The main finding of this study is the identification of heterogeneous factors of cardiac rhythm, valvular morphology and primary status of pulmonary arterial pressure as predictors of adverse cardiac events occurring in the long-term follow-up of patients who underwent PTMC for rheumatic MS. Furthermore, low IMVA (< 2 cm2) was found to be an independent predictive variable for both adverse cardiac events and restenosis.
To our knowledge this is the second study of the long-term outcomes of PTMC in Iran, and is one of the few such studies in the Middle East region [10, 13, 16]. According to epidemiologic studies worldwide, Iran is no longer an endemic area for rheumatic fever, in contrast to the situation in this country about 4 decades ago [2, 21]. However, we should not underestimate the existing burden of RHD and its major consequences such as MS, while a large group of sufferers are young adults under the age of 50 [1, 2]. This study also reconfirmed that when PTMC is undertaken successfully and without acute complications, there would be a significant decrease in morbidity and mortality among the patients with MS even in a relatively long-term scale, given that 83.3% of our patients had no major adverse cardiac events, 59.6% did not develop restenosis, and 68.2% were still in NYHA functional class ≤ 2 by the end of the follow-up period.
We identified AF rhythm, Wilkins score > 8, l IMVA < 2 cm2, and high pre-PTMC pulmonary arterial pressure (reflected as higher sPAP) as independent predictive factors of clinical cardiac events. Several studies have also reported at least one the first three factors to be a prognostic factor of PTMC results in the long-term [11,12,13,14,15,16,17,18, 22].
Aside from thromboembolic events, which can be a direct consequence of AF rhythm, our study is consistent with earlier works reporting that AF rhythm correlates positively with the incidence of cardiac events [13, 14, 16, 22]. Patients with AF in the present study were older and had higher NYHA functional classes and higher Wilkins scores than patients in sinus rhythm, in line with reports by other authors [16, 22]. Bouleti et al. suggested that although AF rhythm per se does not compromise mitral valve function, its presence is an indicator of more advanced stages of underlying rheumatic disease; thus the rate of clinical events will be higher in long-term [14]. A further implication is that impaired hemodynamics and subsequently more severe clinical symptoms in these groups of patients make re-intervention inevitable within a shorter time frame.
Considering Wilkins score, our results are also in line with multiple studies reporting that favorable morphological characteristics before the procedure can play a significant role in the long-term success of PTMC [10, 13, 14, 22]. Although other scoring systems have been introduced, based on estimating variables such as commissural calcium, commissural area or subvalvular characteristics, to date none has been as widely validated or used as Wilkins score [8, 23, 24]. Given that some authors have noted a universal consensus that PTMC will be most effective when valvular and commissural morphology are optimal, the actual impact of PTMC lies in reversing commissural fusion, i.e. the pathognomonic characteristic of rheumatic MS, and in avoiding severe MR – an effect which becomes more likely when the valve is markedly deformed [1, 8, 25, 26].
An unexpected finding in the present study was the detection of higher pre-PTMC sPAP as an independent variable for predicting adverse cardiac events. Although a few studies have reported higher post-PTMC sPAP to be among the predictive factors, none indicated a similarly significant impact for pre-PTMC sPAP [24, 27]. Because of missing data regarding immediate post-procedural sPAP in some cases, we were unable to analyze the impact of this factor separately. However, some studies have shown that patients with high baseline pulmonary arterial pressure had poorer hemodynamic results in intermediate and late follow-up periods [28, 29]. Ozkan et al. suggested that because of the decrease in hemodynamic response to PTMC in patients with severe pulmonary hypertension in the long-term, it would be reasonable to perform PTMC at earlier stages [28]. In light of our parallel clinical finding, we also hypothesize that patients with high pulmonary arterial pressure, despite the documented substantial initial improvement after PTMC, may have surpassed the window of opportunity for this procedure, making it reasonable to opt directly for surgical management in some of these individuals.
The most significant predictive factor in the present study was IMVA, which proved to be clearly influential in predicting both cardiac events and restenosis. This finding is consistent with the results of earlier studies [13, 15, 18, 22], especially that by Song et al. [15]. In contrast with other studies, however, we obtained a slightly higher cut-off value of 2.025 for predicting restenosis and 1.925 for predicting adverse cardiac events [15, 22]. The respective ROC curves to evaluate the diagnostic ability of IMVA are shown in Fig. 2. Song et al. suggested that IMVA is a significant indicator of the efficacy of the procedure, and at least for some more recent target groups of PTMC such as the patients with higher pre-PTMC MVA, a higher cut-off for success than the conventional ≥ 1.5 cm2 value should be considered [15]. Tomai et al. also noted that better event-free outcomes in cases with higher IMVA reflect higher procedural quality in this group as well as a less advanced stage of rheumatic MS [22]. We also suggest, based on the present findings, that patients who have less than optimal IMVA results should be followed more closely during follow-up, as they are supposedly more prone to restenosis and more likely to be candidates for re-intervention.
To the best of our knowledge, the present study provides the first analysis of the possible impact of continuing secondary antibiotic prophylaxis on the mid-term outcome in patients who underwent PTMC. Because there was no valid system to monitor patients’ adherence to secondary penicillin prophylaxis at the participating centers, we assumed that patients who did not complete their post-intervention antibiotic regimen might have had a worse clinical outcome. This hypothesis was based on the fact that the repeated occurrence of subclinical rheumatic attacks can affect the post-intervention course of MS. However, this impact was not statistically significant in our results for the incidence of cardiac events or restenosis. In addition, we noted that except for one patient, all those who continued their antibiotic prophylaxis regimen were younger than 50 years of age. This was a logical finding given that based on guidelines for non-endemic area, we recommend that patients continue prophylaxis to around the age of 40. However, our analysis of the results in patients younger than 50 again showed that this impact was statistically nonsignificant. Nevertheless, we suggest that further research on this topic is needed, as only limited number of patients, in other words less than one third of all cases in this study, continued proper antibiotic prophylaxis regimen. Furthermore, regardless of whether continuing the secondary antibiotic prophylaxis or not, the majority of cases in this study suffered from neither adverse cardiac events nor restenosis. Additionally, few valid recommendations have been produced for non-endemic countries, particularly about the duration of continuing antibiotic prophylaxis after PTMC [30]. It is also noteworthy to mention that the points discussed here should not be confused with the proven effect of secondary antibiotic prophylaxis following acute rheumatic fever (ARF) to prevent recurrences of ARF and progression of primary RHD in young patients [1, 30], as all the patients included in this study were proven cases of advanced rheumatic MS at the time of PTMC.
Other factors such as age or NYHA functional class have also been reported in similar studies to be decisive variables in predicting the late outcome of PTMC [14, 15, 18]; however, our findings were inconclusive regarding the impact of these factors, probably because of the smaller size of our study population in comparison to other studies. In addition, all participating hospitals in the present study were referral centers, and as a result more than 75% of the patients included here were in NYHA functional class > 2 at the time of the PTMC. This may have had an impact on the present results.
Additionally, based on our results, ITMPG was not a significant predictor for both adverse cardiac events and mitral restenosis. This is in agreement with the findings of several previous studies [15, 18, 22]. However, there have been reports, in which ITMPG has been singled out as a main predictor of late events, although they had implemented different study designs and endpoints [14, 24]. As Bouleti et al. have reported, ITMPG was the main predictor of the long-term events in older patients, especially after the age of 70 [14]. Nunes et al. have also indicated that they had investigated a heterogeneous group of patients in regard of age and valvular morphology [24]. Therefore, we assume that the different age structure of our study population, in which only 7 patients were of the age of 70 or older have had an impact on our findings in this regard.
It is also noticeable, that in comparison to other similar studies, the rate of left ventricular dysfunction (EF < 50%) at the time of PTMC procedure was lower among our patients (9.13%). We consider the implemented criteria, such as excluding the patients with significant rheumatic involvement of aortic valve or the ones with high grade MR, and again the relatively younger mean age of our case as possible explanations for this difference.
Limitations
Our study had certain limitations. To obtain an acceptable number of patients, we had to collect data from multiple centers. However, by applying specific criteria and including only cases with immediate success and an initial event-free interval of 6 months, we tried to decrease the operator bias. In contrast, the protocols for echocardiographic imaging and the PTMC technique were completely the same at all centers.
The retrospective nature of this study is an added limitation. We lost a considerable proportion of our patients (15.4%) during follow-up. Additionally, the exact timing of the initiation of restenosis was unknown in some cases, thus we had to apply logistic regression to analyze the results for this factor. Furthermore, the available information about the cause of death in 2 of our deceased patients was limited and mostly based on interviews with first-degree relatives. However, we were able to obtain and recheck the relevant documentation in 2 other cases.
