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The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 62:760-765 (2007)
© 2007 The Gerontological Society of America

The Association Between Metabolic Syndrome and Restrictive Ventilatory Dysfunction in Older Persons

Filippo Luca Fimognari, Patrizio Pasqualetti, Leo Moro, Alessandro Franco, Gianfranco Piccirillo, Ruggero Pastorelli, Paolo Maria Rossini and Raffaele Antonelli Incalzi

1 Division of Internal Medicine, Leopoldo Parodi-Delfino Hospital, Azienda Sanitaria Locale Roma G, Colleferro (Rome), Italy.
2 Division of Geriatrics, University Campus Biomedico of Rome, Italy.
3 AfaR (Associazione Fatebenefratelli per la Ricerca), Rome, Italy.
4 Department of Aging Science, University La Sapienza, Rome, Italy.

Address correspondence to Filippo L. Fimognari, MD, Centro per la Salute dell'Anziano (CeSA), University Campus Biomedico of Rome, Via dei Compositori 130, 00128, Rome, Italy. E-mail: filippo.fimognari{at}virgilio.it


   Abstract
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 Abstract
Methods
 Results
 Discussion
 References
 
Background. The restrictive, but not the obstructive respiratory dysfunction, is associated with an increased risk of developing type 2 diabetes mellitus. Our aim was to verify in an elderly nondiabetic population whether a restrictive respiratory pattern was associated with a higher prevalence of metabolic syndrome and increased insulin resistance than were obstructive and normal respiratory patterns.

Methods. We performed a cross-sectional study of 159 consecutive nondiabetic elderly persons attending two social centers. According to their spirometric pattern, volunteers were classified into the following categories: normal spirometry, obstructive (forced expiratory volume in 1 second/forced vital capacity < 0.70), and restrictive pattern (forced vital capacity < 80% predicted, forced expiratory volume in 1 second/forced vital capacity ≥ 0.70). Independent correlates of the metabolic syndrome were identified.

Results. The prevalence of metabolic syndrome was higher in restrictive (56%) than in both normal (21.4%, p =.001) and obstructive volunteers (12.9%, p =.001). Insulin resistance, as assessed by the log transformation of the HOmeostasis Model Assessment (HOMA), was higher in restrictive than in obstructive and normal volunteers (1 ± 0.6 vs 0.3 ± 0.6 and 0.5 ± 0.5, p <.001). Restriction was an independent correlate of metabolic syndrome, also after adjustment for waist circumference and body mass index (odds ratio = 3.23, 95% confidence interval, 1.23–8.48; p =.01).

Conclusion. Restrictive, but not obstructive respiratory pattern, is associated with metabolic syndrome and insulin resistance, and does not only reflect a limitation of ventilation due to visceral obesity. Metabolic abnormalities likely mediate cardiovascular risk in patients with restrictive respiratory impairment.

A generic condition of "impaired lung function," as expressed by depressed forced vital capacity (FVC) or forced expiratory volume in 1 second (FEV1), is a risk factor for cardiovascular events and death, independent of smoking and other potential confounders (1), and a low peak expiratory flow predicts the growth of new carotid atherosclerotic plaques (2). To clarify this association, the relationship between factors known to favor atherothrombosis and lung function has been extensively investigated. Persons with depressed pulmonary function show systemic low-grade inflammation (3). Prospective studies demonstrate that middle-aged individuals with low lung volumes are at increased risk of developing hypertension (4), insulin resistance (5,6), and diabetes (7,8). Moreover, depressed pulmonary function is strongly associated with insulin resistance in cross-sectional reports of elderly persons (9–11) and typically complicates diabetes mellitus (12). In these studies, however, the type of respiratory dysfunction has never been characterized.

Mannino and colleagues (13,14) found that both obstructive and restrictive patterns are associated with an increased risk of death, even after adjustment for age, sex, race, and smoking status. A restrictive pattern is present in 10%–15% of persons older than 70 years and may result from several pathological conditions, such as obesity, diabetes, muscular weakness, heart failure, thoracic kyphosis, and nonspecific lung fibrosis in the absence of typical interstitial lung disease (15). This syndrome, however, remains poorly defined. Serum fibrinogen and C-reactive protein have been found to be as elevated in restricted as in obstructed patients, thus suggesting that systemic inflammation characterizes both conditions (16). On the contrary, a restrictive, but not an obstructive pattern, is associated with an increased risk of developing type 2 diabetes mellitus (17). Accordingly, the restrictive pattern is expected to be selectively and significantly associated with the metabolic syndrome (MS) and insulin resistance in nondiabetic persons. In fact, MS is a prediabetic cluster of metabolic risk factors that recognizes insulin resistance as its underlying abnormality. Importantly, MS may be diagnosed in about 20%–28% of elderly persons and increases cardiovascular risk also after adjustment for its individual components (18). If proved, the association between MS and restrictive pattern, two conditions increasing the burden of cardiovascular risk, may represent novel and relevant information in geriatric medicine.

We designed the present study to investigate the relationship existing between lung function and MS in a population of unselected, community-dwelling, nondiabetic elderly persons. Our objective was to assess whether generically any lung dysfunction or selectively a restrictive or obstructive pattern is associated with MS.


   METHODS
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 Methods
Results
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Patients
A cross-sectional study was conducted over a series of 159 elderly persons attending the Day Care Centre of the Alberto Sordi Foundation (Rome) and the Social Centre for Elderly of Carpineto Romano, near Rome, and recruited between October 2002 and June 2003. Type 2 diabetes mellitus (fasting blood glucose ≥126 and/or treatment for type 2 diabetes mellitus), cancer, recent (< 6 months) surgery, history of asthma (19), and current acute illness were exclusion criteria. We also excluded patients with interstitial lung diseases, congestive heart failure in III or IV New York Heart Association class, and spinal column deformations, which might be obvious causes of a restrictive pattern. The study was approved by the local Ethical Committee, and patients gave their informed written consent.

All patients underwent a complete physical examination and filled in a standardized questionnaire assessing medical history, drug use, and cigarette consumption. Body mass index (BMI, weight in kilograms divided by the square of height in meters) and waist circumference (WC) were measured. Cigarette pack-years were calculated by multiplying the number of years of smoking by the average number of cigarettes smoked per day and dividing by 20. Systolic and diastolic blood pressure was measured using a manual sphygmomanometer after a 10-minute rest; a mean value of at least two measurements was considered.

Lung Function Measurements
Spirometry was performed by using a Medical International Research (MIR, Rome, Italy) spirometer (Spirolab) based on a turbine flow sensor and complying with the American Thoracic Society 24/26 waveforms. During the test, the volunteers were in the standing position and with noseclips in place. Volunteers performed the slow vital capacity, then the FVC manoeuvre. The measured volumes were adjusted for sex, age, and height using equations from a reference population of nonsmoking Caucasians and were expressed as a percentage of expected value (20). The ratio of FEV1 to FVC (FEV1/FVC) was calculated, and a value ≥0.70 was considered to be normal.

Patients were divided in three groups according to whether their respiratory pattern was normal (FEV1/FVC ≥ 0.70, FVC ≥ 80% and VC ≥ 80% predicted), obstructive (FEV1/FVC < 0.70), or restrictive (FVC <80% predicted, FEV1/FVC ≥ 0.70) (13,21).

Laboratory Assays, Diagnosis of MS, and Concomitant Diseases
Plasma samples were drawn after an overnight fast, and all laboratory measurements were performed within 2 hours after blood collection. Glucose plasma levels were measured by using the glucose–oxidase method. Serum total cholesterol (TC) and triglycerides (TG) were measured enzymatically, whereas the high-density lipoprotein (HDL) fraction was measured after precipitation of low-density and very low-density lipoproteins by using dextran sulfate and magnesium chloride (22). Low-density lipoprotein (LDL) cholesterol was estimated according to the Friedewald formula (LDL = TC – TG/5 – HDL). Insulin was measured by a Microparticle Enzyme Immunoassay (AxSYM System; Abbott, Abbott Park, IL) (23). The intra-assay and inter-assay coefficients of variation were 3% and 5%, respectively. The HOmeostasis Model Assessment (HOMA) was calculated according to the following formula: fasting insulin x fasting glucose/22.5. This parameter was used as a quantitative index of insulin resistance (24). MS was diagnosed according to the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults guidelines on the basis of the coexistence in the same patient of at least three of the following five factors: abdominal obesity (WC > 102 cm in men and > 88 cm in women), increased TG (≥ 150 mg/dL), reduced HDL cholesterol (< 40 mg/dL in men and < 50 mg/dL in women), elevated blood pressure(≥ 130/≥ 85 mmHg and/or treatment for hypertension), and high fasting glucose (110–125 mg/dL) (25). Atrial fibrillation, congestive heart failure, coronary artery disease and cerebrovascular disease were diagnosed according to standardized criteria (26).

Statistical Analysis
Differences among groups were assessed by the chi-square test for categorical variables and by analysis of variance (ANOVA) or Kruskal–Wallis test for continuous variables, as appropriate. The Tukey test and the Mann–Whitney test (with Bonferroni correction) were used to supplement, respectively, ANOVA and Kruskal–Wallis test for pairwise comparisons between groups.

A simple logarithmic transformation successfully allowed us to obtain a Gaussian and homoscedastic distribution of HOMA; thus, Log.HOMA was used in data analysis.

Independent correlates of MS (dependent variable) compared to persons without MS (reference category) were identified with a logistic regression analysis including age, sex, restrictive and obstructive patterns, WC, and BMI as independent variables. Odds ratios (OR) and 95% confidence intervals (CI) were obtained. A parameter was considered to be an independent correlate of the outcome if its 95% CI of the OR did not include the value 1, after taking into account the effect of the other variables.


   RESULTS
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Discussion
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General, clinical, and respiratory characteristics and prevalence of cardiovascular diseases in the three respiratory groups are shown in Table 1. According to the spirometric results, 103 patients (64.8%) had a normal, 31 (19.5%) had an obstructive, and 25 (15.7%) had a restrictive pattern. Patients with an obstructive pattern were significantly older than those with both restrictive (p =.007) and normal patterns (p =.026) and were less frequently female (p =.015 and p =.003 for comparison with people with normal or restrictive pattern, respectively). Individuals with restriction had greater BMI than patients with normal patterns (p =.004) and patients with obstruction (p =.001). Patients with obstruction reported more years of smoking and pack-years than both normal and restrictive patients (p <.05). The prevalence of cardiovascular diseases was not different across groups.


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  		Table 1. Demographic, Clinical, and Respiratory Function Variables and Comorbid Diseases in the Three Groups.

 
Table 2 shows the average values of components of MS and selected other metabolic variables in the three groups. Insulin levels and HOMA were strongly increased in persons with restriction compared to persons with obstruction (p <.001 for both variables) and controls (p <.001 for insulin and p =.003 for HOMA). Restriction was also associated with larger WC compared to both normal (p =.012) and obstructive patterns (p =.011). The mean values of the other components of MS were similar in the three groups.


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  		Table 2. Components of Metabolic Syndrome and Selected Other Metabolic Variables in the Three Groups.

 
MS was observed in 40 individuals (25.1%). Figure 1 shows the prevalence of MS and its individual components within groups. MS was more prevalent in the group with restriction (14/25) than in the normal (22/103) and obstructive pattern groups (4/31) (p <.001; p =.001 for both comparisons) (Figure 1). Among the individual components of MS, both visceral obesity and, to a lesser extent, hypertriglyceridemia were significantly more prevalent in restrictive than in both obstructive (p =.002 for visceral obesity and p =.04 for hypertriglyceridemia) and normal groups (p =.003 for visceral obesity and p =.02 for hypertriglyceridemia). A low HDL level was more prevalent in the restrictive than in the obstructive group (p =.02). The prevalence of hypertension and hyperglycaemia did not distinguish groups.


Figure 01
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  		Figure 1. Prevalence of metabolic syndrome (MS) and its individual components in the three respiratory groups. Bars indicate the prevalence (as a percentage) of MS and its components. HDL = high density lipoproteins

 
A logistic regression analysis showed that MS was significantly associated only with the restrictive pattern (OR = 3.23, 95% CI, 1.23–8.48; p =.01) after adjustment for WC, BMI, age, sex, and the obstructive pattern (Table 3). In a model without BMI, however, WC nearly reached statistical significance (OR = 1.03, 95% CI, 1–1.07; p =.052), and the restrictive pattern was again the only significant correlate of MS (OR = 3.34, 95% CI, 1.28–8.74; p =.01).


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  		Table 3. Logistic Regression Analysis With MS Status as Dependent Variable.

 

   DISCUSSION
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 Abstract
 Methods
 Results
 Discussion
References
 
The main finding of this study is that restrictive, but not obstructive respiratory pattern, is associated with MS. This result is consistent with the recently reported increased risk of diabetes in restrictive, but not in obstructive lung disease (17).

The coexistence of MS and restrictive pattern in elderly persons does not merely reflect the mechanical obstacle to lung expansion posed by visceral obesity, a component of MS. Indeed, the restrictive pattern was the only significant correlate of MS also after adjustment for WC and BMI.

Previous cross-sectional studies reporting an independent association between low lung volumes and insulin resistance did not distinguish obstruction from restriction (9–11). Our study clarifies that a restrictive, but not an obstructive pattern, is associated with MS. Accordingly, HOMA was much higher in restriction than in both the obstruction and the normal group. The mechanisms potentially accounting for the diminished sensitivity to insulin in the restrictive pattern are unclear. Prospective studies showed that middle-aged persons with impaired lung function are at greater risk of developing insulin resistance, diabetes mellitus, hypertension, and cardiovascular disease within 10 years (4–8). This finding suggests that the ventilatory impairment may precede the metabolic abnormalities. Theoretically, some defect in respiratory muscle function might either underlie the restrictive pulmonary function pattern or herald the decline of sensitivity to insulin.

Confirming previous findings (13,15), we found a 15.7% prevalence of restrictive pattern in elderly persons free from evident risk factors for restriction, such as spinal column deformations and interstitial lung diseases. Such a high prevalence is expected to be clinically relevant because the restrictive pattern is associated with increased mortality (13,14), functional limitation (15), systemic inflammation (16), comorbidity (27), and risk of diabetes (17,28). The clustering of proatherosclerotic metabolic abnormalities demonstrated in this study might help to explain the relationship between restrictive pattern and cardiovascular disease, also in the absence of diabetes. In addition, these persons are younger than those with obstruction, suggesting that the restrictive ventilatory impairment may develop starting in childhood or youth. However, data are sparse, and prospective studies are needed to investigate clinical characteristics, correlates, and outcomes of the restrictive pattern.

Symptoms of chronic bronchitis increase the risk of myocardial infarction (29) and stroke (30). Chronic bronchitis is a clinical manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by airflow obstruction with an FEV1/FVC ratio < 0.70 (21). We excluded persons with a history of asthma; therefore, our obstructed patients were supposed to be affected by COPD. The prevalence of obstructive pattern in other elderly populations, including also asthmatics, ranges from 20% to 30% (13,15), which fits well the 20% prevalence found in our series of individuals without asthma. As expected, the obstructive pattern was associated with older age, male sex, and greater smoke exposure. Interestingly, both insulin sensitivity and the prevalence of MS were normal in patients with obstruction. Thus, insulin resistance is unlikely to mediate the relationship between bronchial obstruction and cardiovascular accidents (1,29,30). Furthermore, low BMI (31) and decreased lipid blood levels (32), which would protect from atherothrombosis, are common findings in severe COPD. Thus, alternative pathogenic mechanisms [inflammation (33), platelet hyperactivity (34), oxidative stress (35), and clotting activation (36)] likely account for the high prevalence of cardiovascular diseases in COPD.

This study has three main limitations. First, the diagnosis of restrictive pattern was made on the basis of low dynamic lung volumes according to the American Thoracic Society standard, but a definitive diagnosis would require the finding of decreased total lung capacity (37). Therefore, the possibility cannot be excluded that a few patients classified in the restrictive group had increased residual volume and, then, normal total lung capacity. However, our definition (FVC < 80% and FEV1/FVC ≥ 0.70) has been found to have a high diagnostic accuracy versus a diagnosis of restrictive pattern based on total lung capacity measurement (37). Second, even though visceral obesity is a component of MS, in our logistic regression analysis WC was not significantly correlated with MS. This could depend on the fact that visceral obesity is only one of the five factors requested for defining MS, as well as upon colinearity between BMI and WC. Finally, being cross-sectional in nature, this study needs to be prospectively replicated to compare changes in lung volumes and metabolic parameters.

Conclusion
Our study proves that MS is common in elderly patients with a restrictive, but not an obstructive pattern. Thus, patients with a restrictive pattern should be considered at risk of and screened for MS. On the other hand, patients with MS should be screened for respiratory dysfunction, and the effects of improving insulin sensitivity on lung function should be assessed to verify whether insulin resistance has a direct pathogenic role.


   Acknowledgments
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We thank Ottorino Saccucci and Luciano Colaluca (Social Centre for Elderly, Carpineto Romano) for their assistance.

The study was performed in the Centro per la SAlute dell' Anziano, University Campus Biomedico of Rome.


   Footnotes
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Decision Editor: Luigi Ferrucci, MD, PhD

Received May 15, 2006

Accepted October 1, 2006


   References
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