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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

	Abstract

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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

	Introduction

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Cardiac output and total peripheral resistance are the major hemodynamic determinants of BP.¹ In patients with established hypertension, an increase in total peripheral vascular resistance associated with normal or reduced cardiac index is a characteristic hemodynamic finding.¹ Increased HR in these patients is commonly viewed as a compensatory response to a diminished stroke volume, which may be due to diastolic or systolic myocardial dysfunction.^{1 2 3} In contrast, in the early stages of hypertension in both humans and experimental animals, an increased HR is not uncommonly seen in the absence of compromised left ventricular function.¹ In the presence of normal total peripheral resistance, this results in an increased cardiac output and consequently in a rise in peripheral BP. Thus, whereas an increased HR most likely represents a secondary phenomenon in established hypertension, it has been argued that an early increase in HR may contribute directly to the pathogenesis of hypertension.^{1 4} This hypothesis requires that one postulate a primary, presumably genetically determined alteration of baseline HR regulation. Thus far, no direct evidence has been presented to support such a possibility. The aim of the current study was to investigate this question by use of an experimental animal model that displays both hypertension and accelerated HR, namely, the SHRSP_HD.

	Methods

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Animals and Genetic Crosses
Animals were obtained from our colonies of SHRSP_HD, WKY-0_HD, and WKY-1_HD rats at the University of Heidelberg, Germany.⁵ WKY-0_HD denotes the wild-type WKY_HD strain, whereas WKY-1_HD is a congenic line (two genetically almost identical strains that differ only in a defined area of their genome) that carries an SHRSP-homologous (ie, derived from the SHRSP genome), BP-relevant locus, BP/SP-1a, on chromosome 10.⁶ The experimental procedures for animal housing and breeding have been reported previously.⁵ The reciprocal (ie, either derived from a male SHRSP/female WKY mating or from the opposite constellation) F₂(WKY-0_HDxSHRSP_HD) (n=115) and F₂(WKY-1_HDxSHRSP_HD) (n=139) cohorts analyzed in the present study have been the subject of previous reports.^{5 6 7 8 9 10}

BP Measurement
The protocol for the hemodynamic characterization of the F₂ rats and the WKY-0_HD and SHRSP_HD progenitor strains (n=11 and 12 males and females, respectively) was identical. It included femoral artery cannulation and intermittent on-line recordings as reported previously.¹⁰ Two consecutive femoral artery cannulations to measure BP and HR at baseline and after a period of 12 days of dietary NaCl exposure (1% NaCl in the drinking water) were performed.¹⁰ During measurements, the animals were shielded from the investigator, and three independent readings were taken while the animals were resting quietly.¹⁰

Genotype Determination
A total genome screen was performed using polymorphic SSLPs (microsatellites: stretches of repetitive DNA that tend to be unstable, thus often polymorphic, ie, different from strain to strain, and thus useful for genetic mapping) obtained from previously published panels of SSLPs,^{7 8 11 12} from new library screenings,¹¹ and from GenBank data searches. SSLP markers were amplified by PCR from 50 ng of genomic DNA in a final reaction volume of 10 µL, containing 100 nmol/L of each primer, 200 µmol/L dNTPs, 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 10 mmol/L Tris-HCl (pH 9.0 at 25°C), 0.1% Triton X-100, and 0.25 U of Taq DNA polymerase. The forward primer was labeled with [-³²P]ATP (specific activity of 3000 Ci · mmol^-1, DuPont/NEN) using T4 polynucleotide kinase (NEB). PCR reactions were processed on an MJ Research thermal cycler (PTC 100) using the following protocol: initial denaturation at 92°C for 3 minutes followed by 30 cycles of denaturation at 92°C for 15 seconds, annealing at 55°C for 1 minute, and extension at 72°C for 1 minute, followed by a final extension step at 72°C for 7 minutes. Subsequent to the PCR, the samples were analyzed by polyacrylamide gel electrophoresis and autoradiography as described previously.⁷

Statistical Analysis and Linkage Analysis
Interstrain comparisons were performed by two-way ANOVA to test the effects of strain and sex. Statistical evaluation of the effect of genotypes on HR phenotype in the F₂ intercrosses was performed by ANCOVA) to account for sex, cross, and parental constellation of the reciprocal crosses and to adjust for BP, respectively. For combined linkage analysis in both F₂ intercrosses, means in each group were adjusted for cross, sex, and reciprocal cross status where appropriate.⁷ Linear regression analysis was performed by calculating the coefficient of determination, R². Chromosomal mapping and lod score calculations were performed using the MAPMAKER/EXP and MAPMAKER/QTL programs.¹³ All phenotype parameters are expressed as mean±SD.

	Results

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We previously reported¹⁰ that at 16 weeks of age, basal systolic BP differs by 70 and 90 mm Hg in female and male SHRSP_HD compared with female and male WKY-0_HD rats, respectively. Oral NaCl loading led to an additional BP increase of 30 mm Hg in both female and male SHRSP_HD, whereas BP in WKY-0_HD remained unchanged.¹⁰ HR at baseline conditions was significantly higher in male SHRSP_HD than in male WKY-0_HD (P=.0003), with no statistically significant difference among females (P=.55; Table 1). In contrast, after oral NaCl loading, HR was significantly elevated among both female (+60 bpm) and male (+80 bpm) SHRSP_HD rats (Table 1). BP, as determined by radiotelemetry measurements, was modestly elevated in WKY-1_HD compared with WKY-0_HD, as previously reported,⁶ whereas HR demonstrated no difference among the two WKY strains (data not shown).

View this table: [in this window] [in a new window]   Table 1. HR (bpm) in SHRSPHD and WKYHD

In both F₂ cohorts, no significant correlation between systolic or diastolic BP and HR was observed either at baseline (R²=.09, P=.15 and R²=.02, P=.64, respectively) or after NaCl loading (R²=-.06, P=.35 and R²=-.10, P=.14, respectively). The genome screen identified suggestive linkage between a marker on chromosome 3 (Scn2a1) and HR after NaCl loading in both F₂ crosses. ANCOVA revealed no significant differences between WKY homozygotes and heterozygotes. Accordingly, under assumptions of a recessive mode of inheritance (both alleles must carry the "mutant" genotype), zygosity (ie, constellation of alleles) at Scn2a1 demonstrated significant linkage to HR after NaCl loading in the F₂(WKY-0_HDxSHRSP_HD) (P=.0062) and the F₂(WKY-1_HDxSHRSP_HD) (P=.0012) populations. Basal HR showed evidence for linkage to the same locus in the F₂(WKY-1_HDxSHRSP_HD) (P=.0008) cohort but not in the other cross (P=.33). Analysis for HR and BP phenotypes in both crosses combined demonstrated highly significant linkage between Scn2a1 and HR after NaCl loading (Table 2). In animals homozygous (ie, carrying two identical alleles) for the SHRSP allele, HR was 30 bpm higher than in heterozygotes (ie, carrying one allele each from the progenitor strains) or WKY homozygotes. A maximum lod score of 5.9 was observed by QTL mapping, yielding a 100:1 CI for placement of the implicated gene, HR-SP1, that spans 32 cM (Figure). HR-SP1 accounted for 14% of the overall variance of HR after NaCl loading. As expected, no linkage was found between BP phenotypes and HR-SP1 (Table 2). Adjustment for BP by ANCOVA had no effect on the linkage data for HR-SP1 and HR either at baseline or after NaCl loading (data not shown).

View this table: [in this window] [in a new window]   Table 2. Cosegregation Analysis for BP and HR in Relation to Genotype at Scn2a1

View larger version (9K): [in this window] [in a new window]   Figure 1. Linkage map of chromosome 3 and the placement of HR-SP1 based on combined multilocus linkage analysis in the F2(WKY-0HDxSHRSPHD) and F2(WKY-1HDxSHRSPHD) crosses. The numbers given to the left of the chromosome indicate the genetic distance in centimorgans. The bar on the right represents the 100:1 odds interval for localization of HR-SP1.

	Discussion

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Under physiological conditions, HR is predominantly determined via regulatory feedback loops integrated within the autonomous nervous system to ensure maintenance of an appropriate cardiac output. The increased HR observed in spontaneously hypertensive rats and SHRSP may be viewed as the result of increased sympathetic tone that has been implicated in the pathogenesis of hypertension in this model, particularly after oral NaCl loading.^{14 17} However, all these reports are based on the observation of mere associations, and no definite causal relationship between increased sympathetic activity and hypertension has ever been shown.

The lack of correlation between HR and BP phenotypes in our analysis argues against a causal contribution of increased HR to hypertension in SHRSP at the developmental stage examined. It also rules out the possibility that the observed alteration of HR in SHRSP is a secondary, hypertension-induced event. The genome screening analysis, on the other hand, demonstrated that HR variance is, at least in part, directly determined by the influence of a genetic locus, HR-SP1, on rat chromosome 3. Allelic status at HR-SP1 was not associated with differences in BP, and adjustment for BP before linkage analysis had no effect on the results. These data indicate that the influence of HR-SP1 was maintained across the entire range of blood pressures (136 to 210 mm Hg systolic) observed in the F₂ crosses.

The finding that significant linkage to HR-SP1 in the overall population was only detected after oral NaCl loading may point to an ecogenetic (gene-environment) interaction between HR-SP1 and dietary NaCl content. Alternatively, the failure to obtain overall significant linkage to HR-SP1 at baseline may be attributed to a higher environmental noise present during normal salt intake that may act as a confounder, preventing the detection of the HR-SP1 effect under normal dietary conditions.⁷

The presence of the gene that encodes the brain isoform of the -1 polypeptide of the type 2 voltage-gated sodium channel (Scn2a1) at the center of the HR-SP1 locus allowed the identification of a homologous region on human chromosome 2q23-2q24.3.¹⁸ This segment carries the human SCN2A gene and exhibits conservation with a corresponding region on mouse chromosome 2.¹⁹ Interestingly, the gene encoding a human G-protein–coupled, inwardly rectifying K⁺ channel, GIRK1, was recently mapped to human chromosome 2q24.1.²⁰ GIRK1 represents one of the two inwardly rectifying K⁺ channel subunits that make up K_ACh, which is involved in HR regulation in response to vagal stimulation via activation of muscarinic receptors.²¹ Therefore, we may speculate that the rat homologue of GIRK1, Kir3.4, may represent a candidate gene for HR-SP1, even though one obviously needs to be mindful of the fact that the 100:1 CI for mapping HR-SP1 spans a genetic distance of 32 cM. This is a segment large enough to be expected to contain some 1500 genes, among which multiple other candidate genes may be present. Analysis of the currently available homology data for human, mouse, and rat revealed no other plausible candidate genes.

At present, without knowledge of the nature of the relevant gene at HR-SP1 and in the absence of information concerning a large number of potentially interesting intermediate phenotypes that relate to HR, we can only speculate whether the effect of HR-SP1 is a "direct" one (eg, a mutation affecting the cardiac pacemaker channel) or a more "remote" phenomenon (eg, mediated via modulation/resetting of one of the complex regulatory circuits that modulate cardiovascular function). We can say with certainty, however, that the portion of HR variance determined by HR-SP1 is not correlated nor collinear with BP and therefore is not a function of resetting the threshold or gain of classic pathways.

As is always the case in experiments of this kind, any conclusions and generalizations from these results regarding the effects of HR-SP1 must be made with great caution. Strictly speaking, our data and interpretations apply only to the strains and crosses as well as the particular experimental settings examined and, equally important, only to the specific developmental period under investigation in this study. Therefore, we cannot exclude the possibility that at a different developmental stage HR, and thus genes affecting HR regulation, may contribute to BP variance in SHRSP_HD.

In summary, our study provides the first evidence that allelic variation at an HR-relevant genetic locus has the potential to affect HR in a primary, direct fashion that is independent of BP. Moreover, it provides the first example of identifying such an HR-relevant genetic locus by means of linkage analysis. Our data highlight the power of dissecting complex cardiovascular traits by molecular genetic means. Continued efforts along this line of investigation will lead to a better understanding of the complex interplay of heritable and environmental factors and of primary genetic and secondary, reflex-mediated mechanisms that govern cardiovascular function.

	Selected Abbreviations and Acronyms

 

BP = blood pressure HR = heart rate PCR = polymerase chain reaction QTL = quantitative trait mapping, in contrast to "classic" linkage analysis for categorical traits SHRSPHD = stroke-prone spontaneously hypertensive rats SSLP = simple sequence-length polymorphism WKY = Wistar-Kyoto rats WKY-0HD = wild-type hypertensive Wistar-Kyoto strain of rats WKY-1HD = a congenic line to WKY-0HD rats

	Acknowledgments

 
This work was supported by NIH SCOR (P50HL5500) from the National Heart, Lung, and Blood Institute, the EurHypGen concerted action of the European Economic Community, and the Deutsche Forschungsgemeinschaft (Dr Kreutz, Kr1152/1-2 and GA175/8-1). Dr Kreutz is the recipient of a Howard Hughes Medical Institute Research Fellowship for Physicians, and Dr Lindpaintner is the recipient of NIH Research Career Development Award K04HL03039.

Received May 16, 1997; revision received June 4, 1997; accepted June 6, 1997.

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