Author + information
- Received October 12, 2007
- Revision received December 21, 2007
- Accepted January 15, 2008
- Published online May 6, 2008.
- Christian Butter, MD⁎,⁎ (, )
- Sharad Rastogi, MD†,
- Hans-Heinrich Minden, MD⁎,
- Jürgen Meyhöfer, MD⁎,
- Daniel Burkhoff, MD, PhD‡ and
- Hani N. Sabbah, PhD†
- ↵⁎Reprint requests and correspondence:
Dr. Christian Butter, Heart Center Brandenburg Bernau/Berlin, Ladeburger Strasse 17, 16321 Bernau/Berlin, Germany.
Objectives The objective of this study was to test whether cardiac contractility modulation (CCM) electric signals induce reverse molecular remodeling in myocardium of patients with heart failure.
Background Heart failure is associated with up-regulation of myocardial fetal and stretch response genes and down-regulation of Ca2+ cycling genes. Treatment with CCM signals has been associated with improved symptoms and exercise tolerance in heart failure patients. We tested the impact of CCM signals on myocardial gene expression in 11 patients.
Methods Endomyocardial biopsies were obtained at baseline and 3 and 6 months thereafter. The CCM signals were delivered in random order of ON for 3 months and OFF for 3 months. Messenger ribonucleic acid expression was analyzed in the core lab by investigators blinded to treatment sequence. Expression of A- and B-type natriuretic peptides and α-myosin heavy chain (MHC), the sarcoplasmic reticulum genes SERCA-2a, phospholamban and ryanodine receptors, and the stretch response genes p38 mitogen activated protein kinase and p21 Ras were measured using reverse transcription-polymerase chain reaction and bands quantified in densitometric units.
Results The 3-month therapy OFF phase was associated with increased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase, and p21 Ras and decreased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors. In contrast, the 3-month ON therapy phase resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase and p21 Ras and increased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors.
Conclusions The CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2+ cycling and stretch response genes. These changes may contribute to the clinical effects of CCM.
Supported, in part, by research grants from Impulse Dynamics USA, Inc., and by the National Heart, Lung, and Blood Institute, #P01 HL074237-04. Dr. Burkhoff is an employee of Impulse Dynamics. Dr. Sabbah is a consultant to Impulse Dynamics.
- Received October 12, 2007.
- Revision received December 21, 2007.
- Accepted January 15, 2008.
- American College of Cardiology Foundation