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(Chest. 2004;125:1292-1298.)
© 2004 American College of Chest Physicians

Altered Exercise Gas Exchange as Related to Microalbuminuria in Type 2 Diabetic Patients*

Arthur Chun-Wing Lau, FHKAM; Matthew Kwok-Wing Lo, FRCP; Godwin Tat-Chi Leung, FHKAM; Frankie Pak-Tat Choi, FHKAM; Loretta Yin-Chun Yam, FRCP, FCCP and Karlman Wasserman, MD, FCCP

* From the Department of Medicine (Drs. Lau, Lo, Leung, and Yam) and Department of Nuclear Medicine (Dr. Choi), Pamela Youde Nethersole Eastern Hospital, Hong Kong, China; and Division of Respiratory and Critical Care Physiology and Medicine (Dr. Wasserman), Department of Medicine, Harbor-UCLA Medical Center, Torrance, CA.

Correspondence to: Arthur Chun-Wing Lau, FHKAM, Division of Respiratory and Critical Care Medicine, Department of Medicine, Pamela Youde Nethersole Eastern Hospital, 3 Lok Man Rd, Hong Kong SAR, PRC; e-mail: drcwlau{at}hkstar.com


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Microalbuminuria in diabetes mellitus is a risk factor for cardiovascular disease. We hypothesized that microalbuminuria in type 2 diabetic patients is related to impaired cardiopulmonary function during exercise, and that the severity of impairment is correlated with the degree of microalbuminuria.

Design: Twenty of each of the following categories of subjects performed symptom-limited cardiopulmonary exercise testing on a cycle ergometer: (1) type 2 diabetic patients with normoalbuminuria (daily urinary albumin excretion [UAE] < 30 mg/d); (2) type 2 diabetic patients with microalbuminuria (daily UAE, 30 to 300 mg/d); and (3) normal control subjects.

Measurements and results: Oxygen consumption (O2) of patients with microalbuminuria was lower than that of control subjects at anaerobic threshold (AT) [p < 0.001], and was lower than both control subjects (p < 0.001) and patients with normoalbuminuria (p = 0.015) at peak exercise. There was a progressive worsening in gas exchange efficiency at the lungs, as measured by minute ventilation (E)/carbon dioxide production (CO2) at AT or {Delta}E/{Delta}CO2 slope, (p = 0.006 and p = 0.019, respectively) going from control subjects to patients with normoalbuminuria and then to patients with microalbuminuria. Left ventricular ejection fractions and BP were similar in patients with normoalbuminuria and microalbuminuria. More patients with microalbuminuria (n = 9) than with normoalbuminuria (n = 2) demonstrated diastolic dysfunction (p = 0.013). These 11 patients had lower peak O2 values (p = 0.001) and higher daily UAE (p = 0.028). An inverse linear relationship was found between peak O2 and log10 daily UAE (r = – 0.57, r2 = 0.29, p < 0.001).

Conclusions: Abnormalities reflecting reduced oxygen transport and impaired gas exchange efficiency were found during exercise, and were especially profound in patients with microalbuminuria. These changes could be secondary to pulmonary microangiopathy and myocardial interstitial changes. Increases in capillary permeability to proteins may take place in the myocardium as they do in the kidneys, and contribute to impaired myocardial distensibility and hence diastolic dysfunction.

Key Words: exercise • gas exchange • microalbuminuria • type 2 diabetes


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Diabetes mellitus is a significant public health problem worldwide. The Framingham study1 showed that diabetes doubled the risk of developing cardiovascular disease in men and tripled the risk in women. The Multiple Risk Factor Intervention Trial2 demonstrated an adjusted relative risk of 3.0 for cardiovascular mortality in diabetic men. The presence of microalbuminuria has been postulated as a marker of vascular dysfunction and a risk factor for cardiovascular disease.34 Type 2 diabetic patients with microalbuminuria were approximately four times as likely to die prematurely from a cardiovascular event as those with normoalbuminuria.5 Impaired exercise capacity in patients with type 1 diabetes67 or type 2 diabetes8 suggests the presence of underlying cardiopulmonary abnormalities. We hypothesized that microalbuminuria in type 2 diabetic patients is related to impaired cardiopulmonary function during exercise, and that the severity of impairment is correlated with the degree of microalbuminuria.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subject Recruitment
From November 2000 to June 2002, three categories of subjects were recruited from Pamela Youde Nethersole Eastern Hospital, Hong Kong: (1) type 2 diabetic patients with normoalbuminuria (defined as daily urinary albumin excretion [UAE] < 30 mg/d), (2) type 2 diabetic patients with microalbuminuria (defined as daily UAE of 30 to 300 mg/d), and (3) normal control subjects. The latter were volunteers free of diabetes mellitus, and were recruited from among the hospital staff. Subjects of both genders aged 20 to 75 years were identified. The three groups were matched for age (within 10 years) and gender. All control and diabetic subjects had to be free of symptoms of decreased exercise tolerance, exertional angina, and overt signs of cardiovascular disease. Informed consents were obtained from all subjects. The study protocol was approved by the Hospital Ethics Committee.

Patients were evaluated with resting forced spirometry, lung volume (N2 washout), and diffusion capacity corrected for alveolar volume (DLCO/VA) [single-breath carbon monoxide diffusion] measurements, hemoglobin level, and resting ECG. All diabetic patients were also evaluated with two, 24-h urine collections for UAE, hemoglobin A1c, and renal function tests. Daily physical activity was classified as follows: no regular exercise and having a sedentary job, or regular exercise or job duty with at least 2 h/wk of moderate-to-heavy exertion, defined as that which could lead to sustained limbs tiredness, sweating, or tachypnea. Exclusion criteria were as follows: (1) known cardiovascular diseases or arrhythmia, including poorly controlled BP (resting systolic BP > 160 mm Hg or diastolic BP > 90 mm Hg) and significant peripheral vascular disease; (2) known obstructive, restrictive, or chronic infective pulmonary diseases; (3) musculoskeletal disease that may affect exercise performance, including chest wall deformities; and (4) others: hemoglobin < 10 g/dL, pregnancy, creatinine levels > 130 µmol/L, macroalbuminuria (daily UAE > 300 mg/24 h), and inability to perform a good-quality cardiopulmonary exercise testing.

Exercise Protocol
All eligible subjects were informed to continue their diet and drug treatment as usual, and to refrain from smoking for at least 1 day before the test if they were smokers. Each subject performed a symptom-limited cardiopulmonary exercise test in the seated position on a calibrated, electronically braked cycle ergometer (Lode Corival; Groningen-Holland Medical Technology; Groningen, the Netherlands) in an air-conditioned laboratory (20°C) at least 2 h after a light lunch. All tests were supervised by one of the authors (A.C-W.L.). During the test, subjects breathed room air through a mouthpiece connected to a flow transducer, the signal of which was converted to volume, and a sampling capillary tube for O2 and CO2 measurement by a metabolic cart (Medical Graphics CardioO2 Combined O2/ECG Exercise System; Medical Graphics Corporation; St. Paul, MN). After 3 min of rest and 3 min of unloaded pedaling at 60 revolutions per minute, the work rate (WR) was increased linearly (ramp pattern). This rate of WR increment was chosen so that the increasing WR period of the test would last approximately 8 to 12 min. The following parameters were measured breath by breath: oxygen consumption (O2), carbon dioxide production (CO2), tidal volume (VT), respiratory rate, and hence minute ventilation (E). Oxygen saturation by pulse oximetry was measured by a pulse oximeter (Novametrix Model 515B; Novametrix Medical Systems; Wallingford, CT). BP was monitored by an automated sphygmomanometer for exercise testing (Sun Tech Tango; Sun Tech Medical Instruments; Raleigh, NC). Heart rate (HR) and 12-lead ECG were continuously monitored. All subjects were asked to exercise until exhaustion, until they were unable to maintain a pedaling frequency of > 45 revolutions per minute, or until the physician considered that further exertion was inappropriate for patient safety reasons (eg, angina pectoris, evidence of unstable vital signs).

Measurements
Baseline characteristics were collected, including age, gender, body weight, body height, duration of diabetes, smoking history, diet and drug history, and physical activity. For spirometry, FEV1, FVC, and FEV1/FVC ratio were obtained according to the criteria of the American Thoracic Society.9 The following exercise parameters were derived: respiratory exchange ratio (RER), oxygen pulse, ventilatory equivalents for CO2 (E/CO2) at anaerobic threshold (AT), {Delta}O2/{Delta}WR slope, slope of VT to natural logarithm of E ({Delta}VT/{Delta}lnE). Resting values were obtained at the end of the 3-min rest period, just before unloaded exercise began. AT was determined by the modified V-slope method.10 Peak O2 and peak CO2 were defined as the highest value attained during the 20-s period just before the exercise was terminated. RER was obtained by dividing CO2 by the simultaneous O2. Oxygen pulse was obtained by dividing O2 by the simultaneous HR. {Delta}O2/{Delta}WR was obtained by linear regression during the period of ramp exercise, with the first 2-min and last 1-min ramp period data excluded, so that only the linear portion was measured. {Delta}VT/{Delta}lnE, and {Delta}HR/{Delta}O2 slopes were obtained by linear regression of the entire ramp exercise period. {Delta}E/{Delta}CO2 slopes were obtained by linear regression of the linear portion from the beginning of ramp exercise to the respiratory compensation point. The indirect maximum voluntary ventilation (MVV) was obtained by FEV1 x 40.

Transthoracic echocardiography with Doppler studies (Acuson 128XP; American Lab & Medical Equipment; Miami, FL) was performed in all diabetic patients (normoalbuminuria and microalbuminuria) by a cardiologist (G.T-C.L.), who was blinded to the level of UAE to rule out significant structural heart disease. Left ventricular ejection fraction was measured by twodimensionally guided M-mode method. Left ventricular diastolic dysfunction was classified as abnormal relaxation pattern, pseudonormal pattern, or restrictive filling pattern as previously described.111299mTc-sestamibi myocardial perfusion single-photon emission CT with a dual-head gamma camera and high-resolution collimator (SP-6D Helix & HPC-45; Elscint; Haifa, Israel) was performed in diabetic patients with abnormal exercise ECG results, defined as > 1-mm horizontal or downsloping ST-segment depression in two consecutive leads, to look for evidence of myocardial ischemia.

Statistical Analysis
Baseline characteristics were compared using {chi}2 test for categorical variables and independent-samples t test or analysis of variance (ANOVA) for continuous variables where appropriate. Comparison of exercise test parameters at different stages of exercise in the three groups was done using ANOVA, with the Bonferroni procedure for multiple comparisons when significance was found. For power estimation, 20 patients in each group were required to detect a minimum difference in O2 per kilogram of 3 mL/min/kg, when the estimated SD was up to 3.3 mL/min/kg ({alpha} = 0.05, 1 – ß = 0.80). Correlation between the O2 at peak exercise and the log10 daily UAE was performed using the Pearson correlation. All statistical significance was set at p < 0.05. Statistical analysis was done using SPSS (version 9.0; SPSS; Chicago, IL).


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Twenty patients were recruited into each of the three groups: control, normoalbuminuria, and microalbuminuria. Their baseline characteristics are shown in Table 1 . There were no statistical differences among the three groups for age, body weight, and height. The three groups also had similar resting lung function (Table 2 ).


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  		Table 1.. Subject Baseline Characteristics*

 

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  		Table 2.. Resting Lung Function of Control Subjects and Normoalbuminuric and Microalbuminuric Type 2 Diabetic Patients*

 
Exercise testing parameters are shown in Table 3 . All subjects exercised until exhaustion. All stopped exercise because of leg fatigue or generalized weakness, none because of dyspnea. Adequacy of stress was confirmed by RER > 1 at the peak of exercise, with no statistical difference among groups. No patient complained of chest discomfort suggestive of myocardial ischemia during exercise and recovery. There was significant overall difference in peak O2 (both uncorrected and corrected for body weight) among the three groups at AT and at peak exercise. Peak O2 of control subjects was higher than that of microalbuminuria by 6.1 ± 1.4 mL/min/kg (p < 0.001), and that of normoalbuminuria was higher than that of microalbuminuria by 4.2 ± 1.4 mL/min/kg (p = 0.0015) [mean ± SD]. At rest, patients with microalbuminuria had the highest HR, such that there was significant difference of 8.8 ± 3.4 beats/min between patients with microalbuminuria and control subjects (p = 0.038). However, at peak exercise, patients with microalbuminuria had the lowest HR. The difference of 11.5 ± 4.1 beats/min was statistically significant between patients with microalbuminuria and patients with normoalbuminuria (p = 0.018). Patients with microalbuminuria tended to have a lower oxygen pulse as exercise progressed, but the difference was only significant at AT. {Delta}HR/{Delta}O2 slope, {Delta}O2/{Delta}WR slope, exercise E, maximum exercise E/indirect MVV ratio, and exercise {Delta}VT/{Delta}lnE slope were similar among the three groups (Table 3). There was progressively higher {Delta}E/{Delta}CO2 slope from control subjects to patients with normoalbuminuria to patients with microalbuminuria (p = 0.019). The difference was statistically significant only between control subjects and patients with microalbuminuria (p = 0.017), with patients with microalbuminuria 4.57 ± 1.59 higher than control subjects. Among the three groups, patients with microalbuminuria had the highest ventilatory equivalents for carbon dioxide (E/CO2) at AT. The difference between control subjects and patients with microalbuminuria was 4.04 ± 1.23 (p = 0.005). Partial pressure of end-tidal CO2 (PETCO2) at AT was also similar. There was some inverse linear relationship between peak O2 per kilogram and log10 daily UAE (r = – 0.57, r2 = 0.29, p < 0.001; Fig 1 ).


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  		Table 3.. Gas Exchange at Rest and AT, and Peak Exercise for Control Subjects and Normoalbuminuric and Microalbuminuric Type 2 Diabetic Patients*

 


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  		Figure 1.. Correlation between the daily UAE (plotted on a log scale) and peak O2 per kilogram in diabetic patients (n = 40; Pearson correlation r = – 0.57, r2 = 0.29; p < 0.001).

 
Transthoracic echocardiography with Doppler studies was performed in all 40 diabetic patients. None had systolic dysfunction or regional wall motion abnormality suggestive of coronary artery disease. Left ventricular ejection fractions were similar between patients with normoalbuminuria and patients with microalbuminuria: 68.45 ± 6.10% vs 63.44 ± 21.30%, respectively (p = 0.323). Diastolic dysfunction was only related to the presence of microalbuminuria but not to chronic hypertension (Table 4 ). 99mTc-sestamibi scan did not confirm myocardial ischemia in five patients with abnormal exercise ECG results (three patients with normoalbuminuria and two patients with microalbuminuria).


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  		Table 4.. Characteristics of the 40 Diabetic Patients With and Without Diastolic Dysfunction*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our findings confirmed that cardiopulmonary abnormalities were present in type 2 diabetic patients during exercise, and the severity of some of these abnormalities were correlated with the level of microalbuminuria. Impaired exercise capacity in terms of peak O2 or WR has been documented in both type 1 diabetes711131415 and type 2 diabetes16 to be related to longstanding disease,11 higher total glycosylated hemoglobin A1,14 higher body mass index, female sex, older age, higher resting systolic BP, higher pack-years of smoking, and African-American race.17 In type 1 diabetes, Jensen et al6 found that peak O2 of normal control subjects and patients with normoalbuminuria was similar. Microalbuminuric and macroalbuminuric patients also had similar peak O2, but this was approximately 40% lower than that of normal control subjects and patients with normoalbuminuria. We found an inverse linear relationship between peak O2 and log10 daily UAE. Log transformation of UAE was done because the relationship between peak O2 and non-log transformed UAE appears inversely curvilinear. The implication of such finding is that peak exercise capacity decreased steeply with the onset of even low levels of microalbuminuria.

Lower oxygen pulse in microalbuminuria reflected lower cardiac output at peak exercise. Lower left ventricular end-diastolic volume index and cardiac index in normotensive type 1 diabetic patients had been found to be related to increasing levels of albuminuria, suggesting that diastolic dysfunction (as reflected by reduced left ventricular compliance) could be a major factor in explaining their impaired aerobic capacity.18 In another group of African type 2 diabetic patients with normoalbuminuria and microalbuminuria, ventricular mass had been found to correlate with UAE rate but not with BP.19 This diastolic dysfunction has been suggested to be an early manifestation of diabetic cardiomyopathy,20 while the systolic ventricular function is still normal.21 This diabetic cardiomyopathy has been postulated to be due to small and microvascular disease, interstitial fibrosis,22 autonomic dysfunction,23 and myocardial oxidative damage.24 Other possible explanations for the lower peak O2 in diabetic patients include impaired capillary function,25 thickened skeletal-muscle capillary basement membrane,26 and impaired nitric oxide-dependent dilation of skeletal muscle arterioles,27 but not activity of muscle mitochondrial enzymes, which had been found to be normal.28

A ventilation-perfusion scintigram study29 of both type 1 and type 2 diabetics has found that perfusion defects predominated over ventilation defects, and the number of perfusion defects correlated with decreases in diffusing capacity. Diabetic microangiopathy and the severity of microalbuminuria were found to be related to reduction in diffusion capacity of the lung for carbon monoxide.30 Although we have not checked blood gas and bicarbonate values, there was no reason to believe that significant metabolic acidosis, hyperventilation, or differences in pulmonary mechanics were the cause of increased {Delta}E/{Delta}CO2 slope and E/CO2 at AT, given the similar baseline characteristics, renal functions, PETCO2 at AT, resting lung function test results, and dynamic {Delta}Vt/{Delta}lnE slopes. These abnormalities could thus be related to increased dead space ventilation, as previously described in diabetic patients.31

In summary, our study showed that the severity of microalbuminuria in type 2 diabetic patients was correlated with impaired cardiovascular function and oxygen transport during exercise. A unified hypothesis may herein be generated that microalbuminuria may signal a state of generalized microvascular dysfunction, with increased capillary permeability to macromolecules, such as plasma proteins. Not only is this reflected in impairment of renal function, but in the case of the heart this could be associated with an increase in interstitial fluid, rich in protein, which may become organized with fibrocytes. The resulting interstitial fibrosis may be one of the causes of reduced ventricular compliance, ie, diastolic dysfunction, the typical form of cardiomyopathy found in diabetics. Corresponding pulmonary microangiopathy in the lung circulation of these patients may account for ventilation-perfusion mismatching and increased ventilatory response to exercise. These hypothesized changes are deserving of further research through histologic and molecular studies.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; AT = anaerobic threshold; DLCO/VA = diffusion capacity corrected for alveolar volume; HR = heart rate; MVV = maximum voluntary ventilation; PETCO2 = partial pressure of end-tidal carbon dioxide; RER = respiratory exchange ratio; UAE = urinary albumin excretion; CO2 = carbon dioxide production; E = minute ventilation; O2 = oxygen consumption; VT = tidal volume; WR = work rate

This work was performed at the Departments of Medicine and Nuclear Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.

All expenses were supported by the Department of Medicine, Pamela Youde Nethersole Eastern Hospital, Hong Kong, China.

Received for publication May 13, 2003. Accepted for publication September 19, 2003.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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