The major findings of the present study were as follows: (i) increased LVWT was associated with a higher rate of AVR surgery, (ii) In patients with increased LVWT, the all-cause and cardiovascular death rates were both significantly lower in the AVR group than in the non-AVR group, and (iii) Increased LVWT was an independent predictor for cardiovascular death in patients with severe native AS.
Although the presence of extreme LVH in severe AS indicates poor prognosis, current guidelines do not consider LVH an indication for surgical replacement in patients with AS [13]. The indications for AVR are primarily based on the presence of clinical symptoms. However, the clinical symptoms of patients with severe AS are often difficult to differentiate from the symptoms of comorbid diseases, such as lung disease or coronary artery disease, in clinical practice. A few studies of severe AS have focused on the prognostic outcome of patients with higher LV mass or LVWT. In patients with severe AS, preoperative concentric LVH was associated with increased mortality after AVR [14]. Higher LV mass was related with worse clinical outcomes after transcatheter AVR in severe symptomatic AS [15]. In a prospective study, increased LV mass index was independently related with increased cardiovascular morbidity and mortality in AS patients [16]. In addition, increased cardiovascular mortality and morbidity have been reported for asymptomatic patients with severe AS and excessive LVH [8]. Thus, we believe that increased LVWT could be an important prognostic factor in severe AS, regardless of symptoms. Although LVH in severe AS is a compensatory phenomenon to reduce wall stress and maintain cardiac output [17], it eventually causes ischemia, fibrosis, and myocardial dysfunction [18,19]. Myocardial fibrosis independently predicts risk of mortality in patients with moderate to severe AS [20].
Increased LVWT and AVR
Because clinical decisions should be based on the risk of mortality, AVR might not a suitable endpoint in conservatively treated patients with severe AS. However, AVR is also the most important decision in the course of treatment for severe AS from a doctor’s point of view. In our study, the main causes of AVR were the development of symptoms (92/157, 58.6%) and LV dysfunction (29/157, 18.5%). Although LV hypertrophy was not considered a risk factor at the time of AVR, this retrospective study showed that patients with increased LVWT underwent AVR much more frequently than those without LVWT (60.1% vs. 39.0%, p = 0.001, Table 1). Furthermore, the cardiovascular death rate in patients with increased LVWT was significantly lower in the AVR group than in the non-AVR group (Figure 2B). These results imply that LV hypertrophy may be an important risk factor in AVR decisions.
Mortality
The multivariate regression analysis in this study showed that increased LVWT was independently correlated with cardiovascular death in patients with severe AS. In this study, 108 patients (108/208, 51.9%) with increased LVWT had no or mild symptoms. In addition, 36 patients (36/125, 28.8%) with increased LVWT who underwent AVR had no or mild symptoms. This may imply that symptom-based decisions for interventions in severe AS might miss a chance for surgery in patients (about 30%) with no significant symptoms. Thus, LVH could be used as a more sensitive marker than symptomatic criteria for AS surgery decisions. Previous studies reported that LVH was associated with an increased rate of cardiovascular events in severe AS independent of other prognostic covariates, even in asymptomatic patients [14-16,21,22]. Recently, Kang reported that the incidence of cardiovascular death was significantly lower in those who underwent early AVR surgery than asymptomatic patients with very severe AS who received conservative care [23]. In our study, patients with increased LVWT had a 4.45-fold higher risk of cardiovascular death than those with normal LVWT. Interestingly, the predictors of cardiovascular death in this study were age, symptoms, AVR surgery, CAD, and increased LVWT, not LVEF. LV dysfunction is a well-known strong predictor of worse long-term survival, but our results did not agree with those of previous studies [24]. Although LV dysfunction caused by severe AS itself is a very important risk factor for cardiovascular death and a class I indicator for AVR surgery, LV dysfunction can develop from other combined valve diseases, or post-myocardial infarction. In our study, the LVEF was not significantly different between the AVR and non-AVR group. Additionally, among 42 patients with systolic dysfunction, 12 patients were asymptomatic, and only four patients (4/125, 3.2%) had AVR surgery attributable to LV dysfunction itself (Figure 2). Among the 29 deaths in non-AVR patients, 6 deaths (2 cardiac and 4 non-cardiac) were observed even in patients with normal systolic function. These are asymptomatic but had increased LV wall thickness. This implies that LVEF would not be a perfect indicator of AVR surgery in real practice. In contrast, increased LVWT was more common in the AVR group and showed statistical significance as a variable correlated with cardiovascular death. LVH as a factor modifying the timing for AVR is not a new concept. Previous reports clearly demonstrated associations between pre-operative LVH and post-AVR mortality [25,26]. Thus, it might be a good additional index for AVR surgery decisions in patients with severe AS, in addition to symptoms. Bicuspid aortic valve (BAV) is associated with aortic root dilation and progressive dilatation of ascending aorta was reported [27,28]. By contrast, others demonstrated that long-term clinical outcomes and aortic root dilatation were similar between BAV and tricuspid AV (TAV) [29,30]. We examined whether BAV can be other prognostic factors in severe AS. However, mortality of patients with BAV were similar with those of TAV patients (10.4% vs. 15.7%, p = 0.818). Honda et al have reported that concomitant AR in severe AS patients had significantly worse clinical outcomes [31]. In present study, significant AR was observed in 12.7% of severe AS patients and mortality of patients with concomitant significant AR was not significantly different from those of patients without concomitant significant AR (11.6% vs. 12.4%, p = 0.661). The prevalence of CAD in death patients was significantly higher than that in survived patients (66.7% vs. 39.0%, p = 0.012). Likewise, mortality of CAD patients was significantly higher than that of patients without CAD in severe AS (25.0% vs. 9.6%, p = 0.012). This study had limitations. First, because this was a retrospective study, the clinical data may be incomplete. Second, the follow-up period was clearly too short and the absolute number of patients was too small to have strong statistical power. Third, LVH may be a consequence or reflection of the AS severity, not be the independent factor, because it was obtained by narrow-range analysis of LV wall thickness. Forth, we tried to incorporate LVH as an indication for AVR with classic symptoms and LV dysfunction, but this approach is incomplete comparison, because considerable patients with symptoms or LV dysfunction did not have AVR due to their very old age and poor health condition.