A decreasing heart rate (HR) in patients with sinus node dysfunction (SND) aggravates the symptoms related to bradycardia such as fatigue, dizziness, dyspnea, and syncope, which are indications for a permanent pacemaker implantation (Alt et al., 1985; Tung et al., 1994). However, some patients are reluctant to undergo permanent pacing due to the fear of having a device implanted in their body. Clinically, some patients may not have severe bradycardia requiring a pacemaker implantation but cannot be observed without some kind of treatment. Some helpful messages have been proposed in several studies (Ling and Crouch, 1998; Moriya et al., 2004; Sonoura et al., 2019; Verza et al., 1996) regarding pharmacological therapy to increase the HR in patients with sick sinus syndrome (SSS).

Theophylline and cilostazol have been shown to have positive chronotropic effects, which may be useful for relieving symptoms related to bradycardia in patients with SND. However, no previous studies or trials have been performed comparing the positive chronotropic effects of these two agents. Therefore, in this study, we compared the effects of theophylline and cilostazol on the HR in patients with SSS.

SND is often related to age-dependent, progressive, and degenerative fibrosis of the sinus nodal tissue and surrounding atrial myocardium. SSS is a clinical syndrome characterized by SND. However, historically, SND used to be referred to as SSS. In the present study, when we emphasized the histopathologic characteristics, we used “SND”. When the symptoms were emphasized, we used “SSS”.

The increment in the HR is helpful for improving symptoms such as general weakness, fatigue, dizziness, and syncope in patients with SSS (Alt et al., 1985; Tung et al., 1994). Permanent pacemaker implantations are the most frequently used and most effective treatment option and are almost always considered as a first-line treatment. Therefore, only a few studies have investigated the effectiveness of the pharmacological therapy for SSS, and thus far, the diversity of the various pharmacological therapies for these patients is still low.

There have been many reports on the positive chronotropic effects of theophylline, which acts to block adenosine and leads to an increase in sinus node automaticity and atrioventricular (AV) conduction (Gambhir et al., 1995; Szentmiklosi et al., 1980). Several studies have shown that theophylline improves the severity of bradycardia-related symptoms in newborn babies, and that theophylline increases the HR in patients with late advanced AV block complicated with acute myocardial infarction and who undergo heart transplantations (Altun et al., 1998; Ellenbogen et al., 1988; Myers et al., 1980; Shannon et al., 1975). Thus, this agent could be used to increase the HR in patients with SND. However, a prospectively assessed randomized controlled trial (THEOPACE) has revealed that permanent pacemakers are more effective than theophylline in reducing the occurrence of syncope (Alboni et al., 1997). Cilostazol, a phosphodiesterase-III (PDE-III) inhibitor, was first developed in Japan for the treatment of symptoms of intermittent claudication in patients with peripheral arterial occlusive disease. Cilostazol has anti-platelet effects and positive hemodynamic effects on peripheral circulatory defects by the selective inhibition of cyclic nucleotide PDE-III in platelets and vascular smooth muscle. Therefore, this agent is first treatment option for vascular inflammatory diseases, such as coronary artery disease or peripheral arterial occlusive disease (Kambayashi et al., 2003; Kawamura et al., 1985; Liu et al., 2001; Shintani et al., 1985).

Cilostazol is considered to have positive chronotropic effects via several speculated mechanisms (MacDonald et al., 2020; Mangoni and Nargeot, 2008). Firstly, Fischmeister et al. (2006) revealed that cyclic adenosine monophosphate (cAMP) plays an important role in the beta-adrenergic receptors that stimulate the HR. Gs-protein (stimulatory G-protein) activation (e.g., via $\beta$-adrenoceptors) induces adenylyl cyclase. The adenylyl cyclase dephosphorylates adenosine triphosphate (ATP) to form cAMP. The cAMP then activates protein kinase-A (PK-A) and causes an increased cellular influx of Ca${}^{++}$ by phosphorylation and activation of L-type calcium channels, and an enhanced release of Ca${}^{++}$ by the sarcoplasmic reticulum in the heart. These events increase the inotropy and chronotropy (Klabunde, 2012; Mangoni and Nargeot, 2008). cAMP is degradated by PDE-III. Eventually, cilostazol (PDE-III inhibitor) would increase the chronotropy (Liu et al., 2001; Moriya et al., 2004). Secondly, the increased cAMP level also can lead to the activation of the I${}_f$ currents and an increase in the HR (DiFrancesco, 2010; Irisawa et al., 1993). However, the increment in the HR due to cAMP is not only due to the I${}_f$ current but also to the voltage-gated calcium currents and intracellular Ca${}^{++}$ dynamics described above (Lakatta et al., 2010). Thirdly, cilostazol induces systemic vasodilation, and thus it produces reflex adrenergic stimulation (in other words, a baroreceptor reflex) that contributes to positive chronotropy (Klabunde, 2012). Fourthly, cilostazol may have inhibitory effects on the adenosine uptake or may have an antagonizing effect on adenosine triphosphate (Liu et al., 2001). Finally, cilostazol can improve the coronary blood supply to the sinus node (SA) or AV node. If the patient has ischemia of the SA or AV node, it may improve the automaticity or conductivity.

Therefore, it was considered that cilostazol would be a reasonable pharmacological treatment for SSS by increasing the HR, and several studies on that have been performed. Ueda et al. (2001) evaluated 24-hour ambulatory ECG monitoring after cilostazol administration and revealed that the HR increases and the frequency of sinus pauses decreases after cilostazol administration.

The present study compared the positive chronotropic effects between theophylline and cilostazol, and although the HR significantly increased after the administration of theophylline and cilostazol, there was no difference between the two groups. Moreover, the symptoms such as dyspnea, chest discomfort, and dizziness improved after the administration of theophylline and cilostazol. Interestingly, in terms of the dizziness, cilostazol resulted in a significant improvement when compared to theophylline. We believed that the max RR interval increment, which is shown in Table 2, could explain the significant improvement in the dizziness in the cilostazol group. Also, as we described above, it might be a result of the positive chronotropic and vasodilation effects.

Theophylline has a narrow therapeutic index, and theophylline toxicity may occur at toxic levels. That includes symptoms from mild gastrointestinal symptoms such as nausea, vomiting, and diarrhea to severe and fatal cardiac arrhythmias or a central nervous system manifestation such as seizures. In this study, nausea was the most frequent adverse effect. Therefore, regular evaluation of the serum theophylline level may be required and helpful to minimize the adverse drug reactions (Gaudreault and Guay, 1986). However, the optimum dose of cilostazol has been determined (100 mg twice daily) and there is no need to monitor the serum levels. The vasodilation effect of cilostazol causes some side effects such as headaches and diarrhea, but they are almost always mild symptoms and improve after conservative treatment and the discontinuation of the cilostazol (Liu et al., 2001). In this study, there were 4 patients with headaches and 1 with diarrhea in the cilostazol group. The headaches disappeared by their next clinic visit.

This study had some limitations. First, the study was a retrospective and single center-based study, so selection bias and recall bias may have occurred and the baseline patient characteristics could have influenced the outcome. Second, we did not control the dosage of theophylline and cilostazol, so it may have been difficult to accurately investigate the effects of both agents. Further, since we used the ECG to evaluate the patient’s HR, the HR only reflected that at the time of the ECG. Twenty-four hour ambulatory ECG monitoring may be required to evaluate the continuous HR, including the circadian rhythms, in the patients. In the overall patients, the symptoms improved significantly and also tended to improve when the patients were divided into the theophylline and cilostazol groups, however, some improvements in the overall patients were not statistically significant. This may have been due to the lack of an adequate number of patients or because the symptoms were subjective, and we did not classify the severity of the symptoms.

In conclusion, this study suggested that cilostazol, like theophylline, might be used for supportive management in patients with SSS, especially when the patients do not want a pacemaker or their symptoms are not very severe. Moreover, there are some advantages to using cilostazol. Since SSS frequently occurs in elderly patients and they tend to have comorbid peripheral arterial occlusive disease, there may be an advantage of using cilostazol in elderly patients. However, further studies are needed due to several limitations of this study.

ITJ was a major contributor to the writing of the manuscript. NY contributed to the design, literature search, experimental studies, data acquisition, data analysis, manuscript preparation, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. HKJ contributed to the literature search, experimental studies, data analysis, statistical analysis, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. KHL contributed to the manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. HWP contributed to the conception of the work, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. JGC contributed to the conception of the work, definition of the intellectual content, manuscript editing, manuscript review, approval of the final version of the manuscript, and agreement of all aspects of the work. All authors read and approved the final manuscript.

The study was approved by the ethics committee at Chonnam National University Hospital, Gwangju, Korea (CNUH-2017-033), where exempted informed consent from enrolled patients because of retrospective study protocol.

We gratefully acknowledge Mr. John Martin, RN, BSN, for the linguistic assistance with the manuscript.

The authors declare that there are no conflicts of interest regarding the publication of this article.