Download Reduced Myocardial Flow in Heart Failure Patients With Preserved

Original Article
Reduced Myocardial Flow in Heart Failure Patients With
Preserved Ejection Fraction
Kajenny Srivaratharajah, MD; Thais Coutinho, MD; Robert deKemp, PhD; Peter Liu, MD;
Haissam Haddad, MD; Ellamae Stadnick, MD; Ross A. Davies, MD; Sharon Chih, MD;
Girish Dwivedi, MD; Ann Guo, MSc; George A. Wells, MD; Jordan Bernick, MSc;
Robert Beanlands, MD*; Lisa M. Mielniczuk, MD*
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Background—There remains limited insight into the pathophysiology and therapeutic advances directed at improving
prognosis for patients with heart failure with preserved ejection fraction (HFpEF). Recent studies have suggested a role
for coronary microvascular dysfunction in HFpEF. Rb-82 cardiac positron emission tomography imaging is a noninvasive,
quantitative approach to measuring myocardial flow reserve (MFR), a surrogate marker for coronary vascular health.
The aim of this study was to determine whether abnormalities exist in MFR in patients with HFpEF without epicardial
coronary artery disease.
Methods and Results—A total of 376 patients with ejection fraction ≥50%, no known history of obstructive coronary artery
disease, and a confirmed diagnosis of heart failure (n=78) were compared with patients with no evidence of heart failure
(n=298), further stratified into those with (n=186) and without (n=112) hypertension. Global and regional left ventricular
MFR was calculated as stress/rest myocardial blood flow using Rb-82 positron emission tomography. Patients with
HFpEF were more likely to be older, female, and have comorbid hypertension, diabetes mellitus, dyslipidemia, atrial
fibrillation, anemia, and renal dysfunction. HFpEF was associated with a significant reduction in global MFR (2.16±0.69
in HFpEF versus 2.54±0.80 in hypertensive controls; P<0.02 and 2.89±0.70 in normotensive controls; P<0.001). A
diagnosis of HFpEF was associated with 2.62 times greater unadjusted odds of having low global MFR (defined as <2.0)
and remained a significant predictor of reduced global MFR after adjusting for comorbidities.
Conclusions—HFpEF, in the absence of known history for obstructive epicardial coronary artery disease, is
associated with reduced MFR independent of other risk factors. (Circ Heart Fail. 2016;9:e002562. DOI: 10.1161/
CIRCHEARTFAILURE.115.002562.)
Key Words: comorbidity
■
coronary circulation
■
echocardiography
H
eart failure (HF) with preserved ejection fraction
(HFpEF) was recognized as a separate entity from systolic HF or HF with reduced ejection fraction >30 years ago.1
However, it continues to be one of the largest unmet needs in
cardiovascular medicine.2 During the past 5 to 10 years, many
advances have been made in the understanding of HFpEF
pathogenesis, including abnormalities in diastolic function,
arterial stiffness, ventricular–arterial coupling, endothelial
function, and chronotropic incompetence, among others.3–5
Despite these advances, HFpEF remains a clinical syndrome
without effective preventive or therapeutic options, as all
randomized clinical trials in the field have yielded neutral or
negative results to date.
■
heart failure
■
positron emission tomography
Recently, experts have proposed a paradigm shift in the
pathophysiology of HFpEF, suggesting that this syndrome
results from a sequence of events initiated by a comorbiditydriven proinflammatory state associated with microvascular
dysfunction, which in turns promotes left ventricular hypertrophy, remodeling, fibrosis, and stiffness.6 Subsequently, this
hypothesis has been strengthened by a postmortem study that
demonstrated that patients with HFpEF have lower left ventricular coronary microvascular density than controls with
noncardiac causes of death.7 In addition, a recent exercise
hemodynamic study of HFpEF patients demonstrated reduced
peak transcardiac oxygen gradient suggesting the possibility
of impaired myocardial oxygen delivery in HFpEF patients as
a cause of abnormal diastolic flow reserve.8
Cardiac positron emission tomography (PET) is a noninvasive quantitative imaging modality that is capable of
See Editorial by Mohammed et al
See Clinical Perspective
Received June 30, 2015; accepted May 12, 2016.
From the Division of Cardiology, University of Ottawa Heart Institute, Ontario, Canada.
*Drs Beanlands and Mielniczuk are co-senior authors.
The Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.115.002562/-/DC1.
Correspondence to Lisa M. Mielniczuk, MD, Division of Cardiology, University of Ottawa Heart Institute 40 Ruskin St, Ottawa, Ontario, Canada K1Y
4W7. E-mail [email protected]
© 2016 American Heart Association, Inc.
Circ Heart Fail is available at http://circheartfailure.ahajournals.org
DOI: 10.1161/CIRCHEARTFAILURE.115.002562
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2 Srivaratharajah et al Reduced MFR in HFpEF
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accurately quantifying myocardial flow reserve (MFR), the
ratio of myocardial blood flow (MBF) at peak stress to MBF
at rest, which in turn represents the vasodilatory reserve of the
coronary circulation. In patients without significant epicardial
disease, MFR can be considered a marker of microvascular
function and a surrogate for coronary vascular health.9,10 In
addition, MFR has been shown to have prognostic value in
patients with suspected epicardial coronary artery disease
(CAD),11 and in the absence of CAD, changes in MFR reflect
alterations in coronary microvascular function.
Given the gaps in knowledge about potential in vivo abnormalities in coronary microvascular function in patients with
HFpEF, this study was designed to evaluate MFR in HFpEF
patients undergoing clinically indicated cardiac PET imaging,
in the absence of significant epicardial CAD. We hypothesized
that MFR would be reduced in HFpEF patients compared with
controls without HF, representing microvascular dysfunction.
Methods
Study Design and Patients
A retrospective database review of quantitative MBF and MFR in
patients referred for cardiac PET at the University of Ottawa Heart
Institute between May 2010 and September 2013 was conducted. The
final sample size was determined after 3 levels of screening to identify
patients with HFpEF and controls (Figure I in the Data Supplement).
At the first level, subjects undergoing clinically indicated PET who
had data available for quantification of MFR, with ejection fraction
≥50% and summed stress score <4 (suggestive of low likelihood of
obstructive epicardial CAD)11–13 were considered eligible for further
screening (1169 subjects). At the second level of screening, subjects
were further subdivided into controls, based on absence of HF or dyspnea (n=405) and those with possible HF (n=764), based on New
York Heart Association (NYHA) symptom classification ≥1. The
third level of screening involved the adjudication of a diagnosis of
HFpEF by detailed review of medical records. Of note, no stringent
criteria were used to identify and exclude those patients in the study
with significant left-sided valvular heart disease or infiltrative cardiomyopathy. A final diagnosis of HFpEF was established when all
3 criteria were met: (1) NYHA ≥1 class symptoms, (2) left ventricle
ejection fraction ≥50% at the time of PET evaluation, and (3) confirmed diagnosis of HFpEF from medical records. This included any
of a consultant diagnosis or a visit or admission to hospital for HF.
The presence of clinical HF was adjudicated by a reviewer blinded
to imaging data. Any subject with evidence of epicardial CAD was
excluded from the study. This included any of (1) abnormal perfusion summed stress score (SSS ≥4), (2) documented history of myocardial infarction, angina, acute coronary syndrome, or myocardial
revascularization from review of the medical records, (3) coronary
angiography or computed tomography angiography demonstrating a
significant degree of coronary artery obstruction (≥70% luminal obstruction), the latter of which was available in ≈12% of those designated as having HFpEF. Because hypertension is the most prevalent
comorbidity among HFpEF patients, controls were subdivided into
hypertensive and normotensive based on self-reporting at the time of
PET scan. After this detailed review, a total of 78 HFpEF subjects and
298 non-HF controls (112 normotensive and 186 hypertensive) were
included in the study. The study was approved by the University of
Ottawa Heart Institute’s Research Ethics Board, and study subjects
provided informed consent.
PET Imaging Protocol
Rb-82 PET imaging protocol has been described previously.14,15 In
short, patients were positioned in a Discovery 690 or RX PET-CT
system (GE Healthcare, Waukesha, WI). After a low-dose computed
tomography scan acquired for attenuation correction,14,15 10 MBq/kg
of Rb-82 was administered intravenously as a 30-second square-wave
using a feedback-controlled elution system (Jubilant DraxImage,
Montreal, QC). Dynamic Rb-82 PET images were acquired during
10 minutes using a list-mode acquisition.
After the rest PET acquisition, dipyridamole (0.14 mg/kg/min for
5 minutes) was administered to induce vasodilation for stress imaging. Rb-82 infusion was initiated at the 3-minutes mark after completion of the dipyridamole infusion. Dynamic images were acquired
as per rest imaging. A low-dose computed tomography scan was repeated after stress imaging for attenuation correction.
Dynamic, static, and gated images were reconstructed using the
vendor iterative algorithm (VuePoint HD) with 8, 12, and 16 mm
Hann postfilter, respectively, as previously described.14,15
Image Interpretation
Semi-quantitative perfusion analysis was based on the static images,
performed by nuclear cardiology experts blinded to clinical data. A
standard 17-segment (5-point) model was used to score the extent
and severity of relative perfusion defects in the whole heart and also
divided into left anterior descending artery, left circumflex artery, and
right coronary artery territories. The summed stress score, summed
rest score, and summed difference score were calculated. Corridor4DM software (INVIA, Ann Arbor, MI) was used to determine left
ventricle ejection fraction during rest and peak stress.
Automated FlowQuant software (Ottawa, Ontario, Canada) was
used to reorientate images and define myocardial and left ventricle
cavity time–activity curves. Polar maps of absolute MBF at rest and
poststress were generated. MFR was calculated as the ratio of the
stress/rest MBF11,15,16 (Figure II in the Data Supplement for sample
Rubidium-82 PET myocardial perfusion and flow quantification images in a 57-year-old female patient with HFpEF).
Echocardiographic Analysis
To determine the relationship between MFR and echocardiographic parameters of diastolic dysfunction in this study cohort,
we identified subjects with transthoracic 2D and Doppler echocardiogram performed within 6 months of the PET scan. Subjects
with mitral stenosis, severe mitral regurgitation, or severe mitral
annular calcification were excluded from these analyses, because
these conditions make diastolic assessment inaccurate. A total of
115 subjects were eligible and included in the echocardiographic
analysis. The detailed methodology and results can be found in the
Data Supplement.
Statistical Analyses
Mean and SD were calculated for continuous variables, whereas frequencies and percentages were determined for categorical variables.
Continuous variables were compared between HFpEF subjects,
normotensive controls, and hypertensive controls using one-way
ANOVA with post hoc Tukey procedure to determine the significance
of pairwise comparisons, whereas categorical variables were compared using χ2 test. Pearson correlation coefficients were used to assess the relationship of left ventricular mass and echocardiographic
parameters of diastolic function with MFR.
To determine whether the presence of HFpEF was an independent
predictor of lower global and regional MFR, we performed multivariable linear regression analyses using global MFR, left anterior descending artery MFR, left circumflex artery, MFR, and right coronary
artery MFR (in separate models) as dependent variables and presence
of HFpEF as an independent variable. In addition, multivariate logistic regression was used to identify significant predictors of a low
global MFR, which was defined as <2 on the basis of previous studies
suggesting lower normal limits between 2 and 2.5.10,17 Models were
adjusted for the following parameters: age, sex, body mass index,
mean arterial pressure, heart rate, and history of hypertension, diabetes mellitus, dyslipidemia, statin use, atrial fibrillation, and smoking. All analyses were performed using IBM SPSS statistic software
(versions 22–23), and statistical significance was defined as P≤0.05
(2 sided).
3 Srivaratharajah et al Reduced MFR in HFpEF
Table 1. Baseline Clinical Characteristics
Variable
Age, y
HFpEF (n=78)
Hypertensive Control (n=186)
Normotensive Control (n=112)
P Value
68±9
63±11
58±10
<0.001*
0.001†
Sex
0.034‡
Male
21 (27)
80 (43)
38 (34)
Female
57 (73)
106 (57)
74 (66)
34±8
33±8
30±9
Body mass index, kg/m2
0.005*
0.531†
NYHA classification (1–4)
No dyspnea
No dyspnea
…
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1
42 (54)
…
…
…
2
24 (31)
…
…
…
3
10 (13)
…
…
…
4
2 (2)
…
…
…
Chest pain
35 (47)
88 (49)
59 (54)
…
Dyspnea
26 (35)
11 (6)
8 (7)
…
Preoperative
7 (9)
35 (20)
12 (11)
…
Arrhythmia
0 (0)
11 (6)
6 (6)
…
Other
7 (9)
34 (19)
24 (22)
…
23 (29)
62 (33)
9 (8)
<0.001‡
Reason for scan
Diabetes mellitus
IDDM
7 (30)
11 (18)
1 (11)
NIDDM
16 (70)
51 (82)
8 (89)
Dyslipidemia
51 (65)
135 (73)
39 (35)
<0.001‡
0.300‡
Smoking
39 (50)
101 (54)
50 (45)
Current
7 (18)
24 (24)
16 (32)
Past
32 (82)
77 (76)
34 (68)
HbA1c, %
6.7±1.7
6.7±1.5
6.2±1.4
Hemoglobin, g/L
128±15
133±19
137±13
0.322*
0.998†
0.004*
0.167†
Serum creatinine, µmol/L
95±51
90±83
70±20
0.044*
0.863†
Medications
ACE inhibitor
43 (57)
113 (62)
7 (6)
<0.001‡
Antiarrhythmic
5 (7)
2 (1)
1 (1)
0.010‡
ARB
3 (4)
11 (6)
0 (0)
0.033‡
ASA
46 (61)
99 (54)
47 (43)
0.035‡
7 (9)
8 (4)
4 (4)
0.181‡
Plavix
Coumadin
11 (15)
9 (5)
3 (3)
0.003‡
β-Blocker
30 (40)
58 (32)
13 (12)
<0.001‡
Ca blocker
24 (32)
58 (32)
4 (4)
<0.001‡
Digoxin
2 (3)
2 (1)
2 (2)
0.652‡
Diuretic
47 (63)
72 (39)
5 (5)
<0.001‡
(Continued )
4 Srivaratharajah et al Reduced MFR in HFpEF
Table 1. Continued
Variable
HFpEF (n=78)
Hypertensive Control (n=186)
Normotensive Control (n=112)
P Value
Statin
50 (67)
117 (64)
36 (33)
<0.001‡
Nitrates
8 (11)
6 (3)
1 (1)
0.003‡
Insulin
22 (29)
61 (33)
6 (5)
<0.001‡
Nitroglycerin, sublingual,
when necessary
10 (13)
24 (13)
11 (10)
0.644‡
Family history of CAD
38 (51)
93 (51)
50 (45)
0.624‡
Pre menopausal
3 (7)
10 (12)
13 (24)
Post menopausal
42 (93)
73 (88)
41 (76)
Atrial fibrillation
16 (21)
19 (10)
7 (6)
Estrogen status
0.006‡
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Values are represented as mean±SD or n (%). ACE indicates angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA,
acetylsalicylic acid; CAD, coronary artery disease; HbA1c, hemoglobin A1c; HFpEF, heart failure with preserved ejection fraction; IDDM, insulindependent diabetes mellitus; NIDDM, non–insulin-dependent diabetes mellitus; and NYHA, New York Heart Association.
*P value comparing HFpEF to normotensive controls (post hoc Tukey test).
†P value comparing HFpEF to hypertensive controls (post hoc Tukey test).
‡P value comparing HFpEF, normotensive controls, and hypertensive controls in χ2 analysis.
Results
Baseline Characteristics of HFpEF Versus Non-HF
Controls
Table 1 shows the characteristics of subjects included in the
study. The vast majority of these patients were referred for
chest pain (≈50%). The remaining patients were referred for
dyspnea (35% of those with HFpEF), preoperative assessment
(mostly prebariatric surgery in those with cardiac risk factors),
arrhythmia, and other nonclassic indications, such as abnormal
screening exercise stress test, methoxy-isobutyl-isonitrile scan,
or ECG in asymptomatic patients. The mean age was 63±11
years, and 63% were women, of whom 66% were post menopausal. Approximately 85% of those in the HFpEF group had
NYHA class 1 to 2 symptoms with the remaining 13% and 2%
falling into NHYA classes 3 and 4, respectively. The prevalence of hypertension was higher in the HFpEF cohort when
compared with the non-HF control group (78% versus 62%;
P=0.006). Patients with HFpEF were also more likely to be
older, female, and have renal dysfunction, dyslipidemia, diabetes mellitus, atrial fibrillation, relative obesity, and anemia
when compared with normotensive controls. Medication use
reported at the time of PET scan is shown in Table 1. There
was a greater use of antihypertensive medications, diuretics,
antiplatelet agents, anticoagulant, and insulin in the HFpEF
group compared with controls, which is not surprising given
the relatively higher prevalence of comorbid hypertension,
atrial fibrillation, and diabetes mellitus in this group.
Table 2 outlines baseline PET parameters of subjects
included in the study (please also refer to Table I in the Data
Supplement containing baseline echocardiographic parameters of the study subjects). There was no statistical difference between the summed stress score of HFpEF compared
with controls (hypertensive or normotensive; P=0.466). In
fact, more than three fourth of patients in either group had a
summed stress score of 0. No statistical difference was seen
between mean heart rate and mean arterial pressure (rest or
stress) documented at the time of the PET scan. Resting MBF
was significantly greater in the HFpEF group compared with
normotensive controls. The resting rate pressure product was
also significantly higher in HFpEF compared with normotensive controls. Importantly, stress MBF, on the contrary, was
significantly lower in the HFpEF group compared with that in
the normotensive controls. These values in the hypertensive
control group were not significantly different from either the
HFpEF or normotensive controls, albeit a trend toward significance was noted in stress MBF in hypertensive versus normotensive controls.
MFR in HFpEF Versus Non-HF Controls
HFpEF was associated with lower global and regional MFR
than non-HF controls (Table 3). The mean global MFR was
2.16±0.69 in HFpEF, which was significantly lower compared with 2.54±0.80 (P=0.001) in hypertensive controls and
2.89±0.70 (P<0.001) in normotensive controls. When data were
further stratified on the basis of NYHA class subgroups (no
dyspnea or control group versus classes 1–2 versus 3–4), MFR
decreased as HF severity increased (Table 3). The mean global
MFR was 2.67±0.78 in non-HF controls, 2.21±0.71 (P<0.001)
in HFpEF subjects with NYHA class 1–2 symptoms, and
1.88±0.53 (P<0.005) in HFpEF subjects with NYHA class 3–4
symptoms. The presence of HFpEF was significantly associated
with reduced global MFR independently of potential confounders including age, sex, and history of hypertension and diabetes
mellitus (Table 4). The results of logistic regression analyses to
determine the effect of HFpEF and other covariates on the presence of low global MFR (<2.0) revealed that HFpEF was associated with an unadjusted 2.62 times greater odds (P<0.001)
of having a global MFR <2.0. After adjustment for summed
stress score, rest and stress HR, mean arterial pressure, age, sex,
and history of smoking, diabetes mellitus, dyslipidemia, hypertension, atrial fibrillation, and statin use, the odds of having a
global MFR <2.0 was 1.40 (P=0.279) for patients with HFpEF.
The global and regional MFR was also determined for the
628 patients excluded from the HFpEF group on the basis of
5 Srivaratharajah et al Reduced MFR in HFpEF
Table 2. Baseline Imaging Characteristics
Cardiac PET Parameters
Resting LVEF, %
HFpEF (n=78)
Hypertensive Control (n=186)
Normotensive Control (n=112)
P Value
62±7
61±7
62±7
0.883*
0.862†
SSS (0–3)
0.466‡
0
60 (77)
147 (79)
1
9 (12)
19 (10)
9 (8)
2
6 (8)
11 (6)
3 (3)
3
3 (4)
9 (5)
2 (2)
72±15
71±13
69±13
Resting HR, beats per min
98 (88)
0.193*
0.772†
Resting MAP, mm Hg
92±13
92±13
88±12
0.134*
1.000†
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Stress HR, beats per min
86±21
87±13
90±15
0.256*
0.915†
Stress MAP, mm Hg
98±17
101±16
96±14
0.501*
9800±2678
9314±2410
8432±2060
<0.001*
0.440†
Rate pressure product (rest)
0.302†
Rate pressure product (stress)
12 278±3912
12 344±2790
11 723±2637
0.445*
0.986†
Resting MBF, mL/min/g
0.92±0.26
0.84±0.35
0.79±0.25
0.021*
0.153†
0.439§
Stress MBF, mL/min/g
1.90±0.61
1.99±0.65
2.16±0.54
0.011*
0.487†
0.055§
Global MFR, stress/rest ratio
<0.001‡
<2.0
31 (40)
49 (26)
11 (10)
≥2.0
47 (60)
137 (74)
101 (90)
Values are represented as mean±SD or n (%). HFpEF indicates heart failure with preserved ejection fraction; HR, heart rate; LVEF, left
ventricle ejection fraction; MAP, mean arterial pressure; MBF, myocardial blood flow; MFR, myocardial flow reserve; PET, positron emission
tomography; and SSS, summed stress score.
*P value comparing HFpEF to normotensive controls (post hoc Tukey test).
†P value comparing HFpEF to hypertensive controls (post hoc Tukey test).
‡P value comparing HFpEF, normotensive controls, and hypertensive controls in χ2 analysis.
§P value comparing hypertensive to normotensive controls (post hoc Tukey test).
no documented clinical evidence of HF despite presence of
NYHA class ≥1. The MFR of these excluded patients was significantly greater than patients with a confirmed diagnosis of
HFpEF (global MFR 2.80±0.87 versus 2.16±0.69; P<0.001)
and not significantly different from the controls (P=0.092). A
small subset (9 out of the 78 HFpEF patients) had obstructive CAD excluded via invasive coronary angiography or
noninvasive computed tomography angiography. The MFR
of this subset was not significantly different from the HFpEF
patient cohort with no documented angiogram (global MFR
2.25±0.76 versus 2.15±0.69; P=0.679; Table 3).
Baseline echocardiographic data and analysis of global
and regional MFR in those with identified echocardiographic
evidence of diastolic dysfunction can be found in Table I in the
Data Supplement and Table 5, respectively. When MFR was
compared between those with any level of diastolic dysfunction
(grades 1–4, regardless of the presence of HF) and normal diastolic function, a significant reduction was noted in the former
(global MFR 2.03±0.55 in those with any degree of diastolic
dysfunction versus 2.83±0.69 with no diastolic dysfunction;
P<0.001; Table 5). Please refer to the Data Supplement for full
details on echocardiographic methodology and results.
Discussion
This study demonstrated reduced MFR in patients with a
diagnosis of HFpEF when compared with hypertensive and
6 Srivaratharajah et al Reduced MFR in HFpEF
Table 3. Global and Regional MFR in HFpEF, Controls, and a Subset of Excluded Patients
Global MFR
Regional MFR
LV
LAD
LCx
RCA
2.16±0.69*†‡§
2.20±0.71*†‡§
2.09±0.67*†‡§
2.16±0.71*†‡§
NYHA 1–2 (n=66)
2.21±0.71*†‖
2.26±0.73*†‖
2.13±0.68*†‖
2.22±0.73*†‖
NYHA 3–4 (n=12)
HFpEF
All (n=78)
1.88±0.53*†‖
1.90±0.51*†‖
1.89±0.64*†‖
1.83±0.49*†‖
Statin use (n=50)
2.18±0.74
2.24±0.76
2.10±0.71
2.18±0.75
No statin use (n=25)
2.11±0.62
2.13±0.63
2.07±0.60
2.12±0.65
Previous angiogram (n=9)
2.25±0.76
2.29±0.80
2.24±0.69
2.20±0.82
No documented angiogram (n=69)
2.15±0.69
2.19±0.70
2.08±0.67
2.16±0.70
All (n=298)
2.67±0.78
2.71±0.81
2.61±0.77
2.68±0.79
Normotensive control (n=112)
2.89±0.70
2.95±0.74
2.81±0.72
2.86±0.69
Hypertensive control (n=186)
2.54±0.80
2.56±0.82
2.49±0.78
2.57±0.82
NYHA class ≥1, excluded¶ (n=628)
2.80±0.87
2.85±0.90
2.70±0.85
2.79±0.86
Controls
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Values are represented as mean±SD. HF indicates heart failure; HFpEF, heart failure with preserved ejection fraction; LAD, left
anterior descending artery; LCx, left circumflex artery; LV, left ventricle; MFR, myocardial flow reserve; NYHA, New York Heart
Association; and RCA, right coronary artery.
*P<0.001 when compared with normotensive controls (post hoc Tukey test).
†P<0.05 when compared with hypertensive controls (post hoc Tukey test).
‡P<0.001 when compared with all controls.
§P<0.001 when compared with 628 excluded patients.
‖P<0.005 when compared with all controls (post hoc Tukey test).
¶Analysis of the 628 patients excluded from the HFpEF group because of no clinical documentation of HF.
normotensive controls in the absence of a known history of
obstructive epicardial CAD. The relationship of reduced MFR
to presence of HFpEF was independent of age, sex, hypertension, smoking status, diabetes mellitus, dyslipidemia, body
mass index, statin use, baseline angina history, and presence
of atrial fibrillation. To the best of our knowledge, this is the
first report of (1) cardiac PET demonstrating abnormal MFR
in individuals with HFpEF and (2) inferred in vivo coronary
microvascular dysfunction in a large sample of individuals with HFpEF with no known history of obstructive CAD.
These results contribute toward a better understanding of the
pathogenic processes predisposing to HFpEF, an important
step in the development of novel diagnostic, preventative, and
therapeutic strategies for this condition.
Mechanistically, 2 potential explanations for impaired
MFR in HFpEF include (1) abnormal microvascular function and (2) an absolute decrease in the number of resistance
vessels of the microcirculation. Systemic and local vascular
responses to exercise have been demonstrated to be abnormal
in HFpEF patients, implicating microvascular dysfunction in
this group.4,18 In addition, an autopsy study by Mohammed
et al7 on those with antemortem diagnosis of HFpEF showed
a greater prevalence of microscopic hypertrophy and fibrosis
in this group. This study found lower coronary microvascular density in those with HFpEF and an inverse relationship
between microvascular density and myocardial fibrosis. Thus,
reduced MFR may promote the development of the HFpEF
syndrome through the development of fibrosis and hypertrophy. A review by Paulus and Tschöpe6 further supports this
view by proposing that coronary artery microvascular inflammation and dysfunction as a downstream consequence of a
proinflammatory cascade leads to hypertrophy and myocyte
stiffening, resulting in HFpEF. After this, van Empel et al8
showed that measured exercise transcardiac oxygen gradient was significantly lower in HFpEF patients compared with
healthy and hypertensive controls, suggesting impaired myocardial oxygen delivery (presumably because of microvascular dysfunction, although epicardial coronary arteries were
not assessed) in this group. To further validate this possibility,
we proposed examining MFR in a cohort of patients who had
undergone clinically indicated PET scans at our institution.
MFR has been studied as a surrogate for coronary vascular health. In fact, MFR has been shown to have prognostic value in those with hypertrophic cardiomyopathy, cardiac
transplantation, and suspected epicardial CAD.11,15,19 Cardiac
PET evaluation of patients with hypertrophic cardiomyopathy
demonstrated that reduced MFR was a significant predictor of
systolic dysfunction and increased end-diastolic left ventricle
dimensions, identifying the prognostic importance of reduced
MFR and progressive HF in these patients.19 McArdle et al15
showed that MFR was a significant predictor of a composite
of all-cause death, acute coronary syndrome, and hospitalization for HF in those ≥12 months postcardiac transplantation.
Similarly, Ziadi et al11 demonstrated that low MFR (<2.0)
was a significant predictor of hard events (cardiac death and
myocardial infarction) and major adverse cardiac events (cardiac death, myocardial infarction, late revascularization, and
cardiac hospitalization) in those being evaluated for cardiac
7 Srivaratharajah et al Reduced MFR in HFpEF
Table 4. Multivariate Linear Regression Analysis Examining
Global MFR as Continuous Dependent Variable Modeled
Against Comorbidities Including HFpEF
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 13, 2017
β±SE
P Value
HFpEF
−0.213±0.094
0.025
Age
−0.021±0.004
<0.001
Female sex
−0.113±0.076
0.136
Body mass index
−0.003±0.005
0.444
Smoking history
0.015±0.072
0.840
Diabetes mellitus
−0.012±0.087
0.887
Hypertension
−0.101±0.084
0.231
Hyperlipidemia
−0.080±0.147
0.587
SSS (3 vs 0)
−0.105±0.183
0.097
Resting HR
−0.032±0.004
<0.001
Stress HR
0.015±0.004
<0.001
Resting MAP
−0.003±0.004
0.473
Stress MAP
−0.000±0.003
0.867
Statin use
0.117±0.144
0.418
Angina history
0.070±0.085
0.410
Atrial fibrillation
−0.0275±0.116
0.812
HFpEF indicates heart failure with preserved ejection fraction; HR, heart rate;
MAP, mean arterial pressure; MFR, myocardial flow reserve; and SSS, summed
stress score.
ischemia. Subsequently, a larger study conducted by Murthy
et al20 showed that in all patients referred for cardiac PET
imaging with suspected or known CAD, MFR values in the
lowest tertile (MFR <1.5) were associated with higher 3-year
cardiac mortality and risk of cardiac death compared with
those with MFR in the highest tertile (MFR >2). Global MFR
has also been studied in patients with renal insufficiency and
was noted to be impaired in this population despite normal
regional perfusion and left ventricle function.21
To our knowledge, this is the first study to demonstrate
reduced MFR using PET imaging in patients with HFpEF,
extending and supporting recent work in this area. In this study,
we showed that MFR was significantly lower in HFpEF than in
controls, and more pronounced in HFpEF subjects with severe
symptomatic HF (NYHA functional class 3–4). The presence of
HFpEF was a strong independent predictor of global MFR. In
addition, global MFR was significantly reduced in the presence
of echocardiographic evidence of diastolic dysfunction. Whether
reduced MFR has a causal or consequential role in the severity
of diastolic dysfunction cannot be determined from this study.
A diagnosis of HFpEF was associated with an unadjusted 2.62
times increased odds of having reduced global MFR (defined
as <2.0). The loss of significance in odds after adjustment for
variables, such as age, sex, hypertension, and diabetes mellitus,
may be because of statistical power and sample size or possibly
reflect other unidentified confounders affecting the relationship
between MFR and HFpEF. Previous studies have demonstrated
that MFR <2.0 is associated with a significant increase in the
risk of cardiac events and death.11,21,22 In addition to adding
pathophysiologic insight into associations of HFpEF, the results
of this study justify further research to determine if MFR may
represent a novel prognostic risk factor for patients with HFpEF.
There was a stepwise decrease in MFR when comparing
normotensive controls to hypertensive controls to patients
with HFpEF. This finding is consistent with recent work by
our group demonstrating a relationship between reduced MFR
and higher pulsatile arterial load in older hypertensive women,
who are at highest risk for HFpEF (T. Coutinho, et al, unpublished data, 2016). Thus, hypertension and hemodynamic load
may adversely affect the coronary microvasculature, a mechanism that could predispose to HFpEF. Taken together, these
results support the role for microvascular dysfunction in the
pathophysiology of HFpEF.
Resting MBF was significantly higher in HFpEF compared
with normotensive controls. This likely reflects increased resting metabolic demand, as supported by the significantly higher
resting rate pressure product. It is unlikely that resting flow
values alone explain the reduced MFR in HFpEF. This is supported by the observation that the percentage difference in
mean global flow MFR for HFpEF versus normotensive controls is greater than the percentage difference between rest flow
in these groups. More importantly, stress flow is significantly
reduced in HFpEF compared with normotensive controls.
Blunted vasodilator response of coronary microvascular bed to
acetylcholine in HFpEF as a result of coronary microvascular
endothelial inflammation has been previously described6 and
can account for the lower stress MBF noted in this group.
There are currently no therapies to directly and selectively
target patients with HFpEF. Large clinical trials examining
the role of various therapeutic agents, such as β-blockers,23–26
angiotensin receptor blockers,27,28 aldosterone antagonists,29,30
digoxin,31 and phosphodiesterase type 5 inhibitors,32 in HFpEF
have yielded neutral or negative results. Some trials have shown
a trend toward benefit including less HF hospital admissions
in Candestartan in Hart Failure: Assessment of Mortality and
Morbidity (CHARM)-preserved and Treatment of Preserved
Cardiac Function Heart Failure with an Aldosterone Antagonist
(TOPCAT).27,30 The Prospective Comparison of ARNI With
ARB on the Management of Heart Failure with Preserved
Ejection Fraction (PARAMOUNT) trial showed a reduction in
N terminal prohormone of brain natriuretic peptide-brain natriuretic peptide with use of LCZ696, a first-in-class angiotensin
receptor–neprilysin inhibitor; however, its clinical effects are
currently under study.33 Studies that examined the benefit of
statin therapy in HFpEF have been equivocal.34,35 This study
also shows that there was no difference in MFR in patients
with or without background statin use. Whether there is a role
for statin therapy introduced early in the course of HFpEF,
the optimal dose, and compliance were not addressed in this
study. At present, the mainstay long-term treatment of HFpEF
remains aggressive risk factor modification and diuresis in
decompensated patients. Given the lack of HFpEF therapeutic
options, deeper understanding of its pathophysiology is needed
to control this syndrome and improve outcomes. Our study
shows that HFpEF is associated with abnormal MFR, a surrogate of microvascular dysfunction. Whether this represents
a potential novel prognostic marker or can serve as a novel
therapeutic target in HFpEF needs to be elucidated in further
mechanistic and prospective studies.
8 Srivaratharajah et al Reduced MFR in HFpEF
Sources of Funding
Table 5. Global and Regional MFR in the Presence or
Absence of Diastolic Dysfunction
Global MFR
LV
Regional MFR
LAD
LCx
RCA
Any diastolic
dysfunction*
2.03±0.55† 2.04±0.56† 1.99±0.55†
2.06±0.56†
Normal diastolic
function
2.83±0.69
2.79±0.65
2.86±0.70
2.82±0.76
Values are represented as mean±SD. LAD indicates left anterior descending
artery; LCx, left circumflex artery; LV, left ventricle; MFR, myocardial flow
reserve; and RCA, right coronary artery.
*Indeterminate diastolic function excluded.
†P<0.001 when compared with those with normal diastolic function.
Study Limitations
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 13, 2017
The main limitation of this study includes the single-center,
cross-sectional, and retrospective design (which limits us
from making inferences on the causality and temporality of
the associations noted herein). However, it provides a novel
description and foundation on which to base future prospective studies. In addition, the diagnosis of HFpEF and CAD was
dependent on the adequacy and availability of medical records.
Objective measures such as echocardiographic data at time of
study inclusion and BNP values may have offered more robust
enrollment criteria. Despite this, the MFR of the 628 patients
excluded from the study, with no documented evidence of
HFpEF diagnosis despite having an NYHA classification ≥1,
was similar to the control group and significantly greater than
the HFpEF cohort. In addition, the MFR was similar in HFpEF
patients regardless of whether CAD was excluded from evidence of angiography (available in only 12% of subjects) or
medical records. Echocardiographic data were available in
≈54% of HFpEF subjects within 6 months of initial PET scan,
and the observed relationships between echocardiographic
assessment of diastolic function and diagnosis of HFpEF support the classification schema used in this study. This study
included a referral population, presumably with greater burden
of comorbidities, and thus, referral bias cannot be excluded. In
addition, many subjects in this study were referred for symptoms of angina, and this may not reflect a cohort of HFpEF
patients not referred for a PET study. However, the prevalence
of cardiovascular comorbidities such as hypertension, diabetes mellitus, and dyslipidemia was comparable to that seen in
similarly aged adults from the general population,36 improving
the generalizability of our findings. Finally, the findings are
limited by the lack of reported outcome data; however, these
results confirm and extend previous work in this area and justify further prospective, outcome-based studies.
Conclusions
Microvascular dysfunction, represented here by reduced MFR,
is present in HFpEF and may serve as a diagnostic, screening,
or therapeutic target in this population. Longitudinal studies
are needed to clarify the prognostic role of MFR in HFpEF.
To this end, quantification of blood flow using PET may serve
as a beneficial tool for risk stratification and prognostication
in this population and may add further insight into the pathophysiology of this disease.
Dr Mielniczuk is a clinician scientist supported by Heart and Stroke
Foundation of Ontario. Dr Beanlands is a career investigator supported
by the Heart and Stroke Foundation of Ontario, Tier 1 Research Chair
supported by the University of Ottawa, and University of Ottawa.
Heart Institute Vered Chair in Cardiology. The study was supported in
part by the Canadian Institute of Health Research IMAGE HF Team
grant. Dr Beanlands is principal investigator and Dr Mielniczuk is
co-principal investigator of IMAGE HF IA study.
Disclosures
Dr deKemp is a consultant for and has received grant funding from
Jubilant DraxImage and receives revenues from Rubidium-82 generator technology licensed to Jubilant DraxImage and from sales of
FlowQuant software. Dr Beanlands is or has been a consultant for
and receives grant funding from GE Healthcare, Lantheus Medical
Imaging, and Jubilant DraxImage.
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Clinical Perspective
Despite a high prevalence and known significant morbidity and mortality, heart failure with preserved ejection fraction
remains a disease with unclear mechanisms and no targeted evidence-based therapies. The first step to determine potential
therapeutic choices is to further elucidate the pathophysiology of this entity. To this end, we have shown here that myocardial flow reserve, a surrogate measure for myocardial inflammation, is significantly reduced in those with heart failure with
preserved ejection fraction compared with controls, in the absence of a known history of obstructive epicardial coronary
artery disease. Further study is warranted to determine the prognostic value of this and whether or not this has a role in the
diagnosis or risk stratification of these patients or can serve as a potential treatment target.
Reduced Myocardial Flow in Heart Failure Patients With Preserved Ejection Fraction
Kajenny Srivaratharajah, Thais Coutinho, Robert deKemp, Peter Liu, Haissam Haddad, Ellamae
Stadnick, Ross A. Davies, Sharon Chih, Girish Dwivedi, Ann Guo, George A. Wells, Jordan
Bernick, Robert Beanlands and Lisa M. Mielniczuk
Downloaded from http://circheartfailure.ahajournals.org/ by guest on May 13, 2017
Circ Heart Fail. 2016;9:
doi: 10.1161/CIRCHEARTFAILURE.115.002562
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REDUCED MYOCARDIAL FLOW IN HEART FAILURE PATIENTS WITH
PRESERVED EJECTION FRACTION
Running Title: Reduced MFR in HFpEF
Kajenny Srivaratharajah MD, Thais Coutinho MD, Robert deKemp PhD, Peter Liu MD,
Haissam Haddad MD, Ellamae Stadnick MD, Robert A. Davies MD, Sharon Chih MD,
Girish Dwivedi MD, Ann Guo MSc, George A. Wells MD, Jordan Bernick MSc, Robert
Beanlands MD1, Lisa M. Mielniczuk MD1
Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario
1
denotes co-senior authorship
SUPPLEMENTAL MATERIAL
CIRCHF/2015/002562-T1/ R3
1
Supplementary Methods
a. Study Design and Patients
1169 Patients with EF ≥ 50% and SSS < 4
Control, n= 405
No dyspnea
HFpEF, n=764
NYHA Class ≥ 1
Exclusions:
1) 83 Cardiac transplant
2) 13 significant CAD
3) 11 with documented HF**
Exclusions:
1) 27 Cardiac transplant
2) 35 significant CAD
3) 628 with no documented HF
N=298
Normotensive, n= 112
N=78**
Hypertensive, n= 186
** 4 Controls with HF symptoms
were reassigned to HFpEF group
after chart-review
Figure 1: Retrospective database review study profile.
Data from patients referred for cardiac PET at the University of Ottawa Heart Institute
between May 2010 and September 2013. SSS=Summed stress score, score <4 is
suggestive of low likelihood of coronary artery disease (CAD); EF= Ejection fraction,
cut-off of ≥50% used to exclude those with systolic dysfunction; NYHA= New York
Heart Association classification; HFpEF= Heart failure with preserved ejection fraction;
significant CAD is defined as ≥ 70% luminal stenosis; HF= heart failure.
**Detailed chart review of the 11 patients with EF≥50% without dyspnea but presence of
clinical HF (on the basis of documentation suggesting a consultant diagnosis of, or a visit
or admission to hospital for HF) was undertaken. The majority of these patients were
those who had a previous diagnosis of dilated cardiomyopathy with improved and
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normalized ventricular function. We did not consider these patients as having HFpEF. In
four of these patients, detailed chart review demonstrated a history of fluid retention
requiring Lasix and echocardiographic features of diastolic dysfunction with no evidence
of systolic impairment. These 4 patients were re-classified as having HFpEF.
b. PET imaging interpretation
Figure 2. Rubidium-82 PET myocardial perfusion and flow quantification images in
a 57 year-old female HFpEF patient. Conventional rest and stress perfusion images
(left) appear normal as shown in the standard short-axis (SA), horizontal long-axis (HLA)
and vertical long-axis (VLA) views. Polar-maps of rest and stress perfusion and
stress/rest reserve also appear normal (red = 100% of maximum), whereas the flow
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quantification polar-maps (right) demonstrate uniformly reduced stress/rest flow reserve
~1.8.
c. Echocardiographic analysis
The following parameters were measured according to published guidelines [1] and
recorded: left ventricular septal and posterior wall thickness, end-diastolic and endsystolic left ventricular diameter, left atrial volume index measured by the area/length
method, mitral inflow E/A ratio, deceleration time and tissue Doppler septal and lateral
E’ velocities. Left ventricular mass index was calculated and indexed to body surface
area according to guidelines [1]. Diastolic function was assessed according to the
algorithm proposed by Kane and colleagues [2] except that a left atrial volume index ≥ 32
cc/m2 was used as a second measure of increased filling pressures since it has been
correlated with the presence of diastolic function [3]. According to this modified
algorithm, diastolic dysfunction was graded using the following criteria:
1. Grade 1 (mild) diastolic dysfunction: E/A ratio ≤ 0.75.
2. Grade 2 (moderate) diastolic dysfunction: 0.75 < E/A ratio < 2.0 AND septal
E/e’ ≥ 15 AND LAVI ≥32.
3. Grade 3-4 (severe) diastolic dysfunction: E/A ratio ≥ 2.0 AND septal E/e’ ≥15
AND LAVI ≥32.
4. Normal diastolic function: E/A ratio > 0.75 AND septal E/e’ ≤10 AND LAVI
<32.
5. If none of these criteria were met, diastolic function was classified as
indeterminate.
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Left ventricular filling pressures were assessed from pulmonary capillary wedge pressure
(PCWP) estimation on the basis of echocardiographic data as presented in prior studies
using the following formula: PCWP = 11.96 + 0.596*septal E/e’ [4].
Supplementary Results
Echocardiographic assessment of diastolic function in HFpEF vs. non-HF controls
When echocardiographic parameters were compared between HFpEF and non-HF
controls, significantly higher medial E/e’ ratio and calculated PCWP were noted in the
HFpEF group, suggesting higher left ventricular filling pressures in HFpEF when
compared to normotensive and hypertensive controls. Trends towards increased left
ventricular septal and posterior wall thickness, increased mass index and left atrial
volume index were also noted in the patients with HFpEF when compared to
hypertensive and normotensive controls (Supplemental Table).
Non-adjusted Pearson correlation demonstrated an inverse relationship between the
severity of echocardiographic assessment of left ventricular structure/diastolic function
and global MFR (Medial E/e’ velocity: r=-0.206, p-value 0.03; DT: -0.307, p-value
0.001; E/A ratio: 0.188, p-value 0.048).
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Supplemental Table: Baseline Imaging Characteristics
Echocardiographic Parameters
HFpEF (n=42) Hypertensive
Control
(n=46)
LV septal thickness [mm]
10.6±2.0
9.8±2.1
Normotensive
Control
(n=27)
9.6±2.0
LV posterior wall thickness [mm]
10.2±2.5
9.8±2.0
9.2±1.8
LV end-diastolic diameter [mm]
46.5±5.9
46.5±5.3
46.8±4.3
LV end-systolic diameter [mm]
29.6±6.6
27.7±4.9
29.0±3.4
LV mass index [g/m2]
106.9±33.9
96.4±28.1
93.9±23.9
Left atrial volume index [cc/m2]
30.1±10.6
27.4±8.6
26.4±6.5
PCWP [mmHg]
20.5±3.7
18.5±2.3
17.8±2.1
Mitral inflow E/A ratio
1.0±0.5
1.0±0.4
1.2 ±0.4
Deceleration time [ms]
224.8±64.5
220.0±60.9
198±33.3
Tissue Doppler septal E’ velocity [m/s]
0.06±0.02
0.07±0.02
0.08±0.02
Tissue Doppler lateral E’ velocity [m/s]
0.07±0.02
0.09±0.02
0.11±0.03
Medial E/e’ ratio
14.7±5.8
11.5±3.1
10.2±3.1
Normal diastolic function
4 (10)
10 (22)
14 (52)
Grade 1 diastolic dysfunction
15 (36)
9 (20)
0 (0)
Grade 2 diastolic dysfunction
8 (19)
0 (0)
1 (4)
Grades 3-4 diastolic dysfunction
1 (2)
1 (2)
0 (0)
Any grade diastolic dysfunction
24 (57)
10 (22)
1 (4)
Indeterminate diastolic function
14 (33)
25 (56)
12 (44)
P-value
0.118 *
0.150 †
0.176 *
0.593 †
0.958 *
1.000 †
0.905 *
0.247 †
0.191 *
0.230 †
0.223 *
0.360 †
0.001 *
0.005 †
0.059 *
0.911 †
0.140 *
0.920 †
<0.001 *
<0.001 †
<0.001 *
<0.001 †
<0.001 *
0.003 †
<0.001 ‡
Values are mean ± standard deviation or n (%)
*
P-value comparing HFpEF to normotensive controls (post-hoc Tukey test).
† P-value comparing HFpEF to hypertensive controls (post-hoc Tukey test).
‡ P-value comparing HFpEF, normotensive and hypertensive controls in chi square analysis.
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