ORIGINAL ARTICLE

White Coat May be an Initial Sign of the Metabolic Syndrome

Mehmet R. Helvaci1, Hasan Kaya1, Mehmet Gundogdu2 1 Medical Faculty of the Mustafa Kemal University. 31100, Serinyol, Antakya, Hatay, Turkey. Correspondence mail: [email protected] 2 Professor of Internal Medicine, Medical Faculty of the Ataturk University, Erzurum, Turkey.

ABSTRAK Tujuan: untuk memahami peran dan pentingnya WCH dalam sindrom metabolik. Metode: Penelitian ini dilakukan di Poliklinik Bagian Ilmu Penyakit Dalam Universitas Dumlupinar pada Agustus 2005 hingga Maret 2007. Kami mengambil pasien yang berusia 20 tahun ke atas. Kriteria yang disertakan memiliki kebiasaan merokok, DM, dislipidemia, mempelajari obat-obatan yang digunakan, dan rutin periksa laboratorium glukosa plasma puasa (FPG), trigliserida (TG), density lipoprotein kolesterol tinggi (HDL-C), low density lipoprotein kolesterol (LDL-C), dan elektrokardiografi. Perbandingan proporsi digunakan sebagai metode analisis statistik. Hasil: Penelitian ini menyertakan 1.068 kasus. Prevalensi berat badan berlebih meningkat secara bertahap mulai dari dekade ketiga (28,7%) hingga dekade ketujuh (87,0%) (p<0,05 hampir pada seluruh tahapan), dan kemudian menurun pada dekade kedelapan kehidupan (78,5%, p<0,05). Peningkatan paling bermakna terlihat pada peralihan dekade ketiga ke dekade keempat (28,7% vs 63,6%, p<0,001) yang juga serupa untuk kebiasaan merokok. Hiperbetalipoproteinemia, hipertrigliserida, dislipidemia dan toleransi glukosa terganggu /impaired glucose tolerance (IGT), dan WCH mempunyai karakteristik serupa terhadap berat badan berlebih, yakni terus meningkat hingga dekade ketujuh dan kemudian menurun pada dekade selanjutnya (p<0,05 hampir pada semua tahapan). Sedangkan hipertensi (HT), diabetes mellitus tipe 2 (DM), dan penyakit jantung koroner / coronary heart disease (CHD ) selalu meningkat tanpa adanya penurunan prevalensi seiring dengan bertambahnya dekade (p<0,05 hampir pada semua tahapan), yang menunjukkan sifatnya yang ireversibel. Kesimpulan: WCH dapat merupakan tanda awal dari proses aterosklerosis sitemik yang dapat dideteksi dengan mudah dan dicegah dengan kecenderungan menurunkan berat badan.

Kata kunci: hipertensi kerah putih, sindroma metabolik, aterosklerosis.

ABSTRACT Aim: to understand the role and significance of WCH in definition of the metabolic syndrome. Methods: the study was performed in the Internal Medicine Polyclinic of the Dumlupinar University between August 2005 and March 2007. We took consecutive patients at and above the age of 20 years. Their medical histories including smoking habit, DM, dyslipidemia, and already used medications were learnt, and a routine check up procedure including fasting plasma glucose (FPG), triglyceride (TG), high density lipoprotein (HDL-C), low density lipoprotein cholesterol (LDL-C), and an electrocardiography was performed. Comparison of proportions was used as the method of statistical analysis. Results: the study included 1,068 cases. Prevalences of excess weight increased from the third (28.7%) up to the seventh decades (87.0%), gradually (p<0.05 nearly in all steps), and then decreased in the eighth (78.5%, p<0.05) decade of life. The most significant increase was seen during the passage from the third to the fourth decades (28.7% versus 63.6%, p<0.001) with a similar fashion to smoking. Hyperbetalipoproteinemia, hypertriglyceridemia, dyslipidemia, impaired glucose tolerance (IGT), and WCH had a similar fashion with excess weight by increasing until the seventh decade and decreasing afterwards (p<0.05 nearly in all steps). Whereas hypertension (HT), type 2

222 Acta Medica Indonesiana - The Indonesian Journal of Internal Medicine Vol 44 • Number 3 • July 2012 White Coat Hypertension May be an Initial Sign of the Metabolic Syndrome diabetes mellitus (DM), and coronary heart disease (CHD) always increased without any decrease by decades (p<0.05 nearly in all steps), indicating their irreversible natures. Conclusion: WCH may be an initial sign of the systemic atherosclerotic process that can be detected easily and prevented by a trend towards weight loss.

Key words: white coat hypertension, metabolic syndrome, .

INTRODUCTION METHODS A causative relationship between excess The study was performed at the Internal weight and systemic atherosclerosis is known Medicine Polyclinic of the Dumlupinar University for many years under the title of metabolic between August 2005 and March 2007. We took syndrome.1,2 The syndrome is characterized consecutive patients at and above the age of 20 by a low-grade chronic inflammatory process, years. Their medical histories including smoking probably initiated in early life3, and it can habit, DM, dyslipidemia, and already used probably be slowed down during the early phases medications were learnt, and a routine check with appropriate nonpharmaceutical approaches up procedure including fasting plasma glucose including lifestyle changes, diet, and exercise (FPG), triglyceride (TG), high density lipoprotein to prevent excess weight.4 But probably the cholesterol (HDL-C), low density lipoprotein syndrome can not be prevented completely, cholesterol (LDL-C), and an electrocardiography since aging alone may be one of the significant was performed. Current smokers with six pack- facilitator factor of the systemic atherosclerotic months and cases with a history of five pack-years process. The metabolic syndrome may contain were accepted as smokers, and cigar or pipe early reversible indicators such as white coat smokers were excluded. Patients with devastating hypertension (WCH), impaired fasting glucose illnesses including type 1 DM, malignancies, (IFG), impaired glucose tolerance (IGT), acute and chronic renal failure, chronic liver hypertriglyceridemia, hyperbetalipoproteinemia, diseases, hyper- or hypothyroidism, and heart dyslipidemia, overweight, and smoking for the failure were excluded to avoid their possible development of irreversible diseases including effects on weight. Body mass index (BMI) of obesity, hypertension (HT), type 2 diabetes each case was calculated by the measurements of mellitus (DM), peripheric disease (PAD), the Same Physician instead of verbal expressions. coronary heart disease (CHD), chronic obstructive Weight in kilograms is divided by height in pulmonary disease (COPD), cirrhosis, and meters squared, and underweight is defined as stroke.5 In another view, the syndrome induced a BMI of lower than 18.5, normal weight as systemic atherosclerosis is probably the leading 18.5-24.9, overweight as 25–29.9, and obesity cause of death for both sexes. On the other hand, as a BMI of 30.0 kg/m2 or greater.8 Cases with WCH is a well-known clinical entity defined an overnight FPG level of 126 mg/dL or greater as the persistently elevated on two occasions or already using antidiabetic (BP) in doctor's office whereas normal in other medications were defined as diabetics. An oral conditions. It was reported in Ohasama study glucose tolerance test with 75-gram glucose that WCH is a risk factor for development of was performed in cases with a FPG level home HT.6 Similarly, intima-media thickness between 110 and 126 mg/dL, and diagnosis of and cross-sectional area of carotid artery were cases with a 2-hour plasma glucose level 200 found as similar in patients with WCH and HT, mg/dL or higher is DM and 140-199 mg/dL is which were significantly higher than cases with IGT. Additionally, patients with dyslipidemia sustained normotension (NT).7 Additionally, were detected, and we used the National plasma homocysteine levels were higher, and Cholesterol Education Program Expert Panel’s left ventricle mass index was greater in WCH recommendations for defining dyslipidemic group compared to NT cases (p<0.001 in both). subgroups.8 Dyslipidemia is diagnosed when We tried to understand the role and significance LDL-C is 160 or higher and/or TG is 200 or of WCH in definition of the metabolic syndrome higher and/or HDL-C is lower than 40 mg/dL. in the present study.

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A stress electrocardiography was performed mmHg.9 Eventually, prevalences of smoking, in suspected cases via the electrocardiography excess weight, hyperbetalipoproteinemia, or any history about angina pectoris, and a hypertriglyceridemia, dyslipidemia, IGT, WCH, coronary angiography was obtained just for the DM, HT, and CHD were detected in decades and stress electrocardiography positive cases. So compared in between. Comparison of proportions CHD was diagnosed either angiographically was used as the method of statistical analysis. or with a history of coronary artery stenting and/or coronary artery bypass graft surgery. RESULTS Office blood pressure (OBP) was checked after The study included 1,068 cases (628 females a 5-minute of rest in seated position with a and 440 males). Due to the just 20 cases in the mercury sphygmomanometer on three visits, and ninth decade, they were not included for the no smoking was permitted during the previous statistical comparison. There were only 1.7% 2-hour. A 10-day twice daily measurement of (19) of cases with underweight and 28.7% (307) blood pressure at home (HBP) was obtained in with normal weight, so as a very high prevalence, all cases, even in normotensives in the office due 69.4% (742) of cases at and above the age of to the risk of masked HT after a brief education 20 years had excess weight. The prevalence 9 about proper BP measurement techniques. An of excess weight increased from 28.7% in the additional 24-hour ambulatory blood pressure third to 87.0% in the seventh decades, gradually monitoring (ABP) was obtained just in cases (p<0.05 nearly in all steps), and then decreased with a higher OBP and/or HBP measurements. to 78.5% in the eighth (p<0.05) and to 60.0% It was performed with oscillometrical equipment in the nineth decades of life. Interestingly, the (SpaceLabs 90207, Redmond, Washington, USA) prevalence of excess weight showed its most set to take a reading every 10-minute throughout significant increase during the passage from the 24-hour. Normal daily activities were the third to the fourth decades of life (28.7% allowed, and subjects were told to keep the arm versus 63.6%, p<0.001) with a similar fashion as relaxed during measurements. Eventually, HT to the smoking. Prevalence of smoking had is defined as a BP of 135/85 mmHg or greater on a significant progression during the passage 9 mean daytime (between 10 AM to 8 PM) ABP. from the third to the fourth decades of life, too WCH is defined as an OBP of 140/90 mmHg (11.0% versus 32.4%, p<0.001). As the most or greater, but mean daytime ABP of <135/85 significant finding of our study, prevalences of

Table 1. Characteristics of the study cases

Third p- Fourth p- Fifth p- Sixth p- Seventh p- Eighth Variables decade value decade value decade value decade value decade value decade

Number 181 157 246 249 108 107 Prevalence of 11.0% *** 32.4% ns† 28.8% ns 31.7% ns 23.1% ns 23.3% smoking Prevalence of 28.7% *** 63.6% *** 78.4% ns 83.1% ns 87.0% * 78.5% excess weight Prevalence of hyper- 1.6% *** 12.7% ns 15.8% ns 19.6% ns 23.1% * 14.0% betalipoproteinemia Prevalence of hyper- 5.5% *** 15.2% * 20.3% * 25.7% ns 24.0% ** 11.2% triglyceridemia Prevalence of 6.6% *** 26.7% ns 31.7% * 38.9% ns 39.8% *** 20.5% dyslipidemia Prevalence of IGT‡ 0.5% ns 1.2% *** 10.1% *** 19.6% ns 21.2% ns 15.8% Prevalence of white 23.2% ns 24.2% ** 33.3% *** 44.5% ns 40.7% ** 25.2% coat hypertension Prevalence of 0.5% ns 1.9% *** 11.7% *** 21.6% ns 25.0% ns 26.1% diabetes mellitus Prevalence of 0.0% ** 5.0% *** 10.4% *** 20.4% ** 31.4% ns 38.3% hypertension Prevalence of CHD§ 0.0% ns 0.0% * 3.6% *** 12.8% ** 22.2% ns 24.2%

*p<0.05 **p<0.01 ***p<0.001 †Nonsignificant (p>0.05) ‡Impaired glucose tolerance §Coronary heart disease

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Table 2. Mean blood pressure values of the study cases

Sustained normotension Variables WCH* (n=349) Hypertension (n=168) (n=551) Prevalence 51.5% 32.6% 15.7% Mean age (year) 38.8 ± 12.3 (15-83) 48.2 ± 11.3 (15-79) 55.3 ± 10.3 (33-85) Female ratio 57.1% (315) 63.3% (221) 65.4% (110) Mean OBP† 117.3 ± 4.7/78.3 ± 5.1 153.3 ± 5.4/97.3 ± 9.3 167.5 ± 5.6/108.3 ± 5.7 Mean HBP‡ 97.7 ± 13.3/73.1 ± 5.1 121.1 ± 5.5/74.1 ± 5.3 149.5 ± 6.3/97.3 ± 7.3 Mean ABP§ Not performed 123.7 ± 5.3/77.1 ± 5.3 150.7 ± 7.7/98.7 ± 7.3 Mean heart rate (beat/minute) 65.1 ± 11.5 (52-129) 75.3 ± 13.3 (61-149) 80.5 ± 11.3 (63-167)

*White coat hypertension, †Office blood pressure, ‡Home blood pressure, §24-hour ambulatory blood pressure monitoring

hyperbetalipoproteinemia, hypertriglyceridemia, by increasing until the seventh decade of life and dyslipidemia, IGT, and WCH had a similar decreasing afterwards (p<0.05 nearly in all steps) fashion to the excess weight by increasing until in the present study. On the other hand, prevalences the seventh decade and decreasing afterwards, of HT, DM, and CHD always continued to increase significantly (p<0.05 nearly in all steps). On without any decrease by decades (p<0.05 nearly the other hand, prevalences of HT, DM, and in all steps) indicating their irreversible natures. CHD always increased without any decrease After development of one of the final diseases, by decades, significantly (p<0.05 nearly in the nonpharmaceutical approaches will provide all steps), indicating their irreversible natures little benefit to prevent development of the others against the reversible patterns of excess weight, probably due to cumulative effects of the risk hyperbetalipoproteinemia, hypertriglyceridemia, factors on systems, especially on the endothelial dyslipidemia, IGT, and WCH. On the other hand, system for a long period of time.11,12 According to 517 cases with WCH and HT were diagnosed our opinion, obesity should be included among both via HBP and ABP, and no difference was the final diseases of the metabolic syndrome since observed between the two methods according after development of the obesity, pharmaceutical to the total number of cases diagnosed. Mean and nonpharmaceutical approaches will provide systolic/diastolic OBP, HBP, ABP values and little benefit either to heal obesity or to prevent mean heart rates of the groups were summarized its complications. in Table 2. It was reported in the literature that WCH is associated with some features of the metabolic DISCUSSION syndrome13, and more than 85% of cases with Excess weight is probably the basic underlying the syndrome have elevated BP levels in another cause of the metabolic syndrome.10 Actually, study.4 On the other hand, we observed very high the syndrome is a group of reversible and final prevalences of WCH even in early decades in the indicators for the development of systemic present study, 23.2% in the third and 24.2% in the atherosclerosis, and symptomatic atherosclerosis fourth decades of life. The very high prevalences is probably the leading cause of death for both of WCH in society were also shown by some other sexes in human beings. So definition of the authors.14-16 When we compared the sustained syndrome includes both some reversible indicators NT, WCH, and HT groups in another study17, including overweight, smoking, WCH, IFG, IGT, prevalences of nearly all of the health problems hypertriglyceridemia, hyperbetalipoproteinemia, including IGT, obesity, DM, and CHD had dyslipidemia together with some final diseases significant progressions from the sustained NT including aging, obesity, HT, DM, CHD, towards the WCH and HT groups, and the WCH PAD, stroke, COPD, and cirrhosis.11,12 For group was found as a progression step in between. example, prevalences of hypertriglyceridemia, But as an interesting finding, the prevalence of hyperbetalipoproteinemia, dyslipidemia, IGT, dyslipidemia was the highest in the WCH group, and WCH had a parallel fashion to excess weight and it was 41.6% among them versus 19.6%

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(p<0.001) of the sustained NT and 35.5% of the limitation of excess weight as an excessive HT groups’ (p<0.05).17 Similar results indicating tissue in and around abdomen under the heading the higher prevalences of dyslipidemia in WCH of abdominal obesity is meaningless, instead it cases were also observed in another study18, should be defined as overweight or obesity via against to the other study indicating serum TG BMI, since adipocytes function as an endocrine and cholesterol levels did not differ significantly organ that produces a variety of cytokines and between NT, WCH, and sustained HT cases hormones in anywhere of the body.4 The resulting in men in the literature.19 The relatively lower hyperactivity of sympathetic nervous system and prevalence of dyslipidemia in the HT group may renin-angiotensin-aldosterone system is probably be explained by the already increased adipose associated with chronic endothelial , tissue per taken fat in the already HT cases, since elevated BP, and insulin resistance. Similarly, the prevalence of obesity was significantly higher in Adult Treatment Panel III reported that although the HT against the WCH groups (p<0.01).17 So some people were classified as overweight with the detected higher prevalences of WCH even in a large muscular mass, most of them also have early decades, despite the lower prevalences of excess fat tissue, and excess weight does not excess weight in these age groups, may show a only predispose to CHD, stroke, and numerous trend of getting weight and many final diseases. other atherosclerotic consequences, it also has a Probably all of the associations are closely related high burden of other CHD risk factors including with the metabolic syndrome since WCH and dyslipidemia, type 2 DM, and HT.8 dyslipidemia may be two initial signs of the syndrome. On the other hand, we accept the CONCLUSION WCH as a different entity from borderline/mild Metabolic syndrome is a systemic HT due to the completely normal HBP and ABP atherosclerotic process terminating with PAD, values of WCH, whereas they are abnormal in CHD, stroke, and probably with cirrhosis mild HT cases, but both patients can benefit from and COPD. It contains some reversible life style modification including exercise, weight indicators including smoking, overweight, loss, animal-poor but fruit and vegetable-rich diet hyperbetalipoproteinemia, hypertriglyceridemia, with some extent. dyslipidemia, IFG, IGT, and WCH together with Excess weight probably leads to a chronic some final diseases including aging, obesity, and low-grade inflammatory process in many DM, and HT. The final diseases and terminal systems, especially the endothelial system of the consequences are probably due to the excess body, and risk of death from all causes including weight induced chronic inflammatory process cardiovascular diseases and cancers increases on systems, especially on the endothelial system parallel to the range of moderate to severe for a long period of time. WCH may be an initial 20 weight excess in all age groups. The effects of sign of the systemic atherosclerotic process that weight on BP were also shown previously that can be detected easily and prevented by a trend the prevalence of sustained NT was significantly towards weight loss. higher in the underweight (80.3%) than the normal weight (64.0%) and overweight cases (31.5%, REFERENCES p<0.05 for both) in a study21, and 55.1% of cases 1. Eckel RH, Grundy SM, Zimmet PZ. The metabolic with HT had obesity against 26.6% of cases with syndrome. Lancet. 2005;365:1415-28. 22 NT (p<0.001) in another study. So the dominant 2. Grundy SM, Brewer HB Jr, Cleeman JI, Smith SC Jr, underlying causative factor of the metabolic Lenfant C. Definition of metabolic syndrome: Report of syndrome appears as an already existing excess the National Heart, Lung, and Blood Institute/American weight or a trend towards excess weight, which Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433-8. is probably the main cause of insulin resistance, 3. Tonkin AM. The metabolic syndrome(s)? Curr dyslipidemia, IGT, and WCH.4 Even prevention Atheroscler Rep. 2004;6:165-6. of the accelerating trend of weight with diet or 4. Franklin SS, Barboza MG, Pio JR, Wong ND. Blood exercise, even in the absence of a prominent pressure categories, hypertensive subtypes, and the metabolic syndrome. J Hypertens. 2006;24:2009-16. weight loss, will probably result with resolution 5. Helvaci MR, Kaya H, Gundogdu M. Gender differences of many reversible indicators of the metabolic in coronary heart disease in Turkey. Pak J Med Sci. syndrome.23-25 But according to our opinion, 2012;28:40-4.

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