Objectives: We evaluated exercise capacity and other exercise parameters in patients with metabolic syndrome and angiographically normal coronary arteries.

Study design: Sixty-one patients with angiographically normal coronary arteries were evaluated in two groups according to the presence (n=32; 24 females, 8 males; mean age 59±10 years) or absence (n=29; 18 females, 11 males; mean age 59±9 years) of metabolic syndrome as proposed by the International Diabetes Federation. All the patients underwent exercise treadmill testing with the modified Bruce protocol, whereby the following variables were determined: workload achieved in metabolic equivalents, total exercise time, percentage of target heart rate achieved, double product, heart rate recovery, chronotropic response and incompetence. The relationships between exercise parameters and echocardiographic and clinical variables were evaluated.

Results: The two groups were similar with respect to age, left ventricular dimensions, left ventricular mass index, ejection fraction, and left atrial diameters. The incidence of diastolic dysfunction was significantly higher in patients with metabolic syndrome (71.9% vs 41.4%; p=0.016). The maximum workload achieved was significantly lower (10±2 ml/kg/min vs 12±2 ml/kg/min; p=0.024) and the initial double product was significantly higher (11.6x10³ mmHg.pulse/min vs 10.1x10³ mmHg.pulse/min, p=0.04) in patients with metabolic syndrome. Hypertensive patients exhibited significantly lower maximum workload and total exercise time (p<0.05). Hyperglycemic subjects had significantly lower maximum workload (p<0.05).

Conclusion: Metabolic syndrome is associated with decreased exercise capacity and each component of this syndrome affects exercise test parameters individually.

Key words: Exercise test; exercise tolerance; heart rate; metabolic syndrome X/complications; ventricular function, left.

 

 

It is known that exercise capacity determined by treadmill or bicycle ergometry is an important predictor for adverse cardiac events. A wide variety of exercise test parameters have been used as predictors for prognosis and clinical course in patients with heart failure and coronary artery disease.

Metabolic syndrome has been an increasing health problem worldwide for the last three decades.^[1,2] It has been demonstrated that increases in age, body mass index, and waist circumference are associated with decreased exercise capacity in diabetic, obese female patients.^[3] However, sufficient data are absent on how exercise test parameters are affected in metabolic syndrome patients having normal coronary arteries.

In this study, we investigated how exercise capacity and other exercise test parameters are affected in patients with metabolic syndrome in the absence of occlusive coronary artery disease as shown by coronary angiography.

PATIENTS AND METHODS

Patients. The study sample was selected among patients who presented to the cardiology outpatient clinic between September 2006 and February 2007 and underwent exercise test and coronary angiography. Patients in whom coronary angiography showed no significant stenosis in epicardial coronary arteries were included into the study in a prospective design in two groups depending on the presence and absence of metabolic syndrome. The diagnosis of metabolic syndrome was made according to the criteria of the International Diabetes Federation.^[4] Considering that the relationship between abdominal obesity and other risk factors for metabolic syndrome shows variations between diverse ethnic groups, we used the thresholds defined for Europeans, namely, ≥94 cm for males, and ≥80 cm for females.^[4] Among 61 patients (42 females, 19 males) evaluated in the study, metabolic syndrome was present in 32 patients (24 females, 8 males; mean age 59±10 years) and absent in 29 patients (18 females, 11 males; mean age 59±10 years). Approval of the local ethics committee and oral informed consent of the subjects were obtained. All procedures were carried out in agreement with the World Medical Association Declaration of Helsinki, and guidelines for Good Clinical Practice and Good Laboratory Practice.

Exclusion criteria. Exclusion criteria included the presence of the following: left ventricular ejection fraction below 50%, valvular stenosis, moderate or advanced valvular regurgitation, left bundle branch block on resting ECG, use of beta-blockers or calcium-channel blockers for antihypertensive treatment, detection of rhythms other than sinus rhythm on resting ECG (atrial fibrillation, atrial flutter, etc.), left ventricular wall thickness ≥12 mm, and systemic diseases (rheumatoid diseases, chronic obstructive pulmonary disease, hyperthyroidism, hypothyroidism, etc.).

Exercise test. The exercise test was performed on a treadmill (Kardiosis Treadmill exercise test system, Turkey) according to the modified Bruce protocol. Blood pressure measurements were made by a sphygmomanometer during rest, maximal exercise, and recovery. Heart rate was monitored from rest till the end of the recovery period and 12-lead ECG recordings were obtained. The following parameters were calculated:

1- Exercise capacity was defined as the maximal MET value achieved during maximal exercise. One MET is equal to approximately 3.5 ml O₂ consumption per kilogram of body weight per minute.

2- Heart rate recovery was defined as the change from the peak heart rate to the heart rate at the first minute of recovery. Heart rate recovery is an important predictor of mortality in coronary artery disease, all degrees of left ventricular systolic dysfunction, and in clinical heart failure of whatever etiology. It can play an ancillary role in estimating prognosis.^[5-8]

3- The target heart rate is the maximum heart rate of subjects calculated before test in relation to their age (The target heart rate = 220 minus age).

4- Percentage of maximum heart rate indicates what percentage of the maximum heart rate predicted by age is achieved at the end of the test (Percentage of maximum heart rate = Heart rate achieved / target heart rate x 100).

5- Double product is an index of myocardial oxygen demand (Double product = Systolic blood pressure x heart rate).

6- Maximum exercise time.

7- Chronotropic response to exercise was defined as the percent of heart rate reserve used.

Echocardiographic evaluation. In all the patients, echocardiographic evaluation was made in the left lateral decubitus position with the Vivid 7 Dimension echocardiography system (Vingmed Ultrasound, GE, Horten, Norway). Left ventricular diameters, interventricular and posterior wall thicknesses were measured using M-mode parasternal long-axis images. Left ventricular ejection fraction was calculated using the modified Simpson method.^[9] Pulmonary arterial pressure was estimated using continuous-wave Doppler curves obtained from tricuspid valve regurgitant flow with the modified Bernoulli equation.^[10] All measurements were made by taking the average of three cycles. Pulsed-wave Doppler transmitral flow velocity patterns were derived using apical four-chamber images. Transmitral E velocity (E), A velocity (A), the ratio of E velocity to A velocity (E/A), isovolumetric relaxation time (IVRT), and deceleration time of E velocity (DT) were recorded. Pulsed-wave tissue Doppler imaging was performed by placing the sample volume in the lateral annulus of the mitral valve. Peak velocity of early diastolic flow (Ea) was measured and the ratio of transmitral E velocity to Ea was obtained as an index for left ventricular diastolic pressure.

Left ventricular mass (LVM) was calculated using the Devereux formula: LVM = 1.04 x [(LVEDD + IVS + PWT)³ - (LVEDD)³] - 13.6 g. (LVEDD: Left ventricular end-diastolic diameter; IVS: Interventricular septum thickness; PWT: Posterior wall thickness).^[11] The patients were classified according to the presence or absence of diastolic dysfunction based on transmitral Doppler echocardiography findings.

Statistical analysis. All statistical analyses were made using the SPSS statistical package for Windows, version 11.5. Quantitative and qualitative data were expressed as mean±standard deviation and percentages, respectively. The Student’s t-test was used to compare differences between two groups. The Pearson’s correlation analysis was performed to assess correlations between echocardiographic variables. Repeated measures analysis of variance was used to evaluate multiple measurements of the exercise test. A p value of less than 0.05 was accepted as statistically significant.

RESULTS

The clinical and laboratory data of 61 patients are summarized in Table 1.

Patients with metabolic syndrome exhibited high blood pressure (44%), increased glucose levels (36%), hypertriglyceridemia (31%), and low HDL-cholesterol levels (30%).

Exercise test parameters. The mean workload of the study group was 11.6±2.3 METs. The mean heart rate recovery response was 35.9±13 (range 6 to 66), and the mean chronotropic response was 0.92±14 (range 0.33 to 1.37). The maximum workload achieved was 10±2 ml/kg/min in the metabolic syndrome group, and 12±2 ml/kg/min in the control group (p=0.024). The baseline double product was higher in the metabolic syndrome group than in the control group, being 11.6x10³ mmHg.heart-rate/min and 10.1x10³ mmHg.heart-rate/min, respectively (p=0.04). Resting pulse pressure was also higher in patients with metabolic syndrome (52±9 mmHg vs 45±11 mmHg, respectively, p=0.014) (Table 2). Pulse pressures during other exercise stages were found similar in two groups (p>0.05).

When the metabolic syndrome criteria were considered individually, hypertensive patients exhibited significantly lower maximum workload and total exercise time compared to those without hypertension (p<0.05). Patients with hyperglycemia also had significantly lower maximum workload (p=0.044). The other two criteria of metabolic syndrome (hypertriglyceridemia and decreased HDL-cholesterol levels) showed no significant relationship with exercise test parameters.

Echocardiographic data. Conventional echocardiographic Doppler and pulsed-wave tissue Doppler findings are summarized in Table 3. Conventional Doppler findings for left ventricular end-diastolic diameter, left ventricular end-systolic diameter, ejection fraction, left atrial diameter, and left ventricular mass were similar in the two groups (p>0.05).

The incidence of diastolic dysfunction was significantly higher in patients with metabolic syndrome. Diastolic dysfunction was present in 23 patients (71.9%) with metabolic syndrome, and in 12 patients (%41.4) in the control group (p=0.016).

Relationship between clinical, echocardiographic, and exercise test parameters. The maximum exercise time was significantly correlated with conventional Doppler transmitral E/A (r=0.28; p=0.03), transmitral A velocity (r=-0.315; p=0.013), and IVRT (r=0.261; p=0.042).

The maximal exercise capacity (METs) was correlated with transmitral A velocity (r=-0.33; p=0.01) and IVRT (r=0.26; p=004). No significant relationship was found between the maximal exercise capacity and other Doppler findings.

Heart rate recovery was correlated with transmitral A velocity (r=-0.28; p=0.032) and transmitral E/A ratio (r=0.350; p=0.006).

Percentage of maximum heart rate achieved was in significant correlation with transmitral E velocity (r=-0.31; p=0.016) and left ventricular E/Ea ratio (r=-0.546, p=0.0001). Chronotropic response was correlated with E/Ea ratio (r=-0.532, p=0.0001).

DISCUSSION

It has been shown that exercise capacity and the maximum workload achieved are associated with prognosis in cardiac failure and coronary artery disease. In a study performed in patients with coronary artery disease, it was found that metabolic syndrome was associated with decreased exercise capacity and heart rate recovery, suggesting that decreased exercise capacity could contribute to adverse cardiac events in these patients.^[12] However, there is not sufficient information about the significance and utility of exercise test parameters in individuals without occlusive coronary artery disease and with normal left ventricular systolic function.

Decreased exercise capacity and decreased heart rate recovery have been shown to be independent association with cardiovascular and all-cause mortality.^[13] Our data demonstrated that patients with metabolic syndrome had lower maximum workload. However, the lack of a significant difference between the two groups with respect to heart rate recovery emphasizes the need for further studies to determine whether this parameter may be a predictor for coronary artery disease.

It has been claimed that systolic functions such as resting left ventricular ejection fraction are weak predictors for determining exercise capacity.^[14] While the relationship between left ventricular diastolic functions and exercise capacity is frequently mentioned even in healthy individuals,^[15] there are claims that abnormal left ventricular systolic response to exercise shows depressed contractile reserve, and that this condition might be responsible for decreased exercise capacity.^[16] Studies on the effect of mild-to-moderate diastolic blood pressure elevation on left ventricular systolic function documented that there was no difference with the control group in terms of resting left ventricular functions, but hypertensive patients exhibited significantly increased end-systolic volume and decreased ejection fraction during exercise.^[17,18] Wong et al.^[19] demonstrated that patients with metabolic syndrome had decreased systolic and diastolic functions in the absence of left ventricular hypertrophy, and that, despite normal findings in stress echocardiography, they might have decreased exercise capacity. In parallel with this finding and despite the absence of left ventricular hypertrophy, patients with metabolic syndrome in our study had a significantly higher incidence of diastolic dysfunction compared to the control subjects. Despite normal coronary angiography and absence of left ventricular hypertrophy, the presence of diastolic dysfunction in these patients suggests a molecular and cellular physiopathology rather than ischemia.

It has been postulated that decreased diastolic compliance may also contribute to increased cardiac filling pressure and exercise intolerance.^[20] Impaired diastolic compliance occurs in the early stages of obesity and is thought to be an important component in decreased cardiac reserve in obese individuals.^[21] Likewise, the frequency of diastolic dysfunction in our study was found to be higher in patients with metabolic syndrome. In addition, it was observed that the maximum exercise time and the maximum workload achieved were correlated with the parameters of left ventricular diastolic function in these patients.

Double product is an indirect measure of myocardial oxygen demand and can be used to assess cardiovascular performance. Most of the patients with ischemic heart disease rarely achieve a value beyond 25 mmHg x pulse/min x 10³. Since this value can also be confounded by cardiac medications, it may not always be useful. In our study, patients with metabolic syndrome exhibited higher double product values and pulse pressures at rest; however, these parameters did not differ from the control group during the exercise test.

Mule et al.^[22] compared hypertensive patients with and without metabolic syndrome with respect to stroke volume index-to-pulse pressure ratio and found this ratio to be significantly lower in metabolic syndrome, but they did not evaluate its association with exercise.

Increased pulse pressure at rest is mainly associated with arterial wall stiffness; thus, it may contribute to increased cardiovascular mortality in hypertensive patients with metabolic syndrome.^[23]

Abnormal heart rate recovery after exercise is accepted as an indicator of autonomic dysfunction, having association with mortality.^[24]

Several studies demonstrated that myocardial ischemia was closely related with heart rate recovery in diabetic patients and suggested that heart rate recovery was related with the severity of myocardial ischemia.^[25]

Deniz et al.^[26] studied heart rate recovery in female patients with metabolic syndrome and in obese patients lacking other criteria of metabolic syndrome and found significant worsening in heart rate recovery in patients with metabolic syndrome. The authors emphasized that heart rate recovery might have a determinant prognostic value for vascular events in patients with metabolic syndrome.

In another study in which the association between the components of metabolic syndrome and heart rate recovery was investigated, abnormal heart rate recovery was found to be significantly correlated with increased waist circumference, decreased HDL-cholesterol levels, fasting plasma glucose levels, and increased triglyceride levels.^[27]

In our study, heart rate recovery was similar in patients with and without metabolic syndrome and this may result from the fact that all subjects had normal coronary arteries. Even though we did not investigate myocardial ischemia and perfusion, we were of the opinion that ischemia was not of sufficient degree to affect heart rate recovery.

A study in which only patients with type II diabetes were included reported that factors decreasing exercise capacity were female gender, advanced age, obesity, and long duration of diabetes, and that patients with preserved diastolic parameters and normal heart rate recovery had a better exercise capacity.^[28]

In conclusion, our data showed that, in the absence of coronary artery disease, patients with metabolic syndrome had significantly decreased exercise capacity. Even though systolic dysfunction and vascular pathology may be absent in these patients, decreased exercise capacity may contribute to cardiovascular mortality. Moreover, further randomized clinical trials are necessary to determine whether decreased exercise capacity in these patients is associated with isolated diastolic dysfunction.

Study limitations. Although we eliminated occlusive coronary artery disease by coronary angiography, we could not eliminate angina syndrome, known as “cardiac syndrome X”, that refers to angina in the presence of normal coronary arteries.

In our study, gas analysis was not performed during exercise test, and exercise capacity was measured with METs.

The diagnosis of insulin resistance was not based on laboratory tests, it was based on clinical parameters as used in clinical studies.

Considering literature data reporting normal coronary arteries and angina syndrome to be more frequent in women, we could not distinguish the effect of sex on both echocardiographic parameters and exercise capacity among our study population in which women accounted for the majority.

 

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