Introduction
Aortic valve stenosis (AS), the most commonly acquired valve disorder, is emerging as a new epidemic in the western world due to ageing populations [
1].
Diabetes mellitus (DM) adversely affects morbidity and mortality for major atherosclerosis-related cardiovascular diseases [
2]. Following cardiac surgery and particularly coronary artery bypass surgery, patients with DM have been shown to suffer higher rates of adverse events including higher mortality rates [
3‐
5]. Furthermore, DM is associated with increased risk for the development of AS [
6,
7], and was found to be the second most significant factor associated with AS after hypertension [
8]. Aortic valves from diabetic patients with AS who require valve replacement have shown more calcification, with a higher grade of mineralization than non-diabetic patients [
9].
Clinical data regarding the impact of DM on outcomes of patients undergoing aortic valve replacement (AVR) have revealed inconsistent results [
10,
11]. The aim of the current study was to investigate and compare the impact of type 2 DM on short-, intermediate- and long-term mortality between DM and non-DM patients who undergo isolated AVR for the first time.
Discussion
This study, carried out in a contemporary cohort of patients who underwent their first isolated AVR, demonstrates several important implications regarding the impact of type 2 DM on in-hospital, mid- and long-term mortality. We have shown that long-term mortality was higher in DM patients than in non-DM patients, and that mortality rate was affected by the diabetic treatment strategy with worse outcomes in patients treated with insulin as compared with patients not treated with insulin.
While the impact of diabetes on short-term mortality after AVR remains controversial, DM has been included in the Society of Thoracic Surgeons (STS) risk score [
15] as a marker of poor prognosis after cardiac surgery. EuroSCORE II is a very good predictor of in-hospital mortality after cardiac surgery and can be safely be used for quality assurance and risk assessment [
16] and insulin-treated DM has been specifically included in it [
17]. Both the STS score and the EuroSCORE II were validated to predict 30-day mortality after cardiac surgery [
15,
17]. López-de-Andrés et al. [
18] reported a significantly lower in-hospital mortality rate among DM patients (3.9–8.9%) than among non-DM patients (5.1–7.8%) (p < 0.001), and Abramowitz et al. [
19] reported a lower 30-day mortality rate among DM compared with non-DM patients (5% vs. 5.9%, p < 0.001), while Linke et al. [
20] found no differences in 30-day mortality between DM and non-DM patients: 6.2% vs. 7.5%. Anyway, data are controversial since DM has been found to be significantly and consistently associated to higher in-hospital mortality in a huge Spanish population after major cardiovascular events [
21], and also Mendez-Bailon et al. [
22] reported a lower in-hospital mortality rate in patients with, compared to those without DM (4.4% vs. 6.3%, p < 0.01). About a third of our study patients were diabetic, with 55 of them (16%) receiving insulin treatment.
We report here that in-hospital mortality among DM and non-DM patients, was 3.5% and 2.5%. In the non-insulin (N = 291) compared with the insulin-treated (N = 55) subgroup of patients, in-hospital mortality was 2.7% and 7.3%, p = 0.201. While our findings were not statistically significant, the difference reported by us could be clinically relevant. Whereas our small sample size was underpowered to reach conclusive results, a larger cohort might have shown significantly higher early mortalities among DM patients, particularly in those on insulin therapy.
However, the impact of diabetes on mid- and long-term mortality after isolated AVR surgery has been consistent in several reports. Linke et al. [
20] found significantly higher 1- and 3-year mortality rates between DM and non-DM patients: 21.6% vs. 20.5% (p = 0.02) and 33.4% vs. 28.4% (p < 0.01). A post hoc analysis of the PARTNER trial, stratified according to the DM status of patients randomly assigned to undergo AVR, revealed a 1-year mortality rate of 27.4% in DM patients and 23.7% in non-DM patients [
23]. At 1-year, Abramowitz et al. [
19] reported that DM was significantly associated with a higher mortality hazard (HR 1.3 95% CI 1.13–1.49, p < 0.001). This association was stronger among insulin-treated patients (HR 1.57 95% CI 1.28–1.91, p < 0.001). We report here the results of a longer follow-up period than previously published, with a mean follow-up of 69 ± 43 months, demonstrating consistent results toward a worse rate of survival among DM patients, particularly those receiving insulin.
Diabetes mellitus is one of the major causes of heart failure in patients with reduced ejection fraction [
24], and even in cases in which ejection fraction is preserved [
25,
26]. In general, insulin-treated DM patients have more co-morbidities than non insulin-treated DM patients [
5,
27,
28] and are prone to more revascularization procedures [
16,
29]. The presence of insulin treatment as a marker for more rapid prosthetic valve deterioration remains debatable. Furthermore, its underlying biological mechanism has not yet been fully elucidated. Insulin may be related to the impact of a procoagulant imbalance, chronic exposure to high glucose levels, and direct effects of hyperinsulinemia. Further studies are needed to examine whether insulin-treated DM patients should be included in risk stratification algorithms for patients who undergo first-time AVR.
Aortic valve replacement and transcatheter aortic valve implantation (TAVI) are the only effective treatments for severe AS. Currently, however, TAVI is limited to moderate-high risk patients only, when the risk of TAVI is estimated to be lower than the risk of AVR, taking into consideration the fact that long-term results of TAVI are still unknown [
30]. While we and others have reported that DM is a significant risk factor for late mortality after AVR [
10], long-term mortality after TAVI for DM patients still needs further investigation.
Among the entire cohort of patients in our study who underwent isolated AVR, those with DM were older. One could surmise that, as in ischemic heart disease, DM patients present with less symptoms and therefore tend to be diagnosed later, resulting in treatment delays. However, we believe that this is not the case in DM AVR patients. Compared with DM patients, non-DM patients in our study had a significantly higher presence of bicuspid aortic valve, that tended to deteriorate at a higher rate, and therefore were operated on at an earlier stage of disease progression. We have shown that mortality was affected by the presence of DM regardless of patient age. While in the general population type 2 DM is associated with excess mortality compared with those without DM, with a HR of 1.15 at 5 years [
31], we report here that DM had a greater impact on patients who underwent first-time isolated AVR (HR of 1.58 at 5 years).
Limitations
There are a few limitations in our study. First, despite it being retrospective in design, data were collected prospectively and recorded in a well-defined database. Second, our study was conducted in a single-center cardiac surgery department. Third, we had no information regarding the main cause of death, the rate of cardiac events and data regarding prosthetic valve performance during the follow-up period. Analysis of cardiac events could reinforce the conclusion that DM provides less favorable results after AVR. The lack of information regarding the main cause of death weakens the conclusions of this study.