 μm in diameter) serve as conduit arteries thatcontribute little pressure drop (


resistance artery sizes in animals as well as in humans,38 but inthe coronarymicrocirculation in vivo it is particularly prominentin arterioles

Fig 3 – Schematic drawing of an arteriole (top) and of endothelium, vascular smoothmuscle and cardiomyocyte (at the bottom)illustratingmechanisms for control of vasomotor toneanddiameter. Neurohumoral, endothelial, andmetabolic influencesaredetailedin the bottom part of the figure. Abbreviations: KCa, calcium-activated K+ channel; KATP, ATP-sensitive K+ channel; KV, voltage-gated K+

channel; KIR, inward rectifying K+ channel; Trp, transient receptor potential channels; O2, oxygen; ATP, adenosine triphosphate; NO,nitric oxide;TXA2, thromboxaneA2and receptor; 5HT, 5-hydroxytryptamineand receptor; P2,purinergic type2 receptor;M,muscarinicreceptor; H1 and H2, histamine type 1 and 2 receptors; B2, bradykinin type 2 receptor; ECE, endothelin-converting enzyme; bET-1, bigendothelin-1; ET-1, endothelin-1; eNOS, endothelial nitric oxide synthase; L-arg, l-arginine; COX-1, cyclooxygenase 1; CYP450,cytochrome P450; ACE, angiotensin-converting enzyme; AI, angiotensin I; AII; angiotensin II; AT1, angiotensin type 1 receptor; AT2,angiotensin type 2 receptor; ETA, endothelin typeA receptor; ETB, endothelin type B receptor; PG, prostaglandins; AA, arachidonic acid;EDHF, endothelium-derived hyperpolarizing factor; O2-, superoxide anion; VGCC, voltage-gated calcium channels; IP, prostacyclinreceptor; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids; H2O2, hydrogenperoxide;α1,α1-adrenergic receptor;α2,α2-adrenergic receptor; β2, β2-adrenergic receptor; ACh, acetylcholine; NE, norepinephrine; NPY, neuropeptide Y; P1, purinergictype 1 receptor; and Y1, neuropeptide Y receptor. Reproduced from Laughlin et al.39 with permission.


coronary vascular tree to grow commensurate with the degree ofLVH. Separating the role of an epicardial stenosis from coronaryresistance vessels can be accomplished by simultaneously

assessing coronary flow and distal coronary pressure usingintracoronary transducers that are currently available for clinicalcare and reviewed elsewhere.19,45,46


Coronary artery stenosis

Stenosis pressure-flow relationIn the healthy heart, the angiographically visible epicardialcoronary arteries are able to accommodate large increases incoronary flow without producing a significant drop inpressure and hence serve truly as conduit vessels to transportblood to the coronary resistance vasculature. This changesdramatically in CAD where the epicardial artery resistance(which increases with stenosis severity), becomes dominantand limits maximal myocardial perfusion.47

It is helpful to consider the idealized relation betweenstenosis severity, pressure drop, and flow, which has beenvalidated in animals as well as humans studied in circum-stances in which diffuse atherosclerosis and risk factors thatcan impair microcirculatory resistance vessel control areminimized.48 Fig 4A summarizes the major determinants ofstenosis energy losses. The relation between pressure dropacross a stenosis and coronary flow for stenoses between 30%and 90% diameter reduction can be described using theBernoulli principle. The total pressure drop across a stenosis isgoverned by three hydrodynamic factors — viscous losses,separation losses, and turbulence. The single most importantdeterminant of stenosis resistance for any given level of flow isthe minimum lesional cross-sectional area within thestenosis.48 Because resistance is inversely proportional to thefourth power of radius, small dynamic changes in luminal areacaused by thrombi or vasomotion in eccentric lesions (wherevascular smooth muscle can relax or constrict in a portion ofthe stenosis) lead to major changes in the stenosis pressure-flow relation and impact on maximal perfusion. Separationlosses determine the curvilinearity or “steepness” of thestenosis pressure-flow relation and become increasingly im-portant as stenosis severity and/or flow rate increases.

Fig 4 – A. Fluid mechanics of a stenosis. The pressure drop acrosinversely related to the minimum stenosis cross-sectional area aincreases. Abbreviations: ΔP, pressure drop; Q = flow; f1, viscousAn, area of the normal segment; L, stenosis length; μ, viscosity ofartery stenosis pressure flow relation (B), and the distal coronaryflow and blue circles and lines maximal vasodilation for stenosethe stenosis pressure flow relation becomes extremely nonlinearpressure drop across a 50% stenosis, and distal coronary pressurstenosis critically impairs flow and, because of the steepness of tcoronary pressure. Modified from Canty and Duncker6 with perm

Stenosis pressure drop and resistance increase exponential-ly as minimum cross-sectional area of the lesion decreases(Fig 4B). This reflects the fact that it becomes flow-dependentand varies with the square of the flow or flow velocity. As aresult, the instantaneous stenosis resistance progressivelyincreases during resistance vessel dilation. This becomesparticularly important in determining the stenosis pressure-flow behavior for severely narrowed arteries and leads to asituation in which small reductions in luminal area result inlarge reductions in post-stenotic coronary pressure that limitmaximum coronary perfusion.

Interrelation among distal coronary pressure, flow, and stenosisseverityBecause maximum myocardial perfusion is ultimately deter-minedby the coronarypressuredistal to a stenosis, it ishelpful toplace the epicardial stenosis pressure-flow relation into thecontext of the coronary autoregulatory and vasodilated coronarypressure-flow relations, as depicted in Fig 4C. The effects of astenosis on resting and vasodilated flows as a function ofpercentage diameter reduction, when diffuse intraluminalnarrowing is absent and coronary microcirculatory resistance isnormal, are summarized in Fig 4C. In the absence of microcircu-latory dysfunction coronary flow can normally increase appro-ximately five times from the resting flow values.47 As illustratedin Fig 4C, there is no significant pressure drop across a stenosis(ΔP) or stenosis-related alteration in maximal myocardial perfu-sion until stenosis severity exceeds a 50% diameter reduction(cross-sectional area reduction of 75%). As stenosis severityexceeds 50%, the curvilinear coronary stenosis pressure flowrelation steepens and increases in stenosis resistance areaccompanied by concomitant increases in ΔP across the stenosis(Fig 4B). This reduces distal coronary pressure, the majordeterminant of perfusion to themicrocirculation, andmaximum

s a stenosis can be predicted by the Bernoulli equation. It isnd varies with the square of the flow rate as stenosis severitycoefficient; f2, separation coefficient; As, area of the stenosis;blood; ρ, density of blood. Interrelation among the epicardialpressure-flow relation (C). Red circles and lines depict restings of 50, 70, and 90% diameter reduction. As shown in panel B,as stenosis severity increases. As a result, there is very littlee and vasodilated flow remain near normal. However, a 90%he pressure flow relation, causes a marked reduction in distalission.


vasodilated flow (and CFR) decreases. A critical stenosis,one in which subendocardial flow reserve is completelyexhausted at rest, usually develops when stenosis severityexceeds 90%. Under these circumstances, pharmacologicalvasodilation of subepicardial resistance vessels results ina reduction in distal coronary pressure that actuallyredistributes flow away from the subendocardium, leadingto a “transmural steal” phenomenon.16

Concept of maximal perfusion and CFRThe concept of CFR was originally proposed by Gould.45 Withtechnological advances, it has become possible to characterizethis inhumansusing invasive catheter-basedmeasurements ofintracoronary pressure and flow as well as with noninvasiveimaging of myocardial perfusion with positron emissiontomography (PET), single-photon emission tomography(SPECT) and, more recently, cardiac magnetic resonanceimaging (CMR). With these measurements, it has also becomeincreasingly apparent that abnormalities in coronary microcir-culatory control contribute to the functional significance ofisolated epicardial artery stenosis in many patients with CAD,as well as lead to impaired CBF responses in the presence ofnormal coronary arteries. Because of these complexities,multiple complimentary approaches are frequently requiredto define limitations in myocardial perfusion that arise fromstenosis severity vs. abnormalities of the coronarymicrocirculation6,45,49 The major indices currently used toquantify CFR are absolute flow reserve (maximal flow dividedby basal flow), relative flow reserve (maximal myocardialperfusion in the stenosis regiondivided bymaximalmyocardialperfusion in the non-stenosis region) and fractional flowreserve (post-stenotic coronary pressure divided by aorticpressure during maximal vasodilation). For an in depthdiscussion of these indices the reader is referred to recentreviews published elsewhere.6,45

Impact of a chronic epicardial stenosis on the coronarymicrocirculation

As discussed above, an acute coronary artery inflow obstruc-tion produces potent coronary resistance vessel dilation. Incontrast, there is evidence that a chronic coronary arterystenosis, not only results inmyocardial and interstitial,6,50 butalso in structural and functional microvascular alterationsdistal to the stenotic artery. Thus, arteriolar inwardremodeling5 and rarefaction51 have been reported, as well asincreased vasoconstrictor responses to endothelin (due to aloss of ETB-mediated vasodilation) and blunting of myogenicresponses.52 These findings support the concepts that endo-thelial dysfunction contributes to microvascular dysfunctiondistal to a stenosis, and does so via alterations in the controlof vascular tone as well as through structural changes inmicrovessel diameter5 and densities.51 These findings indi-cate that a chronic epicardial stenosis may not only limit flowreserve by increasing proximal artery resistance, but also byproducing microvascular dysfunction. This explains, at leastin part, the observation that many patients with a significantcoronary artery stenosis show an exaggerated reduction incoronary flow reserve for the level of stenosis severity.46

Impact of a chronic coronary artery occlusion on the coronarymicrocirculation

Following a total occlusion of a coronary artery, residualperfusion to the affected myocardium can be provided by pre-existing coronary collateral channels that are recruited whenan intercoronary pressure gradient between the source andrecipient vessel develops. Inmost animal species, the collateralflow during occlusion is less than 10% of the resting flow levelsand is insufficient to maintain tissue viability for longer than20 minutes. Coronary pressure during balloon angioplastyocclusion in patients undergoing percutaneous coronary inter-vention (PCI) is indicative of coronary collateral flow andexhibits considerable variability. In humans in which theexisting coronary collaterals are sparse, coronary pressureduring balloon angioplasty occlusion falls to ~10 mm Hg, andischemia develops. However in some patients, collateralsdevelop to the point where they are sufficient to not onlymaintain resting perfusion normal but also prevent stress-induced ischemia at submaximal cardiac workloads. The“collateral flow index” is calculated as coronarywedge pressureduring PCI balloon occlusionminus venous pressure divided bythe mean arterial blood pressure. If this index is greater than0.25, collateral flow is sufficient and ischemia does not developduring PCI balloon occlusion at rest.19 These patients have alower CVD event rate and improved survival in a largeobservational cross sectional study.53

Regulation of CBF in the collateralized heart

The control of CBF to collateral-dependent myocardium isgoverned by a series resistance arising from interarterialcollateral anastomoses, largely epicardial, as well as thenative downstream microcirculation. Collateral resistance istherefore the major determinant of perfusion and coronarypressure distal to a chronic occlusion which is already nearthe lower autoregulatory pressure limit. Because of this,subendocardial perfusion is critically dependent on meanaortic pressure and LV preload with ischemia easily provokedby systemic hypotension, increases in LV end-diastolicpressure, and tachycardia. Like the distal resistance vessels,collaterals constrict when NO synthesis is blocked, whichaggravates myocardial ischemia and can be overcome bynitroglycerin.4,16 Experimental studies have demonstratedthat coronary collaterals are under tonic dilation fromvasodilator prostaglandins, and blocking cyclooxygenasewith aspirin exacerbates myocardial ischemia in dogs.23 Therole of prostanoids in human coronary collateral resistanceregulation is unknown.

The distalmicrocirculatory resistance in collateral-dependentmyocardium appears to be regulated by mechanisms similar tothose present in the normal circulation but is characterized byattenuated endothelium-dependent vasodilation as compared tonormal vessels,16 similar to what has been observed with achronic coronary artery occlusion.52 Interestingly, the remotenormally perfused zone in collateralized hearts also showsalterations in coronary resistance vessel control, suggesting thatabnormalities are not restricted to the collateral-dependentregion. The extent that these microcirculatory abnormalities


alter the normal metabolic and coronary autoregulatoryresponses in collateral-dependent and remote myocardialregions is unknown.16

Impact of cardiac hypertrophy on the coronary microcirculation

The effects of cardiac hypertrophy on CBF and its regulationare complex (Fig 5) and need to be thought of in terms of theabsolute flow level (e.g., measured with an intracoronaryDoppler probe) aswell as the flowper gram ofmyocardium (e.g.measured by positron emission tomography). With acquiredLVH (such as in hypertension), resting flow per gram ofmyocardium remains constant, but the increase in LV massnecessitates an increase in the absolute level of resting flow(ml/min) through the coronary artery.10,54 In terms of maximalperfusion, pathological LVH does not result in appreciablevascular proliferation (as opposed to physiological LVH pro-duced by exercise training) and coronary resistance vesseldensities remain essentially unchanged. Thus, while maxi-mum absolute flow (ml/min) during vasodilation remainsunchanged, the increase in LV mass reduces the maximumperfusion per gramofmyocardium. Thenet effect of LVH is thatCFR at any given coronary arterial pressure is reduced in afashion that is inversely related to the change in LV mass. Forexample, in the absence of a change in mean aortic pressure, atwo-fold increase in LV mass, as is associated with severe LVH,

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Fig 5 – Effects of hypertrophy on absolute flow (ml/min) and flowmyocardial mass increaseswithout proliferation of themicrocircuA. The increase in LV mass causes a proportional increase in abminute during vasodilation remains unchanged. B. When tissue(as obtained using PET for example), the maximum flow per gracontrast, the resting flow per gram of myocardium remains constto the increase in LV mass. Regardless of whether absolute flowactions is to decrease coronary flow reserve at any coronary presreserve in the absence of a coronary stenosis, the functional signheart could approach a more severe stenosis (in the example, 70ischemia with normal coronary arteries during stress. Modified

can reduce CFR in a non-stenotic artery from 4 to 2. This willincrease the functional severity of any anatomical degree ofcoronary artery narrowing and can even precipitate subendo-cardial ischemia with normal coronary arteries. Moreover,structural alterations in microvessels, most notably medialhypertrophy in arterioles in pressure-overload hypertrophy,2,11

will further contribute to a reduction in coronary reserve.Finally, it is likely that the increased diffusion distance due tothe increased size of cardiac fibers and reduced capillarydensity also contribute to the development of tissue hypoxia.10

In patients with coronary artery disease, some degree ofLVH is common, as hypertension is an important risk factorfor CAD. The presence of LVH will contribute to reductions inCFR, independently of stenosis severity.55 The actual CFR inLVH will be critically dependent on the underlying cause ofLVH and its effects on coronary driving pressure. A similardegree of hypertrophy caused by untreated systemic hyper-tension will have a higher CFR than in aortic stenosis, inwhich mean arterial pressure remains normal.10 Similarly,when LVH is from systolic hypertension with increased pulsepressure caused by reduced aortic compliance, the accom-panying reduction in diastolic pressure will result in a lowercoronary flow reserve, as myocardial perfusion occursprimarily in diastole. Conversely, the increase in LV diastolicfilling pressure that typically accompanies LVH results inelevated Pf = 0, thereby further contributing to a reduction in

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70%

CORONARY PRESSURE (mmHg)

per gm of tissue (ml/min/gm). A. With acquired hypertrophy,latory resistance arteries. Absolute LV flow is shown in panelsolute flow at rest although the maximum absolute flow perperfusion is assessed using flow per gm of myocardiumm of tissue falls inversely with the increase in LV mass. Inant since the increase in absolute resting flow is proportionalor flow per gm is measured, the net effect of these opposingsure in LVH. As a result of the reduction in microcirculatoryificance of a 50% stenosis (triangles) in the hypertrophied%, circles) in normal myocardium. This can even result infrom Canty and Duncker6 with permission.


CFR.23 Finally, there is also evidence that alterations in thecontrol of coronary microvascular tone may occur in heartswith pathological LVH. These include endothelial dysfunc-tion, enhanced α-adrenergic vasoconstriction, downregula-tion of K+ channels and enhanced expression of smoothmuscle Ca2+ channels.3,11 These observations suggest thatnot only structural but also functional abnormalities of thecoronary microcirculation contribute to perturbations in theregulation of CBF in the hypertrophied heart.

Coronary microvascular dysfunction

Measurements of coronary flow reserve in humans withrisk factors for atherosclerosis are systematically lowerthan in healthy individuals without CAD risk factors.54,56,57

Much of this may arise from abnormal local resistancevessel control via impaired endothelial-dependent vasodi-lation arising from NO inactivation associated with riskfactors for CAD.3 Kuo and colleagues have demonstratedthat experimental hypercholesterolemia markedly attenu-ates the dilation of coronary arterioles in response to shearstress as well as pharmacological agonists that stimulateNO synthase in the absence of epicardial stenosis.58 This wasreversedwith L-arginine, suggesting reduced substrate availabil-ity or overcoming the effect of endogenously produced methyl-ated L-arginines, suchasADMAthat are responsible for impairedNO synthesis or availability.59

These in vitro abnormalities in NO-mediated vasodilationcan be functionally significant and impair the ability of thecardiac muscle to regulate CBF. Fig 6A shows the effects of

Fig 6 – Impaired microcirculatory control with abnormal NO-medA. Effects of blocking nitric oxide synthase (NOS) with the L-arginan increase in the lower autoregulatory pressure limit, resultingversus 45 mm Hg under normal conditions that occurred withouB. Transmural perfusion before and after blocking NO-mediated dstenosis. Although coronary pressure and hemodynamics wereblocking NOS and was not overcome by metabolic dilator mechasupport the notion that abnormalities in endothelium-dependentof a proximal coronary stenosis (modified from Duncker and BacLNAME, NG-nitro-L-arginine methyl ester; LNNA, NG-nitro-L-argi

inhibiting NO on the regulation of CBF in normal healthydogs.60 Although resting blood flow is not altered, there is amarked increase in the coronary pressure at which intrinsicautoregulatory adjustments become exhausted, with flowbeginning to decrease at a distal coronary pressure of 60versus 45 mm Hg, approximately similar to the shift occur-ring in response to a twofold increase in heart rate. In vivomicrocirculatory studies have demonstrated that inhibitingNO production prevents resistance arteries from dilatingmaximally in response to shear stress.62 This likely reflectsexcess resistance in the transmural penetrating arteries,which are upstream ofmetabolic stimuli for vasodilation andextremely dependent on shear stress as a stimulus for localvasodilation. These functional abnormalities amplify thephysiological effects of a coronary stenosis, resulting in thedevelopment of subendocardial ischemia at a lower work-load (Fig 6B).61

The prognostic importance of abnormalities in coronaryresistance vessel control is underscored by data in womenevaluated for chest pain felt to be of ischemic origin.63,64

Abnormalities in CFR and endothelium-dependent vasodila-tion are common in womenwith insignificant epicardial CAD.These changes negatively affect prognosis and can producemetabolic evidence of myocardial ischemia as assessed byCMR spectroscopy.65 While these findings underline theimportance of understanding gender differences in theregulation of CBF and development of CAD,64 a recent studyindicates that coronary microvascular dysfunction is equallyprevalent in both men and women and imparts a similarlypoor prognosis.66

iated endothelium-dependent resistance artery dilation.ine analog LNAME in chronically instrumented dogs. There isin the onset of ischemia at a coronary pressure of 61 mm Hgt a change in heart rate (modified from Smith and Canty60).ilation with LNNA in exercising dogs subjected to a coronarysimilar, blood flow was lower in each layer of the heart afternisms during ischemia. Collectively, these experimental datamicrovascular vasodilation can amplify the functional effectshe61). Abbreviations: Endo, endocardium; Epi, epicardium;nine. Reprinted from Canty and Duncker6 with permission.


Impact of coronary microvascular dysfunction on physiologicalmeasures of stenosis severity

If microcirculatory function is normal, quantitativemeasures ofstenosis severity during vasodilation that are derived usingabsolute flow reserve and fractional flow reserve should all beclosely related. Unfortunately, this is the exception rather thanthe rule andmicrovascular dysfunction and/or variability in themicrocirculatory response to pharmacological vasodilationdissociate the idealized relations between various indices ofCFR for a given stenosis severity. Fig 7A summarizes theobserved variability, showing the relation between pairedinvasive measurements of absolute flow reserve vs. distalcoronary pressure derived FFR.46 These measurements demon-strate several points. As shown in Fig 7A, hemodynamicallyinsignificant stenoses (i.e. FFR > 0.8) can have absolute flowreserves that vary between 1 and over 5. While this variabilitydecreases when FFR is less than 0.8 it is still considerable untilFFR falls below 0.5. There is also a wide variation betweenindices of absolute flow reserve and relative perfusion differ-ences derived fromquantitative PETperfusionmeasurements.46

Experimental studies show that the variability in microvas-cular dysfunction and submaximal pharmacological vasodila-tor responses can have a significant impact on assessing thephysiological significance of a coronary stenosis using FFR (orrelative perfusion with imaging). This is schematized in Fig 7B.The two dashed lines show idealized relations betweenabsolute flow reserve and FFR. Microvascular dysfunction inthe presence of normal coronary arteries (0% stenosis) attenu-ates CFR despite an FFR of 1. Conversely, for any given stenosis,the FFRmeasured in the presence ofmicrovascular diseasewillbe higher than when vasodilator responses are normal. As the

Fig 7 – A. There is awide variation in pairedmeasurements of functthe same patient. Simultaneous intracoronary catheter based meaflowreserve (FFR). This variability reflects differences in the contrib(adapted from Johnson et al.46). B. Hypothetical effects of microvasmeasurements of fractional flow reserve. The upper blue dashed lreserve andFFRwhen the coronarymicrocirculation isnormal andrelation between absolute flow reserve and FFR when there is micthe solid blue lines. The presence ofmicrovascular dysfunctionwiland overestimate stenosis severity. In contrast, since distal coronaflow reserve, and relative flow reserve will underestimate stenosisvariability demonstrated in Fig 7A. Modified from Canty and Dunc

pressure-drop across the stenosis is flow-dependent, FFR willunderestimate the physiological severity of the stenosis whenmaximum vasodilation is not achieved. All of these factorscontribute to at least some of the discordance between FFR andCFR observed in clinical studies and underscore the importanceof combining both pressure- and flow-derived indices to assessvasodilator reserve of the total coronary vascular bed. Indeed,the availability of high-fidelity pressure and flow measure-ments on a single wire has now facilitated the development ofapproaches to assess the stenosis pressure-flow relation aswellas abnormalities in microcirculatory reserve by determiningFFR and absolute CFR simultaneously.49,67 When assessedtogether, these measurements have the potential to identifycircumstances in which mixed abnormalities from a stenosisand abnormal microcirculation contribute to the functionalimpact of a coronary stenosis.

Future perspectives

The major factors determining myocardial perfusion and O2delivery that were established several decades ago have beenincorporated into how we manage patients with angina andhave stood the test of time. The basic understanding of thefluid mechanical behavior of coronary stenoses has also beentranslated to the cardiac catheterization laboratory wheremeasurements of coronary pressure distal to a stenosis andCBF are routinely obtained. These physiological concepts nowfacilitate routine clinical decision making in a fashion thatfavorably impacts outcomes.

Despite progress in advancing our mechanistic under-standing of the coronary circulation in health and CAD,

ional stenosis severity using different indices of flow reserve insurements of absolute flow reserve are compared to fractionalutionof themicrocirculation and stenosis in individual patientscular dysfunction on the stenosis pressure flow relation andine shows the idealized linear relation between absolute flowmaximally vasodilated. The lower reddashed line indicates therovascular dysfunction. Individual stenoses are illustrated byl limit vasodilation. Thus, absolute flow reservewill be reducedry pressure is higher with submaximal vasodilation, fractionalseverity. It is likely that these interactions contribute to the

ker6 with permission.


important gaps remain in our basic knowledge as well as thetranslation of this to the clinical setting. For example, whilebasic research has identified the importance of physicalfactors such as shear stress and local coronary pressure inregulating isolated coronary resistance vessels, how thesemechanisms interact in a complex vascular network to bringabout the phenomenon of autoregulation and metaboliccoronary vasodilation remains unanswered. Finally, althoughthe role of microcirculatory dysfunction in symptoms as wellas prognosis of patients with CAD is increasingly recognized,the mechanisms behind the cross-talk between the differentcell-types in the heart and their impact on cardiac structureand function are a particularly important area of futureinvestigation. For example, there is evidence that risk factorsresulting in endothelial dysfunction in the coronary micro-circulation can adversely affect fibroblast and cardiomyocytefunction through paracrine signaling,68,69 contributing tomyocardial stiffening and possibly heart failure with pre-served ejection fraction.70 These observations underscore theimportance of the need for continued bench to bedsidetranslational investigation in these and other areas in orderto expand our fundamental knowledge and improve the careof patients with chronic IHD.

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Regulation of Coronary Blood Flow �in Health and Ischemic Heart DiseaseRegulation of CBF in the healthy heartAutoregulation of CBFMechanical and hemodynamic determinants of CBFExtravascular compressive forcesCoronary vascular resistanceTransmural variations in minimum CVR and diastolic drivingpressureTransmural variations in autoregulation

Structure and function of the coronary microcirculationHemodynamic forces regulating CVRResistance vessel responses to changes in shear stressResistance vessel responses to changes in wall stress

Endothelium-dependent modulation of CVRNeural control of CVRMetabolic control of CVR

Regulation of CBF in pathophysiological statesCoronary artery stenosisStenosis pressure-flow relationInterrelation among distal coronary pressure, flow, and stenosis severityConcept of maximal perfusion and CFR

Impact of a chronic epicardial stenosis on the coronary microcirculationImpact of a chronic coronary artery occlusion on the coronary microcirculationRegulation of CBF in the collateralized heartImpact of cardiac hypertrophy on the coronary microcirculationCoronary microvascular dysfunctionImpact of coronary microvascular dysfunction on physiological measures of stenosis severity

Future perspectivesReferences

Documents

Regulation of Coronary Blood Flow in Health and Ischemic ......Regulation of Coronary Blood Flow in Health and Ischemic Heart Disease Dirk J. Dunckera,⁎, Akos Kollerb,c, Daphne Merkusa,