doi: 10.1161/CIRCULATIONAHA.108.772483
(Circulation. 2008;117:2570-2572.)
© 2008 American Heart Association, Inc.
Editorial |
Quest for Diastolic Prognostic Indicators of Clinical Outcome After Acute Myocardial Infarction
From the University of Pennsylvania Medical Centre, Philadelphia.
Correspondence to Martin St. John Sutton, John Bryfogle Professor of Cardiac Imaging, University of Pennsylvania Medical Centre, 3400 Spruce St, Philadelphia, PA 19104. E-mail suttonm{at}mail.med.upenn.edu
Key Words: Editorials • myocardial infarction • outcomes research
Immediately after acute infarction, the region of the myocardium ceases to contract, and over the next 72 hours, the infarct zone stretches and thins, a process known as infarct expansion. This regional left ventricular wall thinning and failure to contract perturb the normally uniform distribution of the stress/strain relationship that preserves cardiac architecture and function. Simultaneous with these early biomechanical changes, myocyte necrosis releases a number of cytokines that, together with the local increase in the regional myocardial deformation, cause stretch activation of a portfolio of matrix metalloproteinases that initiate myocardial repair.
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The stability of myocardial repair after acute myocardial infarction is determined by the balance between the distending forces from ventricular dilatation resulting from infarct expansion and the restraining forces from deposition of a viscoelastic collagen scaffold by the extracellular matrix that increases the tensile strength of the scar. The dynamic equilibrium between collagen degradation and collagen deposition is modulated by a number of activated cytokines and neurohormones that normally result in buttressing the infarct and adjacent border zones, preventing progressive remodeling to heart failure.
Changes in the composition of the myocardium in terms of increased collagen content during and after repair of the infarct zone in forming a fibrous tissue scar alter the material properties of the myocardium after myocardial infarction and confer on the heart increased myocardial and chamber stiffness. These alterations in left ventricular composition, architecture, and chamber/myocardial stiffness affect left ventricular filling dynamics, the rate of detachment of cross-linking, and sequestration of cytosolic calcium by the sarcoplasmic reticulum, all of which affect diastolic function as much as systolic function. However, most studies of the predictors of clinical outcome after myocardial infarction have focused almost exclusively on ejection-phase indexes of systolic contraction.
Factors shown to be powerful predictors of clinical outcome after myocardial infarction include left ventricular end-systolic volume index, ejection fraction, infarct size as peak cardiac enzyme release, infarct location and transmurality, mitral regurgitation, left ventricular hypertrophy (left ventricular mass), frequent ventricular arrhythmias, and progressive ventricular remodeling.1–4 In contrast, there is a remarkable absence of any measure of left ventricular diastolic function that predicts clinical outcome after myocardial infarction. The diastolic phase of the cardiac cycle has been overlooked as a prognostic indicator despite the important relationship between left ventricular filling and stroke volume described by Starling’s law of the heart. The reason for this absence is due in part to the fact that until relatively recently the significance of diastolic left ventricular dysfunction was not appreciated. Although diastolic dysfunction was observed to often precede the onset of systolic dysfunction in ischemic heart disease, diastolic heart failure with preserved ejection fraction (>50%) was believed to be relatively uncommon and was regarded as relatively benign. Furthermore, there was no reliable and reproducible measure of diastolic function that was independent of age, heart rate, and left ventricular loading conditions that was predictive of clinical outcome after myocardial infarction. The wide spectrum of abnormalities of diastolic filling is based largely on transmitral and pulmonary vein blood flow velocity profiles recorded by Doppler echocardiography and myocardial velocities recorded with Doppler tissue imaging during the passive rapid filling phase and atriosystolic contraction. For practical purposes, the left ventricular filling patterns are divided into 4 different stages.5–9 The first stage, abnormal left ventricular filling pattern, describes mild diastolic dysfunction caused by abnormal myocardial relaxation that is reversible. In the second stage, moderate diastolic dysfunction, the ventricular filling pattern is pseudonormal and reversible. Stages 3 and 4 describe severe diastolic dysfunction characterized by a restrictive filling pattern typified by an elevated E-wave velocity, a truncated deceleration time of <140 ms, and an increased E/A peak velocity.5–9 Stage 3 is still reversible; stage 4 is irreversible. A few small studies have indicated that restrictive filling, the most advanced impairment of left ventricular filling, predicts clinical outcome,10,11 but other studies have failed to demonstrate the predictive value of restrictive diastolic filling.12,13 Hitherto, no previous study has investigated the importance of a restrictive pattern of left ventricular filling in predicting mortality after infarction independently of left ventricular size, ejection fraction, and Killip class.
The true importance of diastolic function has emerged over the last decade because currently between one third and one half of all patients presenting with clinical heart failure have severe diastolic dysfunction and preserved systolic function.14 This combination has been variously called diastolic heart failure or heart failure with preserved systolic function as evidenced by an ejection fraction of 
50%.14,15
Whalley et al,16 on behalf of the Meta-Analysis Research Group in Echocardiography Acute Myocardial Infarction (MeRGE AMI) investigators, report in this issue of Circulation the results of a meta-analysis of 12 prospective postinfarction clinical trials in which restrictive left ventricular filling was estimated to occur in 
20% of a large cohort of 3739 survivors of acute myocardial infarction. No attempt was made by the authors to differentiate between patients with stage 3 and stage 4 diastolic dysfunction, that is, to determine whether the restrictive filling pattern was reversible. The prespecified aims were to determine the difference in mortality between patients with nonrestrictive and restrictive filling pattern and, in particular, to determine whether the restrictive filling pattern predicted mortality independently of end-systolic left ventricular volume index, ejection fraction, and Killip class after infarction.
The study population comprised a large number (3396) of postinfarction patients followed up for 4 years. Patients with atrial fibrillation and technically limited Doppler echocardiograms were excluded.
Restrictive filling was predefined somewhat imprecisely as a "high" E/A ratio or a deceleration time of the E wave of <140 ms. In addition, the precise timing of the Doppler transmitral flow velocity acquisition relative to the time of infarction is not stated in this study or in another report17 other than that it was obtained within the first 2 weeks after infarction. The timing of the echocardiography is important in that left ventricular chamber and myocardial stiffness may fluctuate before and after the infarct repair process is completed.14 Patients were dichotomized at the time of their Doppler echocardiogram as to whether they had restrictive left ventricular diastolic filling or nonrestrictive filling patterns. Left ventricular volumes indexed to body surface area and ejection fractions were estimated. Comparison of the patient population with restrictive filling and the population without restrictive filling revealed some major differences in baseline demographics with regard to risk factor profiles and left ventricular morphology and function. The restrictive filling group had a greater prevalence of diabetes, hyperlipidemia, and anterior myocardial infarctions. In addition, this group had significantly larger left ventricular volumes, lower ejection fractions, and higher Killip class than the group with nonrestrictive left ventricular filling patterns. Doppler peak E/A velocity ratio and deceleration time were both statistically significantly different by definition between the 2 patient groups. The important major finding in this study is the almost 3-fold difference in the 90% survival times: 39 days (29%) in the group with the restrictive left ventricular filling pattern versus 802 days (11%) in those with nonrestrictive filling pattern. Throughout the 4-year follow-up available in this meta-analysis, a restrictive left ventricular filling pattern was associated with a significantly reduced survival compared with a nonrestrictive filling pattern.
Targeted subgroup analysis was performed to determine whether the predictive power of restrictive diastolic filling pattern for mortality was independent of ejection fraction. Quartile analysis based on left ventricular ejection fraction showed that patients in the lowest quartile were older and had larger left ventricular volumes and a higher incidence of both anterior infarction and Killip class III/IV. The prevalence of restrictive filling and mortality varied inversely with ejection fraction from quartile 1 through quartile 4. However, the relationship between restrictive filling pattern and mortality within each quartile was maintained. The 90% survival times were reduced in patients with restrictive filling patterns compared with nonrestrictive filling in each quartile, and an important finding was that no interaction was found between ejection fraction and restrictive filling pattern for predicting mortality after infarction.
Estimations of left ventricular end-systolic volume index were available in almost half of the study population. When patients were dichotomized using the median end-systolic volume index of 35 mL/m2, there were significantly more patients with restrictive filling pattern with end-systolic volume indexes greater than the median (36% versus 15%) than below the median end-systolic volume index. However, regardless of left ventricular volume index, a restrictive left ventricular filling pattern remained a significant predictor for mortality.
Killip class was determined in half the patients (51%). Of the patients who had heart failure diagnosed in hospital, 61% had a restrictive filling pattern, whereas heart failure was present in only 30% of patients with nonrestrictive filling. There was a stepwise increase in restrictive filling with increasing Killip class, but there was no interaction between restrictive filling pattern and Killip class in predicting clinical outcome after infarction. Multivariate analysis showed no significant interaction with age and sex for risk of death associated with restrictive left ventricular filling. However, when clinical data such as diabetes, β-adrenergic receptor blockers, and angiotensin-converting enzyme inhibitors were added to the statistical model, restrictive filling pattern remained a robust predictor of clinical outcome. Diabetes reduced mortality but angiotensin-converting enzyme inhibitors improved mortality.
This meta-analysis of 12 prospective clinical trials of survivors of acute myocardial infarction, designed to determine whether simple, universally available Doppler echocardiographic measurements of left ventricular diastolic function predict clinical outcome, provides important and thought-provoking findings. Despite no data on the impact of the precise timing of the Doppler echocardiogram, the different baseline demographics, and the potential influence of discordant postinfarction pharmacotherapies between the 2 groups, 2 indelibly clear messages emerge. The first message is that a restrictive left ventricular filling pattern predicts clinical outcome after infarction even in the presence of a normal ejection fraction. Restrictive filling is associated with a 3-fold increase in risk of death. A restrictive filling pattern provides incremental prognostic information over and above that of left ventricular volumes and Killip class. The second message is that left ventricular filling profiles should be evaluated in every patient after myocardial infarction to stratify patients at increased risk of death. The tools used to measure diastolic function in this study were simple and typify the strategy used for clinical trials. Today, diastolic function can be dissected more completely into its components by measurements of propagation velocity, automated tissue tracking, strain, strain rate, and Doppler tissue imaging so that the effects of left ventricular loading conditions and abnormal relaxation can be resolved.6,9
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Acknowledgments |
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Disclosures
None.
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Footnotes |
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The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
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References |
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