Imaging Coronary Blood Flow in AS

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 67, NO. 12, 2016

ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2016.01.053

EDITORIAL COMMENT

Imaging Coronary Blood Flow in AS Let the Data Talk, Again* K. Lance Gould, MD, Nils P. Johnson, MD

I

n this issue of the Journal, Ahn et al. (1) correlate

AS. Moreover, the wide scatter provides contravening

an index of relative myocardial perfusion reserve

physiological insights. Although no optimal cutoff of

(MPRI) by magnetic resonance imaging (MRI) in

MPRI for angina is plotted, the data points plotted in

patients with aortic stenosis (AS) and angina pectoris,

Figure 4 (1) suggest that MPRI at a threshold of 0.9

those with AS without angina, and control patients

identified only 60% of patients with angina, thereby

without aortic stenosis. The results confirm previously

leaving 40% failing to fit the microvascular hypoth-

established inverse relationships of coronary flow

esis for angina in severe AS. Furthermore, w35% to

reserve (CFR), severity of AS, and left ventricular (LV)

40% of asymptomatic patients had MPRI <0.9, again

hypertrophy (LVH) or mass. They sorted data into 3

failing to fit the microvascular hypothesis.

groups in Figure 4 (1): patients with the most severe

Such great scatter with 35% to 40% of cases not

AS with angina, those with less severe AS without

fitting the microvascular hypothesis suggests another

angina, and control subjects with no AS, LVH, or angina

mechanism for angina in AS. As detailed in the

for the expected continuum of clinical AS in Figure 5.

following, previous literature indicates data that the

On the basis of the reduced mean MPRI in the AS-

authors may, or should, have to test the microvas-

angina group, the authors conclude that microvascular

cular hypothesis. However, they did not report the

dysfunction explains angina in severe AS.

critical data, perhaps due to their retrospective anal-

SEE PAGE 1412

ysis rather than a hypothesis-testing design. Moreover, MPRI is a relative ratio of stress-to-rest upslope of the MRI signal. Therefore, lowered relative MPRI is

STATISTICS VERSUS PHYSIOLOGY

likely due to increased resting perfusion associated with LVH and high-pressure workload than due to

Although the mean differences among the 3 groups

reduced stress perfusion. The “why angina in AS” is

are statistically significant, the data overlap is

not new, as addressed in a series of papers and edi-

so great as to preclude predicting who gets angina in

torials since 1997 with cumulative data supporting a potentially definitive alternative answer reviewed in the following (2–11).

*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From the Division of Cardiology, Department of Medicine, McGovern

CORONARY PHYSIOLOGY AND SUBENDOCARDIAL PERFUSION

Medical School at the University of Texas Health Science Center, Houston, Texas; and the Memorial Hermann Hospital, Houston, Texas.

Let us start with a brief review of coronary physiology

Dr. Gould received internal funding from the Weatherhead PET Center

before returning to the current MRI paper. Hyperemia

for Preventing and Reversing Atherosclerosis and is the 510(k) applicant

of coronary blood flow follows every systole as a rapid

for CFR Quant (K113754) and HeartSee (K143664), for software for quantifying absolute flow using cardiac positron emission tomography

increase in diastolic coronary blood flow after systolic

and analysis, including absolute flow quantification. Dr. Johnson receives

compression, as illustrated in Figure 1 (2). Experimen-

internal funding from the Weatherhead PET Center for Preventing and

tally, the rate of increase in coronary blood flow in early

Reversing Atherosclerosis and significant institutional research support from St. Jude Medical (for CONTRAST, NCT02184117) and Volcano/Philips

diastole is fastest in the epicardium and slowest in the

Corporation (for DEFINE-FLOW, NCT02328820), makers of intracoronary

subendocardium. The time delay in subendocardial

pressure and flow sensors.

after subepicardial hyperemia is significant, even for a

Gould and Johnson

JACC VOL. 67, NO. 12, 2016 MARCH 29, 2016:1423–6

Mechanisms of Angina in Aortic Stenosis

myocardial perfusion in AS before and after aortic

F I G U R E 1 Subendocardial and Subepicardial Reactive Hyperemia

Coronary Blood Flow (% Maximum Mean Coronary Flow)

1424

valve replacement (AVR) (3,4). In patients with severe AS undergoing quantitative PET perfusion imaging

150

with

Subepicardial flow Subendocardial flow & peak flow delayed 20 sec

dipyridamole

stress,

transmural

CFR

and

the subendocardial-to-subepicardial perfusion ratio decrease directly with the decrease in hyperemic

100 Average transmural flow 50

diastolic perfusion time (Figure 5 in Rajappan et al. [3]). Follow-up studies after AVR showed a direct relationship

between

improved

CFR,

increased

hyperemic diastolic perfusion time, and increased 0

20 Control 90 sec Occlusion

40

60

80

100 120

140 160 180

aortic valve area (4). The relationship of CFR and the subendocardial-to-subepicardial perfusion ratio to

Seconds After Release of 90-Sec LAD Occlusion

the hyperemic diastolic perfusion time before and after AVR indicates that hemodynamic conditions

During reactive hyperemia after brief occlusion, the rapid rise and peak sub-

determine CFR, not microvascular disease. Micro-

endocardial perfusion is delayed by up to 10 seconds after the subepicardial

vascular disease would be expected to reduce

rise and peal perfusion. Reduced diastolic perfusion time of tachycardia plus slow subendocardial perfusion may cause subendocardial perfusion and ischemia. Adapted from Downey et al. (2).

perfusion uniformly throughout the LV wall and remain fixed transmurally without a subendocardialsubepicardial perfusion gradient that is directly related to diastolic perfusion time.

normal heart with a 10- to 20-s delay in peak hyperemia in the 2 different myocardial layers. With tachycardia, the diastolic filling time is reduced, which would impair subendocardial perfusion in a normal heart, but subendocardium vasodilates further to maintain the rapid early diastolic hyperemia. Many factors impede this rapid early diastolic hyperemia including segmental or diffuse coronary artery disease, hypotension, diastolic dysfunction, delayed diastolic relaxation, LVH, AS, sympathetic overdrive, localized coronary spasm, endothelial dysfunction, and rarely myocardial bridges, all separate and independent of microvascular disease. As these hemodynamics or pathophysiologies reduce the rapid early diastolic hyperemia, tachycardia shortens the diastolic perfusion time in direct proportion to heart rate. As the diastolic perfusion time shortens,

INVASIVE HEMODYNAMICS BEFORE AND AFTER PERCUTANEOUS AVR In patients with angina and severe AS, invasive pressures and flow velocities have been measured before and after percutaneous AVR. The impaired CFR before valve replacement immediately normalizes after AVR with immediate relief of angina. This observation indicates that the impaired CFR and angina are due to hemodynamic factors with immediate normalization of CFR and relief of angina when the hemodynamic factors were corrected. These observations rule against microvascular dysfunction as causing the reduced CFR and angina because microvascular disease would not correlate so closely with hemodynamic factors or normalize immediately after valve replacement (8).

there is not enough time between serial systoles for

QUANTITATIVE PERFUSION FOR

impeded, slowly increasing diastolic coronary blood

DIFFERENTIATING HEMODYNAMIC MECHANISMS

flow to supply the subendocardium with adequate

AND MICROVASCULAR DISEASE

blood flow. Subendocardial ischemia ensues with angina and ST-segment depression on electrocardi-

The gold standard for microvascular dysfunction is

ography that are directly related to the dual interact-

coronary vascular bed resistance from invasive pres-

ing

impediments

to

flow-shortened

diastolic

sure and flow velocity measurements during vasodi-

perfusion time and slowed early diastolic hyperemia.

lator hyperemia (9). Therefore, one might ask

Therefore, reduced hyperemia or CFR is commonly

whether perfusion alone can uniquely define micro-

due to hemodynamics that are not synonymous with

vascular dysfunction. On the basis of coronary phys-

microvascular disease.

iology, there is an observation on perfusion alone that should differentiate pure isolated microvascular dis-

SUBENDOCARDIAL PERFUSION IN AS

ease from other causes that reduce hyperemic perfusion or CFR. The clue is absolute subendocardial

Although positron emission tomography (PET) imag-

and subepicardial perfusion and their ratio. Micro-

ing lacks the resolution of MRI, it has clarified

vascular disease should be uniform throughout the

Gould and Johnson

JACC VOL. 67, NO. 12, 2016 MARCH 29, 2016:1423–6

Mechanisms of Angina in Aortic Stenosis

LV wall and uniformly reduce transmural myocardial perfusion

reserve

without

a

THE “MRI SILO” OF EXPERTISE

subendocardial-to-

subepicardial perfusion gradient. In contrast, all

The complexity of cardiovascular medicine, e.g.,

other pathophysiologies reducing hyperemic perfu-

imaging, interventions, prevention, medical man-

sion or CFR cause an abnormally low subendocardial-

agement, is so great that expertise derives from

to-subepicardial

absolute

highly focused skills, thinking, and reading. The

reduction in subendocardial perfusion to ischemic

resulting “silos of expertise” are understandable but

low-flow levels associated with angina and electro-

carry great risk of isolation from fundamental

cardiographic changes.

clinical coronary physiology. This incomplete paper

perfusion

ratio

with

MRI has better spatial resolution than PET suffi-

by clearly experts in the “MRI silo” overlooks

cient to examine subendocardial and subepicardial

essential physiology in the literature, perhaps what a

perfusion in milliliters/minute/gram and absolute

skeptic might call a “physiology silo.” However, the

CFR (10,11). Consequently, one might expect MRI to

latter is basic to life, whereas the former is a tech-

provide uniquely definitive data on perfusion alone

nology intended to see truths in the physiological

to differentiate microvascular disease from hemody-

silo of life.

namic or other causes of reduced CFR by measuring

Nature is a complex of processes and truths that

absolute subendocardial and subepicardial perfusion

care little about our mental silos and preconceptions

correlated with diastolic perfusion times.

from which we view nature. Our task as medical sci-

INSTRUCTIVE ERRORS OF OMISSION

entists is not dedication to a methodology “silo” but to use that silo of expertise to see nature’s truths, to let the data talk to us, and to tell us nature’s truths for

With current literature as the basis for a potentially definitive MRI study, do the data in the current paper resolve the mechanism of angina in AS? The essential fundamental data not reported are hyperemic heart rate, blood pressure, diastolic perfusion time, subendocardial and subepicardial perfusion in milliliters/ minute/gram, their ratio, and absolute CFR. In the literature, these data explained reduced stress flow, CFR, angina, and their normalization with relief of angina after valve replacement. Perhaps their omission derives from the retrospective analysis as opposed to hypothesis-testing design. Therefore, the conclusion that microvascular dis-

improving our patients lives. With this paper and editorial as a springboard, perhaps another carefully designed MRI study will measure diastolic perfusion time, hyperemic blood pressure and heart rate, rest and hyperemic subendocardial and subepicardial perfusion in milliliters/ minute/gram, their ratio, and absolute CFR. Such definitive physiological data would then be the classic paper on angina in AS that would lay to rest this old question, perhaps worthy of a final editorial integrating the technology of myocardial perfusion imaging

with

clinical

coronary

physiology

across

different silos of expertise.

ease causes angina in AS is simply not related to reduced MPRI because no data on the hemodynamic or microvascular mechanisms are reported. Although the

REPRINT REQUESTS AND CORRESPONDENCE: Dr. K.

references acknowledge some of the literature on the

Lance Gould, Weatherhead P.E.T. Center for Pre-

topic, the lesson of “let the data talk” (5–7) seems to

venting and Reversing Atherosclerosis, University of

have gotten lost in a retrospective analysis to support a

Texas Medical School, 6431 Fannin, Room 4.256MSB,

preconceived notion rather than measuring data

Houston, Texas 77030. E-mail: k.lance.gould@uth.

designed to challenge the hypothesis as true or not.

tmc.edu.

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3. Rajappan K, Rimoldi OE, Dutka DP, et al. Mechanisms of coronary microcirculatory dysfunction in

5. Gould KL. Why angina pectoris in aortic stenosis. Circulation 1997;95:790–2.

angina in severe AS: prospective adenosinestress CMR study. J Am Coll Cardiol 2016;67: 1412–22.

patients with aortic stenosis and angiographically normal coronary arteries. Circulation 2002;105: 470–6.

6. Gould KL, Carabello BA. Why angina in aortic stenosis with normal coronary arteriograms?

2. Downey HF, Crystal GJ, Bashour FA. Asynchronous transmural perfusion during coronary reactive hyperemia. Cardiovasc Res 1983;17: 200–6.

4. Rajappan K, Rimoldi OE, Camici PG, et al. Functional changes in coronary microcirculation after valve replacement in patients with aortic stenosis. Circulation 2003;107:3170–5.

Circulation 2003;107:3121–3. 7. Gould KL, Johnson NP. Myocardial perfusion in aortic stenosis – let the data talk. J Am Coll Cardiol Img 2012;5:190–2.

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JACC VOL. 67, NO. 12, 2016 MARCH 29, 2016:1423–6

Mechanisms of Angina in Aortic Stenosis

8. Davies JE, Sen S, Broyd C, et al. Arterial pulse wave dynamics after percutaneous aortic valve replacement: fall in coronary diastolic suction with increasing heart rate as a basis for angina symptoms in aortic stenosis. Circulation 2011;124:1565–72. 9. Ng MKC, Yueng AC, Fearon WF. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of

index of microcirculatory resistance compared with coronary flow reserve. Circulation 2006;113:2054–61. 10. Wang L, Jerosch-Herold M, Jacobs DR, et al. Coronary calcification and myocardial perfusion in asymptomatic adults. J Am Coll Cardiol 2006;48: 1018–26. 11. Wang L, Jerosch-Herold M, Jacobs DR, et al. Coronary risk factors and myocardial perfusion in

asymptomatic adults: the Multi-Ethnic Study of Atherosclerosis (MESA). J Am Coll Cardiol 2006; 47:565–72.

KEY WORDS cardiac magnetic resonance, exertional angina, left ventricular mass index, myocardial perfusion reserve