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Original Articles

The association between left ventricular mass index and serum sirtuin 3 level in patients with hypertension

Karayiğit, Orhana; Çelik, Muhammet Cihatb; Kiziltunç, Emrullaha; Çiçekçioğlu, Hülyaa; Topçuoğlu, Cananc; Doğanay, Birsena; Çetin, Mustafaa

Author Information
Cardiovascular Endocrinology & Metabolism: June 2021 - Volume 10 - Issue 2 - p 99-105
doi: 10.1097/XCE.0000000000000231
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Abstract

Introduction

Hypertension is a major health problem throughout the world, with estimates putting the prevalence of hypertension at approximately one billion. Furthermore, approximately 13% of deaths per year (7.1 million) occur due to hypertension-related causes [1]. Hypertension is causally related to cardiac remodeling, including left ventricular (LV) hypertrophy, myocardial fibrosis, and LV systolic and diastolic dysfunction. It increases the risk of morbidity, mortality, and sudden cardiac death due to cardiovascular diseases, such as stroke, heart failure, atrial fibrillation, and acute coronary syndromes [2].

Despite treatment with multiple drugs, the blood pressure (BP) of many hypertensive patients remains poorly controlled. This situation is likely associated with the underlying mechanisms contributing to hypertension that are unaffected by current treatments. One of these mechanisms is oxidative stress, which has been suggested to contributes to the development of hypertension and end-organ damage [3,4]. The mitochondria are an important source of superoxide radicals, and some previous studies have shown that there are dysfunctions in the mitochondria of persons with hypertension, and they have defined a novel role of mitochondrial oxygen in this disease. Furthermore, genetic manipulation of mitochondrial antioxidant enzymes has been shown to affect BP, leading to the development of mitochondria-targeted therapies that effectively lower BP [5,6].

The Sirtuins are a family of NAD+-dependent deacylases and ADP-ribosyltransferases. In mammalian cells, there are seven Sirtuins (from SIRT1 to SIRT7). Amongst the Sirtuins, SIRT3 localizes to the mitochondrial matrix, where it may function as a primary stress-responsive protein deacetylase. Recent studies have revealed that SIRT3 has beneficial effects on hypertensive heart diseases by blocking cardiac hypertrophy through activation of FOXO3-dependent antioxidants, manganese superoxide dismutase, and catalase while also suppressing the reactive oxygen species–mediated renin-angiotensin system activation and downstream mitogen-activated protein kinase (also known as extracellular signal-regulated kinase) and phosphoinositide 3-kinase/protein kinase B signaling pathways [7–9]. Additionally, in some mice models, it was demonstrated that alterations in SIRT3 levels resulted in significant increases in cardiomyocyte hypertrophy and decreases in ejection fraction [8]. In the light of such studies, overexpression or pharmacological activation of SIRT3 has emerged as a candidate therapeutic strategy for the treatment of mitochondrial disorders in various cardiac pathologies.

The aim of this study was to determine the relationship between serum SIRT3 levels and cardiac hypertrophy in patients with hypertension and to investigate the relationship between diastolic parameters such as left atrial volume, myocardial early diastolic velocity, and mitral annular contractions.

Methods and materials

Ethics statement

During the conduct of the study, the Good Clinical Practices Guidelines and the Declaration of Helsinki were followed. The study was approved by the Ethics Committee of the University of Health Sciences Ankara Numune Education and Research Center with the decision number E-18-2103 (Chairperson Prof H. Bodur) on 26 June 2018. The design of the study was an all-comers study design; all of the patients who were eligible for the study during the enrollment phase and gave informed consent for participation were included in the study.

Patient selection

This was a cross-sectional study of 83 patients with hypertension who applied to the Cardiology Clinic of Ankara Numune Training and Research Hospital from April 2018 to October 2018. Left ventricular mass index (LVMI) was calculated using the formula put forth by the American Echocardiography Association, and patients were divided into two groups; those with increased LVMI and those with normal LVMI. The inclusion criteria were as follows: being older than 18 years of age, accepting to participate in the study and receiving antihypertensive therapy or being newly diagnosed with hypertension, and starting to receive medical treatment (office blood pressure measurement according to the Eight Joint National Committee criteria ≥140/90 mmHg). Exclusion criteria were not accepting to participate in the study, being under 18 years of age, having an active infection or any type of disease-causing systemic inflammation, having chronic renal failure (serum creatinine level > 1.4 mg/dl) or chronic liver disease. Additionally, patients with diseases of the heart valves, cardiomyopathy (that could cause hypertrophy), those with atrial fibrillation, calcifications restricting fibrillary movements, secondary hypertension, and those who had a history of heart failure (ejection fraction < 50%). Finally, those who had undergone coronary artery bridging treatment or coronary revascularization with the percutaneous coronary intervention were excluded from the study.

Biochemical and laboratory analysis

The age, sex, medical history, cardiovascular risk factors, medications, physical examination findings, and laboratory analysis [including complete blood count and standard biochemical parameters, pro-brain natriuretic peptide (BNP)] of all patients were recorded electronically. BMI and body surface area of all patients were calculated. Blood samples taken for the measurement of SIRT3 were centrifuged at 4°C or 10 min at 4000 rpm and were stored until quantification was performed. Serum SIRT3 levels were measured with a commercial ELISA kit (SunRed Biotechnology Campany, Shanghai Sunred Biological Technology Co., Ltd, Baoshan District, Sanghani, China, CAT No: 201-12-2560, REF No: DZE201122560, LOT: 201811).

Echocardiographic evaluation

In the study, two-dimensional, M-mode, tissue Doppler echocardiographic parameters were obtained by using a Vivid 7 Digital ultrasound device (Horten, Norway, GE) with a 3.5-MHz S5-1 transducer. During the procedure, patients were in the left lateral position, and echocardiographic evaluation was performed on parasternal and apical images. LV dimensions, interventricular septum, and LV posterior wall measurements were obtained from the mitral leaf ends by vertical cutting of the long axis with M-mode. LV myocardial mass and LV mass index were calculated using the American Echocardiography Association formula. Septal and lateral mitral annulus systolic (Sm) and diastolic function (Em and Am) parameters were determined using isovolumetric contraction time, computed tomography, isovolumetric relaxation time tissue doppler. The myocardial performance index used for the evaluation of global left ventricular function was evaluated from the basal septal region.

Statistical analysis

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software version 20 for Windows (IBM SPSS Inc., Chicago, Illinois, USA). Normality of distribution of the continuous variables was tested using Kolmogorov–Smirnov test. Results are presented as mean ± SD for normally distributed variables and as median (interquartile range, 25–75) for abnormally distributed variables. Statistical comparisons between continuous variables were performed with independent samples t test or Mann–Whitney U test, in accordance with normality test results. Statistical comparisons of categorical variables were performed using the Chi-square test. We performed multivariate logistic regression analysis to determine independent predictors of the presence of LVH. Possible factors identified using univariate analysis (variables with an unadjusted P value < 0.10) were further involved in the logistic regression model. Spearman’s Rho was used to determine the correlation between serum SIRT3 levels and other study parameters. A P value < 0.05 was considered statistically significant.

Results

We included 83 patients (41 males and 42 females) into our study, and the mean age was 56.4 ± 10.1 years. The patients’ systolic BP ranged from 137 to 165 mmHg, the median was 150 mmHg; the diastolic BP ranged between 80 and 99 mmHg and the median was 90 mmHg.

LVMI was increased in 31 patients (37.3%); 18 (58.1%) of these patients were female, and 13 (41.9%) were male. There were no significant differences between patients with high LVMI and normal LVMI in terms of age, sex, smoking, diabetes, blood pressure levels, and BMI (Table 1).

Table 1 - Distribution of the baseline characteristics of patients in regard to left ventricular mass index
High LVMI Normal LVMI P value
N = 31 (37.3) N = 52 (62.7)
Age (year) 58.3 ± 11.3 55.2 ± 9.3 0.171
Gender 0.294
 Male 13 (41.9) 28 (53.8)
 Female 18 (58.1) 24 (46.2)
Smoking 7 (22.6) 15 (28.8) 0.805
Diabetes mellitus 5 (16.1) 11 (21.2) 0.575
SBP (mmHg) 150 (131–173) 150 (138–160) 0.654
DBP (mmHg) 85 (80–99) 90 (77–99) 0.854
BMI (kg/m2) 29.0 (26.6–33.8) 29.1 (27.0–33.3) 0.767
DBP, diastolic blood pressure; LVMI, left ventricular mass index; SBP, systolic blood pressure.

Patients with high level LVMI had lower mean total cholesterol level (189 ± 35 versus 205 ± 38 mg/dl, P = 0.048), mean total potassium level (4.2 ± 0.3 versus 4.4 ± 0.3 mg/dl; P = 0.041) than those with normal LVMI (Table 2). Patients with high level LVMI had higher median pro-BNP level (69 versus 41 ng/ml; P = 0.019) than those who normal LVMI (Fig. 1).

Table 2 - Independent predictors for left ventricular mass index in patients with hypertension
Risk factors Univariate regression Multivariate regression
OR 95% CI P value OR 95% CI P value
Potassium 0.286 0.084–0.978 0.046a
Total cholesterol 0.987 0.974–1.000 0.054 0.986 0.972–0.999 0.040a
LDL cholesterol 0.596 0.023a
pro-BNP 1.007 1.001–1.013 0.021a
Hypertension duration (>5 years) 4.861 1.531–15.436 0.007a 4.920 1.495–6.194 0.009a
Antihypertensive drug use 0.596 0.023a
CI, confidence interval; LDL, low-density lipoprotein; OR, odds ratio; pro-BNP, pro-brain natriuretic peptide.
aP < 0.05 is considered significant for statistical analyses.

Fig. 1
Fig. 1:
Relationship between left ventricle mass index and pro-BNP. pro-BNP, pro-brain natriuretic peptide.

There were no significant differences between patients with high LVMI and normal LVMI in terms of SIRT3 levels (5.8 versus 5.4 ng/ml; P = 0.914) (Fig. 2).

Fig. 2
Fig. 2:
Relationship between left ventricle mass index and serum sirtuin 3 levels.

In terms of echocardiographic findings, median left atrium diameter (3.6 versus 3.5 cm; P = 0.008), median left atrium volume index (18.4 versus 15.6 ml/m2; P = 0.034), median relative wall thickness (0.47 versus 0.44 mm; P = 0.024), basal lateral mitral annular region isovolumetric contraction time (71 versus 63 ms; P = 0.041) of patients with increased LVMI were found to be higher than those with normal LVMI. Myocardial systolic velocity, which was measured from the basal septal region, was found to be lower in patients with increased LVMI (7.5 versus 8.6 cm/s; P = 0.09) (Table 3). Additionally, a positive correlation between the SIRT3 levels and Sm velocity was determined (r = 0.338; P = 0.002); on the other hand, there was no significant relationship between SIRT3 levels and other diastolic echocardiography parameters. There was no significant relationship between SIRT3 levels and relative wall thickness (P = 0.327).

Table 3 - Distribution of the laboratory and echocardiographic parameters in regard to left ventricular mass index
High LVMI Normal LVMI P value
N = 31 N = 52
Urea (mg/dl) 30 (25–36) 32 (26–36) 0.604
Creatinine (mg/dl) 0.8 ± 0.2 0.8 ± 0.1 0.950
Sodium (mmol/L) 141 ± 2 140 ± 2 0.373
Potassium (mmol/L) 4.2 ± 0.3 4.4 ± 0.3 0.041a
Triglyceride (mg/dl) 131 (102–224) 162 (113–215) 0.225
Total cholesterol (mg/dl) 189 ± 35 205 ± 38 0.048a
HDL (mg/dl) 46 (37–59) 46 (40–55) 0.955
LDL (mg/dl) 108 ± 27 122 ± 32 0.058
Sirtuin 3 (ng/ml) 5.8 (3.2–13.0) 5.4 (3.3–10.4) 0.914
hs-CRP (mg/L) 3.0 (1.4–5.2) 2.8 (1.6–6.0) 0.989
pro-BNP (ng/ml) 69 (37–164) 41 (25–81) 0.019a
Left atrium diameter (cm) 3.6 (3.5–4.0) 3.5 (3.2–3.7) 0.008a
Left atrium volume (ml) 33 (25–41) 29 (26–35) 0.130
Left atrium volume index (ml/m2) 18.4 (14.5–22.3) 15.6 (14.3–18.7) 0.034a
Deceleration time (ms) 222 (200–250) 244 (217–312) 0.060
RWT (mm) 0.47 (0.44–0.49) 0.44 (0.40–0.47) 0.024a
MPI 0.53 (0.47–0.60) 0.4+ (0.45–0.57) 0.216
Sm (cm/s) 7.5 (6.5–8.7) 8.6 (7.8–10.0) 0.009a
Septal mitral annular region contraction time (ms) 282.7 ± 32.0 273.9 ± 26.5 0.179
Lateral mitral annular region contraction time (ms) 273.1 ± 30.4 273.6 ± 28.4 0.939
Septal mitral annular region IVCT (ms) 67 (58–75) 65 (54–75) 0.685
Lateral mitral annular region IVCT (ms) 71 (58–92) 63 (50–73) 0.041a
Septal mitral annular region IVRT (ms) 79 (63–100) 79 (67–94) 0.738
Lateral mitral annular region IVRT (ms) 71 (63–83) 72 (63–88) 0.716
E/Em ratio 8.5 (6.3–10.4) 7.2 (6.0–8.1) 0.052
E, mitral early diastolic wave; Em, myocardial early diastolic velocity; HDL, high-density lipoprotein; hs-CRP, high sensitive C-reactive protein; IVCT, isovolumetric contraction time; IVRT, isovolumetric relaxation time; LDL, low-density lipoprotein; LVMI, left ventricular mass index; MPI, myocardial performance index; pro-BNP, pro-brain natriuretic peptide; RWT, relative wall thickness; Sm, myocardial systolic velocity measured from the basal septal region.
aP < 0.05 is considered significant for statistical analyses. Normally distributed numerical variables were shown as mean ± SD. The numerical variables not showing normal distribution were shown as median (interquartile range, 25–75).

The potential risk factors associated with high LVMI were potassium level, total cholesterol level, LDL cholesterol level, pro-BNP level, hypertension duration (>5 years), and antihypertensive drug use. Accordingly, in the multivariate logistic regression model, where possible risk factors were included, total cholesterol level [odds ratio (OR) =  0.986; 95% confidence interval (CI): 0.972–0.999; P = 0.040] and the duration of hypertension (>5 years) (OR = 4.920; CI: 1.495–16.194; P = 0.009) were found to be independent predictors of higher LVMI values (Table 2).

Discussion

Hypertension is a disease with high morbidity and mortality, primarily due to damage caused to end organs, such as the heart, kidney, brain, eye, and peripheral vessels [2]. Left ventricular hypertrophy is arguably the most serious end-organ damage caused by hypertension [10]. LVMI, which is calculated by dividing left ventricular mass by the body surface area, shows hypertrophy in the early period [11]. Many studies have shown that increased LVMI leads to increased cardiovascular morbidity and mortality [12].

Recent studies suggest that SIRT3 may regulate mitochondrial function and biosynthetic pathways, such as glucose and fatty acid metabolism, and the tricarboxylic acid cycle, oxidative stress, and apoptosis through reversible protein lysine deacetylation. SIRT3 regulates glucose and lipid metabolism and maintains myocardial ATP levels, which protects the heart from metabolic disturbances. SIRT3 can also protect cardiomyocytes from oxidative stress-mediated cell damage and block the development of cardiac hypertrophy. The mitochondria melatonergic pathway is suggested to be closely associated with LV hypertrophy. Many factors like gut dysbiosis, inflammation, and stress may also adversely affect this melatonergic pathway. A decrease in mitochondrial melatonin has a number of consequences related to LV hypertrophy. Melatonin increases mitochondrial SIRT3 with resulting protection of mitochondrial functions in many cell types, so dysregulation of the mitochondrial melatonergic pathway may consequent in alterations of mitochondrial SIRT3 functions and cause LV hypertrophy [13]. In addition to LV hypertrophy, recent reports show that SIRT3 may have a protective effect against several heart diseases [9,14,15].

In our study, the relationship between LVMI and SIRT3 serum levels in hypertensive patients was evaluated. In this study, serum SIRT3 levels were found to be correlated with Sm velocity, which is an indicator of early diastolic dysfunction. However, no correlation was found between LVMI and serum SIRT3 levels.

In a study by Koentges et al. [8], it was shown that an increase in the pressure load after transverse aortic constriction led to a significant increase in cardiomyocyte hypertrophy and cardiac fibrosis in SIRT3 defective mice. Similarly, in a study by Sundaresan et al., Angiotensin-II infusion showed that cardiac contraction improved, and fibrosis degree decreased with cardiomyocyte-specific overexpression of SIRT3 [16]. However, in our study, there was no significant difference in SIRT3 levels between patients with increased LVMI and normal LVMI. Similarly, in a previous study, it was found that the values of myocardial systolic function (Sm) in the basal septal region were lower in patients with increased LVMI, which may show that the basal septal region is the first area affected by LVH in patients with hypertension [17].

All of the above-mentioned studies evaluated the effect of SIRT3 at the tissue level. SIRT3 is located in the mitochondria and is expressed by nearly all cells like adipocytes, myocytes, hepatocytes, neurons, leukocytes, muscle cells, pancreatic cells, and endothelial cells [18–22]. Although the effects of SIRT3 in particular cells have been widely investigated, there is a lack of evidence if there is any effect of circulating SIRT3 on different tissues. There exist only a few studies investigating the potential effect of the serum SIRT3 in different diseases. For example, serum SIRT3 levels were found to be higher in esophageal squamous cell carcinoma patients [23]. In another study, serum SIRT3 levels were found to be similar in acute myocardial infarction patients and control subjects [24]. In this study, we evaluated whether serum levels of SIRT3, which has a protective effect against hypertrophy at the cellular level, are related to hypertrophy, and we directly measured serum SIRT3 levels. Although our results cannot conclude about the role of myocardial SIRT3 on left ventricular hypertrophy, it is the first study evaluating the association between serum SIRT3 levels in hypertensive patients.

We also found that pro-BNP levels were higher in hypertensive patients with high LVMI. Various studies have reported similar findings; pro-BNP levels have been shown to increase in hypertensive patients and are shown to have prognostic significance in hypertensive patients with preserved ejection fraction heart failure [25,26]. In a study in which normotensive individuals without known heart disease were observed, it was found that pro-BNP levels increased before the patients were diagnosed with hypertension [27].

Limitations of the study

Our study findings should be interpreted with some caution due to the following limitations. First, the cross-sectional single-center design may cause bias. However, we believe that our strict inclusion and exclusion criteria and all-comers study design would have reduced confounding factors to a minimum. However, this also reduced the number of patients included in the study, which may be considered as the second most important limitation of our study. Another limitation is the data of hypertension degree. Most of the patients in this study did not have an ambulatory blood pressure monitoring, and only office blood pressure value is not enough to determine the hypertension degree, correctly. So, we did not evaluate if there was an association between SIRT3 and hypertension degree. Last, serum SIRT3 levels may not reflect the function and expression of the sirtuin molecule in myocytes; therefore, tissue-specific measurements and their comparison with echocardiographic and clinical findings may provide more data for the identification of the effects of sirtuins in hypertension.

Conclusion

In our study, the serum levels of SIRT3, a molecule that was suggested to have protective effects against hypertrophy in myocytes, were correlated with Sm velocity, which is an indicator of myocardial early diastolic dysfunction but no correlation was found with LVMI. Our study is one of the preliminary studies investigating serum SIRT3 levels and clinical importance of the LVMI. Further and larger studies are required to elucidate the role of sirtuins in hypertension and other heart diseases.

Acknowledgements

We would like to thank the staff of the Cardiology Department of Ankara Numune Education and Research hospital for their support. O.K., E.K., and MC.Ç. analyzed and interpreted the data and wrote the manuscript; O.K., B.D., and H.Ç. performed experiments and collected data. E.K., C.T., and M.Ç. have paid considerable attention to the critical input of the manuscript. All authors contributed to the writing and gave final approval.

Conflicts of interest

There are no conflicts of interest.

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Keywords:

hypertension; left ventricular hypertrophy; sirtuin

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