Gereç ve Yöntem: Bu kesitsel çalışmada kardiyoloji polikliniğine başvuran hipertansiyon hastaları değerlendirildi. Ofiste ölçülen kan basıncı değerlerinin; sistolik kan basıncı ≥140 mmHg ve/veya diyastolik kan basıncı ≥90 mmHg olması ya da hastanın antihipertansif tedavi alması hipertansiyon olarak tanımlandı. Tüm hastaların 24 saatlik ambulatuvar kan basıncı ölçümü yapıldı. Hastalar DHT ve NDHT olarak iki gruba ayrıldı. Hastaların ekokardiyografisi yapıldı ve bu hastalardan alınan kan örneklerinde serum OPN düzeyi Elisa yöntemi ile ölçüldü.

Bulgular: Çalışmaya 40 DHT ve 40 NHDT olan hasta dahil edildi. Bu hastalarda serum OPN düzeylerinde anlamlı farklılık saptandı (NDHT: 215.5±114.4, DHT: 152.1±92.7 p=0,008). NDHT grubunda, DHT grubuna göre sol ventrikül kütlesinde ve sol atriyum çapında istatiksel olarak anlamlı bir fark saptandı (İnterventriküler septum; NDHT: 11.6±1.2, DHT: 10.3±1.5 p<0.001 sol ventrikül kütlesi; NDHT:175±40.7, DHT: 159.3±36.3 p<0.001, sol atriyum; NDHT: 37.9±3.9, DHT: 33.5±3.3 p<0.001). NDHT grubunda, DHT grubuna göre total kolesterol düzeyi istatiksel açıdan anlamlı olarak daha yüksek bulundu (NDHT: 209.1±28.2, DHT: 189.7±33.2 p=0.006).

Sonuç: Çalışmamızda NDHT grubunda, serum OPN düzeyinin DHT grubuna göre daha yüksek olduğu saptanmıştır.

Rather than the classic cardiovascular risk factors, other risk factors such as inflammation, pro-thrombotic factors, and gene mutations have recently been shown as treatment targets for CVD ^10,11. In a series of experimental animal studies, an increase was observed in osteopontin (OPN) expression in aortic tissues with HT, and OPN expression was shown to be related to systolic blood pressure ¹². OPN also plays an important role in the correction of cardiac hypertrophy with matrix metalloproteinase (MMP) as a response to chronic pressure loading ^13,14. OPN has a functional role in ischaemic heart diseases, hypertension, heart failure, dilated cardiomyopathy, atherosclerosis and various cardiomyopathies, and several other cardiac diseases. Many stimuli, including cytokines (IL-10, MCSF), oxidized LDL, angiotensin II, hyperglycemia, hypoxia, and epigenetic mechanisms stimulate the expression of OPN ^15-19.

OPN is a pro-inflammatory cytokine and is effective in the formation of the cell-mediated immune response ^20-23. In the light of these data, the aim of this study was to investigate the potential relationship of serum OPN levels with changes in nocturnal blood pressure values in DHT and NDHT patients.

Subjects: This case-control study was conducted by evaluating patients with who admitted to the Cardiology outpatient clinic between and were newly diagnosed or had been previously diagnosed with hypertension.

Before measuring the blood pressure (BP) of the patients, they were asked for at least 10 minutes of rest and had been instructed to avoid physical exercise, eating, and smoking for at least 30 mins. HT was defined as systolic blood pressure (SBP) ≥140 mmHg and/or diastolic blood pressure (DBP) ≥90 mmHg, or the patient receiving anti-hypertensive treatment. 24-hour ambulatory BP monitorisation was applied to these patients. With the measurements performed with the ambulatory blood pressure monitoring, the diagnoses were made of DHT when there was a decrease of ≥10% in the nocturnal BP value compared to the daytime value, and NDHT when the decrease was <10%. All participants were devited in to two groups as DHT and NDHT. Study exclusion criteria were; coronary artery disease history, chronic renal failure (serum creatinine level ˃ 2.0 mg/dL), diabetes mellitus (type 1 or type 2), ejection fraction ˂50%, cardiomyopathies (ischemic and other cardiomyopathies), secondary hypertension (eg. pheochromocytoma, aorta coarctation, renal parenchymal and renovascular diseases, endocrine diseases), familial hyperlipidemia, liver failure (acute or chronic), cerebrovascular diseases (ischemic or hemorrhagic), significant heart valve diseases (regurgitation or stenosis), atrial fibrillation, patients with active infectious disease or inflammation and patients for whom ambulatory BP measurements could not be performed for technical reasons (extremely obese).

Laboratory Measurements: In newly diagnosed patients, the average of 3 consecutive measurements taken at 5-min intervals was accepted as the clinical BP value. The BP measurement was taken using a mercury blood pressure device with an appropriately sized cuff. Ambulatory 24-hour BP was monitored in all the patients. Together with the BP records, venous blood samples were taken from the patients after at least 8 hours fasting. Plasma glucose, creatinine, total cholesterol, triglycerides, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and full blood count were examined from the blood samples. Then, transthoracic echocardiographic measurements were performed for all the patients.

Ambulatory Blood Pressure Measurement: The blood pressure measurements were taken with a portable digital recording device by placing an appropriatly sized cuff on the upper part of the left arm in an appropriate position (AND A&D Medical Doctor Pro3 1-243 Asahi, Kitamo-shi, Saitama 364-8585 JAPAN). The device was set to take measurements every 20 mins from 08:01 to 22:59 and every 30 mins from 23:00 to 08:00. The device was also set to automatically reduce pressure at the rate of 3 mmHg. It was explained to the patients that they should continue with normal daily activities, avoid intense exercise, and remain still while the measurement was taken. Patients were also asked to record unusual events and duration of sleep during the day.

Blood Sample Collection: The blood samples were withdrawn into tubes not containing anticoagulant. After being left at room temperature for a minimum of 30 mins and maximum 2 hours, the tubes were centrifuged at 4000 xg for 15 mins. The serum samples obtained were placed in Eppendorf tubes and stored at -80°C until assay of the biochemical parameters.

The OPN levels in the serum samples were examined with the ELISA method according to the manufacturer’s instructions (Sunred Biotechnology Company. Human Osteopontin ELISA Kit, Catalog Number: 201-12-1526).

Statistical Analysis: Data obtained in the study were analyzed statistically using SPSS vn. 21 software (Statistical Package for Social Sciences). Descriptive statistics were stated as arithmetic mean±standard deviation (SD) for numerical variables and as number (n) and percentage (%) for categorical variables. Conformity of the variables to normal distribution was assessed with the Kolmogorov-Smirnov test. The parametric independent samples t-test was used in the comparisons of variables showing normal distribution. The Chi-square test was used in the comparisons of categorical data. A value of p<0.05 was accepted as statistically significant in all the analyses.

We calculated our sample size before enrollment of participants and found 80 participants were enough for 0.5 type-1 error and 95% confidence interval with 80% of power.

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Table 1: Demographic characteristics of the patients

In the echoocardiographic evaluation, a significant difference was determined between the groups in respect of left ventricular systolic and end diastolic diameter, and ejection fraction. The interventricular septum (IVS) and posterior wall (PW) thickness values, left atrium diameter, LV mass, and LV mass index values were significantly higher in the patients with NDHT compared to the DHT group (Table 2).

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Table 2: Echocardiographic parameters

The mean of 24-hour systolic BP was 152.05 mmHg (±6.35) in the NDHT group, and 154.45 mmHg (±7.21) in the DHT group (p=0.125). The mean of 24-hour diastolic BP was 86.65 mmHg (±9.25) in the NDHT group, and 91.85 mmHg (±9.60) in the DHT group (p=0.012). The groups were evaluated in terms of mean daytime and nocturnal systolic and diastolic BP. The daytime mean systolic BP was 154.15 mmHg (±6.66) in the NHDT group, and 159.52 mmHg (±7.72) in the DHT group (p=0.010). The daytime mean diastolic BP was 87.02 mmHg (±12.5) in th NHDT group, and 95.65 mmHg (±12.34) in the DHT group (p=0.003). The nocturnal mean systolic BP was 145.45 mmHg (±6.20) in the NHDT group, and 134.55 mmHg (±7.71) in the DHT group (p˂0.001). The nocturnal mean diastolic BP was 85.50 mmHg (±8.44) in the NHDT group, and 78.82 mmHg (±9.15) in the DHT group (p=0.001) (Table 3 and Figure 1).

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Table 3: Ambulatory blood pressure values

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Figure 1: Change in systolic blood pressure between the groups

A statistically significant difference was found between the groups in respect of total cholesterol and triglyceride levels. The total cholesterol level was determined to be 209.15 (±28.24) mg/dL in the NDHT group, and 189.72 (±33.25) mg/dL in the DHT group (p=0.006). The triglyceride level was 184.67 (±61.10) mg/dl in the NDHT group, and 143.45 (±60.52) mg/dL in thee DHT group (p=0.003) (Table 4).

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Table 4: Comparisons of the laboratory parameters of the groups

The mean OPN value was 215.50 (±114.44) pg/ml in the NDHT group and 152.12 (±92.76) pg/ml (p=0.008) in the DHT group, which was significantly higher in the NDHT group when compared (Table 5 and Figure 2).

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Table 5: Osteopontin levels of the groups

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Figure 2: Osteopontin levels of the groups

The circadian blood pressure changes occur due to the hormones that form the autonomic nervous system (sympathetic and parasympathetic nervous system, vasopressin, acetylcholine, adrenocorticotropic hormone, cortisol, insulin, ghrelin, adiponectin, and leptin, and partially the renin-angiotensin-aldosterone system). These fluctuations in hormone levels are responsible for higher BP during the day and lower BP at night. There are several potential mechanisms that are responsible for nocturnal hypertension; increased sympathetic nervous system activity, hyperactivity of the renin-angiotensin-aldosterone system, sodium retention, renal dysfunction, obstructive sleep apnea syndrome and other sleep disorders, obesity, inflammation, ageing, stress, and diabetes. Nocturnal hypertension may be the first symptom of sympathetic hyperactivity, and this is generally associated with adverse cardiovascular events (stroke, coronary artery disease, heart failure) or other target organ damage (renal failure, cognitive disorder, peripheral artery disease) ²⁵.

Target organ damage and endothelial dysfunction are seen more often in nocturnal hypertension. Therefore, the determination of the risk factors and treatment directed at the potential mechanisms of nocturnal hypertension are extremely important in respect of morbidity and mortality.

OPN is a matricellular protein without collagen that is mainly located in the bone matrix and encoded by the SPP1 gene. OPN plays a role in the proliferation and migration of smooth muscle and the re-shaping of endothelial cells. It functions as a chemotactic molecule to encourage migration of inflammatory cells to an injured region, and as an adhesive protein to keep the cells in the region. At the same time, OPN functions as a pro-inflammatory cytokine, and can modulate the immune response by increasing the expression of Th 1 cytokines and matrix degrading enzymes ²⁶.

Inflammation and immune system activation have been shown to lead to high blood pressure ²⁷. The plasma level of OPN, which is a pro-inflammatory mediator, has been reported to be associated with systolic blood pressure ⁹.

In many studies, OPN has been shown to be effective in remodelling the heart in clinical conditions such as myocardial infarction and heart failure ^28,29. Moreover, OPN plays an important role in mediating remodelling caused by hypertension has been revealed in the literature (30). Some studies have shown that OPN is expressed in various cell types, including cardiac myocytes, fibroblasts, and myofibroblasts ³¹. Therefore, OPN has been associated with pathophysiological processes such as CVDs, the inflammatory process, biomineralisation, cell vitality, and wound healing ³². OPN is also known to increase cardiac atrophy and heart failure because of myocardial remodelling probably due to biomechanical stress ²⁹.

It has been reported that because of the nocturnal pressure burden, patients with NDHT are at greater risk of developing left ventricular hypertrophy, left atrial dilatation, and left ventricular diastolic dysfunction ³³. In the echocardiography examinations of this study, it was found that the interventricular septum and posterior wall thicknesses and the left atrial dimensions were significantly higher in the NDHT group. LV mass and LV mass indices wewre also significantly higher in the NDHT group.

Our study has some limitations. First of all, this was a single-center study, so our sample size was relatively small. As a second limitation, inflammatory markers other than OPN were not measured; and lastly, this was a cross-sectional study therefore we could not speculate about pathogenetic relationship or prognostic effect of OPN in patients with NDHT. The actual mechanism of OPN or its potential prognostic effect have to be studied by prospective and randomized trials.

In conclusion, we found that serum OPN levels were significantly higher in NDHT group compared to DHT group. Future studies are warranted for OPN’s role as a potential marker in this particular population.

1) Stanaway JD, Afshin A, Gakidou E, et al. Global, regional, and national comparative risk assessment of 84 behavioural, environmental and occupational, and metabolic risks or clusters of risks for 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2018; 392: 1923-1994.

2) Pickering TG. The clinical significance of diurnal blood pressure variations. Dippers and nondippers. Circulation 1990; 81: 700-702.

3) Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-1913.

4) O'Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013; 31: 1731-1768.

5) Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Cardiology (ESC) and the European Society of Hypertension (ESH) Eur Heart J 2018; 39: 3021-3104.

6) Tilea I, Petra D, Ardeleanu E, Hutanu A, Varga A. Clinical conditions and predictive markers of non-dipper profile in hypertensive patients. Acta Marisiensis Seria Medica 2018; 64: 10-16.

7) Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. New England Jjournal of Medicine 2000; 342: 836-843.

8) Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation 2019; 140: 563-595.

9) Grundy SM, Stone NJ, Bailey AL, et al. Cardiology/American Heart Association task force on clinical practice guidelines. Circulation 2019; 139: 1082-1143

10) Dhindsa D.S., Sandesara P.B., Shapiro M.D., Wong N.D. The Evolving Understanding and Approach to Residual Cardiovascular Risk Management. Front Cardiovasc Med 2020; 7: 88.

11) Kim KI, Lee JH, Chang HJ, et al. Association between blood pressure variability and inflammatory marker in hypertensive patients. Circ J 2008; 72: 293-298.

12) Seo KW, Lee SJ, Ye BH, et al. Mechanical stretch enhances the expression and activity of osteopontin and MMP-2 via the Akt1/AP-1 pathways in VSMC. J Mol Cell Cardiol 2015; 85:13-24.

13) Xie Z, Singh M, Singh K. Osteopontin modulates myocardial hypertrophy in response to chronic pressure overload in mice. Hypertension 2004; 44: 826-831.

14) Singh K, Balligand JL, Fischer TA, Smith TW, Kelly RA. Glucocorticoids increase osteopontin expression in cardiac myocytes and microvascular endothelial cells. Role in regulation of inducible nitric oxide synthase. J Biol Chem 1995; 270: 28471-28478.

15) Shirakawa K, Endo J, Kataoka M, et al. IL (Interleukin)-10-STAT3-galectin-3 axis is essential for osteopontin-producing reparative macrophage polarization after myocardial infarction. Circulation 2018; 138: 2021-2035.

16) Shirakawa K, Sano M. Sodium-glucose Co-transporter 2 inhibitors correct metabolic maladaptation of proximal tubular epithelial cells in high-glucose conditions. Int J Mol Sci 2020; 21: 7676.

17) Kusuyama T, Yoshiyama M, Omura T, et al. Angiotensin blockade inhibits osteopontin expression in non-infarcted myocardium after myocardial infarction. J Pharmacol Sci 2005; 98: 283-289.

18) Xie Z., Pimental D.R., Lohan S., et al. Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: Role of p42/44 mitogen-activated protein kinase and reactive oxygen species. J Cell Physiol 2001; 188: 132-138.

19) Lamort AS, Giopanou I, Psallidas I, Stathopoulos GT. Osteopontin as a link between inflammation and cancer: the thorax in the spotlight. Cells 2019; 8: 815.

20) Kaleta B. The role of osteopontin in kidney diseases. Inflamm. Res. Off. J. Eur. Histamine Res. Soc 2019; 68: 93–102.

21) Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem 2018; 59: 17-24.

22) Cho HJ, Cho HJ, Kim HS. Osteopontin: A multifunctional protein at the crossroads of inflammation, atherosclerosis, and vascular calcification. Curr Atheroscler Rep 2009; 11: 206-213.

23) Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet 2005; 365: 217-223.

24) Ino‐Oka E, Yumita S, Sekino H, et al. The effects of physical activity and autonomic nerve tone on the daily fluctuation of blood pressure. Clinical and Experimental Hypertension 2004; 26: 129-136.

25) Tadic M, Cuspidi C, Grassi G, Mancia G. Isolated nocturnal hypertension: What do we know and what can we do? Integrated Blood Pressure Control 2021; 13: 63-69.

26) Lund SA, Giachelli CM, Scatena M. The role of osteopontin in inflammatory processes. Journal of Cell Communication and Signaling 2009; 3: 311-322.

27) Scatena M, Liaw L, Giachelli CM. Osteopontin: A multifunctional molecule regulating chronic inflammation and vascular disease. Arteriosclerosis, Thrombosis, and Vascular Biology 2007; 27: 2302-2309.

28) Caesar C, Lyle AN, Joseph G, et al. Cyclic strain and hypertension increase osteopontin expression in the aorta. Cell Mol Bioeng. 2017; 10: 144-52.

29) Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clinical Biochemistry 2018; 59: 17-24.

30) Podzimkova J, Palecek T, Kuchynka P, et al. Plasma osteopontin levels, but not its myocardial expression, reflect heart failure severity in recently diagnosed dilated cardiomyopathy. Herz 2020; 45: 105-110.

31) Cheong KI, Leu HB, Wu CC, et al. The clinical significance of osteopontin on the cardiovascular outcomes in patients with stable coronary artery disease. Journal of the Formosan Medical Association 2023; 122: 328-337.

32) Yang Y, Wang Y, Gao PJ. Osteopontin associated with left ventricular hypertrophy and diastolic dysfunction in essential hypertension. Journal of Human Hypertension 2020; 34: 388-396.

33) Verdecchia P, Angeli F, Mazzotta G, Gentile G, Reboldi G. Home blood pressure measurements will not replace 24-hour ambulatory blood pressure monitoring. Hypertension 2009; 54: 188-195.