The impact of apelin and relaxin plasma levels in masked hypertension and white coat hypertension

Abstract

Masked hypertension (HTN) and white coat hypertension represent two reverse forms of clinical HTN with questionable prognostic significance. Recent evidence supports that low apelin and relaxin plasma levels contribute to vascular damage accelerating atherogenesis and predisposing to HTN and cardiovascular (CV) events. The aim of this study was to compare apelin and relaxin plasma levels between patients with masked hypertension (MH) and those with white coat HTN (WCH). Overall, 130 patients not receiving antihypertensive therapy were studied. All patients underwent 24‐hour ambulatory BP monitoring (ABPM) and office BP measurements. Plasma apelin and relaxin levels were measured by ELISA method. According to BP recordings, 24 subjects had MH (group A) and 32 had WCH (group B). Apelin (200 ± 111 pg/mL vs 305 ± 127 pg/mL, P < 0.01) and relaxin (35.2 ± 6.7 pg/mL vs 46.8 ± 23.6 pg/mL, P < 0.01) plasma levels were significantly lower in patients with MH compared to those with WCH, respectively. In conclusion, our findings showed that patients with MH had significantly lower apelin and relaxin levels compared to those with WCH. This observation implies an additional prognostic role for adipokines supporting the concept that MH is closer to essential HTN whereas WCH is a more benign condition.

1. INTRODUCTION

Currently, masked hypertension (HTN) and white coat hypertension represent two distinct yet reverse forms of arterial HTN detected in every day clinical practice with unexplored and debatable prognostic significance and outcomes.1, 2

Masked hypertension (MH) is characterized by elevated ambulatory blood pressure (BP) values and normal clinical BP measurements.3, 4 This condition is frequently associated with increased hazard for essential HTN along with other diseases including diabetes mellitus (DM). Existing evidence supports that these patients are at higher risk for target organ damage and CV morbidity similar to hypertensives.1, 5, 6

Conversely, white coat HTN (WCH) is defined as elevated office BP at repeated visits and normal out‐of‐office BP measurements.9 Numerous studies have revealed that organ damage and CV events are less prevalent compared to essential HTN.10, 11 However, other reports indicate that WCH is not entirely devoid of an increased CV event rate.12, 13

Nowadays, there is growing interest in a variety of bioactive factors secreted by adipose tissue, the so‐called adipokines, and their correlation with HTN and CV diseases. Several adipokines including apelin and relaxin have been identified.14 Apelin is considered a cardioprotective parameter because of its opposite effects to renin‐angiotensin‐aldosterone system and, thus, low levels have been associated with arterial HTN.15, 16 Moreover, apelin has been inversely correlated with the severity of coronary artery disease (CAD) and positively related with the stability of atherosclerotic plaque.19 Relaxin regulates CV function modulating BP, inflammation, cell injury/death, fibrosis, and angiogenesis. It also induces vasodilation ameliorating endothelial dysfunction in HTN.20, 21

The aim of this study was to calculate the apelin and relaxin plasma levels in patients with MH and WCH in an effort to identify an additional prognostic factor for the development of essential HTN and subsequent CV events related to these clinical entities.

2. METHODS

2.1. Study population

The study enrolled a total of 130 patients that were referred to the Hypertension Excellence Centre of our hospital. None of them was receiving any antihypertensive therapy. Subjects with secondary HTN, CAD, cardiac arrhythmias, renal failure, liver disease, cancer, thyroid disease or chronic inflammatory diseases and pregnant females were excluded. The present study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of our Hospital. A written informed consent was obtained from each participant.

2.2. BP measurements

All subjects underwent ambulatory BP monitoring (ABPM) and office BP measurements. Daytime mean BP, nighttime mean BP, and 24‐hour mean BP were measured. ABPM was performed with the patient wearing a BP measuring device on the non‐dominant arm for 24 hours. BP was measured every 15 minutes in daytime and 30 minutes in nighttime. Any symptoms and events that might influence BM were recorded. If at least 70% of them were not satisfactory, ABPM was repeated.

Office BP was the average of two measurements spaced 1‐2 minutes that were carried out on the right arm in the supine position after the subject had rested for 3‐5 minutes. All measurements were performed by the same trained nurse that was not aware of patient's history.

2.3. Definitions

Masked hypertension was defined as office BP <140/90 mm Hg and 24‐hour mean BP >130/80 mm Hg and/or daytime mean BP ≥135/85 mm Hg and/or nighttime mean BP >120/70 mm Hg. WCH was defined as office BP ≥140/90 mm Hg and 24‐hour mean BP <130/80 mm Hg and daytime mean BP <135/85 mm Hg and nighttime mean BP <120/70 mm Hg.3, 22 BMI was calculated as bodyweight in kilograms divided by height in meters squared and was estimated for all participants.

2.4. Laboratory assessment

Blood sampling was performed after 12‐hour overnight fasting. Plasma apelin and relaxin levels were measured by ELISA method. Concentrations of total cholesterol (TC), low‐density cholesterol (LCL‐C), high‐density cholesterol (HDL‐C), and triglycerides (TG) were calculated by standardized enzymatic methods as well.

2.5. Statistical analysis

Continuous variables were expressed as mean values ± standard deviations (SD). Comparisons of continuous variables were performed by one‐way analysis of variance (ANOVA). Categorical data were expressed as absolute and relative frequencies. All data were analyzed using Statistical Package for the Social Sciences (SPSS) version 18.0 and P‐value <0.05 was considered statistically significant.

3. RESULTS

Of 130 patients, 24 subjects had MH (group A) and 32 had WCH (group B). There were no differences regarding age, gender, BMI, and lipid profile between the two groups. ABPM readings showed that 24‐hour systolic (146 ± 5 mm Hg vs 129 ± 8 mm Hg, P < 0.01) and diastolic BP values (88 ± 5 mm Hg vs 79 ± 6 mm Hg, P < 0.01) were significantly greater in MH group compared to WCH group. On the contrary, office systolic (135 ± 9 mm Hg vs 145 ± 8 mm Hg, P = 0.4) and diastolic BP values (86 ± 4 mm Hg vs 92 ± 3 mm Hg, P = 0.2) were higher in patients with WCH, but the differences were not statistically significant.

In terms of laboratory measurements, apelin (200 ± 111 pg/mL vs 305 ± 127 pg/mL, P < 0.01) and relaxin plasma levels (35.2 ± 6.7 pg/mL vs 46.8 ± 23.6 pg/mL, P < 0.01) were significantly lower in MH group compared with WCH group. All data are presented in Table 1.

Table 1.

Demographic, clinical and laboratory data of patients with MH and WCH

	Group A MH (n = 24)	Group B WCH (n = 32)	P‐value
Age (y)	46 ± 7	42 ± 5	0.3
Males	11	20	0.8
BMI (kg/m2)	25.9 ± 2.1	26.7 ± 2.4	0.6
Office SBP (mm Hg)	135 ± 9	145 ± 8	0.4
Office DBP (mm Hg)	86 ± 4	92 ± 3	0.2
24‐hour SBP (mm Hg)	146 ± 5	129 ± 8	<0.01
24‐hour DBP (mm Hg)	88 ± 5	79 ± 6	<0.01
Total cholesterol (mg/dL)	234 ± 26	232 ± 25	0.7
HDL‐C (mg/dL)	43 ± 6	42 ± 4	0.6
LDL‐C (mg/dL)	125 ± 20	114 ± 21	0.6
Triglycerides (mg/dL)	111 ± 22	100 ± 21	0.7
Apelin (pg/mL)	200 ± 111	305 ± 127	<0.01
Relaxin (pg/mL)	35.2 ± 6.7	46.8 ± 23.6	<0.01

BMI, body mass index; DBP, diastolic blood pressure; HDL‐C, high‐density lipoprotein; LDL‐C, low‐density lipoprotein; MH, masked hypertension; SBP, systolic blood pressure; WCH, white coat hypertension.

Linear regression analysis showed strong correlation between apelin and relaxin plasma levels with systolic BP in both MH and WCH patients (Figure 1).

Figure 1.

Linear regression analysis of apelin (A) and relaxin (C) plasma levels in relation to SBP in MH patients and of apelin (B) and relaxin (D) plasma levels in relation to SBP in WCH patients. MH, masked hypertension; SBP, systolic blood pressure; WCH, white coat hypertension

4. DISCUSSION

The major finding in this study was that patients with MH had significantly lower apelin and relaxin levels compared to those with WCH. This observation might be correlated with increased incidence of HTN and CV events in MH group confirming the notion that MH is closer to essential HTN whereas WCH is a more benign condition.

Masked hypertension is linked to target organ damage and poor CV prognosis.23 Available data indicate that risk for future occurrence of CV events is approximately twofold higher in MH patients compared to normotensives and similar to hypertensives.1, 8 This condition has also been correlated with markers of target organ damage such as increased aortic pulsed wave velocity and urinary albumin‐to‐creatinine ratio along with greater risk for CV events and mortality.24 The estimated prevalence ranges from 10% to 18% and several factors including smoking, alcohol consumption, physical activity, exercise‐induced HTN, anxiety, job stress, obesity, DM, chronic kidney disease (CKD), and family history of HTN seem to predispose to this entity.1, 3, 8 In the current study, 24 out of 130 subjects had MH reflecting the estimated prevalence worldwide. Moreover, none of them was receiving antihypertensive therapy since all of them were unfamiliar with their condition prior to enrollment.

In general, patients with WCH are at higher risk for developing essential HTN compared to normotensives. Existing data correlate this condition with several risk factors such as higher serum TC, TG, uric acid, glucose values, waist circumference, and BMI. An independent association between WCH and left ventricular hypertrophy, diastolic dysfunction, carotid intima‐media thickening, renal damage, micro‐ and macro‐vascular alterations has also been reported.2, 13 The overall prevalence ranges from 9% to 16% and runs up to 32% among hypertensives involving mostly female, non‐smokers, and older patients.3, 8, 25 In this study, 32 out of 130 untreated patients had WCH according to the BP measurements. However, there were no differences regarding age, gender, BMI, and lipid profile with those with MH.

It is well established that adipose tissue is no longer just a triglycerides‐storage depot. It is considered an endocrine organ that plays a crucial role in CV function and development of essential HTN through the release of adipokines such as apelin and relaxin.26

Apelin has cardioprotective and positive inotropic effects. This hormone conduces to nitric oxide (NO)‐dependent vasodilation and prevents vasoconstriction caused by angiotensin II.26, 27 Low levels have been correlated with HTN, CAD, and heart failure.15, 16, 17, 18 According to a recent meta‐analysis, circulating apelin was significantly decreased in hypertensives compared to normotensives, especially in Caucasian populations.17 Another study also demonstrated that subjects with MH had lower apelin levels compared to those with normal BP.30 Reduced plasma values have been observed in CAD patients highlighting the atheroprotective role of this adipokine against CAD development and progression.31 In our study, MH group had significantly lower apelin levels in comparison with WCH group. This finding underlines the potential role of apelin in the development of HTN and CV events in MH patients supporting the concept that these patents have worst CV prognosis compared to WCH counterparts.

Relaxin is a pleiotropic hormone with positive chronotropic and inotropic effects that triggers NO, vascular endothelial growth factors (VEGFs), and matrix metalloproteinases (MMPs) release and inhibits endothelin and angiotensin II.32, 33 In terms of HTN, relaxin levels are significantly lower in hypertensives34 and patients with MH30 compared to normotensives. Nonetheless, a recent trial of 117 patients with acute heart failure revealed that greater admission relaxin values were correlated with pulmonary HTN and right heart overload.35 A cross‐sectional study also concluded that plasma levels were higher in patients with acute myocardial infarction (AMI) identifying it as a biomarker for early detection of AMI.36 This study showed that relaxin levels were significantly lower in MH group compared to WCH group contributing potentially to the development of essential HTN.

4.1. Limitations

The present study had several limitations. First, it was a single center study. Second, the number of recruited patients was relatively small. Third, it was a cross‐sectional study and there were no follow‐up data.

5. CONCLUSIONS

Our findings suggest that subjects with MH have significantly lower apelin and relaxin levels compared to those with WCH. This observation implies an additional prognostic significance for future HTN and CV events confirming the concept that MH is closer to essential HTN whereas WCH is a more benign condition. Even though close monitoring including ABPM and recurrent examinations for target organ damage is the gold standard to estimate CV risk in these patients, plasma apelin and relaxin levels could potentially be used as biomarkers for early detection of essential HTN and concomitant CV events.

DISCLOSURES

None.

Sanidas E, Tsakalis K, Papadopoulos DP, et al. The impact of apelin and relaxin plasma levels in masked hypertension and white coat hypertension. J Clin Hypertens. 2019;21:48–52. 10.1111/jch.13449