TY - JOUR
T1 - Pacemaker-induced transient asynchrony suppresses heart failure progression
AU - Kirk, Jonathan A.
AU - Chakir, Khalid
AU - Lee, Kyoung Hwan
AU - Karst, Edward
AU - Holewinski, Ronald J.
AU - Pironti, Gianluigi
AU - Tunin, Richard S.
AU - Pozios, Iraklis
AU - Abraham, Theodore P.
AU - De Tombe, Pieter
AU - Rockman, Howard A.
AU - Van Eyk, Jennifer E.
AU - Craig, Roger
AU - Farazi, Taraneh G.
AU - Kass, David A.
N1 - Funding Information:
We thank N. Witayavanitkul, A. Dvornikov, and M. Phillip for their technical expertise and assistance. This work was supported by the NIH [P01-HL077180 to D.A.K. and J.E.V.E.; T32-HL007227, P01-HL059408, and Abraham and Virginia Weiss and Michael and Janet Huff Endowments to D.A.K.; NHLBI-HV-10-05(2) to J.E.V.E.; HHSN268201000032C to J.E.V.E.; R01-AR034711 to R.C.; and P01-HL75443 to H.A.R.], the American Heart Association (14SDG20380148 to J.A.K.), and the BurroughsWellcome Fund (1012753 to J.A.K.). J.A.K. and D.A.K. are listed as inventors on a pending patent on the use of temporary dyssynchrony to improve cardiac function in failing hearts. H.A.R. is a scientific cofounder for Trevena Inc., a company that is developing G protein-coupled receptor-targeted drugs. E.K. and T.G.F. hold stocks in St. Jude Medical Inc., which developed the pacemaker system and software.
PY - 2015/12/23
Y1 - 2015/12/23
N2 - Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qualifies for CRT. We show that heart failure with synchronous contraction is improved by inducing dyssynchrony for 6 hours daily by right ventricular pacing using an intracardiac pacing device, in a process we call pacemaker-induced transient asynchrony (PITA). In dogs with heart failure induced by 6 weeks of atrial tachypacing, PITA (starting on week 3) suppressed progressive cardiac dilation as well as chamber and myocyte dysfunction. PITA enhanced β-adrenergic responsiveness in vivo and normalized it in myocytes. Myofilament calcium response declined in dogs with synchronous heart failure, which was accompanied by sarcomere disarray and generation of myofibers with severely reduced function, and these changes were absent in PITA-treated hearts. The benefits of PITA were not replicated when the same number of right ventricular paced beatswas randomly distributed throughout the day, indicating that continuity of dyssynchrony exposure is necessary to trigger the beneficial biological response upon resynchronization. These results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.
AB - Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qualifies for CRT. We show that heart failure with synchronous contraction is improved by inducing dyssynchrony for 6 hours daily by right ventricular pacing using an intracardiac pacing device, in a process we call pacemaker-induced transient asynchrony (PITA). In dogs with heart failure induced by 6 weeks of atrial tachypacing, PITA (starting on week 3) suppressed progressive cardiac dilation as well as chamber and myocyte dysfunction. PITA enhanced β-adrenergic responsiveness in vivo and normalized it in myocytes. Myofilament calcium response declined in dogs with synchronous heart failure, which was accompanied by sarcomere disarray and generation of myofibers with severely reduced function, and these changes were absent in PITA-treated hearts. The benefits of PITA were not replicated when the same number of right ventricular paced beatswas randomly distributed throughout the day, indicating that continuity of dyssynchrony exposure is necessary to trigger the beneficial biological response upon resynchronization. These results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.
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U2 - 10.1126/scitranslmed.aad2899
DO - 10.1126/scitranslmed.aad2899
M3 - Article
C2 - 26702095
AN - SCOPUS:84954426403
SN - 1946-6234
VL - 7
JO - Science translational medicine
JF - Science translational medicine
IS - 319
ER -