Prognostic influence of mitral regurgitation prior to a first myocardial infarction

José Zamorano*, Leopoldo Perez de Isla, Lucía Oliveros, Carlos Almería, José Luis Rodrigo, Adalía Aubele, José Banchs and Carlos Macaya

Echocardiographic and Cardiovascular Imaging Laboratory, Hospital Clínico San Carlos, Plaza de Cristo Rey, 28040 Madrid, Spain

Received 4 January 2004; revised 20 October 2004; accepted 28 October 2004; online publish-ahead-of-print 9 December 2004.

* Corresponding author. Tel: +34 91 330 32 90; fax: +34 91 330 32 92. E-mail address: jlzamorano{at}vodafone.es

See page 319 for the editorial comment on this article (doi:10.1093/eurheartj/ehi090)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
Aims Mitral regurgitation (MR) following an acute myocardial infarction (AMI) confers an adverse prognosis during long-term follow-up. There are no studies evaluating the influence of pre-AMI MR in the short- and long-term prognosis of such patients. Our aim was to assess the prognostic value of pre-AMI MR in the short- and long-term follow-up of patients who suffered a first AMI and to assess its influence on left ventricular haemodynamics.

Methods and results Sixty-eight consecutive patients with a first AMI and an echocardiographic study before AMI (<3 months) were included in the study. The pre-AMI echo was performed for various reasons. Of these 68 patients, 42 had pre-AMI MR (Group 1) and 26 showed no pre-AMI MR (Group 2). The presence of degenerative changes at the level of the mitral valve was confirmed in all cases. Patients with any other cause of MR were excluded. Clinical and echocardiographic variables for both phases (pre-AMI and post-AMI) were analysed and patients were followed up. Mean age was 75.5±9.5 years; there were 38 males (55.9%). There were no statistical differences in baseline clinical variables between the groups, except for the presence of pre-AMI atrial fibrillation, which was more frequent in Group 1 (21.4 vs. 0%; P=0.01). After AMI, only end-diastolic left ventricular diameter was significantly larger in Group 1 (54.9±4.7 vs. 48.1±5.6 mm; P<0.001). During long-term follow-up, median survival times were 912 days (interquartile range: 690 days) in Group 1 and 1423 days (interquartile range: 520 days) in Group 2 (Log-rank P=0.02). The multivariable analysis showed that the presence of pre-AMI MR relates to a statistically significant relationship with a worse post-AMI evolution [relative risk (95% confidence interval): 3.8 (1.1–13.1); P=0.037].

Conclusion The present study shows that the presence of pre-AMI MR is an independent prognostic marker among those patients suffering a first AMI.

Key Words: Myocardial infarction • Mitral regurgitation • Prognosis


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
Despite advances in the treatment of acute myocardial infarction (AMI), mitral regurgitation (MR) persists as a common complication. It has been reported that up to 1% of all patients with AMI develop significant MR.13 Numerous studies support different mechanisms for ischaemic MR: motion abnormalities in the infarct region that induces ventricular and papillary muscle dysfunction; restricted leaflet closure; leaflet tethering; and poor left ventricular (LV) contraction after AMI.48

Adverse influence of ischaemic MR after an AMI has been described extensively.910 Nevertheless, to our knowledge, there are no reports evaluating the influence of pre-existing non-ischaemic MR before a first MI in the prognosis of patients. In addition, how pre-AMI MR influences the LV haemodynamics following an AMI has not been studied. Our aim was two-fold: to determine the influence of pre-AMI MR in LV haemodynamics, after an AMI, and to assess how it influences the short- and long-term prognosis of these patients.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
Patients
The study group comprised 68 consecutive patients with a first AMI having an echocardiographic evaluation in the 3 months preceding the AMI event. Pre-AMI echocardiographic evaluation was performed for different reasons (Table 1). In all cases, a post-AMI (<10 days after AMI) repeat echocardiographic evaluation was performed. Exclusion criteria included: previous AMI, post-AMI mechanical complications (i.e. papillary muscle rupture, interventricular septum rupture), MR due to congenital heart disease, or previous cardiac surgery.


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Table 1 Indications for the pre-AMI echocardiographic study
 
Patients were classified into two groups according to the presence (Group 1) or absence (Group 2) of MR in the echo study performed prior to AMI.

AMI definition
The diagnosis of AMI was established using the criteria of the cardiac enzyme creatine kinase twice above the upper normal limit, the presence of ST-segment elevation, and the development of new Q-waves. This was preferably accompanied by symptoms compatible with typical ischaemic chest pain. Infarct location was determined from ECG changes and echocardiographic wall motion abnormalities.

Echocardiographic study
Echocardiographic studies were performed in all patients previous to the AMI (<3 months) and in the acute phase of the first AMI (during hospitalization). Cardiac chamber dimensions, including left atrial and left ventricular diameters, were obtained. LV ejection fraction was calculated using the modified Simpson's rule. Interrogation of the tricuspid valve yielded an estimation of pulmonary artery pressure by measuring the gradient between the right ventricle and the right atrium during systole and adding to it the estimated right atrial pressure.

The diagnosis of MR was based on the presence of regurgitation demonstrated by Doppler echocardiography. The diagnosis of degenerative MR was established when the presence of degenerative changes at the level of the mitral valve was demonstrated and any other cause of MR was excluded. Those cases with other aetiology than degenerative MR in the pre-AMI echocardiogram were excluded from the study. MR was considered as ischaemic regurgitation when the mitral valve itself was anatomically normal and regurgitation was present secondary to LV abnormalities. MR severity was quantitatively assessed by PISA and Helmcke criteria.11,12 Colour Doppler echocardiographic settings were adjusted by the expert cardiologist following recommendations given elsewhere.11,12 Concordance between the two methods was found in 52 patients (76.5%). In the case of discordance of the results of the two methods, we used the PISA method as the reference. Trace MR was considered as a physiological phenomenon and was not included in the analysis. Trace MR was defined as too small for any method of quantification with regurgitant flow limited only to the supravalvular mitral plane.

Follow-up
Only those patients with AMI and a previous echocardiogram were enrolled and all of them were prospectively followed. A clinical history was obtained from each patient. Clinical charts were periodically reviewed and patients were followed up. Cardiac death was considered as the primary endpoint for follow-up. Secondary endpoints were a recurrent MI, hospital admission due to heart failure, non-cardiovascular death, and the need for cardiac surgery. All the endpoints were defined before initiating the enrolment. In those cases in which a patient was admitted to hospital due to any of the pre-defined endpoints and death occurred during the same admission, the event was recorded as death only. The first cardiac event was used in the statistical analysis. Long-term echocardiographic study was performed 378±78 days after the index AMI in Group 1 and 457±65 days in Group 2.

Statistical analysis
The statistical package used was SPSS version 11.0. Quantitative data were expressed as mean±standard deviation. Qualitative data were expressed as number (percentage). Comparison of qualitative data was assessed by the {chi}2 test or Fisher's exact test when appropriate and comparison of quantitative data was assessed by Student's t-test and Fisher's exact test when appropriate; two-sided tests were used. The sample size was estimated using: {alpha}=10, ß=20, proportion of events in unexposed=3% based on previous clinical data, and minimum expected relative risk (RR)=8. Using these parameters, the estimated number of patients was 28 per group. Survival curves were estimated using the Kaplan–Meier method and curves were compared using the Log-rank test. The effects of all the parameters were studied with univariate regression analysis (proportional hazards model). Afterwards, a statistical adjustment using multivariable regression analysis was performed including those variables statistically significant in the univariate analysis and those variables that, using an epidemiological approach, are known to have a clear effect on mortality in this subset of patients (diabetes mellitus, atrial fibrillation, multivessel disease, and LV ejection fraction). The basic conditions to use the model were confirmed (residuals analysis to test the log-linear assumption and a graphic test to confirm the proportionality assumption). Comparisons were considered significant in the presence of a P-value<0.05.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
Study population
During the inclusion period, a total of 287 patients were admitted to our hospital because of a first AMI. Sixty-eight consecutive patients with a first AMI comprised the study group (23.7%). Baseline characteristics of the study population were compared with baseline characteristics of the total group of patients with a first MI during this period and no statistically significant differences were found between the groups. Mean age was 75.5±9.5 years and 38 were male (55.9%). Among all the patients, 42 showed MR before AMI (Group 1) and 26 showed no MR before AMI (Group 2). No statistically significant difference was found between Groups 1 and 2 in the baseline characteristics except pre-AMI atrial fibrillation, which was more frequent in Group 1 [9 (21.4%) vs. 0 (0%) in Group 1 and Group 2 respectively, P=0.01]. Thus, both groups are comparable and this is an important fact in order to be able to draw conclusions from any difference between the groups. No patient had functional MR before the AMI. The mechanism of the pre-AMI MR was degeneration of the mitral valve in all patients. Patients with MR developed prior to AMI were, on average, older than patients without MR and there were more females among this group but this was not statistically significant (Table 2). In patients with ST-segment elevation, time to reperfusion was 4.5±2.7 h in Group 1 and 4.7±3.2 h in Group 2.


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Table 2 Demographic and clinical characteristics
 
Clinical and echocardiographic characteristics are listed in Table 2. There were no significant differences in demographic data and risk factors between groups, and no significant differences in the incidence of co-morbid diseases such as hypertension, diabetes mellitus, chronic obstructive pulmonary disease, and renal disease. Only the presence of atrial fibrillation was significantly different between the groups, being more frequent in the MR Group (21.4 vs. 0%, P=0.01). Medical treatment after AMI was similar among those patients with or without pre-AMI MR. The use of therapeutic agents such as beta-blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers, nitrates, and diuretics was similar between the groups.


    AMI size and location
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
Peak creatine kinase was similar in both groups (368±156 in Group 1 and 410±172 in Group 2; P=0.2). Location of infarct was determined to be anterior in 32 patients and inferior or lateral in 36 (no statistical differences between groups). Primary angioplasty was performed in 24 patients, whereas thrombolytic therapy was used in 23 patients. Eleven patients did not undergo reperfusion therapy. No statistical differences were found regarding the reperfusion strategy among study groups. Coronary angiography was performed in 48 of the 68 patients, showing significant coronary artery disease in all subjects. The extension of the disease was deemed single-vessel disease in 19 patients, two-vessel in 13, and three-vessel in 16. Again, no significant statistical differences were seen between groups.

Regarding the echocardiographic variables (see Table 3), no significant differences were found between groups comparing the baseline study with the post-AMI study except for the post-AMI end-diastolic left ventricular diameter (EDLVD): in Group 1, mean EDLVD was 54.9±4.7 mm and in Group 2 it was 48.1±5.6 mm (P<0.001). The cause of pre-AMI MR was valvular degeneration in all cases. There was no patient with MR and no degenerative changes in the mitral valve.


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Table 3 Echocardiographic characteristics
 
The severity of MR was classified according to PISA and Helmcke criteria (Table 3). In Group 1, 24 patients had grade I MR and 18 patients showed grade II–III previous to AMI. After AMI, grade I MR remained in 22 patients, 15 patients had grade II–III MR, and it progressed to grade IV in five patients. In Group 2, 18 patients developed grade I MR, seven patients showed grade II–III, and one patient grade IV after AMI.

Clinical events and survival (Table 4)
Of the 68 patients, six died during the first 15 days following the AMI event. All six were from Group 1 [six from Group 1 (14.3%), none from Group 2, Log-rank P=0.05] (Figure 1). All patients had 15 day follow-up available. All discharged patients were followed up, with a median follow-up time of 489 days [interquartile range (IQR): 55.6 days]. Of the 62 discharged patients after AMI, 20 died during long-term follow-up due to cardiovascular causes: 17 (40.5%) in Group 1 and three (11.5%) in Group 2. Median survival times were 912 days (IQR: 690 days) in Group 1 and 1423 days (IQR: 520 days) in Group 2 (Log-rank P=0.02). There were no deaths due to non-cardiovascular related causes. Afterwards, the data were analysed using Cox analysis. In the univariate analysis, the only two variables related to a worse prognosis were age [RR (95% CI): 1.05 (1.002–1.1); P=0.041] and the presence or pre-AMI MR [RR (95% CI): 4.03 (1.2–13.8); P=0.026]. After the statistical adjustment, the multivariable analysis showed that the presence of pre-AMI MR relates to a statistically significant relationship with a worse post-MI evolution in these patients [RR (95% CI): 3.8 (1.1–13.1); P=0.04] (Table 5). In our findings, the presence of MR previous to an AMI independently confers a 3.8-fold increase in the probability of death. Figure 2 shows the ROC curve representing the capability of the presence of pre-AMI MR to predict the occurrence of death during follow-up. The area under the curve is 0.7.


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Table 4 Clinical events
 


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Figure 1 Cumulative survival curves (follow-up in days). The numbers under the chart show the patients at risk at each moment.

 

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Table 5 Results obtained from the multivariable analysis (see text for more details)
 


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Figure 2 ROC curve representing the capability of the presence of pre-AMI MR to predict the occurrence of death during follow-up.

 
The effect of various degrees of MR was analysed by dividing the patients with MR into two groups: patients with mild degree MR and patients with more than mild degree MR. We compared their follow-up outcomes and did not find any statistically significant difference (Log-rank P=0.1).

Other variables analysed during follow-up were the need for hospitalization due to heart failure (nine patients in Group 1, five in Group 2), the need for hospitalization due to a new AMI (three patients in Group 1, two in Group 2), and the need for mitral surgical intervention (Table 4).


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
MR seems to be a common finding after AMI.13 Previous large-scale trials, such as the SAVE study, suggested that even mild MR is associated with high mortality after AMI.13 In addition, it has been well established that the presence of ischaemic MR is influenced by the size and location of the infarction.1415 The presence of MR is associated with the presence of a larger LV diameter, indicating more extensive changes in LV geometry following AMI. This could also be associated with a poor outcome of this population.

Although there are many studies pointing to echocardiographic predictors of poor outcome after AMI, limited data exist regarding pre-existing echocardiographic features that would translate into worse outcomes. This may, obviously, be related to the fact that few patients have echo studies closely preceding AMI events and therefore there is an intrinsic limitation in analysing such patients. In fact, there is no prior literature regarding the potential risk of the presence of MR prior to an AMI and both the immediate and long-term prognosis of such patients. We know that the existence of non-ischaemic MR is an age-related phenomenon.15 The results of this study show that the presence of non-ischaemic MR developed prior to an AMI confers higher risk for LV dilation and is negatively associated with survival. The presence of moderate and severe MR appears to identify a higher risk group of patients who often progress early to congestive heart failure because of irreversible LV dysfunction and are at a higher risk for sudden death. This fact emphasizes the importance of MR as a marker of adverse outcome and suggests a cautious approach of such patients following AMI.

Influence of pre-AMI MR in LV function and geometry
The mechanism of MR on ischaemic heart disease has been extensively elucidated.4,5,14,15 The location and chronicity of ischaemia, papillary muscle involvement, and the state of the LV geometry play important roles in the outcome of patients.1619

In our study, among those patients with pre-AMI MR, a larger end-diastolic volume can be seen after AMI. Of interest is the extension of the coronary vessel involvement, being that the reperfusion strategy or pharmacological therapy used was similar among those patients with or without pre-AMI MR. Furthermore, the infarction extension evaluated by means of the peak creatine kinase value was similar in both groups. Therefore, the differences in LV end-diastolic volumes are strongly related to the presence or absence of pre-existing MR. MR, even in a mild case, could be the reason for the enlargement of the ventricle in Group 1 compared with Group 2. This fact could have played an important role in the worse outcome of such patients. In addition, MR itself could dilate the left ventricle and MR itself depends on additional LV dilation that alters the balance on mitral leaflets and causes an increase in MR severity.

Our study shows that worse prognosis with MR preceding MI is not due to a larger infarct size or worse baseline LV function. Interestingly, it has been observed that depressed systolic function without LV dilation does not result in significant MR.17,18 Significant MR must be associated with outward papillary muscle displacement, annular dilation, and possibly a reduction in leaflet closing forces. In our study population there were no significant differences in LV systolic function between patients with or without pre-existing MR. Non-significant differences in post-infarction ejection fraction were later seen among both patient groups. Ejection fraction in patients with significant MR should be carefully evaluated. It is conceivable that a higher ejection fraction due to acute LV volume overload early in the course of MI may mask the true extent of myocardial damage. The ejection fraction as an index of myocardial contractility is inversely correlated with afterload. Patients with MR, and therefore reduced LV afterload, often exhibit elevations in ejection phase indices of myocardial contractility. Therefore, normal values for the ejection phase indices of myocardial performance in patients with MR may actually reflect impaired myocardial function. Since, in our study, no significant objective difference in ejection fraction existed between study groups, the fact that more patients with worse NYHA class (III–IV) were among the MR group could indeed be reflecting a worse, undetected LV function in those patients with pre-existing MR.

Study limitations
In our analysis we have only included those patients with a first MI. Our findings will therefore not apply to those patients with a history of previous MI and subsequent MR. In addition, we have excluded those patients with mechanical complications after AMI (papillary muscle rupture, septal rupture) since they undoubtedly have a different prognosis and therefore would have altered our results. The lack of a statistically significant difference when analysing the prognosis of various degrees of MR may be due to the relatively small number of patients enrolled.

If the study group were larger, it is probable that some variables, such as the presence of multi-vessel disease or the existence of atrial fibrillation, would reach statistical significance. Nevertheless, the fact that the presence of pre-AMI MR is an independent marker shows its strength as a predictor of outcome.

The validity and interpretation of the results depend on how comparable the study population and the global population of patients with a first AMI are. The lack of differences between the groups allows the generalization to a broader population. Furthermore, statistically significant differences were not found between the groups. Thus, both groups are comparable and this is important in order to be able to draw conclusions from any difference between them.


    Conclusions and practical implications
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
The presence of MR, previous to a first MI, is an independent predictor that translates to worse outcomes in these patients in the immediate and long-term follow-up period. This is observed independently of other baseline characteristics or reperfusion strategy. Changes in LV dimensions, in particular end-diastolic volumes after AMI, are seen among patients with pre-existing MR. This merits special attention, and close continuity of care is recommended when these findings are present.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 
We would like to thank to Dr Paylos and Fundacion Mapfre Medicina for their support.


    References
 Top
 Abstract
 Introduction
 Methods
 Results
 AMI size and location
 Discussion
 Conclusions and practical...
 Acknowledgements
 References
 

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  16. Kumonohoso T, Otsuji Y, Yoshifuku S et al. Mechanism of higher incidence of ischemic mitral regurgitation in patients with inferior myocardial infarction: quantitative analysis of left ventricle and mitral valve geometry in 103 patients with prior myocardial infarction. J Thorac Cardiovasc Surg 2003;125:135–143.[Abstract/Free Full Text]
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