(Hypertension. 1999;33:769-774.)
© 1999 American Heart Association, Inc.
Scientific Contributions |
Parental Hyperdynamic Circulation Predicts Insulin Resistance in Offspring
The Tecumseh Offspring Study
From Dipartimento di Medicina Clinica e Sperimentale, University of Padova, Padova, Italy (P.P., O.V.); and the Division of Hypertension, University of Michigan, Ann Arbor, Mich (S.N., J.A., S.M., M.V., S.J.).
Correspondence to Paolo Palatini, MD, Dipartimento di Medicina Clinica e Sperimentale-Clinica Medica 4, University of Padova, via Giustiniani, 2, 35128 Padova, Italy. E-mail palatini{at}ux1.unipd.it
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Abstract |
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Abstract—Controversy surrounds the pathogenetic mechanisms of the relationship between hyperdynamic circulation and insulin resistance. Two hundred eight children and young adults (mean age, 17.2±3.0 years; range, 11 to 26 years) from the Tecumseh Offspring Study whose parents had been assessed with Doppler echocardiography at the age of 34 years during the previous Tecumseh Blood Pressure Study were considered for this analysis. Offspring data were stratified according to tertiles of parental cardiac index. Parents in the top cardiac index tertile had increased heart rate (P=0.001), stroke volume (P=0.0001), left ventricular fractional shortening (P=0.02), and plasma epinephrine (P=0.02) compared with parents in the other tertiles. Body mass index (BMI) and blood pressure were similar in all groups. Offspring of parents with a high cardiac index had greater BMI (P=0.001), skinfold thickness (P=0.008), and waist/hip ratio (P=0.02), higher diastolic blood pressure (P=0.02) and plasma insulin level (P=0.001), and higher heart rate during Stroop's color test (P=0.02) than offspring of parents with a lower cardiac index. In a multivariate regression analysis, offspring BMI was predicted by parental BMI and cardiac index (P=0.0001 and 0.003, respectively). The mother-child relationship explained most of the cardiac index–BMI association. In summary, parental hyperdynamic circulation was an important predictor of overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia in offspring. Our results illustrate the complexity of interaction between a genetic tendency and its phenotypic expression. We speculate that the degree of ß-adrenergic responsiveness may be a major determinant of the phenotypic differences between the parents and offspring found in this study.
Key Words: sympathetic tone • insulin • obesity • heart rate • hemodynamics • hypertension
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Introduction |
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An association between sympathetic overactivity, overweight, and insulin resistance has been reported to occur in a large proportion of patients with hypertension.1 2 3 4 5 6 7 8 9 10 11 However, it is not known which of these factors is the key element in the observed association. A scenario in which eating behavior leads to weight gain, which causes oversecretion of insulin and insulin resistance, which then increase sympathetic tone, has been proposed by some investigators.6 7 8 According to others, insulin resistance is the primary phenomenon, and increased plasma insulin level causes sympathetic overactivity, hypertension, and dyslipidemias.2 3 The Ann Arbor group9 10 11 postulated the primacy of the enhanced sympathetic drive for the causation of both insulin resistance and hypertension. Although each of the proposed schemes is supported by data from studies performed in humans, most results were obtained from cross-sectional analyses in populations, making it difficult to distinguish cause and effect.
Studying these associations in siblings may help us to better understand the pathophysiological mechanisms of this condition. Recently, we had the opportunity to study the offspring of subjects previously enrolled in the Tecumseh Blood Pressure Study.12 The aim of the present study was to investigate the hemodynamic, neurohumoral, and metabolic features in offspring of parents who had a hypersympathetic-hyperdynamic circulation characterized by increased heart rate, elevated stroke volume, and enhanced cardiac contractility.
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Methods |
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The aims, nature, and methods of the Tecumseh Blood Pressure Study have been extensively reported elsewhere.9 12 The Tecumseh Offspring Study was initiated in 1995. Two hundred fifty-one subjects aged 11 to 26 years whose parents had been studied between 1987 and 1990 were enrolled. Data from 347 parents were available from the previous Tecumseh data set.9 12 A complete set of hemodynamic and biochemical measurements was available for 290 parents (Table 1). For 96 children, we had data from both mothers and fathers; for 69 children, only the data from the fathers were available, and for 86 children, only the data from the mothers were available. All variables were similar in the 3 groups except for body mass index (BMI), which was slightly greater in the children for whom only data from the fathers were available (P=0.02).
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Offspring
Two hundred eight children aged 11 to 26 years for whom
parents' echocardiographic data were available were
included in this analysis. Their clinical characteristics by
gender are reported in Table 1. The children were examined at
the same field office in Tecumseh, Mich, in which their parents had
been examined.9 12 A battery of psychosocial,
anthropometric, hemodynamic, and biochemical measures
was obtained in each subject. All subjects read and signed an informed
consent form, and the study was approved by the Institutional Ethics
Review Board of the University of Michigan.
Measurements
Procedures used for clinical heart rate, blood pressure, cardiac
index, and left ventricular fractional shortening
measurements, anthropometric data collection, and blood sample
processing in the children were the same as those used for parents in
the Tecumseh Blood Pressure Study.12 Heart rate was also
measured during Stroop's color test, a computerized conflict-evoking
test.9 Skinfold thickness was measured in triplicate at
the triceps, biceps, and subscapular and suprailiac areas with a manual
caliper, and the average of the 12 measurements was defined as
skinfold thickness.
The method used to measure cardiac output in parents and children has been reported previously.12 In brief, cardiac output was assessed by a 2D Doppler echocardiography technique using images of the aortic root. The diameter of the aortic root was measured at the level of aortic leaflets during midsystole, and the aortic cross-sectional area was calculated. Aortic outflow was measured with a continuous Doppler transmitter from the suprasternal notch using previously described procedures.12
Data Analysis
Offspring data were analyzed according to their
parents' cardiac index. Determinants of cardiac index were assessed by
linear regression analysis, with cardiac index as the dependent
variable and age, gender, and BMI as independent variables.
Cardiac index values were adjusted for age, gender, and BMI by standard
statistical methods. Parents were subsequently grouped into tertiles of
adjusted cardiac index, and children were grouped according to whether
their parents' cardiac index was in the bottom, middle, or top
tertile. When data from both parents were available, the average of the
readings from mother and father (midparent) was used in the
classification.13 Between-tertile differences were
assessed using a general linear model procedure. Data were adjusted for
possible confounders. The independent association of children's BMI
with parents' clinical characteristics was studied with multiple
forward regression analysis using children's BMI as the
dependent variable and parents' age, BMI, cardiac index, blood
pressure, and heart rate as independent variables. Data are
mean±SEM unless specified otherwise. Significance was accepted at
P<0.05.
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Results |
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Echocardiographically measured cardiac index was available for 290 parents. Cardiac index was similar in fathers and mothers (mean±SD=2.7±0.5 and 2.9±0.5 L/min per m2, respectively; P=NS). Data of parents classified according to their cardiac index are reported in Table 2. No significant differences in gender distribution was found between the 3 groups. Parents in the top tertile had a slightly smaller BMI than those in the other tertiles. Blood pressure was similar in all groups. Resting heart rate, measured at the visit and during echocardiographic assessment, was elevated in parents in the top tertile, as were stroke volume and left ventricular fractional shortening (Figure 1 and Table 2). Plasma epinephrine level was also higher in parents with a high cardiac index (Figure 1), whereas among the metabolic parameters, only triglycerides were slightly increased in the top tertile. However, the between-tertile differences did not attain the level of statistical significance.
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Offspring of parents with a high cardiac index were heavier, had an increased degree of adiposity, and had a greater waist/hip ratio than offspring of parents with an intermediate or low cardiac index (Table 3 and Figure 2). Blood pressure was higher in offspring of parents in the top tertile, a difference that was significant for diastolic blood pressure (Table 3). Child's heart rate tended to increase with increasing level of parents' cardiac index, especially when measured during the Stroop test. Insulin and insulin/glucose ratio were both elevated in offspring of parents with hyperdynamic circulation (Figure 2 and Table 3); these children also had higher levels of triglycerides. Children's cardiac index and left ventricular fractional shortening did not differ between the 3 groups (Table 3).
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To determine which parental clinical variables influenced children's BMI and plasma insulin level, a series of multiple linear regression analyses was performed, first keeping the parents grouped together and then separating fathers from mothers, using parents' age, BMI, cardiac index, clinical heart rate, systolic and diastolic blood pressures, and gender (where applicable) as independent variables. As expected, parental BMI was the strongest predictor of offspring BMI (P=0.0001), followed by parental cardiac index (P=0.003) and age (P=0.05). This association was mostly explained by the mother-child relationship (P=0.009 for cardiac index), whereas the cardiac index–BMI association did not reach statistical significance for the father-child relationship. Similar relationships with cardiac index were found when children's plasma insulin level was considered as the dependent variable (P=0.003 for parents taken together, 0.01 for mothers, and NS for fathers).
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Discussion |
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In the past few years, our understanding of the pathophysiological correlates of insulin resistance syndrome has increased greatly. A number of studies suggest that people who have hyperdynamic circulation tend to display many of the features of insulin resistance syndrome, including obesity, unfavorable fat distribution, hyperinsulinemia, and metabolic disturbances.1 2 3 4 5 6 7 8 9 10 11 In contrast, however, the mechanisms of initiation and development of insulin resistance remain controversial. Furthermore, there is still considerable dispute about the most probable genetic mechanism that leads to the observed familial clustering of the features of insulin resistance syndrome.
In this study, parents with hyperdynamic circulation did not differ from other parents in body weight or metabolic variables. Nevertheless, the results show that offspring of parents with hyperdynamic circulation have a genetic predisposition to development of overweight and other features of insulin resistance syndrome. In fact, offspring of parents in the top tertile of cardiac index had an increased BMI and degree of adiposity, abnormal fat distribution, higher diastolic blood pressure, hyperinsulinemia, and slightly elevated triglyceride levels. After adjustment for BMI, most of these differences disappeared. The latter finding is in agreement with the results of Stern et al2 obtained in subjects with hyperdynamic circulation, in whom an attenuation of the relationship between hyperkinetic state and features of insulin resistance syndrome was found when BMI was accounted for. The importance of the relationship between parental hyperdynamic circulation and the features of insulin resistance is emphasized by the positive independent association between parental cardiac index and offspring BMI found in multiple regression analysis, in which parental BMI was included. It is noteworthy to observe that most of this association was explained by mother-child relationship. Parental BMI was a strong predictor of children's BMI, confirming the results of other investigators.14
As a result of the cardiac index stratification, there were large differences in heart rate, left ventricular contractility, and plasma epinephrine level between the 3 groups of parents, documenting the existence of increased sympathetic tone in the top cardiac index tertile. In the offspring, we could still detect some evidence of enhanced sympathetic tone (faster resting heart rate and excessive tachycardia in response to the Stroop test), but the leading features were overweight, elevated plasma insulin level, and higher blood pressure.
At first glance, it is difficult to explain why the phenotypes
in parents and offspring are so different. However, the fascinating
association of parental circulatory abnormalities with
metabolic abnormalities in offspring may in part reflect
the classification of parents. A substantial downregulation of
ß-adrenergic responsiveness (presumably in response to a
long-standing sympathetic overdrive) has been described in patients
with "normokinetic" borderline hypertension15 and with
hypertension in general.16 17 18 Along the line of our
interest in the hyperkinetic state9 12 19 in this study,
we classified the parents according to tertiles of cardiac index. It is
likely that the top tertile consisted of individuals able to respond to
the sympathetic overdrive with high cardiac output, increased stroke
volume, fast heart rate, and enhanced cardiac
contractility. Generally, cardiac output and heart rate
decrease with age,20 and in the top cardiac index tertile,
we identified subjects in the fourth decade of life whose
ß-adrenergic responsiveness had been preserved. In a series of
experiments, Landsberg and Kreiger6 documented that
enhanced sympathetic tone increases feeding-induced facultative
thermogenesis. This increase in metabolic rate is viewed as
an essential compensatory mechanism to ward off future increases in
body weight. Importantly, the thermogenic effect of sympathetic
stimulation is mediated through ß-adrenergic
receptors.21 22 If both circulatory and
metabolic ß-adrenergic responsiveness had been preserved
in parents in the present study, metabolic
ß-adrenergic responsiveness may have prevented them from gaining
weight. In fact, in a previous report of the Tecumseh study, we
noted that patients with hyperkinetic hypertension (whose
ß-adrenergic responsiveness was similarly preserved as in
normotensive hyperdynamic individuals in the present report) were
not obese.10 The fact that children of hyperkinetic
parents had no increase in cardiac index and left
ventricular ejective function suggests that their
ß-adrenergic responsiveness did not differ from that of their peers.
If the sympathetic overactivity of parents in the present study has
been passed on to children but the offspring did not share the parents
resistance to downregulation of ß-adrenergic responsiveness, they may
have responded to sympathetic stimulation with insulin resistance,
dyslipidemia, and increased body weight. The mechanism by
which sympathetic stimulation causes insulin resistance and
dyslipidemia has been discussed elsewhere.23
Our data suggest that in the future, it may well be worth testing the
hypothesis that downregulation of ß-adrenoreceptor
responsiveness, against a background of enhanced sympathetic tone,
leads to overweight. The recent observation that markedly obese
children have increased baseline plasma epinephrine levels and
have a diminished lipolytic response to infusions of
physiological doses of adrenaline24
adds further credence to the hypothesis. Decreased mobilization of
triglycerides in these children may contribute to the
accumulation of fat in adipocytes. However, at present, it is not
known whether the defective lipolytic response to adrenaline is
mediated by 
, ß2, or
ß3 adrenoreceptors.
A body of evidence suggests that elevated heart rate is a risk factor for future hypertension and development of atherosclerotic lesions.25 26 27 This seems to be due to the coaggregation of fast heart rate with high blood pressure, overweight, increased plasma insulin level, and dyslipidemias.28 Sympathetic overactivity underlying tachycardia is the likely explanation for this association, even though other factors can interact to promote this clinical condition, as recently postulated by some investigators.29 The results of the present study suggest that this coaggregation can be genetically transmitted, even though the expression of the genetic defect may differ among siblings. As indicated above, we believe that ß-adrenergic responsiveness may affect the phenotypic expression of the underlying sympathetic overactivity in parents and offspring. The nature of these modifiers of the phenotype is not understood. It is conceivable that other genetic factors affect ß-adrenergic responsiveness, but environmental factors could also play a role. Diet may have an influence on offspring modifying the phenotypic manifestations of the syndrome. It has been reported that sodium intake affects ß-adrenergic responsiveness.30 31 32 It is also possible that the education and socioeconomic status of the offspring differed from those of the parents and that these environmental differences had some other unknown effect on the phenotype.
In summary, we found that parental hyperdynamic circulation was an important predictor of the child's overweight, abnormal fat distribution, increased blood pressure, and hyperinsulinemia. The mother-child relationship accounted for most of this association. These data suggest that sympathetic overactivity underlying hyperdynamic circulation is a key factor in the development of obesity and insulin resistance. The clinical traits related to insulin resistance syndrome are a complex coaggregation of factors in which the clinically defined phenotype can arise through a wide array of pathophysiological mechanisms. Nongenetic or genetic factors affecting ß-adrenergic responsiveness may play a role in modulating expression of the genetic defect.
Received September 17, 1998; first decision October 26, 1998; accepted November 19, 1998.
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