Masked hypertension is associated with end organ damage in geriatric age: Geriatric MASked Hypertension and End organ damage (G-MASH-End organ Study)

Abstract

Purpose: It is a question whether masked hypertension (MH) leads to end-organ damage in the geriatric age group. The aim of this study is to evaluate the associations between MH and end-organ damage such as left ventricular hypertrophy (LVH) and proteinuria in geriatric population.

Materials and methods: One hundred and two patients who were admitted to the outpatient clinic were included in the study. These patients were also included in the GMASH-Cog study in 2016, which examined the relationship between MH and cognitive function. All patients underwent ambulatory blood pressure measurement procedures. Cardiac functions of all patients were determined by echocardiography. Spot urine albumin/creatinine ratio (ACR) was measured in all patients.

Results: Forty four of 102 patients (43%) were diagnosed with MH. ACR was 9.61 mg/gr in the MH group and 7.12 mg/gr in the normal group (p = .021). In addition, left ventricular mass index (LVMI) was found to be higher in the MH group than in the normal group. Mean LVMI scores were 107.76 ± 16.37 in patients with MH and 100.39 ± 19.32 in the normotensive group (p = .046).

Conclusion: MH is associated with end-organ damage in geriatric patients. Urinary albumin excretion and LVH which are the parameters of end-organ damage were significantly higher in MH patients. MH may cause end-organ damage and should not be overlooked in geriatric patients.

Keywords:

• Masked hypertension
• proteinuria
• hypertrophy
• left ventricle

Introduction

Masked hypertension (MH) is diagnosed when the patients blood pressure is lower than 140/90 mmHg in office measurements, but the average of ambulatory blood pressure values are higher than the normal limits described in ESC2013 and ESC2018 guidelines [1,2].

In the literature, the effects of uncontrolled MH on left ventricular mass index (LVMI) and proteinuria have been examined. In these studies, patients with chronic renal damage were enrolled into the follow-up. Patients who were diagnosed with MH by ambulatory blood pressure measurement were shown to have cardiovascular and renal morbidity rates similar to those who were diagnosed with hypertension during long-term follow-up [3–7]. In a meta-analysis, when the long-term effects of masked uncontrolled hypertension and controlled hypertension were examined, it was shown that masked uncontrolled hypertension carries greater risk in cardiovascular events and all-cause mortality in all ethnic groups [8]. In a similar study, uncontrolled MH was shown to be riskier in older patients than controlled hypertension [9]. In a study of 436 patients with chronic kidney disease, a 24-hour ambulatory blood pressure measurement was shown to be a more effective method of predicting end-stage renal failure and cardiovascular event development compared to office measurements [10]. However, the effects of MH on end-organ damage in the geriatric population, regardless of chronic kidney disease, are not clearly known. This is a novel area of research. In various studies, patients with chronic renal damage were investigated [11,12]. However, there are no studies investigating the end-organ damage in geriatric patients who have not yet been diagnosed with hypertension and who do not have chronic kidney damage.

Purpose

In this study, we aimed to calculate the ratio of spot urinary albumin/creatinine, calculate the LVMI, and examine whether there is a difference between the MH group and the normotensive group in terms of these two parameters indicating end organ damage in the geriatric age group.

Materials and methods

The study was conducted in a geriatric medicine outpatient clinic of a university hospital between December 2015 and May 2016. Consecutive 1555 patients, who were all Caucasians, admitted during the study period were examined. The details of the method are described in detail in G-MASH-Cog study [13]. Patients with known hypertension and those using any antihypertensive medication were excluded. After applying exclusion criteria, consecutive 102 patients (60 female/42 male) aged 65 years with an office blood pressure measurement lower than140/90 mmHg, who did not meet the exclusion criteria, and agreed to participate in the study were included after receiving written and verbal informed consent.

After 12 h of fasting, antecubital vein blood samples were taken for the laboratory examinations of the patients. Laboratory tests included haemoglobin, creatinine, BUN, ALT, fasting plasma glucose, TSH, spot urine albumin/creatinine ratio, serum iron, sodium, potassium, chlorine, calcium, phosphorus, uric acid, vitamin D level, folic acid, ferritin, and saturated iron-binding capacity. Spot urine albumin/creatinine ratio above 30 mg/g was accepted as microalbuminuria.

All patients underwent transthoracic echocardiography (ECHO). Echocardiography was performed by General Electric Vivid S5 model. Echocardiographic parameters of patients, ascending aorta diameter, left ventricular diastolic and systolic end diameter, right ventricular diastolic width, pulmonary artery pressure, insufficiency of heart valves, strictures, diastolic posterior wall and diastolic septum thickness and diastolic dysfunction parameters were recorded in each patient. There are many formulas for calculating LVMI by using echocardiography. The calculation of the formula requires the measurement of left ventricular end-diastolic diameter, left ventricular posterior wall thickness, left ventricular diastolic septum thickness, and left ventricular end-diastolic diameter. In addition, patients’ height and weight were recorded for calculation of body surface areas. The LVMI formula used in this study is shown below.

LV Mass (g) = 0.8{1.04[([LVEDD + IVSd + PWd]³ − LVEDD³)]} + 0.6 [14]

where, LVEDD: LV end-diastolic dimension (mm), IVSd: Interventricular septal thickness at end-diastole (mm), PWd: Posterior wall thickness at end-diastole (mm), 1.04: Specific gravity of the myocardium (g/cm3), Weight: Weight (kg or lb), Height: Height (cm or in), LV Mass Index Formula: LV Mass/Body Surface Area.

The ambulatory blood pressure measuring device was a CONTEC ABPM 50 device. The details of the method are described in detail in G-MASH-Cog study. Patients with mean blood pressure above the reference values for ABPM were included in the MH group. Patients with normal blood pressure values according to reference values were considered as the normotensive control group.

Statistical analyses

Statistical analyses were performed by using SPSS software version 15.0. The variables were evaluated by visual (histograms, probability plots) and analytical methods (Kolmogorov–Smirnov/Shapiro–Wilk test) to determine whether or not they are normally distributed. Descriptive analyses were presented using means and standard deviation (mean ± SD) for normally distributed variables, and by median, minimum–maximum values for skew distributed variables. Categorical variables were expressed as numbers and percentages (%). For comparison between groups, Mann–Whitney U test and t-test were used for continuous variables, and Chi-square test was used for categorical variables. A multiple linear regression model was used to identify independent predictors of LVMI. For the multivariate analyses, the possible factors identified with univariate analyses were further entered into the logistic regression analysis to determine independent predictors of microalbuminuria. Linear regression analyses were also conducted to analyse the independent effect of MH and comorbidities on end organ damage. A 5% type-I error level was used to infer statistical significance.

Results

One hundred and two patients were included in the study. Demographic characteristics of the participants are given in Table 1. Forty two of the patients were male (41.2%) and the mean age was 71.9 ± 5.7 years. There was no statistically significant difference between the MH and normotensive groups in terms of age, gender, body mass index, other demographic properties, and comorbidities (Table 1).

Table 1. Demographic features of the patients according to groups.

	Total (n = 102)	Masked Hypertension (n = 44)	Normal (n = 58)	p
Age	71.92 ± 5.72	72.89 ± 5.53	71.19 ± 5.79	.13
Sex (Male)	42 (41.2%)	19 (43.2%)	23 (39.7%)	.72
(Female)	60 (58.8%)	25 (56.8%)	35 (60.3%)
Education
Primaryschool /illiterate	57 (55.9%)	30 (68.2%)	27 (46.6%)
Seconadryschool	15 (14.7%)	3 (6.8%)	12 (20.7%)
High school	11 (10.8%)	4 (9.1%)	7 (12.1%)
University	19 (18.6%)	7 (15.9%)	12 (20.7%)
Body Mass Index	27.48 (17.7–42.2)	27.95 (19.4–38.1)	26.97 (17.7–42.2)	.27
Smokers	16 (15.7%)	6 (13.6%)	10 (17.2%)	.47
Alcohol	12 (11.8%)	5 (11.4%)	7 (12.1%)	.91
Diabetesmellitus	22 (21.6%)	10 (22.7%)	12 (20.7%)	.80
Hyperlipidaemia	22 (21.6%)	10 (22.7%)	12 (20.7%)	.80

The ABPM results of patients are shown in Table 2. According to these results, the patients in the MH group had higher blood pressure values both in office measurements and ABPM results than the normal group.

Table 2. Office and ambulatuary blood pressure measurements (ABPM) results.

	Total (n = 102)	Masked hypertension (n = 44)		Normal (n = 58)
Office blood pressure
Systolic	128.3 ± 12	130.2 ± 10.5		126.8 ± 12.9
Diastolic	79.5 ± 8.8	80.1 ± 8.3		79 ± 9.1
Home measurements
Systolic	120.9 ± 12	129.2 ± 8.6		114.6 ± 11
Diastolic	74.8 ± 8.6	79.6 ± 7.1		71.2 ± 8
ABPM
24 h
Systolic	124.8 ± 10.2	133.8 ± 6.4		117.9 ± 6.7
Diastolic	68.3 ± 7.3	70.7 ± 7.2		66.5 ± 6.9
Day time
Systolic	126 ± 10.3	134.5 ± 7.5		119.6 ± 7.1
Diastolic	69.6 ± 7.8	71.6 ± 7.7		68.1 ± 7.1
Night time
Systolic	116.4 ± 14.7	129.9 ± 10.6		106.4 ± 7.6
Diastolic	61.7 ± 8	65.9 ± 7.1		57.4 ± 6.5

Laboratory test results of the patients are given in Table 3. The median albumin/creatinine value in the MH group was 9.61 mg/day (2–123) and in the group with normal blood pressure values was 7.12 mg/day (2–137). There was a statistically significant difference between the two groups (p = .021). When the urine Alb/creatinine ratio was regrouped as microalbuminuria (>30 mg/day) in the database, no statistically significant difference was found between groups (p > .05). The relationship between urine Alb/creatinine ratio and MH is shown in Figure 1. There were no significant differences between the two groups regarding other laboratory test results (Table 2).

Figure 1. Relationship between masked hypertension and spot urine alb/cre ratio.

Table 3. Laboratory results of the patients according to groups.

	Total (n = 102)	Masked Hypertension (n = 44)	Normal (n = 58)	p value
Haemoglobin (g/dL)	13.47 ± 1.36	13.38 ± 1.3	13.53 ± 1.4	.57
Creatinine (mg/dL)	0.74 (0.48–1.49)	0.71 (0.48–1.33)	0.74 (0.5–1.49)	.23
BUN (mg/dL)	15 ± 3.63	14.96 ± 3.46	15.03 ± 3.78	.93
ALT (U/L)	16(6–61)	15.5(6–61)	16.5(8–54)	.44
Fasting plasma glucose (mg/dL)	98(73–309)	100(82–255)	96(73–309)	.1
TSH(mIU/L)	1.47 (0.02–26)	1.41 (0.02–26)	1.48 (0.02–3.74)	.94
Vitamin B12 (pg/ml)	261 (116–1500)	216 (116–1500)	305 (118–932)	.1
Vitamin D(µg)	23(5–101)	21(5–63)	26(7–101)	.11
Folic acid (ng/mL)	10.87 ± 4.90	11.15 ± 4.76	10.65 ± 5	.61
Ferritin (mg/L)	45.35 (5.40–829	36.6 (5.4–200)	49.5 (7–829)	.18
Iron binding capacity (saturated) (µg/dL)	344 ± 49	349 ± 47	340 ± 50	.36
Iron (µg/dL)	80(16–320)	75.5(16–320)	83.5(36–167)	.22
Na (mEq/L)	139 (132–143)	139 (136–143)	139 (132–143)	.95
K (mEq/L)	4.43 ± 0.31	4.39 ± 0.33	4.46 ± 0.3	.24
P (mg/dL)	3.38 ± 0.45	3.43 ± 0.44	3.35 ± 0.47	.43
Uric acid (mg/dL)	4.98 ± 1	5.06 ± 1.06	4.91 ± 0.97	.49
UrineAlb/Creatinineratio (mg/day)	8.12(2–137)	9.61(2–123)	7.12(2–137)	.021

BUN: Blood Urea Nitrogen, ALT: Alanine Aminotransferase, TSH: Thyroid Stimulating Hormone, Na: Sodium, K: Potassium, P: Phosphorus

The bold values indicate that the p values are statistically significant.

Left ventricular diastolic posterior wall thickness (p = .03) and left ventricular diastolic septal thickness (p = .03) were found to be significantly higher in the MH group. Mitral annular septal E’ (p = .007) and mitral annular lateral E’ (p = .015) values were significantly lower in the MH group. Other echocardiographic data are shown in Table 4.

Table 4. Echocardiography findings of the patients according to groups.

	Total (n = 102)	Masked Hypertension (n = 44)	Normal (n = 58)	p value
Ascendan aorta (cm)	3.53 ± 0.39	3.56 ± 0.39	3.51 ± 0.39	.55
Anulus (cm)	2.1 (1.7–2.6)	2.1 (1.8–2.6)	2.0 (1.7–2.5)	.15
Left ventricular end diastole diameter (cm)	4.5 (3.9–6.4)	4.6 (3.9–5.9)	4.5 (3.9–6.4)	.30
Left ventricle end systole diameter (cm)	2.9 (2.3–5.1)	2.9 (2.3–3.7)	2.9 (2.4–5.1)	.97
EF (%)	64 (41–73)	64 (45–71)	64 (41–73)	.53
End diastolic posterior wall thickness (cm)	1.0 (0.7–3.4)	1.0 (0.8–1.2)	0.9 (0.7–3.4)	.03
Diastolic septum thickness (cm)	1.0 (0.7–1.2)	1.0 (0.8–1.2)	1.0 (0.7–1.2)	.03
Right diastolic width (cm)	2.6 (1–4.5)	2.7 (2.3–3.3)	2.6 (1–4.5)	.16
Epic	0.58 (0.34–1.44)	0.59 (0.35–0.91)	0.57 (0.34–1.44)	.47
Apic	0.87 (0.5–1.7)	0.89 (0.55–1.26)	0.85 (0.5–1.7)	.21
İvrt (milisecond)	107 ± 20	108 ± 19	107.4 ± 20	.9
Edes	216.7 ± 69	223 ± 68	212 ± 70	.44
AOS	35 (27–47)	35 (27–43)	35 (30–47)	.51
AOD	33 (25–44)	32.5 (25–39)	33 (27–44)	.31
Lateral E’	8 (4–23)	7 (5–12)	8 (4–23)	.01
Septal E’	7 (4–14)	6 (4–11)	7 (4–14)	.007
PAB (mmHg)	30 (20–70)	30 (20–45)	30 (20–70)	.28
LeftAtrium (cm)	3.62 ± 0.53	3.64 ± 0.49	3.61 ± 0.56	.76
LeftVentricularMass Index (g/m2)	86 (60–127)	91 (63–121)	83.5 (60–127)	.017

EF: Ejectionfraction; IVRT: Isovolemic Relaxation Time; PAB: Pulmonary arterial pressure

One of the parameters showing end organ damage and showing the negative effect of hypertension on the heart is the LVMI. LVMI calculated according to the formula was 86 (60–127)g/m² in all patients. It was calculated as 91 (63–121) g/m² in the MH group and 83.5 (60–127)g/m² in the normal group. Among the two groups, LVMI of MH group was significantly higher (p = .017). The relationship between MH and LVMI is shown in Figure 2. LVMI value above 115 g/m² was accepted as hypertrophy in men. In women, LVMI value above 95 g/m² was accepted as hypertrophy. Accordingly, there were 3 patients above the reference value in men and 11 patients in women. A total of 14 patients had hypertrophy. There was no significant difference between patients with and without MH regarding hypertrophy.

Figure 2. Relationship between masked hypertension and left ventricular mass index.

There was no statistically significant difference between two groups regarding left atrial diameter, ascending aorta and annulus diameter, ejection fraction, pulmonary artery pressure, left ventricular diastole or end-systolic diameter.

Linear regression analysis was performed to investigate the independent factors affecting LVMI. When daytime systolic and diastolic blood pressure, night-time systolic and night-time diastolic blood pressure variables were put into equation, night-time systolic blood pressure was found to be independently associated with LVMI (p: .01; %95 CI 0.006–0.44). Furthermore, linear regression analysis was performed to determine the variables affecting LVMI. When diabetes mellitus, hyperlipidaemia and MH were included in the model, a significant relationship was found between MH and LVMI (p: .05), independent from other comorbidities. In the logistic regression analysis, the factors affecting microalbuminuria was investigated. Age, sex, daytime systolic and diastolic blood pressure and night-time systolic and diastolic blood pressure variables were included in the model. Night-time systolic blood pressure was found to be independently associated with microalbuminuria (p: .038; %95 CI 1.04–1.1). The results revealed that the increase in systolic blood pressure at night, which can be detected only by ambulatory blood pressure, is the most important parameter that is linked with the end-organ damage. In another linear regression analysis model, the presence of MH, diabetes mellitus and hyperlipidaemia, were included in the model to determine the independent correlates of spot urine alb/creatinine ratio. In conclusion, diabetes mellitus was found to be a statistically significant factor on alb/creatinine ratio (p: .001).

Discussion

This study conducted 102 patients admitted to a geriatric medicine outpatient clinic who did not have hypertension diagnosis and antihypertensive medication usage. The results revealed that MH is associated with increased left ventricular hypertrophy (LVH) and proteinuria in geriatric patients. This result shows that MH is associated with end organ damage in geriatric age. To the best of our knowledge, this is the first study demonstrating this result in older adults.

LVH is an important end organ damage of hypertension and can be diagnosed with ECG and ECHO [15]. ECG has a low sensitivity for the diagnosis of LVH. It can detect 7–35% of patients with mild hypertrophy and 10–50% of cases with moderate hypertrophy [16]. The presence of LVH is a clinically important condition, and its relationship with hypertension is well known. It has an impact on morbidity and mortality including increased incidence of heart failure and ventricular arrhythmias, increased post-myocardial infarction mortality, decreased left ventricular ejection fraction, sudden cardiac death, aortic dilatation and increased frequency of cerebrovascular events. Hypertension is a factor that causes end-organ damage, and the heart itself is one of the organs affected by end-organ damage. In a prospective study of 1033 patients, patients with essential hypertension over 50 years of age without a history of cardiovascular event were followed up for an average of three years. At the end of the study, it was found that major cardiovascular events (fatal-nonfatal MI, all-cause mortality, severe heart failure or heart disease requiring dialysis need) were 29% higher in patients with increased LVMI. It has been reported that LVMI over 125 g/m² is a cardiovascular risk and every 39 g/m² increment is reported to increase the risk of major cardiovascular events by 40% [17]. In the Framingham study of 3661 patients over 40 years of age, the rate of patients with LVH was calculated as 22%.These patients had a 2.16-fold higher risk of sudden death [18]. The relationship between LVMI and hypertension is well known, but the relationship between MH and LVMI is not clear. There are a few studies on this subject, but there is no study done for geriatric patients. Our study is the first to be specifically designed for old patients. The importance of our study is demonstrating that MH is related to end-organ damage in geriatric patients.

Relationship between LVMI and MH is a novel area of research. MH patients were found to have a significantly higher LVMI than normotensive patients in a study group with a mean age of 45 [19]. While many studies have shown that MH causes LVH in children, adolescents and chronic kidney disease [20–22], this effect has never been investigated in geriatric patients. In our study, the mean age was higher than the other studies. Similar to the studies examining hypertension, significantly increased LVMI levels were detected in our group with MH compared to the normal group. These results suggest that MH may cause LVH just as hypertension does. Considering the essential consequences of LVH, our results put forward the importance of MH in geriatric age group.

The negative effect of hypertension on kidney is another important element of the end-organ damage. Serum creatinine and albumin-creatinine ratio in spot urine were evaluated in our study to predict renal injury in patients with MH. While there was no difference between two groups regarding serum creatinine value, albumin/creatinine ratio in spot urine was higher in MH group compared to the control group. When the groups were compared in terms of microalbuminuria, (>30 mg/day or <30 mg/day), there was no difference between the MH and the control group. Although there was no difference in terms of microalbuminuria, the higher ratio of spot urine albumin/creatinine in the MH group allowed us to see the negative impact of MH on renal damage. In a study of patients over 40 years of age in Japan, the effect of MH, white coat hypertension and resistant hypertension on albuminuria was investigated in the general population [23]. It has been shown that these three different conditions ultimately increased albumin excretion, thus the effect of high blood pressure on the end organ damage has been shown. In another study examining the effects of MH in chronic kidney disease, MH was found to be associated with proteinuria [12]. These studies were designed differently from our study as the patient population was different. Our study showed that MH is a factor that increases proteinuria in the geriatric patient.

This study has several limitations. It was very difficult to find and include patients without hypertension in the geriatric age group. Therefore, the number of patients included in the study was not very high. Due to the difficulty in designing the study, 102 patients were included in the study. Another common chronic disease in this age group is diabetes mellitus. In prospective studies involving patients without diabetes mellitus, the effects of MH on end organ damage will be more clearly understood.

Due to the increase of age-related comorbidities and additional diseases, age is often a criterion of exclusion in large studies. The availability of available information for geriatric patients has always been controversial. Whether the reference range for the general population is valid for geriatric patients is another topic of discussion. The reference values for hypertension are recently expressed differently in different guidelines even in the general population. It is another difficulty to determine correct reference values for geriatric patients for hypertension diagnosis. Whether the geriatric patient with MH should be treated is unclear. The side effects that may develop with antihypertensive treatment and the long-term effects of hypoperfusion are more common in the geriatric population and have more serious consequences. Long-term studies will allow us to see the effects of treatment of MH in the geriatric age group. We believe that this study can shed light to future studies to determine the management of MH, as our results revealed that MH has clinical implications in geriatric age group. Awareness of MH should be increased and it should not be overlooked.

Conclusion

This study has detected end-organ damage, namely excessive renal albumin excretion and LVH, in MH compared to normotensive controls in the geriatric age group. Further studies with longitudinal follow-up are needed to examine whether or not treatment of MH in geriatric age can prevent end organ damage.

Disclosure statement

No potential conflict of interest was reported by the authors.