Diffuse idiopathic skeletal hyperostosis prevalence in subjects with severe atherosclerotic cardiovascular diseases

Authors


Abstract

Objective

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by ossification of different entheseal sites. Several metabolic factors have been suggested to be involved in DISH development. We assessed the prevalence of DISH and its relationship to traditional vascular risk factors in a cohort of patients diagnosed with cardiovascular diseases.

Methods

Among the 521 consecutive patients admitted to the heart diseases rehabilitation program in our Rehabilitative Cardiology Unit, only those (n = 436) with recent coronary artery bypass grafting (CABG), a heart valve replacement (HVR), or congestive heart failure (CHF) were enrolled (45 CHF, 338 CABG, and 53 HVR). All patients underwent a rheumatologic examination, blood sample collections, and chest radiographs. Body mass index (BMI), blood pressure, and information about sex, age, smoking habit, and other vascular risk factors were recorded. DISH was established according to the Resnick and Niwayama criteria.

Results

In the setting (77.1% men), the mean ± SD age was 65.44 ± 9.66 years and the overall prevalence of DISH was 30.3%. A logistic regression analysis showed that both age (odds ratio [OR] 1.076, 95% confidence interval [95% CI] 1.044–1.109; P < 0.001) and obesity (OR 2.28, 95% CI 1.33–3.89; P = 0.003) were significant predictors of the presence of DISH. An increasing OR for the presence of DISH was found for increasing tertiles of age and BMI. No difference resulted according to other traditional vascular risk factors. BMI and age directly correlated with C-reactive protein levels.

Conclusion

The overall prevalence of DISH was 30.3%. This is expected because of the study population. Obese and older individuals exhibit a higher risk of DISH development.

Introduction

Diffuse idiopathic skeletal hyperostosis (DISH) is characterized by calcification and ossification of different entheses. Ossification of the anterolateral aspect of the thoracic spine is considered to be the hallmark of the disease. The most commonly used classification criteria were defined by Resnick and Niwayama (1). DISH is asymptomatic in many patients, although polyarticular pain, acute monarticular synovitis, and limited spinal motion have been described. Therefore, this condition is not limited to the spinal column and has often been reported to involve peripheral sites as well. The etiology of DISH is unknown. The available literature suggests that several metabolic, genetic, and constitutional factors may be associated with the condition, although their presence is not mandatory to establish the diagnosis of DISH (1). In particular, these include obesity, a high waist circumference ratio, hypertension, diabetes mellitus, hyperinsulinemia, dyslipidemia, elevated growth hormone levels, elevated insulin-like growth factor 1, hyperuricemia, and genetic factors (2). A study by Mader et al showed that subjects with DISH are frequently affected by metabolic syndrome and exhibit an increased risk for cardiovascular morbidity (3). Most of the subjects with DISH have been evaluated in order to assess the likelihood of being affected by metabolic syndrome or traditional vascular risk factors (2, 3). Our study aimed to evaluate the prevalence of DISH and its relationship to traditional vascular risk factors in a cohort of patients diagnosed with severe cardiovascular diseases (CVDs).

Significance & Innovations

  • In patients diagnosed with severe cardiovascular diseases, traditional vascular risk factors such as hypertension and diabetes mellitus do not affect the opportunity of diffuse idiopathic skeletal hyperostosis (DISH) development.

  • Only obesity and aging are significantly associated with DISH development in patients with cardiovascular disease.

  • Obesity has been recognized as a chronic low-grade systemic inflammatory disease.

Materials and methods

Study design.

From December 2007 to January 2009, 521 consecutive patients admitted to the heart diseases rehabilitation program in the Rehabilitative Cardiology Unit of the “Salvatore Maugeri” Foundation Rehabilitation Centre in Telese Terme, Italy, were screened for enrollment in this study. Only subjects who had undergone coronary artery bypass grafting (CABG) because of myocardial infarction, heart valve replacement (HVR), or congestive heart failure (CHF) entered the study. At admission, all of the patients underwent a complete rheumatologic examination by a trained staff member, blood sample collections, and chest radiographs. Body mass index (BMI), blood pressure, and information about sex, age, smoking habit, and other vascular risk factors were recorded. Blood samples included fasting serum glucose, triglycerides, total cholesterol, high-density lipoprotein cholesterol, erythrocyte sedimentation rate, and C-reactive protein (CRP) level. Moreover, the prevalence of traditional vascular risk factors was assessed in all patients and according to validated criteria (4), hypertriglyceridemia was defined as triglyceride levels ≥150 mg/dl; hypercholesterolemia with low high-density lipoprotein cholesterol was defined as total cholesterol ≥200 mg/dl, and with high-density lipoprotein cholesterol was defined as total cholesterol ≤40 mg/dl for men and ≤50 mg/dl for women; hypertension was defined as blood pressure ≥130/85 mm Hg; and impaired fasting glucose was defined as a fasting glucose level ≥100 mg/dl. Obesity was defined as BMI values ≥30 kg/m2. Chest radiographs were performed for formal assessment of thoracic diseases. Images were acquired with computed radiography equipment (Prestige SI, GE Healthcare) using a standardized technique (125 kV with 2 lateral fields; 200-cm focus-to-film distance). Images were examined by a radiologist (EM) blinded to rheumatologic and metabolic evaluations. DISH was established when the radiologic criteria of Resnick and Niwayama were fulfilled on the posteroanterior or lateral view or both (1). These criteria require the involvement of at least 4 contiguous thoracic vertebral segments, preservation of intervertebral disc spaces, and the absence of apophyseal joint degeneration or sacroiliac inflammatory changes. Individuals with inconclusive radiographs were scored as non-DISH subjects.

Exclusion criteria were lack of informed consent, cardiac surgery different from CABG or HVR, cardiac disease other than CHF, presence of rheumatic diseases other than DISH, vertebral fractures or severe spine deformity, malignancy, and unstable medical conditions. The study was approved by the institutional review board.

Statistical analysis.

Statistical analysis was performed with the SPSS system, version 16. Continuous data are expressed as the mean ± SD; categorical variables are expressed as the percentage. The t-test was performed to compare continuous variables; the chi-square test was employed to analyze categorical data. When the minimum expected value was <5%, Fisher's exact test was used.

The entire population was stratified according to age tertiles and BMI tertiles. To adjust for all of the other demographic and clinical variables and to evaluate the odds ratio (OR) for the presence of DISH, a multivariate logistic regression analysis (stepwise method) was adopted, with the presence of DISH as the dependent variable and CRP level, sex, age, smoking habit, obesity, diabetes mellitus, hypercholesterolemia, hypertriglyceridemia, hypertension, metabolic syndrome, and the number of cardiovascular risk factors as the independent variables.

Moreover, a second multivariate logistic regression analysis also including BMI tertiles and age tertiles as the independent variables was performed. All of the results are shown as 2-tailed values with statistical significance if P values were less than 0.05.

Results

Among the 521 consecutive patients screened, 85 were excluded (66 underwent percutaneous transluminal coronary angioplasty, 2 underwent heart transplantations, and 17 were diagnosed with rheumatic or spine diseases other than DISH); therefore, only 436 subjects (45 with CHF and 338 and 53 who had undergone CABG and HVR, respectively) entered the study. Clinical and demographic features of the study population are shown in Table 1. In 3 noncollaborative subjects (classified as non-DISH), chest radiographs were inconclusive.

Table 1. Demographic and clinical features of the study population and stratification according to DISH and non-DISH criteria achievement*
 Overall (n = 436)Non-DISH (n = 304)DISH (n = 132)P
  • *

    Values are the number (percentage) unless otherwise indicated. DISH = diffuse idiopathic skeletal hyperostosis; IFG = impaired fasting glucose.

  • For trend.

Age, mean ± SD years65.44 ± 9.6663.86 ± 9.8669.10 ± 8.12< 0.001
Male sex336 (77.1)231 (76.0)105 (79.5)0.458
Obesity117 (26.8)70 (23.0)47 (35.6)0.009
Hypertension288 (66.1)194 (63.8)94 (71.2)0.153
Hypercholesterolemia240 (55.0)167 (54.9)73 (55.3)1.000
Hypertriglyceridemia164 (37.6)109 (35.9)55 (41.7)0.282
Diabetes mellitus + IFG190 (43.6)129 (42.4)61 (46.2)0.528
Smoking habit   0.196
 Former183 (42.0)120 (39.5)63 (47.7) 
 Current110 (25.2)83 (27.3)27 (20.5) 

The mean ± SD age of the study population was 65.44 ± 9.66 years, and 77.1% of the subjects were men. The overall prevalence of DISH in the cohort was 30.3%. With the exception of age and obesity, DISH and non-DISH subjects showed a similar prevalence of all traditional vascular risk factors (Table 1).

In particular, our results revealed that patients achieving the DISH diagnostic criteria showed an increased prevalence of obesity and older age. Moreover, a logistic regression analysis showed that, after adjusting for all of the other variables, both age (OR 1.076, 95% confidence interval [95% CI] 1.044–1.109; P < 0.001) and obesity (OR 2.28, 95% CI 1.33–3.89; P = 0.003) were significant predictors of the presence of DISH. Stratified according to the different heart diseases, subjects in the group that had undergone HVR less frequently achieved the DISH diagnostic criteria as compared to the CABG and CHF groups (n = 10 [18.9%], n = 103 [30.5%], and n = 19 [42.2%], respectively; P < 0.005 for trend).

No significant difference was observed according to sex distribution and the other traditional vascular risk factors. The multivariate analysis showed that an increasing number of traditional vascular risk factors slightly predicted the presence of DISH (OR 1.14, 95% CI 1.004–1.305; P = 0.043). In contrast, CRP values did not enter the regression model (P = 0.970). The risk of DISH development according to increasing tertiles of age and BMI is shown in Figure 1. Of interest, BMI and age directly correlated with CRP serum levels (Figure 2), suggesting higher inflammatory activity in obese and older subjects as compared to nonobese and younger patients. Finally, in 98.1% of the affected subjects, the diagnosis of DISH could be established on the posteroanterior view radiographs versus 46.0% on the lateral view.

Figure 1.

Risk of diffuse idiopathic skeletal hyperostosis development according to increasing tertiles of age and body mass index (BMI). OR = odds ratio; 95% CI = 95% confidence interval.

Figure 2.

Body mass index and age correlations with C-reactive protein serum levels.

Discussion

The correlation between rheumatic diseases and CVDs is widely discussed (5). To our knowledge, this is the first study assessing the prevalence of DISH in patients with severe atherosclerotic CVDs and its association with traditional vascular risk factors. The overall prevalence of DISH in the setting was higher as compared with other groups, but expected in considering the cardiometabolic status of our population. In detail, Weinfeld et al, evaluating 2,300 subjects from a major American Midwest city hospital over 50 years, found a DISH prevalence of 25% and 15% in men and women, respectively (6). In line with these findings, Kiss et al, in a population-based study in Hungarian people ages >50 years, showed a DISH prevalence of 27.3% and 12.8% in men and women, respectively (7). In 2005, our group, evaluating 93 Italian women, reported a DISH prevalence of 15.1% (8). Interestingly, in the Finnish general population, the prevalence of DISH was 3.8% for men and 2.6% for women (9). More recently, Westerveld et al, in a cohort of patients ages >50 years in The Netherlands, found a DISH prevalence of 17.0% (10). These discording findings are probably due to the different populations evaluated and to the DISH diagnostic criteria used.

In our setting, only older age and obesity significantly predicted the presence of DISH. Such an association is known, since early descriptions assumed a pathophysiologic mechanism of fat accumulation and/or one that was insulin resistance related. Increasing evidence demonstrates that adipose tissue is metabolically active, representing a source of inflammatory mediators known as adipokines, leading to a proinflammatory substrate in obese subjects (11). Accordingly, we found a direct correlation between BMI and CRP levels. In keeping with reports showing that aging is associated with low-grade inflammation (12), we found that age directly correlated with CRP levels. No other traditional vascular risk factor was found to be significantly associated with DISH. This is in line with previous reports showing that even if glucose intolerance, hyperlipidemia, and hypertension often have been reported in patients with DISH, this notion is not widely shared (13, 14). Therefore, at present, such an association remains questionable. In the HVR group, 10 subjects achieved the DISH criteria. Of interest, in patients who had undergone HVR because of end-stage valvular disease, Mohler et al (15) found heterotopic ossification, an active process of tissue repair, suggesting that immune cells enter the valve in response to endothelial injury, leading to heterotopic ossification. A similar pathophysiologic mechanism also may be involved in entheses ossification in DISH. To validate the finding that DISH prevalence was lower in the HVR group than in the other CVD groups, the mean age and the prevalence of obesity (major predictors of DISH in our sample) were evaluated in the HVR group as compared with the other CVD groups. Of interest, both the mean ± SD age (64.00 ± 12.08 and 65.64 ± 9.28 years, respectively; P = 0.247) and the prevalence of obesity (24.5% and 27.2%, respectively; P = 0.744) were similar between the 2 groups. We found a trend toward a progressive increase in the prevalence of DISH for an increasing number of traditional vascular risk factors. However, it is not fully understood if a reduced prevalence of traditional vascular risk factors might reduce the progression of the disease. Some limitations need to be addressed. A healthy control group was not enrolled; therefore, we performed a descriptive evaluation of the setting. The choice of the groups determined the unbalanced simple sizes, but it reflects the heterogeneity of the population that is referred to a cardiac rehabilitative program. Finally, no stratification according to the metabolic syndrome was performed. We evaluated only the risk of DISH development according to the growing number of traditional vascular risk factors. In conclusion, even if DISH is often asymptomatic, older and obese subjects with atherosclerotic CVDs and reporting spine stiffness and back pain should be investigated for the presence of DISH. Larger controlled studies are needed to delineate the entire spectrum of this condition.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Iervolino had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Zincarelli, Iervolino, Di Minno, Rengo, Nicolino, Pappone.

Acquisition of data. Iervolino, Miniero, Di Gioia.

Analysis and interpretation of data. Di Minno, Vitale, Furgi.

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