Impact of Duration of Ischemia on Left Ventricular Diastolic

Properties Following Reperfusion for Acute Myocardial Infarction

Sandhir B. Prasad, MBBSa, Valerie See, BSca, Paula Brown, BSca, Tania McKay, BSca,
Arun Narayan, BSca, Pramesh Kovoor, MBBS, PhDa, and Liza Thomas, MBBS, PhDa,b,*
We sought the correlation between duration of myocardial ischemia and severe left ven-
tricular (LV) diastolic dysfunction (restrictive filling pattern [RFP]) in patients with acute
ST-elevation myocardial infarction (STEMI). Duration of ischemia determines infarct size
and survival after STEMI. However, the impact of duration of ischemia on LV diastolic
function has not been previously studied. Ninety-five consecutive patients with first-ever
STEMI underwent transthoracic echocardiography 3 days after primary percutaneous
coronary intervention (PCI). RFP was defined as a mitral inflow E/A ratio >2.0 and/or
E-wave deceleration time <140 ms. Composite major adverse cardiovascular events (death,
reinfarction, heart failure, revascularization) were determined at 12 months. Twenty pa-
tients (21%) had RFP on day 3. Symptom-to-reperfusion time in the RFP group was 413 ⴞ 287
versus 252 ⴞ 138 minutes in the non-RFP group (p ⴝ 0.014). Peak troponin T levels were
higher in the RFP group (12.2 ⴞ 8.4 vs 5.7 ⴞ 3.6 ng/ml, p ⴝ 0.002). Logistic regression
identified symptom-to-reperfusion time (hazard ratio 1.02, 95% confidence interval 1.01 to 1.03,
p ⴝ 0.010) and infarct size by peak troponin T levels (hazard ratio 1.54, 95% confidence interval
1.14 to 2.10, p ⴝ 0.005) as independent predictors of RFP. Major adverse cardiovascular events
occurred in 10 patients (50%) in the RFP group and 6 patients (8%) in the non-RFP group. On
multivariate Cox proportional hazards analysis, RFP was an independent predictor of major
adverse cardiovascular events at 12 months (hazard ratio 5.43, 95% confidence interval 1.52 to
19.39, p ⴝ 0.001). In conclusion, delayed reperfusion after STEMI was associated with severe
LV diastolic dysfunction, which in turn independently predicted adverse long-term outcomes.
LV diastolic dysfunction represents a significant pathophysiologic link among duration of
myocardial ischemia, infarct size, and outcomes. © 2011 Elsevier Inc. All rights reserved. (Am
J Cardiol 2011;108:348 –354)

In Doppler echocardiographic assessment of left ventric-
ular (LV) diastolic function, mitral inflow restrictive filling
pattern (RFP) is associated with severe LV diastolic dys-
function and increased LV filling pressures.1,2 RFP has been
extensively studied as a prognostic marker after acute myo-
cardial infarction, with a recent meta-analysis demonstrat-
ing a threefold increase in risk of death in patients with RFP
after acute myocardial infarction.3 However, although the
prognostic importance of diastolic dysfunction after acute
myocardial infarction has been reported, the impact of
symptom-to-reperfusion time and infarct size on LV dia-
stolic function after acute myocardial infarction has not
been defined. We sought to determine the relation between
symptom-to-reperfusion time and severe LV diastolic dys-
function defined as RFP in patients presenting with first-
ever ST-elevation myocardial infarction (STEMI) who un-
derwent successful reperfusion with primary percutaneous
a
Westmead Hospital, Westmead, Sydney, New South Wales, Australia;
b
Liverpool Hospital/University of New South Wales, Sydney, New South
Wales, Australia. Manuscript received February 17, 2011; revised manu-
script received and accepted March 22, 2011.
Dr. Prasad was supported by Grant 1602 from the National Heart
Foundation of New Zealand, Auckland, New Zealand during the prepara-
tion of this report.
*Corresponding author: Tel: 02-9828-3797; fax: 02-96870422.
E-mail address: l.thomas@unsw.edu.au (L. Thomas).
coronary intervention (PCI). We hypothesized that severity
of LV diastolic impairment after acute MI would be time
dependent and that RFP would be associated with a longer
symptom-to-reperfusion time.
Methods
We prospectively studied 95 consecutive patients pre-
senting with first-ever STEMI who underwent primary PCI.
All patients enrolled in the present study were part of a
larger multicenter prospective study to evaluate the mortal-
ity benefit of prehospital triage of patients with STEMI, the
results of which have been previously published.4 The study
was approved by the institutional human research ethics
committee and written informed consent was obtained from
each participant. Patients with significant valvular disease
(greater than moderate regurgitation or stenosis or a pros-
thetic valve), atrial fibrillation, paced rhythm, known car-
diomyopathy, and previous acute MI were excluded, as
were patients with significant hemodynamic instability (re-
quirement for mechanical ventilation, inotropes, or intra-
aortic balloon pump and those with ventricular tachyar-
rhythmia). Patients with failed reperfusion (n ⫽ 4) were also
excluded because of an inability to accurately pinpoint a
“reperfusion” time. All clinical, angiographic, and fol-
low-up data were prospectively collected by a team of
clinical monitors and cardiologists. Echocardiographic data

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. www.ajconline.org
doi:10.1016/j.amjcard.2011.03.051
 Coronary Artery Disease/Ischemia Duration and LV Diastolic Function 349

were collected separately by an independent team of inves- Table 1

tigators blinded to clinical, angiographic, and outcome data. Baseline clinical and angiographic characteristics
This process ensured blinding of investigators in the 2 teams Characteristic RFP Group Non-RFP Group p Value
to key data elements during data collection. (n ⫽ 20) (n ⫽ 75)
Comprehensive transthoracic echocardiography was per- Age (years) 62.3 ⫾ 12.4 63.4 ⫾ 13.1 0.788
formed on day 3 using a Vivid 7 machine (General Electric, Men 14 (70%) 56 (77%) 0.484
Horton, Norway) with tissue Doppler imaging software and Hypertension 11 (55%) 49 (65%) 0.313
a 2.5- to 5-MHz variable-frequency phased-array transtho- Diabetes mellitus 7 (35%) 13 (17%) 0.062
racic transducer. It was assumed that a patient’s clinical Hypercholesterolemia 9 (45%) 45 (60%) 0.310
status and loading conditions would be stabilized by day 3 Smoker 8 (40%) 25 (33%) 0.285
after STEMI. The echocardiographic protocol (performed Previous percutaneous 1 (5%) 7 (9%) 0.465
by 2 experienced sonographers, P.B. and T.M.) followed a coronary
intervention
standard format with image acquisition from parasternal, Acute pulmonary 6 (30%) 6 (8%) 0.033
apical, and subcostal acoustic windows and included 2-di- edema
mensional, color flow mapping, continuous and pulse-wave Thrombolysis In
Doppler, and tissue Doppler imaging. Detailed measure- Myocardial
ments of day 3 echocardiograms were performed offline by Infarction flow
2 trained sonographers (S.B.P. and V.S.) who were blinded grade
to angiographic and outcomes data. Three measurements Before percutaneous
were obtained for each parameter and averaged. coronary
intervention
LV systolic function was assessed by LV ejection frac-
0 14 (70%) 56 (75%) 0.523
tion obtained using the Simpson biplane method of discs 1 1 (5%) 1 (1%)
from apical 4- and 2-chamber views. Mitral inflow Doppler 2 2 (10%) 8 (11%)
was obtained by placing a 1-mm pulse-wave sample box at 3 3 (15%) 12 (16%)
the mitral leaflet tips in the apical 4-chamber view at end- After percutaneous
expiration using a sweep speed of 100 mm/s. Tissue Dopp- coronary
ler imaging was obtained by placing a 2-mm pulse-wave intervention
sample box at the septal and lateral mitral annulus. In 0 0 0 0.544
1 0 1 (1%)
addition, the average of septal vector of left ventricular
2 2 (10%) 2 (3%)
relaxation in early diastole as measured by tissue Doppler 3 18 (90%) 72 (96%)
(e=) and lateral e= velocities were calculated (average e=) Number of arteries 0.220
according to American Society of Echocardiography rec- narrowed
ommendations.1 The ratio of mitral inflow E-wave velocity 1 7 (35%) 36 (48%)
to e= was calculated using mitral inflow E-wave velocity and 2 6 (30%) 22 (29%)
septal e=, lateral e=, and average of septal and lateral e=. 3 7 (35%) 19 (25%)
Grades of diastolic dysfunction was defined as follows: RFP Proximal narrowings 4 (20%) 10 (13%) 0.158
was defined as mitral inflow E/A ratio ⬎2.0 and/or E-wave Angiographic success 19 (95%) 71 (95%) 0.786
deceleration time ⬍140 ms, and pseudonormal filling was
recognized as a mitral inflow E/A ratio of 1.0 to 2.0, decel- Key data elements concerning time of infarct symptom
eration time 140 to 250 ms, and an average of septal and onset and time of reperfusion were collected initially in real
lateral e= values (average e=) ⬍8 cm/s.1 Patients with neither time at time of presentation and treatment and then verified
RFP nor pseudonormal filling were grouped together as at a later time point by a clinical nurse monitor and cardi-
having normal/mild diastolic dysfunction. ologist. Symptom-to-reperfusion time (see definitions be-
Angiographic coronary artery stenosis was defined as low) in particular was verified and documented on 2 occa-
luminal diameter narrowing ⱖ50%. Coronary artery blood sions: (1) by the interventional cardiologist at time of PCI
flow was defined according to standardized Thrombolysis In and (2) by the treating cardiologist and clinical nurse mon-
Myocardial Infarction grades 0 to 3: grade 0, no contrast itor on the ward the next day. Disagreements were recon-
flow beyond site of occlusion (no perfusion); grade 1, con- ciled by a committee of the 2 cardiologists and the clinical
trast flow beyond site of occlusion but failing to opacify nurse monitor. Troponin T assays (peak troponin T) were
entire artery; grade 2, contrast flow beyond site of occlusion performed serially at admission and then at 12, 24, 48, and
and opacification of entire artery but at a rate slower than 72 hours to determine enzymatic infarct size based on pre-
normal; and grade 3, normal flow with opacification of vious studies showing excellent correlation between peak
entire artery at a normal rate.5 A culprit artery was defined troponin levels and the “gold standard” comparator of car-
as an artery with an identifiable thrombotic and hemody- diac magnetic resonance imaging in the postinfarct setting.6
namically significant lesion on angiogram corresponding to Telephone follow-up was obtained in all patients at 12
electrocardiographic changes. Angiographic success was months by an independent research nurse who was blinded
defined as ⬍30% residual stenosis and Thrombolysis In to echocardiographic data. When patients were unable to be
Myocardial Infarction grade 3 flow. Angiographic data were contacted, contact was made with next of kin or the family
prospectively entered into a dedicated institutional primary doctor to verify mortality status. Composite end point of
PCI database. major adverse cardiac events, comprising cardiac death,
350 The American Journal of Cardiology (www.ajconline.org)

Table 2
Echocardiographic data
Variable RFP Group Non-RFP Group p Value
(n ⫽ 20) (n ⫽ 75)

Biplane left ventricular ejection fraction (%) 45.7 ⫾ 8.5 51.2 ⫾ 7.0 0.004
Heart rate (beats/min) 82 ⫾ 18 71 ⫾ 12 0.001
Systolic blood pressure (mm Hg) 132 ⫾ 19 137 ⫾ 33 0.871
Diastolic blood pressure (mm Hg) 84 ⫾ 12 78 ⫾ 18 0.671
Left ventricular end-diastolic dimension (mm) 53.3 ⫾ 6.7 50.1 ⫾ 6.0 0.044
Left ventricular end-systolic dimension (mm) 39.0 ⫾ 8.0 34.7 ⫾ 5.7 0.008
Septal thickness (mm) 10 ⫾ 2 11 ⫾ 2 0.212
Posterior wall thickness (mm) 10 ⫾ 2 11 ⫾ 2 0.183
Left atrial volume (ml) 47.3 ⫾ 25.2 34.4 ⫾ 12.6 0.017
Mitral inflow E wave (cm/s) 87.4 ⫾ 26.6 70.9 ⫾ 16.8 0.002
Mitral inflow A wave (cm/s) 41.3 ⫾ 15.0 71.1 ⫾ 14.3 ⬍0.001
Mitral inflow E/A ratio 2.1 ⫾ 0.6 1.1 ⫾ 0.9 ⬍0.001
Mitral E deceleration time (ms) 125.9 ⫾ 20.3 215.2 ⫾ 46.8 ⬍0.001
Septal e= (cm/s) 5.7 ⫾ 1.5 6.0 ⫾ 2.0 0.422
Lateral e= (cm/s) 8.7 ⫾ 2.5 7.7 ⫾ 2.2 0.240
Average septal/lateral e= (cm/s) 7.1 ⫾ 1.8 6.8 ⫾ 1.7 0.651
E-wave velocity/septal e= 15.5 ⫾ 4.7 12.0 ⫾ 4.8 0.011
E-wave velocity/lateral e= 9.6 ⫾ 2.7 10.1 ⫾ 4.6 0.716
E-wave velocity/average septal/lateral e= 11.4 ⫾ 2.9 11.0 ⫾ 3.8 0.759
Pulmonary vein S-wave velocity (cm/s) 5.2 ⫾ 1.2 5.4 ⫾ 1.2 0.423
Pulmonary vein D-wave velocity (cm/s) 5.1 ⫾ 1.6 4.0 ⫾ 1.0 ⬍0.001
Pulmonary vein S-wave/D-wave ratio 1.1 ⫾ 0.5 1.4 ⫾ 0.3 0.004
Pulmonary vein A-wave velocity (cm/s) 3.9 ⫾ 1.6 3.2 ⫾ 1.6 0.299

reinfarction, target vessel revascularization (coronary artery
bypass grafting or PCI), and heart failure, were used to
adjudicate long-term outcomes.
Acute STEMI was defined according to current guide-
lines as a cluster of chest pain or equivalent presenting
symptoms, electrocardiogram showing STE ⱖ1 mm in ⱖ2
contiguous leads, or new-onset left bundle branch block and
enzymatic confirmation with cardiac troponin T increase to
3 times the upper limit of normal.7 Symptom-to-reperfusion
time was defined as time from first symptom referable to
acute STEMI (usually chest pain or discomfort) to restora-
tion of Thrombolysis In Myocardial Infarction grade 3 flow
in the catheterization laboratory. RFP was defined as mitral
inflow E/A ratio ⬎2.0 and/or E-wave deceleration time
⬍140 ms based on definitions in current guidelines.1 This
definition was previously used by the Meta-Analysis Re-
search Group in Echocardiography Acute Myocardial In-
farction (MeRGE-AMI) collaborators in a large meta-anal-
ysis of patients with restrictive filling after acute AMI and is
thus reflective of a large body of previous work in this
field.6 Significant coronary stenosis was defined as luminal
diameter narrowing ⱖ50% on coronary angiogram.
Heart failure during follow-up was defined as dyspnea
accompanied by findings of increased jugular venous pres-
sure, basal crepitations, and peripheral edema with radio-
graphic confirmation on chest x-ray. Hypercholesterolemia
was defined as fasting total serum cholesterol level ⬎5
mmol/L. Hypertension was defined as serial blood pressure
measurements ⬎140/90 mm Hg.
Continuous variables are expressed as mean ⫾ SD and
were compared using unpaired t test if data were normally
distributed or Mann–Whitney U test if data were not nor-
mally distributed. Group comparisons for symptom-to-reper-
fusion time and peak troponin T used nonparametric methods
(Mann–Whitney U test) because data were skewed. Categori-
cal variables are presented as number (percentage) and com-
pared using Fisher’s exact test. Independent predictors of
RFP were identified using logistic regression analysis. Vari-
ables significant at a p value ⬍0.05 on univariate analysis
were entered into multivariate logistic regression analysis.
Survival was plotted using the Kaplan–Meier method, and
mortality rates were compared using log-rank test. Further
survival analysis was performed using Cox proportional
hazard models. Individual predictors of outcome were iden-
tified using univariate Cox analysis, and independent pre-
dictors of outcome were determined using multivariate Cox
analysis incorporating factors significant at a p value ⬍0.05
in univariate analysis. Correlation between symptom-to-
reperfusion time and LV ejection fraction were determined
using Pearson correlation coefficient. Three-way between-
group comparisons among restrictive, pseudonormal, and normal/
mild diastolic dysfunction groups were performed with 1-way
analysis of variance with post hoc comparisons using the
Tukey honest significance test (HSD) test. A p value ⬍0.05
was considered statistically significant. All statistical anal-
yses were carried out using SPSS 14 (SPSS, Inc., Chicago,
Illinois).
Results
Ninety-five patients met the study criteria; 20 patients
(21%) had RFP and 75 (79%) did not. Table 1 presents
clinical characteristics and angiographic data. There were
no significant differences between the 2 groups in age,
gender, or cardiovascular risk factors, although diabetes did
show a trend toward greater prevalence in the RFP group (7
 Coronary Artery Disease/Ischemia Duration and LV Diastolic Function 351

Figure 1. Comparison of peak troponin (Trop) T levels.

Figure 2. Comparison of symptom-to-reperfusion times.

in RFP group, 35%, vs 13 in non-RFP group, 17%, p ⫽
0.10). More patients in the RFP group had acute pulmonary
edema (6 in RFP group, 30%, vs 6 in non-RFP group, 8%,
p ⫽ 0.033). However, all 12 patients with evidence of LV
failure on presentation were clinically stable at the time of
day 3 echocardiogram. There were no baseline differences
between the 2 groups in rates of prescription of aspirin,
statins, ␤ blockers, and angiotensin-converting enzyme in-
hibitors or angiotensin receptor blockers after admission to
the coronary care unit.
There were no differences between groups in culprit
artery, pre- and postprocedure Thrombolysis In Myocar-
352 The American Journal of Cardiology (www.ajconline.org)
Table 3
Multivariable predictors of restrictive filling
Variable OR 95% CI
Symptom-to-reperfusion time 1.02 1.01–1.03
Peak troponin T 1.54 1.14–2.10
Left atrial volume 1.04 0.99–1.08
CI ⫽ confidence interval; OR ⫽ odds ratio.
dial Infarction flow grades, or extent of coronary artery
disease (Table 1). Approximately 1/2 of all patients had
evidence of left anterior descending coronary artery in-
volvement, 70% had complete occlusion of the culprit
artery (Thrombolysis In Myocardial Infarction grade 0
flow), and Thrombolysis In Myocardial Infarction grade
3 flow was successfully restored in ⱖ90% of patients in
the 2 groups. Only 2 proximal left anterior descending
coronary artery lesions were present in the entire study
group. No difference was present between groups in
presence of proximal lesions (4 in RFP group, 20%, vs 10
in non-RFP group, 13%, p ⫽ NS), although the number
of proximal lesions was small.
A summary of echocardiographic data are presented in
Table 2. LV end-systolic dimension was significantly in-
creased in the RFP group (39.0 ⫾ 8.0 vs 34.7 ⫾ 5.7 mm,
p ⫽ 0.008), whereas LV ejection fraction was significantly
lower in the RFP group (45.7 ⫾ 8.5% vs 51.2 ⫾ 7.0%, p ⫽
0.004). Left atrial volume was larger in the RFP group (47.3 ⫾
25.2 vs 34.4 ⫾ 12.6 ml, p ⫽ 0.017). One patient in each
group had moderate mitral regurgitation (severe mitral re-
gurgitation was an exclusion criterion). Mitral inflow pat-
tern had, by definition, a higher mitral inflow E-wave ve-
locity, lower mitral inflow A-wave velocity, increased
mitral inflow E/A ratio, and shorter mitral inflow E-wave
deceleration time in the RFP group. Septal e= velocity was
decreased in the 2 groups, suggesting at least mild diastolic
dysfunction in the 2 groups (5.7 ⫾ 1.5 cm/s in RFP group
vs 6.0 ⫾ 2.0 cm/s in non-RFP group, p ⫽ NS). However,
noninvasively determined filling pressures using the ratio
of mitral inflow E-wave velocity to septal e= suggested
increased filling pressures only in the RFP group (ratio of
mitral inflow velocity E-wave velocity to septal e= 15.5 ⫾
4.7 in RFP group vs 12.0 ⫾ 4.8 in non-RFP group, p ⫽
0.011).
Symptom-to-reperfusion time was significantly longer in
the RFP group (413 ⫾ 287 minutes in RFP group vs 252 ⫾
138 minutes non-RFP group, p ⫽ 0.014; Figure 1). Three-
way group comparisons of symptom-to-reperfusion time by
analysis of variance with post hoc Tukey HSD test demon-
strated a significant difference between the RFP group and
the pseudonormal and the normal/mild diastolic dysfunction
groups but no significant differences between the latter
2 groups (RFP group 413 ⫾ 287 minutes vs pseudonormal
group 258 ⫾ 166 minutes vs normal/mild diastolic dysfunc-
tion group 248 ⫾ 142 minutes, p ⫽ 0.005). Furthermore,
when patients were divided into quartiles of symptom-to-
reperfusion time, 9 patients (45%) in the RFP group were in
the highest quartile of symptom-to-reperfusion time com-
pared to 17 (23%) in the non-RFP group (p ⫽ 0.021).
Peak troponin T levels were higher in the RFP group
(12.2 ⫾ 8.4 ng/ml in RFP group vs 5.7 ⫾ 3.6 ng/ml in
non-RFP group, p ⫽ 0.002; Figure 2), suggesting an asso-
ciation between RFP and enzymatically determined infarct
p Value size. Three-way group comparisons of peak troponin T
levels by analysis of variance with post hoc Tukey HSD test
0.010
suggested a significant difference between the RFP group
0.005
0.066
and the pseudonormal and the normal/mild diastolic dys-
function groups but no significant differences between the
latter 2 groups (RFP group 12.2 ⫾ 8.4 ng/ml vs pseudonor-
mal group 6.2 ⫾ 3.3 ng/ml vs normal/mild diastolic dys-
function group 5.5 ⫾ 4.0 ng/ml, p ⬍0.001).
In a logistic regression model incorporating significant
individual predictors of RFP (symptom-to-reperfusion time,
peak troponin T, left atrial volume, biplane LV ejection
fraction), symptom-to-reperfusion time and peak troponin T
levels emerged as independent predictors of RFP (Table 3).
Left atrial volume, although not statistically significant,
showed a trend toward an independent association with RFP
(Table 3).
There were 16 major adverse cardiovascular events at
12-month follow-up, with 10 events in the RFP group
(50%) and 6 events in the non-RFP group (8%). Events
were driven mainly by heart failure (5 events, 32%) and
revascularization (8 events, 50%), with only 2 deaths in the
entire cohort that occurred in the RFP group. On univariate
Cox proportional hazards analysis, RFP (p ⫽ 0.001), peak
troponin T (p ⫽ 0.002), LV ejection fraction (p ⫽ 0.022),
LV end-systolic dimension (p ⫽ 0.019), and left atrial
volume (p ⫽ 0.007) were individual predictors. In multi-
variable Cox proportional hazards regression model incor-
porating individual predictors, RFP emerged as the only
independent predictor of outcomes (odds ratio 5.431, 95%
confidence interval 1.521 to 19.391, p ⫽ 0.001). Kaplan–
Meier survival curves (Figure 3) similarly showed a signif-
icant difference in major adverse cardiovascular event–free
survival between the 2 groups, with worse outcomes in the
RFP group (log-rank chi-square 24.6, p ⬍0.001).
Although subgroup numbers were small, we explored the
interaction between RFP and systolic function by stratifying
the 2 groups based on an LV ejection fraction of 44%,
which was the cutoff for the lowest quartile of LV ejection
fraction, as presented in Figure 4. Importantly, ⬎1/2 of
patients in the RFP group had an LV ejection fraction higher
than the lowest quartile. However, there were more patients
in the RFP group with an LV ejection fraction in the lowest
quartile compared to the non-RFP group (9 in RFP group,
45%, vs 17 in non-RFP group, 23%, p ⫽ 0.05).
Discussion
The salient finding of the present study is that duration of
ischemia determined by symptom-to-reperfusion time is a
major determinant of severity of diastolic dysfunction after
acute MI. Furthermore, severe diastolic dysfunction was an
independent predictor of adverse outcomes at 12 months.
Thus, severity of diastolic dysfunction represents a signifi-
cant pathophysiologic link between duration of ischemia
and long-term outcomes and explains in part the well-
established prognostic significance of symptom-to-reperfu-
sion time. Although it is intuitive that longer duration of
ischemia with consequently larger infarct size would be
associated with more severe diastolic dysfunction, these
 Coronary Artery Disease/Ischemia Duration and LV Diastolic Function
Figure 3. Kaplan–Meier survival analysis of restrictive versus nonrestrictive filling pattern. MACE ⫽ major adverse cardiovascular event.
Figure 4. Interaction between systolic and diastolic function. Bi LVEF ⫽
biplane left ventricular ejection fraction; Pts ⫽ patients.
inter-relations have not been previously examined in the
same group of patients. Similarly, although the prognostic
significance of severe diastolic dysfunction after acute MI
has been well demonstrated previously, this study provides
novel insights into the actual determinants of any observed
diastolic dysfunction after acute MI.
Duration of ischemia is well established as a powerful
prognostic marker after reperfusion for acute MI,8,9 and
there is considerable emphasis on minimizing duration of
ischemia to improve survival after acute MI.10 Duration of
ischemia determines infarct size: Reimer et al11 demon-
strated the wave front of cell death sweeping from the
subendocardium to the subepicardium in a time-dependent
fashion after coronary occlusion. Infarct size in turn affects
systolic and diastolic LV functional indexes.12,13 Hasche et
al12 demonstrated the impact of duration of ischemia on LV
systolic function, with decreasing wall motion scores seen
with longer duration of ischemia. Although some studies
have established a relation between decreased systolic func-
tion (LV ejection fraction) and adverse outcomes,13 others
353
have demonstrated that LV end-systolic volume index is a
better predictor of long-term outcomes.14 In contrast, other
studies have uniformly demonstrated a strong relation be-
tween diastolic indexes, particularly RFP, and outcomes in
the setting of acute MI.3
Duration of ischemia is a major determinant of infarct
size, and RFP and decreased LV ejection fraction represent
functional correlates of any given infarct size. The results of
this study would suggest that the interaction between dura-
tion of ischemia and diastolic dysfunction occurs from in-
farct size, with significantly higher peak troponin T levels in
the RFP group. Other determinants of infarct size include
proximal occlusion of the infarct-related artery, degree of
occlusion, extent of ischemic preconditioning and collateral
formation, and efficacy of tissue level reperfusion.15 Al-
though most of these factors were considered as possible
contributors to diastolic dysfunction in the present study,
only duration of ischemia and infarct size emerged as inde-
pendent correlates. Proximal infarct location surprisingly
did not have a significant impact on diastolic dysfunction in
our study. However, only 12 proximal lesions were encoun-
tered (4 in RFP group, 20%, and 8 in non-RFP group, 11%,
p ⫽ NS), with only 2 proximal left anterior descending
coronary artery lesions in the entire cohort. Therefore, lack
of a statistically significant association is probably due to
the small number of proximal occlusions.
The prognostic significance of diastolic dysfunction after
acute MI has been extensively studied.3,16 –21 Although re-
strictive filling, deceleration time, noninvasively determined
filling pressure estimations with tissue Doppler (ratio of
mitral inflow E-wave velocity to e=), and left atrial volume
have been shown to be independent predictors of mortality,
the most extensive and robust body of data relates to
RFP.3,16 –21 In the MeRGE-AMI meta-analysis of 12 pro-
spective studies (⬎3,200 patients), a threefold increased
risk of mortality was observed in patients with RFP.3 From
354 The American Journal of Cardiology (www.ajconline.org)
a clinical perspective, the emphasis on RFP is justifiable
because it is an easily recognized and highly reproducible
measurement of diastolic dysfunction.
Pre-existing diastolic dysfunction in the study population
was not quantified because patients did not have echocar-
diograms before presentation with STEMI. The issue of
pre-existing diastolic dysfunction thus represents an impor-
tant confounding factor. Previous reports have consistently
documented a point prevalence of RFP of ⬃20% in patients
in the early phase after an acute MI similar to the prevalence
found in the present study.3 However, this prevalence of
severe diastolic dysfunction is an overestimate for a com-
munity-dwelling population without previous acute MI or
cardiomyopathy. Redfield et al22 demonstrated a point prev-
alence of severe diastolic dysfunction (defined as mitral
inflow E/A ratio ⬎1.5 and/or deceleration time ⬍140 ms) of
only 0.7% (95% confidence interval 0.3 to 1.1) from a
randomly selected community sample (n ⫽ 2,042, mean age
62.8 ⫾ 10.6 years) from Olmsted County, Minnesota.
Moreover, there were no differences in rates of diabetes and
hypertension between the RFP and non-RFP groups in the
present study, with the 2 conditions being known to predis-
pose to diastolic dysfunction. Based on these consider-
ations, the observed 20% prevalence of RFP in patients after
STEMI is probably linked to duration of ischemia and
infarct size rather than pre-existing diastolic dysfunction.
This study has some limitations. The number of pa-
tients recruited represents a moderate sample. Measure-
ment of systolic function in the early phase after reper-
fusion may underestimate LV ejection fraction from
myocardial stunning. Administration of medications such
as glyceryl trinitrate, ␤ blockers, and angiotensin-con-
verting enzyme inhibitors in the peri-infarction period
would influence loading conditions and heart rate and
thus potentially confound measurements. However, be-
cause the RFP and non-RFP groups were on similar
baseline medications, the 2 groups would be equally
affected. Follow-up echocardiograms were not obtained
to determine serial changes in diastolic function beyond
admission for acute MI. The large proportion of patients
with pre-existing hypertension and diabetes would result
in a background level of diastolic dysfunction in the
study population before the index acute MI, which was
not quantified.
Acknowledgment: The contribution of Professor Thomas
Marwick, MBBS, PhD, toward data analysis in this study is
gratefully acknowledged.
1. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth
OA, Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A.
Recommendations for the evaluation of left ventricular diastolic func-
tion by echocardiography. J Am Soc Echocardiogr 2009;22:107–133.
2. Oh JK, Hatle L, Tajik AJ, Little WC. Diastolic heart failure can be
diagnosed by comprehensive two-dimensional and Doppler echocar-
diography. J Am Coll Cardiol 2006;47:500 –506.
3. MeRGE-AMI Collaborators. Independent prognostic importance of a restric-
tive left ventricular filling pattern after myocardial infarction: an individual
patient meta-analysis: Meta-Analysis Research Group in Echocardiography
Acute Myocardial Infarction. Circulation 2008;117:2591–2598.
4. Sivagangabalan G, Ong AT, Narayan A, Sadick N, Hansen PS, Nelson GC,
Flynn M, Ross DL, Boyages SC, Kovoor P. Effect of prehospital triage on
revascularization times, left ventricular function, and survival in patients with
ST-elevation myocardial infarction. Am J Cardiol 2009;103:907–912.
5. TIMI Study Group. The Thrombolysis In Myocardial Infarction
(TIMI) trial, phase 1 findings: TIMI Study Group. N Engl J Med
1985;312:932–936.
6. Ingkarnison WP, Rhoads KL, Aletras AH, Kellman P, Arai AE.
Gadolinium delayed enhancement cardiovascular magnetic resonance
correlates with clinical measures of myocardial infarction. J Am Coll
Cardiol 2004;43:2253–2259.
7. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand
M, Hochman JS, Krumholz H, Kushner FG, Lamas GA, Mullany CJ,
Pearle DL, Sloan MA, Smith JC Jr, Alpert JS, Anderson JL, Faxon DP,
Fuster V, Gibbons RJ, Gregoratos G, Halperin JL, Hiratzka LF, Hunt
SA, Jacobs AK, Ornato JP. ACC/AHA guidelines for the management
of patients with ST-elevation myocardial infarction— executive sum-
mary: a report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines (Writing Committee to
Revise the 1999 Guidelines for the Management of Patients With
Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:671–719.
8. Newby LK, Rutsch WR, Califf RM, Simoons ML, Aylward PE, Armstrong
PW, Woodlief LH, Lee KL, Topol EJ, Van de Werf F. Time from symptom
onset to treatment and outcomes after thrombolytic therapy. GUSTO-1 In-
vestigators. J Am Coll Cardiol 1996;27:1646–1655.
9. Cannon CP, Gibson CM, Lambrew CT, Shoultz DA, Levy D, French
WJ, Gore JM, Weaver WD, Rogers WJ, Tiefenbrunn AJ. Relationship
of symptom-onset-to-balloon time and door-to-balloon time with mor-
tality in patients undergoing angioplasty for acute myocardial infarc-
tion. JAMA 2000;283:2941–2947.
10. Bradley EH, Nallamothu BK, Herrin J, Ting HH, Stern AF, Nembhard
IM, Yuan CT, Green JC, Kline-Rogers E, Wang Y, Curtis JP, Webster
TR, Masoudi FA, Fonarow GC, Brush JE Jr, Krumholz HM. National
efforts to improve door-to-balloon time results from the Door-to-
Balloon Alliance. J Am Coll Cardiol 2009;15:2423–2429.
11. Reimer KA, Lowe JE, Rasmussen MM, Jennings RB. The wavefront
phenomenon of ischemic cell death. 1. Myocardial infarct size vs
duration of coronary occlusion in dogs. Circulation 1977;56:786 –794.
12. Hasche ET, Fernandes C, Freedman SB, Jeremy RW. Relation be-
tween ischemia time, infarct size, and left ventricular function in
humans. Circulation 1995;92:710 –719.
13. Mollema SA, Nucifora G, Bax JJ. Prognostic value of echocardiogra-
phy after acute myocardial infarction. Heart 2009;9:1732–1745.
14. White HD, Norris RM, Brown MA, Brandt PW, Whitlock RM, Wild CJ.
Left ventricular end-systolic volume as the major determinant of survival after
recovery from myocardial infarction. Circulation 1987;76:44–51.
15. Wright J, Adriaenssens T, Dymarkowski S, Desmet W, Bogaert J.
Quantification of myocardial area at risk with T2-weighted CMR:
comparison with contrast-enhanced CMR and coronary angiography.
JACC Cardiovasc Imaging 2009;2:832– 834.
16. St John Sutton M, Sharpe D. Quest for diastolic prognostic indicators
of clinical outcome after acute myocardial infarction. Circulation
2008;117:2570 –2572.
17. Moller JE, Pellikka P, Kober L, Poulsen SH, Nayad O, Torp-Pedersen
C. Prognostic importance of systolic and diastolic function after acute
myocardial infarction. Am Heart J 2003;145:147–153.
18. Temporelli P, Gianuzzi P, Nicolosi G, Latini R, Franzosi M, Gentile F,
Tavazzi L, Maggioni A. Doppler-derived mitral deceleration time as a
strong prognostic marker of left ventricular remodelling and survival
after acute myocardial infarction: results of the GISSI-3 Echo sub-
study. J Am Coll Cardiol 2004;43:1646 –1653.
19. Møller JE, Pellikka PA, Hillis GS, Oh JK. Prognostic importance of
diastolic function and filling pressure in patients with acute myocardial
infarction. Circulation 2006;114:438 – 444.
20. Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, Park SW,
Bailey KR, Pellikka PA. Left atrial volume: a powerful predictor of survival
after acute myocardial infarction. Circulation 2003;107:2207–2212.
21. Hillis GS, Moller JE, Pellikka PA, Gersh BJ, Wright RS, Ommen SR,
Reeder GS, Oh JK. Noninvasive estimation of left ventricular filling
pressure by E/e= is a powerful predictor of survival after acute myo-
cardial infarction. J Am Coll Cardiol 2004;43:360 –367.
22. Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR,
Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunc-
tion in the community: appreciating the scope of the heart failure
epidemic. JAMA 2003;289:194 –202.