Renin-angiotensin system phenotyping as a guidance toward personalized medicine for ACE inhibitors: can the response to ACE inhibition be predicted on the basis of plasma renin or ACE?

PURPOSE & METHODS: Not all hypertensive patients respond well to ACE inhibition. Here we determined whether renin-angiotensin system (RAS) phenotyping, i.e., the measurement of renin or ACE, can predict the individual response to RAS blockade, either chronically (enalapril vs. enalapril + candesartan) or acutely (enalapril ± hydrochlorothiazide, HCT). RESULTS: Chronic enalapril + candesartan induced larger renin rises, but did not lower blood pressure (BP) more than enalapril. Similar observations were made for enalapril + HCT vs. enalapril when given acutely. Baseline renin predicted the peak changes in BP chronically, but not acutely. Baseline ACE levels had no predictive value. Yet, after acute drug intake, the degree of ACE inhibition, like Δrenin, did correlate with ΔBP. Only the relationship with Δrenin remained significant after chronic RAS blockade. Thus, a high degree of ACE inhibition and a steep renin rise associate with larger acute responses to enalapril. However, variation was large, ranging >50 mm Hg for a given degree of ACE inhibition or Δrenin. The same was true for the relationships between Δrenin and ΔBP, and between baseline renin and the maximum reduction in BP in the chronic study. CONCLUSIONS: Our data do not support that RAS phenotyping will help to predict the individual BP response to RAS blockade. Notably, these conclusions were reached in a carefully characterized, homogenous population, and when taking into account the known fluctuations in renin that relate to gender, age, ethnicity, salt intake and diuretic treatment, it seems unlikely that a cut-off renin level can be defined that has predictive value.

Impaired hormonal counterregulation to biochemical hypoglycaemia does not explain the high incidence of severe hypoglycaemia during pregnancy in women with type 1 diabetes.

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.

Prospective associations of B-type natriuretic peptide with markers of left ventricular function in individuals with and without type 2 diabetes: an 8-year follow-up of the Hoorn Study.

OBJECTIVE: Heart failure is common in individuals with type 2 diabetes, and early detection of individuals at risk may offer opportunities for prevention. We aimed to explore 1) prospective associations of B-type natriuretic peptide (BNP) levels in a non-heart failure range with changes in markers of left ventricular (LV) function and 2) possible effect modification by type 2 diabetes in a population-based cohort. RESEARCH DESIGN AND METHODS: Echocardiographic measurements were performed at baseline (2000-2001) and follow-up (2007-2009), together with standardized physical examinations and BNP measurements on 300 individuals (mean age 66 years, 32% with type 2 diabetes) of the longitudinal Hoorn Study. Multivariate linear regression analyses were performed to investigate associations of baseline BNP (<100 pg/mL) in individuals without prevalent heart failure at baseline with changes in LV mass index, LV ejection fraction, left atrial volume index, and ratio of early diastolic LV inflow velocity (E) to early diastolic lengthening velocity (e') (E/e'). RESULTS: In all individuals, higher BNP was associated with 8-year increases in left atrial volume index. Higher BNP was also associated with increasing LV mass index and E/e'. These associations were significantly stronger in individuals with type 2 diabetes compared with the nonsignificant associations in individuals without type 2 diabetes. CONCLUSIONS: This 8-year follow-up study shows that higher BNP levels in a non-heart failure range were associated with an increased LV mass and deteriorated LV diastolic function, particularly in individuals with type 2 diabetes. This implies that the presence or absence of type 2 diabetes should be taken into account if BNP levels are used to assess future heart failure risk.

Atrial Natriuretic Peptide (ANP) in early pregnancy is associated with development of preeclampsia in type 1 diabetes.

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.

Daily red wine consumption improves vascular function by a soluble guanylyl cyclase-dependent pathway.

BACKGROUND: Polyphenols in red wine are supposed to improve endothelial function. We investigated whether daily red wine consumption improves in-vivo vascular function by reducing endothelin-1 (ET-1). Additional pathways mediating this effect were studied using porcine coronary arteries (PCAs). METHODS: Eighteen young healthy women drank red wine daily for 3 weeks. Vascular function was evaluated by determining forearm blood flow (FBF) responses to endothelium-dependent (acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside (SNP)) vasodilators. PCAs were suspended in organ baths and exposed to the endothelium-dependent vasodilator bradykinin, the nitric oxide (NO) donor S-nitroso-N-acetyl-L,L-penicillamine (SNAP) and/or red wine extract (RWE). RESULTS: ACh-induced and SNP-induced FBF increases were equally enhanced after 3 weeks of red wine consumption, but an immediate enhancement (i.e., after drinking the first glass) was not observed. Vice versa, plasma ET-1 levels were not decreased after 3 weeks, but we observed an acute drop after drinking one glass of wine. RWE relaxed preconstricted PCAs in an endothelium-, NO-, and soluble guanylyl cyclase (sGC)/guanosine-3',5'-cyclic monophosphate (cGMP)-dependent manner. Short RWE exposure reduced the response to bradykinin and SNAP by inactivating sGC. This effect disappeared upon prolonged RWE exposure. CONCLUSIONS: The enhanced FBF response following 3 weeks of red wine consumption, but not after one glass, reflects a change in smooth muscle sensitivity. Alterations in sGC responsiveness/activity, rather than changes in ET-1, appear to underlie this phenomenon.

Response to angiotensin-converting enzyme inhibition is selectively blunted by high sodium in angiotensin-converting enzyme DD genotype: evidence for gene-environment interaction in healthy volunteers.

BACKGROUND: Renin-angiotensin-aldosterone system blockade is a cornerstone in cardiovascular protection. Angiotensin-converting enzyme (ACE)-DD genotype has been associated with resistance to angiotensin-converting enzyme inhibition (ACEi), but data are conflicting. As sodium intake modifies the effect of ACEi as well as the genotype-phenotype relationship, we hypothesize gene-environment interaction between sodium-status, the response to ACEi, and ACE genotype. METHOD: Thirty-five male volunteers (26 ± 9 years; II n = 6, ID n = 18, DD n = 11) were studied during placebo and ACEi (double blind, enalapril 20 mg/day) on low [7 days 50 mmol Na/day (low salt)] and high [7 days 200 mmol Na/day (high salt)] sodium, with a washout of 6 weeks in-between. After each period mean arterial pressure (MAP) was measured before and during graded infusion of angiotensin II (Ang II). RESULTS: During high salt, ACEi reduced MAP in II and ID, but not in DD [II: 88 (78-94) versus 76 (72-88); ID: 87 (84-91) versus 83 (79-87); both P < 0.05 and DD: 86 (82-96) versus 88 (80-90); ns, P < 0.05 between genotypes]. However, during low salt, ACEi reduced MAP in all genotype groups [II: 83 (78-89) versus 77 (72-83); ID: 88 (84-91) versus 82 (78-86); DD: 84 (80-91) versus 81 (75-85); all P < 0.05]. During high salt + ACEi, the Ang II response was blunted in DD, with an 18% rise in MAP during the highest dose versus 22 and 31% in ID and II (P < 0.05). Low salt annihilated these differences. CONCLUSION: In healthy participants, the MAP response to ACEi is selectively blunted in DD genotype during high salt, accompanied by blunted sensitivity to Ang II. Low salt corrects both abnormalities. Further analysis of this gene-environment interaction in patients may contribute to strategies for improvement of individual treatment efficacy.

Slightly elevated B-type natriuretic peptide levels in a non-heart failure range indicate a worse left ventricular diastolic function in individuals with, as compared with individuals without, type 2 diabetes: the Hoorn Study.

AIMS: Higher plasma B-type natriuretic peptide (BNP) in a non-heart failure (HF) range predicts HF and cardiovascular disease (CVD) mortality in the general population. Heart failure is highly prevalent in type 2 diabetes mellitus (T2DM), but associations of BNP to left ventricular (LV) mass and function in individuals with a different glucose status have not been compared. We therefore aimed to explore (i) the association of BNP levels in a non-HF range with structural and functional markers of LV function, and (ii) possible effect modification by glucose tolerance categories. METHODS AND RESULTS: Linear regression analyses were performed to investigate associations of BNP with 2D echocardiographic measures of LV mass index, LV systolic function, and markers of LV diastolic function in a population-based study of men and women with normal glucose metabolism (NGM, n = 197), impaired glucose metabolism (IGM, n = 128), or T2DM (n = 204). Patients were aged between 50 and 87 years, had BNP levels below 50 pmol/L, and no LV wall motion abnormalities. B-type natriuretic peptide levels ranged from 0.4 to 46.1 pmol/L, the median was 4.2 pmol/L. Higher BNP was significantly associated with increased LV mass and deteriorated LV diastolic function, but not with LV systolic function. B-type natriuretic peptide was more strongly associated with LV diastolic function in T2DM compared with NGM and IGM. CONCLUSION: B-type natriuretic peptide was associated with LV mass and markers of LV diastolic function, and the association of BNP with the latter appeared to be particularly strong in individuals with T2DM. This implies that the presence or absence of T2DM should be taken into account if BNP levels are used to assess CVD risk.

Cognitive performance, symptoms and counter-regulation during hypoglycaemia in patients with type 1 diabetes and high or low renin-angiotensin system activity.

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.

Vascular endothelial growth factor during hypoglycemia in patients with type 1 diabetes mellitus: relation to cognitive function and renin-angiotensin system activity.

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.

Renal effects of aliskiren compared with and in combination with irbesartan in patients with type 2 diabetes, hypertension, and albuminuria.

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.

Clinical outcome 5 to 18 years after the Fontan operation performed on children younger than 5 years.

OBJECTIVE: This study assessed clinical condition at midterm follow-up after total cavopulmonary connection for a functionally univentricular heart performed on children younger than 5 years. METHODS: Thirty-four Fontan patients (median age 10.4 years, range 6.8-20.7 years, 22 boys, median follow-up 7.8 years, 5.0-17.8 years) underwent electrocardiography, Holter monitoring, bicycle exercise testing, cardiac magnetic resonance imaging, and N-terminal prohormone brain natriuretic peptide (NT-pro-BNP) analysis. RESULTS: Twenty-three patients (68%) were in sinus rhythm. Holter monitoring demonstrated normal mean heart rate, low maximal heart rate, and no clinically significant arrhythmias or sinus node dysfunction. With maximal bicycle ergometry (n = 19), maximum workload (60% of normal), maximum heart rate (90% of normal), and maximal oxygen uptake (69% of normal) were all significantly lower in the Fontan group than in a control group (P < .001). Variables of submaximal exercise indicated less efficient oxygen uptake during exercise in all Fontan patients. Ejection fraction was lower than in control subjects (59% +/- 13% vs 69% +/- 5%, P < .001). Mean end-diastolic and end-systolic volumes and ventricular mass were higher than in control subjects (P < .001). Mean NT-pro-BNP levels were increased relative to reference values, but only 8 patients had levels above the upper reference limit. CONCLUSION: At midterm follow-up, Fontan patients were in acceptable clinical condition, with preserved global ventricular function, moderately decreased exercise capacity, and NT-pro-BNP levels within reference range. Systemic ventricular mass was elevated, however, suggesting contractility-afterload mismatch. Long-term consequences for ventricular function merit further investigation.

Osmomediated natriuresis in humans: the role of vasopressin and tubular calcium sensing.

BACKGROUND: The aim was to investigate the unknown mechanism of osmomediated natriuresis. This is the phenomenon by which hypertonic saline (HS) produces a larger natriuresis than isotonic saline (IS), despite the same sodium content. METHODS: Seven healthy volunteers first received HS and then IS (both 3.85 mmol sodium/kg). To investigate the role of calcium metabolism, four patients received HS, two with an activating mutation (ADH) and two with an inactivating mutation (FHH) of the calcium-sensing receptor (CaSR). RESULTS: In healthy volunteers, HS produced mild hypernatraemia, a 4-fold rise in vasopressin (to 2.2 +/- 0.85 pg/mL) and a 3-fold rise in natriuresis compared with a 1.5-fold rise with IS (P = 0.002). This confirmed osmomediated natriuresis. HS caused calciuresis to increase 1.4-fold and then reduced it 1.4-fold, whereas IS failed to increase calciuresis and caused it to fall 3.7-fold (P = 0.05). Natriuresis and calciuresis in ADH patients were similar to healthy volunteers receiving HS, whereas a blunted response was seen in FHH patients. Patient vasopressin levels did not exceed 1.3 pg/mL and changes from baseline were variable. In one FHH patient, a 3-fold rise in vasopressin did not prevent the blunted natriuresis and calciuresis. In one ADH patient, natriuresis and calciuresis were similar to healthy volunteers despite a 1.7-fold fall in vasopressin. CONCLUSIONS: Our data suggest that not only vasopressin (possibly via its V1a receptor), but also the CaSR (which is sensitive to high sodium concentrations) may play a role in osmomediated natriuresis. These results shed new light on osmomediated natriuresis and suggest roles for the CaSR beyond calcium regulation.

Autoregulation of glomerular filtration rate during spironolactone treatment in hypertensive patients with type 1 diabetes: a randomized crossover trial.

BACKGROUND: Autoregulation of GFR, i.e. maintenance of relative constancy of GFR despite variations in mean arterial pressure (MAP) >80 mmHg, is impaired in diabetic kidney disease; furthermore, some antihypertensive drugs may jeopardize autoregulation. The aim of our study was to establish if spironolactone affects the ability to autoregulate GFR. METHODS: Sixteen hypertensive type 1 diabetic patients with persistent normoalbuminuria (presumed normal autoregulation) completed this randomized, double-masked, crossover trial. After a 4-week wash-out period, patients received spironolactone 25 mg o.d. and matched placebo for 4 weeks in random order. After each treatment period, the ability to autoregulate GFR was determined by measuring GFR ((51)Cr-EDTA clearance) before (basal) and after acute blood pressure reduction by intravenous injection of clonidine. RESULTS: During placebo, the mean (SE) basal GFR was 115 (5) ml/min/1.73 m(2) and the BP was 146 (4)/81 (2) mmHg corresponding to a MAP of 103 (2) mmHg. Spironolactone did not significantly reduce GFR or BP. Injection of clonidine induced a significant reduction in the MAP of 17 (2) and 19 (1) mmHg during placebo and spironolactone treatment, respectively, and an overall reduction in GFR of 11 and 15 ml/min/1.73 m(2) (both comparisons NS between treatment periods). Signs of impaired autoregulation were present in nine patients during placebo and in nine patients during spironolactone treatment. Relative changes in GFR on placebo treatment correlated with diabetes duration (R = 0.67, P < 0.01) but were not related to duration of hypertension, baseline BP, GFR, HbA1c or to changes in BP. CONCLUSION: Spironolactone did not change the overall ability to autoregulate GFR in 16 hypertensive type 1 diabetic patients with normoalbuminuria. Our data are suggestive that the ability to autoregulate GFR is gradually impaired with increasing diabetes duration, a phenomenon not previously described in normoalbuminuric patients.

Angiotensin converting enzyme-regulated, noncholinergic sympathoadrenal catecholamine release mediates the cardiovascular actions of human 'new pressor protein' related to coagulation beta-factor XIIa.

BACKGROUND: Human 'new pressor protein' (NPP), related to coagulation beta-factor XIIa (beta-FXIIa), potently releases sympathoadrenal catecholamines in bioassay rats, with concurrent elevation of systolic and diastolic blood pressure (SBP/DBP) and heart rate (HR). Elevated plasma NPP/beta-FXIIa levels in hypertensive anephric pediatric patients on hemodialysis associated with fluid status and blood pressure changes were previously reported, suggesting that NPP/beta-FXIIa contributed to their hypertension. OBJECTIVE: To investigate the mechanism of action of NPP/beta-FXIIa. METHODS: Hemodynamic and sympathoadrenal responses to NPP (20 microL plasma equivalent/rat) or coagulation beta-FXIIa (300 ng/kg intravenously) were measured in rats treated with pentolinium (ganglion blockade [+GB]) and/or captopril (+CAP; angiotensin converting enzyme [ACE] inhibition). RESULTS: In controls not receiving GB or CAP (-GB-CAP), NPP/beta-FXIIa raised plasma epinephrine (E) sixfold, SBP/DBP by 14/8 mmHg and HR by 15 beats/min. With blockade of the cholinergic pathway to the sympathoadrenal system (+GB), basal E, norepinephrine (NE), SBP, DBP and HR all dropped. However NPP/beta-FXIIa remained capable of raising E 20-fold, NE fourfold, SBP/DBP by 27/11 mmHg and HR by 20 beats/min, suggesting that it acted through a 'noncholinergic' mechanism. With +CAP alone, NPP/beta-FXIIa raised plasma E 18-fold, NE threefold, SBP/ DBP by 29/8 mmHg and HR by 73 beats/min, implicating an ACE-regulated 'peptidergic' mechanism. Combining +GB with +CAP potentiated NPP/beta-FXIIa actions further by raising E 50-fold, NE sevenfold, SBP/DBP by 55/20 mmHg and HR by 87 beats/min, strengthening the efficacy of this alternate pathway. CONCLUSIONS: The cardiovascular effects of NPP/beta-FXIIa are considerably mediated by a noncholinergic (peptidergic) ACE-regulated mechanism for sympathoadrenal catecholamine release that is enhanced by +GB and/or +CAP. Under inflammatory procoagulant conditions, endogenously produced NPP/beta-FXIIa may interfere with the antihypertensive effects of ACE inhibition therapy.

The impact of left ventricular assist device-induced left ventricular unloading on the myocardial renin-angiotensin-aldosterone system: therapeutic consequences?

AIMS: Angiotensin-converting enzyme inhibitors (ACE-Is) prevent the rise in myocardial angiotensin II that occurs after left ventricular assist device (LVAD) implantation, but do not fully normalize cardiac function. Here, we determined the effect of LVAD implantation, with or without ACE-Is, on cardiac renin, aldosterone, and norepinephrine, since these hormones, like angiotensin II, are likely determinants of myocardial recovery during LVAD support. METHODS AND RESULTS: Biochemical measurements were made in paired LV myocardial samples obtained from 20 patients before and after LVAD support in patients with and without ACE-I therapy. Pre-LVAD renin levels were 100x normal and resulted in almost complete cardiac angiotensinogen depletion. In non-ACE-I users, LVAD support, by normalizing blood pressure, reversed this situation. Cardiac aldosterone decreased in parallel with cardiac renin, in agreement with the concept that cardiac aldosterone is blood-derived. Cardiac norepinephrine increased seven-fold, possibly due to the rise in angiotensin II. Angiotensin-converting enzyme inhibitor therapy prevented these changes: renin and aldosterone remained high, and no increase in norepinephrine occurred. CONCLUSION: Although LV unloading lowers renin and aldosterone, it allows cardiac angiotensin generation to increase and thus to activate the sympathetic nervous system. Angiotensin-converting enzyme inhibitors prevent the latter, but do not affect aldosterone. Thus, mineralocorticoid receptor antagonist therapy during LVAD support may play a role in further promoting recovery.

Differential associations between renal function and "modifiable" risk factors in patients with chronic heart failure.

BACKGROUND: Reduced glomerular filtration rate (GFR) is strongly associated with reduced survival in patients with chronic heart failure (CHF). Our aim was to determine different pathophysiologic markers that are associated with reduced renal function in CHF. METHODS AND RESULTS: We studied 86 patients with CHF (58+/-12 years, 78% male). GFR and renal blood flow (RBF) were determined by (125)I-Iothalamate and (131)I-Hippuran clearances. Filtration fraction (FF) was calculated. We determined haemoglobin levels, endothelial function, inflammatory status, plasma renin activity (PRA) and N-terminal pro brain natriuretic peptide (NT-proBNP). Urinary albumin excretion (UAE) was measured in 24 h urine. Mean GFR was 74+/-28 ml/min/1.73 m(2). GFR was strongly related to RBF (r=0.915, P<0.001), FF (r=0.546, P<0.001), but only weakly to endothelial function and PRA. In multivariate analysis, RBF (r=0.938, P < 0.001), FF (r=0.786, P < 0.001) and haemoglobin levels (r= -0.520, P<0.001) were independently associated with GFR. UAE was mainly dependent on RBF (r= -0.401, P < 0.001) and increased exponentially with decreasing RBF. RBF was mainly associated with NT-proBNP (r= -0.561, P<0.001) and PRA (r= -0.422, P<0.001). CONCLUSION: Reduced GFR is mainly dependent of decreased RBF in patients with CHF. Endothelial function and neurohormonal activation showed only mild associations with GFR. NT-proBNP showed a strong relationship with RBF, and may be used as a marker of reduced renal perfusion.

Assessment of biventricular functional reserve and NT-proBNP levels in patients with RV volume overload after repair of tetralogy of Fallot at young age.

PURPOSE: To assess biventricular functional reserve (FR), NT-proBNP levels and exercise performance, in relation to right ventricular volume in patients with pulmonary regurgitation (PR) after repair of tetralogy of Fallot (TOF) at young age. METHODS: In 53 TOF patients (maximum age at repair 2.0 years, interval since repair 15 (5) years) without residual lesions except PR, biventricular FR (derived from magnetic resonance imaging with dobutamine stress), NT-proBNP levels, maximal workload, and peak oxygen uptake were assessed. RESULTS: Mean right ventricular end-diastolic volume was 140(38) ml/m(2). Median pulmonary regurgitant fraction was 37% (range 0-57%). Biventricular systolic stress response was normal: mean (SD) ESV decreased (DeltaRVESV -17(8) ml/m(2), DeltaLVESV -11(5)), SV increased (DeltaRVSV +12(9) ml/m(2), DeltaLVSV +9(6)), FR was positive in all (RV-FR +11(5)%, LV-FR +13(6)). No serious adverse effects to dobutamine were encountered. NT-proBNP was increased in 2 patients. Median level was 10 pmol/L (range 2-42). NT-proBNP correlated with PR-percentage but not with right ventricular size. High-risk levels of NT-proBNP indicated a smaller RV-FR and a smaller decrease of biventricular ESV. Mean (SEM) VO2(max) was 96(3)%, mean Workload(max) 89(2)% of predicted. CONCLUSION: At mid to long term follow-up overall NT-proBNP levels are normal and biventricular functional reserve and exercise tolerance are well preserved in TOF repaired at young age, irrespective of RV volume. This questions the validity of isolated PR or RV volume criteria for pulmonary valve replacement in this group. Low-dose dobutamine stress testing is well tolerated and may be a useful additional tool for clinical decision making.

N-terminal pro-brain natriuretic peptide testing in the emergency department: beneficial effects on hospitalization, costs, and outcome.

BACKGROUND: N-terminal pro-brain natriuretic peptide (NT-proBNP) is an established biomarker for heart failure. Assessment of this biomarker in patients with acute dyspnea presenting to the emergency department (ED) may aid diagnostic decision-making, resulting in improved patient care and reduced costs. METHODS: In a prospective clinical trial, patients presenting with acute dyspnea to the ED of the Erasmus Medical College, Rotterdam, the Netherlands, were randomized for either rapid measurement or no measurement of NT-proBNP. For ruling out heart failure, cutoff values of 93 pg/mL in male and 144 pg/mL in female patients were used, and for ruling in heart failure, a cutoff value of 1,017 pg/mL was used. Time to discharge from the hospital and costs related to hospital admission were primary end points. Bootstrap analysis was used for comparison of costs and 30-day mortality between the NT-proBNP and control group. RESULTS: A total of 477 patients (54% male) was enrolled. The mean age was 59 years, with 44% of patients having a history of cardiac disease. Median time to discharge from the hospital was 1.9 days (interquartile range [IQR], 0.12-8.4 days) in the NT-proBNP group (n = 241) compared with 3.9 days (IQR, 0.16-11.0 days) in the control group (n = 236) (P = .04). Introduction of NT-proBNP testing resulted in a trend toward reduction in costs related to hospital admission and diagnostic investigations of $1,364 per patient (95% CI $-246 to $3,215), whereas 30-day mortality was similar (15 patients in the NT-proBNP and 18 patients in the control group). CONCLUSIONS: Introduction of NT-proBNP testing for heart failure in the ED setting reduces the time to discharge and is associated with a trend toward cost reduction.

Cardiac repolarization during hypoglycaemia in type 1 diabetes: impact of basal renin-angiotensin system activity.

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.

Integrative control of coronary resistance vessel tone by endothelin and angiotensin II is altered in swine with a recent myocardial infarction.

Several studies have indicated an interaction between the renin-angiotensin (ANG II) system and endothelin (ET) in the regulation of vascular tone. Previously, we have shown that both ET and ANG II exert a vasoconstrictor influence on the coronary resistance vessels of awake normal swine. Here, we investigated whether the interaction between ANG II and ET exists in the control of coronary resistance vessel tone at rest and during exercise using single and combined blockade of angiotensin type 1 (AT(1)) and ET(A)/ET(B) receptors. Since both circulating ANG II and ET levels are increased after myocardial infarction (MI), we investigated if the interaction between these systems is altered after MI. In awake healthy swine, coronary vasodilation in response to ET(A)/ET(B) receptor blockade in the presence of AT(1) blockade was similar to vasodilation produced by ET(A)/ET(B) blockade under control conditions. In awake swine with a 2- to 3-wk-old MI, coronary vasodilator responses to individual AT(1) and ET(A)/ET(B) receptor blockade were virtually abolished, despite similar coronary arteriolar AT(1) and ET(A) receptor expression compared with normal swine. Unexpectedly, in the presence of AT(1) blockade (which had no effect on circulating ET levels), ET(A)/ET(B) receptor blockade elicited a coronary vasodilator response. These findings suggest that in normal healthy swine the two vasoconstrictor systems contribute to coronary resistance vessel control in a linear additive manner, i.e., with negligible cross-talk. In contrast, in the remodeled myocardium, cross-talk between ANG II and ET emerges, resulting in nonlinear redundant control of coronary resistance vessel tone.