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(Circulation. 1997;96:1078-1081.)
© 1997 American Heart Association, Inc.

Articles

Evidence for Primary Genetic Determination of Heart Rate Regulation

Chromosomal Mapping of a Genetic Locus in the Rat

Reinhold Kreutz, MD; Berthold Struk, MD; Phillippe Stock, MD; Norbert Hübner, MD; Detlev Ganten, MD, PhD; ; Klaus Lindpaintner, MD

From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Department of Cardiology, Children's Hospital, Harvard Medical School (R.K, B.S., P.S., K.L.), Boston, Mass; the Department ofClinical Pharmacology, Benjamin Franklin Hospital (R.K., N.H., D.G.), Berlin, Germany; and the Max Delbrück Centre for Molecular Medicine (D.G., K.L.), Berlin, Germany.

Correspondence to Klaus Lindpaintner, MD, Cardiovascular Division, Brigham and Women's Hospital, 75 Francis St - Thorn 1103, Boston, MA 02115. E-mail kl{at}calvin.bwh.harvard.edu

Background We investigated whether an accelerated heart rate (HR), observed in the stroke-prone spontaneously hypertensive rat (SHRSP_HD), is a primary, genetically determined trait and whether it contributes to blood pressure (BP) regulation in this model of polygenic hypertension.

Methods and Results We measured BP and HR in SHRSP_HD and normotensive Wistar-Kyoto rats (WKY), as well as in F₂ hybrids bred from crossing the two strains, at baseline and after 12 days of dietary NaCl loading. Random marker genome screening and cosegregation analysis were performed on F₂ hybrids derived from SHRSP_HD/WKY-0_HD (n=115) and SHRSP_HD/WKY-1_HD (n=139) crosses (WKY-0_HD and WKY-1_HD are two congenic WKY strains). HR in SHRSP_HD was significantly higher than in WKY-0_HD both at baseline (404±30 versus 375±46 bpm; P=.0034) and after NaCl (437±23 versus 364±40 bpm; P=10^-9). BP in F₂ hybrids showed no significant correlation with HR either at baseline or after NaCl loading. HR after NaCl loading but not at baseline was significantly linked in a recessive fashion to a locus on chromosome 3: in animals homozygous for the SHRSP_HD allele, HR was 414±49 compared with 383±44 bpm in heterozygotes and WKY homozygotes (F_210,1=19.7, P=1.4x10^-5, lod score=5.9). The putative BP-relevant gene at this locus, termed HR-SP1, showed no evidence of linkage to any of the BP parameters measured.

Conclusions Our results demonstrate that a genetic locus on rat chromosome 3, HR-SP1, contributes directly to the regulation of HR in SHRSP_HD but exhibits no effect on BP. Thus, in addition to its modulation by reflex-mediated neurohumoral mechanisms, HR is also under the direct influence of primary genetic factors.

Key Words: genes • hypertension • heart rate • blood pressure

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