Download Comprehensive Bio‐Imaging Using Myocardial Perfusion Reserve

American Journal of Transplantation 2014; 14: 2607–2616
Wiley Periodicals Inc.
C
Copyright 2014 The American Society of Transplantation
and the American Society of Transplant Surgeons
doi: 10.1111/ajt.12924
Brief Communication
Comprehensive Bio-Imaging Using Myocardial
Perfusion Reserve Index During Cardiac Magnetic
Resonance Imaging and High-Sensitive Troponin
T for the Prediction of Outcomes in Heart
Transplant Recipients
N. P. Hofmann1, C. Steuer1, A. Voss2, C. Erbel1,
S. Celik1, A. Doesch1, P. Ehlermann1,
E. Giannitsis1, S. J. Buss1, H. A. Katus1
and G. Korosoglou1,*
1
Department of Cardiology, University of Heidelberg,
Heidelberg, Germany
2
Department of Psychology, University of Heidelberg,
Heidelberg, Germany
Corresponding author: Grigorios Korosoglou,
[email protected]
We sought to determine the ability of quantitative
myocardial perfusion reserve index (MPRI) by cardiac
magnetic resonance (CMR) and high-sensitive troponin
T (hsTnT) for the prediction of cardiac allograft vasculopathy (CAV) and cardiac outcomes in heart transplant
(HT) recipients. In 108 consecutive HT recipients (organ
age 4.1 4.7 years, 25 [23%] with diabetes mellitus) who
underwent cardiac catheterization, CAV grade by
International Society for Heart & Lung Transplantation
(ISHLT) criteria, MPRI, late gadolinium enhancement
(LGE) and hsTnT values were obtained. Outcome data
including cardiac death and urgent revascularization
(‘‘hard cardiac events’’) and revascularization procedures were prospectively collected. During a follow-up
duration of 4.2 1.4 years, seven patients experienced
hard cardiac events and 11 patients underwent elective
revascularization procedures. By multivariable analysis,
hsTnT and MPRI both independently predicted cardiac
events, surpassing the value of LGE and CAV by ISHLT
criteria. Furthermore, hsTnT and MPRI provided complementary value. Thus, patients with high hsTnT and
low MPRI showed the highest rates of cardiac events
(annual event rate ¼ 14.5%), while those with low hsTnT
and high MPRI exhibited excellent outcomes (annual
event rate ¼ 0%). In conclusion, comprehensive ‘‘bioimaging’’ using hsTnT, as a marker of myocardial
microinjury, and CMR, as a marker of microvascular
integrity and myocardial damage by LGE, may aid
personalized risk-stratification in HT recipients.
Abbreviations: CAD, coronary artery disease; CAV,
cardiac allograft vasculopathy; CCT, cardiac computed
tomography; CMR, cardiac magnetic resonance;
hsTnT, high-sensitive troponin T; HT, heart transplant;
IDI, discrimination improvement; ISHLT, International
Society for Heart & Lung Transplantation; IVUS,
intravascular ultrasound; LGE, late gadolinium enhancement; MPRI, myocardial perfusion reserve index;
NTproBNP, N-terminal pro-brain natriuretic peptide;
PCI, percutaneous coronary intervention; ROC, receiver
operating characteristics
Received 11 March 2014, revised 11 June 2014 and
accepted for publication 29 June 2014
Introduction
Despite advances in the immunosuppressive medication
regimes, long-term survival is currently still limited by the
occurrence of cardiac allograft vasculopathy (CAV) (1). To
date, the clinical gold standard for the surveillance of CAV is
X-ray coronary angiography. However, this technique is
invasive, associated with radiation and contrast media
exposure and provides limited information on microvascular
integrity (2).
Conversely, the versatility of cardiac magnetic resonance
(CMR) allows for the evaluation of myocardial function and
perfusion with excellent blood-to-tissue contrast and
without ionizing radiation (3). The high-sensitive troponin
T (hsTnT) on the other hand, is a well-established marker of
cardiovascular risk in patients with coronary artery disease
(CAD) (4) and was recently shown to predict short- and longterm survival in heart transplant (HT) recipients (5).
In our study, we sought to investigate the ability of MPRI
and hsTnT to predict CAV progression over time and cardiac
outcomes in HT recipients.
Methods
Patient characteristics
We prospectively studied 108 consecutive HT recipients who underwent
cardiac catheterization (coronary angiography and myocardial biopsy for
clinical reasons) and CMR between July 2007 and May 2012 (prospective
cohort study). Acute or ongoing rejection (International Society for Heart &
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Hofmann et al
Lung Transplantation (ISHLT) class > IA) was excluded by histological
analysis (6). HT recipients, who had contraindications to gadolinium,
adenosine or CMR, such as metal implants, or MDRD < 30 mL/min/
1.73 m2 were not enrolled. All procedures complied with the Declaration
of Helsinki, were approved by our local ethic committee and all patients gave
written informed consent. Part of our patients (n ¼ 63 of 108, 58% of the
present cohort) were included in previous reports, where the ability of
angiographic myocardial blush grade was investigated to predict cardiac
outcomes in transplant recipients (7).
CMR examination
HT recipients were examined in a clinical 1.5-T whole-body CMR scanner
Achieva system (Philips Medical Systems, Best, the Netherlands). This is
part of our institutional protocol, performed in HT recipients, as described
previously (7–9). Briefly, a standardized imaging protocol was used, aiming at
the assessment of baseline parameters of the left ventricle such as left
ventricular (LV) diameters, septal and lateral wall thickness and, ejection
fraction using cine imaging. Myocardial perfusion reserve was assessed
during pharmacologic hyperemia with adenosine in all patients. By this
approach, a mean myocardial perfusion reserve index (MPRI) was calculated
by dividing the blood pool corrected upslope at pharmacologic hyperemia
through the blood pool corrected upslope at rest in 16 myocardial segments,
which served as a semi-quantitative estimate of the global perfusion reserve
in each patient (8,10). Late gadolinium enhancement (LGE) images were
scored visually using a 17-segment model. Hereby, both ischemic (infarctrelated) and atypical noninfarct-related patterns of LGE were analyzed (11).
Cardiac catheterization and assessment of CAV
Coronary angiograms were performed in a standardized fashion, as
described previously (7). Coronary vessels were classified by coronary
angiography, based on the ISHLT nomenclature for CAV (12).
Biomarkers
Blood samples were drawn from a peripheral vein before the CMR
examination and samples were stored immediately at 808C. HsTnT was
measured using the new hsTnT quantitative electrochemiluminescence
immunoassay (Cobas 411; Roche Diagnostics, Mannheim, Germany) as
described previously (13). A concentration of 14 ng/L has been identified as
the 99th percentile of a healthy reference population with a coefficient of
variation of <10%.
Definition of study end points
Study nurses unaware of the CMR imaging and coronary angiography results
contacted each subject and the date of this contact was used for the
calculation of the follow-up time duration. Cardiac death (death due to
intractable heart failure or myocardial infarction or sudden death due to
infarction or severe arrhythmia) and all-cause mortality were recorded. Other
cardiac events included nonfatal myocardial infarction and percutaneous
coronary intervention (PCI). The reasons for PCI (myocardial infarction,
unstable angina or heart failure symptoms including progressive dyspnea as
an equivalent of angina in HT recipients and elective PCI during surveillance
heart catheterization due to angiographically significant coronary artery
stenosis (70%) in combination with the presence of inducible ischemia by
stress echocardiography, CMR or fractional flow reserve) were also reported
in this context. Our primary analysis included the combined end point of
cardiac death, nonfatal myocardial infarction and clinically indicated PCI. A
secondary analysis was conducted for hard cardiac events, including cardiac
death, myocardial infarction and urgent PCI.
Statistical analysis
Analysis was performed using commercially available software MedCalc9.3
(MedCalc software, Mariakerke, Belgium). Continuous variables were
expressed as mean standard deviation and categorical variables as
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proportions. Unpaired Student t-tests were used to compare continuous
variables. Group differences between continuous variables were tested
using analysis of variance with Bonferroni adjustment for multiple
comparisons. Differences between ordinal variables were tested using
the exact Mann–Whitney test, and differences between nominal variables
were assessed using the Fisher exact test. All tests were two-tailed.
Receiver operating characteristics (ROC) were used to determine the
prognostic value of hsTnT and MPRI for the prediction of outcomes.
Subsequently, patients were separated in two groups according to ROC
optimized threshold values, and corresponding Kaplan–Meier curves were
generated for the estimation of the primary and secondary end point.
Furthermore, the association between clinical parameters with CMR and
angiography was investigated using Cox proportional-hazards models and
multivariable procedures. Discrimination improvement (IDI) values were
calculated using the ‘‘survIDINRI’’ software package. Intra- and interobserver variability for quantification analysis of MPRI were calculated by
repeated analysis of 30 randomly selected patients by two observers with
more than 5 years experience in cardiovascular imaging who were blinded to
clinical and CMR data (NPH, GK). Differences were considered statistically
significant at p < 0.05.
Results
Clinical outcomes
During a median follow-up duration of 4.2 1.4 years, 18
patients experienced cardiac events. Seven patients had
hard cardiac events including four with cardiac death and
three who underwent urgent PCI due to myocardial
infarction (n ¼ 2) or unstable angina pectoris (n ¼ 1). Eleven
patients underwent revascularization procedures during
surveillance heart catheterization. Five patients died of
noncardiac reasons (three due to sepsis, two due to
cerebral-vascular complications).
Patient characteristics are illustrated in Table 1. 106 of 108
(98%) patients exhibited preserved LV function (ejection
fraction >50%). Similar baseline characteristics were
present in patients with versus those without cardiac
events. Patients with hard cardiac events exhibited higher
values of hsTnT and septal wall thickness compared to those
without cardiac events. In addition, patients with revascularization procedures exhibited higher CAV grades compared
both to those with hard and without cardiac events.
Relation of MPRI to CAV and cardiac outcomes
Patients with hard cardiac events and revascularization
procedures exhibited markedly lower MPRI compared to
those without cardiac events (Figure 1A). Increasing MPRI
values on the other hand, were observed with decreasing
CAV by ISHLT criteria (Figure 1B). Furthermore, a weak
inverse correlation was observed between MPRI and
hsTnT (r ¼ 0.21, p ¼ 0.03).
Survival analysis
ROC optimized cutoff values for hsTnT and MPRI
(Figure S1) were selected for survival analysis, which can
be appreciated in Figure 2. Corresponding cumulative event
rates are also provided. Hereby, hsTnT and MPRI sharply
American Journal of Transplantation 2014; 14: 2607–2616
Myocardial Perfusion and hsTnT for HT Outcome
Table 1: Demographic, laboratory and CMR findings in patients with and without cardiac events
Parameters
Clinical data
Age (years)
Organ age (years)
Male gender, n (%)
Arterial hypertension, n (%)
Hyperlipidemia or statin therapy, n (%)
Smoking, n (%)
Diabetes mellitus, n (%)
BMI (kg/m2)
CAV (grades 0–3)
Number of grade 2/3 rejections
Laboratory data and biomarkers
Serum creatinine (mg/dL)
Serum urea (mg/dL)
MDRD (mL/min/1.73 m2)
Total cholesterol (mg/dL)
LDL (mg/dL)
HDL (mg/dL)
NTproBNP (pg/mL)
Hs-TnT (pg/mL)
CMV high risk (Dþ/R), n (%)
Cardiac magnetic resonance data
Ejection fraction (%)
End-diastolic LV volume (mL)
End-systolic LV volume (mL)
End-diastolic LV diameter (mm)
Septal wall thickness (mm)
Lateral wall thickness (mm)
LV mass (g)
Infarct-typical LGE, n (%)
Infarct-atypical LGE, n (%)
LGE (typical and atypical patterns), n (%)
Hemodynamic data
Mean blood pressure (mmHg)
Mean heart rate (bpm)
Cardiac and immunosuppressive medications
b-blockers, n (%)
ACE inhib./AT II blockers, n (%)
Aspirin or clopidogrel, n (%)
Diuretics, n (%)
Statins, n (%)
Tacrolimus, n (%)
Mycophenolate, n (%)
Sirolimus, n (%)
Everolimus, n (%)
Cyclosporine A, n (%)
Cortisone, n (%)
All patients
(n ¼ 108)
Patients
w/o cardiac
events (n ¼ 90)
Patients
with revasc.
procedures
(n ¼ 11)
Patients with
hard cardiac
events (n ¼ 7)
p-Values
55 12
4.1 4.7
82 (76%)
71 (66%)
103 (95%)
15 (14%)
25 (23%)
26 4
0.7 0.6
0.5 0.8
55 12
3.8 4.7
67 (74%)
59 (66%)
87 (98%)
13 (14%)
20 (22%)
26 5
0.7 0.5
0.7 1.0
59 12
6.5 5.7
10 (91%)
9 (82%)
11 (100%)
1 (9%)
3 (27%)
27 3
1.2 0.9
0.8 1.5
53 8
3.1 0.6
5 (71%)
3 (43%)
5 (71%)
1 (14%)
2 (29%)
24 4
0.6 0.5
0.4 0.8
NS
NS
NS
NS
0.001
NS
NS
NS
0.01
0.01
1.4 0.4
59 27
57 20
182 37
100 30
57 17
942 1188
18.5 16.3
51 (47%)
1.4 0.4
59 26
57 21
183 37
99 28
53 17
916 1067
16.5 15.1
43 (48%)
1.4 0.5
60 34
56 17
175 47
98 42
41 12
589 519
23.6 12.4
5 (45%)
1.4 0.5
55 20
52 17
177 19
111 30
55 19
1833 2573
35.9 26.1
3 (43%)
NS
NS
NS
NS
NS
0.09
0.08
0.005
NS
64.6 6.8
136 31
49 18
49.6 5.4
11.2 2.1
7.9 1.6
82.2 20.1
9 (8%)
24 (22%)
33 (31%)
64.3 6.6
137 32
50 18
49.8 5.5
11.0 2.0
7.9 1.7
81.7 20.2
6 (7%)
18 (20%)
24 (27%)
67.0 8.3
139 29
47 19
49.1 4.6
13.3 2.3
7.7 1.1
90.7 21.5
2 (18%)
2 (18%)
4 (36%)
65.6 6.8
125 30
43 12
47.6 4.2
9.8 1.0
7.3 0.8
74.7 13.7
1 (14%)
4 (57%)
5 (71%)
NS
NS
NS
NS
0.001
NS
NS
NS
0.07
0.04
80 31
78 9
79 32
78 9
91 11
78 8
71 35
77 10
NS
NS
45
89
42
59
98
57
82
4
31
33
37
37
74
31
47
82
47
71
3
23
28
32
6 (55%)
10 (91%)
9 (82%)
7 (64%)
11 (100%)
5 (45%)
7 (64%)
1 (9%)
5 (45%)
3 (27%)
2 (18%)
2 (29%)
5 (71%)
2 (29%)
5 (71%)
5 (71%)
5 (71%)
4 (57%)
0 (0%)
3 (43%)
2 (29%)
3 (43%)
NS
NS
0.008
NS
NS
NS
NS
NS
NS
NS
NS
(42%)
(82%)
(39%)
(55%)
(91%)
(53%)
(76%)
(4%)
(29%)
(31%)
(34%)
(41%)
(82%)
(34%)
(52%)
(91%)
(52%)
(79%)
(3%)
(26%)
(31%)
(36%)
Data are presented as mean SD or as proportions. ACE, angiotensin-converting enzyme; AT, angiotensin; CAV, cardiac allograft
vasculopathy; CMR, cardiac magnetic resonance; CMV, cytomegalovirus; Dþ/R, donor positive and receiver negative; hs-TnT, highsensitive troponin T; LGE, late gadolinium enhancement; LV, left ventricular; NTproBNP, N-terminal pro-brain natriuretic peptide.
discriminated between patients with and without cardiac
events (Figure 2A and 2B). In addition the two markers
exhibited complementary value for the assessment of hard
and all cardiac events (Figure 2C and 2D). Thus, patients
with both high hsTnT and low MPRI showed the highest
American Journal of Transplantation 2014; 14: 2607–2616
rates of hard and all cardiac events (annual event rates ¼
7.7% and 14.5%, respectively), followed by those with
either high hsTnT or low MPRI (annual event rates ¼ 1.2%
and 2.2%, respectively), while those with both low hsTnT
and high MPRI exhibited excellent outcomes without
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Hofmann et al
Representative CMR perfusion images (Figure 4A and 4B)
in a patient with markedly reduced MPRI of 1.1 (Figure 4C
and 4D). This patient also exhibited infarct-typical LGE and
increased hsTnT of 40 pg/mL, albeit only mild CAV (<50%
stenosis) by angiography (Figure 4E and 4F). During
1.3 years of follow-up, he underwent urgent PCI.
Prediction of CAV progression
Ninety-one of 108 patients underwent more than one
surveillance coronary angiographic study after the index
CMR scan (mean time duration of 2.1 1.6 years). MPRI
was significantly higher in patients with stable CAV
between the two invasive procedures (n ¼ 82), compared
with those who showed significant CAV progression,
converting from absent/mild to moderate/severe CAV
(n ¼ 9). A nonsignificant trend was observed in the same
context for hsTnT (Figure S2).
Observer agreement and time spent
Quantification of MPRI yielded intra- and inter-observer
variability of 9% and 12%, respectively. Time spent for
MPRI quantification was 17.8 3.1 min per patient.
Discussion
Figure 1: Association of myocardial perfusion reserve index
(MPRI) with cardiac allograft vasculopathy (CAV) and cardiac
events. (A) Patients with hard cardiac events and revascularization
procedures exhibited significantly lower MPRI compared to those
without cardiac events. (B) In addition, decreasing MPRI was noted
with increasing CAV by International Society for Heart & Lung
Transplantation (ISHLT) criteria.
occurrence of any single cardiac event (annual event rates
of 0% for both).
Univariate, multivariable and IDI analysis
By univariate analysis CAV by ISHLT criteria, N-terminal probrain natriuretic peptide (NTproBNP), hsTnT and LGE and
myocardial perfusion reserve by CMR were significantly
associated with outcomes (Table 2). By multivariable
analysis, hsTnT and MPRI provided the most robust
prediction of both hard and all cardiac events, surpassing
the value of organ age, LV hypertrophy, LGE and CAV by
ISHLT criteria (Table 3).
Using a series of Cox models hsTnT and MPRI offered
incremental information for the assessment of the primary
and secondary end point by chi-square and IDI analysis
(Figure 3A and 3B).
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To the best of our knowledge our study is the first to
simultaneously investigate the value of cardiac troponins and
myocardial perfusion by CMR for the prediction of cardiac
outcomes in HT recipients. Cardiac troponins were assessed
using the high sensitivity assay, which was also recently used
in the PEACE study (Prevention of Events With AngiotensinConverting Enzyme Inhibitor Therapy) (4), whereas a
standardized semi-quantitative approach was applied for
the assessment of MPRI. Hereby, we demonstrated that
(i)
Noninvasive MPRI by CMR is associated both with
CAV by ISHLT criteria and with cardiac outcomes,
(ii) HsTnT and MPRI independently predict cardiac outcomes but also demonstrate complementary value to
each other. Thus, patients with low hsTnT and high
MPRI exhibit excellent outcomes, whereas patients
with high hsTnT and low MPRI show extremely poor
outcome (mean annual event rate of 14.5%).
(iii) MPRI is also predictive for CAV progression.
Such a comprehensive bio-imaging approach presented
herein may provide personalized risk assessment and aid
tailoring diagnostic procedures (reduce the necessity for
frequent invasive procedures) or specific immunosuppressive pharmacologic treatments according to the individual
risk for future cardiac events in HT recipients.
Previous studies for detection of CAV using CMR
Myocardial perfusion imaging by CMR has been validated
as a versatile noninvasive clinical tool for the diagnostic
American Journal of Transplantation 2014; 14: 2607–2616
Myocardial Perfusion and hsTnT for HT Outcome
Figure 2: Kaplan–Meier analysis. Both myocardial perfusion reserve index (MPRI) (A) and high-sensitive troponin T (hsTnT) (B) were
predictive for cardiac events separately. Patients with low hsTnT and high MPRI exhibited excellent outcome with no single cardiac event
during the follow-up duration. Patients with high hsTnT and low MPRI on the other hand, demonstrated extremely poor outcome (mean
annual event rates of 7.7% for hard cardiac and of 14.5% for all cardiac events) (C–D).
classification and risk-stratification of patients with CAD
(reviewed in [14]). Fewer studies however, investigated the
role of stress perfusion CMR for the detection of CAV. In
this regard, we and others previously reported that the
myocardial perfusion reserve during vasodilator stress
CMR is associated with CAV in HT recipients (8,15). In
addition, Miller et al (16) recently demonstrated, using
CMR, intravascular ultrasound (IVUS) and fractional flow
reserve measures in HT recipients, that MPRI is independently associated with both epicardial and microvascular
components of CAV, surpassing the value of surveillance
coronary angiography for early CAV detection.
In the present study the relation between CAV and MPRI
was confirmed and association between MPRI and cardiac
outcomes could be established. Interestingly, the cutoff
value of <1.3 used for the detection of patients with poor
outcomes is close to 1.4, which was selected as cutoff
value for CAV detection (8). Different patterns of both
infarct-related and infarct-atypical LGE on the other hand,
were previously demonstrated in HT recipients and were
American Journal of Transplantation 2014; 14: 2607–2616
shown to be associated with the degree of CAV (11). In our
study, LGE was observed in 33 (31%) patients and a trend
was noted for cardiac events in the presence of either
typical or atypical LGE patterns. However, using multivariable analysis LGE did not prove to be an independent
predictor of cardiac events. Septal hypertrophy on the other
hand was significantly associated with cardiac events,
while a nonsignificant trend was observed for LV mass. This
is in line with previous observation, where LV hypertrophy
was identified as an independent risk for cardiovascular
outcomes after HT (17).
We and others previously proposed other invasive and
noninvasive imaging modalities including echocardiography, cardiac computed tomography (CCT) and IVUS for
monitoring CAV in HT recipients ([18], reviewed in [19]).
However, CMR is better suited for the serial evaluation of
such patients due to (i) its tomographic nature, ensuring
reproducibility of serial measurements, (ii) its noninvasive
nature and (iii) the absence of radiation exposure for the
patients.
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Table 2: Univariate value of demographic, clinical, hsTnT, NTproBNP and CMR data for the prediction of hard cardiac events and
revascularization procedures
Prediction of hard cardiac events
Parameters
Age (years)
Organ age (years)
Male gender, n (%)
Arterial hypertension, n (%)
Hyperlipidemia or statin therapy, n (%)
Smoking, n (%)
Diabetes mellitus, n (%)
BMI (kg/m2)
Ejection fraction (%)
Septal wall thickness (mm)
LV mass (g)
Infarct-typical LGE
Infarct-atypical LGE
LGE (typical and atypical patterns)
CAV by ISHLT criteria (0–3)
NTproBNP (pg/mL)
HsTnT (pg/mL)
MPRI
Prediction of all cardiac events
p-Value
Hazard ratios
Confidence interval
p-Value
Hazard ratios
Confidence interval
NS
NS
NS
NS
0.003
NS
NS
NS
NS
0.08
0.04
NS
0.03
0.03
NS
0.04
0.005
0.006
0.99
0.55
0.88
0.36
0.08
0.76
1.23
0.93
1.03
0.69
0.98
1.89
5.19
6.28
0.86
1.0
1.04
0.0007
0.94–1.05
0.20–1.49
0.17–4.51
0.08–1.61
0.02–0.41
0.09–6.16
0.24–6.30
0.77–1.12
0.91–1.15
0.46–1.05
0.94–1.02
0.23–15.6
1.16–23.0
1.22–32.2
0.22–3.42
1.00–1.001
1.01–1.08
0.00–0.12
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
0.06
0.01
NS
0.005
<0.0001
1.02
1.03
1.72
0.96
0.06
0.60
1.18
1.01
1.04
1.16
1.01
2.22
1.92
2.47
3.02
1.00
1.03
0.0001
0.97–1.05
0.93–1.13
0.51–5.93
0.36–2.56
0.06–1.05
0.13–2.60
0.42–3.30
0.90–1.12
0.97–1.13
0.93–1.44
0.98–1.03
0.64–7.67
0.72–5.11
0.98–6.21
1.28–7.10
0.99–1.00
1.00–1.05
0.00–0.004
CAV, chronic allograft vasculopathy; CMR, cardiac magnetic resonance; HsTnT, high-sensitive troponin T; ISHLT, International Society for
Heart & Lung Transplantation; LGE, late gadolinium enhancement; LV, left ventricular; MPRI, myocardial perfusion reserve index;
NTproBNP, N-terminal pro-brain natriuretic peptide.
Biomarkers for the detection of CAV
Cardiac troponins, which are highly sensitive and specific
markers of myocardial injury and established markers of
cardiovascular risk, were previously shown to predict
development of CAV, graft failure and cardiac mortality in
HT recipients (20). In the same line, and using a highly
sensitive assay, we recently demonstrated that measurements of hsTnT predict both short- and long-term survival
after HT (5). Thus, patients with a cutoff value of
hsTnT 33 pg/mL measured within the first 6 weeks after
HT exhibited a more than sixfold risk for cardiac mortality
during the following 5 years compared to patients with
hsTnT < 33 pg/mL. Of course elevated hsTnT values may
be attributed to several other causes apart from CAV, such
as increased myocardial strain due to volume or pressure
overload and myocardial hypertrophy. This is also indicated
by the weak association between hsTnT and impaired
myocardial perfusion reserve, as noted in our study. In
addition, other conditions, such as acute allograft rejection,
impaired cell membrane integrity due to systemic inflammatory response or apoptosis and extracardiac disease
such as end-stage renal failure may result to hsTnT
elevation in the absence of significant CAV (21).
Combination of biochemical markers with imaging
Fewer studies have combined biomarkers with imaging
modalities aiming at a more comprehensive assessment of
CAV in HT recipients so far. In this regard, an association
between hsTnT and coronary intimal thickness was
demonstrated using optical coherence tomography, which
exhibited better observer variability than IVUS for the
determination of intimal thickness (22). However, both
Table 3: Multivariable value of organ age, septal wall thickness, CAV, hsTnT and myocardial perfusion reserve index (MPRI) for the
prediction of hard cardiac events and revascularization procedures
Prediction of hard cardiac events
Parameters
Septal wall thickness (mm)
CAV by ISHLT criteria (0–3)
LGE (typical and atypical patterns)
NTproBNP (pg/mL)
HsTnT (pg/mL)
MPRI
Prediction of all cardiac events
p-Value
Hazard ratios
Confidence interval
p-Value
Hazard ratios
Confidence interval
NS
NS
NS
NS
NS
0.002
0.64
1.17
3.10
1.00
1.01
0.002
0.36–1.12
0.19–7.19
0.41–23.2
0.99–1.00
0.97–1.05
0.00–0.65
NS
0.003
NS
NS
0.01
<0.0001
0.96
4.71
0.87
0.99
1.03
0.00
0.75–1.23
1.68–13.15
0.26–2.82
0.99–1.00
1.00–1.06
0.00–0.001
CAV, chronic allograft vasculopathy; hsTnT, high-sensitive troponin T; ISHLT, International Society for Heart & Lung Transplantation; LGE,
late gadolinium enhancement; NTproBNP, N-terminal pro-brain natriuretic peptide.
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Myocardial Perfusion and hsTnT for HT Outcome
Figure 3: Chi-square and IDI analysis. (A and B) Using a series of Cox models high-sensitive troponin T (hs-TnT) and myocardial perfusion
reserve index (MPRI) offered incremental information for the assessment of hard (secondary end point) and of all cardiac events (primary
end point) both by chi-square and by discrimination improvement (IDI) analysis.
IVUS and optical coherence tomography are invasive
techniques, which are therefore less appropriate for the
serial evaluation of CAV compared to CMR.
To our knowledge we demonstrated for the first time that
hsTnT and vasodilator stress CMR provide complementary
value for the identification of patients at high risk for future
cardiac events. Patients with both increased hsTnT and
reduced myocardial perfusion reserve exhibited the highest
rates of urgent PCI, cardiac death and coronary revascularization, whereas patients with low hsTnT and higher
myocardial perfusion reserve exhibited excellent outcomes. Hereby, a cutoff value of 14 pg/mL was selected
by ROC analysis, which is lower than that proposed in
previous studies with HT patients, but identical to the upper
reference limit of 14 pg/mL (99th percentile for hsTnT). This
difference to previous HT studies may be attributed to the
time point of hsTnT assessment, which was previously set
within the first 6 weeks after HT, where inflammatory and
immunologic processes may trigger hsTnT leakage from
the transplanted heart, in contrast to the present study
where hsTnT measures were assessed at a mean time of
4.1 years after HT.
Potential pathophysiologic mechanisms
Both in HT recipients and in patients with stable CAD
increased hsTnT levels indicate severe myocardial injury or
irreversible myocyte death, possibly caused by silent
plaque rupture, microembolization and microvascular
obstruction, which may precede the clinical manifestation
of myocardial infarction (23). Interestingly, a recent optical
coherence tomography study demonstrated the presence
American Journal of Transplantation 2014; 14: 2607–2616
of complicated coronary lesions with intimal laceration,
intraluminal thrombus and plaque ruptures in a significant
proportion of asymptomatic HT recipients (24). This underlines our hypothesis, that repetitive plaque ruptures in HT
recipients may cause chronic myocardial microinjury,
reflected both by increased hsTnT blood levels and by
the presence of LGE in such patients. The presence of both
infarct-typical and -atypical LGE patterns in patients with
increased hsTnT levels and future cardiac events, however,
indicate that further mechanisms apart from plaque rupture
and microembolization may be involved in hsTnT leakage,
including myocardial hypertrophy due to pressure overload
and fibrosis due to hypertrophy and systemic inflammatory
response. An overview of potential mechanisms of
myocardial injury in HT recipients with CAV is given in
Figure S3.
Our study has some limitations. First of all, the number of
patients included in our study (n ¼ 108), and the number of
cardiac events (n ¼ 7) and revascularization procedures
(n ¼ 11) was small. Furthermore, serial measures of MPRI
and hsTnT were not available. IVUS and optical coherence
tomography on the other hand were not used to evaluate
the wall of coronary vessels, which may show increased
intimal thickness despite normal appearance on coronary
angiograms (25). Humoral rejection characterized by
induced and complement-mediated activation of endothelial cells and macrophages, may also have a significant
impact both on myocardial perfusion and on outcomes
(26,27). In our study, however, the presence of antibodymediated rejection was not systematically evaluated,
which is a limitation, particularly in light of its potential
impact on microvascular function (28).
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Hofmann et al
Figure 4: Patient case. Representative cardiac magnetic resonance images (A–B) used for the assessment of myocardial perfusion in a
heart transplant recipient with markedly reduced myocardial perfusion reserve index (¼1.1) (C–D). This patient exhibited infarct-typical late
gadolinium enhancement and increased high-sensitive troponin T of 40 pg/mL, albeit only mild chronic allograft vasculopathy (<50%
stenosis) by invasive angiography (E–F). At 1.3 years of follow-up, he underwent percutaneous coronary intervention due to unstable angina.
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American Journal of Transplantation 2014; 14: 2607–2616
Myocardial Perfusion and hsTnT for HT Outcome
Conclusion
Our study demonstrates the complementary value of
hsTnT and quantitative myocardial perfusion reserve during
vasodilator CMR for the prediction of outcomes and of CAV
progression in cardiac transplant recipients. Our findings
implicate that apart from microembolization of atherothrombotic debris, other mechanisms like myocardial
hypertophy and inflammation may be involved in hsTnT
elevation in such patients and underscore the potential
value of such a comprehensive ‘‘bio-imaging’’ approach,
aiding the personalized risk-stratification and prediction of
future cardiac events.
Acknowledgments
This project was supported by an institutional grant provided by the
Landesstiftung foundation Baden-Württemberg. Furthermore, we thank our
medical secretary Mrs. Gerda Baumann for her support in terms of data
collection for our study and Birgit Hörig, Daniel Helm and Angela StöckerWochele for their excellent technical assistance with the acquisitions of all
CMR scans.
Disclosure
The authors of this manuscript have no conflicts of interest
to disclose as described by the American Journal of
Transplantation.
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Supporting Information
Additional Supporting Information may be found in the
online version of this article.
Figure S1: ROC analysis. Both hsTnT (A–B) and MPRI (C–
D) were significantly associated with hard cardiac and with
all cardiac events including revascularization procedures by
2616
ROC analysis. Cutoff values of hsTnT ¼ 14 pg/mL and
MPRI ¼ 1.3 were selected for subsequent Kaplan–Meier
analysis.
Figure S2: Association of MPRI and hsTnT with CAV
progression. (A) MPRI was significantly higher in patients
with stable CAV, compared with those who showed
significant CAV progression, converting from absent/mild
to moderate/severe CAV. (B) A similar albeit nonsignificant
trend was observed for hsTnT.
Figure S3: Potential mechanisms of myocardial injury
in HT recipients with CAV. Both in HT recipients
increased hsTnT levels indicate myocardial injury, possibly
caused by silent plaque rupture, microembolization and
microvascular obstruction, which may precede the clinical
manifestation of myocardial infarction and heart failure.
American Journal of Transplantation 2014; 14: 2607–2616