abnormal heart rate recovery after maximal cardiopulmonary

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Clinical Endocrinology (2008) 68, 88–93 doi: 10.1111/j.1365-2265.2007.03004.x

© 2007 The Authors88 Journal compilation © 2007 Blackwell Publishing Ltd

O R I G I N A L A R T I C L E

Blackwell Publishing Ltd

Abnormal heart rate recovery after maximal cardiopulmonary

exercise stress testing in young overweight women with

polycystic ovary syndrome

Francesco Giallauria*, Stefano Palomba†, Francesco Manguso§, Alessandra Vitelli*, Luigi Maresca*,

Domenico Tafuri¶, Gaetano Lombardi‡, Annamaria Colao‡, Carlo Vigorito* and Francesco Orio‡,**

*

Department of Clinical Medicine, Cardiovascular and Immunological Sciences, Cardiac Rehabilitation Unit, University

‘Federico II’ of Naples, Naples, †

Unit of Reproductive Medicine and Surgery, ‘Magna Graecia’ University of Catanzaro,

Catanzaro, ‡

Department of Molecular & Clinical Endocrinology and Oncology, and §

Department of Clinical and Experimental

Medicine, Gastroenterology Unit, University ‘Federico II’ of Naples, Naples, ¶

Chair of Methods and Teaching of Sportive Activity,

Faculty of Exercise Sciences and **

Department of Endocrinology, Faculty of Motor Science, University ‘Parthenope’ of Naples,

Naples, Italy

Summary

Objective

Heart rate recovery (HRR) is a measure derived from

exercise test, defined as the fall in heart rate during the first minute

after maximal exercise. Abnormal HRR is a measure of autonomic

dysfunction associated with an increased mortality. This study was

performed to evaluate the HRR in polycystic ovary syndrome (PCOS).

Design

Prospective controlled clinical study.

Patients

Seventy-five PCOS women compared to 75 healthy women

matched for age (21·7 ±

2·1 years vs.

21·9 ±

1·8 years, respectively)

and body mass index (BMI) (29·0 ±

2·6 kg/m

2

vs.

29·1 ±

2·9 kg/m

2

,

respectively).

Measurements

Subjects were studied for their hormonal and

metabolic profile, and underwent cardiopulmonary exercise test (CPX).

Results

PCOS women showed a significantly reduced HRR

(12·9 ±

1·8 vs.

20·4 ±

3·1 beats/min,

P < 0·001) compared to healthy

controls, an impairment in maximal oxygen consumption

(18·0 ±

2·3 ml/kg/min vs.

29·3 ±

3·9 ml/kg/min) and in oxygen

consumption at anaerobic threshold (13·6 ±

2·6 ml/kg/min vs.

24·2 ±

3·0 ml/kg/min). In PCOS women, abnormal HRR was

inversely correlated to BMI (

r

=

−

0·582, P

< 0·001) and to the area

under the curve for insulin (

r

=

−

0·596, P

< 0·001).

Conclusions

Our data demonstrate an abnormal HRR after

maximal CPX in young overweight PCOS patients, and that HRR

should be investigated as a further potential marker of increased

cardiovascular risk in PCOS.

(Received 2 April 2007; returned for revision 22 April 2007; finally

revised 24 May 2007; accepted 22 June 2007)

Introduction

Polycystic ovary syndrome (PCOS) is a relatively common

endocrine-metabolic disorder predominantly characterized by

chronic anovulation, hyperandrogenism and insulin-resistance

(IR).

1,2

Heart rate recovery (HRR) is an easily obtained measure derived

from exercise stress testing and is defined as the fall in heart rate

during the first minute after maximal exercise.

3

HRR is a marker of

autonomic function and is directly correlated to parasympathetic

activity. Abnormal HRR is an independent cardiovascular risk

(CVR) factor

4

and a powerful predictor of all-cause mortality in

patients with or without coronary artery disease.

5–8

PCOS is a multifaceted syndrome associated with a wide range of

cardiovascular risk (CVR) factors including dyslipidaemia, hyper-

tension, glucose intolerance and diabetes.

9

Although IR is not a key

factor to diagnose PCOS,

10

it is clearly documented that subjects

affected by this syndrome are more insulin resistant than healthy

women, even taking into account body weight.

2

Moreover, in a large cohort of PCOS women, we recently

documented an IR-related impairment of cardiopulmonary

functional capacity compared to age- and body mass index (BMI)-

matched healthy women.

11

Even if no increased mortality for cardiovascular disease (CVD)

has yet been demonstrated in PCOS,

12

several observations suggest

that subjects affected by this syndrome show a complex mixture of risk factors that may predispose to an elevated CVR.

13–15

Abnormal autonomic function as evaluated by HRR is strongly

associated with elevated fasting plasma glucose levels

16

and with

diabetes.

17

It has also been reported that in diabetic patients, an

abnormal HRR was independently predictive of cardiovascular and

all-cause deaths.

18

To date, there are no data available regarding autonomic function

assessment in PCOS. Therefore, this study was aimed at evaluating

autonomic function as determined by end-exercise HRR in PCOS

patients compared to healthy young controls.

Correspondence: Francesco Orio, Faculty of Exercise Sciences, University of

Naples ‘Parthenope’, Naples and Department of Molecular & Clinical

Endocrinology and Oncology, University of Naples ‘Federico II’, Via S.

Pansini 5, 80131 Naples, Italy. Tel: +39 3477676883; Fax: +39 0892574878;

E-mail: [email protected]



Heart rate recovery in PCOS

89

© 2007 The Authors

Journal compilation © 2007 Blackwell Publishing Ltd, Clinical Endocrinology

, 68

, 88–93

Subjects and methods

Subjects

Seventy-five consecutive young nonsmoking PCOS patients were

enrolled in the study protocol. All the PCOS patients achieved the

European Society for Human Reproduction and Embryology/

American Society for Reproductive Medicine criteria for the

diagnosis of PCOS.

2

Polycystic ovaries were identified by transvaginal (TV) or pelvic

ultrasonography (USG) examination and hirsutism by Ferriman-

Gallwey (FG) score > 8 and an elevated total testosterone (normal

range < 2·0 nmol/l) levels.

Exclusion criteria included pregnancy, glucose intolerance [as

screened by a 2-h oral glucose tolerance test (OGTT)] and diabetes,

hypothyroidism, hyperprolactinaemia, Cushing’s syndrome,

nonclassical congenital adrenal hyperplasia, and use of oral con-

traceptives, glucocorticoids, antiandrogens, ovulation induction

agents, and antipsychotic, antidiabetic or antiobesity drugs, or other

hormonal drugs within the previous 6 months. Subjects with

neoplastic, hepatic, respiratory and any cardiovascular disorder orother concurrent medical illness (i.e. heart failure, lung or renal

disease) were also excluded from the study.

Another 75 healthy age- and BMI-matched women acted as controls.

Each control was defined as age- and BMI-matched with PCOS case

when the differences between the case and control was < 2 years and

< 1 kg/m

2

for age and BMI, respectively. The healthy state of the

controls was determined by medical history, physical and pelvic

examination, and complete blood chemistry. Their normal ovula-

tory state was confirmed by transvaginal ultrasonography (TV-USG)

and plasma progesterone (P) assay. Both procedures were performed

during the luteal phase of the menstrual cycle (7 days before the

expected menses). The presence of fluid in the cul-de-sac at TV-USG

and a plasma P assay greater than 31·8 nmol/l (> 10 ng/ml) were

considered criteria for ovulation having occurred.

19

None of the subjects (PCOS and controls) drank alcoholic

beverages.

Study protocol

A common core of assessments was performed at enrolment: blood

sampling for a hormonal assessment, lipid profile, and fasting

glucose and insulin levels (see below). During the same visit, all

subjects underwent cardiovascular and endocrinological examination,

12-lead electrocardiography, TV-USG, cardiopulmonary exercise

test (CPX), anthropometric measurements such as height, weight,BMI (ratio between the weight and the square of the height) and

waist to hip ratio (WHR, ratio between the smallest circumference

at the torso and the widest circumference at the hip), and completed

a leisure-time physical activity (LTPA) questionnaire (No, Low,

Moderate, High).

20

All clinical assessments were performed by the same physician

who was blinded to the patient condition. All study procedures were

completed under the same conditions.

The study was conducted according to the guidelines of the

Declaration of Helsinki, and the Institutional Ethical Committee of

the University of Naples ‘Federico II’ approved the study protocol.

The purpose of the protocol was explained to each subject, and written

informed consent was obtained from each patient before the start

of the study.

Biochemical assays

All blood samples were obtained in the morning between 08·00 h

and 09·00 h after an overnight fasting during the early follicularphase (2nd–4th day) of progesterone (P)-induced menstrual cycle.

Blood samples were collected into tubes containing EDTA after a

30-min resting period in the supine position. All blood samples were

immediately centrifuged at 4 °

C for 20 min at 1600 g

and stored at

–20 °

C until assayed.

Plasma LH, FSH, prolactin (PRL), oestradiol (E

2

), P, 17

α

-

hydroxyprogesterone (17-OH-P), T, androstenedione (A) and

DHEAS levels were measured by specific radioimmunoassays (RIA)

as previously described.

13,14

The levels of SHBG were measured using

an immunoradiometric assay (IRMA)

7,8

and the free androgen index

was calculated [T (nmol/l)/SHBG (nmol/l) ×

100]. Blood insulin

and glucose levels were measured by a solid-phase chemiluminescentenzyme immunoassay and the glucose oxidase method, respectively.

13,14

The glucose and insulin area under curve (AUC), and the AUC

GLU

/

AUC

INS

ratio

21

in response to the OGTT were also calculated.

Haemochrome analysis was performed according to standard

evaluation. C-reactive protein (CRP) was measured as recently

described.

22

Cardiopulmonary exercise test

PCOS and healthy control women underwent a symptom-limited

CPX with Bruce treadmill protocol.

23

Heart rate and blood pressure

at baseline and peak exercise, heart rate 1 min into a walking

cool-down period (1·7 mph at 0% grade), and treadmill speed and

grade at peak exercise were recorded.

HRR was calculated as the difference between heart rate at peak

exercise and heart rate after the first minute (HRR) of the cool-down

period. Abnormal HRR was defined as ≤

18 beats/min

3

for standard

exercise testing.

Both PCOS and healthy women underwent two cardiopulmonary

exercise stress tests at maximal interval of 3 days and in the same

conditions. Short-term test-retest concordance of HRR values was

assessed for individual patients. The coefficient of variation (CV)

between test-retest HRR values was less than 5%. Respiratory gas

exchange measurements were obtained breath-by-breath with use of

a computerized metabolic cart (Vmax 29C, Sensormedics, YorbaLinda, CA) as previously described.

24

Statistical analysis

Pearson χ

2

-test was used for categorical data. Continuous data are

expressed as mean ±

SD. The unpaired Student’s t

-test was used to

compare the two groups. Bivariate correlations computing Pearson’s

coefficient with their significance levels were calculated between

HRR and other variables. In PCOS women as well as in controls,

multiple linear regression analysis (stepwise method) was performed



90

F. Giallauria et al.

© 2007 The Authors

Journal compilation © 2007 Blackwell Publishing Ltd, Clinical Endocrinology

, 68

, 88–93

to test a relationship between HRR as dependent variable and age,

BMI, VO

2max

, AUC

INS

, AUC

GLU

/AUC

INS

ratio as independent

variables. Moreover, we performed another multiple linear regression

analysis (stepwise method) pooling the data of PCOS and control

subjects using HRR as dependent variable and age, BMI, VO

2max

,

AUC

INS

, and AUC

GLU

/AUC

INS

ratio, together with PCOS as a factorial

variable (Controls/PCOS coded 0/1). In assessing the suitability of

the data for linear regression models, the collinearity diagnostics

were evaluated. All tests of significance were two-sided. A P-

value ≤

0·05 was considered as significant. SPSS software for

Windows (release 15·0·0, SPSS Inc, Chicago, IL) was used for

statistical analysis.

Results

Clinical and hormonal profiles of the study population are presented

in Table 1. The groups were closely matched for age and BMI. All

PCOS patients showed a significant difference (

P < 0·001) in FG

score LH, P, 17OH-P, T, A, DHEA-S, SHBG and FAI when comparedto the control group (Table 1).

All PCOS patients (100%) showed polycystic ovaries and

anovulation, 66 (88%) had clinical and 51 (68%) biochemical

hyperandrogenism.

Anthropometrical, metabolic and CVR profiles of PCOS and

control groups are summarized in Table 2. No difference was

detected in fasting glucose and AUC

GLU

whereas fasting insulin levels

and AUC

INS

were significantly higher (

P < 0·001) in PCOS than control

women (Table 2). AUC

GLU

/AUC

INS

ratio was also significantly lower

(

P < 0·001) in PCOS women compared to the control group. CRP

concentrations were significantly increased (

P < 0·001) in PCOS

women compared to the control group.Baseline cardiopulmonary exercise stress test parameters are

summarized in Table 3.

In PCOS women, we observed a significant impairment in VO

2max

(18·0 ±

2·3 ml/kg/min vs.

29·3 ±

3·9 ml/kg/min, P < 0·001) and

VO

2AT

(13·6 ±

2·6 ml/kg/min vs.

24·2 ±

3·0 ml/kg/min) and an

abnormal HRR (12·9 ±

1·8 beats/min vs.

20·4 ±

3·1 beats/min)

compared to the healthy control group. In PCOS women, abnormal

HRR is inversely correlated to BMI (

r

=

−

0·582, P

< 0·001) (Fig. 1)

and to AUC

INS(

r

=

−

0·596, P

< 0·001) (Fig. 2). No significant difference

was observed in resting and peak exercise heart rate (HR), systolic

Table 1. Clinical and hormonal profile in polycystic ovary syndrome (PCOS)

women and healthy controls

PCOS

(N = 75)

Controls

(N = 75) P -value

Age (years) 21·7 ± 2·1 21·9 ± 1·8 0·503

BMI (kg/m2) 29·0 ± 2·6 29·1 ± 2·9 0·753

WHR 0·87 ± 0·3 0·85 ± 0·2 0·599

Ferriman-Gallwey score 13·1± 4·1 4·2 ± 1·3 < 0·001

FSH (IU/l) 11·5 ± 4·9 11·0 ± 4·7 0·499

LH (IU/l) 25·8 ± 8·5 12·8 ± 10·7 < 0·001

PRL (mU/l) 216 ± 50 206 ± 34 0·118

E2 (pmol/l) 122·8 ± 69·7 117·9 ± 49·3 0·595

P (nmol/l) 1·4 ± 0·3 1·9 ± 0·4 < 0·001

17-OHP (nmol/l) 1·8 ± 0·7 0·9 ± 0·5 < 0·001

T (nmol/l) 2·5 ± 1·0 0·8 ± 0·7 < 0·001

A (nmol/l) 5·7 ± 2·8 1·8 ± 0·5 < 0·001

DHEAS (μmol/l) 4209 ± 985 2867 ± 754 < 0·001

SHBG (nmol/l) 25·0 ± 6·8 38·7 ± 5·4 < 0·001

FAI 9·8 ± 4·8 2·3 ± 1·0 < 0·001

Data expressed as mean ± standard deviation.A, androstenedione; BMI, body mass index; DHEAS,

dehydroepiandrosterone sulphate; E2, oestradiol; FAI, free androgen index;

PRL, prolactin (1 μg/l = 20 mU/l); T, testosterone; WHR, waist to hip ratio;

17-OHP, 17-hydroxyprogesterone.

Table 2. Anthropometrical, metabolic and cardiovascular risk profile of

polycystic ovary syndrome (PCOS) women and healthy controls

PCOS

(N = 75)

Controls

(N = 75) P -value

Fasting glucose (mmol/l) 5·18 ± 0·30 5·25 ± 0·34 0·226

Fasting insulin (mU/l) 19·8± 3·3 12·3 ± 2·1 < 0·001

AUCGLU 12 001 ± 2166 11 687 ± 1786 0·290

AUCINS 16 661 ± 837 3748 ± 240 < 0·001

AUCGLU/AUCINS ratio 0·72 ± 0·1 3·1 ± 0·5 < 0·001

CRP (mg/l) 1·81 ± 0·7 0·61 ± 0·3 < 0·001

Hb (g/dl) 13·3 ± 0·8 13·1 ± 1·0 0·603

Data expressed as mean ± standard deviation.

AUCGLU, area under curve for glucose; AUC INS, area under curve for insulin;

AUCGLU/AUCINS, glucose/insulin area under curve ratio; BMI, body mass

index; CRP, C-reactive protein; Hb, haemoglobin.

Table 3. Cardiopulmonary exercise test parameters in polycystic ovary

syndrome (PCOS) women and healthy controls

PCOS

(N = 75)

Controls

(N = 75) P -value

VO2max (ml/kg/min) 18·0 ± 2·3 29·3 ± 3·9 < 0·001

VO2AT (ml/kg/min) 13·6 ± 2·6 24·2 ± 3·0 < 0·001

VE/VCO2slope 28·2 ± 4·7 28·6 ± 5·4 0·594

RER 1·08 ± 0·04 1·09 ± 0·06 0·810

HRrest (beats/min) 77·4 ± 4·9 77·5 ± 4·3 0·872

HRpeak (beats/min) 146·3 ± 13·7 147·4 ± 13·8 0·582

SBPrest (mmHg) 118·9 ± 9·6 120·8 ± 8·4 0·147

SBPpeak (mmHg) 166·6 ± 8·2 167·5 ± 8·8 0·459

DBPrest (mmHg) 76·1 ± 4·7 75·7 ± 4·9 0·494

DBPpeak

(mmHg) 85·3 ± 4·1 85·8 ± 3·6 0·422

HRR (beats/min) 12·9 ± 1·8 20·4 ± 3·1 < 0·001

Data expressed as mean ± standard deviation.

DBPpeak, diastolic blood pressure at peak exercise; DBPrest, diastolic blood

pressure at rest; VO2max, maximal oxygen consumption; VO2AT, oxygen

consumption at anaerobic threshold; VE, ventilation; VCO2, carbon dioxide

production (l/min); RER, respiratory exchange ratio; HRrest, heart rate at rest;

HRpeak, heart rate at peak exercise; SBPrest, systolic blood pressure at rest;

SBPpeak, systolic blood pressure at peak exercise; HRR, heart rate recovery at

the first minute after maximal exercise.



Heart rate recovery in PCOS 91

© 2007 The Authors

Journal compilation © 2007 Blackwell Publishing Ltd, Clinical Endocrinology , 68, 88–93

blood pressure (SBP) and diastolic blood pressure (DBP) between

PCOS and control group (Table 3).

In PCOS patients, multiple linear regression analysis showed a

significant inverse relationship between HRR, our dependent variable

and BMI [unstandardized coefficient (B) ± SE, –0·057 ± 0·018,

standardized coefficient (β) –0·087, P = 0·002], AUCINS (B

0·000 ± 0·000, β –0·137, P < 0·001), and a direct relationship with

VO2max (B 0·121 ± 0·051, β 0·156, P = 0·02) and AUCGLU/AUCINS

ratio (B 10·239 ± 1·052, β 0·698, P < 0·001), with a constant of 9·805.

No other parameter showed a relationship to HRR. Pooling together

data from PCOS and control subjects, multiple linear regression

analysis showed a significant inverse relationship between HRR and

AUCINS (B –0·001 ± 0·000, β –1·371, P = 0·003) and a direct relation-

ship with VO2max (B 0·162 ± 0·059, β 0·228, P = 0·007), AUCGLU/

AUCINS ratio (B 1·301 ± 0·531, β 0·359, P = 0·015) and PCOS status

(B 9·642 ± 3·907, β 1·069, P = 0·015), with a constant of 15·243.

No significant differences between PCOS patients and healthy

controls were observed in LTPA level (Table 4).

Discussion

The rapid deceleration of heart rate immediately following exercise

is regulated by various intrinsic, neural and humoral factors.

However, autonomic nervous system responses, in particular

parasympathetic reactivation, are a major determinant of HRR.25,26

Slower HRR may therefore be indicative of decreased parasympathetic

responsiveness.

27

In healthy subjects, HRR has been shown to be inversely associated

to IR and other risk factors that tend to cluster with IR, such as BMI,

abdominal obesity, low HDL-cholesterol28

and triglyceride/

HDL-cholesterol ratio.29

Although IR is not a criterion to diagnose PCOS,2

it is well

known30

that PCOS subjects are more insulin resistant than healthy

women independently of their body weight. In the present study,

an abnormal HRR is shown in PCOS patients when compared to

healthy controls and this alteration is significantly correlated to BMI

and markers of IR, suggesting a close and complex relationship

between autonomic function and glucose metabolism in young

overweight PCOS women. Furthermore, PCOS is probably only

linked to HRR via IR.

This study also highlights the cardiopulmonary impairment

observed in young PCOS women.11,24

Maximal oxygen consumption

represents a validated index for assessing cardiovascular functional

capacity 31

and it is also considered a strong determinant of the

insulin sensitivity index in both men and women.32

Abnormal HRR following exercise has been linked to the Metabolic

Syndrome and to several of its components in cross-sectional

studies.16,28,29,33,34

Recently, Kizilbash et al.35

observed that abnormal

HRR does not precede development of the Metabolic Syndrome,

but appears after syndrome components are present, probably playing

a role in increasing cardiovascular diseases (CVD) morbidity and

mortality.Our data suggest that IR leads to a reduced cardiopulmonary

functional capacity (as expressed by a reduced VO 2max) and to

autonomic dysfunction (as expressed by an abnormal HRR) that

may be responsible for the increased CVR profile in PCOS women.

In women referred for cardiac rehabilitation, Kavanagh et al.36

reported that oxygen consumption was a strong independent

predictor of cardiac mortality and that each increase of 1 ml/kg/min

of initial maximal oxygen consumption was associated with a 10%

lower cardiac mortality. Although these results refer to women with

proven coronary artery disease, the study have confirmed the

Fig. 1 Correlation between baseline values of body mass index (BMI) and

heart rate recovery (HRR) in young polycystic ovary syndrome (PCOS)

women.

Fig. 2 Correlation between baseline values of the area under the curve for

insulin (AUCINS) and heart rate recovery (HRR) in young polycystic ovary

syndrome (PCOS) women.

Table 4. Leisure time physical activity (LTPA) levels in polycystic ovary

syndrome (PCOS) women and healthy controls

PCOS

(N = 75)

Controls

(N = 75) P -value

LTPA, N (%) 0·979

No 26 (35) 26 (35)

Low 22 (29) 24 (32)

Moderate 20 (27) 19 (25)

High 7 (9) 6 (8)



92 F. Giallauria et al.

© 2007 The Authors


powerful prognostic significance of maximal oxygen consumption

also in subjects of both sexes without CVD.37

Therefore, we believe

that these results can be extended also to our young PCOS women

if we take into consideration their long-term risk.

Abnormal HRR also represents a powerful independent predictor

of cardiovascular and all-cause mortality in healthy adults.12–15

Therefore, it appears that the abnormal HRR after maximal exercise

could be used as an outcome tool that could help to identify patients

at increased risk for cardiovascular event.Further studies will be necessary to extend our results to a larger

and older PCOS women population and long-term follow-up studies

are required in order to evaluate if an improvement of autonomic

function per se and/or cardiopulmonary function could represent a

protective factor for reducing CVR in PCOS women. Moreover,

adding data on visceral fat mass [i.e. dual energy X-ray absorptiometry

(DEXA) measurements] might help to explain the marked differences

in VO2max and HRR in PCOS.

In conclusion, PCOS seems to be characterized by several

alterations that could increase the risk for CVD. Among these factors,

cardiopulmonary impairment and abnormal HRR should be

considered as further markers of cardiovascular risk.

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