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JACC: HEART FAILURE
VOL. 2, NO. 4, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 2213-1779/$36.00
http://dx.doi.org/10.1016/j.jchf.2014.03.009
CLINICAL RESEARCH
Coronary Microvascular Dysfunction
Is Related to Abnormalities in
Myocardial Structure and Function
in Cardiac Amyloidosis
Sharmila Dorbala, MD,*yz Divya Vangala, MA,y John Bruyere JR, MA,y Christina Quarta, MD,z Jenna Kruger, BS,z
Robert Padera, MD,x Courtney Foster, MSC, CNMT,y Michael Hanley, MD,* Marcelo F. Di Carli, MD,*yz
Rodney Falk, MDz
ABSTRACT
OBJECTIVES The purpose of this study was to test the hypothesis that coronary microvascular function is impaired in
subjects with cardiac amyloidosis.
BACKGROUND Effort angina is common in subjects with cardiac amyloidosis, even in the absence of epicardial coronary artery disease (CAD).
METHODS Thirty-one subjects were prospectively enrolled in this study, including 21 subjects with definite cardiac
amyloidosis without epicardial CAD and 10 subjects with hypertensive left ventricular hypertrophy (LVH). All subjects
underwent rest and vasodilator stress N-13 ammonia positron emission tomography and 2-dimensional echocardiography. Global left ventricular myocardial blood flow (MBF) was quantified at rest and during peak hyperemia, and coronary
flow reserve (CFR) was computed (peak stress MBF/rest MBF) adjusting for rest rate pressure product.
RESULTS Compared with the LVH group, the amyloid group showed lower rest MBF (0.59 0.15 ml/g/min vs.
0.88 0.23 ml/g/min; p ¼ 0.004), stress MBF (0.85 0.29 ml/g/min vs. 1.85 0.45 ml/g/min; p < 0.0001), and
CFR (1.19 0.38 vs. 2.23 0.88; p < 0.0001) and higher minimal coronary vascular resistance (111 40 ml/g/min/mm Hg
vs. 70 19 ml/g/min/mm Hg; p ¼ 0.004). Of note, almost all subjects with amyloidosis (>95%) had significantly
reduced peak stress MBF (<1.3 ml/g/min). In multivariable linear regression analyses, a diagnosis of amyloidosis,
increased left ventricular mass, and age were the only independent predictors of impaired coronary vasodilator
function.
CONCLUSIONS Coronary microvascular dysfunction is highly prevalent in subjects with cardiac amyloidosis, even
in the absence of epicardial CAD, and may explain their anginal symptoms. Further study is required to understand
whether specific therapy directed at amyloidosis may improve coronary vasomotion in amyloidosis. (J Am Coll Cardiol HF
2014;2:358–67) © 2014 by the American College of Cardiology Foundation.
From the *Noninvasive Cardiovascular Imaging Program, Heart and Vascular Center, Departments of Radiology and Medicine
(Cardiology), Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; yDivision of Nuclear Medicine and
Molecular Imaging, Department of Radiology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts;
zCardiovascular Division and Cardiac Amyloidosis Program, Department of Medicine, Brigham and Women’s Hospital, Harvard
Medical School, Boston, Massachusetts; and the xDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical
School, Boston, Massachusetts. This study was supported by the Amyloid Foundation, American Society of Nuclear Cardiology
Foundation, National Institutes of Health (National Heart, Lung, and Blood Institute grant K23HL092299), and in part by the
Demarest Lloyd, Jr. Foundation (Dr. Falk). Dr. Dorbala has received a research grant from Astellas Global Pharma Development.
Dorbala et al.
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A
359
Microvascular Dysfunction in Cardiac Amyloidosis
myloidosis is a rare systemic disorder charac-
Table 1). Ten subjects with hypertensive
ABBREVIATIONS
terized by the extracellular deposition of
LVH on 2-dimensional (2D) echocardiography
AND ACRONYMS
misfolded protein in various organ systems,
(LV wall thickness >11 mm) served as con-
including the heart (1,2). Among the several types of
trols. Hypertensive subjects with LVH did not
amyloid fibrils, the light chain and transthyretin am-
have documented kidney disease, peripheral
yloid proteins most commonly affect the heart. Car-
vascular disease, cerebrovascular disease, or
diac amyloid deposits result in increased ventricular
CAD (no history of chest pain, myocardial
CT = computed tomography
wall thickness and produce a restrictive cardiomyop-
infarction, angiographic CAD, or coronary
LV = left ventricular
athy presenting primarily as biventricular congestive
revascularization). Amyloidosis was diag-
LVH = left ventricular
heart
of
nosed by endomyocardial biopsy (n ¼ 10) or
hypertrophy
ischemia have been reported in some patients with
by a positive extracardiac biopsy specimen
MBF = myocardial blood flow
cardiac amyloidosis without obstructive epicardial
with typical features of cardiac involvement
PET = positron emission
coronary artery disease (CAD) (3–6). Autopsy studies
on 2D transthoracic echocardiography (n ¼ 11)
tomography
have shown amyloid deposits around and between
(e.g., wall thickness measurements >11 mm,
2D = 2-dimensional
failure.
Anginal
symptoms
and
signs
AL = amyloid light chain
CAD = coronary artery disease
CFR = coronary flow reserve
cardiac myocytes in the interstitium (7), the perivas-
bright echogenic myocardium, and echocardiographic
cular regions (8), and the media of intramyocardial
evidence of diastolic dysfunction). All biopsy speci-
coronary vessels (9,10). Amyloidosis is thus a prime
mens stained positive for amyloid with either
example of a disorder with the potential to cause cor-
sulfated alcian blue or congo red stain, and amyloid
onary microvascular dysfunction via 3 major mecha-
typing was determined by a battery of stains,
nisms: structural (amyloid deposition in the vessel
including immunoperoxidase stain for transthyretin
wall causing wall thickening and luminal stenosis),
and immunofluorescence stain for immunoglobulins
extravascular (extrinsic compression of the microvas-
G, M, A, kappa, lambda, protein A, and transthyretin.
culature from perivascular and interstitial amyloid
In equivocal cases, biopsy specimens underwent
deposits and decreased diastolic perfusion), and
proteomics evaluation.
functional (autonomic and endothelial dysfunction).
This
study
was
approved
by
the
Partners
Accordingly, we sought to test the hypothesis that
Human Research Committee. All study subjects were
coronary flow reserve (CFR), a measure of microvas-
prospectively enrolled, provided written informed
cular function, is reduced in subjects with cardiac
consent, and underwent evaluation of coronary
amyloidosis without evidence of epicardial CAD.
microvascular function by a research test and vasodi-
Next, we sought to explore the hypothesis that
lator stress N-13 ammonia positron emission tomog-
reduced CFR is a function of increased myocardial
raphy/computed tomography (PET/CT) (except for 3
mass and increased left ventricular (LV) filling pres-
subjects with LVH who underwent clinical N-13
sures and is associated with subclinical abnormalities
ammonia PET/CT). Obstructive epicardial CAD was
in LV systolic dysfunction (strain). Therefore, our pri-
carefully excluded in all subjects with amyloidosis by
mary aim was to study coronary microvascular func-
coronary angiography, as described in the following
tion in subjects with cardiac amyloidosis compared
text. All subjects also underwent 2D transthoracic
with subjects with hypertensive left ventricular hy-
echocardiography with strain analysis to study cardiac
pertrophy (LVH). Our secondary aim was to study
morphology and function. Detailed characterization of
the morphological and functional correlates of coro-
the amyloid subtype was available for all subjects with
nary microvascular dysfunction in subjects with car-
amyloidosis, including staining of biopsy specimens.
diac amyloidosis.
PET. Rest and vasodilator stress N-13 ammonia PET/
CT was performed by using standard protocols and
METHODS
standard preparation (see the Online Appendix).
Imaging of all subjects was performed with a whole
PATIENT
COHORT. We
prospectively enrolled 31
body PET/CT scanner (Discovery Lightspeed VCT 64;
subjects into 2 study groups. The amyloid group
GE Healthcare, Milwaukee, Wisconsin) after an over-
consisted of 21 subjects with confirmed light chain
night fast. Rest N-13 ammonia images were obtained
(n ¼ 15) or transthyretin (n ¼ 6) amyloidosis using
for 20 min in 2D list mode after intravenous injection
pre-defined inclusion and exclusion criteria (Online
of N-13 ammonia (w20 mCi). One hour after rest
Dr. Di Carli has received a research grant from Gilead Sciences. All other authors have reported that they have no relationships
relevant to the contents of this paper to disclose. Ms. Vangala and Mr. Bruyere contributed equally to this work.
Manuscript received January 14, 2014; revised manuscript received February 24, 2014, accepted March 7, 2014.
Dorbala et al.
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perfusion imaging, vasodilator stress was performed
Global LV myocardial blood flow (MBF) (ml/g/min)
by using a standard infusion of adenosine (n ¼ 9),
was quantified at rest and during peak hyperemia
dipyridamole (n ¼ 18), or regadenoson (n ¼ 4). At peak
by using a previously validated one-compartment
hyperemia, a second dose of N-13 ammonia (w20 mCi)
model (12) and commercially available software
was given intravenously and stress images were
(FlowQuant, University of Ottawa Heart Institute,
recorded in the same manner. The estimated whole
Ottawa, Canada). CFR was computed as the ratio of
body effective radiation dose for the rest and stress N-
stress MBF to rest MBF and is referred to as CFR*
13 ammonia PET/CT study was 5.4 mSv. Images were
throughout this report. CFR was adjusted for rest rate
interpreted semiquantitatively and independently by
pressure product and computed as the ratio of stress
2 experienced observers (interobserver reliability
MBF to normalized rest MBF (rest MBF/rest rate
kappa: 0.95) (11) by using a standard 17-segment model
pressure product) , 10,000, and is referred to as CFR
and a 5-point (0–4) scoring system. The global sum-
throughout this report. Coronary vascular resistance,
med stress score, summed rest score, and summed
the ratio of mean arterial pressure to MBF at rest
difference score (the difference between the summed
(maximal coronary vascular resistance) and peak hy-
stress score and summed rest score) were computed.
peremia (minimal coronary vascular resistance) was
A summed stress score >0 was considered abnormal.
also calculated. Reduced peak stress MBF, reduced
CFR, and increased minimal coronary vascular resistance were considered to represent coronary micro-
T A B L E 1 Baseline Data on Patient Characteristics and Hemodynamics
LVH Group (n ¼ 10)
Age, yrs
62.6 12.3
Female
60
Body mass index, kg/m2
33.5 6.4
Amyloid Group (n ¼ 21)
61.7 9.5
38
25.4 3.1
vascular dysfunction. Stress MBF images from one
p Value
subject in the amyloid group were uninterpretable
0.8
due to poor counts.
0.3
CORONARY ANGIOGRAPHY. Epicardial obstructive
<0.0001
CAD was excluded in all subjects with amyloidosis by
Hypertension
100
43
0.002
Dyslipidemia
60
33
0.2
Diabetes
30
5
0.05
Chest pain
20
24
0.8
the PET study) reports were reviewed, and only sub-
Dyspnea
30
62
0.09
jects with <70% CAD in all coronary arteries were
Jaw claudication
0
15
0.6
invited to participate in the study. All except one
Buttock claudication
0
5
0.7
NYHA functional class $II
subject with amyloidosis underwent coronary angi-
0
45
40
19
coronary angiography. Clinically performed invasive
coronary angiography (a median of 164 days before
Symptoms
<0.0001
Medications
Beta-blockers
clinical invasive coronary angiography or research CT
0.2
ography to exclude CAD within the 2-year window
(1 patient underwent coronary angiography within
ACE inhibitors
50
10
0.01
3 years). In 9 subjects with amyloidosis, research CT
Diuretics
60
62
0.9
coronary angiography was performed within a me-
Aspirin
90
19
<0.0001
Cholesterol medications
60
24
0.05
ECG
Limb-lead voltage, mm
9.0 2.5
5.7 1.9
<0.0001
Chest-lead voltage, mm
12.6 5.0
9.4 2.9
0.03
Atrial fibrillation/flutter
14
26
69 16
72 10
Rest systolic BP, mm Hg
Rest RPP, beats/min $ mm Hg
Rest diastolic BP, mm Hg
Stress heart rate, beats/min
Stress systolic BP, mm Hg
Stress RPP, beats/min $ mm Hg
Stress diastolic BP, mm Hg
Delta heart rate, beats/min
tocols (Online Appendix).
ECHOCARDIOGRAPHY. All subjects underwent 2D
transthoracic echocardiography within a median of
1 day (interquartile range: 31 to þ24 days) of the
PET
Hemodynamics
Rest heart rate, beats/min
dian of 1 day of the PET study with standard pro-
0.5
149 22
114 15
<0.0001
10,298 3,173
8,169 1,358
0.01
74 15
67 9
0.1
study.
Digitally
acquired
echocardiography
images in DICOM format with acceptable image
quality (n ¼ 27) were uploaded and processed using
vendor-independent offline 2D Cardiac Performance
Analysis software (TomTec Imaging System, Munich,
81 17
77 15
148 22
101 18
<0.0001
12,094 3,627
7,790 2,302
<0.0001
75 15
58 11
0.001
Throughout this report, we use the term “strain” to
0.06
represent LV strain.
0.04
PRIMARY OUTCOME MEASURES. The primary out-
12 12
Delta systolic BP, mm Hg
0.6 12
Delta RPP, beats/min $ mm Hg
1,795 1,761
4 9.7
13 16
379 14,840
0.5
0.001
Values are mean SD or %.
ACE ¼ angiotensin-converting enzyme; BP ¼ blood pressure; ECG ¼ electrocardiography; LVH ¼ left ventricular hypertrophy; NYHA ¼ New York Heart Association; RPP ¼ rate pressure product.
Germany) to compute peak LV longitudinal, radial,
and circumferential strain values (Online Appendix).
come measures of this study were peak stress MBF,
CFR, and minimal coronary vascular resistance.
STATISTICAL ANALYSIS. The characteristics of the
subjects are described as mean SD compared with
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Microvascular Dysfunction in Cardiac Amyloidosis
the Student t test. Nonparametric variables are
listed as medians and compared with the MannWhitney U test. Discrete variables are described
as proportions and compared with the chi-square
test. Correlations were performed using Pearson R
or nonparametric methods (Spearman rho) as indicated. Multivariable linear regression analyses were
performed to study the independent contributions of
various parameters on stress MBF, CFR, and minimal
coronary vascular resistance. A parsimonious model
with stepwise forward selection (probability of F for
entry of 0.05 and for removal of 0.10) was performed
to minimize model overfitting.
RESULTS
Baseline data on patient characteristics and hemodynamics are listed in Table 1. Notably, the amyloid
group had lower body mass than the LVH group and
38% were women. Approximately one-half of the
amyloid group had a history of New York Heart Association functional class $II heart failure. The amyloid group had ischemic symptoms of chest pain
(24%), shortness of breath (62%), and jaw or buttock
claudication (20%) with clinical evidence of autonomic (19%) or peripheral neuropathy (19%), proteinuria suggesting renal involvement (14%), or
amyloid deposition in the liver (5%). Nine of the 15
subjects with amyloid light chain (AL) amyloidosis
received
specific
chemotherapy
for
amyloidosis
F I G U R E 1 Rest and Vasodilator Stress N-13 Ammonia PET Images From a Subject With
Familial Transthyretin Amyloidosis
before this study. As expected, the mean limb lead
and chest lead electrocardiographic voltage was lower
in the amyloid group compared with the LVH group.
REGIONAL MYOCARDIAL PERFUSION. A variety of
perfusion patterns (no ischemia to severe ischemia)
(A) Mildly abnormal N-13 ammonia myocardial perfusion images from a subject with
transthyretin amyloidosis. (B) CT coronary angiogram and histopathology images. The
images are shown in short axis, horizontal long axis, and vertical long axis projections and
demonstrate a reversible perfusion defect in the mid and basal septum despite normal
epicardial coronary arteries on CT coronary angiography. The coronary flow reserve was 1.3
(significantly impaired). The low-power photomicrograph of the myocardial biopsy spec-
and high-risk scan findings (transient cavity dilation
imen (H&E stain) shows near complete loss of myocytes with extensive amyloid deposition.
and right ventricular tracer uptake) were observed in
The second and third high-power photomicrographs (H&E and sulfated alcian blue stains,
the amyloid group (Fig. 1, Online Fig. 1). In the amy-
respectively) show a small vessel in which the lumen has been obliterated by vascular
loid group, despite no epicardial CAD, 57% of the
amyloid deposition. ANT ¼ anterior; CT ¼ computed tomography; H&E ¼ hematoxylin and
subjects (12 of 21) had ischemic scans; 3 subjects
had severe ischemia. High-risk scan features, such as
increased right ventricular tracer uptake (62%; 13
eosin; HLA ¼ horizontal long axis; INF ¼ inferior; LAD ¼ left anterior descending coronary
artery; LAT ¼ lateral; LCX ¼ left circumflex coronary artery; OM ¼ obtuse marginal coronary artery; PET ¼ positron emission tomography; RCA ¼ right coronary artery; SA ¼
short axis; SAB ¼ sulfated Alcian Blue; SEP ¼ septum; VLA ¼ vertical long axis.
of 21 subjects) and transient cavity dilation of the
left ventricle on the post-stress images (76%; 16 of
21 subjects), were frequently seen. The mean transient cavity dilation ratio was significantly higher
in the amyloid group than in the LVH group (1.18 0.12 vs. 1.04 0.18; p ¼ 0.03). None of the
subjects with LVH had perfusion defects on the N-13
ammonia study.
group (rest MBF: 0.59 0.15 ml/g/min vs. 0.88 0.23 ml/g/min [p ¼ 0.004]; stress MBF: 0.85 0.29
ml/g/min vs. 1.85 0.45 ml/g/min [p < 0.0001];
CFR: 1.19 0.38 vs. 2.23 0.88 [p < 0.0001]; CFR*:
1.44 0.36 vs. 2.20 0.67 [p < 0.0001]) (Table 2).
Because the LVH group had significantly lower LV
CORONARY VASOMOTOR FUNCTION. The mean rest
mass than the amyloid group, we normalized the
MBF, stress MBF, CFR, and CFR* were significantly
rest MBF, stress MBF, and CFR to LV mass as fol-
lower in the amyloid group compared with the LVH
lows: (MBF or CFR/LV mass) , 100. The values for
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extracellular volume fraction may be expanded and
T A B L E 2 Results of Rest and Stress Myocardial Perfusion Imaging
LVH Group
(n ¼ 10)
the functioning myocardial mass as estimated by
Amyloid Group
(n ¼ 21)
p Value
Myocardial perfusion imaging
Summed stress score, mean rank
echocardiography may thus be lower in the amyloid
group compared with control subjects (22). Hence,
we performed sensitivity analysis assuming a func-
11
18
0.018
Summed difference score, mean rank
12.7
17.6
0.173
tioning myocardial mass of 0.50 and 0.75; stress
Summed rest score, mean rank
13.5
17.2
0.306
MBF was significantly lower at an LV mass of 0.75
(trend to lower stress MBF at an LV mass of 0.5), and
62.7 20
49 8
0.01
Rest MBF, ml/g/min
0.88 0.23
0.59 0.15
<0.0001 to 0.004
Rest MBF*, ml/g/min
0.92 0.34
0.73 0.20
0.07
Rest MBF per unit LV mass
0.47 0.19
0.22 0.16
0.001
Stress MBF, ml/g/min
1.85 0.45
0.85 0.29
<0.0001
Stress MBF per unit LV mass
1.00 0.42
0.34 0.29
<0.0001
CFR
2.23 0.88
1.19 0.38
<0.0001
maximal hyperemia (111 40 ml/g/min/mm Hg
CFR*
2.20 0.67
1.44 0.36
<0.0001
vs. 70 19 ml/g/min/mm Hg; p ¼ 0.004). All except
CFR per unit LV mass†
2.20 0.67
1.20 0.38
<0.0001
one of the subjects in the amyloid group had a signif-
Rest LV ejection fraction, %
MBF
CFR values remained significantly lower in the amyloid
group.
Coronary
vascular
resistance
was
significantly higher in the amyloid group compared
with the LVH group at rest (147 41 ml/g/min/mm Hg
vs. 117 28 ml/g/min/mm Hg; p ¼ 0.05) and during
Maximal CVR, ml/g/min/mm Hg
117 28
147 41
0.05
70 19
111 40
icantly reduced peak stress MBF of <1.3 ml/g/min.
Minimal CVR, ml/g/min/mm Hg
0.004
The patterns of distribution of quantitative rest and
Values are n or mean SD. *Unadjusted for rest rate pressure product; all stress values are also unadjusted for
rest rate pressure product. †CFR per unit LV mass remained the same for an assumed LV mass of 0.5 or 0.75 of
functioning myocardial tissue.
CFR ¼ coronary flow reserve; CVR ¼ coronary vascular resistance; LV ¼ left ventricular; MBF ¼ myocardial
blood flow; other abbreviations as in Table 1.
stress MBF were significantly different with much
lower stress MBF values in the amyloid group
compared with the LVH group (Online Fig. 2). Finally,
rest MBF, stress MBF, CFR, and minimal coronary
vascular resistance did not differ in subjects with AL
amyloidosis compared with subjects with trans-
rest MBF, peak stress MBF, and CFR per unit LV
thyretin amyloidosis.
mass were significantly lower in the amyloid group
compared with the LVH group (Fig. 2), suggesting
CARDIAC MORPHOLOGICAL AND FUNCTIONAL PARAMETERS
differences independent of LV mass. The myocardial
IN THE STUDY GROUPS. Morphologically, despite lower
voltage QRS complexes on electrocardiography, the
mean LV wall thickness and mass were higher in the
amyloid group than in the LVH group (Table 3),
consistent with amyloid deposition in the LV myocardium. We also reviewed the available myocardial
biopsy specimens from 8 subjects in the amyloid
group. Microscopically, while one specimen was
inadequate, perivascular amyloid deposits (Fig. 1B)
were found in 5 of 8 subjects; the amyloid burden
ranged from 10% to 70%. Functionally, although the
mean E/A ratio was similar, the e0 and a 0 (early and late
mitral annular tissue relaxation velocities) were
significantly lower and the E/e0 ratio was significantly
higher in the amyloid group, likely related to restrictive heart disease from amyloid infiltration. Also, the
maximal left atrial size (4.5 0.6 cm vs. 3.8 0.6 cm;
p ¼ 0.003) and left atrial volume indexed to body
surface area (40.5 13.4 ml/m 2 vs. 23.2 9.6 ml/m 2;
F I G U R E 2 Mean Rest and Stress MBF as Well as CFR per Unit
LV Mass in the LVH and Amyloid Groups
p ¼ 0.002) were significantly higher in the amyloid
group than in the LVH group, suggesting greater
chronic left atrial hypertension with or without amy-
The rest MBF was higher in the LVH group. Peak stress MBF, CFR
(CFR unadjusted)*, and CFR values were significantly lower in
the amyloid group than in the LVH group. CFR ¼ coronary flow
reserve; LV ¼ left ventricular; LVH ¼ left ventricular hypertrophy;
MBF ¼ myocardial blood flow; other abbreviations as in Table 1.
loid atrial disease. Finally, the mean longitudinal
strain (but not circumferential strain) was significantly
lower in the amyloid group than in the LVH group
(11.50 2.99 vs. 17.78 3.41; p < 0.0001), particularly at the base and the midventricular regions (Fig. 3),
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Microvascular Dysfunction in Cardiac Amyloidosis
consistent with previous reports of greater mid and
basal contractile impairment.
ASSOCIATIONS
BETWEEN
LV
STRUCTURE
T A B L E 3 Cardiac Morphological Features in the Study Groups
LVH Group
(n ¼ 10)
AND
CORONARY VASCULAR FUNCTION. We found that
Wall thickness, cm
1.33 0.13
parameters of coronary microvascular function were
LV mass, g
inversely correlated to increased LV mass (Fig. 4),
LV end-diastolic diameter, cm
increased diastolic filling pressures, and subclinical
LV end-systolic diameter, cm
Amyloid Group
(n ¼ 20)
p Value
1.80 0.36
<0.0001
204 64
335 123
0.004
4.1 1.0
4.1 0.7
0.89
2.8 0.9
2.9 0.6
0.48
59.5 7.0
53.9 12.3
0.19
Peak E velocity, m/s
0.9 0.4
0.8 0.2
0.52
Peak A velocity, m/s
0.9 0.4
2.8 8.2
0.46
stress MBF and CFR were lower in the amyloid group
Peak E/A ratio
1.4 1.6
1.6 0.8
0.69
than in the LVH group (Fig. 4). The mean e 0 , a0 , and E/e 0
Average e0 velocity, cm/s
0.08 0.03
0.05 0.01
0.001
ratio were inversely related to stress MBF, CFR, and
Average a0 velocity, cm/s
0.05 0.02
<0.0001
minimal coronary vascular resistance (Table 4). Sub-
E/e0 ratio
17.98 8.06
0.045
clinical systolic dysfunction (mean LV longitudinal
Left atrial size, cm
systolic dysfunction. Notably, in the few subjects with
an LV mass of <300 g, for any given degree of LV mass,
strain) was linearly related to rest MBF, stress MBF,
CFR, minimal coronary vascular resistance, and LV
LV ejection fraction, %
Left atrial volume index, ml/m2
Longitudinal strain, global
Circumferential strain
mass (Table 4, Fig. 5). In stepwise forward multiple
linear regression models (R ¼ 0.87; p < 0.0001)
including rest MBF, stress MBF, LV mass, and presence
0.1 0.02
11.99 5.2
3.79 0.55
4.52 0.57
0.003
23.21 9.62
40.48 13.44
0.002
17.78 3.41
23.09 0.5.66
11.50 2.99
<0.0001
25.38 7.17
0.49
Values are mean SD. Echocardiogram was unevaluable for 1 subject in the amyloid group.
Abbreviations as in Tables 1 and 2.
of amyloid, only LV mass (beta ¼ 0.21; p < 0.0001) and
amyloid (beta ¼ 2.3; p ¼ 0.04) were significant inde-
impaired coronary microvascular flow in our subjects
pendent predictors of impaired longitudinal strain.
was almost universal and similar regardless of the
MULTIVARIABLE CORRELATES OF MBF, CFR, AND
underlying type of amyloid deposits (light chain or
CORONARY VASCULAR RESISTANCE. Cardiac amy-
transthyretin). Minimal coronary vascular resistance
loidosis was associated with worse coronary micro-
was markedly increased in the amyloid group; with
vascular function independent of LV mass, age, and
stress, substantial reductions in stress MBF and
subclinical myocardial dysfunction. On separate
CFR were found when compared with the hyperten-
stepwise forward multiple linear regression analyses
sive LVH group. Coronary microvascular dysfunction
for rest MBF, stress MBF, CFR, and minimal coronary
was associated with several classic imaging features
vascular resistance, we adjusted for known con-
of cardiac amyloidosis such as increased LV mass
founders including age, LV mass, and mean longitu-
and myocardial relaxation abnormalities such as
dinal strain. In these models (rest MBF model: R ¼ 0.65;
p < 0.001; stress MBF model: R ¼ 0.89; p < 0.0001; CFR
model: R ¼ 0.75; p < 0.0001 and minimal coronary
vascular resistance: R ¼ 0.50; p ¼ 0.009), cardiac
amyloidosis was independently associated with lower
rest MBF (beta ¼ 0.645; p < 0.0001), stress MBF
(beta ¼ 0.801; p < 0.0001), and CFR (beta ¼ 0.665;
p < 0.0001) and higher minimal coronary vascular
resistance (beta ¼ 0.5; p ¼ 0.009). Older age was an
independent predictor of lower CFR (beta ¼ 0.386;
p ¼ 0.01), and higher LV mass was an independent
predictor of lower stress MBF (beta ¼ 0.001; p ¼ 0.03).
DISCUSSION
We prospectively studied coronary microvascular
function in the absence of epicardial CAD in subjects
F I G U R E 3 Longitudinal Strain at the Base, Midventricle,
and Apex
with documented cardiac amyloidosis. The findings
of
our
study
provide
novel
insights
into
the
morphological correlates of coronary microvascular
Mean longitudinal strain at the base, midventricle, and apex
in the LVH group compared with the amyloid group. Mean
longitudinal strain was significantly reduced in the amyloid
dysfunction and underscore the role of microvas-
group compared with the LVH group only in the base and
cular dysfunction as a probable mechanism for
midventricular regions. Abbreviations as in Figure 2.
anginal
symptoms
in
these
subjects.
Of
note,
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Dorbala et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:358–67
Microvascular Dysfunction in Cardiac Amyloidosis
F I G U R E 4 Relationship Between LV Mass and Rest MBF, Stress MBF, CFR, and Minimal CVR in the Study Groups
The relationship between LV mass and rest MBF, stress MBF, CFR, and CVR in the LVH group (green) and the amyloid group (red) is shown. LV
mass was lower in the LVH group than in the amyloid group. However, at similar degrees of LV mass, subjects in the amyloid group had lower
rest MBF, stress MBF, and CFR and higher minimal CVR. Abbreviations as in Figure 2. CVR ¼ coronary vascular resistance.
low mitral annular relaxation velocities, high left
correlation between longitudinal dysfunction and
atrial pressures (E/e 0 ), and impaired longitudinal
microvascular impairment. However, only the pres-
myocardial strain. Taken together, these findings
ence of amyloidosis and higher LV mass were inde-
allow us to postulate that amyloid deposits in the
pendent determinants of lower longitudinal strain,
interstitium and perivascular regions of the heart
suggesting a relation mediated via higher amyloid
increase coronary microvascular resistance and LV
burden. Koyama and Falk (13) showed that reduced
filling pressures leading to coronary microvascular
longitudinal strain is associated with worse survival
dysfunction and may explain a greater vulnerability
in subjects with AL amyloidosis. Indeed, our findings
to ischemia and subclinical impairment of LV sys-
combined with those of Koyama and Falk suggest that
tolic function.
coronary microvascular dysfunction from higher am-
Longitudinal strain is often severely and disproportionately
reduced
in
patients
with
cardiac
amyloidosis. Because the majority of longitudinal fi-
yloid mass may be the mechanistic link between
impaired longitudinal strain and worse survival in
subjects with AL amyloidosis.
bers are subendocardial and this area of the myocar-
Increased wall thickness from amyloid deposition
dium is most vulnerable to ischemia, it might be
in the heart may impede subendocardial perfusion
postulated that disturbed microvascular function
due to vascular rarefaction and compression. Higher
plays a role in longitudinal impairment. Support for
LV mass was related to microvascular dysfunction and
this hypothesis comes from our finding of univariable
to reduced rest MBF and reduced longitudinal strain.
Dorbala et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:358–67
Microvascular Dysfunction in Cardiac Amyloidosis
T A B L E 4 Univariable Correlations Between Cardiac Morphological Features and Myocardial Blood Flow Parameters in the Study Groups
Rest MBF
Variable
LV mass, g
LVED diameter, cm
Stress MBF
R Value
p Value
R Value
0.49
0.006
0.60
0.03
0.8
0.005
LVES diameter, cm
0.21
0.3
0.20
LV wall thickness, cm
0.59
0.001
0.66
LV ejection fraction, %
0.25
0.2
p Value
0.001
0.9
0.3
<0.0001
CFR
R Value
0.41
CVR
p Value
0.03
R Value
0.44
p Value
0.02
0.9
0.05
0.8
0.09
0.6
0.12
0.5
0.47
0.009
0.54
0.0004
0.22
0.3
0.06
0.8
0.05
0.003
0.8
Peak E velocity, m/s
0.23
0.2
0.07
0.7
0.09
0.6
0.007
0.9
Peak A velocity, m/s
0.07
0.8
0.031
0.9
0.03
0.9
0.19
0.4
E/A ratio
0.23
0.3
0.19
0.4
0.07
0.7
0.29
0.1
0.50
0.006
0.67
<0.0001
Mean e0 velocity, cm/s
Mean a0 velocity, cm/s
0.24
0.3
0.49
0.008
0.41
0.02
0.004
0.49
0.01
0.55
E/e0 ratio
0.13
0.5
0.47
0.01
0.47
0.01
0.42
0.03
Indexed left atrial volume, ml/m2
0.32
0.11
0.48
0.01
0.31
0.13
0.36
0.07
0.67
<0.0001
0.44
0.03
0.12
0.6
0.56
0.002
Longitudinal strain, global
0.60
0.001
Circumferential strain
0.07
0.7
0.03
0.9
ECG: limb lead voltage, mm
0.43
0.02
0.48
0.009
0.51
0.004
ECG: chest lead voltage, mm
0.27
0.2
0.23
0.2
0.33
0.07
0.48
0.11
0.39
0.08
0.01
0.6
0.04
0.7
ED ¼ end diastolic; ES ¼ end systolic; other abbreviations as in Tables 1 and 2.
F I G U R E 5 Relation Between Left Ventricular Longitudinal Strain and Rest, Stress Myocardial Blood Flow, Coronary Flow Reserve
and Minimal Coronary Vascular Resistance in the Study Groups
The relationship between mean longitudinal LV strain and rest MBF, stress MBF, CFR, minimal CVR, and LV mass in the LVH group (green)
and the amyloid group (red) is shown. Abbreviations as in Figures 2 and 4.
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Dorbala et al.
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Microvascular Dysfunction in Cardiac Amyloidosis
Although these findings reinforce the notion that
the p values presented were not corrected for multiple
higher LV mass contributes to coronary microvascular
testing. Further, because of excellent blood pressure
dysfunction, rest MBF, stress MBF, and CFR normal-
control in the current era, hypertensive LVH without
ized to LV mass were also significantly lower in the
other end-organ damage is rare, limiting our enroll-
amyloid group compared with the LVH group.
ment of patients with hypertensive cardiomyopathy
This finding, along with the high frequency of vascular
to subjects without severe LVH. Therefore, we studied
amyloid deposition in a small sample of subjects in our
CFR values normalized to LV mass (including assumed
study, argues for additional mechanism(s), such as the
functioning LV mass of 0.5 and 0.75), and they were
role of vascular amyloid deposition (Fig. 1B), presum-
significantly lower in the amyloid group. Some of the
ably resulting in mechanical impairment of micro-
subjects in the amyloid group received specific ther-
vascular vasodilation and angina.
apy for amyloidosis before study enrollment, poten-
Additionally, autonomic dysfunction (either covert
tially attenuating the effects of amyloid on MBF.
or overt) is prevalent in transthyretin and in
However,
AL amyloidosis manifesting clinically with abnormal
observed between the study groups, suggesting a large
vascular autonomic (sympathetic) modulation and
effect size and strengthening the study findings.
impaired baroreflex function (14). Autonomic dener-
Although the precise clinical implications of all our
vation limits stress MBF and CFR, primarily via
findings are not known, we believe that they may
norepinephrine-mediated mechanisms and also by
explain some of the functional limitations and poor
changes in metabolic autoregulation and endothe-
prognosis seen in patients with cardiac amyloidosis.
significant
differences
in
MBF
were
lial dysfunction in diabetic autonomic dysfunction
(15–17). Although not specifically evaluated in this
CONCLUSIONS
study, autonomic dysfunction may also contribute to
microvascular dysfunction in amyloidosis.
Coronary vasodilation and minimal coronary vascular
Coronary microvascular dysfunction has been
resistance are significantly impaired in subjects with
described in hypertrophic and infiltrative heart dis-
cardiac amyloidosis even in the absence of epicardial
eases, including hypertensive heart disease, aortic
CAD. Our findings suggest that increased myocardial
stenosis, hypertrophic cardiomyopathy, and Fabry
amyloid burden (mass) correlates with microvascular
disease (18). Microvascular dysfunction in these dis-
dysfunction. Because increased amyloid mass is as-
eases may be mechanistically related to coronary
sociated with more widespread cardiac disease, it is
microvascular remodeling, rarefaction and interstitial
likely that vascular amyloid deposits also play a role.
fibrosis (hypertensive heart disease), small-vessel
An additional role of autonomic dysfunction in coro-
disease, relatively reduced capillary density, in-
nary microvascular dysfunction remains speculative
creased LV end-diastolic pressures and systolic
and needs to be further explored. Coronary micro-
compression of the septal coronary arteries (19), or
vascular dysfunction in amyloidosis also correlates
increased LV mass (20). Some or all of these mecha-
with diastolic dysfunction and subclinical systolic
nisms may explain the coronary vasomotor dysfunc-
dysfunction. Successful hematologic treatment of AL
tion in cardiac amyloidosis. The magnitude of the
amyloidosis is associated with a decrease in cardiac
microvascular dysfunction in our patients with
biomarkers before a change in standard echocardio-
amyloidosis is not only more severe than those seen
graphic features. Thus, further study is required to
in hypertensive disease but is also more severe than
determine if coronary microvascular function may im-
previously reported data in dilated cardiomyopathy
prove after specific therapy for cardiac amyloidosis.
(21) and Fabry disease (20,22).
A C K N O W L E D G M E N T S The
STUDY LIMITATIONS. To the best of our knowledge,
subjects who participated in this study and their
this is the first prospective study to characterize
colleagues at the Brigham and Women’s Hospital
coronary microvascular function noninvasively in
Cardiac Amyloidosis Program and the Boston Uni-
carefully selected subjects with cardiac amyloidosis
versity Amyloidosis Program.
authors
thank
the
and no obstructive epicardial CAD. In this study,
detailed characterization of epicardial coronary anat-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
omy and microvascular function was performed to
Sharmila Dorbala, Noninvasive Cardiovascular Imag-
distinguish microvascular dysfunction from flow-
ing Program, Heart and Vascular Center, Departments
limiting epicardial CAD. The study size was modest
of Radiology and Medicine (Cardiology), Brigham
because of our stringent inclusion and exclusion
and Women’s Hospital, 70 Francis Street, Shapiro 5th
criteria and the relative rarity of cardiac amyloidosis
Floor, Room 128, Boston, Massachusetts 02115.
and may have limited the multivariable models. Also,
E-mail: [email protected].
Dorbala et al.
JACC: HEART FAILURE VOL. 2, NO. 4, 2014
AUGUST 2014:358–67
Microvascular Dysfunction in Cardiac Amyloidosis
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