American Heart Journal
Volume 154, Issue 3 , Pages 460.e1-460.e7, September 2007

Heart rate recovery is more strongly associated with the metabolic syndrome, waist circumference, and insulin sensitivity in women than in men among the elderly in the general population

  • Göran Nilsson, MD

      Affiliations

    • Department of Medicine, Central Hospital, Västerås, Sweden
    • Department of Clinical Research, Uppsala University, Karolinska Institutet, Stockholm, Sweden
    • ,
  • Pär Hedberg, MD

      Affiliations

    • Department of Physiology, Central Hospital, Västerås, Sweden
    • ,
  • Tommy Jonason, MD

      Affiliations

    • Department of Physiology, Central Hospital, Västerås, Sweden
    • ,
  • Ingemar Lönnberg, MD

      Affiliations

    • Department of Medicine, Central Hospital, Västerås, Sweden
    • ,
  • John Öhrvik, PhD

      Affiliations

    • Department of Clinical Research, Uppsala University, Karolinska Institutet, Stockholm, Sweden
    • Cardiology Research Unit, Karolinska Institutet, Stockholm, Sweden
    • Corresponding Author InformationReprint requests: John Ohrvik, PhD, Cardiology Research Unit, Department of Medicine, Karolinska Institutet, SE-17176 Stockholm, Sweden.

Received 19 February 2007; accepted 19 June 2007.

Article Outline

Background

Low heart rate recovery (HRR) at exercise test and the metabolic syndrome (MetS) are both predictors of cardiovascular morbidity and mortality. We studied in 75-year-old women and men, representative of the general population, the relationship between (1) HRR and the MetS, (2) HRR and the individual components of the MetS, and (3) HRR and insulin sensitivity.

Methods

A cross-sectional study of randomly selected 75-year-olds from a general population was performed (191 women and 194 men). The MetS was defined according to the National Cholesterol Education Program criteria. Heart rate was measured as beats per minute immediately after exercise and at 4 minutes into recovery.

Results

Heart rate recovery (median and interquartile range, beat/min) was 48 (37-58) for women and 49 (38-58) for men. Thirty-seven percent of the women and 25% of the men had the MetS. Heart rate recovery was 52 (42-61) for women with the MetS and 42 (31-49) for those without. The corresponding values for men was 50 (39-61) and 47 (35-54); the difference between individuals with and without the MetS was significant for women (P < .001) but not for men (P = .084). The following significant correlation coefficients between HRR and MetS components were found: for women, waist circumference (−0.43, P < .001), high-density lipoprotein cholesterol (0.37, P < .001), insulin sensitivity (−0.37, P < .001), fasting plasma glucose (−0.30, P < .001), and triglycerides (−0.24, P = .001); for men, triglycerides (−0.20, P = .005). The sex disparity in the strength of correlation reached statistical significance for insulin sensitivity (P < .001) and waist circumference (P = .042).

Conclusion

Among 75-year-olds, the MetS and related components are more strongly correlated to HRR in women than in men.

 

The metabolic syndrome (MetS) is a risk factor for cardiovascular disease (CVD) and diabetes. According to the most commonly used definitions (the National Cholesterol Education Program [NCEP] criteria1 and the International Diabetes Federation criteria [www.idf.org]2) this syndrome is defined by cutoff points in its principal components: waist circumference, serum high-density lipoprotein cholesterol (HDL-C), serum triglycerides, blood pressure, and fasting plasma glucose. The pathogenesis of the syndrome involves insulin resistance, and this factor is part of the World Health Organization definition of the syndrome.3

Heart rate recovery (HRR) after exercise test has been demonstrated as a risk factor for cardiovascular and all-cause mortality in healthy adults,4, 5, 6, 7 in individuals with CVD,8 in individuals with risk factors for CVD,9, 10 and in men with diabetes.11 Heart rate recovery has been shown to be inversely associated with insulin resistance.12 Furthermore, associations have been found between HRR and the MetS as well as between HRR and the individual components of the MetS.12, 13 No previous study has specifically addressed possible sex disparity in the relationship between the MetS and HRR.

The purpose of the present investigation was to study in 75-year-old women and men from the general population the relationship between (1) HRR and the MetS, (2) HRR and the individual components of the MetS, and (3) HRR and insulin sensitivity. In particular, possible sex disparity in these relationships was examined.

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Methods 

Study population 

In 1997, there were 1100 inhabitants of the city of Västerås who were born in 1922, making them 75 years old. A sample of 618 of these individuals was randomly selected and invited to participate in a cardiovascular health survey. The city of Västerås is situated about 100 km west of Stockholm, the capital of Sweden, and has a representative Swedish population from a socioeconomic point of view. The invitation was accepted by 433 subjects (223 women and 210 men), corresponding to a participation rate of 70%. The reasons for nonparticipation were diseases under treatment (n = 54), the individual could not be reached (n = 29), locomotive impairment (n = 28), language difficulties or logistic problems (n = 26), the person died before the examination (n = 2), or unknown (n = 46).

Forty-four participants (12 men and 32 women) did not perform an exercise test for the following reasons: logistic reasons (n = 23); locomotor disturbances, mainly hip or knee disease (n = 17); unwillingness (n = 1); never learned bicycling (n = 2); high resting systolic blood pressure (n = 1). Two participants had missing data from the exercise test, and 2 had missing data for individual components of the MetS. The final cohort comprised 191 women and 194 men (62% of the invited cohort).

The study was approved by the research ethics committee at Uppsala University, Uppsala, Sweden.

Exercise test 

Rodby RE 830/990 ergometers (Rodby Innovation AB, Vänge, Sweden) were used with workload beginning at 30 W and increasing in steps of 10 W per minute. Patients were encouraged to exercise until they experienced limiting symptoms, usually breathlessness or general tiredness. Other reasons for discontinuing the exercise test were chest pain (n = 6), pain in hip or knee (n = 7), abnormal blood pressure reaction (n = 6), frequent ventricular ectopic beats (n = 2), or development of excessive ST depression (n = 5). Heart rate was measured immediately after exercise and at 1 and 4 minutes into recovery. Exercise capacity was measured in watts, which were converted to maximum oxygen consumption calculated as metabolic equivalents (MET) using the following formula:

14

The MetS was defined according to the NCEP Adult Treatment Panel (ATP) III criteria15, 16 (any 3 of the following 5 criteria: waist circumference >102 cm in men and 88 cm in women; triglyceride levels ≥1.7 mmol/L; HDL-C levels <1.04 mmol/L in men and <1.30 mmol/L in women; diabetes or fasting plasma glucose ≥6.1 mmol/L; antihypertensive medication or blood pressure ≥130/85 mm Hg).

Waist circumference was measured in the horizontal plane at the midpoint between the lowest rib and the iliac crest.17 Blood pressure was measured to the nearest 5 mm Hg with a mercury sphygmomanometer, with the subjects in a supine position and having relaxed for 5 minutes.

The blood samples were collected in the morning with the subjects in a fasting state. Serum triglycerides and HDL-C were determined enzymatically using an automated analyzer system (Hitachi 717, Boehringer Mannheim, Mannheim, Germany). Low-density lipoprotein cholesterol was calculated using the Friedewald formula. The blood glucose samples were treated with a hemolytic reagent (Merck Diagnostica, Darmstadt, Germany), and glucose was determined enzymatically with glucose dehydrogenase using a Cobas Mira analyzer (Roche Diagnostics Ltd., Rotkreus, Switzerland). Plasma glucose was computed from venous whole blood glucose using the following formula: plasma glucose = 0.558 + 1.119·whole blood glucose.18 Insulin concentration was determined using the 2-site immunometric assay technique19 in plasma samples. Insulin sensitivity was computed by the homeostasis model assessment–insulin resistance (HOMA-IR) index using the following formula:

20

Individuals within the top quartile of the HOMA-IR index for nondiabetic patients in the population examined and given the method of insulin assessment used are often considered as being insulin resistant.3, 20

Statistics 

Continuous variables were expressed as median and quartiles. The Wilcoxon-Mann-Whitney rank sum test was used to compare groups for continuous data. Categorical data were compared using a χ2 test. Associations were assessed by Spearman rank correlation. To estimate the ability of the individual components of the MetS to predict HRR, both single and multiple linear regression models were applied. Both forward and backward stepwise analyses were performed to detect possible collinearity that could disturb our analyses. The inclusion and removal probability limits were set at .05 and .10.

To investigate the sex difference in the strength of association between HRR and variables related to the MetS, an analysis of covariance was performed including sex multiplied by the components of the MetS and the HOMA-IR index, respectively, as interaction terms.

To make the distributions more symmetrical, HOMA-IR index, plasma glucose, HDL-C, and triglycerides were logarithmically transformed before the covariance and regression analyses.

A 2-sided P < .05 was regarded as statistically significant. The SPSS (SPSS Inc, Chicago, IL) version 14.0 statistical package was used for all analyses.

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Results 

Among 191 women, 71 (37%) had the MetS, and 48 (25%) among 194 men had this syndrome (P = .008 for sex difference). Table I shows the basic characteristics of the participants in the health survey. The mean (SD) for waist circumference was 88 (11) for women and 95 (8) for men.

Table I. Baseline characteristics
Women (n = 191)Men (n = 194)
Waist circumference (cm)87 (80-97)94 (89-100)
Body weight (kg)68 (60-77)76 (70-83)
Body mass index26.2 (23.6-28.7)25.1 (23.4-27.1)
Triglycerides (mmol/L)1.48 (1.10-2.10)1.50 (1.10-1.91)
HDL-C (mmol/L)1.60 (1.32-1.93)1.36 (1.18-1.54)
Systolic blood pressure (mm Hg)165 (150-190)160 (150-180)
Diastolic blood pressure (mm Hg)85 (80-90)85 (80-90)
Fasting plasma glucose (mmol/L)5.9 (5.5-6.5)5.8 (5.5-6.5)
Insulin (mU/L)8.8 (5.8-13.3)8.4 (6.3-12.3)
HOMA-IR index2.40 (1.49-3.96)2.26 (1.63-3.41)
Prior myocardial infarction9 (5)30 (16)
Angina pectoris18 (10)31 (16)
Previously known hypertension55 (29)53 (28)
Previously known diabetes13 (7)16 (8)
Newly detected diabetes⁎22 (12)19 (10)
Stroke/transitory ischemic attack7 (4)3 (2)
Atrial fibrillation1 (1)17 (9)
Daily smokers13 (7)24 (12)
β-Blocker use39 (20)39 (20)
Sex hormone replacement therapy2 (1)0
Nondihydropyridine calcium-channel blocker3 (2)3 (2)

Data are median (interquartile range) and number (%).

*Fasting plasma glucose ≥7.0 mmol/L.

Heart rates and maximum exercise test performance are shown in Table II. Sixteen percent of the study participants did not reach a heart rate of 116 beat/min, which is 80% of the age-adjusted maximal heart rate (220 − age)21 for 75-year-olds.

Table II. Values for variables recorded during exercise test
Women (n = 191)Men (n = 194)
Basal heart rate (beat/min)75 (66-85)74 (65-82)
Heart rate at end of exercise (beat/min)139 (123-151)141 (126-152)
Heart rate 1 min after end of exercise (beat/min)123 (109-135)121 (108-133)
Heart rate 4 min after end of exercise (beat/min)90 (81-100)89 (79-100)
Heart rate recovery 1 min (beat/min)15 (10-21)16 (11-23)
Heart rate recovery 4 min (beat/min)48 (37-58)49 (38-58)
Exercise capacity (W)90 (80-110)130 (110-150)
Exercise capacity (MET)6.1 (5.3-7.0)7.2 (6.1-8.1)

Data are median (interquartile range).

In the literature, calculation of HRR is mostly founded on a recovery period of 1 or 2 minutes. We measured HRR based on a recovery period of both 1 and 4 minutes. The associations between HRR and the MetS and between HRR variables related to the MetS were generally somewhat weaker when HRR was measured at 1 minute instead of 4 minutes (Table III). In the sequel, only HRR values based on a recovery period of 4 minutes are discussed.

Table III. Spearman rank correlation coefficient between the components of the MetS and HRR at 1 and 4 minutes
WomenMen
Correlation coefficientPCorrelation coefficientP
Waist circumference
4 min−0.430<.001−0.124.084
1 min−0.250<.001−0.137.057
HDL-C
4 min0.371<.0010.125.083
1 min0.189.0090.023ns
Triglycerides
4 min−0.236.001−0.200.005
1 min−0.080ns−0.151.035
Systolic blood pressure
4 min−0.099ns−0.076ns
1 min−0.002ns−0.024ns
Diastolic blood pressure
4 min−0.073ns−0.056ns
1 min−0.006ns−0.013ns
Fasting plasma glucose
4 min−0.296<.001−0.053ns
1 min−0.222.002−0.142.048
HOMA-IR index
4 min−0.370<.001−0.051ns
1 min−0.239.001−0.133.065
Serum insulin
4 min−0.328<.001−0.034ns
1 min−0.194.007−0.092ns

ns, Not significant.

Figure 1 illustrates the distribution of the HRR among men and women with and without the MetS. The HRR was 42 (31-49) among women with the MetS and 52 (42-61) among those without. Among men, the corresponding values were 47 (35-54) and 50 (39-61). The difference between subjects with and without the MetS was significant among women (P < .001) but not among men (P = .084).

  • View full-size image.
  • Figure 1. 

    Heart rate recovery at 4 minutes in men and women with and without the MetS. Boxes span the 25% to 75% percentiles, and whiskers denote nonoutliers' minimum and maximum values.

Table III shows the Spearman rank correlation coefficient between HRR and components related to the MetS. There were striking sex differences in the strengths of relationship between HRR and the individual components of the MetS. For several of the components of the MetS, the strengths of association were much stronger among women than among men. The sex differences are illustrated in Figure 2 for the relationship between HRR and waist circumference and in Figure 3 for the relationship between HRR and insulin sensitivity as reflected by the HOMA-IR index.

We built a linear regression model with HRR as the dependent variable. Independent variables were the individual components of the MetS and insulin sensitivity, as reflected by the HOMA-IR index. In single-variable analyses, the following variables significantly predicted the HRR in women: HOMA-IR (standardized β coefficient −.42, P < .001), waist circumference (standardized β coefficient −.42, P < .001), fasting plasma glucose (standardized β coefficient −.33, P < .001), HDL-C (standardized β coefficient .33, P < .001), and triglycerides (standardized β coefficient −.23, P = .001). In men, only triglycerides significantly predicted HRR (standardized β coefficient −0.18, P = .014).

In women, waist circumference (standardized β coefficient −.23, P = .005), HOMA-IR (standardized β coefficient −.22, P = .006), and HDL-C (standardized β coefficient .15, P = .037) remained in the final model after forward and backward stepwise multiple analyses including variables that were significant (P < .05) in the single-variable analyses.

Sex disparity in the strengths of association between HRR and MetS components 

There was a significant sex difference in the strengths of association between HRR and HOMA-IR index (standardized β coefficient −.38, t value −4.12, P < .001) as well as between HRR and waist circumference (standardized β coefficient −.95, t value −2.03, P = .043). The sex disparity in the strengths of association between HRR and the remaining components of the MetS did not reach statistical significance.

In all the multiple linear regression analyses, the forward and backward stepwise analyses resulted in the same model indicating no disturbing collinearity problems.

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Discussion 

Heart rate recovery after exercise reflects vagal reactivation as demonstrated by Imai et al22 using atropine to block the first few minutes' decay of heart rate after stopping vigorous exercise. Heart rate recovery is a predictor of mortality and cardiovascular events in clinic-based populations,4 in a cohort of 5234 adults without manifest CVD,23 as well as in patients with ischemic heart disease8 or diabetes.11 An association between HRR and future cardiovascular events among young and middle-aged men and women has also been demonstrated in the Framingham study.5 Heart rate recovery declines with age.13, 24 Our median values for HRR in 75-year-olds are slightly lower than those reported for asymptomatic middle-aged people.25 The prognostic value of HRR found among young and middle-aged people has been confirmed also among the elderly people referred to a hospital for exercise testing26, 27 and among elderly men from the general population.12

Heart rate recovery and the MetS 

An association has been noted between HRR after exercise test and the MetS in elderly men12 and in middle-aged men and women.13 Heart rate recovery has also been found to be associated with individual components of the MetS, such as blood glucose,13, 28 low HDL-C,12, 13 and resting systolic and diastolic blood pressure.13 Panzer et al28 demonstrated a strong inverse relationship between fasting plasma glucose and HRR even at nondiabetic levels among middle-aged healthy men and women. Moreover, HRR is positively associated with insulin sensitivity as measured with a hyperinsulinemic-euglycemic clamp in elderly men.12 Heart rate recovery has been shown to be inversely associated with triglyceride–HDL-C ratio in middle-aged healthy men and women.29

This study adds to the above findings in several respects. We have found no previous study involving both sexes among elderly people representative of the general population in a defined geographic area. Neither did we find any previous study using an analysis stratified by sex. We conclude from our data that HRR is more closely associated with the MetS in women than in men. This sex disparity remains to be explained. It has previously been reported that a relatively low HRR is associated with a much higher mortality in women than in men among asymptomatic middle-aged people.25

Heart rate recovery and waist circumference 

Our findings identify waist circumference as a measure of value for identification of women with impaired HRR. Measurement of waist circumference is a cost-effective and readily available procedure of clinical value in many respects. There is no previous description of a sex-specific association between HRR and waist circumference. Waist circumference is influenced by both subcutaneous and intra-abdominal (visceral) fat. A close relationship between waist circumference, visceral obesity, and insulin sensitivity has been demonstrated using determination of the magnitude of visceral adipose tissue by computer tomographic scan or magnetic resonance imaging in combination with measuring insulin resistance directly by the euglycemic-hyperinsulinemic clamp technique.30

Prognostic implications of the MetS and diabetes in men and women 

Many studies show that the MetS is associated with an approximate 2-fold increased risk of cardiovascular morbidity and mortality. For reviews, see studies of Grundy et al31 and Sarafidis et al.32 Hunt et al33 and McNeill et al34 have reported a higher risk of incident CVD and cardiovascular mortality in women than in men with the MetS. Other reports have not confirmed such a sex disparity.35, 36 The fraction of patients with the MetS is clearly higher among women than among men undergoing coronary artery surgery.37

There are many reports of an excess female risk of fatal coronary disease associated with diabetes.38, 39, 40, 41 An extensive meta-analysis on this topic has recently been performed by Huxley et al.41 Furthermore, according to the Whitehall study, this excess female risk is also found among nondiabetic patients who are glucose intolerant by oral glucose load.39 In short, 2 explaining hypotheses have been put forward: (1) treatment bias that favors men, (2) a more unfavorable cardiovascular risk profile among diabetic women than among diabetic men. On the basis of our findings, a third explaining hypothesis can be derived, implying that autonomic neuropathy, as reflected by reduced HRR, is more closely associated to insulin resistance in women than in men.

Definition and prevalence of the MetS in relation to waist circumference 

The sex specific cut points for waist circumference in NCEP ATP III definition and other definitions of the MetS aim to separate abdominal obesity and the associated risk of CVD. However, the rationale for the specific cut points, as opposed to higher or lower values, seems not to be clear.

The cut points in NCEP ATP III for waist circumference came from the definition in the 1998 National Institutes of Health obesity clinical guidelines. These cut points were claimed to approximately identify the upper quartile of the US population.31 In the population described by us, the sex-specific waist cut points, defined according to NCEP ATP III, correspond approximately to the median waist circumference among women and to the upper quartile limit of waist circumference among men (Table I). This may explain the sex disparity in prevalence of the MetS found by us (25% in men and 37% in women). It is noteworthy that in a large sample from the US population 1988-1991, Park et al42 reported a waist circumference distribution in white men and women around 75 years of age similar to that found by us in a Scandinavian population. White US men were slightly fatter than Scandinavian men.42 Furthermore, the sex-specific prevalence of the MetS in white US citizens around 75 years of age is similar to that found by us in a Scandinavian population.42 Therefore, we judge our population to be reasonably representative of a white North European and North American population.

Strengths and limitations of the study 

Our cross-sectional design does not permit any causal inference. The restriction of our investigation to 1 age class enables us to leave age out of account as a confounding factor, thereby creating the possibility of identifying major sex differences despite the relatively small number of participants in the study. This advantage is, however, obtained at the cost of the inability to generalize our findings to young and middle-aged people. It would be of large interest to perform an analogously designed study in an age class of, for instance, 50-year-olds. Our results have a reasonable generalizability to at least an elderly North European and North American general population.

Several correlations were calculated in the present study. Consequently, false significant correlations could have been found by chance. However, HRR was found to be correlated to components of the MetS and insulin sensitivity consistently, thereby minimizing the risk of false significant correlations.

Information on HRR is easily obtained by routine exercise test. However, this information is often not included in the final report on the test. Our results suggest that information on HRR is of considerable value in the clinical assessment of many patients.

Conclusions 

Among 75-year-olds, representative of a general population, the MetS and related components are more strongly correlated to HRR in women than in men. Especially, there is a strong relationship between HRR and waist circumference in women that is not found in men.

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PII: S0002-8703(07)00529-7

doi:10.1016/j.ahj.2007.06.025

American Heart Journal
Volume 154, Issue 3 , Pages 460.e1-460.e7, September 2007

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