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Coronary Physiology During Exercise andVasodilation in the Healthy Heart and inSevere Aortic Stenosis

Matthew Lumley, BSC,a Rupert Williams, BSC,a Kaleab N. Asrress, PHD,a Satpal Arri, BSC,a Natalia Briceno, BSC,a

Howard Ellis, BSC,a Ronak Rajani, MD,b Maria Siebes, PHD,c Jan J. Piek, PHD, MD,d Brian Clapp, PHD,b

Simon R. Redwood, MD,a,b Michael S. Marber, PHD,a John B. Chambers, MD,b Divaka Perera, MDa,b

ABSTRACT

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BACKGROUND Severe aortic stenosis (AS) can manifest as exertional angina even in the presence of unobstructed

coronary arteries.

OBJECTIVES The authors describe coronary physiological changes during exercise and hyperemia in the healthy heart

and in patients with severe AS.

METHODS Simultaneous intracoronary pressure and flow velocity recordings were made in unobstructed coronary

arteries of 22 patients with severe AS (mean effective orifice area 0.7 cm2) and 38 controls, at rest, during supine bicycle

exercise, and during hyperemia. Stress echocardiography was performed to estimate myocardial work. Wave intensity

analysis was used to quantify waves that accelerate and decelerate coronary blood flow (CBF).

RESULTS Despite a greater myocardial workload in AS patients compared with controls at rest (12,721 vs.

9,707 mm Hg/min�1; p ¼ 0.003) and during exercise (27,467 vs. 20,841 mm Hg/min�1; p ¼ 0.02), CBF was similar in

both groups. Hyperemic CBF was less in AS compared with controls (2,170 vs. 2,716 cm/min�1; p ¼ 0.05). Diastolic time

fraction was greater in AS compared with controls, but minimum microvascular resistance was similar. With exercise and

hyperemia, efficiency of perfusion improved in the healthy heart, demonstrated by an increase in the relative contribution

of accelerating waves. By contrast, in AS, perfusion efficiency decreased due to augmentation of early systolic decel-

eration and an attenuated rise in systolic acceleration waves.

CONCLUSIONS Invasive coronary physiological evaluation can be safely performed during exercise and hyperemia in

patients with severe aortic stenosis. Ischemia in AS is not related to microvascular disease; rather, it is driven by abnormal

cardiac-coronary coupling. (J AmColl Cardiol 2016;68:688–97)©2016by theAmerican College of Cardiology Foundation.

P atients with severe aortic stenosis (AS) and un-obstructed coronary arteries have a reducedcoronary flow reserve (CFR) (1,2), often accom-

panied by angina during exercise, and an increasedrisk of myocardial infarction during noncardiac sur-gery (3). Although the precise mechanisms are yet to

m the aBritish Heart Foundation Centre of Excellence and National

rdiovascular Division, St. Thomas’ Hospital Campus, King’s College L

rdiology, Guy’s and St. Thomas’ NHS Foundation Trust, London, United

ademic Medical Center, University of Amsterdam, Amsterdam, the Neth

nter, University of Amsterdam, Amsterdam, the Netherlands. Supported b

d the Biomedical Research Centre award to King’s College London and Guy

st by the UK National Institute for Health Research. Mr. Lumley is now an

d analysis, he was a PhD student at King’s College London. There is n

nuscript and his current employment. All other authors have reported tha

this paper to disclose.

nuscript received March 21, 2016; revised manuscript received May 5, 20

be elucidated, recent developments have paved theway for a novel approach to studying these phenom-ena. First, it is now possible to carry out detailed inva-sive coronary evaluation in humans during exercise(4). Second, the technique of wave intensity analysis(WIA) provides a powerful tool to study the intimate

Institute for Health, Biomedical Research Centre,

ondon, London, United Kingdom; bDepartment of

Kingdom; cDepartment of Biomedical Engineering,

erlands; and the dHeart Centre, Academic Medical

y a British Heart Fellowship to ML (FS/13/15/30026)

’s & St. Thomas’ National Health Service Foundation

employee of Pfizer, but at the time of data collection

o conflict of interest between the content of this

t they have no relationships relevant to the contents

16, accepted May 10, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

AS = aortic stenosis

AVR = aortic valve

replacement

CBF = coronary blood flow

CFR = coronary flow reserve

EOA = effective orifice area

LV = left ventricular

MR = microvascular resistance

MRdias = diastolic

microvascular resistance

RPP = rate pressure product

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689

relationship between cardiac contraction and coronaryblood flow (CBF), often referred to as cardiac-coronarycoupling. Coronary WIA provides directional, quanti-tative, and temporal information that has been usedto study various human disease processes includingleft ventricular hypertrophy, the response to trans-catheter aortic valve replacement (AVR), the responseto pacing, the “warm-up angina” phenomenon, ven-tricular remodeling following an acute coronary syn-drome, and cardiac resynchronization therapy (4–9).Interestingly, detailed invasive physiological testingandWIA have not previously been used to characterizethe response of the healthy human heart to exerciseor adenosine hyperemia.

SEE PAGE 698

SBP = systolic blood pressure

WI = wave intensity

= wave intensity analysis

In myocardial ischemia investigations, the heart isoften subjected to stress to determine its ability toaugment myocardial blood flow. The stressor can bephysiological (exercise) or pharmacological (usingagents such as adenosine). Although both forms ofstress are chosen to enhance CBF, their influenceon cardiac-coronary coupling may be profoundlydifferent, especially in the diseased heart. The aim ofthis descriptive physiological study is 2-fold: to pro-vide a detailed description of the changes in CBF andcardiac-coronary coupling in response to exercisecompared with adenosine-induced hyperemia in thehealthy heart; and to determine whether patientswith severe symptomatic AS differ in their responsesto these stressors.

METHODS

The index group comprised patients with severesymptomatic aortic stenosis (defined as an effectiveorifice area [EOA] <1 cm2 or peak flow velocity [Vmax]>4 ms�1) being considered for surgical AVR. Thecontrol group comprised patients without AS, butwith normal coronary angiograms, performed duringthe investigation of chest pain. Inclusion criteria werepreserved left ventricular (LV) function (LV ejectionfraction >50%) and unobstructed coronary arteries(no lesion >50% in diameter assessed visually).Exclusion criteria were concomitant valve disease(greater than mild on echocardiography), history ofsyncope, recent acute coronary syndrome or presen-tation with heart failure (within 4 weeks), or any co-morbidity that may influence exercise tolerance. Thestudy protocol was approved by the institutionalresearch ethics committee.

PROTOCOLS. Catheterization was via the right radialartery using standard coronary catheters. All patientshad aspirin (300 mg) and clopidogrel (600 mg)

pre-loading, intra-arterial unfractionatedheparin (70 U/kg), and intracoronary nitro-glycerin before diagnostic angiography andintracoronary physiological measurements.A dual pressure and Doppler sensor-tipped0.014-inch intracoronary wire (Combowire,Volcano Corp, San Diego, California) wasused to measure coronary pressure and flowvelocity. Wire pressure was first normalizedto that recorded by the fluid-filled pressuremanometer and the tip advanced into adistal left coronary artery and manipulateduntil a stable and optimal Doppler velocitytrace was obtained. Hemodynamic mea-surements were taken under resting condi-tions and continuously during supine bicycleexercise.

After full recovery from exercise (return to baselinelevels of heart rate, blood pressure, and average peakvelocity), a second set of resting hemodynamic datawas acquired (rest-2 period). Hyperemia was theninduced with intravenous adenosine. All relativechanges reported with hyperemia use rest-2 forbaseline measurements.

A specially adapted supine cycle ergometer (ergo-sana, Bitz, Germany), which allowed a standardizedincremental increase in workload, was attached to thecatheter laboratory table. Exercise began at a work-load of 30 W and incrementally increased every 2 minby 20 W. Where muscle weakness restricted the use ofincreasing workloads, resistance was fixed at themaximum tolerated level, and exercise continueduntil exhaustion.

Signals were sampled at 200 Hz, with the dataexported into a custom-made study manager program(Academic Medical Center, University of Amsterdam,Amsterdam, the Netherlands) and a minimum of 10consecutive beats extracted for each condition. Pan-cardiac cycle analysis and WIA were performed oncustom-made software, Cardiac Waves (Kings CollegeLondon, London, United Kingdom). Savitzky-Golayfilters were applied to preserve peaks in the datawhile smoothing (10). Ensemble averages of theselected cardiac cycles were performed. Microvas-cular resistance (MR) was calculated as the ratio ofthe distal mean coronary pressure (Pd) and theaverage peak velocity. The diastolic MR (MRdias) wasdefined as the MR during mid-to-late diastole, wheremyocardial compressive forces are at their lowest (11).Measuring MR in this interval gives insight into thevascular component of MR.

For the purposes of WIA, diastole onset wasdefined as the dichotic notch on the arterial pressurewaveform. Net coronary wave intensity (dI) was

WIA

TABLE 1 Patient Demographics

Control(n ¼ 38)

Aortic Stenosis(n ¼ 22) p Value

Male 28 (74) 18 (82) 0.54

Age, yrs 61 � 10 69 � 8 0.001

Hypertension 22 (58) 11 (50) 0.55

Diabetes mellitus 8 (21) 3 (14) 0.47

Hypercholesterolemia 27 (71) 14 (64) 0.55

Smokers 7 (18) 2 (9) 0.33

Values are n (%) or mean � SD.

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calculated as the product of time derivatives (dt) ofensemble-averaged coronary pressure and flow ve-locity (U) as follows: dI ¼ dPd/dt.dU/dt (12). Net waveintensity (WI) was separated into forward and back-ward components.

For each patient, 4 dominant waves were identi-fied and included in our analysis:

1. Early systolic deceleration: associated with CBFdeceleration during isometric contraction (some-times referred to as the backward compressionwave).

2. Systolic acceleration: associated with peak aorticpressure and increasing CBF (sometimes referredto as the forward compression wave).

3. Late systolic deceleration: the fall in aortic pres-sure in late systole leads to CBF deceleration(sometimes referred to as the forward expansion or“suction” wave).

4. Diastolic acceleration: the rapid reduction of LVpressure leads to a fall in compression of intra-myocardial vessels and acceleration of CBF(sometimes known as the backward expansion or“suction” wave).

We reported the magnitude of each wave (its peakWI). The absolute values of the 4 dominant waveswere summed in both the AS and control group atrest, during peak exercise, and hyperemia; plus, thepercentage of accelerating and decelerating WI wascalculated.

Previous coronary WIA studies have demonstrateda wide variation in the magnitude of wave intensitybetween patients (8,13). This is in part related toinherent errors in measurement, but also likely re-flects true population variation. We therefore calcu-lated the percentage change in waves from rest toexercise and rest to hyperemia, thereby allowing eachpatient to act as their own control, helping to elimi-nate some of this inherent variation.

A subset of 13 patients with AS underwent bicyclestress echocardiography to quantify myocardial workby measuring the rate pressure product (RPP). Allpatients in the subset had a full resting transthoracicechocardiographic study followed by a bicycle stressechocardiogram. The exercise protocol used duringthe stress echocardiogram was identical to the pro-tocol used in the catheterization laboratory. The RPPwas defined as the product of heart rate and LV sys-tolic blood pressure (SBP), which correlates withmyocardial oxygen consumption (14). LV pressurewas estimated from the sum of SBP and the trans-valve pressure gradient after pressure recovery (15).In the control cohort, LV pressure was assumed to beequal to aortic pressure in systole; hence, the RPP was

calculated as the product of heart rate and aorticsystolic pressure.

STATISTICAL ANALYSES. Statistical analysis wasperformed using SPSS version 21 (IBM Corp., Armonk,New York). Normality of data was visually assessed(using histograms and the normal Q-Q plot) and usingthe Shapiro-Wilk test. Continuous and normal dataare expressed as mean � SD and compared usingpaired or unpaired Student t tests as appropriate.Non-normal continuous data are expressed as medianwith interquartile range and compared using theMann-Whitney U test or Wilcoxon signed rank test asappropriate. A 2-tailed test for significance was per-formed for all analyses; p # 0.05 was consideredstatistically significant. Correlation was assessed withthe Pearson correlation coefficient. No adjustmentsare made for comparisons across multiple timepoints.

RESULTS

Sixty individuals were recruited into the study:22 with AS and 38 healthy controls (Table 1). AllAS patients and 17 consecutive patients in thecontrol group performed supine bicycle exercise.Hyperemia was induced in 19 patients with AS and30 controls.

The AS cohort all had severe symptomatic AS witha peak aortic valve gradient of 92 � 26 mm Hg, Vmax

across the aortic valve of 4.7 � 0.66 ms�1, and an EOAof 0.74 � 0.16 cm2 (Table 2).

The exercise protocols in the cardiac catheteriza-tion and echocardiography laboratories werecompleted safely in patients with and without AS.There were no significant adverse effects of adeno-sine infusion in either group.

In response to exercise, heart rate and SBPincreased and the diastolic time fraction decreased inAS patients as well as controls (p < 0.001 in bothgroups). There was a significant rise in diastolic bloodpressure in AS, but not in controls. Induction of

TABLE 2 Echocardiographic Characteristics of Patients with

Aortic Stenosis

Vmax, ms�1 4.70 � 0.66

Mean aortic valve gradient, mm Hg 57 � 16

Peak aortic valve gradient, mm Hg 92 � 26

Effective orifice area, cm2 0.74 � 0.16

Ejection fraction, % 59 � 5

Lateral S0, ms�1 7.6 � 2.0

E/E0 10 � 3

Left atrial area, cm2 25 � 7

Left ventricular mass, g 221 � 70

Values are mean � SD.

E/E0 ¼ ratio of mitral inflow velocity to velocity of the mitral valve annulusduring passive left ventricular filling; lateral S0 ¼ peak systolic velocity of thelateral mitral valve annulus; Vmax ¼ maximal velocity across the aortic valve.

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hyperemia led to a rise in heart rate but a fall in SBP inboth groups (p < 0.001). Diastolic blood pressure anddiastolic time fraction did not change in AS butdecreased in controls during hyperemia (Figure 1).

Average peak velocity increased during exercise inboth groups (p < 0.001). Exercise CFR in AS andcontrols was similar (1.7 � 0.6 vs. 1.7 � 0.6, respec-tively; p ¼ 0.57), but hyperemic CFR was less in AS

FIGURE 1 Hemodynamic Response to Stress

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Patients with aortic stenosis (AS) and controls had varying hemodynami

aortic stenosis (orange). *p # 0.05. 1 min ¼ after 1 minute of exercise; 50

hyperemia; LV ¼ left ventricular; peak ¼ immediately before exercise w

patients (1.9 � 0.7 vs. 2.5 � 0.6, respectively;p ¼ 0.006).

Microvascular resistance fell during exercise inboth groups (p < 0.001). The relative change in MRon exercise was not different between AS and con-trols (0.8 � 0.3 vs. 0.8 � 0.3; p ¼ 0.70; the closerthe value is to 1, the smaller the reduction frombaseline). At rest, MRdias was lower in AS patientsthan controls (354 � 172 mm Hg/s�1/m�1 vs. 480 �220 mm Hg/s�1/m�1; p ¼ 0.025). With exercise, MRdias

dropped in both groups relative to baseline, and therewas no between-group difference during exercise.

MR fell with hyperemia in both groups (p < 0.001)(Figure 2); though less so in AS patients (0.6 � 0.3 vs.0.4 � 0.1; p ¼ 0.001). There was no difference in MRduring hyperemia between AS and controls. Fulldetails of hemodynamic parameters are shown inOnline Table 1.

EXTERNAL AND MYOCARDIAL WORK. Controls per-formed more external work than patients with ASduring the catheterization laboratory exercise proto-col (98 � 25 W vs. 77 � 20 W; p ¼ 0.005). The externalwork in the catheterization laboratory was similar

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rol Aortic Stenosis

c responses to supine bicycle exercise and adenosine-induced hyperemia in controls (blue) and

% ¼ 50% of maximal exercise time; bpm ¼ beats per minute; hyperemia ¼ adenosine-induced

as discontinued due to exhaustion; RPP ¼ rate pressure product.

FIGURE 2 Coronary Circulation Response to Stress

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Differences between groups were most pronounced with hyperemia. *p# 0.05. MRdias ¼ diastolic microvascular resistance; other abbreviations

as in Figure 1.

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to the stress echocardiography protocol experi-enced in the 13 patients who had both procedures(78 � 24 W vs. 88 � 28 W; p ¼ 0.07). The cardiac out-put at rest in the 13 AS patients who underwent stressechocardiography was 5.4 � 1.6 l/min�1 and rose to9.3 � 2.5 l/min�1 during peak exercise (p < 0.001).

LV pressure was greater in AS compared withcontrols at rest and at all levels of exercise. Myocar-dial work, estimated as RPP, was significantly higherfor AS patients than controls, at rest (9,707 � 2,925mm Hg/min�1 vs. 12,721 � 3,399 mm Hg/min�1,respectively; p ¼ 0.003) as well as during peak exer-cise (20,841 � 7,622 mm Hg/min�1 vs. 27,467 � 7,260mm Hg/min�1; p ¼ 0.02) (Figure 1).WAVE INTENSITY ANALYSIS. Typical coronarypressure and flow waveforms, with the correspondingWIA curves, at rest and during hyperemia, in a patientwith AS is shown in Online Figure 1. The absolute

values and percentage contribution of each of the4 dominant waves is shown in Online Table 2.

At rest, AS compared with controls had signifi-cantly lower early systolic deceleration and lowersystolic acceleration with no difference in late sys-tolic deceleration or diastolic acceleration. With ex-ercise compared with rest, for both AS and controls,the magnitude of all 4 waves increased. However, inAS, the increase in the early systolic deceleration wasgreater than controls (296% vs. 99%; p ¼ 0.005)(Figure 3).

With hyperemia compared with rest, all wavesincreased significantly in both groups, except earlysystolic deceleration did not change in controls.With hyperemia in AS, the percentage increasein early systolic deceleration was significantlygreater (112% vs. 25%; p ¼ 0.008) (Figure 3)and percentage change in systolic acceleration

FIGURE 3 Change From Baseline in ESD and SA in AS Patients

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Exercise HyperemiaP = 0.992 P = 0.005 P = 0.004 P = 0.008

SystolicAcceleration

Early SystolicDeceleration

SystolicAcceleration

Early SystolicDeceleration

During exercise, patients with aortic stenosis (AS) experienced a pathological augmented rise in early systolic deceleration (ESD); during

hyperemia, there was a pathological attenuation in the increase of systolic acceleration (SA) and augmentation of ESD.

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significantly lower compared with controls (67% vs.164%; p ¼ 0.004).

These differences in percentage change in earlysystolic deceleration and systolic acceleration led to achange in the balance of accelerating and deceler-ating waves from rest to exercise and hyperemia. Atrest, accelerating waves accounted for 80% of theforces driving CBF in the AS group and 70% in con-trols (p ¼ 0.005). On maximal exercise, there was nodiscernible difference between groups (73% vs. 73%;p ¼ 0.95); with the induction of hyperemia, theresting pattern reversed (70% vs. 78%; p ¼ 0.047)(Figure 4).

Resting echocardiographic markers of AS severity,measures of ventricular systolic and diastolic func-tion, and LV mass did not correlate with absolutevalues of any of the dominant waves at rest, duringpeak exercise, or in the hyperemic state.

During hyperemia, EOA correlated with the per-centage contribution of diastolic acceleration to totalWI (r ¼ 0.637; p ¼ 0.006). The same relationship wasobserved between the percentage contribution of allaccelerating waves and EOA (r ¼ 0.603; p ¼ 0.01)(Online Figure 2).

DISCUSSION

We have shown, for the first time, that it is safe andfeasible to carry out supine bicycle exercise duringcardiac catheterization in patients with severe AS.

This was also the first study to invasively characterizecoronary physiological changes in the healthy humanheart during exercise.

The main findings of this study:

1. The mechanism of CBF augmentation in exerciseand adenosine-induced hyperemia is fundamen-tally different.

2. Patients with AS failed to alter their CBF in pro-portion to the increase in cardiac work, making themyocardium vulnerable to ischemia during stress.

3. Minimum MR in AS was not different from con-trols, supporting the hypothesis that microvas-cular disease is not a factor in the reduced CFRseen in AS.

4. Diastolic time fraction was lower in AS comparedwith controls.

5. Although the efficiency of the healthy heart im-proves during exercise and hyperemia due to anincrease in the relative contribution of waves thataccelerate flow, the reverse was observed in ASdue to an increase in the contribution of wavesthat decelerate flow.

RESPONSE TO STRESS. In the healthy heart,exercise-induced flow augmentation was character-ized by a reduction in coronary MR and a rise in heartrate. Hyperemia led to a greater augmentation in CBF,driven by a more marked reduction in MR but a moremodest increase in heart rate than exercise. Animportant observation is that minimum MR and

FIGURE 4 Percentage of Total Wave Intensity

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In control patients, the total percentage of accelerating wave intensity increases in

response to exercise and hyperemia (improved coronary perfusion efficiency); in aortic

stenosis (AS), the opposite pattern is seen (reduced coronary perfusion efficiency).

*p # 0.05 compared with AS. ACC ¼ acceleration; DEC ¼ deceleration.

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MRdias were lower with hyperemia than with exercise,signifying that despite exercising patients toexhaustion or limiting symptoms, some microvas-cular reserve remained.

MR was lower at rest in patients with AS than inhealthy controls, particularly the vascular compo-nent, MRdias. This helped explain diminished flowreserve (1) in AS patients, where resting microvas-cular dilation impairs the capacity to further reduceMR in response to stress, a finding consistent withprevious studies (16). MR fell to a greater degree withhyperemia than with exercise, but the drop in MR wasless in AS than controls. Although MRdias was lower atrest in AS than controls, it was similar in both groupsat hyperemia. This indicated a normal minimalvascular resistance in patients with AS, therebysupporting the hypothesis that abnormal cardiac-coronary coupling, rather than fundamental differ-ences in microvascular function, is responsible forreduced CBF in AS. This fit with previous observa-tions that hemodynamic markers of AS severitycorrelated better with CFR than the degree of LVhypertrophy/mass. Furthermore, several groups haveshown CFR to improve immediately after surgicalAVR before the regression of LV hypertrophy(6,17,18).

Consistent with other reports (19,20), myocardialwork also was greater in AS than controls, pointing toa relative supply/demand imbalance making thesepatients more vulnerable to myocardial ischemia.

WIA AND CORONARY PERFUSION EFFICIENCY. Therelative balance of energy that drives and impedes

flow will determine coronary perfusion efficiency.WIA allows quantification of energy fluxes that bothaccelerate and decelerate coronary flow, providing ameasure of perfusion efficiency. The percentage ofaccelerating wave intensity describes the proportionof energy used in accelerating flow. The greater thisvalue, the greater proportion of coronary energydriving, rather than impeding, coronary flow.

Diastolic acceleration, the principal force drivingCBF in the healthy heart, is determined by the degreeof ventricular lusitropy. This wave has received themost attention in clinical studies to date (4,5,8).Systolic acceleration originates in the ventricle duringventricular contraction and travels via the aorta intothe coronary circulation, thereby accelerating CBF.Early systolic deceleration occurs during isovolumiccontraction and is produced from the transmission ofrapidly rising LV pressure to the intramural vessels,which decelerates coronary flow.

In healthy hearts, each of the 4 dominant coro-nary waves increased with exercise, but the per-centage increase in the systolic acceleration wavewas the greatest. This translated to an increasedproportional contribution of accelerating waves tototal WI, leading to improved coronary perfusionefficiency. During hyperemia, the magnitude of bothaccelerating and decelerating waves increased,keeping with findings in animal studies (7,21). Aswith exercise, the large percentage increase in thesystolic acceleration shifted the balance of forces infavor of accelerating waves, improving coronary flowefficiency.

In AS, the increment in systolic acceleration withstress was attenuated compared with controls,particularly during hyperemia, which may relate tothe pressure drop across the aortic valve. Further-more, there was greater exercise-induced augmenta-tion of early systolic deceleration in AS, which likelyreflected greater compressive forces in this groupduring exercise; the larger changes during hyperemiamay indicate enhanced cardiac-coronary couplingdue to a decrease in vascular resistance. Together,these difference explained the diminished perfusionefficiency during stress in AS.

Although the relative increase in each of the waveswas greater with exercise than hyperemia, this in-crease was more marked with systolic deceleration.Importantly, the augmentation of diastolic accelera-tion from rest to exercise or hyperemia was notdifferent between AS and controls. Therefore,heightened systolic deceleration and shortened dia-stolic perfusion time appear to be primary reasons forreduced CFR during exercise and hyperemia in AS.

CENTRAL ILLUSTRATION Pathological Effects of Aortic Stenosis on the Coronary Circulation

Lumley, M. et al. J Am Coll Cardiol. 2016;68(7):688–97.

In this diagrammatic representation of the pathological environment to coronary flow in aortic stenosis (AS), (A) AS causes an elevation in left ventricular (LV) pressure,

increasing myocardial work. Furthermore, the pressure gradient across the aortic valve leads to reduction in the pressure at the coronary inlet (reduced driving pressure).

Under resting conditions, microvascular resistance is reduced to maintain coronary flow. (B) During isovolumetric contraction (aortic valve closed), greatly elevated LV

pressure leads to increased compression of the intramyocardial vessels and augmented deceleration of coronary flow. (C) Following the opening of the aortic valve,

acceleration of coronary flow is attenuated due to a reduced driving pressure secondary to the pressure gradient across the aortic valve. Ao ¼ aorta; LA ¼ left atrium;

RA ¼ right atrium; RV ¼ right ventricle.

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CLINICAL IMPLICATIONS. With the onset of stress,patients with AS are unable to augment CBF inresponse to increased myocardial work, creating anenvironment vulnerable to ischemia that providesa possible mechanism for exercise-induced anginaand perioperative cardiac events. This inabilityto adequately augment CBF is caused by a patho-physiological imbalance of forces accelerating anddecelerating CBF in AS and an impingement on dia-stolic perfusion time (Central Illustration). Further-more, those with the most severe AS (measured byEOA) are at the highest risk of ischemia.

Although changes in cardiac mechanics are muchgreater during exercise, hyperemia increases thesensitivity of the coronary circulation to myocardialcontraction. Consequently, one might postulate thatpatients with AS may become particularly vulner-able to ischemia during periods of profound vaso-dilation and increased myocardial oxygen demand,such as during anesthesia rather than duringexercise.

Phasic analysis of coronary flow and pressure byWIA provides unique insight into exercise physiologyin AS and has potential diagnostic utility in

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE:

Impaired CFR in patients with severe AS is associated

with angina even in the absence of obstructive coro-

nary disease. The efficiency of perfusion, assessed as

the balance of energy that drives and impedes flow,

increases with exercise in healthy hearts, but de-

creases in patients with AS because of early systolic

deceleration. Ischemia in patients with AS is therefore

due to abnormal cardiac-coronary coupling rather

than microvascular disease.

TRANSLATIONAL OUTLOOK: The development of

noninvasive methods to evaluate phasic coronary flow

could have diagnostic value in identifying asymp-

tomatic patients who should be considered for early

intervention or assessing therapies that favorably in-

fluence cardiac energetics.

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identifying asymptomatic patients who should beconsidered for early intervention, especially if itproves possible to develop a noninvasive method ofobtaining these measurements. Exercise WIA mayalso be useful to assess the effect of therapiesdesigned to increase lusitropy (such as soluble gua-nylate cyclase activators or phosphodiaesterase in-hibitors that increase cyclic guanosinemonophosphate) for AS and other conditions thatadversely affect cardiac coronary coupling.

STUDY LIMITATIONS. This was a single-center studywith relatively small numbers of patients in eachgroup. Patients with AS were older than controls,although we found no correlation between age andabsolute values of WI, relative changes in WI, or thetotal percentage of accelerating or decelerating WIunder any of the 3 conditions. Furthermore, we havecontrolled for differences in baseline parameters bylooking at percentage changes with exercise andhyperemia.

We were unable to measure LV pressure simulta-neously with coronary physiological data in AS pa-tients and instead, were limited to measuring theformer during a separate period of exercise, using anidentical exercise protocol. Future studies of this na-ture would be strengthened by the simultaneousassessment of ventricular dynamics and coronaryphysiology. Additionally, measurement of myocardialwall stress and, hence, rate stress product may givea more accurate estimate of myocardial oxygendemand.

We did not measure LV mass in all our controlcases and thus cannot exclude the possibility thatsome differences observed may have been related toLV hypertrophy. However, in the AS group, there wasno correlation between LV mass and physiologicalmeasurements at rest or during exercise.

We calculated wave speed using the single-pointmethod; however, during hyperemia, the wavespeed estimated using this method might differ fromthe true wave speed (22). We measured MR duringmid-to-late diastole, when myocardial compressiveforces are at their lowest (11), to approximate thevascular component of MR, although this is likely to

be an oversimplification as it does not account formicrovasculature compliance.

CONCLUSIONS

We resolved the debate regarding the cause ofischemia in AS with normal coronary arteries byshowing that AS patients have a higher workload,normal minimum MR, and shorter diastolic perfusiontime compared with controls, thereby demonstratingthat microvascular disease is not a factor in AS. More-over, the data suggested that a greater increase in earlysystolic deceleration (associated with isovolumetricsystolic myocardial compression) was responsible forreduced CFR in AS versus controls. These factorsrestrict coronary flow in the face of higher workloads,hence making the myocardium more vulnerable toischemia during conditions of stress.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Divaka Perera, Department of Cardiology, St. Thomas’Hospital, London SE1 7EH, United Kingdom. E-mail:Divaka.Perera@kcl.ac.uk.

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KEY WORDS coronary blood flow,microvascular resistance, velocity, waveintensity analysis

APPENDIX For supplemental figures andtables, please see the online version of thisarticle.