76 Clinical methods and pathophysiology
Impaired circadian rhythm of blood pressure in normotensive patients with rheumatic mitral valve stenosis Musa Cakicia, Adnan Doganc, Muhammed Oylumluc, Fatih Uckardesb and Vedat Davutoglud Background The aim of the present cross-sectional study was to evaluate either non-dipper-type or dipper-type circadian rhythm of blood pressure (BP) in normotensive rheumatic mitral stenosis (MS) patients. Methods and results Eighty-eight normotensive rheumatic mitral valve disease (RMVD) patients and 41 normal participants were enrolled in the study. All participants underwent ambulatory blood pressure monitoring. Nocturnal BP dipping was calculated as follows: (awake BP – asleep BP) ¾ 100/awake BP. Patients with a nocturnal reduction in average daytime systolic BP and diastolic BP of less than 10% were classified as nondippers. Patients with RMVD were divided into two groups with respect to the top and bottom 1.5 cm2 of the mitral valve area (MVA). There was a highly significant relationship between the two groups with control in the frequency of a nondipping status (v2 = 22.721; d.f. = 2; P < 0.001). Afterwards, the Mann–Whitney U-test was used to compare the two groups and the control group. There was no difference in the frequency of nondipping between patients with an MVA of greater than 1.5 cm2 and the control group (P > 0.05). However, the nondipping level was
Introduction Since the development and clinical application of ambulatory blood pressure monitoring (ABPM), various studies have shown that assessment of the circadian blood pressure (BP) profile is more predictive than office BP readings in estimating cardiovascular risk [1,2]. Arterial BP shows a circadian-type rhythm. This refers to the daily variation in BP, which is generally higher during the day than at night [3]. A number of studies have reported the lack of a nocturnal BP fall, known as nondipping BP [4]. The underlying mechanisms responsible for the blunted nocturnal fall in BP are not completely understood. Nevertheless, there is some evidence to suggest that patients with nondipping BP show impairment in the autonomic system, including abnormal parasympathetic and increased sympathetic nervous system activity [5,6]. Therefore, overactivity of the sympathetic nervous system has been found in patients with mitral stenosis (MS) [7]. Increased sympathetic outflow may impair the circadian rhythm of BP in patients with MS because the sympathetic vascular tone is predominant during the day, whereas the parasympathetic vascular tone is predominant at night [8]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 1359-5237
higher in patients with an MVA of less than 1.5 cm2 than in the control group and in patients with RMVD with an MVA of greater than 1.5 cm2 (P < 0.001 and 1.5 mg/dl), hepatic failure, a history of coronary artery disease, stroke, arrhythmia, diabetes mellitus, and/or those currently smoking, low ejection fraction (< 50%), moderate or severe mitral and/or aortic regurgitation, aortic stenosis, and organic tricuspid valve disease patients were excluded. Those not smoking for at least the last 2 years were considered as nonsmokers. Avoidance of exercise during 24-h ambulatory monitoring was recommended for all participants. The study protocol was approved by the Local Research Ethics Committee and all participants provided their informed consent before being enrolled. Echocardiographic data
Echocardiographic examinations were carried out using a cardiac ultrasound system (Vivid 7; GE Healthcare, Wauwatosa, Wisconsin, USA) for each participant. To determine the transmitral valve gradient, four-chamber apical view was used with the sample volume placed at the mitral valve coaptation point. Transmitral valve gradient was defined as the mean of gradients obtained from three consecutive beats obtained by a continuouswave Doppler study. MVA was measured by planimetry of the mitral valve in short axis view and the mean of three measurements in three different beats was considered as final. MVA of 1 cm2 or less were considered to be very severe, 1–1.5 cm2 were considered to be moderate, and greater than 1.5 cm2 were considered to be mild cases. Color-flow Doppler was used to detect the presence of associated valvular insufficiencies, which were additionally confirmed by Doppler studies. Patients with aortic stenosis and those with moderate or severe mitral and aortic regurgitation were excluded from the study. The modified Bernoulli equation derived from the tricuspid regurgitation jet velocity and estimated right atrial pressure from inferior vena cava collapsibility was used to determine systolic pulmonary artery pressure [9]. The mean pulmonary artery pressure was calculated using the Masuyama method [10]. 24-h ambulatory blood pressure monitoring
Twenty-four-hour noninvasive ABPM using a portable compact digital recorder automatic device was carried out on a weekday (PhisioQuant; EnviteC-Wismar GmbH, Wismar, Germany). To obtain diurnal values, diurnal readings at 20-min intervals (07:00–23:00 h) and nocturnal readings at 30-min intervals (23:00–07:00 h) were recorded. Asleep and awake periods were assessed on the basis of the information obtained from the patients. Asleep BP was defined as the average of BP from the time when the participants went to bed to the time they got out of bed, and awake BP was defined as the average of BP recorded during the rest of the day. The formula 2/ 3 diastolic BP + 1/3 systolic BP was used to calculate
the mean arterial pressure. The nocturnal BP dipping was calculated as follows: (awake mean BP – asleep mean BP) 100/awake mean BP. According to the criterion of Verdecchia et al. [11], patients with a nocturnal reduction in the average daytime systolic BP and diastolic BP of less than 10% were classified as nondippers, whereas those with night-time reduction of 10% or more were classified as dippers [12]. Statistical analysis
Statistical analysis was carried out using SPSS 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA). The onesample Kolmogorov–Smirnov test was used to determine whether the data were distributed normally. The results were reported as mean±SD. Groups were compared using the independent two-sample t-test or the Mann–Whitney U-test, whichever was appropriate. The relationship between nondipping state and groups was compared using a w2-test and was expressed as counts or percentages. Correlation analysis was carried out using Spearman’s test. The backward binary logistic regression analysis was carried out to determine predictive factors for nondipping participants from statistically related confounding variables. A P value of less than 0.05 was considered statistically significant.
Results The baseline characteristics, laboratory values, and echocardiographic findings of normotensive patients with RMVD and a control group are presented in Table 1. The group of patients with RMVD was compared with the control group. There was no significant difference between the groups in terms of age, sex, BMI, plasma urea, plasma creatinine, hemoglobin, day and night-phase systolic/diastolic BP values (P > 0.05). Only left atrial diameters were higher in the RMVD group than in the control group. Therefore, 58 patients within the RMVD group were diagnosed with MS. MS was defined as an MVA of less than 2 cm2. A total of 37 patients with MS had an MVA of less than 1.5 cm2. Patients with RMVD were divided into four groups with respect to MVA. The relationship of dipping and nondipping status between the groups with respect to the MVA is presented with a histogram in Fig. 1. There was a much more significant relationship between the groups in the percentage of a nondipping status (w2 = 23.231; d.f. = 4; P < 0.001). The level of nondipping increased with decreasing MVA (Fig. 1). Afterwards, the Mann–Whitney U-test was used to compare the control group and group 2, which included patients with nonobstructive RMVD. There was no difference in the percentage of nondipping between groups (17.1 vs. 16.7%; P = 0.087, respectively) (Fig. 1). In addition, patients with RMVD were again divided into two groups with respect to the top and bottom 1.5 cm2 of the MVA and compared with the control group. There was a highly significant relationship between the two
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78 Blood Pressure Monitoring 2014, Vol 19 No 2
Baseline characteristics and echocardiographic findings in normotensive patients with rheumatic mitral valve disease and the control group
Table 1
Age (years) Sex (male/female) Plasma urea (mg/dl) Plasma creatinine (mg/dl) BMI (kg/m2) Hemoglobin (g/dl) Left atrial diameter (cm) Mean transmitral gradient (mmHg) Mitral valve area (cm2) Mean pulmonary artery pressure (mmHg) Night-phase systolic blood pressure (mean) (mmHg) Night-phase diastolic blood pressure (mean) (mmHg) Night-phase mean blood pressure (mean) (mmHg) Day-phase systolic blood pressure (mean) (mmHg) Day-phase diastolic blood pressure (mean) (mmHg) Day-phase mean blood pressure (mean) (mmHg)
Dipping (n = 86)
Rheumatic mitral valve disease patients (n = 88)
Control group (n = 41) P values
38.20±8.63 42/46 30.60±5.76 0.70±0.11 26.75±3.73 13.44±1.41 3.87±0.6 8.88±4.32
36.20±11.03 0.409 19/22 0.881 31.51±5.09 0.388 0.69±0.10 0.938 26.22±3.11 0.434 13.26±1.51 0.508 3.16±0.25 < 0.001 – –
1.36±0.38 40.24±8.35
– –
– –
104.25±9.34
104.92±13.74
0.745
61.63±7.52
59.60±8.69
0.177
75.83±7.57
74.71±10.07
0.485
114.01±8.77
117.34±12.40
0.083
69.38±7.78
69.26±8.18
0.939
84.44±7.72
85.29±9.27
0.587
Fig. 1
Percentage
90 80
Dipping
70
Nondipping
60 50
Comparison of groups in the change of blood pressure (dipping and nondipping group)
Table 2
(2: 23.231, d.f.: 4, P < 0.001)
40 30 20 10 0 Group 1 Group 2 Group 3 Group 4 Group 5
Distributions of dipping and nondipping state according to the mitral valve area (MVA) are shown with histograms. Group 1, control; group 2, rheumatic mitral valve disease (RMVD) patients with MVA > 2 cm2; group 3, RMVD patients with MVA 2–1.5 cm2; group 4, RMVD patients with MVA 1.5–1 cm2; group 5, RMVD patients with MVA < 1 cm2.
groups with control in the level of nondipping (w2 = 22.721; d.f. = 2; P < 0.001). Afterwards, the Mann–Whitney U-test was used to compare the two groups and the control group. There was no difference in the level of nondipping between patients with an MVA of greater than 1.5 cm2 and the control group (25.5 vs. 17.1%; P > 0.05, respectively). However, the nondipping percentage was higher in patients with an MVA of less than 1.5 cm2 than in the control group and in patients with RMVD with an MVA of greater than 1.5 cm2 (64.9 vs. 17.1%; P < 0.001 and 64.9 vs. 25.5%; P < 0.001, respec-
Nondipping (n = 43)
P values
Age (years) 37.91±10.35 36.88±7.43 0.565 Sex (male/female) 38/47 23/21 0.418 Plasma urea (mg/dl) 31.22±5.01 30.25±6.48 0.347 Plasma creatinine (mg/dl) 0.68±0.09 0.70±0.12 0.865 26.4±3.7 27.1±3.1 0.479 BMI (kg/m2) Hemoglobin (g/dl) 13±1.49 13.5±1.34 0.610 Left atrial diameter (cm) 3.4±0.52 4.02±0.70 0.000 Mean transmitral gradient (mmHg) 7.5±4.1 10.1±4.2 0.027 1.49±0.39 1.26±0.33 0.020 Mitral valve area (cm2) Mean pulmonary artery pressure 38±8.7 42±7.7 0.049 (mmHg) Night-phase systolic blood pressure 101.64±9.63 110.12±11.16 < 0.001 (mean) (mmHg) Night-phase diastolic blood pressure 59.37±6.97 64.23±8.82 < 0.001 (mean) (mmHg) Night-phase mean blood pressure 73.46±7.28 79.51±9.17 < 0.001 (mean) (mmHg) Day-phase systolic blood pressure 115.29±9.86 114.64±10.79 0.731 (mean) (mmHg) Day-phase diastolic blood pressure 70.23±7.17 67.57±8.98 0.070 (mean) (mmHg) Day-phase mean blood pressure 85.45±7.69 83.25±9.11 0.153 (mean) (mmHg)
tively). The day and night variations in BP in the dipping and nondipping groups are shown in Table 2. When we divided the entire sample population into dipping and nondipping groups, the night-phase systolic/diastolic/ mean BP, left atrial diameter, mean transmitral gradient, and mean pulmonary artery pressure were statistically higher (P < 0.001, P = 0.001, P < 0.001, P < 0.001, P = 0.027, and P = 0.049, respectively) and the MVA was statistically lower (P = 0.020) in the nondipping group than in the dipping group. A nondipping BP was correlated negatively with the MVA (P = 0.024; r = – 0.295), correlated positively with the mean transmitral gradient (P = 0.018; r = 0.310), correlated positively with the mean pulmonary artery pressure (P = 0.032; r = 0.281), and correlated positively with the left atrial diameter (P < 0.001; r = 0.310). Binary logistic regression analysis was carried out using the backward method to identify the variables associated with a nondipping status, including all statistically correlated factors (MVA, mean transmitral gradient, mean pulmonary artery pressure, and left atrial diameter). Only the MVA was determined to be a predictive factor of nondipping BP (P = 0.024) among these variables.
Discussion The major finding of the current study is that MS significantly altered the circadian rhythm of BP, reducing the BP dipping pattern. To the best of our knowledge, these findings have not been reported previously. The level of nondipping BP increased with a decreasing MVA. The level of nondipping BP was similar between patients with RMVD in whom the MVA was greater than 2 cm2 and the normal participants (Fig. 1). Therefore, the level of nondipping BP was significantly higher in patients with
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Impaired circadian rhythm of blood pressure Cakici et al. 79
MS in whom the MVA was less than 1.5 cm2 than in the normal participants and patients with an MVA of greater than 1.5 cm2. These results suggest that nondipping is associated with obstruction of the mitral valve rather than the nature of RMVD and that sympathetic activity (SA) increases when the MVA declines to less than 1.5 cm2. These results are very important because RMVD is still endemic in some countries. BP normally decreases (dips) during sleep, and individuals whose BP dips 10% or less from their daytime baseline BP have been referred to as ‘nondippers’ [12–14]. Nondipping BP is associated with target organ damage and cardiovascular events, independent of the overall BP. The mechanisms of nondipping BP are unclear, and the underlying pathophysiologic processes are not yet fully understood. In developing countries, RMVD remains a significant public health disease. Yuce and colleagues recently reported that RMVD is still endemic in our region [15–17]. Although all of the cardiac valves may be involved in the rheumatic process, the mitral valve is most prominently involved [18]. Obstruction of this valve reduces cardiac output and increases left atrial pressure, which may alter hemodynamics significantly. Elevated left atrial pressure and/or reduced cardiac output may alter SA through cardiopulmonary mechanisms [19]. Ashino and colleagues reported that autonomic nervous system dysfunction in patients with MS may be associated with (a) reduction in cardiac output: a significantly decreased stroke index in patients with congestive heart failure has been related to sympathetic activation in these patients, and a similar mechanism may play a role in patients with MS; (b) increased atrial or pulmonary arterial pressure: the increase in left atrial or pulmonary arterial pressure may alter SA through cardiopulmonary mechanisms; and (c) atrial stretch: stretching the atrium produces a definite increase in SA [20,21]. Overactivity of the sympathetic nervous system has been found in patients with MS [7]. Moreover, there is some evidence to suggest that nondipping BP is associated with autonomic nervous system dysfunction, including abnormal parasympathetic and increased sympathetic nervous system activity [5,6]. As a result, it is plausible to consider an impaired circadian rhythm of BP in patients with MS for these reasons. We already identified a close relationship between nondipping BP and MS despite the fact that the daytime and night-time BPs remained within normal ranges. In this study, impairment of the circadian BP rhythm in patients with MS may be explained by two possible mechanisms. First, vascular tone may be impaired in patients with MS because of increased SA depending on any of the mechanisms mentioned above because parasympathetic tone is predominant for vascular tone during the night [8]. All-day increased sympathetic tone in patients with MS
may prevent the reduction in BP during the night by modifying the vascular tone. Second, release of renin– angiotensin–aldosterone causes retention of body fluids, which increases extracellular volume in patients with MS. The circadian rhythm of BP may be altered for this reason because some authors have proposed that the pathophysiologic processes underlying a nocturnal nondipping profile involve abnormalities in extracellular volume [22,23]. Consequently, we believe that the circadian rhythm of BP might be impaired in patients with MS because of the two possible mechanisms. The results of our study showed that the mean transmitral gradient, mean pulmonary artery pressure, left atrial diameter, and MVA were correlated modestly with nondipping. In addition, the relationship between the left atrial diameter and nondipping was very important (P < 0.001). This result supports the idea that stretching of the atrium produces a definite increase in SA. However, only a decreased MVA was determined to be a predictive factor among the correlated variables. Uzu et al. [24–26] showed that sodium intake restriction and diuretics restored the circadian rhythm into a dipping pattern. These findings consistently indicated the important role of sodium retention in the genesis of the nondipping pattern of the circadian BP rhythm [27,28]. On the whole, we, as cardiologists, recommend restriction of salt intake and the intermittent use of diuretics to restore shortness of breath in patients with MS. These changes may contribute toward a restoration and shift in the circadian rhythm of BP from a nondipping to a dipping pattern. However, further studies are needed to determine whether such changes are beneficial. Study limitations
The major limitation of the present study was the relatively small number of patients (the participants were selected from among normotensive individuals). Another limitation is that the cross-sectional design limited our ability to determine whether the nondipping BP status in patients with MS was improved or not through restriction of salt intake and the use of diuretics. In addition, cardiac output and target organ damage secondary to abnormalities such as microalbuminuria, a high left ventricular mass index, cardiac remodeling, and hypertrophy have not been investigated in nondipping patients with MS [11,29]. Consequently, the current study shows the following: (a) The circadian BP rhythm is impaired and the incidence of nondipping BP is higher in patients with MS than in normal patients. (b) An interesting finding of this study is that the incidence of nondipping increased with decreasing MVA. (c) We believe that autonomic nervous system dysfunction in patients with MS may be efficiently detected using ABPM.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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80
Blood Pressure Monitoring 2014, Vol 19 No 2
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Impaired circadian rhythm of blood pressure in normotensive patients with rheumatic mitral valve stenosis Musa Cakicia, Adnan Doganc, Muhammed Oylumluc, Fatih Uckardesb and Vedat Davutoglud Background The aim of the present cross-sectional study was to evaluate either non-dipper-type or dipper-type circadian rhythm of blood pressure (BP) in normotensive rheumatic mitral stenosis (MS) patients. Methods and results Eighty-eight normotensive rheumatic mitral valve disease (RMVD) patients and 41 normal participants were enrolled in the study. All participants underwent ambulatory blood pressure monitoring. Nocturnal BP dipping was calculated as follows: (awake BP – asleep BP) ¾ 100/awake BP. Patients with a nocturnal reduction in average daytime systolic BP and diastolic BP of less than 10% were classified as nondippers. Patients with RMVD were divided into two groups with respect to the top and bottom 1.5 cm2 of the mitral valve area (MVA). There was a highly significant relationship between the two groups with control in the frequency of a nondipping status (v2 = 22.721; d.f. = 2; P < 0.001). Afterwards, the Mann–Whitney U-test was used to compare the two groups and the control group. There was no difference in the frequency of nondipping between patients with an MVA of greater than 1.5 cm2 and the control group (P > 0.05). However, the nondipping level was
Introduction Since the development and clinical application of ambulatory blood pressure monitoring (ABPM), various studies have shown that assessment of the circadian blood pressure (BP) profile is more predictive than office BP readings in estimating cardiovascular risk [1,2]. Arterial BP shows a circadian-type rhythm. This refers to the daily variation in BP, which is generally higher during the day than at night [3]. A number of studies have reported the lack of a nocturnal BP fall, known as nondipping BP [4]. The underlying mechanisms responsible for the blunted nocturnal fall in BP are not completely understood. Nevertheless, there is some evidence to suggest that patients with nondipping BP show impairment in the autonomic system, including abnormal parasympathetic and increased sympathetic nervous system activity [5,6]. Therefore, overactivity of the sympathetic nervous system has been found in patients with mitral stenosis (MS) [7]. Increased sympathetic outflow may impair the circadian rhythm of BP in patients with MS because the sympathetic vascular tone is predominant during the day, whereas the parasympathetic vascular tone is predominant at night [8]. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 1359-5237
higher in patients with an MVA of less than 1.5 cm2 than in the control group and in patients with RMVD with an MVA of greater than 1.5 cm2 (P < 0.001 and 1.5 mg/dl), hepatic failure, a history of coronary artery disease, stroke, arrhythmia, diabetes mellitus, and/or those currently smoking, low ejection fraction (< 50%), moderate or severe mitral and/or aortic regurgitation, aortic stenosis, and organic tricuspid valve disease patients were excluded. Those not smoking for at least the last 2 years were considered as nonsmokers. Avoidance of exercise during 24-h ambulatory monitoring was recommended for all participants. The study protocol was approved by the Local Research Ethics Committee and all participants provided their informed consent before being enrolled. Echocardiographic data
Echocardiographic examinations were carried out using a cardiac ultrasound system (Vivid 7; GE Healthcare, Wauwatosa, Wisconsin, USA) for each participant. To determine the transmitral valve gradient, four-chamber apical view was used with the sample volume placed at the mitral valve coaptation point. Transmitral valve gradient was defined as the mean of gradients obtained from three consecutive beats obtained by a continuouswave Doppler study. MVA was measured by planimetry of the mitral valve in short axis view and the mean of three measurements in three different beats was considered as final. MVA of 1 cm2 or less were considered to be very severe, 1–1.5 cm2 were considered to be moderate, and greater than 1.5 cm2 were considered to be mild cases. Color-flow Doppler was used to detect the presence of associated valvular insufficiencies, which were additionally confirmed by Doppler studies. Patients with aortic stenosis and those with moderate or severe mitral and aortic regurgitation were excluded from the study. The modified Bernoulli equation derived from the tricuspid regurgitation jet velocity and estimated right atrial pressure from inferior vena cava collapsibility was used to determine systolic pulmonary artery pressure [9]. The mean pulmonary artery pressure was calculated using the Masuyama method [10]. 24-h ambulatory blood pressure monitoring
Twenty-four-hour noninvasive ABPM using a portable compact digital recorder automatic device was carried out on a weekday (PhisioQuant; EnviteC-Wismar GmbH, Wismar, Germany). To obtain diurnal values, diurnal readings at 20-min intervals (07:00–23:00 h) and nocturnal readings at 30-min intervals (23:00–07:00 h) were recorded. Asleep and awake periods were assessed on the basis of the information obtained from the patients. Asleep BP was defined as the average of BP from the time when the participants went to bed to the time they got out of bed, and awake BP was defined as the average of BP recorded during the rest of the day. The formula 2/ 3 diastolic BP + 1/3 systolic BP was used to calculate
the mean arterial pressure. The nocturnal BP dipping was calculated as follows: (awake mean BP – asleep mean BP) 100/awake mean BP. According to the criterion of Verdecchia et al. [11], patients with a nocturnal reduction in the average daytime systolic BP and diastolic BP of less than 10% were classified as nondippers, whereas those with night-time reduction of 10% or more were classified as dippers [12]. Statistical analysis
Statistical analysis was carried out using SPSS 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA). The onesample Kolmogorov–Smirnov test was used to determine whether the data were distributed normally. The results were reported as mean±SD. Groups were compared using the independent two-sample t-test or the Mann–Whitney U-test, whichever was appropriate. The relationship between nondipping state and groups was compared using a w2-test and was expressed as counts or percentages. Correlation analysis was carried out using Spearman’s test. The backward binary logistic regression analysis was carried out to determine predictive factors for nondipping participants from statistically related confounding variables. A P value of less than 0.05 was considered statistically significant.
Results The baseline characteristics, laboratory values, and echocardiographic findings of normotensive patients with RMVD and a control group are presented in Table 1. The group of patients with RMVD was compared with the control group. There was no significant difference between the groups in terms of age, sex, BMI, plasma urea, plasma creatinine, hemoglobin, day and night-phase systolic/diastolic BP values (P > 0.05). Only left atrial diameters were higher in the RMVD group than in the control group. Therefore, 58 patients within the RMVD group were diagnosed with MS. MS was defined as an MVA of less than 2 cm2. A total of 37 patients with MS had an MVA of less than 1.5 cm2. Patients with RMVD were divided into four groups with respect to MVA. The relationship of dipping and nondipping status between the groups with respect to the MVA is presented with a histogram in Fig. 1. There was a much more significant relationship between the groups in the percentage of a nondipping status (w2 = 23.231; d.f. = 4; P < 0.001). The level of nondipping increased with decreasing MVA (Fig. 1). Afterwards, the Mann–Whitney U-test was used to compare the control group and group 2, which included patients with nonobstructive RMVD. There was no difference in the percentage of nondipping between groups (17.1 vs. 16.7%; P = 0.087, respectively) (Fig. 1). In addition, patients with RMVD were again divided into two groups with respect to the top and bottom 1.5 cm2 of the MVA and compared with the control group. There was a highly significant relationship between the two
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78 Blood Pressure Monitoring 2014, Vol 19 No 2
Baseline characteristics and echocardiographic findings in normotensive patients with rheumatic mitral valve disease and the control group
Table 1
Age (years) Sex (male/female) Plasma urea (mg/dl) Plasma creatinine (mg/dl) BMI (kg/m2) Hemoglobin (g/dl) Left atrial diameter (cm) Mean transmitral gradient (mmHg) Mitral valve area (cm2) Mean pulmonary artery pressure (mmHg) Night-phase systolic blood pressure (mean) (mmHg) Night-phase diastolic blood pressure (mean) (mmHg) Night-phase mean blood pressure (mean) (mmHg) Day-phase systolic blood pressure (mean) (mmHg) Day-phase diastolic blood pressure (mean) (mmHg) Day-phase mean blood pressure (mean) (mmHg)
Dipping (n = 86)
Rheumatic mitral valve disease patients (n = 88)
Control group (n = 41) P values
38.20±8.63 42/46 30.60±5.76 0.70±0.11 26.75±3.73 13.44±1.41 3.87±0.6 8.88±4.32
36.20±11.03 0.409 19/22 0.881 31.51±5.09 0.388 0.69±0.10 0.938 26.22±3.11 0.434 13.26±1.51 0.508 3.16±0.25 < 0.001 – –
1.36±0.38 40.24±8.35
– –
– –
104.25±9.34
104.92±13.74
0.745
61.63±7.52
59.60±8.69
0.177
75.83±7.57
74.71±10.07
0.485
114.01±8.77
117.34±12.40
0.083
69.38±7.78
69.26±8.18
0.939
84.44±7.72
85.29±9.27
0.587
Fig. 1
Percentage
90 80
Dipping
70
Nondipping
60 50
Comparison of groups in the change of blood pressure (dipping and nondipping group)
Table 2
(2: 23.231, d.f.: 4, P < 0.001)
40 30 20 10 0 Group 1 Group 2 Group 3 Group 4 Group 5
Distributions of dipping and nondipping state according to the mitral valve area (MVA) are shown with histograms. Group 1, control; group 2, rheumatic mitral valve disease (RMVD) patients with MVA > 2 cm2; group 3, RMVD patients with MVA 2–1.5 cm2; group 4, RMVD patients with MVA 1.5–1 cm2; group 5, RMVD patients with MVA < 1 cm2.
groups with control in the level of nondipping (w2 = 22.721; d.f. = 2; P < 0.001). Afterwards, the Mann–Whitney U-test was used to compare the two groups and the control group. There was no difference in the level of nondipping between patients with an MVA of greater than 1.5 cm2 and the control group (25.5 vs. 17.1%; P > 0.05, respectively). However, the nondipping percentage was higher in patients with an MVA of less than 1.5 cm2 than in the control group and in patients with RMVD with an MVA of greater than 1.5 cm2 (64.9 vs. 17.1%; P < 0.001 and 64.9 vs. 25.5%; P < 0.001, respec-
Nondipping (n = 43)
P values
Age (years) 37.91±10.35 36.88±7.43 0.565 Sex (male/female) 38/47 23/21 0.418 Plasma urea (mg/dl) 31.22±5.01 30.25±6.48 0.347 Plasma creatinine (mg/dl) 0.68±0.09 0.70±0.12 0.865 26.4±3.7 27.1±3.1 0.479 BMI (kg/m2) Hemoglobin (g/dl) 13±1.49 13.5±1.34 0.610 Left atrial diameter (cm) 3.4±0.52 4.02±0.70 0.000 Mean transmitral gradient (mmHg) 7.5±4.1 10.1±4.2 0.027 1.49±0.39 1.26±0.33 0.020 Mitral valve area (cm2) Mean pulmonary artery pressure 38±8.7 42±7.7 0.049 (mmHg) Night-phase systolic blood pressure 101.64±9.63 110.12±11.16 < 0.001 (mean) (mmHg) Night-phase diastolic blood pressure 59.37±6.97 64.23±8.82 < 0.001 (mean) (mmHg) Night-phase mean blood pressure 73.46±7.28 79.51±9.17 < 0.001 (mean) (mmHg) Day-phase systolic blood pressure 115.29±9.86 114.64±10.79 0.731 (mean) (mmHg) Day-phase diastolic blood pressure 70.23±7.17 67.57±8.98 0.070 (mean) (mmHg) Day-phase mean blood pressure 85.45±7.69 83.25±9.11 0.153 (mean) (mmHg)
tively). The day and night variations in BP in the dipping and nondipping groups are shown in Table 2. When we divided the entire sample population into dipping and nondipping groups, the night-phase systolic/diastolic/ mean BP, left atrial diameter, mean transmitral gradient, and mean pulmonary artery pressure were statistically higher (P < 0.001, P = 0.001, P < 0.001, P < 0.001, P = 0.027, and P = 0.049, respectively) and the MVA was statistically lower (P = 0.020) in the nondipping group than in the dipping group. A nondipping BP was correlated negatively with the MVA (P = 0.024; r = – 0.295), correlated positively with the mean transmitral gradient (P = 0.018; r = 0.310), correlated positively with the mean pulmonary artery pressure (P = 0.032; r = 0.281), and correlated positively with the left atrial diameter (P < 0.001; r = 0.310). Binary logistic regression analysis was carried out using the backward method to identify the variables associated with a nondipping status, including all statistically correlated factors (MVA, mean transmitral gradient, mean pulmonary artery pressure, and left atrial diameter). Only the MVA was determined to be a predictive factor of nondipping BP (P = 0.024) among these variables.
Discussion The major finding of the current study is that MS significantly altered the circadian rhythm of BP, reducing the BP dipping pattern. To the best of our knowledge, these findings have not been reported previously. The level of nondipping BP increased with a decreasing MVA. The level of nondipping BP was similar between patients with RMVD in whom the MVA was greater than 2 cm2 and the normal participants (Fig. 1). Therefore, the level of nondipping BP was significantly higher in patients with
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Impaired circadian rhythm of blood pressure Cakici et al. 79
MS in whom the MVA was less than 1.5 cm2 than in the normal participants and patients with an MVA of greater than 1.5 cm2. These results suggest that nondipping is associated with obstruction of the mitral valve rather than the nature of RMVD and that sympathetic activity (SA) increases when the MVA declines to less than 1.5 cm2. These results are very important because RMVD is still endemic in some countries. BP normally decreases (dips) during sleep, and individuals whose BP dips 10% or less from their daytime baseline BP have been referred to as ‘nondippers’ [12–14]. Nondipping BP is associated with target organ damage and cardiovascular events, independent of the overall BP. The mechanisms of nondipping BP are unclear, and the underlying pathophysiologic processes are not yet fully understood. In developing countries, RMVD remains a significant public health disease. Yuce and colleagues recently reported that RMVD is still endemic in our region [15–17]. Although all of the cardiac valves may be involved in the rheumatic process, the mitral valve is most prominently involved [18]. Obstruction of this valve reduces cardiac output and increases left atrial pressure, which may alter hemodynamics significantly. Elevated left atrial pressure and/or reduced cardiac output may alter SA through cardiopulmonary mechanisms [19]. Ashino and colleagues reported that autonomic nervous system dysfunction in patients with MS may be associated with (a) reduction in cardiac output: a significantly decreased stroke index in patients with congestive heart failure has been related to sympathetic activation in these patients, and a similar mechanism may play a role in patients with MS; (b) increased atrial or pulmonary arterial pressure: the increase in left atrial or pulmonary arterial pressure may alter SA through cardiopulmonary mechanisms; and (c) atrial stretch: stretching the atrium produces a definite increase in SA [20,21]. Overactivity of the sympathetic nervous system has been found in patients with MS [7]. Moreover, there is some evidence to suggest that nondipping BP is associated with autonomic nervous system dysfunction, including abnormal parasympathetic and increased sympathetic nervous system activity [5,6]. As a result, it is plausible to consider an impaired circadian rhythm of BP in patients with MS for these reasons. We already identified a close relationship between nondipping BP and MS despite the fact that the daytime and night-time BPs remained within normal ranges. In this study, impairment of the circadian BP rhythm in patients with MS may be explained by two possible mechanisms. First, vascular tone may be impaired in patients with MS because of increased SA depending on any of the mechanisms mentioned above because parasympathetic tone is predominant for vascular tone during the night [8]. All-day increased sympathetic tone in patients with MS
may prevent the reduction in BP during the night by modifying the vascular tone. Second, release of renin– angiotensin–aldosterone causes retention of body fluids, which increases extracellular volume in patients with MS. The circadian rhythm of BP may be altered for this reason because some authors have proposed that the pathophysiologic processes underlying a nocturnal nondipping profile involve abnormalities in extracellular volume [22,23]. Consequently, we believe that the circadian rhythm of BP might be impaired in patients with MS because of the two possible mechanisms. The results of our study showed that the mean transmitral gradient, mean pulmonary artery pressure, left atrial diameter, and MVA were correlated modestly with nondipping. In addition, the relationship between the left atrial diameter and nondipping was very important (P < 0.001). This result supports the idea that stretching of the atrium produces a definite increase in SA. However, only a decreased MVA was determined to be a predictive factor among the correlated variables. Uzu et al. [24–26] showed that sodium intake restriction and diuretics restored the circadian rhythm into a dipping pattern. These findings consistently indicated the important role of sodium retention in the genesis of the nondipping pattern of the circadian BP rhythm [27,28]. On the whole, we, as cardiologists, recommend restriction of salt intake and the intermittent use of diuretics to restore shortness of breath in patients with MS. These changes may contribute toward a restoration and shift in the circadian rhythm of BP from a nondipping to a dipping pattern. However, further studies are needed to determine whether such changes are beneficial. Study limitations
The major limitation of the present study was the relatively small number of patients (the participants were selected from among normotensive individuals). Another limitation is that the cross-sectional design limited our ability to determine whether the nondipping BP status in patients with MS was improved or not through restriction of salt intake and the use of diuretics. In addition, cardiac output and target organ damage secondary to abnormalities such as microalbuminuria, a high left ventricular mass index, cardiac remodeling, and hypertrophy have not been investigated in nondipping patients with MS [11,29]. Consequently, the current study shows the following: (a) The circadian BP rhythm is impaired and the incidence of nondipping BP is higher in patients with MS than in normal patients. (b) An interesting finding of this study is that the incidence of nondipping increased with decreasing MVA. (c) We believe that autonomic nervous system dysfunction in patients with MS may be efficiently detected using ABPM.
Acknowledgements Conflicts of interest
There are no conflicts of interest.
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