Cardiac contractility modulation electrical signals improve myocardial gene expression in patients with heart failure.
OBJECTIVE
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 Ca(2+) 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 alpha-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 alpha-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 alpha-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 Ca(2+) cycling and stretch response genes. These changes may contribute to the clinical effects of CCM.
Butter
Christian
C
Heart Center Brandenburg in Bernau/Berlin, Bernau/Berlin, Germany. c.butter@immanuel.de
Rastogi
Sharad
S
Minden
Hans-Heinrich
HH
Meyhöfer
Jürgen
J
Burkhoff
Daniel
D
Sabbah
Hani N
HN
D002135:Calcium-Binding Proteins / Q000378:metabolism; D018592:Cross-Over Studies; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004311:Double-Blind Method; D004699:Endocardium / Q000503:physiopathology; D017079:Exercise Tolerance; D015870:Gene Expression; D006321:Heart / Q000503:physiopathology*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000235:genetics; D045265:Natriuretic Peptides / Q000378:metabolism; D014176:Protein Biosynthesis; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D011795:Surveys and Questionnaires; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D045265:Natriuretic Peptides; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban; C493956:CDKN1A protein, human; C506946:ATP2A2 protein, human