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CLINICAL RESEARCH: HEART RHYTHM DISORDER

The Effects of Carbenoxolone on Human Myocardial Conduction

A Tool to Investigate the Role of Gap Junctional Uncoupling in Human Arrhythmogenesis

St. Mary’s Hospital, Imperial College, London, United Kingdom.

Manuscript received January 3, 2006; revised manuscript received April 21, 2006, accepted April 25, 2006.

^_* Reprint requests and correspondence: Dr. Prapa Kanagaratnam, Department of Cardiology, St. Mary’s Hospital, Praed Street, London W2 1NY, United Kingdom. (Email: p.kanagaratnam{at}imperial.ac.uk).

OBJECTIVES: This study assessed the effects of carbenoxolone on human myocardial conduction and refractoriness.

BACKGROUND: Carbenoxolone, an antipeptic ulcer drug, has been shown to reduce gap junctional coupling without affecting cellular ion channels. Gap junctions (GJ) are considered to be determinants of cardiac action potential propagation. The effects of GJ uncoupling in the human heart are unknown.

METHODS: Right atrial (RA) and ventricular (RV) activation mapping (Carto, Biosense Webster Inc., Diamond Bar, California) was performed during sinus rhythm. Right atrial and RV wavefront propagation velocity (WPV), specifically in the direction of propagation, was determined from these maps using a triangulation method. Refractoriness at multiple RA and RV sites, sinus rhythm cycle length, and AH, PR, QRS, and QT intervals were measured. The protocol was repeated 1 h after oral administration of 100 mg of carbenoxolone.

RESULTS: In 11 patients, WPV was reduced from 79.6 ± 13.3 cm/s to 57.2 ± 9.1 cm/s (–27.1 ± 12.8%, p < 0.001) in RA and from 98.7 ± 19.8 cm/s to 76.5 ± 21.7 cm/s (–22.7 ± 14.1%, p < 0.01) in RV after carbenoxolone. Conduction slowing was more marked in 6 older patients with ischemic heart disease compared with younger subjects with normal hearts (RA –35.1 ± 5.5% vs. –17.5 ± 12.7%, p = 0.03; RV –33.8 ± 5.1% vs. –9.3 ± 7.7%, p < 0.001). Refractoriness and electrocardiogram parameters remained unchanged.

CONCLUSIONS: Carbenoxolone causes a 27% reduction in human RA WPV and 23% in the RV without affecting refractoriness. The slowing of myocardial conduction by carbenoxolone demonstrates the significance of GJ in regulating human myocardial conduction and provides a tool for investigating the effects of GJ uncoupling on human arrhythmogenesis.

Abbreviations and Acronyms   AERP = absolute effective refractory period   CS = coronary sinus   EPS = electrophysiology studies   IHD = ischemic heart disease   LAT = local activation time   RA = right atrial/atrium   RV = right ventricle/ventricular   WPV = wavefront propagation velocity

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