CLINICAL RESEARCH: HEART FAILURE
Cardiac Contractility Modulation Electrical Signals Improve Myocardial Gene Expression in Patients With Heart Failure
Christian Butter, MD*,*,
Sharad Rastogi, MD ,
Hans-Heinrich Minden, MD*,
Jürgen Meyhöfer, MD*,
Daniel Burkhoff, MD, PhD and
Hani N. Sabbah, PhD
* Heart Center Brandenburg in Bernau/Berlin, Bernau/Berlin, Germany
Division of Cardiovascular Medicine, Henry Ford Health System, Detroit, Michigan
Columbia University, New York, New York.
Manuscript received October 12, 2007;
revised manuscript received December 21, 2007,
accepted January 15, 2008.
* Reprint requests and correspondence: Dr. Christian Butter, Heart Center Brandenburg Bernau/Berlin, Ladeburger Strasse 17, 16321 Bernau/Berlin, Germany. (Email: c.butter{at}immanuel.de).
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  -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 -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 -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.
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Abbreviations and Acronyms
| | CCM = cardiac contractility modulation | | DNA = deoxyribonucleic acid | | HF = heart failure | | MHC = myosin heavy chain | | MLHFQ = Minnesota Living with Heart Failure Questionnaire | | RNA = ribonucleic acid | | SERCA-2a = sarcoplasmic reticulum calcium adenosine triphosphatase | | 6MW = 6-min walk test |
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