Discussion
Stress echocardiography has become an established and mature technique
for the assessment of CAD.1 Interpretation remains
challenging, even with experienced practitioners.1,2Additional parameters can be utilised to assist with this difficult
interpretation, including strain and strain rate,16,17 and assessments of diastolic function.1,18 None of these have become routine practice.
Left ventricular SV is the amount of blood ejected with each heartbeat.
It is the difference between the end-diastolic volume and end systolic
volume. 11,19-20 Exercise results in an increase in
cardiac contractility. The changes in the mechanical properties of
contracting cardiac muscle fibers with changes in inotropy results in an
increase in SV. 11,19-20 A decrease in cardiac
contractility causes a downward shift in the Frank-Starling curve, with
subsequent drop in SV (and an increase in left ventricular end diastolic
pressure). 11,19-20 Myocardial ischemia results in
changes in contractile state of the ventricle. These changes result in
alterations to SV and CO. 11,20-21
Mechanistically, active human systems require a constant blood supply
with delivery of oxygen and nutrients and removal of waste products to
function normally. Exercise increases these requirements. Any alteration
in supply (e.g. inducible myocardial ischemia) reduces provision of
these essential roles, resulting in decreased function. At a ventricular
level this results in a drop in SV (and CO). 11,19-21These alterations are due to changes in systolic (via a loss of
intrinsic inotropy) and diastolic (loss of compliance) function. Left
ventricular contractility has been shown to change similarly to SV.20,22 At a basic science level, nitric oxide
inhibition at an endothelial level results in hemodynamic
changes.24,25
Echocardiography can reliably estimate SV and CO, before and after
stress testing. (see Materials and
Methods).7,11,18,26,27 The changes in SV and measures
of diastolic function have been shown to be reliable when compared to
invasive techniques.18,28-31 Changes in Doppler
echocardiography have been documented in the setting of CAD.32-34 These concepts contributed to the hypothesis
that SV could be a simple and readily measurable parameter to assist
with analysis for stress echocardiography.
This study was designed prospectively to measure SV before and after
treadmill exercise, and then to subsequently look at adverse cardiac
outcomes in follow-up, as a method of validation. Estimation of the SV
before and after exertion provided additional, complimentary and
confirmatory information when added to the traditional stress
echocardiogram analysis. The estimated SV was used for analysis, as it
was a purer and simpler value (there was significantly more variation
with the CO estimations, due to marked variability between patients with
respect to heart rate, at rest and after stress). Indexing SV resulted
in a lower AUC and lower sensitivity and specificity. As such SV was
preferred to SVi. A significant increase in SV with
exertion is a normal response. An inadequate response was shown to be
either a decrease or a mild increase (<10ml). This suboptimal
SV increment with exertion resulted in significantly worse cardiac
prognosis compared to patients who had an appropriate increase in these
volumes.
It is proposed that this suboptimal SV change is a marker of ischemia
and the increase in events were likely to be driven by this. Its
negative predictive value is very high, adding reassurance to negative
studies. An abnormal result associated with a non-ischemic SE may prompt
consideration for a more careful analysis of the regional wall motion
analysis, or further clinical evaluation. The SV analysis appears to
provide statistically incremental analytical and prognostic information
to the standard SE evaluation.
An interesting subset of patients were those with a non-ischemic SE, but
an abnormal ΔSV. These patients had increased risk compared to
non-ischemic patients with a normal ΔSV response to exertion, even
following adjustment for age, gender, EF, exercise capacity and
Framingham risk (see Figure 5). Careful re-evaluation of the SE did not
reveal post exertion regional wall motion abnormalities or reduced
cardiac augmentation. Looking at the individual cases, the events for
this cohort appeared to be ischemic in nature. Possible reasons for an
abnormal ΔSV despite a non-ischemic SE could include a false negative
SE, endothelial dysfunction, subclinical ischemia, inducible diastolic
dysfunction (except that E/e’ did not universally correspond with these
abnormal ΔSV cases), exercise induced pulmonary hypertension, or by
chance. These patients did not have increased wall thickness on
echocardiography compared to those with a normal ΔSV. These changes may
represent myocardial alterations that are too subtle for visual
detection. As the events in this subset appear to be ischemic, this may
the driver and the most likely explanation. This finding suggests an
incremental value for assessing ΔSV in SE.
This technique is quick and readily performed and has been shown here to
be valid when measured after the routine regional wall motion analysis.
It can be performed in the vast majority of patients. It requires no
additional equipment or preparation. It adds only seconds to the resting
echocardiogram and to the post exercise analysis and can be done after
regional wall analysis but before the estimations of diastolic
function.18 The proposed cut-off appears to apply for
the detection of ischemia and for the detection of adverse cardiac
events.
Previous studies have looked at using LV volumes as a marker of coronary
artery disease. 35,36 These studies used planimetry
and the Simpson’s biplane method. This volume measurement essentially
documents a change in EF. This method is more time consuming than the
Doppler technique and has limitations including the geometrical
assumptions used to assess LV function, alignment issues (particularly a
problem during exercise stress echocardiography), frequent
foreshortening of the ventricle, and the influence of load-dependent
factors during functional assessment.10,37 Suboptimal
endocardial definition further reduces the accuracy of this technique.
Regional wall motion abnormalities make dynamic assessment even more
challenging.10,37 The Doppler estimation of SV
measures a change in ventricular volume utilising a different technique
which has been shown here to be independent of EF. This Doppler
technique has previously been shown to be feasible in dobutamine stress
echocardiography to estimate CO 11 but has not been
used in the manner described in this study.
There are limitations with respect to this observational cohort. Ideally
these measurements would have been compared to invasive measurements to
confirm the diagnosis and measure SV invasively, blindly. Practically,
ethically and from the clinical perspective, this was not feasible and
would have negated the non-invasive attribute of stress
echocardiography. The ethical concerns refer to universally invasively
testing low to intermediate risk patients. 19,38-40The accuracy of SE for detection of myocardial ischemia has already been
previously documented and validated. 1,2,39,40 In
general, stress echocardiography is used to attempt to avoid an invasive
test. Clinically, a select group of patients (as determined by the
treating physician, and independent and blinded to the study) had an
anatomical evaluation, which confirmed the efficacy and accuracy of SE.
The median WMSI values were significantly different for non-ischemic
patients in both the derivation and validation cohorts.
Baseline clinical characteristics were documented but blood tests were
not performed. This was done to simplify the study and minimise the
intrusion on the volunteers. Baseline bloods potentially could have
added further data to the interpretation of these results.
Inconsistency in the measurement of SV may lead to a lack of
reproducibility. Significant variability in the SV measurement could
compromise the cut-off values. However, the difference between the mean
ΔSV and the cut-off values were marked (see Table 2) and unlikely to
fall within the margin of error of acquisition. The estimation of SV
requires an accurate measurement of the left ventricular outflow tract.
A small error in this measurement magnifies the
error.10,37 Previous studies have suggested that the
echocardiographic measurement of SV is an accurate and reproducible
technique.3-5, 44 In order to minimise inter-reader
variability, a single experienced, echocardiography subspecialty
cardiologist measured all the stroke volume data, blinded to the
outcomes. This may reduce the applicability of these data to the wider
community but minimised errors.
Whilst patients achieved a mean 98±19% of maximum predicted heart rate
at peak exercise, by the time the SV was acquired, this value had
reduced to 68±25%, well below the value recommended to maximise
sensitivity for detection of ischemia. 38,45,46Despite this, abnormal ΔSV values predicted prognostic differences,
suggesting that delaying this measurement until after the regional wall
motion analysis still provides valid and valuable additional information
to the standard test method.
It is possible that the results were simply due to the presence or
absence of ischemia, or reflective of the changes in ejection fraction
post exertion. However, patients with a normal ΔSV were seen in the
ischemic group, and an abnormal ΔSV was seen in patients with a
non-ischemic SE. All patients with a non-ischemic SE had a normal
increase in EF post exertion. The data presented here suggest that ΔSV
is a more sensitive marker of events than EF or a normal SE response.
The estimation of SV cannot be performed in all patients. Heart rate did
not produce any issues, but peak exercise image quality occasionally
limited the completeness of the Doppler envelope, resulting in
inadequate measurements. In most cases, image quality had less of an
impact on the ability to estimate Doppler signals. Irregular electrical
rhythms, especially bigeminy resulted in Doppler signals that were
difficult to accurately measure. These incomplete measurements only
occurred in a very small percentage of patients. Stroke volume could be
successfully compared pre and post exercise in approximately 94% of
these stress echocardiograms.
In this non-randomized, single center cohort study, there were some
apparent differences between the groups at baseline (see Table 1).
Despite presentation of the adjusted estimates, these baseline
differences may have influenced the outcomes presented here.
The evaluation of the medical records was a potential source of
ascertainment bias. It is possible for events to occur at other centres,
and potentially not be recorded in these patient reviews. The ischemic
patients may have been assessed more closely due to the results of the
stress test, resulting in a higher reporting of events. However, given
these patients had significantly more abnormal ΔSV measurements, an
under-detection of events in this group would not be expected to
influence these results. The SV analysis was conducted after events had
occurred, and the results were not communicated to the clinicians, as
the implications were not apparent at the time of data collection. While
failure to appropriately account for missing data in analyses may lead
to bias and loss of precision, imputation of missing results also
requires additional assumptions. To have completed this analysis with
complete data rather than imputation of missing values may not have been
associated in an epidemiological context with substantial bias in
reported regression estimates.15,41
The multivariable prediction model described in the present study was
derived from echocardiographic observations at a single center. There
were significantly less women than men (a common problem in cardiac
research). This does reflect real world experiences and this particular
study population. 18,42,43 The investigators were not
blinded to the results of the stress test, making it possible for biases
(including ascertainment bias) to occur. Overall event rates were low,
especially in the non-ischemic patients. The present model would benefit
from validation within an independently collected data set from a
separate population.
The broad referral pattern of these patients does suggest that the
utility of measuring SV could be extended to the general stress test
population.