Cardiac resynchronization therapy restores sympathovagal balance in the failing heart by differential remodeling of cholinergic signaling.
BACKGROUND
Cardiac resynchronization therapy (CRT) is the only heart failure (HF) therapy documented to improve left ventricular function and reduce mortality. The underlying mechanisms are incompletely understood. Although β-adrenergic signaling has been studied extensively, the effect of CRT on cholinergic signaling is unexplored.


OBJECTIVE
We hypothesized that remodeling of cholinergic signaling plays an important role in the aberrant calcium signaling and depressed contractile and β-adrenergic responsiveness in dyssynchronous HF that are restored by CRT.


RESULTS
Canine tachypaced dyssynchronous HF and CRT models were generated to interrogate responses specific to dyssynchronous versus resynchronized ventricular contraction during hemodynamic decompensation. Echocardiographic, electrocardiographic, and invasive hemodynamic data were collected from normal controls, dyssynchronous HF and CRT models. Left ventricular tissue was used for biochemical analyses and functional measurements (calcium transient, sarcomere shortening) from isolated myocytes (n=42-104 myocytes per model; 6-9 hearts per model). Human left ventricular myocardium was obtained for biochemical analyses from explanted failing (n=18) and nonfailing (n=7) hearts. The M2 subtype of muscarinic acetylcholine receptors was upregulated in human and canine HF compared with nonfailing controls. CRT attenuated the increased M2 subtype of muscarinic acetylcholine receptor expression and Gαi coupling and enhanced M3 subtype of muscarinic acetylcholine receptor expression in association with enhanced calcium cycling, sarcomere shortening, and β-adrenergic responsiveness. Despite model-dependent remodeling, cholinergic stimulation completely abolished isoproterenol-induced triggered activity in both dyssynchronous HF and CRT myocytes.


CONCLUSIONS
Remodeling of cholinergic signaling is a critical pathological component of human and canine HF. Differential remodeling of cholinergic signaling represents a novel mechanism for enhancing sympathovagal balance with CRT and may identify new targets for treatment of systolic HF.
From the Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD.
Deeptankar
D
DeMazumder
From the Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD.
David A
DA
Kass
From the Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD.
Brian
B
O'Rourke
From the Department of Medicine, Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD. gtomasel@jhmi.edu.
Gordon F
GF
Tomaselli
D000109:Acetylcholine / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling; D058406:Cardiac Resynchronization Therapy; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004285:Dogs; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006321:Heart / Q000294:innervation*; D006333:Heart Failure / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D018721:Muscarinic Agonists / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009200:Myocardial Contraction; D043585:Receptor, Muscarinic M2 / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism; D020127:Recovery of Function; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009435:Synaptic Transmission / Q000187:drug effects; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D016277:Ventricular Function, Left
D000318:Adrenergic beta-Agonists; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D000109:Acetylcholine
acetylcholine; autonomic nervous system; cardiac resynchronization therapy; heart failure; receptors, muscarinic; vagal nerve stimulation