Mean platelet volume in patients with dipper and non-dipper hypertension

Abstract

Patients with non-dipper hypertension are known to carry a high risk of cardiovascular complications. In this study, we hypothesized that non-dippers may be associated with platelet dysfunction and it can be determined by mean platelet volume (MPV). A total of 216 outpatients treated with antihypertensive drugs for at least 6 months were enrolled. Dipper and non-dipper patterns were detected and clinical, laboratory and ambulatory blood pressure recording data were matched between non-dipping and dipping groups. MPV was significantly higher in patients in non-dipping than dipping groups (p<0.001). In correlation analyses, MPV was negatively correlated with the rate of systolic and diastolic fall at night (p<0.001, r=−0.46) and (p<0.001, r=−0.43), respectively. Also MPV was correlated with nocturnal pulse pressure (p=0.001, r=0.22). Other variables were similar between non-dipping and dipping groups. The present study showed that MPV is higher in non-dipping than dipping hypertensive patients. Platelet activation or dysfunction probably is an alternative mechanism for increasing cardiovascular events in non-dippers.

Key Words::

• Dipper and non-dipper hypertension
• mean platelet volume
• platelet

Introduction

Twenty-four-hour ambulatory blood pressure monitoring (ABPM) can easily detect the circadian blood pressure (BP) pattern: systolic (SBP) and diastolic BP (DBP) show a nocturnal fall of at least 10% in normal subjects. Patients whose BP does not decrease during sleep compared with daytime have been defined as non-dippers. Non-dippers, compared with dippers, are known to carry a high risk of cardiovascular events in hypertensive and normotensive subjects (1,2). Prospective studies have demonstrated that non-dipping is associated with target organ damage, including cardiovascular morbidity and mortality, the development and progression of renal dysfunction and cerebrovascular disease (3–6). The mechanisms responsible for abnormal diurnal BP variation remained unclear, but it may be associated with a deterioration of autonomic balance (7). Consequently, a non-dipping pattern may carry additional risk for hypertensives, which can be easily diagnosed with ABPM in evaluating the initial cardiovascular risk in hypertension.

Mean platelet volume (MPV) is an indicator of platelet activation and it has been reported to increase in obesity, acute myocardial infarction (MI), hyper-cholesterolemia, diabetes mellitus, hypertension and acute ischemic stroke (8,9). Platelet dysfunction in hypertensive patients is a potential cause of increased cardiovascular morbidity and mortality (10,11). Our primary hypothesis is that MPV increases in patients with non-dipper hypertension. Therefore, the present study was designed to investigate whether MPV increases in patients with non-dipper hypertension. Our secondary hypothesis – which needs further investigation – is that there may be a link between MPV and poor prognosis in non-dippers.

Materials and methods:

Study design

We conducted a retrospective cohort study of outpatients referred to the Department of Cardiology for ambulatory BP monitoring between January 2008 and June 2009. Clinical information was obtained by a thorough standardized review of the written and electronic medical records. Patients were defined as having a history of hypertension if this diagnosis was listed in their medical history (generally based on office measurements), or if they were prescribed anti-hypertensive medications (whether they were taking them at the time of the BP monitoring). Body mass index was calculated as (weight in kilograms)/(height in meters)2. We defined dipping as a drop in mean nocturnal SBP of >10% as compared with mean daytime values (non-dipping percentage <10%).

A total of 750 consecutive patients between 18 and 80 years of age with essential hypertension and who had been evaluated with ambulatory BP monitoring were enrolled in this study. Two hundred and sixteen patients who had fulfilled the inclusion and exclusion criteria were included in the final analysis. All the patients had been treated with antihypertensive drugs for at least 6 months. Exclusion criteria included secondary hypertension, cardiac failure, recent MI, coronary artery bypass surgery, stroke, valvular diseases, arrhythmias, angina pectoris, chronic renal failure, chronic liver diseases, thromboembolic disorders, hematological abnormalities, drug use that may influence platelet number and function such as aspirin, heparin, oral contraceptives, hormone replacement therapy, anticoagulants and diabetes mellitus. The clinical, laboratory and ambulatory BP recording data were compared between non-dipping and dipping groups. The Institutional Review Board of the Düzce University Faculty of Medicine approved the study, a waiver of consent was granted and patient identity was protected.

Ambulatory BP recordings

Twenty-four-hour ambulatory BP and heart rate monitoring were performed on Rozinn RZ250 ABP recorder SN R 02157/0807, USA. Monitors recorded heart rate, SBP and diastolic BP readings every 15 min during the daytime and every 30 min overnight, for the 24-h period. Daytime was defined as 07:00–23:00 h and night-time was defined as 23:00–07:00 h.

Laboratory testing

Ten milliliters of fasting bloods were drawn from each subject and the samples were immediately centrifuged, and then plasma and serum samples were kept at −20°C until laboratory testing. Serum glucose levels were measured with a standard hexokinase reference method, serum triglyceride, total cholesterol, high-density lipoprotein (HDL), urea nitrogen, creatinine (Jaffe method without deproteinization) and urine creatinine concentrations were determined by standard clinical chemistry methods using an autoanalyzer Architect C8000 (Abbott Diagnostics, Tokyo, JAPAN). The low-density lipoprotein (LDL) and VLDL levels were calculated by Friedewald equation using measured triglyceride, total cholesterol and HDL values.

Complete blood counts were determined by the samples which were drawn into vacutainer tubes containing 0.04 ml of the 7.5% K3 salt of ethylene-diaminetetraacetic acid (EDTA) and then analyzed by a Sysmex XT 2000i analyzer (Roche Diagnostics, Tokyo, Japan). The expected values for MPV in our laboratory ranged from 7.0 to 11 fl.

Statistical analysis

All values are given as mean±standard deviation. The Statistical Package for Social Sciences software (SPSS 10.0, Chicago, IL, USA) was used for comparisons of demographic and clinical variables. Unpaired Student's t-test was used for group comparisons. Categorical data were compared with the chi-square test. Pearson correlation was used to evaluate the association between MPV and demographics or laboratory parameters. Statistical significance was defined as p<0.05.

Results

Comparisons of baseline characteristics of the dipper and non-dipper groups were shown in Table I. There was no significant difference between the two groups regarding the number of medications taken per patient and the proportion of each class of antihypertensive medications. Non-dipper patients were older than their dipper counterparts, but this difference was not statistically significant. Body mass index, lipid profiles, rate of smoking and fasting levels of glucose were similar between the two groups. Serum urea level and creatinine were higher in the non-dipping group, but it could not reach statistical significance.

Table I. Comparison of the basic clinical and biochemical variables between two groups.

	Dippers (n=106)	Non-dippers (n= 110)	p-value
Age (years)	51±13	54±12	0.15
Sex (M/F)	36/70	45/65	0.29
BMI (kg/m2)	24.3±5.4	24.9+4.7	0.46
History of smoking (%)	46	41	0.51
Number of drugs	2.1±0.8	2.0±0.8	0.37
ACE-ARB (%)	57	59	0.81
Ca channel blocker (%)	48	56	0.21
Beta blockers (%)	35	33	0.81
Diuretics (%)	55	53	0.8
Other groups (%)	10	13	0.24
Total cholesterol (mg/dl)	196±47	191±37	0.4
HDL cholesterol (mg/dl)	44±11	45±18	0.54
LDL cholesterol (mg/dl)	119±42	111±34	0.17
Triglyceride (mg/dl)	165±77	156±73	0.42
BUN (mg/dl)	14±4	15±4	0.09
Serum creatinine (mg/dl)	0.78±0.14	0.82±0.17	0.18
Serum urea level (mg/dl)	29.7±9.2	31.6±8.3	0.15
Hemoglobin (g/dl)	13.0±1.7	13.1±1.4	0.82
White blood cells (1×1000)	7.49±2.3	7.44±1.8	0.85
Platelets (1×1000)	256.5±61.8	240.3±62.5	0.063
Mean platelet volume (f)	9.1±1.5	10.5±1.3	<0.001

BMI, body mass index; ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; HDL, high-density lipoprotein; LDL, low-density lipoprotein; BUN, blood urea nitrogen.

White blood cells and hemoglobin levels were not different between non-dipping and dipping groups. Platelet number was fewer in non-dipper group, but it could not reach statistical significance. MPV was significantly higher in non-dippers than dippers (p<0.001). In correlation analyses, MPV was negatively correlated with the rate of systolic and diastolic fall at night (p<0.001, r=−0.46) and (p<0.001, r=0.43), respectively (Figures 1 and 2). Also MPV was mildly correlated with nocturnal pulse pressure (PP; p=0.001, r=0.22). Official BP was similar between non-dipper and dipper groups. The mean of 24 h SBP, DPB and PP were similar between two groups. Daytime SBP and DBP were similar between two groups (129.4±13.2 vs 127.4±13.6 mmHg) and (78.1±8.8 vs 76.3±9.5 mmHg), respectively. However, the nocturnal SBP, DBP and the nocturnal PP were significantly higher in non-dippers compared with dippers as shown in Table II. The mean nocturnal SBP falls were 14.2±4.2 mmHg, and DBP falls was 14.2±6.8 mmHg in dipping group, and mean nocturnal SBP falls were 0.5±5.5 mmHg and DBP falls were 0.98±6.6 mmHg in non-dipping group. The mean of 24-h pulses and nocturnal pulses were similar between the two groups.

Figure 1. Correlation graph of between mean platelet volume and with nocturnal systolic blood pressure falls.

Figure 2. Correlation graph of between mean platelet volume and with nocturnal diastolic blood pressure falls.

Table II. Comparison of the ambulatory blood pressure monitoring variables between two groups.

	Dippers (n=106)	Non-dippers (n=110)	p-value
SBP on physical examination (mmHg)	145±9.1	144.1±9.4	0.48
DBP on physical examination (mmHg)	93±6.4	92.9±8.1	0.88
24-h Ambulatory SBP (mmHg)	124.9±12.8	127.1±13.3	0.21
24-h Ambulatory DBP (mmHg)	75.3±8.7	76.3±13.6	0.56
Mean heart rate (beats/h)	74.3±8.1	72.8±8.7	0.19
Day SBP (mmHg)	129.4±13.2	127.4±13.6	0.29
Day DBP (mmHg)	78.1±8.8	76.3±9.5	0.16
Day pulse pressure (mmHg)	51.1±8.9	51.1±8.3	0.93
Day heart rate (beats/h)	73.9±7.3	74.0±9.1	0.94
Night ambulatory SBP (mmHg)	109.5±16.3	126.6±14.2	<0.001
Night ambulatory DBP (mmHg)	66.6±9.9	75.4±9.3	<0.001
Night heart rates (beats/h)	67.2±8.6	69.1±10	0.13
Nocturnal pulse pressure (mmHg)	43.8±7.6	51.2±9.3	<0.001
The rate of systolic fall in night	14.2±4.2	0.5±5.5	<0.001
The rate of diastolic fall in night	14.2±6.8	0.98±6.6	<0.001

SBP, systolic blood pressure; DBP, diastolic blood pressure.

Discussion

In this study, we have showed that MPV is higher in non-dipping than dipping hypertensive patients. Regarding that MPV is the simple marker of platelet activation, in non-dipper patients impaired diurnal BP variation and autonomic imbalance may lead to relative sympathetic over activity at night causing this phenomena. Therefore, MPV may be the predictor of platelet activation or dysfunction in non-dipper hypertensive patients.

Platelets play a crucial role in the pathogenesis of atherosclerotic complications, contributing to thrombus formation after plaque rupture (11). MPV is a marker of platelet function, i.e. large platelets contain more dense granules and produce more thromboxane A2. Higher MPV levels have been identified as an independent risk factor for death or recurrent vascular events after MI and coronary artery disease (11).

Hypertension is related to increased risk of thrombotic complications. Additionally, non-dipping patients in essential hypertension were at high risk for organ damage such as left ventricular hypertrophy, carotid artery disease, stroke, microalbuminuria and MI (12). Seo et al. reported that non-dipper hypertensive patients were associated with adverse cardiac remodeling and early LV dysfunction (13). Moreover Brotman et al. reported that non-dipping is a risk factor for all cause mortality, independent of mean 24-h BP (7). On the other hand, Scuteri et al. demonstrated that MPV seemed to be associated with increased left ventricular mass and interventricular septum thickness in hypertensive patients (14). Chu et al. reported that elevated MPV is related to acute MI, mortality following MI, and restenosis following coronary angioplasty (15). These data suggest that MPV is a potentially useful prognostic biomarker in patients with cardiovascular disease (15). The relationship between non-dipping hypertension group and MPV has not been studied before. The present study, however, demonstrated that platelet dysfunction occurred in non-dipping hypertensive patients and MPV; a simple marker can determine it. Previous studies have reported that MPV in patients with HT was significantly higher than in normotensive subjects (16,17) and platelet dysfunction in hypertensive patients was a potential cause of increased cardiovascular morbidity (18). In hypertension patients, non-dipping group have high risk for cardiovascular disease. This additive risk may be related with the increased platelet activation in non-dipping patients.

Previous studies demonstrated that renal function also decreases in non-dipper hypertensives, when compared with dipper ones (19–21). Confirming this result, we have also showed a tendency to impaired renal function in non-dipper group. The difference could not reach significance, however, possibly because of our relatively younger cohort. We have also excluded patients who had diabetes mellitus and coronary artery disease, which might weakened the difference in between.

Kengne et al. showed that SBP and PP are the two best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type II diabetes mellitus (22). Weiss et al. also concluded that high PP is an independent predictor of mortality among elderly hospitalized patients (21). The estimated PP with ABPM is a predictor of vascular and cardiac organ damage. García-Ortiz et al. reported that the nocturnal fall and the standard deviation in 24-h SBP measured with the ABPM is a predictor of renal damage (23). We also showed that MPV was correlated with the nocturnal PP. At the mean time, there is no clear link suggesting that MPV may predict cardiovascular events in hypertensive patients. However, there is now a rationale to design prospective larger cohort studies in order to investigate the prognostic capability of MPV in non-dipper hypertensive patients. A possible association will lead clinicians easily to diagnose hypertensive patients at risk and to tailor a more intensive treatment approach in order to prevent cardiovascular adverse events.

Our study has several limitations. This study was a retrospective investigation on a relatively small cohort. Another limitation is the relatively higher number of women participants than men. Also, chronotherapy in hypertensive treatment was not taken into consideration.

Conclusion

The present study showed that MPV is higher in non-dipping than dipping hypertensive patients. Platelet activation or dysfunction probably is an alternative mechanism for increasing cardiovascular events in non-dippers.

Conflict of interest: None.