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Aims. To explore hormonal counterregulation to biochemical hypoglycaemia during pregnancy. Methods. Observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years (range 1-36), HbA1c 6.6% (4.9-10.5) in early pregnancy) and 22 healthy pregnant women. At 8, 14, 21, 27 and 33 weeks (women with diabetes) and 15, 28 and 34 weeks (healthy women) blood was sampled for measurements of glucose, adrenaline, noradrenaline, cortisol and glucagon. Each woman's measurement of serum glucose was matched with her corresponding hormone concentrations. Severe hypoglycaemia (requiring help from another person) was recorded prospectively. Results. During normoglycaemia (serum glucose > 3.9 mmol/L), adrenaline concentrations were higher in early pregnancy compared with late pregnancy in women with diabetes (21 (7-111) pg/ml vs. 17 (2-131), p = 0.02) and healthy women (21 (10-37) pg/ml vs. 13 (5-49), p = 0.046). Biochemical hypoglycaemia (serum glucose ≤ 3.9 mmol/L) occurred in 70 women with diabetes (65%) in at least one of the five samplings. At 8 and 33 weeks, adrenaline concentrations at biochemical hypoglycaemia were similar (30 (5-164) pg/ml and 29 (9-152), p = 0.79). Adrenaline concentrations at biochemical hypoglycaemia increased from normoglycaemia at diabetes duration <16 years (p = 0.03). In first trimester, adrenaline concentrations were comparable in women with or without severe hypoglycaemia (24 (14-164) pg/ml vs. 33 (5-86), p = 0.35). Noradrenaline, glucagon and cortisol concentrations did not increase during biochemical hypoglycaemia. Conclusion. Adrenaline response to biochemical hypoglycaemia was present at similar levels in early and late pregnancy, particularly in shorter diabetes duration, and was not associated with severe hypoglycaemia in early pregnancy.

Aims. To explore hormonal counterregulation to biochemical hypoglycaemia during pregnancy. Methods. Observational study of 107 consecutive pregnant women with type 1 diabetes (median duration 16 years (range 1-36), HbA1c 6.6% (4.9-10.5) in early pregnancy) and 22 healthy pregnant women. At 8, 14, 21, 27 and 33 weeks (women with diabetes) and 15, 28 and 34 weeks (healthy women) blood was sampled for measurements of glucose, adrenaline, noradrenaline, cortisol and glucagon. Each woman's measurement of serum glucose was matched with her corresponding hormone concentrations. Severe hypoglycaemia (requiring help from another person) was recorded prospectively. Results. During normoglycaemia (serum glucose > 3.9 mmol/L), adrenaline concentrations were higher in early pregnancy compared with late pregnancy in women with diabetes (21 (7-111) pg/ml vs. 17 (2-131), p = 0.02) and healthy women (21 (10-37) pg/ml vs. 13 (5-49), p = 0.046). Biochemical hypoglycaemia (serum glucose ≤ 3.9 mmol/L) occurred in 70 women with diabetes (65%) in at least one of the five samplings. At 8 and 33 weeks, adrenaline concentrations at biochemical hypoglycaemia were similar (30 (5-164) pg/ml and 29 (9-152), p = 0.79). Adrenaline concentrations at biochemical hypoglycaemia increased from normoglycaemia at diabetes duration <16 years (p = 0.03). In first trimester, adrenaline concentrations were comparable in women with or without severe hypoglycaemia (24 (14-164) pg/ml vs. 33 (5-86), p = 0.35). Noradrenaline, glucagon and cortisol concentrations did not increase during biochemical hypoglycaemia. Conclusion. Adrenaline response to biochemical hypoglycaemia was present at similar levels in early and late pregnancy, particularly in shorter diabetes duration, and was not associated with severe hypoglycaemia in early pregnancy.

The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting that preeclampsia is associated with cardiovascular changes in early pregnancy.

The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting that preeclampsia is associated with cardiovascular changes in early pregnancy.

The vasoactive markers of cardiac overload Atrial Natriuretic Peptide (ANP) and Brain Natriuretic Peptide (BNP) are elevated in preeclampsia. This study documents higher ANP concentrations as early as at 9 weeks in type 1 diabetic women subsequently developing preeclampsia suggesting that preeclampsia is associated with cardiovascular changes in early pregnancy.

INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity.MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded.RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness.CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

Udgivelsesdato: 2009-Oct, In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.

Udgivelsesdato: 2009-Oct, OBJECTIVE: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS: Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination. CONCLUSIONS: The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Udgivelsesdato: 2009-Dec, INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity. MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded. RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity.MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded.RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness.CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

Udgivelsesdato: 2009-Oct, OBJECTIVE: We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS: Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean +/- SD 24-h blood pressure was 140/73 +/- 15/8 mmHg, and GFR was 89 +/- 27 ml/min per 1.73 m(2). Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m(2) by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m(2) by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m(2) by the combination. CONCLUSIONS: The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with albuminuria than monotherapy.

Udgivelsesdato: 2009-Oct, In healthy adults, levels of vascular endothelial growth factor (VEGF) increase in response to mild hypoglycemia. VEGF is implicated in glucose transport over the blood-brain barrier, and the increase during hypoglycemia has been positively correlated with preservation of cognitive function during hypoglycemia. High activity in the renin-angiotensin system (RAS) is associated with an increased risk of severe hypoglycemia in patients with type 1 diabetes mellitus. Renin-angiotensin system possibly exerts its mechanism in hypoglycemia via VEGF. We studied the impact of mild hypoglycemia on plasma VEGF in patients with type 1 diabetes mellitus and high or low RAS activity and analyzed associations between VEGF levels and cognitive function during hypoglycemia. Eighteen patients with type 1 diabetes mellitus-9 with high and 9 with low RAS activity-underwent a single-blinded, placebo-controlled, crossover study with either mild hypoglycemia or stable glycemia. Cognitive function was assessed by the California Cognitive Assessment Package and the Alzheimer Quick Test. Nadir plasma glucose was 2.2 (0.3) mmol/L. During the control study, plasma VEGF did not change. During hypoglycemia, plasma VEGF increased from 39 to 58 pg/L in the high-RAS group (P = .004) and from 76 to 109 pg/L in the low-RAS group (P = .01), with no difference between RAS groups (P = .9). A weak association between reduced preservation of cognitive function during hypoglycemia and low VEGF response was observed. Plasma VEGF levels increase during mild, short-term hypoglycemia in patients with type 1 diabetes mellitus. The VEGF response is not dependent on RAS activity and only weakly associated with preservation of cognitive function during hypoglycemia. Thus, the previously described association between low RAS activity and better cognitive performance during hypoglycemia does not seem to be mediated by VEGF.

Udgivelsesdato: 2009-Dec, INTRODUCTION: High basal renin-angiotensin system (RAS) activity is associated with increased risk of severe hypoglycaemia in type 1 diabetes. We tested whether this might be explained by more pronounced cognitive dysfunction during hypoglycaemia in patients with high RAS activity than in patients with low RAS activity. MATERIALS AND METHODS: Nine patients with type 1 diabetes and high and nine with low RAS activity were subjected to hypoglycaemia and euglycaemia in a cross-over study using an intravenous insulin infusion protocol. Cognitive function, electroencephalography, auditory evoked potentials and hypoglycaemic symptoms were recorded. RESULTS: At a hypoglycaemic nadir of 2.2 (SD 0.3) mmol/L the high RAS group displayed significant deterioration in cognitive performance during hypoglycaemia in the three most complex reaction time tasks. In the low RAS group, hypoglycaemia led to cognitive dysfunction in only one reaction time task. The high RAS group reported lower symptom scores during hypoglycaemia than the low RAS group, suggesting poorer hypoglycaemia awareness. CONCLUSION: High RAS activity is associated with increased cognitive dysfunction and blunted symptoms during mild hypoglycaemia compared to low RAS activity. This may explain why high RAS activity is a risk factor for severe hypoglycaemia in type 1 diabetes.

OBJECTIVE - We investigated whether the antiproteinuric effect of the direct renin inhibitor aliskiren is comparable to that of irbesartan and the effect of the combination. RESEARCH DESIGN AND METHODS - This was a double-blind, randomized, crossover trial. After a 1-month washout period, 26 patients with type 2 diabetes, hypertension, and albuminuria (>100 mg/day) were randomly assigned to four 2-month treatment periods in random order with placebo, 300 mg aliskiren once daily, 300 mg irbesartan once daily, or the combination using identical doses. Patients received furosemide in a stable dose throughout the study. The primary end point was a change in albuminuria. Secondary measures included change in 24-h blood pressure and glomerular filtration rate (GFR). RESULTS - Placebo geometric mean albuminuria was 258 mg/day (range 84-2,361), mean ± SD 24-h blood pressure was 140/73 ± 15/8 mmHg, and GFR was 89 ± 27 ml/min per 1.73 m2. Aliskiren treatment reduced albuminuria by 48% (95% CI 27-62) compared with placebo (P < 0.001), not significantly different from the 58% (42-79) reduction with irbesartan treatment (P < 0.001 vs. placebo). Combination treatment reduced albuminuria by 71% (59-79), more than either monotherapy (P < 0.001 and P = 0.028). Fractional clearances of albumin were significantly reduced (46, 56, and 67% reduction vs. placebo). Twenty-four-hour blood pressure was reduced 3/4 mmHg by aliskiren (NS/P = 0.009), 12/5 mmHg by irbesartan (P < 0.001/P = 0.002), and 10/6 mmHg by the combination (P = 0.001/P < 0.001). GFR was significantly reduced 4.6 (95% CI 0.3-8.8) ml/min per 1.73 m2 by aliskiren, 8.0 (3.6-12.3) ml/min per 1.73 m2 by irbesartan, and 11.7 (7.4-15.9) ml/min per 1.73 m2 by the combination. CONCLUSIONS - The combination of aliskiren and irbesartan is more antiproteinuric in type 2 diabetic patients with a

Udgivelsesdato: 2008-Jul, AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the 'dead-in-bed syndrome'. METHODS AND RESULTS: Nine subjects with high RAS activity and nine subjects with low RAS activity were subjected to single-blinded placebo-controlled hypoglycaemia (nadir plasma glucose 2.4 mmol/L). QTc/QTcF and QT dynamics were registered by Holter monitoring. QTc prolonged during [8 (+/-2.3) ms, P < 0.01] and after [11 (+/-3) ms, P < 0.001] hypoglycaemia. Dynamic QT parameters reacted ambiguously. Low RAS activity was associated with a slightly more pronounced QT prolongation [6 (+/-3) ms, P = 0.04]. Adrenaline tended to increase more in the low-RAS group (P = 0.08) and was correlated to QTc (r = 0.67, P < 0.01) and QTcF (r = 0.58, P < 0.05) during hypoglycaemia. CONCLUSION: Low basal RAS activity may be associated with a slightly more pronounced QT prolongation during hypoglycaemia, when compared with high RAS activity. The impact, however, is modest and the clinical consequence is unclear.

Udgivelsesdato: 2008-Feb, AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring. Hypoglycaemia and hypoxaemia induced QTc prolongation (P < 0.001, both stimuli). The QT/RR slope and the VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0.04; hypoxia: P = 0.03. RAS activity had no impact on QTc [P = 0.48 (hypoglycaemia) and P = 0.40 (hypoxaemia)] or any of the other outcome variables. CONCLUSION: Basal RAS activity has significant impact on QT dynamics, but not the corrected QT interval, during recovery from hypoglycaemia and hypoxaemia. The impact, however, is modest and more subtle than initially expected. The clinical relevance is unclear.

Udgivelsesdato: 2008-Jul, AIMS: Hypoglycaemia-induced cardiac arrhythmias may be involved in the pathogenesis of the 'dead-in-bed syndrome' in patients with type 1 diabetes. Evidence suggests that the renin-angiotensin system (RAS) influences the occurrence of arrhythmias. The aim of this study was to explore if basal RAS activity affects cardiac repolarization during hypoglycaemia, thereby potentially carrying prognostic information on risk of the 'dead-in-bed syndrome'. METHODS AND RESULTS: Nine subjects with high RAS activity and nine subjects with low RAS activity were subjected to single-blinded placebo-controlled hypoglycaemia (nadir plasma glucose 2.4 mmol/L). QTc/QTcF and QT dynamics were registered by Holter monitoring. QTc prolonged during [8 (+/-2.3) ms, P < 0.01] and after [11 (+/-3) ms, P < 0.001] hypoglycaemia. Dynamic QT parameters reacted ambiguously. Low RAS activity was associated with a slightly more pronounced QT prolongation [6 (+/-3) ms, P = 0.04]. Adrenaline tended to increase more in the low-RAS group (P = 0.08) and was correlated to QTc (r = 0.67, P < 0.01) and QTcF (r = 0.58, P < 0.05) during hypoglycaemia. CONCLUSION: Low basal RAS activity may be associated with a slightly more pronounced QT prolongation during hypoglycaemia, when compared with high RAS activity. The impact, however, is modest and the clinical consequence is unclear.

Udgivelsesdato: 2008-Feb, AIMS: Activity in the renin-angiotensin system (RAS) may influence the susceptibility to cardiac arrhythmia. To study the effect of basal RAS activity on cardiac repolarization during myocardial stress induced by hypoglycaemia or hypoxaemia in healthy humans. METHODS AND RESULTS: Ten subjects with high RAS activity and 10 subjects with low RAS activity were studied on three different occasions: (i) hypoglycaemia (nadir P-glucose 2.7 +/- 0.5 mmol/L), (ii) hypoxaemia (nadir pO(2) 5.8 +/- 0.5 kPa), and (iii) normoglycaemic normoxia (control day). QT parameters were registered by Holter monitoring. Hypoglycaemia and hypoxaemia induced QTc prolongation (P < 0.001, both stimuli). The QT/RR slope and the VR increased as a function of hypoglycaemia, but were unaffected by hypoxaemia. Low RAS activity was associated with a steeper QT/RR slope in the recovery phase after both stimuli: hypoglycaemia: P = 0.04; hypoxia: P = 0.03. RAS activity had no impact on QTc [P = 0.48 (hypoglycaemia) and P = 0.40 (hypoxaemia)] or any of the other outcome variables. CONCLUSION: Basal RAS activity has significant impact on QT dynamics, but not the corrected QT interval, during recovery from hypoglycaemia and hypoxaemia. The impact, however, is modest and more subtle than initially expected. The clinical relevance is unclear.

BACKGROUND: Natriuretic peptides are currently used in the diagnosis and follow-up of patients with Chronic Heart Failure (CHF). However, it is unknown whether there are different influences of age on atrial natriuretic peptide (ANP)/N-terminal-ANP (NT-ANP) or B-type natriuretic peptide (BNP)/N-terminal-proBNP (NT-proBNP). AIMS: To compare the influence of age and gender on plasma levels of ANP/NT-ANP and BNP/NT-proBNP in CHF patients. METHODS AND RESULTS: Natriuretic peptides were measured in 311 CHF patients (68+/-8 years, 76% males, left ventricular ejection fraction (LVEF) 0.23+/-0.08). All natriuretic peptides were significantly related to age (p<0.05) on multivariate regression analysis, with partial correlation coefficients of 0.18, 0.29, 0.28 and 0.25 for ANP, NT-ANP, BNP and NT-proBNP, respectively. The relative increase of both BNP/NT-proBNP were more pronounced than of ANP/NT-ANP (p<0.01). Furthermore, the relative increase of BNP with age was markedly larger than of NT-proBNP (p<0.01). Levels of all natriuretic peptides were also significantly related to cardiothoracic ratio, renal function and LVEF. CONCLUSION: In patients with CHF, BNP/NT-proBNP were more related to age than ANP/NT-ANP, and BNP was more related to age than NT-proBNP. However, in these CHF patients the influence of age on the levels of all natriuretic peptides was modest, and comparable to several other factors.

We studied the hemodynamic, neurohumoral, and biochemical effects of the novel angiotensin type 1 (AT1) receptor antagonist irbesartan in 86 untreated patients with essential hypertension on a normal sodium diet. According to a double-blind parallel group trial, patients were randomized to a once-daily oral dose of the AT1 receptor antagonist (1, 25, or 100 mg) or placebo after a placebo run-in period of 3 weeks. Randomization meditation was given for 1 week. Compared with placebo, 24-hour ambulatory blood pressure did not change with the 1-mg dose, and it fell (mean and 95% confidence interval) by 7.0 (4.2-9.8)/6.1 (3.9-8.1) mm Hg with the 25-mg dose and by 12.1 (8.1-16.2)/7.2 (4.9-9.4) mm Hg with the 100-mg dose. Heart rate did not change during either dose. With the 25-mg dose, the antihypertensive effect was attenuated during the second half of the recording, and with the 100-mg dose, it was maintained for 24 hours. Baseline values of renin and the antihypertensive response to the 25- and 100-mg doses were well correlated (r=.68, P<.01). Renin did not change with the 1-mg dose, but it rose threefold to fourfold with the 25-mg dose and fourfold to fivefold with the 100-mg dose 4 to 6 hours after administration. With the 100-mg dose, renin was still elevated twofold 24 hours after dosing. The changes in renin induced by the AT1 receptor antagonist were associated with parallel increments in angiotensin I and angiotensin II. Aldosterone, despite AT1 receptor blockade, did not fall. Compared with baseline values, plasma norepinephrine increased moderately with the 100-mg but not with 25- or 1-mg dose. Serum uric acid and its 24-hour urinary excretion did not change. In conclusion, in essential hypertension, once-daily irbesartan effectively lowers blood pressure. This effect is maintained for 24 hours with a 100-mg dose. Unlike the AT1 receptor antagonist losartan, irbesartan exerts no uricosuric effect, s