Cilostazol Is Useful for the Treatment of Sinus Bradycardia And

CASE REPORT

Cilostazol Is Useful for the Treatment of Sinus Bradycardia and Associated Hemodynamic Deterioration Following Heart Transplantation Tomoki Uchikawa,1 MD, Takeo Fujino,2 MD, Taiki Higo,1 MD, Kisho Ohtani,1 MD, Akira Shiose,3 MD and Hiroyuki Tsutsui,1 MD

Summary Bradycardia is a common complication at the early postoperative period after heart transplantation (HT). The heart rate (HR) usually recovers within a few weeks; however, several patients need a temporary pacemaker or chronotropic agents to stabilize their hemodynamics. Here, we report the first case of transient bradycardia associated with hemodynamic deterioration following HT, which was successfully treated with cilostazol, a phosphodiesterase-3-inhibiting agent. A 59-year-old man received HT for advanced heart failure due to ischemic cardiomyopathy. General fatigue persisted even after the HT. His HR was around 60 beats per minute (bpm) with sinus rhythm. Echocardiography showed no abnormal findings. Right heart catheterization showed that the cardiac index (CI) was 1.9 L/minute/m2. Continuous intravenous infusion of isoproterenol (0.003 μg/kg/minute) increased the HR to 80 bpm and CI to 2.7 L/minute/m2 and improved his symptoms. Isoproterenol was switched to oral administration of cilostazol (100 mg, twice a day), which maintained the HR at around 80 bpm and CI of 2.5 L/minute/m2. The patient’s HR gradually recovered and cilostazol could be discontinued three months after the HT. Oral administration of cilostazol can be a therapeutic option for patients with sinus bradycardia following HT, who need positive chronotropic support. (Int Heart J 2019; 60: 1222-1225) Key words: Advanced heart failure, Phosphodiesterase 3 inhibitor, Complication

rthotopic heart transplantation (HT) is an estab- nor’s heart rate (HR) just before the harvest was around lished strategy for advanced heart failure refrac- 70 beats per minute (bpm) with normal sinus rhythm. The O tory to medical therapy.1) Bradycardia is a com- total ischemic time was 261 minutes. After HT, immuno- mon complication during the early period following HT, suppressive therapy with our standard regimen using which is reported to occur among 14-44% of patients.2,3) tacrolimus, mycophenolate mofetil, and prednisolone was This is mainly due to sinus node dysfunction and usually started. The recipient was taking esomeprazole before HT, recovers spontaneously within a few weeks.2) However, and we continued it after HT to prevent gastrointestinal several patients need a temporary pacemaker or positive damage due to perioperative stress, prednisolone, and an- chronotropic agents to stabilize their hemodynamics. tithrombotic drugs. A temporary epicardial pacemaker was Here, we report the first case of sinus bradycardia as- needed following the reperfusion of the donor’s heart. sociated with hemodynamic deterioration following HT, Even after HT, general fatigue and shortness of which was successfully treated with cilostazol, a breath persisted, classified as New York Heart Association phosphodiesterase-3- (PDE3-) inhibiting agent. (NYHA) class III. Two weeks after the HT, the HR was around 60 bpm and the plasma brain natriuretic peptide (BNP) concentration was 292 pg/mL (Table). Chest X-ray Case Report showed cardiomegaly and slight pulmonary congestion A 59-year-old man with advanced heart failure due (Figure 1A). Electrocardiogram showed sinus rhythm with to ischemic cardiomyopathy received HT using the bicaval HR of 68 bpm (Figure 1B). Echocardiography showed technique following mechanical support with a normal left ventricular systolic function with end-diastolic continuous-flow left ventricular assist device. The donor diameter of 41 mm and ejection fraction of 70%. Right was a male in his late 50s with hypoxic encephalopathy, heart catheterization (RHC) under intravenous milrinone who did not have any history of cardiac diseases; the do- infusion showed cardiac index (CI) of 1.9 L/minute/m2

From the 1Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan, 2Department of Advanced Cardiopulmonary Failure, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan and 3Department of Cardiovascular Surgery, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. Address for correspondence: Takeo Fujino, MD, Department of Advanced Cardiopulmonary Failure, Faculty of Medical Sciences, Kyushu University, 3-1-1, Maidashi, Higashiku, Fukuoka, 812-8582, Japan. E-mail: [email protected] Received for publication March 3, 2019. Revised and accepted April 17, 2019. Released in advance online on J-STAGE September 4, 2019. doi: 10.1536/ihj.19-116 All rights reserved by the International Heart Journal Association. 1222 IntHeartJ September 2019 CILOSTAZOL AFTER HEART TRANSPLANTATION 1223

Table. Laboratory Data at Two and Eight Weeks after HT

Two weeks Eight weeks WBCs (/μL) 13,160 5,970 Hemoglobin (g/dL) 10.3 9.8 Platelets (104/μL) 15.7 12.4 Total protein (g/dL) 5.7 6.0 Albumin (g/dL) 3.0 3.6 Total bilirubin (mg/dL) 1.1 0.6 AST (IU/L) 69 15 ALT (IU/L) 283 14 BUN (mg/dL) 23 16 Creatinine (mg/dL) 1.44 1.04 Sodium (mmol/L) 126 140 Potassium (mmol/L) 4.9 4.0 CRP (mg/dL) 2.31 0.24 BNP (pg/mL) 292 77 WBCs indicates white blood cells; AST, aspartate aminotransferase; ALT, alanine aminotransferase; BUN, blood urea nitrogen; CRP, C-reactive protein; and BNP, brain natriuretic peptide.

Figure 1. Chest X-ray and electrocardiogram two weeks after HT. A: Chest X-ray showing cardiomegaly and slight pulmonary congestion. B: Electrocardiogram showing sinus rhythm with an HR of 68 bpm. with HR of 60 bpm (Figure 2, blue arrows). The mean tained his HR around 80 bpm, and his symptoms did not right atrial pressure was 5 mmHg and mean pulmonary exacerbate even after the discontinuation of isoproterenol capillary wedge pressure was 9 mmHg. Endomyocardial infusion. RHC showed that the CI was 2.5 L/minute/m2, biopsy showed grade 1A acute cellular rejection with no and his BNP concentration decreased to 77 pg/mL (Table evidence of antibody-mediated rejection. Coronary angiog- and Figure 2). He was discharged 62 days after the HT. raphy showed no significant lesions on the coronary arter- We continued cilostazol after the discharge, and his HR ies. On the basis of these findings, sinus bradycardia was gradually increased up to 90 bpm. We then discontinued considered to be the main cause of the low cardiac output cilostazol at three months after the HT, under close in- in this patient. Intravenous infusion of isoproterenol hospital monitoring. His HR was maintained around 75 (0.003 μg/kg/minute) was started, and the CI markedly in- bpm and he remained asymptomatic. Four months after creased to 2.7 L/minute/m2, associated with the increase the HT, RHC showed that the CI was 2.4 L/minute/m2 of the HR to 85 bpm (Figure 2, red arrows). As a result and BNP concentration was 46 pg/mL (Figure 2). He did of hemodynamic improvement, he achieved symptomatic not suffer from any bleeding event during the course. relief (NYHA class II). Three weeks after the HT, his cardiac output re- Discussion mained low, with CI of 1.7 L/minute/m2 and HR of 63 bpm without isoproterenol. We then switched the intrave- This is the first case report claiming that cilostazol is nous infusion of isoproterenol to an oral administration of safe and effective for treating sinus bradycardia during the cilostazol, a selective inhibitor of PDE3, to maintain his early period after HT. In our patient, his HR was about 60 HR. Cilostazol (100 mg, twice a day) successfully main- bpm after HT and he experienced symptoms due to low IntHeartJ 1224 UCHIKAWA, ET AL September 2019

Figure 2. Time-dependent change of the HR, CI, and plasma BNP concentration after HT. The blue and red arrows indicate the HR and CI before and after starting isoproterenol, respectively. HR indicates heart rate (beats per minute); CI, cardiac index; and BNP, brain natriuretic peptide. cardiac output. HR under 70 bpm is considered significant fective against sinus bradyarrhythmia.13) In our case, we bradycardia in HT recipients.4) used cilostazol to treat symptomatic bradycardia and In the current era of extended donor criteria such as showed its positive chronotropic effect in a transplanted older age and longer ischemic time, bradycardia is still a heart. We then successfully switched from intravenous iso- serious problem after HT.5) Bradycardia occurs among 14- proterenol to oral cilostazol. The major side effect of 44% of HT recipients and the majority of them are due to cilostazol is bleeding, due to its antiplatelet activity, al- sinus node dysfunction during the early period after HT, though its risk is low.14) Our patient did not suffer from which spontaneously recovers within a few weeks.2,3) any side effects from cilostazol during the course. However, several patients need chronotropic support or We here reported the first case of bradycardia after pacemaker implantation to stabilize their hemodynamics. HT, which was successfully treated with cilostazol. Al- Jones, et al. reported that only 32% of HT recipients who though the role of theophylline and β-adrenergic receptor had received permanent pacemaker implantation were agonists is established in this situation, cilostazol can be pacemaker-dependent during long-term follow-up.5) There- an alternative option for HT recipients who need positive fore, less invasive but effective therapy other than perma- chronotropic support. nent pacemaker implantation is required. The guideline from International Society for Heart and Lung Transplan- tation recommends positive chronotropic agents, such as Disclosures isoproterenol or theophylline, to increase the HR in such cases.6) Theophylline, an adenosine receptor antagonist, is Conflicts of interest: None. reported to be effective for bradycardia after HT.7) How- ever, it may interact with other drugs, such as antibiotics, References and careful monitoring of drug concentration is required. Furthermore, because our patient suffered from 1. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines tacrolimus-induced tremor, we were hesitant to start an for the diagnosis and treatment of acute and chronic heart fail- oral administration of theophylline or β-adrenergic recep- ure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology tor agonists which could exacerbate his symptoms. (ESC)Developed with the special contribution of the Heart Fail- Cilostazol is a PDE3-inhibiting agent and is effective ure Association (HFA) of the ESC. Eur Heart J 2016; 37: 2129- for peripheral arterial diseases8) and the secondary preven- 200. tion of cerebral infarction.9-11) Because it increases the HR 2. Melton IC, Gilligan DM, Wood MA, et al. Optimal cardiac pac- via upregulating cyclic adenosine monophosphate in the ing after heart transplantation. Pacing Clin Electrophysiol 1999; myocardium and sinus node,12) it is also known to be ef- 22: 1510-27. IntHeartJ September 2019 CILOSTAZOL AFTER HEART TRANSPLANTATION 1225

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