In this cohort study, the prevalence of diabetes was 36.3%, over one-third of naïve PPM recipients. During a mean follow-up of 7.8 ± 4.8 years, after PSM, the incidences of cardiovascular events and HF hospitalization were significantly higher in the diabetic group compared to the non-diabetic group. Moreover, the cumulative incidences of cardiovascular events and HF hospitalization were significantly higher in the diabetic matched group compared to the non-diabetic matched group. Furthermore, by multiple Cox regression analysis, diabetes remained as an independent predictor for cardiovascular events in patients after naïve PPM implantation.
The prevalence of diabetes in patients receiving pacemakers
The global prevalence of diabetes is rising from 8% in 1980 to 9.3% in 2019, and is estimated to be 10.9% by 2045, which may be attributable to population growth and ageing [1,2]. In the Taiwanese population, the annual prevalence of diabetes increased significantly from 5.8% in 2000 to 8.3% in 2007, especially in the subgroup of men, age ≥80 years, and individuals residing in aging society areas [3]. In the elderly ≥65 years, around 15%-20% of people live with diabetes [1,21]. In this study, PPM recipients were aged and the prevalence of diabetes was 36.3%, which was higher than general population [1-3,21] and was compatible with previous data of PPM recipients [13,14]. Moreover, similar to other reports [1-3,21], the trend in the prevalence of diabetes in this study, also increased from 28.8% (between 2003 and 2007) and 36.0% (between 2008 and 2012) to 41.4% (between 2013 and 2017).
Prior study reported that diabetes was possibly associated with sinus nodal dysfunction and cardiac conduction abnormalities [9-11,22]. Movahed et al. reported that the incidence of complete atrioventricular block in the diabetic patients was 1.1%, which was 3-fold increased risk compared to the non-diabetic patients [11]. Diabetic patients of this study had a higher prevalence of atrioventricular block compared to non-diabetic patients (44.0% vs. 35.8%, P=0.001) (Table 1), similar to other reports [10-12]. From a national diabetes registry study, Rautio et al. reported that diabetes increased 1.6-fold risk for implantation of PPM after adjustments for age, sex, and other factors [12]. Therefore, type 2 diabetes is a risk factor for PPM implantation and vigilant follow-up for bradyarrhythmia in diabetic patients is necessary.
Heart failure hospitalization in diabetic patients after pacemaker implantation
The prevalence of diabetes in HF patients is around 20%, and diabetes increased 1.74-fold risk and 1.95-fold risk of HF in men and women, respectively [6,23]. The reasons for increasing risk of HF in diabetic patients included combined comorbidities such as hypertension, acceleration of the development of coronary atherosclerosis, and diabetic cardiomyopathy, which was related to microangiopathy, metabolic factors or myocardial fibrosis [23]. Moreover, a study using the National Readmission Database showed that the most common cause for readmission in PPM recipients was HF hospitalization [24]. In this study, we showed that the incidence of HF hospitalization was significantly higher in the diabetic group compared to the non-diabetic group before and after PSM. Diabetic cardiomyopathy is characterized by diastolic relaxation abnormalities in its early stage and later systolic dysfunction [25]. The pathophysiological mechanisms of diabetic cardiomyopathy include systemic metabolic disorders, inappropriate activation of the renin–angiotensin–aldosterone system, subcellular component abnormalities, oxidative stress, inflammation and dysfunctional immune modulation and finally, interstitial fibrosis of cardiac tissue, which contributed to substantial cardiac stiffness with diastolic dysfunction and later, systolic dysfunction [25]. Furthermore, diabetes is an important phenotype for HF with preserved LVEF, and is also an independent predictor for HF hospitalization, despite under treatments of ACEi/ARB [26]. Interestingly, the study population in this study had preserved LVEF and the administration of ACEi/ARB was higher in the diabetic group compared to the non-diabetic group before PSM (Table 1). In this study, prescription for ACEi/ARB was an independent risk for cardiovascular events (Table 3). Of note, patients prescribed with ACEi/ARB were older and had higher prevalence of hypertension, hyperlipidemia and CKD, and had larger LV end-systolic volume and lower LVEF (even within the normal range) compared to those without prescribed with ACEi/ARB (supplementary Table 1), consequently worse clinical outcome. These findings deserve further investigations regarding angiotensin receptor-neprilysin inhibitor or sodium-glucose cotransporter 2 inhibitor in diabetic patients with preserved LVEF for PPM implantation [27,28].
Right ventricular pacing is associated with HF hospitalization [29]. Recently, physiological pacing, such as His bundle pacing, has been reported to reduce HF hospitalization compared to right ventricular pacing [30]. Our study was the first to show that diabetes was an independent predictor for cardiovascular events, including HF hospitalization, in patients after right ventricular PPM implantation. Our findings provided the hypothesis for future studies of physiological pacing in diabetic patients who required PPM implantation.
Other predictors for cardiovascular events in patients after pacemaker implantation
Previous studies reported that type 2 diabetes was associated with higher risk of HF in women than men [6,23]. There are several potential explanations including poorer glycemic control in women, under-treatment for diabetic women contributing to the development of diabetic cardiomyopathy, prolonged exposure to hyperglycemia during the prediabetic state in women, diastolic dysfunction of LV more common in women and deteriorations in major cardiovascular risk factors in women than in men [6]. In this study, women, compared with men, had a 1.72-fold increased risk for cardiovascular events (Table 3), which was compatible with other studies [6,23]. In diabetic patients with diabetic nephropathy, the risk of cardiovascular events increased by the decline of eGFR and the presentation of macroalbuminuria [31]. This study showed that CKD and presentation of albuminuria were independent risk factors for cardiovascular events (Table 3). Therefore, regular follow-up of renal function and serial measurement for albuminuria for PPM recipients, especially in women, is necessary.
Limitation
In this study, some potential limitations existed. First, although this was a retrospective single-center study, the sample size was large. Still, the potential bias inherent to nonrandomized investigations cannot be excluded. However, we performed PSM to minimize the bias between diabetic and non-diabetic groups. Second, the compliance period and dosage of prescription for beta-blocker, ACEi/ARB, diuretic agents, and statin during follow-up period were not available in this study. Third, the duration of diagnosed diabetes before PPM implant was unknown. Finally, the pre-procedural echocardiographic parameters of diastolic function by tissue Doppler or speckle-tracking imaging were not performed.