RESEARCH ARTICLE Open Access [600682]

RESEARCH ARTICLE Open Access
Angina at Low heart rate And Risk of
imminent Myocardial infarction (the ALARM
study): a prospective, observational proof-
of-concept study
Yuk-ki Wong1*, Shelley Stearn1, Sally Moore1and Beverley Hale2
Abstract
Background: Myocardial infarction (MI) is often preceded by unstable angina. Helping patients identify the onset of
unstable angina rather than MI may result in earlier treatment and improve outcomes. Unstable angina is angina
occurring at a lower-than-usual workload. Since heart rate (HR) is correlated with degree of exertion, we hypothesised
that angina occurring at low HR is a warning signal for unstable angina and MI.
Methods: In this prospective study, 111 patients with acute coronary syndrome (ACS) or prognostically significant
coronary disease were recruited. Each patient ’s HR was measured using a portable electrocardiogram (ECG) recorder
after regular class III exercise on the Canadian Cardiovascular Society Angina Grading Scale and the cumulative moving
average and three-sigma (standard deviation) range were calculated for each new measurement. The HR was
subsequently measured at the beginning of angina; a HR lower than the preceding three-sigma ranges for class III or
anginal HR was regarded as a ‘warning signal ’. The proportion of warning signals associated with ACS occurring in the
following 2 weeks was compared with that for non-warning signals.
Results: Nine cases of ACS occurred in eight patients. Two cases were preceded by warning signals; a signal marked
the onset of ACS in a third patient, and four patients failed to make anginal ECG recordings. There were 591
documented episodes of angina during the study and ECGs were available for 383 (64.8 %) of these of which 55 were
warning signals. Of these warning signals, 4 occurred in the 2 weeks preceding ACS, compared with 4 of 328 non-
warning signals (odds ratio, 6.4; 95 % confidence interval, 1.5 –26.2; p= 0.01; positive predictive value, 7.3 %; negative
predictive value, 98.8 %).
Conclusions: Low HR angina may identify unstable angina and serve as an early warning for MI. In addition, angina
that does not occur at a low heart rate indicates that ACS is very unlikely.
Keywords: Unstable angina, Myocardial infarction, Myocardial preinfarction syndrome, Acute coronary syndrome, Heart
rate
* Correspondence: [anonimizat]
1Department of Cardiology, St. Richard's Hospital, Western Sussex Hospitals
NHS Foundation Trust, Spitalfield Lane, Chichester, West Sussex PO19 4SE, UK
Full list of author information is available at the end of the article
© 2015 Wong et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Wong et al. BMC Cardiovascular Disorders (2015) 15:148
DOI 10.1186/s12872-015-0140-z

Background
Myocardial infarction (MI) should ideally be treated in
the first ‘golden hour ’. However, most patients do not
seek help until 2 h after symptom onset [1, 2] and treat-
ment delays can occur after hospital arrival [3]. Al-
though some patients are taught to recognise the onset
of a heart attack [4, 5], ideally patients should seek inter-
vention prior to occurrence of the critical ischaemic
event. In theory, this should be possible because more
than 50 % of heart attacks are preceded by a prodromal
period (up to 2 weeks or more) of unstable angina, in
which angina occurs on reduced exertion [6 –10]. Help-
ing patients to identify the onset of unstable angina
rather than MI may result in the ability to provide earl-
ier treatment and improve outcomes.
Heart rate (HR) has a linear relationship with cardiac
output [11] and is used as a measure of exertion during
treadmill exercise testing, during which angina occurring
at a low HR is considered to be more clinically signifi-
cant than that occurring at a high HR [12]. Therefore,
we hypothesised that if patients could measure their HR
at the onset of angina and if an episode occurred where
the HR was significantly lower than that of previous
episodes, this might be a warning indicator of unstable
angina. Since many patients with diagnosed coronary
disease are asymptomatic due to therapy, they may have
no previous anginal episodes with which to compare the
HR. However, because the general consensus is that
asymptomatic patients who subsequently experience an-
gina of at least class III severity on the Canadian Cardio-
vascular Society Angina Grading Scale may be at high
risk for MI [13], a reasonable comparator HR under
these circumstances is one corresponding to exertion
normally associated with class III angina; i.e., one flight
of stairs or ‘one to two blocks ’on a flat surface at a
normal pace [14]. We therefore investigated whether
angina occurring at a low HR is a marker of unstable
angina and MI.
Methods
Study overview
All participants gave informed consent and ethical
approval was obtained from Brighton West Research
Ethics Committee (Ref No 09/H1111/23). The study was
included in the National Institute for Health Research
Clinical Research Portfolio (study ID 6974) and the
study period was July 2009 to October 2011.
Inclusion and exclusion criteria
Patients aged 54 years or older at relatively high risk
for subsequent acute coronary syndrome (ACS) were
recruited. Two groups were included in the study. The
first group was enrolled within 6 weeks of hospital ad-
mission and comprised patients with ACS characterisedby angina of at least 5-min duration associated with
either dynamic electrocardiogram (ECG) changes or an
elevated serum troponin I level. The second group had
significant coronary disease diagnosed by coronary
angiography (stenosis of at least 70 % in the left main
artery or proximal left anterior descending artery and
one other coronary artery or in all three main coronary
arteries) but revascularisation had either been declined
or was considered to be impossible or inappropriate.
The main exclusion criteria were a pacemaker in situ
and chronic arrhythmia.
Study protocol and ECG measurements
All patients were given a pocket ECG recorder and
instructed to carry it with them at all times (MD100B;
Beijing Choice Electronic Technology Co., Ltd. or PC-80B;
Shenzhen Creative Industry C o . ,L t d . ) .Al a b e ld i s p l a y i n g
advice to seek help in case of angina lasting ≥15 min
despite the use of sublingual glyceryl trinitrate every
5 min was positioned to hide the displayed HR.
During an initial consultation, the patients were
observed using the ECG recorder before and after a
300 m walk and before and after a climb of one flight of
stairs (12 steps of 17 cm height), equivalent to class III
exertion. The patients were asked to identify a walk of
similar distance near their home, including stairs where
available, and the HR was measured before and after
these activities daily for 7 days and weekly thereafter.
The patients made recordings as soon as possible after
the start of angina and documented the details in a diary.
The quality of documentation and recordings were
checked at 2 weeks and, where necessary, at 4 weeks. If
quality was poor after 4 weeks, the patients were excluded;
otherwise, they had follow-up visits every 3 months. At
each visit, supervised class III exercises were performed
and ECGs recorded using the patient ’s ECG recorder. All
exercises were preceded by 15 min of rest.
There were no restrictions on treatment; however, if
medication changes were expected to affect HR or a
revascularisation procedure or ACS occurred, unsuper-
vised class III exercises were performed daily for the
7 days following the therapy change before reverting to a
weekly schedule.
ECG analysis
ECG data were downloaded at each visit and manually
analysed. For each 30 s recording, the HRs correspond-
ing to the first and last five consecutive R waves were
calculated; ectopic beats were allowed if the first and last
R wave of any run was a sinus beat. The difference in
HR between the first and last run was used as an
estimate of the speed of HR decline following exercise. If
there were no five-beat runs, four- or three-beat runs
were used, and the relative proportion of these runs wasWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 2 of 7

used as a measure of the quality of ECG recordings.
If no three-beat runs could be identified, the ECG
was considered uninterpretable. Additional measures
of ECG quality were how early the first run started
and how late the second run started. The HR from
the first run was used when different ECGs were
compared.
Outcome measures
The main outcomes were unstable angina and MI occur-
ring after enrolment. MI was diagnosed according to the
universal definition [15]. Unstable angina was diagnosed
if angina occurred at rest or persisted for more than 15
min after MI had been excluded. Atypical angina was
defined as symptoms that patients thought were angina
but that differed from previous anginal symptoms. The
cause of death was ascertained from the death
certificate.
Statistical analysis
All statistical analyses were performed using IBM SPSS
Statistics for Windows, Version 21.0 (IBM Corp.,
Armonk, NY). A two-tailed 0.05 significance level was
used for all tests. For each patient, the cumulative
moving average and standard deviation (SD) for angina
and class III HRs were recalculated with each new meas-
urement, but following changes in chronotropic medica-
tions or revascularisation and ACS, readings prior to
these events were disregarded. Also for each patient, the
coefficients of variation (CV) were calculated for class
III HRs after 7 days and at 3, 6, 12, and 18 months
following enrolment to assess the variation of HR mea-
surements over time. For each episode of angina, the HR
was compared with the three-sigma (SD) ranges for
preceding angina and preceding unsupervised class III
exercises. If the HR was below any of these ranges,
angina was considered to have occurred at a low HR and
represented a ‘warning signal ’. Otherwise, it was a ‘non-
warning signal ’. The proportion of warning signals
preceding a diagnosis of ACS in the subsequent
2 weeks was compared with that for non-warning sig-
nals using the χ2test with calculation of the oddsTable 1 Patient characteristics, ECG findings, and clinical events
Patient characteristics
Number of patients recruited 111 (13
withdrew)
Number of patients not recruited due to poor
quality of ECG recordings or diary documentation4
Male 87 (78.4 %)
Mean age (SD) 68.1 years (8.0)
Recruited with prognostically significant coronary
disease found at cardiac catheterisation38 (34.2 %)
Recruited after acute coronary syndrome 73 (65.8 %)
Mean follow-up period between first and last
heart rate recording (SD)445.6 days
(204.6)
Prescribed a negative chronotropic drug at start
of study92 (82.9 %)
Mean resting supine heart rate at start of study (SD) 58.4 bpm (9.4)
Number of patients with ECG recordings
Unsupervised 300-m walk 111 (100 %)
Unsupervised flight of stairs 82 (73.9 %)
Angina 43 (38.7 %)
Number of diary-documented events
Unsupervised 300-m walk (percentage of expected) 6705 (85.4 %)
Unsupervised flight of stairs (percentage of
expected)4082 (74.2 %)
Angina 591
Interpretable ECGs for diary-documented events
Unsupervised 300-m walka5144 (76.7 %)
Unsupervised flight of stairsa3423 (83.9 %)
Angina 383 (64.8 %)
Supervised 300-m walka688
Supervised flight of stairsa685
ECG quality (interpretable ECGs)
ECGs with two heart rate measurements 96.5 %
Heart rate calculations based on five
consecutive R waves93.4 %
Mean start of first heart rate calculation (SD) 2.0 s (3.8)
Mean start of second heart rate calculation (SD) 25.2 s (4.2)
Mean difference in heart rate between the
beginning and end of 30-s ECGs
Rest ECG for unsupervised 300-m walk (SD) −0.8 bpm (4.0)
Postexertional unsupervised stairs (SD) −2.0 bpm (5.7)
Postexertional unsupervised 300-m walk (SD) −4.1 bpm (5.0)
Angina (SD) −2.0 bpm (5.4)Table 1 Patient characteristics, ECG findings, and clinical events
(Continued)
Clinical events during follow-up
ST elevation myocardial infarction 0
Non-ST elevation myocardial infarction
(number of patients)2 (2)
Unstable angina (number of patients) 6 (5)
Coronary death diagnosed postmortem 1
aECGs were recorded at rest and post-exercise, but the numbers refer to
interpretable post-exercise ECGsWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 3 of 7

ratio (OR), 95 % confidence interval (CI), positive
predictive value (PPV), and negative predictive value
(NPV).
Results
In total, 111 patients were recruited for this study,
and their compliance with unsupervised class III exer-
cises was good ( ≥74 %) (Table 1). For angina, 43 pa-
tients reported this symptom with 591 documented
episodes and ECGs were available for 383 (64.8 %) of
these of which 55 were signals and 328 were non-
warning signals. For all indications, there were 29,593
ECGs and 94.5 % of these were interpretable
(Table 1).
The CVs for HR measurements tended to increase
with time (Fig. 1), and class III exercise CVs were lowest
after the daily readings from the first 7 days.
During follow-up, nine cases of ACS occurred in eight
patients (Table 1). Four cases of ACS were characterised
by a single episode of severe and prolonged pain for
which no ECG was recorded. In a fifth case, the patient
missed a clinic visit due to feeling unwell and died
1 week later without an ECG recording. This patient did
not have prior heart failure and the post-mortem diag-
nosis was ‘left ventricular failure secondary to coronary
disease ’. In a sixth case, the patient ’s unstable angina was
caused by unexplained nocturnal sinus tachycardia. A
seventh case had a warning signal at the onset of
unstable angina (rest pain) whilst the eighth case was
preceded by a warning signal that occurred 1 dayprior to further pain and a diagnosis of Non-ST
elevation MI. The ninth case was preceded by 4
warning signals of which the earliest occurred 68 days
prior to diagnosis of unstable angina with another 6
signals occurring after diagnosis.
In terms of warning signals, 4 of 55 occurred during the
2-week period preceding ACS compared with 4 of 328
non-warning signals (OR, 6.4; 95 % CI, 1.5 –26.2; p=0 . 0 1 ;
PPV, 7.3 %; NPV, 98.8). In total, 20 patients had at least
one signal, but 6 patients had symptoms that were judged
to be atypical, accounting for 45.5 % of all signals. When
patients with atypical chest pain were excluded from the
analysis, the corresponding proportions were 4 of 30 com-
pared with 4 of 253 (OR, 9.6; 95 % CI, 2.3 –40.6; p=0 . 0 0 2 ;
PPV, 13.3 %; NPV, 98.4 %).
For the patient who had 4 signals prior to diagnosis of
unstable angina, there was a prodrome of angina occur-
ring on less exertion. During this period, there was a grad-
ual reduction in comparator HRs and widening of the
corresponding three-sigma ranges, which was more
marked when climbing stairs (Fig. 2). Anginal HRs were
also lower during this period; however, because of the
wider three-sigma ranges for the comparator HRs, a signal
was only generated when anginal HRs were compared
with the walk, and not with the stairs or preceding angina.
In total, 10 patients had signals along with comparator
HRs from both stairs and walking. Of their 42 signals, only
6 were triggered by both comparators.
Two additional patients had signals associated with
histories strongly suggestive of ACS but they did not
Fig. 1 Box-and-whisker plots for coefficients of variation of heart rate measurements after various time periodsWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 4 of 7

seek medical attention at the time and a diagnosis of
ACS could not be definitely confirmed.
Discussion
We found that episodes of angina occurring at a low HR
in patients with known coronary disease were more likely
to occur in the 2 week period leading up to an ACS. The
case for accurately identifying prodromal symptoms in
order that ‘myocardial infarction might be averted in
many instances ’has been made before [8]. To the best of
our knowledge, however, the present study is the first to
use HR to objectively identify unstable angina. Another
important finding of this study is that angina which does
not occur at a low heart rate indicates that a diagnosis of
ACS is very unlikely with a NPV of 98.8 %. This compares
with a PPV of 13.3 % at best. Unfortunately, angina HR
data was missing from 4 cases of ACS. In addition, 2 pa-
tients with warning signals did not present at the time of
their likely ACS. These missing data may have adversely
affected the PPV. The clinical implications of these find-
ings are that warning signals may help patients identify
unstable angina and non-warning signals may help to re-
duce the significant number of patients admitted to hos-
pital with chest pain but who do not have ACS.
We defined a ‘warning signal ’HR for angina as one
that was less than the lower limit of comparator three
sigma ranges (i.e., a 1:370 chance that the warning signal
had occurred by chance); choosing this level of strin-
gency minimised the possibility of false positive results.
The sensitivity for detecting a signal HR is increased if
the CVs for the comparator HRs are small, since the as-
sociated three sigma ranges will be narrower. In this
study, the Class III comparator three sigma ranges were
continuously re-calculated and over time, the CVs
tended to increase (Fig. 1). It was found that the initial
seven daily measurements were sufficient to achieve thelowest CV and an alternative strategy would be to recal-
culate the three sigma ranges with seven new daily mea-
surements at regular intervals such as after every 3
months.
We found that during the prodrome of unstable
angina, there can be widening of the comparator three
sigma ranges that made it difficult to detect a signal
(Fig. 2). It has been reported that most cases of unstable
angina are less than 2 weeks in duration. Therefore, a
possible algorithm could be to use a comparator period
ending at least 2 weeks before the episode of angina
under consideration.
We found in one patient that signals may continue in the
period after ACS has been diagnosed. We speculate that
such signals may indicate pers isting clinical instability.
From a diagnostic point of view, such signals cannot be
considered an early warning si n c et h e yh a v eo c c u r r e da f t e r
the event. However, in our pre-specified analysis, we did
not distinguish between sign als that occurred before or
after the event but in future studies and for the purposes of
m a k i n gam o r ea c c u r a t ea s s e s s m e n to fp r e d i c t i v ev a l u e s ,i t
may be best to exclude all signals and non-warning signals
after an ACS until patients are clinically stable. Similarly, in
the same patient, we found that signals could precede the
clinical diagnosis by up to 68 days. In this study, signals oc-
curring earlier than 2 weeks before diagnosis were false
positives but in this patient, it could be argued on clinical
grounds that they were true positives. Nevertheless, it has
been reported in the literature that most cases of unstable
angina last for up to 2 weeks and that is why we chose this
as a cut-off for an early warning period.
A high proportion of signals were associated with
symptoms that were considered to be atypical for angina.
To reduce such false positive signals, patients could be
advised that the character of angina rarely changes,
except in diabetics and after cardiac surgery.
Fig. 2 Heart rates before and after diagnosis of unstable angina for the ninth case of ACSWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 5 of 7

Strengths and limitations of this study
The main strengths of this study are its prospective
design and the lack of restrictions on treatment. In fact,
prescription of negatively chronotropic drugs was high
(Table 1) and yet, signal HRs were recorded from 20 of
43 patients who had angina.
A limitation of our study was the relatively small
sample size because despite the fact that we had selected
a high risk population, there was a smaller than antici-
pated number of ACS events. It remains to be seen
whether our findings would be replicated in a population
with lower risk coronary disease although there appears
to be no biological reason to expect a difference. Less
than 50 % of heart attacks occur de novo in patients
without known coronary disease and an interesting
question would be how successful a strategy of measur-
ing HR would be in people presenting for the first time
with chest pain that could be angina.
Unfortunately, HR data were only available for
64.8 % of documented angina episodes and patients
did not always have their ECG recorders with them.
It is possible that modern technology which in-
creases the portability and availability of suitable de-
vices may improve the compliance for HR
measurements.
Comparison with other studies
We are not aware of any other study that has attempted
to determine whether an episode of angina is unstable
by measuring a physiological variable. In clinical prac-
tice, patients are taught to recognise the features of chest
pain that may indicate the onset of MI [5] but still,
patients often present late. Even in this study where
patients received continuous reminders of the character-
istics of unstable angina, 2 patients failed to seek medical
attention at the time of unstable symptoms. Further
investigation is needed to determine whether HR data
indicative of unstable angina coupled with an appropri-
ate alarm helps patients to seek medical attention earlier.
Hopefully, patient self-monitoring will augment the trad-
itional approach of patient education and improve
clinical outcomes.
Conclusions
Low HR angina may identify unstable angina and warn
of impending myocardial infarction. In contrast, angina
at higher heart rates indicates that ACS is very unlikely.
Therefore, HR data may help high risk patients receive
earlier treatment whereas it may reduce hospital admis-
sions amongst those without ACS. Whether anginal HR
can improve clinical outcomes needs to be tested in an
interventional study.Competing interests
YK Wong holds US Patent No. 8 260 410, European patent No 07824606.3
2319 and Japanese patent No 2009-536793 for a Myocardial Infarction Early
Warning Device.
Authors ’contributions
YW generated the idea for the study. YW, SM and SS developed the study.
YW and BH analysed the data. YW wrote the paper. All authors reviewed and
revised the paper and have given final approval. YW is guarantor.
Acknowledgements
This article represents independent research funded by the Department of
Health under the NIHR Research for Innovation, Speculation and Creativity
(RISC) Programme (grant number RC-PG-0308-10219). The views expressed in
this publication are those of the authors and not necessarily those of the
NHS or the Department of Health. We thank Michal Ong, Steven Dixon, and
Suneil Aggarwal for help with reading the ECGs. We also thank all of our
patients, who recorded almost 30,000 ECGs.
Author details
1Department of Cardiology, St. Richard's Hospital, Western Sussex Hospitals
NHS Foundation Trust, Spitalfield Lane, Chichester, West Sussex PO19 4SE,
UK.2Statistics and Research, University of Chichester, Chichester, UK.
Received: 22 June 2015 Accepted: 2 November 2015
References
1. Birkhead JS, Walker L, Pearson M, Weston C, Cunningham AD, Rickards AF.
Improving care for patients with acute coronary syndromes: initial results
from the National Audit of Myocardial Infarction Project (MINAP). Heart.
2004;90(9):1004 –9.
2. Saczynski JS, Yarzebski J, Lessard D, Spencer FA, Gurwitz JH, Gore JM, et al.
Trends in prehospital delay in patients with acute myocardial infarction
(from the Worcester Heart Attack Study). Am J Cardiol.
2008;102(12):1589 –94.
3. Spencer FA, Montalescot G, Fox KA, Goodman SG, Granger CB, Goldberg RJ,
et al. Delay to reperfusion in patients with acute myocardial infarction
presenting to acute care hospitals: an international perspective. Eur Heart J.
2010;31(11):1328 –36.
4. Educational strategies to prevent prehospital delay in patients at high risk
for acute myocardial infarction: a report by the National Heart Attack Alert
Program. J Thromb Thrombolysis. 1998; 6(1):47 –61.
5. Khavandi A, Potts K, Walker PR. Advising patients on dealing with acute
chest pain. BMJ. 2007;335(7609):3 –4.
6. Kouvaras G, Bacoulas G. Unstable angina pectoris as a warning symptom
before acute myocardial infarction. Q J Med. 1987;64(244):679 –84.
7. Madsen JK. Ischaemic heart disease and prodromes of sudden cardiac
death. Is it possible to identify high risk groups for sudden cardiac death? Br
Heart J. 1985;54(1):27 –32.
8. Stowers M, Short D. Warning symptoms before major myocardial infarction.
Br Heart J. 1970;32(6):833 –8.
9. Wood P. Acute and subacute coronary insufficiency. Br Med J.
1961;1(5242):1779 –82.
10. Solomon HA, Edwards AL, Killip T. Prodromatan acute myocardial infarction.
Circulation. 1969;40(4):463 –71.
11. Higginbotham MB, Morris KG, Williams RS, McHale PA, Coleman RE, Cobb
FR. Regulation of stroke volume during submaximal and maximal upright
exercise in normal man. Circ Res. 1986;58(2):281 –91.
12. Wong YK, Dawkins S, Grimes R, Smith F, Dawkins KD, Simpson IA. Improving
the positive predictive value of exercise testing in women. Heart.
2003;89(12):1416 –21.
13. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey Jr DE, et
al. ACC/AHA 2007 guidelines for the management of patients with unstable
angina/non-ST-Elevation myocardial infarction: a report of the American
College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Revise the 2002 Guidelines for the
Management of Patients With Unstable Angina/Non-ST-Elevation
Myocardial Infarction) developed in collaboration with the American
College of Emergency Physicians, the Society for Cardiovascular
Angiography and Interventions, and the Society of Thoracic SurgeonsWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 6 of 7

endorsed by the American Association of Cardiovascular and Pulmonary
Rehabilitation and the Society for Academic Emergency Medicine. J Am Coll
Cardiol. 2007;50(7):e1 –e157.
14. Campeau L. Letter: grading of angina pectoris. Circulation. 1976;54(3):522 –3.
15. Thygesen K, Alpert JS, White HD, Jaffe AS, Apple FS, Galvani M, et al. Universal
definition of myocardial infarction. Circulation. 2007;116(22):2634 –53.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
www.biomedcentral.com/submitWong et al. BMC Cardiovascular Disorders (2015) 15:148 Page 7 of 7