Right ventricular pacing with mechanical dyssynchrony causes apoptosis interruptus and calcium mishandling.
BACKGROUND
Mechanical dyssynchrony associated with rapid pacing induces cardiac cell stress and myocardial apoptotic pathway activation that has been implicated in the pathophysiology of left ventricular (LV) dysfunction. Effects of dyssynchrony per se are not fully understood. The objective of our study was to test whether ventricular dyssynchrony would elicit myocardial alterations in LV calcium handling regulation and cell survival or apoptosis signalling in right ventricular-paced swine.


METHODS
Implantation of pacemaker was performed under anaesthesia. Endocardial bipolar screw lead was inserted into the right jugular vein and positioned either in the right atrium or at the right ventricular (RV) apex. Swine were paced at 150 beats per minute for 3 weeks.


RESULTS
Compared with right atrial pacing, RV pacing led to abnormal LV sarcoplasmic reticulum calcium uptake (315 ± 65 vs 155 ± 55 nmol/min/mg, P < 0.05) and LV calcium-handling protein expression, ie, 35% reduction in ryanodine receptor 2, 25% decline in sarcoplasmic reticulum Ca(2+) ATPase, 70% increase in Na(+)/Ca(2+) exchanger, and 10% increase in phospholamban. RV pacing also elicited activation of LV apoptotic cascades without nuclear apoptosis. So-called interrupted apoptosis was the result of increased expression of X-linked inhibitor of apoptosis protein. Apoptosis and calcium mishandling were documented in absence of depressed heart function (ejection fraction 62 ± 8% vs 57 ± 12%, in right atrial- and RV-paced hearts, respectively, P > 0.05).


CONCLUSIONS
Slow rate RV pacing causes mechanical dyssynchrony and profound LV alterations in both apoptotic pathways and calcium handling in the early stages of pacing-induced cardiomyopathy.
EA 4484, Département de Physiologie, Université Lille 2, Faculté de Médecine de Lille, Lille, France.
Didier
D
Klug
Stephane
S
Boule
Ludivine
L
Wissocque
David
D
Montaigne
Xavier
X
Marechal
Sidi Mohamed
SM
Hassoun
Remi
R
Neviere
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000209:etiology* / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival; D004452:Echocardiography; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006339:Heart Rate; D006352:Heart Ventricles / Q000378:metabolism / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D020169:Caspases; D019837:Ryanodine Receptor Calcium Release Channel; D014409:Tumor Necrosis Factor-alpha; D000099211:Phospholamban