ORCID Profile
0000-0002-6295-4905
Current Organisations
Asian Heart and Vascular Centre
,
Heart Rhythm Society
,
National University of Singapore
,
National University Hospital
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Publications
Effect of Diabetes Mellitus on Cardiac Resynchronization Therapy and to Prognosis in Heart Failure (from the Prospective Evaluation of Asian With Cardiac Resynchronization Therapy for Heart Failure St
Publisher: Elsevier BV
Date: 09-2019
DOI: 10.1016/J.AMJCARD.2019.06.004
Abstract: The association of diabetes mellitus (DM) with cardiac resynchronization therapy (CRT) response and cardiovascular outcomes in Asian patients with heart failure (HF) is unclear. This study aims to investigate the effects of DM on CRT response and cardiovascular outcomes in Asian HF patients. Consecutive Asian HF patients receiving CRT were enrolled in the Prospective Evaluation of Asian with CRT for Heart Failure (PEACH) study from 2011 to 2017. CRT response and super-response were defined as decrease in end-systolic volume index ≥15% and ≥30%, respectively. Primary endpoint was time to composite of HF-hospitalization and all-cause mortality. Among 161 patients followed for 3.3 ± 1.5 years (age 66.7 ± 11.2 years, 22% females, mean QRS duration 154.3 ± 22.4 ms, 83% left bundle branch block), 84 (52%) were CRT responders and 57 (35%) were super-responders. Of 82 (51%) patients with DM (100% type 2, mean HbA1c 7.3 ± 1.9%), 35 (43%) were responders. DM attenuated reverse remodeling (CRT response: AOR 0.44, 95% confidence interval [CI] 0.20 to 0.98, p < 0.05 super-response: AOR 0.42, 95% CI 0.18 to 0.97, p <0.05), and DM increased HF-hospitalization and all-cause mortality (AHR 1.68, 95% CI 1.00 to 2.82, p = 0.05). The extent of CRT-response correlates with higher event-free survival (CRT response: AHR 0.5, 95% CI 0.30 to 0.81, p = 0.005 super-response: AHR 0.27, 95% CI 0.14 to 0.52, p < 0.001). In conclusion, the extent of reverse remodeling post-CRT is the strongest predictor of event free survival. However, DM is detrimental to the CRT recipient by attenuating reverse remodeling, inducing end organ dysfunction and is independently associated with worsened clinical outcomes among Asian HF patients.
Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone andN-Desbutyl Dronedarone
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 21-10-2015
Abstract: Dronedarone is an antiarrhythmic agent approved in 2009 for the treatment of atrial fibrillation. An in-house preliminary study demonstrated that dronedarone inhibits cytochrome P450 (CYP) 3A4 and 3A5 in a time-dependent manner. This study aimed to investigate the inactivation of CYP450 by dronedarone. We demonstrated for the first time that both dronedarone and its main metabolite N-desbutyl dronedarone (NDBD) inactivate CYP3A4 and CYP3A5 in a time-, concentration-, and NADPH-dependent manner. For the inactivation of CYP3A4, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 0.87 µM and 0.039 minute(-1), respectively, for dronedarone, and 6.24 µM and 0.099 minute(-1), respectively, for NDBD. For CYP3A5 inactivation, the inactivator concentration at the half-maximum rate of inactivation and inactivation rate constant at an infinite inactivator concentration are 2.19 µM and 0.0056 minute(-1) for dronedarone and 5.45 µM and 0.056 minute(-1) for NDBD. The partition ratios for the inactivation of CYP3A4 and CYP3A5 by dronedarone are 51.1 and 32.2, and the partition ratios for the inactivation of CYP3A4 and CYP3A5 by NDBD are 35.3 and 36.6. Testosterone protected both CYP3A4 and CYP3A5 from inactivation by dronedarone and NDBD. Although the presence of Soret peak confirmed the formation of a quasi-irreversible metabolite-intermediate complex between dronedarone/NDBD and CYP3A4/CYP3A5, partial recovery of enzyme activity by potassium ferricyanide illuminated an alternative irreversible mechanism-based inactivation (MBI). MBI of CYP3A4 and CYP3A5 was further supported by the discovery of glutathione adducts derived from the quinone oxime intermediates of dronedarone and NDBD. In conclusion, dronedarone and NDBD inactivate CYP3A4 and CYP3A5 via unique dual mechanisms of MBI and formation of the metabolite-intermediate complex. Our novel findings contribute new knowledge for future investigation of the underlying mechanisms associated with dronedarone-induced hepatotoxicity and clinical drug-drug interactions.
Multiple modes of inhibition of human cytochrome P450 2J2 by dronedarone, amiodarone and their active metabolites
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.BCP.2016.03.005
Abstract: Dronedarone, a multiple ion channel blocker is prescribed for the treatment of paroxysmal and persistent atrial fibrillation. While dronedarone does not precipitate toxicities like its predecessor amiodarone, its clinical use has been associated with idiosyncratic hepatic and cardiac adverse effects and drug-drug interactions (DDIs). As dronedarone is a potent mechanism-based inactivator of CYP3A4 and CYP3A5, a question arose if it exerts a similar inhibitory effect on CYP2J2, a prominent cardiac CYP450 enzyme. In this study, we demonstrated that CYP2J2 is reversibly inhibited by dronedarone (Ki=0.034 μM), amiodarone (Ki=4.8μM) and their respective pharmacologically active metabolites namely N-desbutyldronedarone (NDBD) (Ki=0.55 μM) and N-desethylamiodarone (NDEA) (Ki=7.4 μM). Moreover, time-, concentration- and NADPH-dependent irreversible inactivation of CYP2J2 was investigated where inactivation kinetic parameters (KI, kinact) and partition ratio (r) of dronedarone (0.05 μM, 0.034 min(-1), 3.3), amiodarone (0.21 μM, 0.015 min(-1), 20.7) and NDBD (0.48 μM, 0.024 min(-1), 21.7) were observed except for NDEA. The absence of the characteristic Soret peak, lack of recovery of CYP2J2 activity upon dialysis, and biotransformation of dronedarone and NDBD to quinone-oxime reactive metabolites further confirmed the irreversible inactivation of CYP2J2 by dronedarone and NDBD is via the covalent adduction of CYP2J2. Our novel findings illuminate the possible mechanisms of DDIs and cardiac adverse effects due to both reversible inhibition and irreversible inactivation of CYP2J2 by dronedarone, amiodarone and their active metabolites.
Coronary venoplasty during cardiac resynchronization therapy device implantations: Acute results and clinical outcomes
Publisher: Elsevier BV
Date: 05-2020
DOI: 10.1016/J.HRTHM.2019.12.012
Abstract: Optimal left ventricular (LV) lead placement improves response to cardiac resynchronization therapy (CRT) but can be hindered by unfavorable venous anatomy. Interventional procedures in the coronary veins have been described with promising short-term outcomes. The purpose of this study was to establish the safety and efficacy of percutaneous coronary venoplasty (PCV) during CRT implantation and assess medium-term lead performances and clinical outcomes against matched controls not requiring PCV. Each consecutive PCV case was matched according to age, gender, and bundle branch morphology to 2 controls from a large prospective registry of CRT recipients. Demographics, procedural success, lead performance, and response to CRT were tracked using a comprehensive electronic medical records system. Of 422 consecutive CRT recipients treated between 2012 to 2018, 29 patients (6.9% mean age 65.7 ± 10.7 years 7 female 17 ischemic cardiomyopathy 22 left bundle branch block) required PCV, which was successful in 21 cases (72%). Target veins measuring 1.1 ± 0.6 mm were dilated by noncompliant balloons with mean diameter 2.8 ± 0.5 mm. No complications occurred. Fluoroscopic and procedural durations were longer in the PCV group (P <.01) Over mean follow-up of 33.0 ± 25.0 months, no differences in lead performance, CRT response, or 2-year survival were observed compared to the control group. PCV during CRT device implant is typically successful, safe and associated with long-term clinical outcomes comparable to patients who did not need PCV. This is an important technique to optimize LV lead placement and maximize CRT response.
Related Organisations
St Bartholomew's Hospital
Location: United Kingdom of Great Britain and Northern Ireland
Imperial College London
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for Pipin Kojodjojo.