1. INTRODUCTION:

Arterial hypertension is one of the major universal health problems associated with various complications involving many organs in the human body. İt represents a main modifiable risk factor for coronary artery disease which is the leading cause of death worldwide¹. There is a wide spectrum of hypertension-related target organ damage making the expected late complications of hypertension to be various. The heart, brain, kidneys, eyes, in addition to both central and peripheral arteries, are among the main organs to be affected by hypertension². Left ventricular hypertrophy (LVH) is a well-known complication of hypertension and has been linked to various cardiovascular events including stroke, coronary artery disease, heart failure and cardiovascular mortality^3,4. LVH is classically defined by increased ventricular mass that is related to increased ventricular wall thickening or ventricular dilatation. Subclassification of LVH has been considered depending on the ratio of the left ventricular wall thickness to the diameter of the ventricular chamber where an increased ratio is designated as concentric while the decreased ratio is designated as eccentric⁵. Unexpectedly, the cardiac adaptation to pressure overload differs according to cause. While cardiac remodelling in response to physical activity is of eccentric type of LVH, the remodelling in response to hypertension is of concentric type of LVH which is a sign of poor prognosis⁶. Aside from all other risk factors of cardiovascular disease including hypertension, LVH represents a prominent predictor of morbidity and mortality related to the cardiovascular system⁷. Fortunately, in hypertensive patients, the reduction of left ventricular mass achieved by treatment with antihypertensive drugs is associated with a reduction in the risk of cardiovascular morbidity and mortality⁸. Despite the presence of specific ECG criteria, the echocardiographic examination is the gold standard diagnostic tool for the diagnosis of LVH⁹. In terms of more specificity, cardiac magnetic resonance imaging has the highest specificity for the diagnosis of LVH¹⁰. Because of the many factors that might affect the result of echocardiographic examination such as obesity and the presence of pulmonary disease¹¹, persistent attempts are present to find a reliable biomarker to assist in the diagnosis of LVH especially in the early stages¹². Various biomarkers are available, each reflects a specific type of cardiac disorder and is used as a marker for diagnosis, prognosis or both. Although there is a prominent overlap between these markers, they can be categorized into 4 major groups: biomarkers of myocardial injury, biomarkers of neurohormonal activation, biomarkers of remodelling and biomarkers of comorbidities¹³. In respect to remodelling, various biomarkers are used including TNF-α, adiponectin, Matrix metalloproteinases, MicroRNA and GDF-15¹⁴. GDF-15 is an emerging biomarker linked to various histopathological findings in cardiac muscle including inflammation, fibrosis and remodelling. It is a stress-responsive cytokine with a growing prognostic role in patients with non-ischaemic dilated cardiomyopathy for being correlated with a progressive reduction in the functional capacity of the heart in addition to its role for risk stratification of arrhythmic death in this group of patients¹⁵. Apart from the placenta, it is expressed in small quantities in most healthy tissues, although, many tissues show overexpression of GDF-15 in response to hypoxia or injury especially lung, kidneys liver and heart¹⁶. İncreasing evidence suggests that GDF-15 can be regarded as an independent prognostic marker of various cardiovascular diseases including coronary artery disease, LVH and heart failure¹⁷. Alongside its correlation with LVH, high circulating GDF-15 is shown to be associated with an irreversible remodelling in certain conditions besides its role as a predictor of increased cardiac mortality¹⁸. Angiotensin-converting enzyme (ACE) inhibitors commonly used in the treatment of hypertension are amongst the most effective drugs used in the treatment and prevention of LVH secondary to hypertension, an effect that is thought to be added to its antihypertensive effect.^19,20 For this correlation between LVH and both hypertension and ACE inhibitors, and GDF-15 being a biomarker of LVH, we intended to investigate the correlation between ACE inhibitors and ARBs with circulating GDF-15 in a group of hypertensive patients^21,22.

2. MATERIALS AND METHODS:

Materials:

2.1 Study subjects:

The current study enrolled hypertensive patients who attended a general hospital in Baghdad for routine follow up during the period between February and July 2020. Sixty individuals with essential hypertension on regular treatment with ACE inhibitors (Captopril, Lisinopril, Enalapril) or ARBs (Losartan, Telmisartan) of at least 5 years duration were randomly selected. The control group included 30 subjects who were apparently healthy.

In addition to serum GDF-15, various laboratory tests were measured in all participants to ensure that they fulfilled the exclusion criteria. These tests include:

· Complete blood count

· Fasting blood glucose

· Lipid profile

· Serum creatinine

· Blood urea

· Liver function test

2.2 Exclusion criteria:

1. Patients with any associated medical condition, related to hypertension itself or not.

2. Patients with poor compliance to treatment.

3. Patients with hypertension of fewer than 5 years.

2.3 Control group:

The control group consisted of 30 healthy persons (men and women), randomly selected from individuals attending private laboratories for routine checking. The age, weight, and body mass index (BMI) were comparable between the studied groups.

These data were statistically analyzed using SPSS software version.²³

3. RESULTS AND DİSCUSSİON:

3.1 Descriptive Statistics:

Mean BMI was 28.9kg/m²; STD. BMI was 5.4 the distribution of individuals according to BMI is shown in table 1.

The participants were classified according to their tests (CBC, Liver function, Lipids profiles, Renal function) and BMI and age into Range, mean. St. Deviation as shown in table 1.

All the parameters mentioned in table 1 were comparable among the studied groups with no significant difference detected.

The drug distribution of the participants included in the current study is shown in table 2. The initial step in the statistical analysis of data was testing of normality using Kolmogorov–Smirnov test and the Shapiro–Wilk test which showed that the data were not normally distributed making the Kruskal-Wallis test the statistical test of choice to complete the final analysis^23,24.

Table 1. Descriptive Statistics

	Mean	Std. Deviation	Range	Minimum	Maximum
Age	52.1	13.96	51	27	78
body mass (BMI)	28.9	5.4	36.55	22	58.5
PCV	38.4	7.9	46.4	8.6	55
WBC	6.6	2.5	13.85	3.15	17
Plates	231.3	81.8	527	35	562
TSB	0.6	0.1	0.5	0.4	0.9
AST	24.1	13.2	109	11	120
ALT	21.2	10.6	50	7	57
ALP	122.2	35.1	179	61	240
HDL	41.4	2.7	13	32	45
LDL	102.4	39.4	177	22	199
VLDL	34.3	13.9	70	18	88
S.CHO	156.8	42.0	222.3	11.7	234
S.TRI	130.1	41.2	173	90	263
B-Urea	33.3	5.2	25.3	16.7	42
Creatinine	0.7	0.1	0.68	0.52	1.2

Table 2. The Type of drugs

	Frequency	Percent
Captopril	9	10%
Lisinopril	13	14.44%
Enalapril	14	15.55%
Losartan	13	14.44%
Telmisartan	11	12.22%
Healthy	30	33.33%
Total	90	100%

Mean serum GDF-15 level in the studied groups was variable. The concentration of GDF-15 in the healthy group (mean=513.70, STD 115.26), the concentration of GDF-15 in ACE inhibitor group (Mean 912.912, STD 680.73) and the concentration of GDF-15 in ARBs inhibitor groups (Mean 640.65, STD 168.34) as shown in table 3.²⁵

Table 3. Descriptive concentration.GDF-15 on groups

Type Groups			Statistic
Concentration GDF-15	Conc. GDF15(healthy control)	Mean	513.7063
		Std. Deviation	115.26
		Minimum	334.64
		Maximum	673.20
	Conc.GDF15 (ACE inhibitor)	Mean	912.912
		Std. Deviation	680.73
		Minimum	253.05
		Maximum	2724.98
Conc.GDF15 (ARBs inhibitor)		Mean	640.65
		Std. Deviation	168.34
		Minimum	274.30
		Maximum	897.55

The current study has shown a higher significant difference in mean serum concertation GDF-15 of patients with ACE inhibitors compared to the healthy control group (912.912 vs 513.7, P<0.001) as shown in table 5. İn addition, there was a significant difference in mean serum GDF-15 concentration between the ARBs group and the healthy group where it was much higher in the ARBs group (640.65 vs 513.7, P 0.008), while there was no significant difference in mean GDF-15 concentration between ACE inhibitors and ARBs group (912.912 vs 640.65, P 0.474).²⁶

Table 4. Pairwise comparisons of type values

Sample 1-Sample 2	Test Statistic	Std. Error	Std. Test Statistic	Sig.	Adj. Sig.^a
conc. GDF15 control-conc GDF15-ARBs	-20.367	6.741	-3.021	.003	.008
conc. GDF15 control-conc. GDF15_ACE	-29.883	6.741	-4.433	.000	.000
conc GDF15-ARBs-conc. GDF15_ACE	9.517	6.741	1.412	.158	.474

The findings of the current study that showed a significant increase in serum level of GDF-15 in patients with hypertension have been confirmed by many similar studies that further emphasized its role as a predictor of CVD risk. İt has an independent association with subclinical atherosclerosis in addition to being a prognostic indicator of coronary artery disease^27-29. There are many aspects regarding the role of GDF-15 in hypertensive patients. For instance, higher GDF-15 levels were independently associated with non-dipper hypertension which is known to have a higher risk of CVD compared with the dipper pattern³⁰. Furthermore, GDF-15 might be of medical importance in differentiating LVH secondary to hypertension from hypertrophic cardiomyopathy as it was significantly higher in patients with hypertensive LVH compared to those with hypertrophic cardiomyopathy³¹. In addition, plasma GDF-15 level has been correlated with deterioration of physical abilities in hypertensive patients such as a prominent decline in walk distance³². In addition to its increase in sera of hypertensive patients, GDF-15 has been considered as a biomarker of renal impairment explained by its correlation with increased renal vascular resistance³³. A recent interesting study enrolling 120 patients newly diagnosed with essential hypertension has found a significant statistical correlation between serum GDF-15 and decreased aortic elasticity in the studied patients suggesting a beneficial role of this marker as a predictor of aortic β-index in patients with essential hypertension³⁴. Surprisingly, a high level of serum GDF-15 has been considered as a promising biomarker of idiopathic pulmonary hypertension in addition to being correlated with NT-proBNP and prognosis in patients who underwent right heart catheterization³⁵.

The net result of the current study has not confirmed any impact of using ACE inhibitors or ARBs as antihypertensive drugs on the level of GDF-15 in the studied patients³⁶. A similar and more obvious result has been concluded in a similar study that has a prospective aspect where a baseline GDF-15 level was taken before using an ACE inhibitor or an ARB therapy for heart failure, where both groups failed to show any impact on circulating GDF-15 after being used³⁷ although a certain study has shown that irbesartan (ARBs) can significantly lower GDF-15 expression in cardiomyocytes³⁸. Although the results of the current study have not confirmed a significant GDF-15 lowering effect of both ACE inhibitors and ARBs, it is important to compare this effect with other groups of antihypertensive drugs before excluding any possible effect of ACE inhibitors and ARBs as plasma level of GDF-15 might be higher in patients treated with other antihypertensive drugs³⁹.

4. CONCLUSION:

1. The current study has confirmed the increase in serum levels of GDF-15 in patients with essential hypertension.

2. No impact has been detected on serum on both ACE inhibitors or ARBs on serum level of GDF-15.

5. CONFLICT OF INTEREST:

Author Roaa Hatem Algburı, author and author Dr. Raıd D. Hashım and, Haydar Ahmed Kadhim, Şevki Adam, haider Abdulkareem Almashhadani, declare that they have no conflict of interest.

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Received on 22.12.2021 Modified on 06.02.2022

Research J. Pharm. and Tech. 2022; 15(8):3466-3470.

DOI: 10.52711/0974-360X.2022.00580