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Nondipping of Nocturnal Blood Pressure Is Related to Urinary Albumin Excretion Rate in Patients With Type 2 Diabetes Mellitus
AJH 1996;9:1139-1143
Nondipping of Nocturnal Blood Pressure Is Related to Urinarv Albumin Excretion Rate in Patients With Type 2 Diabetes Mellitus S. Equiluz-Bwck, C. Scknack, H.P. Kopp, and G. Schemthaner
Although cardiovascular and cerebrovascular morbidity and mortality in type 2 diabetic patients is closely related to urinary albumin excretion rate (UAER), the causative mechanisms are not yet identified. The aim of our study was to define the circadian variation of blood pressure (BP) in 72 type 2 diabetic patients (mean age 60 years, mean diabetes mellitus duration: 12 years) in comparison with 41 nondiabetic controls with essential hypertension (mean age 58 years) by using ambulatory blood pressure measurement. Thirty diabetic patients had normal UAER ( <30 mg/24 h), 27 had microalbuminuria (30 to 300 mg/24 h), ancl 15 had persistent proteinuria ( >300 mg/24 h). Systolic blood pressure during both nighttime and daytime was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls and patients with normal UAER. During nighttime even type 2 diabetic patients with microalbuminuria had significantly
elevated systolic blood pressure compared to controls with essential hypertension. We also observed a correlation of nocturnal blood pressure to UAER (systolic: r = 0.32, P < .007 and diastolic: r = 0.24, P < .04). Nondipping (defined as a reduction of nocturnal BP
H
type 2 diabetes mellitus. The information regarding 24-h blood pressure measurements in type 2 diabetics with normal and increased albumin excretion rate is very limited. Microalbuminuria is considered as a strong predictor of clinical overt nephropathy45 in type 1 diabetes mellitus; in type 2 diabetes mellitus end-stage renal disease develops in a much smaller number of patients. Undoubtable, cardiovascular and cerebrovascular morbidity and mortality are frequent in type 2 diabetes mellitus and closely related to urinary albumin excretion rate (UAER) and hypertension.6-8 Usually the diagnosis of hypertension is done after
ypertension and type-2 diabetes are frequently associated. Moreover, patients may have essential hypertension years before the diagnosis of diabetes mellitus is made. It is also known that increased albumin excretion rate is associated with a rise in blood pressure in
Received April 18, 1995. Accepted July 1, 1996. From the Department of Medicine I, Rudolfstiftung Hospital Vienna, Vienna, Austria. Address correspondence and reprint requests to Professor Guntram Schernthaner, Department of Medicine I, Rudolfstiftung Hospital Vienna, Juchgasse 25, A-11330Vienna, Austria.
01996 by the American ]ownal of Hypertension, Ltd. Published by Ekevim Science, Im.
KEY WORDS: Urinary albumin excretion, diabetes mellitus, circadian variation, nocturnal blood pressure drop, microalbuminuria, hypertension.
0895-7061/96/$15.00 PI1 S0895-7061(96)00302-0
1140 EQUILUZ-BRUCK ET AL
repeated single measurements of blood pressure, but these might be influenced by the phenomenon of “white-coat hypertension.” ‘)-kl Nowadays, ambulatory 24-h blood pressure measurements represent a well established technique that allows the documentation of the circadian variation of blood pressure and the effectiveness of antihypertensive treatment.”[2The aim of our study was to define the circadian variation of blood pressure in a representative number of type 2 diabetic patients and to evaluate the relationship to urinary albumin excretion rate. PATIENTS AND METHODS Seventy-two type 2 diabetic patients (43 men, 29 women ) were compared to a group of 41 nondiabetic controls (17 men, 24 women) with essential hypertension (mean age: 58 years; mean body mass index: 27 ~ 4 kg /m2). Patients with secondary hypertension were excluded from our study. The mean age of the diabetic patients (60 years ), the mean duration of diabetes mellitus (12 years), and the mean body mass index (28 kg /m2) were not different between the three groups of diabetic patients and controls: thirty patients had a normal UAER ( <30 mg/ 24 h), 27 had microalbuminuria (30 to 300 mg /24 h), and 15 persistent macroproteinuria ( >300 mg /24 h). After the inclusion of 30 patients with normal UAER only, patients with increased UAER were further analyzed. Among the type 2 diabetics, mean albumin excretion was 15.1 & 4.6 (range 8 to 24.9) mg /24 h in the normoalbuminuric group, 93.2 ~ 55.7 (30 to 235) mg/24 h in the patients with microalbuminuria, and 1019 f 992 (303 to 4180) mg /24 h in the macroalbuminuric group. The mean UAER of the controls with essential hypertension was 17.3 ~ 5.1 (8 to 27) mg /24 h. Only patients with normal UAER were included. Serum creatinine levels were similar in the normoalbuminuric patients (1.06 f 0.2 mg/dL), in the microalbuminuric group (1.02 t 0.5 mg/dL), and in the controls (1.01 ~ 0.4 mg /dL), whereas the macroalbuminuric patients had significantly higher serum creatinine ( 1.67 ~ 0.6 mg / dL) levels. The diabetic patients were treated with diet alone (n = 16), oral hypoglycemic agents (n = 32), or insulin (n = 24). The antihypertensive treatment of the patients and controls is shown in Table 1. Ambulatory 24 h blood pressure measurement (ABPM) was performed using a oscillometric recorder (SpaceLabs 90207, Redmond, WA); measurements with this device have a strong correlation to auscultation. This recorder satisfies the validation requirements of ABPM and has a proven accuracy.13Blood pressure was measured in intervals of 20 min during the daytime and 30 min during the night. Patients were hospitalized, but free to move in the hospital area during the daily measurements. Recordings were started between 08:00 and 09:00 and ed-
A/H-N0VEMi3ER 1996-VOL. 9, NO. 11, PART 1
TABLE 1. ANTIHYF’ERTENSIVE TREATMENTOF THE DIABETICF’ATIENTSAND CONTROLS Albuminuric’ Antihypertensive Normo Micro Macro Drugs h = 30) (n = 27) (n = 15) ACE inhibitor Ca antagonist a-Blocking agents ,L-Blockingagents Others No treatment Multiple treatment
14 10 4 2 3 10 10
19 14 5 3 3 0 14
13 11 5 1 3 0
12
Controls (n = 41)
27 18 6 3 6 6 19
“ Diabetic patients,
ited automatically. If the recordings had less than go~o of completed measurements, they were discarded. Systolic and diastolic blood pressure were averaged for each hour, and further separated into daytime, considered as 06:00 to 22:00, and nighttime, between 22:00 and 06:00. We also calculated the means and standard deviations for blood pressure and separated them into a daytime and nighttime period. In addition, the percentage of measurements higher than 140/90 mm Hg (defined normal range) and the heart rate profile were examined. Mean arterial blood pressure was calculated by the recorder as the quotient of the integrated area under the curve for systolic blood pressure divided by the duration of pulse rate. Usually blood pressure is reduced during the night; the mean range is 10Yoto ls~o.14 In our study “nondipping” was defined as a reduction of nocturnal blood pressure of <10%. Repeated single measurements of blood pressure were taken in the usually way during the daytime; each patient had 3 to 6 checks a day. UAER was measured by a immunoturbidimetric test for the quantitative determination of human albumin in urine (Tina Quant, Boehringer Mannheim, Mannheim, Germany) using the Hitachi BM 704/717 system (Tokyo, Japan) (detection limit for urinary albumin concentration: 4 mg /L) and assessed as the mean of three 24-h urine samples. Blood samples were taken after an overnight fast; plasma glucose, hemoglobin Al. (by HPLC), serum cholesterol, triglycerides, HDL and LDL, and serum creatinine were analyzed with standard laboratory techniques. Statistical Analysis Data were expressed as mean ~ SD. Comparisons of subgroups with patients of the control group were performed using paired t tests for parametic data, with X2 tests as appropriate. Simple linear regression analysis was used to evaluate the correlation between two parameters. Statistical significance was considered for P < .05. SAS Statistical Software was used for all calculations. (SAS Institute, Cary, NC)
1141
AJH-NOVEMBER 1996-VOL.. 9, NO. 11, PART 1 NONDIPPING OF NOCTURNAL BP IN TYPE 2 DIABETES MELLITUS
TABLE 2. ABPM DURING
Systolic BP Normoalbuminuric Microalbuminuric Macroalbuminuric Controls “ P < .01,t
139 f 145 t 149 t 137 f
18* 15* 19+ 16+
DAYTIME
Diastolic BP 82 85 86 79
~ ~ ~ *
10 10 10+ 15$
(06:00 TO 22:00)
Mean Arterial BP
Heart Rate
102 t 12t 107 t 12t 108 f 11 100 t 12
79 ~ 16 833 16+ 74 t 10*
76 ~ 11
P < ,002 + P <.05.
RESULTS
sure and albumin excretion rate, whereas during daytime no significant relationship between blood pressure and albumin excretion was found. The analysis of correlation of albumin excretion rate to blood pressure values in the subgroups of diabetic patients with normo-, micro-, and macroalbuminuria were not significant. The phenomenon of nondipping was not influenced by antihypertensive treatment or by the intake of ACE inhibitors, further the time of antihypertensive treatment did not influence our data. Furthermore, heart rates were higher in the diabetic patients with macroalbuminuria compared to the patients with essential hypertension (Tables 2, 3). During the night time macroalbuminuric diabetic patients had significantly elevated heart rates compared to diabetic patients with normoalbuminuria (Table 3). Repeated single measurements of blood pressure during the daytime showed significantly higher systolic blood pressure levels than those of the ambulatory blood pressure measurements ( 152 t 23 u 144 ~ 18 mm Hg, P < .001), but there was no significant difference in the diastolic blood pressure (85 ~ 11 ZJ 84 t 10 mm Hg). A strong correlation between ABPM and repeated single measurements was found (r = 0.62; P < .0003).
The data for the blood pressure levels and heart rates for daytime and nighttime are shown in Tables 2 and 3, respectively. Du~ing the-time between 06:00 and 22:00 (Table 2), we found higher systolic and diastolic blood pressure values in patients with macroalbuminuria compared to controls and normoalbuminuric type 2 diabetic patients. Diastolic blood pressure was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls. Mean arterial blood pressure was elevated in micro- and macroalbuminuric type 2 diabetic patients compared to controls (and in macroalbuminuric patients compared to type 2 diabetic patients with normoalbuminuria). In the nighttime period (between 22:00 and 06:00), there was a significant increase of systolic blood pressure and mean arterial blood pressure in type 2 diabetic patients with macroalbuminuria compared to controls and normoalbuminuric type 2 diabetic patients. Systolic blood pressure was significantly elevated compared to controls also in type 2 diabetic patients with microalbuminuria. The differences in diastolic blood pressure were not significant (Table 3). According to the definition of nondipping, 37% of the controls, 43Y0of the type 2 patients without albuminuria, 67$Z0 of the patients with microalbuminuria, and 80Y0of the patients with persistent macroalbuminuria were nondippers (Number of nondipping patients in the control group, diabetic patients with normal albumin excretion compared to diabetic patients with micro- and macroalbuminuria: X2: P < .05). For the diabetic patients we observed a correlation during nighttime between both systolic (r = 0.32, P < .007) and diastolic ( r = 0.24, P < 0.005) blood pres-
DISCUSSION The main findings of this study are threefold. First, there was a significant increase of arterial blood pressure during both daytime and nighttime in type 2 diabetic patients with macroalbuminuria compared to patients with essential hypertension (Controls). During the nighttime, even type 2 diabetic patients with microalbuminuria had a significantly elevated systolic
TABLE 3. ABPM DURING NIGHTTIME (22:00 TO 06:00) Systolic BP Normoalbuminuric Microalbuminuric Macroalbuminuric Controls
* P <.01, t P <.05.
125 137 146 129
~ t t *
80’ 21* 21’ 21*
Diastolic BP 72 75 79 72
f f + ~
10 11 10 12
Mean Arterial BP 91 98 104 93
~ t t ~
12+ 13t 13t lqt
Heart Rate 66 68 73 63
? ? t f
9+ 7t 18* 10*
1142 EQUILUZ-BRUCK ET AL
blood pressure compared to patients with essential hypertension. Second, there was a high incidence of the phenomenon of nondipping of nocturnal blood pressure in type 2 diabetic patients with an elevated albumin excretion rate compared to patients with a normal albumin excretion rate or patients with essential hypertension. Third, a correlation of nighttime blood pressure (systolic and diastolic) to urinary albumin excretion rate was documented, although during daytime no correlation was found. The circadian blood pressure rhythm is the result of various activities of the hypothalamus, which causes a number of hormonal actions. This regulation overlaps the influence of exogenous events, eg, sleep distur. bance. Measurement of serum cathecholamines shows the highest level in the early morning. ’s-[s Similarly, a circadian rhythm exists for heart constriction, ADPinduced aggregability of platelets, and the activity of the clotting system.1’JJ2[’ Steady stimulation of the renin-angiotensin system and serum cathecholamines might be responsible for the lack of decreasing blood pressure at night. There are some events known to be associated with nondipping, eg, secondary hypertension, heart failure, sleep disturbances, shift working, autonomic neuropathy, left ventricle hypertrophy, and performed cardiac transplantation.2’-2’ Nondipping is potentially caused by several mechanisms, such as left ventricle hypertrophy,2s autonomic neuropathy,” and overhydration,’” which have to be clarified in prospective studies. In our study, the phenomenon of nondipping was frequently found in type 2 diabetic patients with elevated UAER. The diabetic patients with macroalbuminuria had higher heart rates than diabetic patients with normal albumin excretion rate and controls. Hausmann et a12gfound an accumulation of silent ischemia as well as cardiac infarction in the early morning in nondiabetic patients. Pasqualetti et also showed in his study an increased frequency for cerebral strokes in nondiabetic patients. However, more of the patients with type 2 diabetes were dying from cerebral stroke and cardiac arrest. Our data suggest that the high frequency of nondipping in type 2 diabetic patients with an increased albumin excretion rate may partially explain the high cardiovascular morbidity and mortality in these patients. Further, the heart rate profiles of our patients also indicate a connection to autonomic neuropathy, as previously suggested.” It might further be speculated that the phenomenon of nondipping of nocturnal blood pressure might precede microalbuminuria in type 2 diabetes. If so, then it should be clarified in prospective studies as to whether intensified antihypertensive treatment prevents the development of microalbuminuria in these patients. Schmitz et alq2described an increase of blood pres-
A/H-NOVEMBER 1996-VOL, 9, NO. 11, PART 1
sure in type 2 diabetic patients, regardless of the prevalence of microalbuminuria. Nevertheless, a correlation of 24 h systolic blood pressure to UAER in patients with microalbuminuria was described, whereas in patients with normal UAER no such correlation was found. However, day and night data were not separated. Nakano et al found a high presence of reversed circadian blood pressure variation with a peak value during night. However only normotensive type 2 diabetic patients were included. The prevalence and degree of autonomic neuropathy and nephropathy were greater in the diabetic patients with this disturbed circadian variation of blood pressure.33 Very recently, a close relationship of increased UAER to the presence of hypertension (documented by ambulatory 24 h blood pressure measurements) was observed in type 2 diabetic patients. Albuminuria, however, was not related to the increased erythrocyte sodium-lithium countertransport, which is associated with diabetic nephropathy in type 1 diabetics, suggesting that different mechanisms determine microalbuminuria in type 1 and type 2 diabetes mellitus.q4In this study, however, the phenomenon of nondipping of nocturnal blood pressure was not observed, but only 20 patients with elevated albumin excretion rate ( >15 ~g /rein) were analyzed. Our data also show the high prevalence of the white-coat phenomen and may indicate the more frequent use of ABPM. The use of ABPM, rather than single measurements, may result in early detection and optimized antihypertensive treatment in relation to the circadian variation of blood pressure of those patients. In our study, it was demonstrated that albuminuria correlates with both systolic and diastolic blood pressure at night and with the phenomenon of nondipping in type 2 diabetic patients. Because of the high cardiovascular mortality of these patients, prospective longterm studies are necessary to evaluate the possible benefits of reduction of nocturnal blood pressure levels. REFERENCES 1.
Schnack CH, Scheithauer W, Gisinger CH, et al: Prevalence of microalbuminuria in maturity onset primarily non-insulin requiring diabetes mellitus: effect of disease duration, glycemic control, and mean systemic blood pressure. J Diabetic Complications 1987;l:132136.
2
Gall MA, Rossing P, Skott P: Prevalence of micro- and macroalbuminuria, arterial hypertension, retinopathy and large vessel disease in European type-2 (non–insulin-dependent) diabetic patients. Diabetologia 1991; 34:655-661.
3
UKPDS III: Prevalence of hypertension and hypotensive therapy in patients with newly diagnosed diabetes: a multicenter study. Hypertension 1985;7:l181113,
AJH-NOVEMBER 1996-VOL. 9, NO. 11, PART 1 NONDIPPING OF NOCTURNAL BP IN TYPE 2 DIABETES MELLITUS
4
Viberti GC, Jarett RJ, Mahud V, et al: Microalbuminuria is a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 19t32;i:1430-1432.
5
Mogensen CE, Christensen CK: Predicting diabetic nephropathy in insulin-dependent patients. N Engl J Med 1984;311:89-93.
6.
Mathiesen E, Ronn RB, Jensen T, et al: Relationshiop between blood pressure and urinary albumin excretion in development of microalbuminuria. Diabetes 1990; 39:245-249.
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Tofler GH, Brezinski D, Schafer AL, et al: Concurrent morning increase in platelet aggreability and the risk of myocardial infarction and sudden cardiac death, N Engl J Med 1987;316:1514-1518.
21.
Padfield PL, Stewart MJ: Ambulatory blood pressure monitoring in secondary hypertension. J Hypertens 1991;9(suppl 8):69-71.
22.
Seidel WF, Roth T, Roehrs T, et al: Treatment of 12h shift of sleep with benzodiazepines. Science 1984; 244:1262-1264.
Schmitz A, Vaeth M: Microalbuminuria: a major risk factor in non–insulin-dependent diabetes; a ten year follow-up study of 503 patients. Diabetic Med 1988; 5:126-134.
23.
Chau NP, Mallion JM, de Gaudermaris R: 24 h ambulatory blood pressure in shift workers. Circulation 1989; 80:341-347.
24.
8. Jarett RJ, Viberti GC, Argyropoulos A, et al: Microalbuminuria predicts mortality in non–insulin-dependent diabetics, Diabetic Med 1984; 1:17-19.
Guilleminault C, Mondini S, Hayes B: Diabetic autonomic dysfunction, blood pressure and sleep. Am Cardiol 1985;55:801-806.
25.
Verdeccia P, Schillaci GH, Guerrieri M: Circadian blood pressure changes and left ventricle hypertrophy in essential hypertension. Circulation 1990;81:528–536.
26.
Reaves RA, Shapiro AP, Thompson ME, Johnson AM: Loss of nocturnal decline in blood pressure after cardiac transplantation. Circulation 1986; 73:401-408.
27.
Gambardella S, Frontoni S, Spallone V,’~t al: Increased left ventricular mass in normotensive diabetic patients with autonomic neuropathy. Am J Hypertens 1993; 6:97-102.
7.
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Pickering TG, James GD, Boddie C, et al: How common is white coat hypertension? JAMA 1988;259:225–228.
10. O.Brien E, O.Malley K: Overdiagnosing hypertension, Br Med J 1988; 197:1211-1213. 11. Middeke M, Kltiglich M, Jahn M, et al: Praxishypertonie oder permanence Hypertonic? (in German). Muench Med Wochenschr 1990; 132:768-771. 12. Schrader J, Schoel G: Benefits of non-invasive blood pressure monitoring during hypertensive treatment. J Ambul Monit 1990;3:203-214. 13. Cates E, Schliissel YR, James GD, Pickering TG: A validation study of SpaceLabs 90207 ambulatory blood pressure monitoring. 1989 (Zulassungsunterlagen).
28. Mulec H, Blohme G, Kullenberg K, et al: Latent overhydration and nocturnal hypertension in diabetic nephropathy. Diabetologia 1995;38:216-220. 29.
15. Turton MB, Deegan T: Circadian variations of plasma cathecolamines cortisol and concentrations in supine subjects. Clin Chim Acta 1974;55:389–397.
Hausmann D, Nikutta P, Hartwig CA, et al: StStrecken-Analyse in 24-h-Langzeit-EKG bei Patienten mit stabiler Angina pectoris und angiographisch nachgewiesener Koronarsklerose (in German). Z Kardiol 1987; 76:554–562.
30.
Lemmer B: Temporal aspects of the effects of cardiovascular drugs in humans, in Lemmer B (ed ): Chronopharmacology: Cellular and Biochemical Interactions. Marcel Dekker, New York–Basel, 1989, pp 525–541.
Pasqualetti P, Natali G, Casale R, Colantonio D: Epidemiological chronorisk of stroke. Acta Neurol Scand 1990;81:71-74,
31.
Liniger C, Favre L, Assal JPH: 24 h heart rate profiles of diabetic patients with abnormal cardiovascular reflexes. Diabetic Med 1991;8:420-427.
32.
Schmitz A, I’edersen MM, Hansen KW. Blood pressure by 24 h ambulatory blood pressure monitoring in type11 diabetics in relationship to urinary albumin excretion. Diabetes Metab Rev 1991; 17:301–307,
33,
Nakano S, Uchida K, Kigoshi T, et al: Circadian rhythm of blood pressure in normotensive NIDDM subjects. Its relationship to microvascular complications. Diabetes Care 1991; 14:707-711,
34.
Pinkney JH, Foyle WJ, Denver AE, et al: The relationship of urinary albumin excretion rate to ambulatory blood pressure and erythrocyte sodium-lithium counter transport in NIDDM. Diabetologia 1995;38: 356-363.
14. Vereccia P, Schilacci G, Porcellati C: Dippers versus non-dippers. J Hypertens 1991;9 (suppl 8) :S42– S44.
16.
17. Lemmer B: Temporal aspects of the regulation of the sympathic nervous system in the rat, in Lemmer B (cd): Chronopharmacology: Cellular and Biochemical Interactions. Marcel Dekker, New York–Basel, 1989, pp 477-508, 18. Linsell CR, Lightman SC, Mullen PE, et al: Circadian rythms of epinephrine and norepinephrine in man. J Clin Endocrinol Metab 1985;60:1210-1215. 19. Andreotti F, Davis GJ, Hackett DR, et al: Major circadian fluctuations in fibrinolytic factors and possible relevance to time on onset of myocardial infarction sudden cardiac death and stroke. Am J Cardiol 1988; 62:635-637.
Nondipping of Nocturnal Blood Pressure Is Related to Urinarv Albumin Excretion Rate in Patients With Type 2 Diabetes Mellitus S. Equiluz-Bwck, C. Scknack, H.P. Kopp, and G. Schemthaner
Although cardiovascular and cerebrovascular morbidity and mortality in type 2 diabetic patients is closely related to urinary albumin excretion rate (UAER), the causative mechanisms are not yet identified. The aim of our study was to define the circadian variation of blood pressure (BP) in 72 type 2 diabetic patients (mean age 60 years, mean diabetes mellitus duration: 12 years) in comparison with 41 nondiabetic controls with essential hypertension (mean age 58 years) by using ambulatory blood pressure measurement. Thirty diabetic patients had normal UAER ( <30 mg/24 h), 27 had microalbuminuria (30 to 300 mg/24 h), ancl 15 had persistent proteinuria ( >300 mg/24 h). Systolic blood pressure during both nighttime and daytime was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls and patients with normal UAER. During nighttime even type 2 diabetic patients with microalbuminuria had significantly
elevated systolic blood pressure compared to controls with essential hypertension. We also observed a correlation of nocturnal blood pressure to UAER (systolic: r = 0.32, P < .007 and diastolic: r = 0.24, P < .04). Nondipping (defined as a reduction of nocturnal BP
H
type 2 diabetes mellitus. The information regarding 24-h blood pressure measurements in type 2 diabetics with normal and increased albumin excretion rate is very limited. Microalbuminuria is considered as a strong predictor of clinical overt nephropathy45 in type 1 diabetes mellitus; in type 2 diabetes mellitus end-stage renal disease develops in a much smaller number of patients. Undoubtable, cardiovascular and cerebrovascular morbidity and mortality are frequent in type 2 diabetes mellitus and closely related to urinary albumin excretion rate (UAER) and hypertension.6-8 Usually the diagnosis of hypertension is done after
ypertension and type-2 diabetes are frequently associated. Moreover, patients may have essential hypertension years before the diagnosis of diabetes mellitus is made. It is also known that increased albumin excretion rate is associated with a rise in blood pressure in
Received April 18, 1995. Accepted July 1, 1996. From the Department of Medicine I, Rudolfstiftung Hospital Vienna, Vienna, Austria. Address correspondence and reprint requests to Professor Guntram Schernthaner, Department of Medicine I, Rudolfstiftung Hospital Vienna, Juchgasse 25, A-11330Vienna, Austria.
01996 by the American ]ownal of Hypertension, Ltd. Published by Ekevim Science, Im.
KEY WORDS: Urinary albumin excretion, diabetes mellitus, circadian variation, nocturnal blood pressure drop, microalbuminuria, hypertension.
0895-7061/96/$15.00 PI1 S0895-7061(96)00302-0
1140 EQUILUZ-BRUCK ET AL
repeated single measurements of blood pressure, but these might be influenced by the phenomenon of “white-coat hypertension.” ‘)-kl Nowadays, ambulatory 24-h blood pressure measurements represent a well established technique that allows the documentation of the circadian variation of blood pressure and the effectiveness of antihypertensive treatment.”[2The aim of our study was to define the circadian variation of blood pressure in a representative number of type 2 diabetic patients and to evaluate the relationship to urinary albumin excretion rate. PATIENTS AND METHODS Seventy-two type 2 diabetic patients (43 men, 29 women ) were compared to a group of 41 nondiabetic controls (17 men, 24 women) with essential hypertension (mean age: 58 years; mean body mass index: 27 ~ 4 kg /m2). Patients with secondary hypertension were excluded from our study. The mean age of the diabetic patients (60 years ), the mean duration of diabetes mellitus (12 years), and the mean body mass index (28 kg /m2) were not different between the three groups of diabetic patients and controls: thirty patients had a normal UAER ( <30 mg/ 24 h), 27 had microalbuminuria (30 to 300 mg /24 h), and 15 persistent macroproteinuria ( >300 mg /24 h). After the inclusion of 30 patients with normal UAER only, patients with increased UAER were further analyzed. Among the type 2 diabetics, mean albumin excretion was 15.1 & 4.6 (range 8 to 24.9) mg /24 h in the normoalbuminuric group, 93.2 ~ 55.7 (30 to 235) mg/24 h in the patients with microalbuminuria, and 1019 f 992 (303 to 4180) mg /24 h in the macroalbuminuric group. The mean UAER of the controls with essential hypertension was 17.3 ~ 5.1 (8 to 27) mg /24 h. Only patients with normal UAER were included. Serum creatinine levels were similar in the normoalbuminuric patients (1.06 f 0.2 mg/dL), in the microalbuminuric group (1.02 t 0.5 mg/dL), and in the controls (1.01 ~ 0.4 mg /dL), whereas the macroalbuminuric patients had significantly higher serum creatinine ( 1.67 ~ 0.6 mg / dL) levels. The diabetic patients were treated with diet alone (n = 16), oral hypoglycemic agents (n = 32), or insulin (n = 24). The antihypertensive treatment of the patients and controls is shown in Table 1. Ambulatory 24 h blood pressure measurement (ABPM) was performed using a oscillometric recorder (SpaceLabs 90207, Redmond, WA); measurements with this device have a strong correlation to auscultation. This recorder satisfies the validation requirements of ABPM and has a proven accuracy.13Blood pressure was measured in intervals of 20 min during the daytime and 30 min during the night. Patients were hospitalized, but free to move in the hospital area during the daily measurements. Recordings were started between 08:00 and 09:00 and ed-
A/H-N0VEMi3ER 1996-VOL. 9, NO. 11, PART 1
TABLE 1. ANTIHYF’ERTENSIVE TREATMENTOF THE DIABETICF’ATIENTSAND CONTROLS Albuminuric’ Antihypertensive Normo Micro Macro Drugs h = 30) (n = 27) (n = 15) ACE inhibitor Ca antagonist a-Blocking agents ,L-Blockingagents Others No treatment Multiple treatment
14 10 4 2 3 10 10
19 14 5 3 3 0 14
13 11 5 1 3 0
12
Controls (n = 41)
27 18 6 3 6 6 19
“ Diabetic patients,
ited automatically. If the recordings had less than go~o of completed measurements, they were discarded. Systolic and diastolic blood pressure were averaged for each hour, and further separated into daytime, considered as 06:00 to 22:00, and nighttime, between 22:00 and 06:00. We also calculated the means and standard deviations for blood pressure and separated them into a daytime and nighttime period. In addition, the percentage of measurements higher than 140/90 mm Hg (defined normal range) and the heart rate profile were examined. Mean arterial blood pressure was calculated by the recorder as the quotient of the integrated area under the curve for systolic blood pressure divided by the duration of pulse rate. Usually blood pressure is reduced during the night; the mean range is 10Yoto ls~o.14 In our study “nondipping” was defined as a reduction of nocturnal blood pressure of <10%. Repeated single measurements of blood pressure were taken in the usually way during the daytime; each patient had 3 to 6 checks a day. UAER was measured by a immunoturbidimetric test for the quantitative determination of human albumin in urine (Tina Quant, Boehringer Mannheim, Mannheim, Germany) using the Hitachi BM 704/717 system (Tokyo, Japan) (detection limit for urinary albumin concentration: 4 mg /L) and assessed as the mean of three 24-h urine samples. Blood samples were taken after an overnight fast; plasma glucose, hemoglobin Al. (by HPLC), serum cholesterol, triglycerides, HDL and LDL, and serum creatinine were analyzed with standard laboratory techniques. Statistical Analysis Data were expressed as mean ~ SD. Comparisons of subgroups with patients of the control group were performed using paired t tests for parametic data, with X2 tests as appropriate. Simple linear regression analysis was used to evaluate the correlation between two parameters. Statistical significance was considered for P < .05. SAS Statistical Software was used for all calculations. (SAS Institute, Cary, NC)
1141
AJH-NOVEMBER 1996-VOL.. 9, NO. 11, PART 1 NONDIPPING OF NOCTURNAL BP IN TYPE 2 DIABETES MELLITUS
TABLE 2. ABPM DURING
Systolic BP Normoalbuminuric Microalbuminuric Macroalbuminuric Controls “ P < .01,t
139 f 145 t 149 t 137 f
18* 15* 19+ 16+
DAYTIME
Diastolic BP 82 85 86 79
~ ~ ~ *
10 10 10+ 15$
(06:00 TO 22:00)
Mean Arterial BP
Heart Rate
102 t 12t 107 t 12t 108 f 11 100 t 12
79 ~ 16 833 16+ 74 t 10*
76 ~ 11
P < ,002 + P <.05.
RESULTS
sure and albumin excretion rate, whereas during daytime no significant relationship between blood pressure and albumin excretion was found. The analysis of correlation of albumin excretion rate to blood pressure values in the subgroups of diabetic patients with normo-, micro-, and macroalbuminuria were not significant. The phenomenon of nondipping was not influenced by antihypertensive treatment or by the intake of ACE inhibitors, further the time of antihypertensive treatment did not influence our data. Furthermore, heart rates were higher in the diabetic patients with macroalbuminuria compared to the patients with essential hypertension (Tables 2, 3). During the night time macroalbuminuric diabetic patients had significantly elevated heart rates compared to diabetic patients with normoalbuminuria (Table 3). Repeated single measurements of blood pressure during the daytime showed significantly higher systolic blood pressure levels than those of the ambulatory blood pressure measurements ( 152 t 23 u 144 ~ 18 mm Hg, P < .001), but there was no significant difference in the diastolic blood pressure (85 ~ 11 ZJ 84 t 10 mm Hg). A strong correlation between ABPM and repeated single measurements was found (r = 0.62; P < .0003).
The data for the blood pressure levels and heart rates for daytime and nighttime are shown in Tables 2 and 3, respectively. Du~ing the-time between 06:00 and 22:00 (Table 2), we found higher systolic and diastolic blood pressure values in patients with macroalbuminuria compared to controls and normoalbuminuric type 2 diabetic patients. Diastolic blood pressure was significantly elevated in type 2 diabetic patients with macroalbuminuria compared to controls. Mean arterial blood pressure was elevated in micro- and macroalbuminuric type 2 diabetic patients compared to controls (and in macroalbuminuric patients compared to type 2 diabetic patients with normoalbuminuria). In the nighttime period (between 22:00 and 06:00), there was a significant increase of systolic blood pressure and mean arterial blood pressure in type 2 diabetic patients with macroalbuminuria compared to controls and normoalbuminuric type 2 diabetic patients. Systolic blood pressure was significantly elevated compared to controls also in type 2 diabetic patients with microalbuminuria. The differences in diastolic blood pressure were not significant (Table 3). According to the definition of nondipping, 37% of the controls, 43Y0of the type 2 patients without albuminuria, 67$Z0 of the patients with microalbuminuria, and 80Y0of the patients with persistent macroalbuminuria were nondippers (Number of nondipping patients in the control group, diabetic patients with normal albumin excretion compared to diabetic patients with micro- and macroalbuminuria: X2: P < .05). For the diabetic patients we observed a correlation during nighttime between both systolic (r = 0.32, P < .007) and diastolic ( r = 0.24, P < 0.005) blood pres-
DISCUSSION The main findings of this study are threefold. First, there was a significant increase of arterial blood pressure during both daytime and nighttime in type 2 diabetic patients with macroalbuminuria compared to patients with essential hypertension (Controls). During the nighttime, even type 2 diabetic patients with microalbuminuria had a significantly elevated systolic
TABLE 3. ABPM DURING NIGHTTIME (22:00 TO 06:00) Systolic BP Normoalbuminuric Microalbuminuric Macroalbuminuric Controls
* P <.01, t P <.05.
125 137 146 129
~ t t *
80’ 21* 21’ 21*
Diastolic BP 72 75 79 72
f f + ~
10 11 10 12
Mean Arterial BP 91 98 104 93
~ t t ~
12+ 13t 13t lqt
Heart Rate 66 68 73 63
? ? t f
9+ 7t 18* 10*
1142 EQUILUZ-BRUCK ET AL
blood pressure compared to patients with essential hypertension. Second, there was a high incidence of the phenomenon of nondipping of nocturnal blood pressure in type 2 diabetic patients with an elevated albumin excretion rate compared to patients with a normal albumin excretion rate or patients with essential hypertension. Third, a correlation of nighttime blood pressure (systolic and diastolic) to urinary albumin excretion rate was documented, although during daytime no correlation was found. The circadian blood pressure rhythm is the result of various activities of the hypothalamus, which causes a number of hormonal actions. This regulation overlaps the influence of exogenous events, eg, sleep distur. bance. Measurement of serum cathecholamines shows the highest level in the early morning. ’s-[s Similarly, a circadian rhythm exists for heart constriction, ADPinduced aggregability of platelets, and the activity of the clotting system.1’JJ2[’ Steady stimulation of the renin-angiotensin system and serum cathecholamines might be responsible for the lack of decreasing blood pressure at night. There are some events known to be associated with nondipping, eg, secondary hypertension, heart failure, sleep disturbances, shift working, autonomic neuropathy, left ventricle hypertrophy, and performed cardiac transplantation.2’-2’ Nondipping is potentially caused by several mechanisms, such as left ventricle hypertrophy,2s autonomic neuropathy,” and overhydration,’” which have to be clarified in prospective studies. In our study, the phenomenon of nondipping was frequently found in type 2 diabetic patients with elevated UAER. The diabetic patients with macroalbuminuria had higher heart rates than diabetic patients with normal albumin excretion rate and controls. Hausmann et a12gfound an accumulation of silent ischemia as well as cardiac infarction in the early morning in nondiabetic patients. Pasqualetti et also showed in his study an increased frequency for cerebral strokes in nondiabetic patients. However, more of the patients with type 2 diabetes were dying from cerebral stroke and cardiac arrest. Our data suggest that the high frequency of nondipping in type 2 diabetic patients with an increased albumin excretion rate may partially explain the high cardiovascular morbidity and mortality in these patients. Further, the heart rate profiles of our patients also indicate a connection to autonomic neuropathy, as previously suggested.” It might further be speculated that the phenomenon of nondipping of nocturnal blood pressure might precede microalbuminuria in type 2 diabetes. If so, then it should be clarified in prospective studies as to whether intensified antihypertensive treatment prevents the development of microalbuminuria in these patients. Schmitz et alq2described an increase of blood pres-
A/H-NOVEMBER 1996-VOL, 9, NO. 11, PART 1
sure in type 2 diabetic patients, regardless of the prevalence of microalbuminuria. Nevertheless, a correlation of 24 h systolic blood pressure to UAER in patients with microalbuminuria was described, whereas in patients with normal UAER no such correlation was found. However, day and night data were not separated. Nakano et al found a high presence of reversed circadian blood pressure variation with a peak value during night. However only normotensive type 2 diabetic patients were included. The prevalence and degree of autonomic neuropathy and nephropathy were greater in the diabetic patients with this disturbed circadian variation of blood pressure.33 Very recently, a close relationship of increased UAER to the presence of hypertension (documented by ambulatory 24 h blood pressure measurements) was observed in type 2 diabetic patients. Albuminuria, however, was not related to the increased erythrocyte sodium-lithium countertransport, which is associated with diabetic nephropathy in type 1 diabetics, suggesting that different mechanisms determine microalbuminuria in type 1 and type 2 diabetes mellitus.q4In this study, however, the phenomenon of nondipping of nocturnal blood pressure was not observed, but only 20 patients with elevated albumin excretion rate ( >15 ~g /rein) were analyzed. Our data also show the high prevalence of the white-coat phenomen and may indicate the more frequent use of ABPM. The use of ABPM, rather than single measurements, may result in early detection and optimized antihypertensive treatment in relation to the circadian variation of blood pressure of those patients. In our study, it was demonstrated that albuminuria correlates with both systolic and diastolic blood pressure at night and with the phenomenon of nondipping in type 2 diabetic patients. Because of the high cardiovascular mortality of these patients, prospective longterm studies are necessary to evaluate the possible benefits of reduction of nocturnal blood pressure levels. REFERENCES 1.
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