Lipid lowering by pravastatin increases parasympathetic modulation of heart rate: Galpha(i2), a possible molecular marker for parasympathetic responsiveness.
BACKGROUND
We have previously demonstrated in an in vitro model for lipid lowering that lipoprotein depletion resulted in a marked increase in the negative chronotropic response to the acetylcholine analogue carbamylcholine. In this study we used heart rate variability analysis to determine the effect of lipid lowering by statins on the response of the heart to parasympathetic stimulation. In parallel, we examined whether changes in parasympathetic responsiveness correlated with changes in the expression of Galpha(i2), a molecular component of the parasympathetic signaling pathway in the heart.


RESULTS
Patients were randomized in a crossover study of pravastatin and simvastatin. R-R interval analysis of Holter monitor studies demonstrated that in patients treated initially with pravastatin, the peak high-frequency power fraction during sleep, which reflects parasympathetic modulation of heart rate, increased by 24.0+/-5.02% (SEM, n=13, P<0.001) compared with the untreated control value. Simvastatin had no significant effect. Western blot analysis of lymphocytes from patients treated with pravastatin demonstrated a 90.1+/-27.3% (n=10, P=0.009) increase in Galpha(i2) expression, whereas simvastatin had no effect. Relative changes in Galpha(i2) correlated significantly with the changes in the fraction of high-frequency power (rho=0.574, P=0.016).


CONCLUSIONS
Taken together with our in vitro data, these data are the first to suggest that cholesterol lowering by pravastatin might increase the response of the heart to parasympathetic stimulation and that changes in Galpha(i2) expression might serve as a molecular marker for this effect.
Welzig
C Michael
CM
The Children's Heart Program, Medical University of South Carolina, Charleston, SC, USA.
Shin
Dong-Gu
DG
Park
Ho-Jin
HJ
Kim
Young-Jo
YJ
Saul
J Philip
JP
Galper
Jonas B
JB
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D018592:Cross-Over Studies; D015716:Electrocardiography, Ambulatory / Q000187:drug effects; D005260:Female; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000032:analysis / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010275:Parasympathetic Nervous System / Q000187:drug effects* / Q000503:physiopathology; D017035:Pravastatin / Q000494:pharmacology* / Q000627:therapeutic use; D011237:Predictive Value of Tests; D011518:Proto-Oncogene Proteins / Q000032:analysis / Q000378:metabolism*; D019821:Simvastatin / Q000627:therapeutic use; D016037:Single-Blind Method
D015415:Biomarkers; D000960:Hypolipidemic Agents; D008055:Lipids; D011518:Proto-Oncogene Proteins; D019821:Simvastatin; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D017035:Pravastatin