ORIGINAL ARTICLE

Stress positron emission tomography is safe andcan guide coronary revascularization in high-riskpatients being considered for transcatheteraortic valve replacement

Paul C. Cremer, MD,a Shaden Khalaf, MD,a Junyang Lou, MD,a

Leonardo Rodriguez, MD,a Manuel D. Cerqueira, MD,a and Wael A. Jaber, MDa

a Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH

Received Feb 27, 2014; accepted May 15, 2014

doi:10.1007/s12350-014-9928-y

Background. The safety and accuracy of regadenoson stress positron emission tomography(PET) in patients with significant aortic stenosis (AS) is unknown. In patients undergoingsurgical aortic valve replacement, coronary artery bypass grafting for coronary artery diseaseis standard, but the appropriate revascularization strategy in patients undergoing TAVR isuncertain. Stress PET may identify patients that benefit from revascularization.

Methods. Fifty consecutive patients who were referred for consideration of TAVR andunderwent a stress PET study were retrospectively identified. We assessed major adversecardiac events and significant decreases in systolic blood pressure. The percentage of jeopar-dized myocardium was determined by combining ischemic and hibernating myocardium.

Results. Our patients were high risk with a mean Society of Thoracic Surgeons mortalityscore of 11.4% and had severe AS with a moderately reduced left ventricular ejection fraction(EF) (mean aortic valve area of 0.78 ± 0.25 cm2 and mean EF of 39 ± 16%). There were nomajor adverse events during testing. Transient hypotension occurred in 16% of the patients.Revascularization was performed in 44% of patients, and 91% of these patients had revascu-larization to territories jeopardized on PET. These patients had substantial jeopardizedmyocardium (median 19%), and only 3 patients underwent revascularization despite less than10% jeopardized myocardium.

Conclusions. Stress cardiac PET with regadenoson can be performed safely in patientswith severe AS. Results of the PET study can accurately direct subsequent revascularization.(J Nucl Cardiol 2014)

Key Words: Aortic stenosis Æ myocardial perfusion imaging Æ myocardial blood flow Æcoronary artery disease Æ transcatheter aortic valve replacement

INTRODUCTION

In patients with severe symptomatic AS, concom-

itant obstructive coronary CAD is common and

increases with age.1-3 During surgical aortic valve

replacement (SAVR), coronary artery bypass grafting

(CABG) for any coronary stenosis greater than 50%-

70% has been the standard.4 Transcatheter aortic valve

replacement (TAVR) is now accepted as a less invasive

treatment option for high-risk patients.5,6 However, the

early TAVR trials generally excluded patients with

significant untreated CAD, and there is no current

consensus on who should receive revascularization prior

to TAVR.5-7

Patients undergoing TAVR are often elderly with

comorbidities including renal insufficiency, decreased

left ventricular EF, previous percutaneous coronary

intervention (PCI), and prior CABG.5,6,8 Such patients

Reprint requests: Paul C. Cremer, MD, Heart and Vascular Institute,

Cleveland Clinic, 9500 Euclid Avenue: Desk J1, Cleveland, OH

44195; paul.cremer@gmail.com

1071-3581/$34.00

Copyright � 2014 American Society of Nuclear Cardiology.

are at the increased risk for contrast nephropathy and

other complications related to PCI; hence, appropriate

patient selection for revascularization is particularly

important. Myocardial perfusion imaging (MPI) using

single photon emission computed tomography (SPECT)

and positron emission tomography (PET) has been used

to select patients for revascularization. Stress SPECT

and PET require dynamic exercise or vasodilators such

as dipyridamole, adenosine, or regadenoson. Vasodilator

stress decreases systemic blood pressure, and this effect

may be unsafe in patients with severe AS and CAD.

PET MPI offers improved resolution and diagnostic

accuracy over SPECT for CAD, but in the presence of

AS, accuracy has not been demonstrated.9 When PET

perfusion is combined with a viability assessment using

F-18 Fluorodeoxyglucose (FDG), it can identify the total

myocardium at risk: the sum of ischemic and hibernat-

ing myocardium. Thus, PET has the potential to identify

high-risk patients with severe symptomatic AS that may

benefit from revascularization. However, given the

potential risks, guidelines have discouraged stress test-

ing in this setting, and there are warnings against using

regadenoson in severe valvular heart disease.10,11 We,

therefore, investigated the safety and clinical utilization

of stress PET with regadenoson in the management of

patients being considered for TAVR.

METHODS

Study Population

We identified 50 consecutive patients who were referred

to our institution for consideration of TAVR and underwent

regadenoson stress cardiac PET from May 2010 through

August 2013. Patient hemodynamic data, comorbidities, and

medications were prospectively entered at the time of stress

testing and were extracted from our database for analysis.

Blood pressure was measured manually by trained personnel at

rest, every minute for four readings during stress, and every

minute for 4 minutes in recovery. Electronic medical records

were reviewed, and Society of Thoracic Surgeons (STS) scores

were determined from an online calculator (riskcalc.sts.org).

Known CAD was defined as a coronary stenosis [50%, pre-

vious myocardial infarction, previous PCI, or a history of

CABG. Hypertension was defined as self-reported history or

use of anti-hypertensive medications. Hyperlipidemia was

defined as an abnormal fasting lipid panel according to ATP III

guidelines, self-reported history, or use of lipid lowering

medications. Diabetes mellitus was defined as fasting blood

glucose C126 mg/dL, self-reported history, or use of glucose

lowering medications. Glomerular filtration rate (GFR) was

calculated from blood work most proximate to the rest-stress

PET. Similarly, the echocardiogram performed using ASE

recommendations closest to the stress test was used for ana-

lysis. Left ventricular EF, aortic valve gradients, aortic valve

area (AVA), dimensionless index (DI), and the severity of

mitral regurgitation were all obtained from the echocardiogram

report.

Positron Emission Tomography

Patients fasted for more than 8 hours and abstained from

caffeine for more than 24 hours. Gated cardiac PET images

using 82-Rubidium or 13N-Ammonia were acquired with two

scanners as previously described.12 Seven patients received

13N-Ammonia, and 43 patients received 82-Rubidium. PET

images were reoriented and displayed using Corridor4DM

software (Invia, Ann Arbor, MI). Stress images were obtained

after the administration of 0.4 mg of intravenous regadenoson,

and viability was assessed with 18F-FDG.13 The perfusion

defects were quantified using semi-automated polar maps with

a 5-point scoring system and a 17-segment model by experi-

enced nuclear cardiologists.14 The PET test was considered

abnormal if there was any perfusion defect not related to

artifact or if the EF was less than 45%. Summed rest score

(SRS), summed stress score (SSS), and summed difference

score (SDS) were recorded. Jeopardized myocardium was

calculated as SDS, the amount of ischemia present, plus the

rest score for any segments deemed viable with this total

divided by 68 and then expressed as a percentage by

multiplying by 100. If a viability study was not performed,

then the SDS alone was used to calculate jeopardized myo-

cardium. Jeopardized coronary territories were determined

prior to revascularization according to established guidelines.15

Global myocardial blood flow (MBF) at rest and during stress

was calculated using a one-compartment model of 82Rb

kinetics and a nonlinear extraction function as previously

validated.16 A region of interest was positioned at the base of

LV to obtain the arterial input function. Myocardial flow

reserve (MFR) was obtained by dividing stress MBF by resting

MBF. We were able to calculate MBF on 26 patients. Among

our cohort, 9 patients were excluded as they had testing

performed before we began routinely measuring MBF, and 15

patients were excluded because they had testing on a PET

scanner that did not have dynamic capability. All tests were

reviewed and scored by an experienced nuclear medicine

physician or cardiologist.

Patient outcomes

Patient medical records were reviewed to assess for major

adverse cardiac events related to the stress test including death,

myocardial infarction, or sustained ventricular tachycardia. A

significant decrease in systolic blood pressure during testing

was defined as a decrease by 20 mmHg with a nadir less than

90 mmHg. Obstructive CAD at coronary angiography was

defined as a stenosis[50% as determined by the interventional

cardiologist. If a bypass graft had a [50% stenosis and

supplied a native coronary artery with a [50% stenosis, then

the stenosis territory was adjudicated according to the native

coronary artery. The severity of stenosis was based upon the

invasive coronary angiography report in the medical record.

Subsequent revascularization was defined as PCI or CABG.

Revascularization territory guided by PET included

Cremer et al Journal of Nuclear Cardiology�Stress PET to guide revascularization in TAVR

revascularization to the coronary artery or bypass graft that

supplied jeopardized myocardium on the stress test. All cause

mortality was assessed from the Social Security Death Index.

The primary safety endpoint was a major adverse cardiac

events at the time of the stress test and included a significant

decrease in blood pressure. For secondary outcomes, we

evaluated whether stress PET results reliably guided coronary

revascularization.

Statistical Analysis

A descriptive analysis was performed using relevant

clinical, PET, and echocardiographic variables. Normally

distributed variables were expressed as means with standard

deviations, whereas non-normal variables were expressed as

medians with interquartile ranges. Categorical variables were

compared using chi-square tests, and continuous variables

were compared using t tests or Wilcoxon Rank Sum tests, as

appropriate. Cox proportional hazard modeling was performed

to assess variables associated with survival time free of all-

cause mortality. A two-sided P value \.05 was considered

statistically significant. All statistical analysis was performed

with JMP, Version 10 (SAS Institute Inc., Cary, NC). Our

institutional review board approved this study.

RESULTS

Patient Characteristics

Background clinical and echocardiographic data are

shown in Table 1. Our patients were elderly males

(82%) with a mean age of 73 years. They were at high

surgical risk with a mean STS mortality score of 11.4%.

This high operative risk was similar to the inoperable

and high-risk PARTNER patients that underwent TAVR

(11.2% and 11.8%, respectively).5,6 Renal insufficiency

was present in 58% of patients, and the median GFR was

35 mL/min/1.73 m2. Most patients had hypertension and

hyperlipidemia, and about half had diabetes mellitus.

The vast majority had known CAD (92%): 44% had a

prior PCI, and 56% had a previous CABG.

Patients had moderately severe to severe aortic

stenosis and a reduced EF. The mean EF was 39 ± 16%.

In 26% of patients, the EF was greater than 50%, and 32%

had an EF less than 30%. Mean aortic valve gradient was

30 mmHg, whereas mean DI and AVA were severely

reduced at 0.23 and 0.78 cm2, respectively.

PET Results

As expected, most PET studies were abnormal

(Table 2). The mean resting ECG-gated EF was com-

parable to the mean echocardiogram EF (35% v. 39%, r2

0.70). A similar percentage of patients had reversible

and fixed perfusion defects on rest and stress images

(68% and 72%, respectively); 56% had both. An

assessment for viability with FDG was performed in

38 (76%) patients. Of these patients, 11 (28%) had

hibernating myocardium with a median (interquartile

range) of 4% (3%,10%) hibernating myocardium. Rest-

regadenoson PET without FDG was performed in 12

(24%) patients. Of these patients, 7 had no or a minimal

resting perfusion defect (SRS B4), and 3 of the

remaining 5 patients had an ejection fraction [35%.

The median amount of jeopardized myocardium,

defined as ischemic plus hibernating myocardium, for all

patients was 12.5%. Representative patient studies are

shown in Figures 1 and 2. Quantitative MBF was

measured in 26 patients. Rest MBF was reduced with

median values (interquartile ranges) of 0.87 (0.76,1.21)

mL/min/g. Stress and MFR were severely reduced [1.01

(0.81,1.37) mL/min/g, and 1.14 (0.91,1.43), respec-

tively]. There were no significant associations between

MBF, number of vessels with significant stenosis, and

the severity of aortic stenosis, suggesting that multiple

factors may explain impaired MBF in these patients.

Safety of Regadenoson Stress Testing

There were no major adverse cardiac events related

to the stress test. Two patients developed symptomatic

hypotension that resolved spontaneously without intra-

venous fluid or aminophylline administration. One

patient with a permanent pacemaker developed a brief

non-sustained wide complex tachycardia. A significant

decrease in systolic blood pressure developed in 8 of the

50 patients. The manufacturer reports that a decrease in

systolic blood pressure of greater than 35 mmHg was

observed in 7% of patients in Phase III clinical trials.11

This decrement was observed in 20% of our patients.

Patients with a significant decrease in systolic blood

pressure were significantly older and had decreased

echocardiographic and PET gated resting EFs (Table 3).

Of note, peak and mean aortic valve gradients were

inversely associated with a significant decrease in

systolic blood pressure, though there was no association

with AVA and DI. These results suggest that, in this

cohort, a significant decrease in systolic blood pressure

was related to decreased ejection fraction and not the

severity of aortic stenosis.

Invasive Coronary Angiography andRevascularization According to Stress PETResults

The relationship between anatomic stenosis, mag-

nitude and territory of jeopardized myocardium, and

revascularization for all patients is shown in Table 4.

Coronary angiography was performed after PET MPI in

Journal of Nuclear Cardiology� Cremer et al

Stress PET to guide revascularization in TAVR

37 (74%) patients, and 36 (95%) of these patients had

obstructive CAD (Table 5). Coronary angiography after

PET MPI was not performed in 13 patients (26%), but

these patients had their coronary anatomy defined in the

past. These 13 patients had minimal to no jeopardized

myocardium (median of 0% with interquartile range of

0-3%). One patient with a normal PET study had a

coronary angiogram that showed no obstructive CAD.

All but one patient with an abnormal PET study had

obstructive CAD upon coronary angiography.

The magnitude of jeopardized myocardium was

associated with revascularization. In the 22 patients with

revascularization, the median jeopardized myocardium

was 19% vs 3% in the 28 patients not referred for

revascularization (P = .002). Revascularization was

based upon ischemic myocardium alone in 11 patients,

ischemic and hibernating myocardium in 9 patients, and

hibernating myocardium alone in 1 patient. Only 3

patients underwent revascularization despite less than

10% jeopardized myocardium.

Among the 14 patients with obstructive CAD and

no revascularization, 3 died waiting to be enrolled in

clinical trials for TAVR, 1 was diagnosed with a

metastatic malignancy, and 1 declined further treatment.

PET results in 4 patients demonstrated B10% jeopar-

dized myocardium. The remaining 5 patients had

significant jeopardized myocardium. In 3 patients,

revascularization was not technically possible, and these

patients had 22%, 21%, and 15% jeopardized myocar-

dium, respectively. Medical management of CAD was

pursued in the final 2 patients who had 12% and 13%

jeopardized myocardium, respectively.

PET results also directed revascularization territory

in 20 of the 22 patients (Figure 3). In these patients, 1

had left main disease, 5 had one vessel disease, 9 had 2

vessel disease, and 5 had 3 vessel disease. One patient

had a PET study with a fixed defect in the territory of the

right coronary artery (RCA) and subsequently under-

went PCI to the left anterior descending artery (LAD).

This patient had a 95% narrowing in the mid LAD and

an occluded RCA with an occluded graft to the RCA.

Another patient had a PET with an LAD territory defect

and then had CABG to the LAD and left circumflex

artery (LCx). On coronary angiography, this patient has

a 90% mid LAD narrowing and a 60% proximal LCx

narrowing. The surgeon elected to bypass both vessels.

All other patients had revascularization to territories that

were jeopardized on PET. Among all patients, 23 had

stenoses [50% that were not jeopardized, and these

lesions were not revascularized. In patients with mul-

tivessel disease that had revascularization, 9 had stenoses

[50% that were not revascularized in territories that

were not jeopardized on PET. These stenoses were

[70% in 6 of the patients. There was no difference in

Table 1. Baseline patient characteristics (n = 50)

Demographics and comorbidities

Age 73 ± 15

Follow-up (Days) 537 ± 364

Female 9 (18%)

STS score 11.4 ± 7.8

Euroscore II 21.8 ± 17

Known CAD 46 (92%)

Previous PCI 22 (44%)

Previous CABG 28 (56%)

Hypertension 46 (92%)

Hyperlipidemia 44 (88%)

Diabetes mellitus 24 (48%)

Estimated GFR 35 ± 29

Medications

Beta-blockers 40 (80%)

ACE inhibitors/ARBs 23 (46%)

Aspirin 44 (88%)

Diuretic 35 (70%)

Statin 42 (84%)

Echocardiographic variables

Ejection fraction 39 ± 16%

AVA 0.78 ± 0.25 cm2

Maximum aortic valve gradient 51 ± 17 mmHg

Mean aortic valve gradient 30 ± 11 mmHg

DI 0.23 ± 0.06

Moderate to severe mitral

regurgitation

27 (54%)

Table 2. Stress cardiac PET characteristics (n = 50)

Abnormal 46 (92%)

Resting heart rate 74 ± 14

Resting systolic blood pressure 129 ± 25

Stress heart rate 83 ± 14

Stress systolic blood pressure 107 ± 25

Resting ejection fraction 35 ± 17%

Stress ejection fraction 33 ±16%

Reversible perfusion defect 34 (68%)

Fixed perfusion defect 36 (72%)

SSS* 15 (8,20)

SRS* 6 (0,13)

SDS* 7 (0,11)

F18DG for viability assessment 38 (76%)

Evidence of hibernating

myocardium

11 (28%)

Jeopardized myocardium* 12.5% (2%,21%)

*Non-normal distribution, expressed as median (Quartile1,Quartile3)

Cremer et al Journal of Nuclear Cardiology�Stress PET to guide revascularization in TAVR

revascularization according to age, EF, or AVA, though

patients that underwent AVR were more likely to have

revascularization (26% vs. 18%, P = .03) (Table 6).

Patients Outcomes

AVR was performed in 42% of patients (Table 5):

SAVR in 11 patients and TAVR in 10 patients. There

were 13 patients that did not undergo AVR as their AS

was not severe enough for inclusion in available clinical

trials for TAVR. Other exclusions included died waiting

for AVR (n = 4), severe aortic regurgitation (n = 3),

very severely reduced EF (n = 2), limiting mitral valve

pathology (n = 2), hematologic reasons (n = 3), and

asymptomatic status (n = 1). During follow-up, 16

(32%) patients died. No patients who had TAVR died,

and one patient with SAVR died. Among the 26 patients

with MBF measurements, 7 (27%) patients died. For

these patients, PET EFs, relative perfusion defects, and

MFR were not associated with increased hazard of

death, when assessed as continuous variables. However,

when assessed as continuous variables, decreased rest

and stress MBF were associated with increased hazard

of mortality. When the median values were used to

delineate as a nominal variable, rest MBF less than

0.9 mL/min/g had a hazard ratio (HR) of 6.01 with 95%

confidence intervals (CI) of 1.02-113 (P = .05). Stress

MBF less than 1 mL/min/g was also associated with

increased mortality (HR 5.52; 95% Confidence Interval

1.18-38.7; P = .03).

DISCUSSION

MPI in Aortic Stenosis

The literature addressing MPI in severe symptom-

atic AS is limited as guidelines recommend coronary

angiography followed by AVR and CABG as indicated.4

Small studies have investigated adenosine stress with

SPECT in patients with AS.17,18 Vasodilator stress

testing was considered safe, but when compared to our

patients, these patients were younger, had higher EFs,

less CAD, and fewer other comorbidities. Moreover, the

SPECT studies mostly evaluated whether the test could

Figure 1. Representative patient with severe AS and EF of 35%. (A) Stress (StrAC), rest (RstAC),and viability (FDGAC) images on short axis (SA), horizontal long axis (HLA), and vertical longaxis (VLA). (B) Polar maps of stress, rest, and FDG images. There is ischemia in the mid and distalseptum, as well as the mid anterior segments. There is hibernation in the distal anterior and apicalsegments. Jeopardized myocardium calculated at 22%. Given LAD ischemia (grey arrow) andhibernation (yellow arrow), the patient underwent PCI with a drug eluting stent to the proximalLAD followed by TAVR with a Sapien-XT 29 mm valve.

Journal of Nuclear Cardiology� Cremer et al

Stress PET to guide revascularization in TAVR

exclude CAD, not whether results could direct revascu-

larization. PET and MRI studies have assessed coronary

flow reserve in patients with AS, but by design, have

excluded patients with CAD.19,20 Our study is the first

investigation of regadenoson stress PET in high-risk

patients with AS and CAD.

Figure 2. Representative patient with severe AS, EF of 20%, and a history of two previous bypasssurgeries. (A) Stress (StrAC), rest (RstAC), and viability (FDGAC) images on short axis (SA),horizontal long axis (HLA), and vertical long axis (VLA). (B) Polar maps of stress, rest, and FDGimages. There is ischemia in the entire septum, inferior, inferolateral, and apical anterior segments.There is scar in the apex, apical septum, and anterolateral segments. Jeopardized myocardiumcalculated at 44%. Transient ischemic dilation is seen, and stress EF decreased to 10%. Given theRCA (white arrow) and LAD (yellow arrow) ischemia with minimal LAD scar and predominantLCx scar (red arrow), the patient underwent PCI with a drug eluting stents to the proximal LADand to the bypass graft to the RCA. He then underwent TAVR with a Sapien 26 mm valve.

Table 3. Patient characteristics and significant decrease in SBP (n = 50)

Significant decreasein SBP (n 5 8)

No significant decreasein SBP (n 5 42) P value

Age 78 ± 6.1 71 ± 12 .04

Echocardiographic EF 27 ± 8.8% 41 ± 16% .004

AVA 0.81 ± 0.29 cm2 0.78 ± 0.25 cm2 .81

Peak gradient 44 ± 5.3 mmHg 53 ± 19 mmHg .02

Mean gradient 25 ± 5.3 mmHg 31 ± 11 mmHg .03

DI 0.23 ± 0.05 0.23 ± 0.09 .91

Mitral regurgitation* 2 (1,2) 2 (0,2) .36

PET resting EF 24 ± 9.5% 38 ± 18% .007

PET stress EF 25 ± 10% 35 ± 17% .05

*Non-normal distribution, expressed as median (Quartile 1, Quartile 3)

Cremer et al Journal of Nuclear Cardiology�Stress PET to guide revascularization in TAVR

Table 4. Anatomic stenoses ([50%), percent jeopardized myocardium, jeopardized territory, andrevascularization territory for all patients (n = 50)

Anatomic territoryJeopardizedmyocardium

Jeopardizedterritory

Revascularizationterritory

LAD,RCA,LCx 44 LAD,RCA LAD, RCA

LM 40 LAD,LCx LM

LAD,LCx,RCA 32 LAD,LCx,RCA LAD,LCx

LAD,LCx,RCA 31 LAD, LCx LAD,LCx

LAD,LCx,RCA 29 RCA None

LAD 29 LAD LAD

LAD,RCA 27 LAD,RCA LAD,RCA

LCx 27 LAD,LCx LCx

LAD,RCA 24 LAD,RCA LAD,RCA

LAD,RCA 22 LAD None

RCA 21 LAD,RCA None

LCx,RCA 21 LCx None

LAD,LCx 21 LAD,LCx LAD

LAD,LCX 21 LAD None

LAD,LCx,RCA 19 LAD LAD,LCx

RCA 19 RCA RCA

LAD 19 LAD LAD

LCx,RCA 18 LCx LCx

LAD,LCx 18 LAD,LCx None

LAD,LCx 15 LAD None

LAD,LCx,RCA 15 LAD,LCx,RCA LAD

RCA 15 LAD None

LAD,LCx,RCA 13 LAD None

LCx,RCA 13 LCx,RCA LCx,RCA

LCx,RCA 13 RCA RCA

LCx,RCA 12 RCA RCA

LAD,LCx,RCA 12 LAD,RCA LAD,RCA

LAD,RCA 12 LAD LAD

RCA 12 LAD None

LCx 10 LCx None

RCA 8.8 RCA RCA

LCx,RCA 5.9 RCA None

None 4.4 LCx,RCA None

LAD,RCA 2.9 LAD LAD

None 2.9 RCA None

LAD,LCx 2.9 LAD None

None 2.9 LCx None

None 1.5 LAD None

None 0 None None

None 0 None None

None 0 None None

None 0 None None

LCx,RCA 0 None None

None 0 None None

None 0 None None

None 0 None None

LAD,RCA 0 None LAD

Journal of Nuclear Cardiology� Cremer et al

Stress PET to guide revascularization in TAVR

PCI in Severe Aortic Stenosis

Since the advent of TAVR is relatively recent, the

published literature regarding PCI in severe symptomatic

AS is small. A retrospective study recently evaluated the

safety of PCI in severe AS.21 Upon propensity matching to

patients without severe AS, there was no difference in

30 day mortality. In the patients with severe AS, however,

older age, EF less than 30%, and chronic kidney disease

were all predictors of increased 30 day mortality after

PCI. As discussed, these comorbidities were common in

our study. Accordingly, stress cardiac PET could be used

to inform which of these particularly high-risk patients

should undergo revascularization.

Revascularization in Patients UndergoingTAVR

The decision and timing of revascularization in

patients undergoing TAVR are also unclear. Studies

have shown both increased and similar mortality in

patients with and without CAD, though many of these

patients have received revascularization prior to

TAVR.7 There are two specific concerns regarding

PCI in patients undergoing TAVR that warrant mention.

First, blood pressure decreases during rapid pacing at the

time of balloon inflation; hence, patients with unrevas-

cularized CAD may be at the increased risk for

protracted myocardial ischemia and hemodynamic com-

promise. Second, PCI after TAVR could be technically

challenging given difficulty engaging the coronary

arteries due to interference from valve struts and could

likewise be dangerous if manipulation of the struts

dislodges the valve. Consequently, in patients with

significant myocardium at risk, PCI before or at the time

of TAVR may be preferable to initial non-invasive

management of obstructive CAD.

Selecting Patients for Revascularizationwith PET MPI

In patients with stable CAD, retrospective data have

demonstrated improved survival with early revascular-

ization with ischemic or hibernating myocardium

exceeding 10%.22,23 However, randomized controlled

trials that have not systematically incorporated MPI

Table 5. Patient management (n = 50)

Management of suspected or known CAD

Coronary angiography 37 (74%)

Abnormal PET and coronary angiography 36 (72%)

Obstructive CAD 35 (70%)

Abnormal PET and obstructive CAD 35 (70%)

Revascularization 22 (44%)

Revascularization territory guided by PET 20 (40%)

Revascularization despite SDS\6 4 (8%)

Revascularization despite jeopardized

myocardium\10%

3 (6%)

Management of aortic stenosis

Transcatheter AVR 10 (20%)

Surgical AVR 11 (22%)

Balloon aortic valvuloplasty 5 (10%)

Aortic stenosis not severe 13 (26%)

Other exclusion* 11 (20%)

Died waiting for AVR 4 (8%)

*Other exclusions include severe aortic regurgitation (n = 3),very severely reduced EF (n = 2), mitral valve pathology(n = 2), hematologic reason (n = 3), and asymptomatic sta-tus (n = 1)

Figure 3. Coronary anatomy, jeopardized territory on PET,and management of patients with revascularization (n = 22).Blue coronary stenosis[50%; Orange jeopardized territory onPET; Red revascularization to territory jeopardized on PET;Purple revascularization to territory not jeopardized on PET.

Table 4 continued

Anatomic territory Jeopardizedmyocardium

Jeopardizedterritory

Revascularizationterritory

None 0 None None

None 0 None None

None 0 None None

Cremer et al Journal of Nuclear Cardiology�Stress PET to guide revascularization in TAVR

have been negative.24 The ongoing ISCHEMIA trial is

designed to directly answer whether patients with

substantial myocardium at risk benefit from revascular-

ization.25 In patients undergoing TAVR, the

ACTIVATION trial will randomize patients with

obstructive CAD to pre-TAVR PCI vs no PCI.26

However, like the previous randomized trials in stable

CAD, the magnitude of myocardium at risk is not

systematically incorporated in the trial. This design

entails the risk of having an overall negative result, even

though certain patients may benefit, a disconnect that

has been observed in PCI trials when a physiologic

assessment of ischemia using fractional flow reserve

(FFR) is incorporated.24,27

In severe AS, FFR has not been validated. More-

over, our MBF results suggest that these patients have an

impaired hyperemic response to vasodilator. If this

impaired response is due to causes other than an

epicardial stenosis, FFR results can be falsely nega-

tive.28 Finally, FFR can increase contrast volume and

procedural time. Contrast volume and EF \40% have

been associated with acute kidney injury in patients

undergoing TAVR, and acute kidney injury after TAVR

is associated with increased mortality.29 Hence, stress

PET may offer a lower risk and more complete

physiologic assessment to guide revascularization.

Limitations

Our retrospective study from a single center is

small, and involved patients referred specifically for

TAVR. The small numbers limit the safety conclusions,

but given the absence of serious events in this sick

cohort, major adverse cardiac events are unlikely.

Further, while we have shown that PET results generally

inform revascularization at our institution, specific

recommendations regarding when to revascularize were

not evaluated. Likewise, as discussed, the concept of a

threshold of myocardium at risk to determine benefit

from revascularization has not been studied in patients

with severe AS. Given the small size and design of our

study, we cannot comment on whether there is a benefit

of revascularization in these patients. Finally, the

association between rest and stress MBF with increased

mortality is considered hypothesis generating given the

small number of patients, differences in treatment, and

because MBF analysis was not a primary focus of the

study.

CONCLUSIONS

This is the first description of regadenoson vasodi-

lator stress PET in patients with significant AS and

CAD. We have shown that stress testing can be

performed safely in these high-risk patients. Transient

hypotension is relatively common, but is related to

reduced EF and not the severity of aortic valve stenosis.

For our patients, stress PET was accurate and high yield

in directing revascularization. Future study should assess

whether the degree of jeopardized myocardium can

identify patients that realize a benefit from

revascularization.

New Knowledge Gained

Regadenoson stress PET is safe in patients with aortic

stenosis being considered for TAVR. PET results can

accurately direct coronary revascularization. The potential

benefit of PET-guided revascularization prior to TAVR should

be assessed prospectively.

Disclosures

Dr Cerqueira is a consultant and is on the speakers’

bureau for Astellas Pharma USA which manufactures regad-

enoson. No other authors have relevant disclosures.

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Table 6. Patient characteristics and revascularization

Revascularization (n 5 22) No revascularization (n 5 28) P value

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Echocardiographic EF 39 ± 16 39 ± 16 .96

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Jeopardized myocardium* 19% (12%, 26%) 3% (0%, 16%) .002

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Cremer et al Journal of Nuclear Cardiology�Stress PET to guide revascularization in TAVR