Pulse pressure and systolic night-day ratio interact in prediction of macrovascular disease in patients with type 2 diabetes mellitus.

Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease (CVD). We examined the predictive ability of 24-hour ambulatory pulse pressure (24-h PP), ambulatory arterial stiffness index (AASI) and diurnal blood pressure (BP) parameters for fatal and non-fatal CVD in patients with type 2 diabetes mellitus. A total of 108 patients with type 2 diabetes mellitus (mean duration 6.6 years) were followed for 9.5 (0.5-14.5) years. At baseline, all patients underwent ambulatory BP monitoring. During follow-up, 45 patients had cardiovascular (CV) events (35 non-fatal and 10 fatal). In bivariate analysis, events during follow-up were predicted by 24-h PP (P<0.01), AASI, 24-h systolic BP and systolic and diastolic night-day BP ratio (P<0.05 for all). In Cox regression analysis adjusted for established risk markers, only 24-h PP and systolic night-day BP ratio predicted CV events, P<0.05 for both. A significant interaction between the two parameters was found, P<0.05; thus, the higher the systolic night-day ratio, the greater the increase in hazard ratio (HR) per mmHg increase in 24-h PP and vice versa. A combined 10 mmHg increase in 24-h PP and 10%-point increase in systolic night-day ratio from the 25th percentile increased the adjusted HR (95% confidence interval) for CV events with 1.29 (0.53; 3.12), whereas a similar increase from the 75th percentile increased the HR with 4.2 (1.54; 11,51). Our study showed that 24-h PP and systolic night-day ratio interact as predictors of CV events in type 2 diabetes patients, and should be considered in conjunction when evaluating the risk of CVD.

Effects of metoprolol on QT interval and QT dispersion in Type 1 diabetic patients with abnormal albuminuria.

AIMS/HYPOTHESIS: The excess mortality in diabetes is mainly due to cardiovascular causes and almost confined to patients with abnormal albuminuria. Compared to healthy subjects, diabetic patients have a prolonged QT interval and increased QT dispersion. In non-diabetic subjects, as well as in Type 1 diabetic patients with overt nephropathy, a prolonged QT interval and increased QT dispersion are associated with cardiac morbidity and mortality. There is an increasing number of studies on effects of beta blocker treatment on QT interval and QT dispersion in non-diabetic subjects. In contrast, there are no studies on the effects of beta blocker treatment on QT interval and QT dispersion in patients with diabetes. The aim of our study was to describe the effects of metoprolol treatment on QT interval and QT dispersion in a group of well-characterised Type 1 diabetic patients with elevated urine albumin excretion. METHODS: We studied the effects of 6 weeks of treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in a randomised, placebo-controlled, double blind, crossover trial including 20 Type 1 diabetic patients. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording and 24-h fractionated urine collections. On days of investigation 12-lead electrocardiograms were recorded and autonomic tests performed. RESULTS: We found strong associations between both daytime and night-time blood pressure and heart-rate-corrected QT interval dispersion (QTc dispersion). Heart rate variability parameters indicating sympathetic and parasympathetic modulation showed strong correlations with heart-rate-corrected QT interval (QTc interval) and with QTc dispersion. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. CONCLUSIONS/INTERPRETATION: This study is the first to address the QTc interval and QTc dispersion in Type 1 diabetic patients treated with metoprolol. Beta blocker treatment caused a decrease in QTc interval but no change in QTc dispersion. These results may in part explain the pronounced cardioprotective effect of beta blocker treatment in diabetic patients with cardiovascular disease.

Effects on heart rate variability of metoprolol supplementary to ongoing ACE-inhibitor treatment in Type I diabetic patients with abnormal albuminuria.

AIMS/HYPOTHESIS: Diabetic nephropathy is associated with a high risk of cardiac mortality including sudden death. This is presumably related to an imbalance between sympathetic and parasympathetic tone resulting in a decreased heart rate variability (HRV). In non-diabetic patients a decreased HRV is known to be a strong predictor of cardiovascular death. Studies in non-diabetic patients have shown that beta-blockers improve HRV parameters known to reflect parasympathetic function. The aim of our study was to investigate effects of additional beta-blocker treatment on: cardiac autonomic function, blood pressure, and urine albumin excretion in ACE-inhibitor treated Type I (insulin-dependent) diabetes mellitus patients with abnormal albuminuria. METHODS: We studied the effects of 6 weeks treatment with metoprolol (100 mg once daily, zero order kinetics formulation) in 20 patients participating in a randomised, placebo controlled, double blind, crossover trial. Patients were simultaneously monitored under ambulatory conditions with 24-h Holter-monitoring, 24-h ambulatory blood pressure recording, and 24-h fractionated urine collections. Heart rate variability was assessed by four different methods; ambulatory HRV analysis was carried out by spectral and time domain analysis, and on days of investigation short-term spectral analysis and bed-side tests were carried out. RESULTS: Metoprolol treatment improved in vagal tone assessed by short-term spectral analysis. The 24-h ambulatory HRV analysis showed improvement in some parameters reflecting vagal function. A minor decrease in daytime diastolic blood pressure was shown, no alterations in diurnal variation of blood pressure or urine albumin excretion were observed. CONCLUSION/INTERPRETATION: These preliminary findings indicate that beta-blocker treatment could improve autonomic function in Type I diabetic patients with abnormal albuminuria and an associated high risk of cardiovascular disease.

What is hypertension in diabetes? Ambulatory blood pressure in 137 normotensive and normoalbuminuric Type 1 diabetic patients.

AIMS: To establish reference data for ambulatory blood pressure (AMBP) in normotensive, normoalbuminuric Type 1 diabetic patients and characterize the relation to clinic blood pressure (BP). To evaluate the statement of the third working party of the British Hypertension Society (BHS) that a target clinic BP in diabetes < 140/80 corresponds to a target day-time AMBP < 130/75 mmHg. PATIENTS AND METHODS: AMBP were performed in 172 normoalbuminuric, adult Type 1 diabetic patients, who had never received anti-hypertensive drugs. Clinic BP was determined as the mean of at least three auscultatory (Hawskley random zero manometer) and as the mean of at least three oscillometric (Spacelabs) BP values obtained just prior to ambulatory monitoring. Five patients with more than three missing hours/24 h were excluded. RESULTS: For 30 patients auscultatory clinic BP exceeded 140 mmHg systolic and/or 90 mmHg diastolic. For the remaining 137 normotensive patients day-time AMBP was 125.7/77.2 mmHg and oscillometric clinic BP was 125.3/76.5 mmHg (mean difference 0.3/0.7 mmHg; 95% confidence interval (CI) -0.9 to 1.5/-0.3 to 1.7 mmHg, P = 0.6/P = 0.2). Sixty-five percent of the patients had a diastolic day-time AMBP > 75 mmHg. CONCLUSIONS: Clinic BP and day-time AMBP measured by the same method were indistinguishable. The target for day-time diastolic AMBP (< 75 mmHg) proposed by the BHS is too low and is based on the misconception that in normotensive subjects day-time AMBP is lower than clinic BP. If the BHS guidelines are strictly adhered to, the consequence may be overtreatment in patients with normoalbuminuria and no end organ damage.

Lisinopril reduces albuminuria during exercise in low grade microalbuminuric type 1 diabetic patients: a double blind randomized study.

BACKGROUND: Antihypertensive treatment is presently recommended in most type 1 diabetic patients with microalbuminuria. The long-term effect of angiotensin converting enzymes (ACE) inhibitor (ACE-i) treatment on exercise urinary albumin excretion (E-UAE) and exercise blood pressure (E-BP) in type 1 diabetic patients with low grade microalbuminuria is not well documented. In addition, the possible predictive effect of baseline E-UAE on the progression of overnight UAE remains to be clarified. DESIGN AND METHODS: In a randomized placebo controlled double blind study the effects of 2 years treatment with either lisinopril (20 mg o.d.) or placebo was evaluated in 21 normotensive type 1 diabetic patients with overnight UAE between 20 and 70 microg min-1. Determinations of E-UAE and E-BP were performed after exercise on an ergometercycle with a load of 70% of estimated maximal VO2 for 20 min. Patients in the placebo and lisinopril groups were similar with regard to age (35.8 +/- 11.3 vs. 29.3 +/- 8.6 years), duration of diabetes (19.4 +/- 8.2 vs. 16.8 +/- 5.3 years), and HbA1c (9.0 +/- 1.0 vs. 9.4 +/- 1.7%). RESULTS: At baseline, E-UAE was similar in the two groups (placebo: 150.1 x or divide 3.7, lisinopril: 96.8 x or divide 1.8 microg min-1 (geometric mean x or divide tolerance factor)). After 2 years treatment E-UAE had increased in the placebo group, whereas E-UAE was reduced in the lisinopril treated patients (placebo: 213.6 x or divide 6.9, lisinopril: 48.3 x or divide 3.1 microg min-1, P = 0.04). The relative increase in E-UAE (E-UAE/Pre-exercise UAE) was similar at baseline in both groups (3.7 x or divide 2.3 vs. 2.8 x or divide 2.0) but significantly higher in the placebo group after 2 years (4.4 x or divide 2.4 compared with 1.6 x or divide 1.7 in the lisinopril group, P < 0.01) These changes over two years in relative increase in E-UAE were significantly different (P = 0.03). Exercise blood pressure was similar in both groups at baseline and over 2 years increased in the placebo group (from 166.5 +/- 15.1-179.9 +/- 35.6 mmHg), in contrast to the lisinopril group where E-BP was slightly reduced (from 168.5 +/- 20.6-165.1 +/- 16.6 mmHg) but the difference in blood pressure over the 2 years did not reach statistical significance. Exercise urinary albumin excretion and E-BP were closely associated (correlation for year 2: r = 0.734, P < 0.001), and also changes over the 2 years in E-UAE and E-BP were positively correlated (r = 0.53, P = 0.01). At year 2, overnight UAE, pre-exercise UAE (pre-E-UAE), E-UAE and E-BP were all closely linked (r-values between 0.6 and 0.9, P-values < 0.01). In the prediction of changes in overnight UAE over 2 years, neither baseline E-UAE nor baseline E-BP conveyed explanatory information in comparison with baseline overnight UAE and HbA1c. CONCLUSIONS: In type 1 diabetic patients with low-grade microalbuminuria, 2 years of ACE-i treatment with lisinopril significantly reduced E-UAE. Strong correlations were found between E-UAE and E-BP and also changes over 2 years in these parameters were significantly associated.

Early ACE-i intervention in microalbuminuric patients with type 1 diabetes: effects on albumin excretion, 24 h ambulatory blood pressure, and renal function.

OBJECTIVES: To study the effects of ACE-i in type 1 diabetic patients with early microalbuminuria with regard to: i) UAE, ii) 24 h AMBP, including the effect on diurnal BP variation, and iii) renal haemodynamics. MATERIAL AND METHODS: 58 patients with urinary albumin excretion (UAE) between 20-70 microg/min were treated for two years with either the ACE inhibitor (ACE-i) lisinopril (20 mg od) or placebo in two randomised placebo controlled double blind studies. In a subgroup of patients (n=22) we performed 24 h ambulatory blood pressure measurements (AMBP) and renal function tests (constant infusion technique). RESULTS: i) Changes in UAE over the two years were significantly different (p<0.01) in the two groups with final UAE in the lisinopril group of 19.1 microg/min x/divide 2.5 (geometric mean x/divide tolerance factor) and 44.1 microg/min x/divide 2.8 in the placebo group. In the lisinopril group 20 patients (60.6%) reversed to normoalbuminuria compared to 6 patients (24%) in the placebo group (p<0.02). ii) Clinical BP measurements revealed no differences between groups, but by AMBP significant reductions were detectable in the lisinopril group, primarily in night AMBP (systolic/diastolic: - 6.9 +/- 8.6/- 6.0 +/- 5.3 mmHg, p<0.01) as opposed to increases in the placebo group (3.1 +/- 9.3/1.9 +/- 7.3 mmHg). iii) Changes in UAE and changes in filtration fraction (FF) were positively correlated in the intervention group (r=0.9, p<0.01), i.e. the patients who showed the greatest fall in UAE were the ones with the greatest fall in FF. CONCLUSIONS: ACE-i treatment in patients with low-grade microalbuminuria reduces 24 h AMBP without attenuating diurnal blood pressure variation, reduces UAE significantly, with changes in UAE being strongly associated with changes in FF. Furthermore, compared to placebo, ACE-i reverses micro- to normoalbuminuria in a significant fraction of patients.

Increased QTc dispersion is related to blunted circadian blood pressure variation in normoalbuminuric type 1 diabetic patients.

A reduced nocturnal fall in blood pressure (BP) and increased QT dispersion both predict an increased risk of cardiovascular events in diabetic as well as nondiabetic subjects. The relationship between these two parameters remains unclear. The role of diabetic autonomic neuropathy in both QT dispersion and circadian BP variation has been proposed, but data have been conflicting. The aim of the present study was to describe associations between QT dispersion and circadian BP variation as well as autonomic function in type 1 diabetic patients. In 106 normoalbuminuric (urinary albumin excretion <20 microg/min) normotensive patients, we performed 24-h ambulatory BP (Spacelabs 90207) and short-term (three times in 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (deep breathing test, postural heart rate, and BP response). No patient had received (or had earlier received) antihypertensive or other medical treatment apart from insulin. In a resting 12-lead electrocardiogram, the QT interval was measured by the tangent method in all leads with well-defined T-waves. The measurement was made by one observer blinded to other data. The QT interval was corrected for heart rate using Bazett's formula. The QTc dispersion was defined as the difference between the maximum and the minimum QTc interval in any of the 12 leads. When comparing patients with QTc dispersion below and above the median (43 ms), the latter had significantly higher night BP (114/67 vs. 109/62 mmHg, P < 0.003/P < 0.001), whereas day BP was comparable (129/81 vs. 127/79 mmHg). Diurnal BP variation was blunted in the group with QTc dispersion >43 ms with significantly higher night/day ratio, both for systolic (88.8 vs. 86.2%, P < 0.01) and diastolic (83.1 vs. 79.5%, P < 0.01) BP. The association between QTc dispersion and diastolic night BP persisted after controlling for potential confounders such as sex, age, duration of diabetes, urinary albumin excretion, and HbA1c. Power spectral analysis suggested an altered sympathovagal balance in patients with QTc dispersion above the median (ratio of low-frequency/high-frequency power: 1.0 vs. 0.85, P < 0.01). In normoalbuminuric type 1 diabetic patients, increased QTc dispersion is associated with reduced nocturnal fall in BP and an altered sympathovagal balance. This coexistence may be operative in the ability of these parameters to predict cardiovascular events.

No deleterious effects of tight blood glucose control on 24-hour ambulatory blood pressure in normoalbuminuric insulin-dependent diabetes mellitus patients.

Intensive therapy aiming at near normalization of glucose levels effectively delays the onset and slows the progression of complications in insulin-dependent diabetes mellitus (IDDM) and is recommended in most patients. However, in a recent report, intensive insulin treatment was found to be associated with deleterious effects on nocturnal blood pressure (BP), the proposed mechanisms being subclinical nocturnal hypoglycemia or hyperinsulinemia. The aim of the present study was to evaluate the association between glycemic control, insulin dose, and 24-h ambulatory BP (AMBP) in a group of well-characterized IDDM patients. Twenty-four-h AMBP was measured in 123 normoalbuminuric [urinary albumin excretion (UAE) < 20 microg/min] IDDM patients using an oscillometric technique (SpaceLabs 90207) with readings at 20-min intervals. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. Tobacco use and level of physical activity was assessed by questionnaire. HbA1c was determined by high-pressure liquid chromatography (nondiabetic range, 4.4-6.4%), and patients were stratified into quartiles according to HbA1c levels. Mean HbA1c values in the four groups were 7.0% (n = 31), 8.0% (n = 31), 8.6% (n = 31), and 9.7% (n = 30). The groups were comparable regarding age, gender, diabetes duration, body mass index, UAE, smoking status, and physical activity. AMBP levels were almost identical in the HbA1c quartiles with night values of (increasing HbA1c order): 110/63, 112/66, 112/66, and 113/65 mm Hg (P = 0.69/P = 0.32). There was no association between tight glucose control and higher nocturnal BP or a more blunted circadian BP variation. On the contrary, a weak positive correlation between night to day ratios of mean arterial BP and HbA1c values was found (r = 0.26, P = 0.005), i.e. blunted circadian BP variation is most frequent in patients with high HbA1c values. Neither did we find doses of insulin to be associated with night BP (r = 0.04, P = 0.68). Tight blood glucose control is not associated with deleterious effects on 24-h AMBP in normoalbuminuric IDDM patients. Intensive therapy can be implemented without concerns of inducing high nocturnal BP and accelerating diabetic complications.

Characteristics and prognosis of normoalbuminuric type 1 diabetic patients.

Intervention in type 1 diabetic patients with increased urinary albumin excretion (UAE) represents a great step forward in modern diabetology. At the moment, the consensus calls for antihypertensive treatment in normotensive type 1 diabetic patients with persistent microalbuminuria. However, recent data indicate that substantial pathophysiological changes have already taken place at the microalbuminuric stage. Thus, prevention of progression from normo- to microalbuminuria would be a major clinical turning point. A considerable number of potential risk factors for progression to microalbuminuria have been proposed, among which are blood pressure elevation and disturbancies in circadian blood pressure variation. We performed 24-h ambulatory blood pressure (AMBP) monitoring in 115 normoalbuminuric (UAE < 20 micrograms/min) patients, along with performing an assessment of circadian blood pressure and heart rate (HR) variation and a short-term power spectral analysis of RR interval oscillations. Patients with UAE above the median had significantly higher systolic and diastolic AMBP compared to the low normoalbuminuric group. The difference in blood pressure between the two groups was most pronounced for the night blood pressure (P < 0.01 and 0.02). A positive correlation between UAE and circadian variation (described as diastolic night/day ratio) was present--that is, the higher the normoalbuminuria, the more blunted the night/day ratio. The patients characterized by a combination of high-normal UAE and blunted circadian variation also proved to have significantly higher HbA1c values, higher 24-h mean arterial blood pressure, and lower vagal activity. In conclusion, high-normal UAE, poor metabolic control, and cigarette smoking are at present the only established risk factors for progression from normo- to microalbuminuria. However, new data emphasizes the close relation between blood pressure and albumin excretion. Pathophysiological abnormalities (poorer glycemic control, higher blood pressure, and attenuated vagal activity) tend to cluster in patients characterized by high-normal UAE and blunted circadian variation of blood pressures, and this patient group might constitute a putative high-risk group.

Effects of smoking on 24-h ambulatory blood pressure and autonomic function in normoalbuminuric insulin-dependent diabetes mellitus patients.

Smoking is an important risk factor for the development and progression of diabetic nephropathy. The mechanisms by which smoking increases albuminuria and promotes nephropathy are unknown. Considering the acute pressor effect of smoking and the close association between blood pressure elevation and development of diabetic nephropathy, blood pressure increase might be implicated in the association between smoking and diabetic nephropathy. However, among nondiabetics, smokers have repeatedly been found to have lower blood pressure than nonsmokers. This is possibly mediated by an autonomic adjustment to sustained sympathetic stimulation by nicotine. Impaired modulation of the sympathovagal activity has been described in diabetes. In diabetic patients, the effect of smoking on blood pressure and autonomic function remains unclarified. We examined 24-h ambulatory blood pressure (oscillometric technique) and autonomic function (short-term power spectral analysis as well as conventional tests) in 24 smokers and 24 nonsmokers matched for sex, age, and diabetes duration. All patients were normoalbuminuric insulin-dependent diabetes mellitus patients. Smoking status was assessed by questionnaire with confirmatory determinations of urinary cotinine. Diabetic smokers had significantly higher 24-h mean arterial blood pressure (94+/-6.7 mm Hg compared to diabetic nonsmokers 90+/-5.8 mm Hg, P = .04) including higher diastolic nighttime blood pressure (68+/-7.3 mm Hg v 64+/-5.2 mm Hg, P = .03). Smokers also had significantly higher 24-h heart rate (80+/-7.2 compared to 72+/-9.2 beats/min, P < .001). In addition, smoking was associated with significantly reduced short-term RR interval variability (supine low frequency component) (5.45+/-1.29 ln ms2 in smokers compared to 6.31+/-1.11 ln ms2 in nonsmokers, P < .02), as well as reduced brake index (33.5+/-14.5 in smokers v 42.1+/-16.0 in nonsmokers, P < .05). Diabetic smokers have significantly higher 24-h blood pressure compared to diabetic nonsmokers. This finding, contrasting the effect of smoking among nondiabetics, is possibly mediated by coexisting abnormal postural responses in autonomic cardiac regulation in diabetic smokers. Blood pressure elevation, persisting throughout 24 h, might be operative in the association between smoking and development of diabetic nephropathy.

24-h ambulatory blood pressure and retinopathy in normoalbuminuric IDDM patients.

The role of blood pressure elevation in the incidence and progression of diabetic retinopathy is not clearly established and results have been conflicting. Blood pressure and urinary albumin excretion (UAE) are closely related. In order to evaluate the independent relationship between retinopathy and blood pressure elevation, precise information on UAE is essential, as confounding by renal disease (incipient or overt), cannot otherwise be excluded. The aim of the present study was to evaluate the association between diabetic retinopathy and 24-h ambulatory blood pressure (AMBP) in a group of well-characterized normoalbuminuric IDDM patients. In 65 normoalbuminuric (UAE < 20 microg/min) IDDM patients we performed 24-h AMBP (Spacelabs 90207) with readings at 20-min intervals. Fundus photographs were graded independently by two experienced ophthalmologists. UAE was measured by RIA and expressed as geometric mean of three overnight collections made within 1 week. HbA1c was determined by HPLC. Tobacco use and level of physical activity were assessed by questionnaire. Fifteen patients had no detectable retinal changes [grade 1], 35 had grade 2 retinopathy; and 15 had more advanced retinopathy [grade 3-6]. Diastolic night blood pressure was significantly higher in patients with diabetic retinopathy compared to patients without retinopathy (68 +/- 8 mmHg [grade 3-6] and 65 +/- 6 mmHg [grade 2], compared to 61 +/- 4 mmHg [grade 1], p = 0.02). Diurnal blood pressure variation was significantly blunted in the patients with retinopathy as indicated by a higher night/day ratio of diastolic blood pressure (84.6% +/- 4 [grade 3-6], and 81.2% +/- 6 [grade 2] compared to 79.1% +/- 4 [grade 1], p = 0.01). Heart rate tended to be higher in patients in group 2 and 3-6 compared to patients without retinopathy with p values of 0.07 and 0.11 for day-time and 24 h values, respectively. Mean HbA1c increased significantly with increasing levels of retinopathy (p < 0.01). Patients were similar regarding sex, age, tobacco use, and level of physical activity. Notably, UAE was almost identical in the three groups (5.0 x /divided by 1.7 [grade 1], 3.9 x /divided by 1.8 [grade 2], and 5.1 x /divided by 1.6 microg/min [grade 3-6]). In conclusion, night blood pressure is higher and circadian blood pressure variation blunted in patients with retinopathy compared to patients without retinopathy despite strict normoalbuminuria and similar UAE levels in the groups compared. Our data suggest that the association between blood pressure and diabetic retinopathy is present also when coexisting renal disease is excluded. Disturbed diurnal variation of blood pressure is a pathophysiological feature related to the development of both retinopathy and nephropathy in IDDM patients.

24-h blood pressure and autonomic function is related to albumin excretion within the normoalbuminuric range in IDDM patients.

Significant changes in both blood pressure, autonomic function and kidney ultrastructure are observed in insulin-dependent diabetic (IDDM) patients with microalbuminuria. Intervention strategies are evaluated at even earlier stages of disease. Identification of patients at risk of developing microalbuminuria must be based on a thorough knowledge of the relations between key pathophysiological parameters in patients with normoalbuminuria. The aim of the present study was to characterize the interactions of urinary albumin excretion (UAE), 24-h ambulatory blood pressure (AMBP), and sympathovagal balance in a large group of normoalbuminuric IDDM patients. In 117 normoalbuminuric (UAE < 20 micrograms/min) patients we performed 24-h AMBP (Spacelabs 90207), with assessment of diurnal blood pressure and heart rate (HR) variation, and short-term (three times 5 min) power spectral analysis of RR interval oscillations, as well as cardiovascular reflex tests (HR variation to deep breathing, postural HR and blood pressure response). Patients with UAE above the median (4.2 micrograms/min) had significantly higher 24-h systolic and diastolic AMBP (125 +/- 10.1/76 +/- 7.2 mmHg) compared to the low normolbuminuric group (120 +/- 8.4/74 +/- 5.1 mmHg), p < 0.01 and 0.02, respectively. Patients with UAE above the median had significantly reduced short-term RR interval variability including both the high frequency component (5.47 +/- 1.36 vs 6.10 +/- 1.43 ln ms2), and low frequency component (5.48 +/- 1.18 ln ms2 compared to 5.80 +/- 1.41 ln ms2), p < 0.02 and p = 0.04 (ANOVA). In addition, patients with high-normal UAE had reduced mean RR level (faster heart rates) 916 +/- 108 compared to 963 +/- 140 ms, p < 0.04. These differences were not explained by age, duration of diabetes, gender, level of physical activity, or cigarette smoking. HbA1c was significantly higher (8.6 +/- 1.2 vs 8.2 +/- 1.0%, p = 0.03) in the group with high normal UAE. Comparing normoalbuminuric IDDM patients with UAE above and below the median value, we found significantly higher AMBP in combination with significant differences in sympathovagal balance and significantly poorer glycaemic control in the group with high-normal albumin excretion. Our data demonstrate interactions between albumin excretion, blood pressure, autonomic function, and glycaemic status, already present in the normoalbuminuric range and may describe a syndrome indicative of later complications.

Elevated ambulatory blood pressure in microalbuminuric IDDM patients is inversely associated with renal plasma flow. A compensatory mechanism?

OBJECTIVE: To evaluate the relationship between renal function, ambulatory blood pressure (AMBP), and glycemic control in microalbuminuric IDDM patients compared with normoalbuminuric patients. RESEARCH DESIGN AND METHODS: Nineteen male patients (age 33 +/- 6 years) with slight microalbuminuria (UAE 20-70 micrograms/min) were compared with 19 normoalbuminuric (UAE < 15 micrograms/min) age-matched (33 +/- 6 years) male patients. Through constant infusion technique, 125I-iothalamate marked the glomerular filtration rate (GFR), and 131I-hippuran marked effective renal plasma flow (RPF). AMBP was measured by oscillometric technique (Spacelabs 90202). RESULTS: The microalbuminuric group had higher daytime systolic AMBP (132 +/- 11 vs. 125 +/- 7 mmHg, P < 0.05) and a poorer glycemic control (HbA1c 9.5 +/- 1.5 vs. 8.2 +/- 1.3%, P < 0.01). GFR (135 +/- 22 and 135 +/- 17 ml/min) and RPF (598 +/- 112 and 542 +/- 98 ml/min) were similar in the two groups. In the microalbuminuric group, daytime systolic AMBP was inversely correlated to both RPF (r = -0.77, P < 0.005) and GFR (r = -0.53, P = 0.02). HbA1c and GFR correlated positively in the microalbuminuric group (r = 0.47, P < 0.04). In contrast, the normoalbuminuric patients exhibited no such associations. CONCLUSIONS: IDDM patients with moderate microalbuminuria have elevated AMBP and a strong negative association between AMBP and RPF. This leaves several possibilities of interpretation. Primary blood pressure increase (of unknown origin) may induce morphological changes leading to reduction in renal function. Alternatively, blood pressure increase early in the course of incipient nephropathy may represent a compensatory mechanism, initially aiming at preservation of renal function, but later becoming maladaptive.

High normo- or low microalbuminuria: basis for intervention in insulin-dependent diabetes mellitus.

Recent studies have further elucidated the association between blood pressure and albumin excretion in insulin-dependent diabetes mellitus (IDDM) patients with (i) normal urinary albumin excretion (UAE), and (ii) moderate microalbuminuria (20 to 70 micrograms/min). In a study comprising 117 normoalbuminuric (UAE < 20 micrograms/min) patients we performed 24-hour ambulatory blood pressure monitoring (AMBP), and short-term power spectral analysis of RR interval oscillations. In comparison with the group with a UAE below the median, patients with UAE above the median were characterized by: significantly higher 24-hour systolic and diastolic AMBP, significantly reduced short-term RR interval variability, and significantly higher HbA1c. In a double blind study, normotensive IDDM patients with moderate microalbuminuria (20 to 70 micrograms/min) were randomized to either lisinopril (20 mg once a day, N = 12) or placebo (N = 10) for two years. In the lisinopril group there were significant reductions in 24-hour systolic and diastolic AMBP compared to the placebo group. Lisinopril did not attenuate the diurnal blood pressure variation. UAE tended to be reduced in the lisinopril group. A significantly positive association between changes in AMBP and changes in UAE was present in the placebo group in contrast to the lisinopril group. Changes in UAE were strongly and positively associated with changes in filtration fraction in the lisinopril treated group. In conclusion, interactions between albumin excretion, blood pressure, autonomic function, and glycemic status are already detectable within the normoalbuminuric range in IDDM patients. Angiotensin converting enzyme inhibitor (ACEi) treatment in a small group of normotensive IDDM patients with moderate microalbuminuria reduces blood pressure without attenuating diurnal blood pressure variation, tends to reduce albumin excretion, and abolishes the association between changes in UAE and changes in blood pressure observed in the placebo group. ACEi intervention in selected normoalbuminuric high risk patients (high-normal UAE, high-normal blood pressure, and poor glycemic control) would be of interest.

Pharmacokinetics of oral idarubicin in breast cancer patients with reference to antitumor activity and side effects.

The pharmacokinetics of orally administered idarubicin (22.5 mg/m2/week) and idarubicinol were studied for 12 weeks in 14 patients with breast cancer. Plasma concentrations were monitored for 72 hours after the first, fourth, and twelfth doses and trough concentrations after 1, 2, 3, 4, 5, 7, 11, and 12 weeks of treatment. The half-lives of idarubicin and idarubicinol were 19 and 60 hours, respectively. No time-dependent changes or cumulation were observed. The metabolic ratio showed little variation. The plasma AUCs of idarubicin and idarubicinol varied between patients but were fairly constant in individual patients. The sum of the plasma AUCs was lower in patients with rapid progression than in patients who responded to treatment. A correlation between this parameter and the relative decrease in the leukocyte counts was demonstrated (p less than 0.05). No correlation was found between the pharmacokinetic parameters and the time to final progression.