The renin-angiotensin system in malignant hypertension revisited: plasma renin activity, microangiopathic hemolysis, and renal failure in malignant hypertension

BACKGROUND: Malignant hypertension is a renin-dependent form of hypertension. However, the variations in renin-angiotensin system (RAS) activation in malignant hypertension are not completely understood. A proposed mechanism for ongoing RAS activation is the presence of microangiopathic hemolysis resulting in renovascular ischemia. METHODS: We prospectively examined the association between plasma renin activity (PRA), microangiopathic hemolysis, and renal dysfunction in 30 consecutive patients with malignant hypertension (n=18) and severe hypertension (n=12). The PRA and aldosterone were measured in the supine position and before initiating therapy. RESULTS: The PRA was 8.8 ng angiotensin I (AI)/mL/h (interquartile range [IQR] 4.8-20) in malignant hypertensive patients and 2.8 ng AI/mL/h (IQR 0.6-6.3) in patients with severe hypertension (P<.01). Aldosterone was 1.30+/-1.02 nmol/L in patients with malignant hypertension compared with 0.44+/-0.37 nmol/L in those with severe hypertension (P<.01). In malignant hypertension, PRA highly correlated with lactic dehydrogenase (LDH) (r=0.76, P<.001), meaning that 58% of the variations in PRA could be explained by LDH. The PRA positively correlated with serum creatinine values at presentation (r=0.50, P=.007), but adjustment for LDH abolished the effect of PRA on creatinine (P=.24). CONCLUSIONS: The PRA and aldosterone were markedly elevated in patients with malignant hypertension but not in severely hypertensive patients despite small differences in blood pressure (BP). The strong logarithmic correlation between PRA, microangiopathic markers, and renal dysfunction suggests a renin-mediated acceleration of vascular damage and renal dysfunction in patients with malignant hypertension.     

Furosemide withdrawal improves postprandial hypotension in elderly patients with heart failure and preserved left ventricular systolic function.

OBJECTIVE: To assess the effects of furosemide withdrawal on postprandial blood pressure (BP) in elderly patients with heart failure and preserved left ventricular systolic function. METHODS: Noninvasive measurement of blood pressure (BP) and heart rate, computation of stroke volume and cardiac output (after a 1247-kJ (297-kcal) meal, and Doppler echocardiography before and 3 months after placebo-controlled withdrawal of furosemide therapy. RESULTS: Of 20 patients with heart failure (mean+/-SEM age, 75+/-1 years; left ventricular ejection fraction, 61%+/-3%), 13 were successfully able to discontinue furosemide therapy. At baseline, 11 (55%) of the 20 patients (had maximum postprandial systolic BP declines of 20 mm Hg or more. In the withdrawal group, the maximum systolic BP decline lessened from -25+/-4 to -11+/-2 mm Hg (P<.001) and the maximum diastolic BP from -18+/-3 to -9+/-1 mm Hg (P= .01), compared with no changes in the continuation group. In the withdrawal group, maximum postprandial declines in stroke volume and cardiac output decreased from -9+/-1 to -4+/-2 mL (P =.01) and from -0.6+/-0.2 to -0.2+/-0.1 L/min) (P = .04), respectively. The baseline maximum postprandial systolic BP decrease was correlated with the ratio of early to late flow (n = 20; Spearman rank correlation coefficient, 0.58; P = .007). For patients in the withdrawal group, the changes in postprandial systolic BP response were independently related to changes in peak velocity of early flow (n = 13; r2= 0.61; P = .003). CONCLUSIONS: Postprandial hypotension is common in elderly patients with heart failure and preserved left ventricular systolic function. The withdrawal of furosemide therapy ameliorates postprandial BP homeostasis in these patients, possibly by improving left ventricular diastolic filling.     

Kidney function and systolic blood pressure new insights from cystatin C: data from the Heart and Soul Study

BACKGROUND: Control of hypertension is paramount in treating chronic kidney disease. The relationship between kidney function and blood pressure (BP) components has been studied in persons with diagnosed CKD, diabetes, or hypertension. Whether kidney function in the normal range is associated with systolic BP (SBP), diastolic BP (DBP), and pulse pressure is unclear. METHODS: We evaluated the association between kidney function and each BP component using cystatin C and 24-h creatinine clearance (CrCl) among 906 participants in the Heart and Soul Study. RESULTS: We observed that SBP was linearly associated with cystatin C concentrations (1.19+/-0.55 mm Hg increase per 0.4 mg/L cystatin C, P=.03) across the range of kidney functions. In contrast, using CrCl, SBP was significantly associated with kidney function only in subjects with CrCl<60 mL/min (6.4+/-2.13 mm Hg increase per 28 mL/min, P=.003) but not >60 mL/min (0.36+/-0.77 mm Hg per 28 mL/min, P=.64). Slopes differed significantly (for spline term P=.001). We found that DBP was not associated with cystatin C (0.34+/-0.40 mm Hg per 0.4 mg/L cystatin, P=.39) or CrCl (0.62+/-0.44 mm Hg per 28 mL/min clearance, P=.16). Pulse pressure was linearly associated with cystatin C (1.28+/-0.55 mm Hg per 0.4 mg/L cystatin, P=.02) and with CrCl<60 mL/min (7.27+/-2.16 mm Hg per 28 mL/min, P=.001). CONCLUSIONS: Both SBP and pulse pressure were significantly associated with kidney function across a wide range of cystatin C concentrations, even in subjects with presumably normal kidney function, by creatinine-based measures. Cystatin C may provide new insights into the association of CKD and hypertension, a relationship that may be an underappreciated barrier to hypertension control.     

Effects of noradrenalin and albumin in patients with type I hepatorenal syndrome: a pilot study

Treatment of hepatorenal syndromes (HRSs) is currently based on vasopressin analogs. The aim of this pilot study was to evaluate the efficacy and safety of noradrenalin (NA) in the treatment of type 1 HRS. Between 1998 and 2000, 12 consecutive patients with type 1 HRS (7 men, 5 women; mean age, 54 +/- 11 years; mean Child-Pugh score, 11.3 +/- 1.7) were treated with intravenous NA (0.5-3 mg/h), in combination with intravenous albumin and furosemide. NA was given for 10 +/- 3 days, at a mean dose of 0.8 +/- 0.3 mg/h. Reversal of HRS was observed in 10 of 12 patients (83%; 95% confidence interval, 52%-98%) after a median of 7 days (range, 5-10 days). Serum creatinine levels fell from 358 +/- 161 to 145 +/- 78 micromol/L (P <.001), creatinine clearance rose from 13 +/- 9 to 40 +/- 15 mL/min (P =.003), and urinary sodium output increased from 8 +/- 14 to 52 +/- 72 mEq/d (P =.002). Changes in renal function under NA treatment were associated with an increase in mean arterial pressure (MAP; 65 +/- 7 to 73 +/- 9 mm Hg, P =.01) and a marked reduction in active renin (565 +/- 989 to 164 +/- 196 ng/L, P =.001) and aldosterone plasma concentrations (1,945 +/- 1,931 to 924 +/- 730 ng/mL, P =.02). There was one episode of reversible myocardial hypokinesia (in a patient on 1.5 mg/h NA) that did not recur after a dose reduction. In conclusion, NA combined with albumin and furosemide appears effective and safe for the treatment of type 1 HRS.     

Regulation of plasma endothelin by salt in salt-sensitive hypertension

BACKGROUND: Salt dependency of blood pressure (BP) characterizes most models of experimental hypertension in which endothelins play a significant vasoconstrictor role. Despite this, there are no data on the regulation of plasma endothelin by salt balance in human hypertension. METHODS AND RESULTS: Plasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (decreasing Na) were assessed in 29 of these patients. Endothelin was higher in hypertensive patients (4.6+/-0.2 fmol/mL) than in 20 control subjects (3.3+/-0.3 fmol/mL, P:<0.002), was correlated with BP, and was negatively associated with PRA (P:<0.04). Salt-sensitive, salt-resistant, and indeterminate groups were defined by the tertiles of the t statistic for the difference in BP before and after decreasing Na. Systolic BP falls were -15+/-1, -2+/-2, and -9+/-1 mm Hg, respectively. PRA, its response to decreasing Na, and its level after decreasing Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to decreasing Na, catecholamines increased more significantly in salt-sensitive patients (+2.4+/-0.9 nmol/L) than in the other groups (0.4+/-0.2 and 0.7+/-0.2 nmol/L for indeterminate and salt-resistant groups, respectively; P:<0.03), whereas endothelin increased in the salt-sensitive group (0.8+/-0.3 fmol/mL), decreased in the salt-resistant group (-0.4+/-0.3 fmol/mL), and sustained minimal change in the indeterminate group (0.2+/-0.3 fmol/mL) (P:<0.04). Thus, endothelin levels in the salt-depleted state were highest in salt-sensitive patients (5.2+/-0.4 fmol/mL) versus the other groups (3.4+/-0.4 and 4.4+/-0.4 fmol/mL for salt-resistant and indeterminate groups, respectively) (P:<0.02). Changes in endothelin during decreasing Na and levels after decreasing Na were correlated with changes in catecholamines (P:<0.02). CONCLUSIONS:-Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.     

Impact of renin-angiotensin-aldosterone system gene variants on the severity of hypertension in patients with newly diagnosed hypertension

BACKGROUND: The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. METHODS: We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, -20A-->C), and aldosterone synthase (CYP11B2)(-344C-->T) genes. RESULTS: The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the -344C allele (n = 75), patients who were homozygous for the -344T allele (n = 156) had both higher ambulatory SBP (150 +/- 1 v 144 +/- 1 mm Hg, P =.002 before and P =.01 after adjusting for multiple genotyping) and office SBP (163 +/- 2 v 156 +/- 2 mm Hg, P =.01 before and P =.05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. CONCLUSION: A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.     

Plasma renin activity and norepinephrine as predictors for antihypertensive effects of nifedipine and captopril

To examine predictors for the efficacy of antihypertensive agents, we investigated the effects of nifedipine and captopril on blood pressure (BP) and humoral factors in patients with essential hypertension. Eleven essential hypertensive patients (mean age: 54) were treated with long acting nifedipine at 20 to 40 mg/day for 8 weeks and 25 essential hypertensives (mean age: 51) were treated with captopril at 37.5 to 75 mg/day. Blood pressure was measured every 2 weeks. Plasma renin activity (PRA), and plasma concentrations of aldosterone, epinephrine and norepinephrine were determined before and at the end of treatment. Both nifedipine and captopril decreased BP (nifedipine: mean BP 119 +/- 3 to 101 +/- 2 mm Hg, captopril: 124 +/- 2 to 100 +/- 2, P less than .01 for each), whereas neither of them affected heart rate. The 8-week treatment of nifedipine showed no significant effect on humoral factors. Captopril increased PRA by 63% (P less than .05) and decreased plasma epinephrine by 42% (P less than .01) and norepinephrine by 35% (P less than .01). The change in mean BP was positively correlated with pretreatment PRA (r = 0.68, P less than .01) in nifedipine-treated patients and inversely with pretreatment norepinephrine (r = -0.53, P less than .01) in captopril treatment. The results suggest that both nifedipine and captopril were effective antihypertensive agents and that the long term treatment of nifedipine is more effective in essential hypertensives with lower PRA, while captopril is more effective in those with higher plasma norepinephrine concentration.     

A polymorphic GT short tandem repeat affecting beta-ENaC mRNA expression is associated with low renin essential hypertension

BACKGROUND: The epithelial sodium channel (ENaC) is a candidate gene associated with the development of essential hypertension. A potentially polymorphic repetitive region (GT dinucleotide short tandem repeat [STR]) was identified in intron 8 of beta-ENaC gene (SCNN1B). The aim of this study was to identify the prevalence and distribution of a polymorphic GT-STR in SCNN1B in Chilean essential hypertensive (EH) patients and to analyze the correlation between the different genotypes with plasma renin activity (PRA) and serum aldosterone (SA), and furthermore, to evaluate the beta-ENaC gene expression in vitro. METHODS: We studied 133 patients with EH and 69 normotensive (NT). In both EH and NT subjects we measured PRA, SA, urine sodium, and genotyped them according to the GT-STR length using sequencing analysis. We detected 11, 13 and 14 GT alleles in EH and NT subjects. Both groups were classified according to genotype: 14/14, 14/13, 13/13, 13/11, and 11/11. Influence of the GT-STR on beta-ENaC minigene expression was evaluated by real-time polymerase chain reaction. RESULTS: In EH, PRA decreased with the length of the STR region 11/13, 1.40 +/- 0.69; 13/13, 1.16 +/- 0.61; 13/14, 0.90 +/- 0.56; 14/14, 0.32 +/- 0.09 ng/mL/h; P < .01. Likewise, PRA in patients with EH with 14/14 or 14/13 genotypes were lower than EH with 13/13 or 13/11 genotypes (0.77 +/- 0.5 v 1.24 +/- 0.6 ng/mL/h; P < .01). Real-time polymerase chain reaction demonstrated an increased beta-ENaC expression in minigenes containing 14 GT-STR. CONCLUSIONS: We have identified a polymorphic GT-STR in the beta-ENaC gene, which is present in the EH and NT Chilean population. Biochemical analysis showed a possible linkage between this polymorphic region and low renin hypertension. The in vitro assay suggests that GT-STR could regulate the beta-ENaC expression.     

Impact of Baseline Renal Function on Outcomes of Renal Artery Stenting in Hypertensive Patients

Renal artery stenting may improve blood pressure (BP) and renal function in resistant hypertension patients; however, benefit may differ depending on the degree of renal dysfunction. The authors analyzed 67 consecutive patients receiving stenting for obstructive renal artery disease between 2002 and 2005. Patients were categorized as normal or mildly impaired according to estimated glomerular filtration rate (eGFR) (≥60 mL/min/1.73 m²), moderately impaired (eGFR 30 to 59 mL/min/1.73 m²), and severely impaired (eGFR <30 mL/min/1.73 m²). In patients with eGFR ≥60, systolic BP did not significantly improve from baseline. However, in patients with an eGFR between 30 and 59 mL/min/1.73 m², systolic BP decreased by 12 mm Hg at 6 months (P=.02) and 14 mm Hg at 12 months (P=.01). Greater benefit was observed in patients with eGFR <30 mL/min/1.73 m², with a 16 mm Hg (P=.10) and 21 mm Hg (P=.02) decrease at 6 and 12 months, respectively. Renal function was stable across all groups. Renal artery stenting reduced BP and produced greatest benefit in patients with baseline impaired renal function.     

Acute hypoxemia increases cardiovascular baroreceptor sensitivity in humans

BACKGROUND: We postulated that acute hypoxemia increases susceptibility to orthostatic hypotension by increasing the sensitivity of cardiovascular baroreceptors. METHODS: Hemodynamics were measured noninvasively in 17 healthy, normotensive subjects while being subjected to decreasing venous return by exposure to lower body negative pressure (LBNP) and breathing either a normobaric normoxic (21% O2) or normobaric hypoxic (12% O2) gas mixture. RESULTS: Hypoxia variably decreased hemoglobin saturation (in percent+/-SEM, from 99%+/-1% to 87%+/-2%, P<.01). Incremental increases in LBNP to -50 mm Hg significantly lowered systolic blood pressure (BP), pulse pressure (PP), forearm blood flow (FBF), and increased heart rate (HR). Hypoxia significantly increased baseline systolic BP, PP, and HR. The maximum change in HR in response to LBNP-induced reductions in PP increased during acute hypoxemia (maximum DeltaHR/DeltaPP, in +/-SEM) from 1.32+/-0.18 beats/min/mm Hg v 1.91+/-0.25 beats/min/mm Hg, P<.05. Those subjects who had the most hemoglobin desaturation during hypoxia, when compared to those subjects who desaturated minimally, had greater systolic BP at rest (128+/-3 mm Hg v 114+/-3 mm Hg, P=.05) and during LBNP (115+/-4 mm Hg v 100+/-1 mm Hg, P=.01). CONCLUSIONS: Acute hypoxia increased compensatory HR responses to LBNP-dependent reductions in BP. Those normotensive individuals with higher BP at rest and during LBNP developed greater degrees of hypoxia-induced hemoglobin desaturation. Patients with sleep apnea with periods of hypoxemia are prone to hypertension; more important, patients with higher BPs also demonstrate greater degrees of hypoxia-induced desaturation of oxyhemoglobin.     

Associations between nondipping of nocturnal blood pressure decrease and cardiovascular target organ damage in strictly selected community-dwelling normotensives

BACKGROUND: In hypertensives, nondippers are more likely than dippers to suffer silent, as well as overt, hypertensive target organ damage. In this study, we investigated whether a nondipper status was associated with target organ damage in normotensives. METHODS: We performed ambulatory blood pressure (BP) monitoring, echocardiography, and carotid ultrasonography and measured natriuretic peptides and urinary albumin (UAE) in 74 normotensive subjects with the following criteria: 1) clinical BP <140/90 mm Hg; 2) average 24-h ambulatory BP <125/80 mm Hg. RESULTS: The left ventricular mass index (LVMI) and the relative wall thickness (RWT) measured by echocardiography were greater in nondippers than dippers (LVMI: 103 +/- 26 v 118 +/- 34 g/m(2), P <.05; RWT: 0.38 +/- 0.07 v 0.43 +/- 0.09, P <.01). Plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) were higher in nondippers than dippers (ANP: 14 +/- 10 v 36 +/- 63 pg/mL, P <.01; BNP: 16 +/- 12 v 62 +/- 153 pg/mL, P <.05). There were no significant differences in UAE and intima-media thickness measured by carotid ultrasonography. CONCLUSIONS: Normotensive nondipping may not reflect renal damage, but may have a predominant effect on cardiac damage. Nondipping of nocturnal BP seems to be a determinant of cardiac hypertrophy and remodeling, and may result in a cardiovascular risk independent of ambulatory BP levels in normotensives.     

Hemodynamic responses to converting enzyme inhibition in patients with renal disease

We studied the effects of lisinopril on mean arterial blood pressure (MAP), plasma renin activity (PRA), and renal hemodynamics in nine patients with chronic renal disease and hypertension, before, and after three months of therapy. Lisinopril normalized blood pressure in five of nine patients (responders) and did not in the remaining four (nonresponders). PRA rose after lisinopril (4.8 +/- 2.6 ng/mL/h to 25 +/- 15 ng/mL/h, P less than 0.05) in responders, but not in nonresponders (2.0 +/- 1.4 ng/mL/h to 3.4 +/- 2.9 ng/mL/h). Glomerular filtration rate remained stable in both groups (responders: 43 +/- 11 mL/min to 43 +/- 22 mL/min; nonresponders: 39 +/- 25 mL/min to 32 +/- 21 mL/min). In the responders renal hemodynamics remained stable after lisinopril (renal plasma flow: 223 +/- 80 mL/min to 216 +/- 91 mL/min; filtration fraction: .20 +/- .04 to .20 +/- .05; renal vascular resistance: 386 +/- 179 to 326 +/- 209 units). In the nonresponders, renal plasma flow decreased (228 +/- 141 mL/min to 162 +/- 117 mL/min, P less than 0.005), filtration fraction increased (.19 +/- .08 to .24 +/- .12, P less than 0.05), and renal vascular resistance increased (695 +/- 747 to 1265 +/- 1574 units, P less than 0.05) after chronic lisinopril therapy. We conclude (1) there is a heterogeneous response to lisinopril in patients with chronic renal disease and hypertension, (2) lisinopril monotherapy may result in effective blood pressure control without renal hemodynamic compromise, and (3) an increase in PRA following converting enzyme inhibition may identify those in whom the circulating renin angiotensin system is participating in systemic hypertension and intrarenal hemodynamic changes.     

Pretreatment plasma renin activity levels correlate with the blood pressure response to telmisartan in essential hypertension

BACKGROUND: Although the therapeutic response to angiotensin II receptor blockers (ARBs) is assumed impaired in patients with low-renin hypertension, data are scarce about the association between levels of plasma renin activity (PRA) before treatment and response of ambulatory blood pressure (ABP) to ARBs in essential hypertension. METHODS: We prospectively studied 11 untreated Japanese patients with essential hypertension (3 women and 8 men, mean age: 50 +/- 9 (mean +/- SD) years). After a 4-week drug-free period, telmisartan 20-40 mg was administered orally once daily for 8 weeks. PRA levels were measured before treatment. The first ABP measurement was performed at the end of the drug-free period and the second measurement at the end of the treatment period with telmisartan. RESULTS: Telmisartan significantly decreased the 24-h ABP by 12 +/- 11 mm Hg systolic (P < 0.01) and 9 +/- 8 mm Hg diastolic (P < 0.01). Reductions in the 24-h systolic and diastolic ABPs were significantly greater in five patients with higher renin levels (> or =0.65 ng/ml/h) than in six patients with lower renin levels (<0.65 ng/ml/h) by 18 mm Hg systolic (P < 0.001) and 11 mm Hg diastolic (P < 0.05). Changes in the 24-h systolic and diastolic ABPs significantly correlated with log PRA before treatment. CONCLUSIONS: The ABP lowering effects of telmisartan were dependent on PRA levels before treatment in patients with essential hypertension. Measurement of PRA levels before treatment is thought to be useful for prediction of the ABP lowering effects of telmisartan.     

Neurohumoral mechanisms and left ventricular hypertrophy: effects of hygienic therapy

To determine the effects of hygienic (non-drug) therapy on blood pressure (BP) control and its relationship to sympathetic tone and left ventricular mass (LVM) in primary hypertension, plasma norepinephrine (NE) and renin activity (PRA), LVM, and nutritional and behavioral status were assessed in 76 borderline to mild hypertensives. Pretherapy plasma NE was related to diastolic blood pressure (DBP) and PRA (r = 0.24, P less than .05 and r = 0.37, P less than .01, respectively). Plasma NE of high renin patients (221 +/- 52) (mean +/- SD) was greater than that of normal renin patients (159 +/- 61, ng/l, P less than .01). LVM was related to systolic blood pressure (SBP) (P less than .001), DBP (P less than .01) and urinary sodium (P less than .05), and inversely related to PRA (P less than .01). Septal wall thickness was related to hostility (r = 0.42, P less than .05). After seven weeks of hygienic therapy, DBP was reduced by 6 mmHg (P less than .01). The change in SBP was related to baseline plasma NE (P less than .05) and inversely related to LVM (P less than .05). These results suggest that raised sympathetic tone may be a pathogenic factor in primary hypertension and that hygienic therapy lowers BP more effectively in patients with raised sympathetic tone and low LVM.     

Twenty-four-hour blood pressure monitoring in normoalbuminuric normotensive type 1 diabetic women during pregnancy

We monitored blood pressure (BP) for a 24-h period in type 1 diabetic women at each trimester of pregnancy (10-13, 20-22, and 30-33 weeks of gestation) to identify early alterations of BP profile in pregnancies complicated by hypertension. PATIENTS AND METHODS: We prospectively studied 71 type 1 diabetic pregnant women and 48 nondiabetic pregnant women (homogeneous by age and pre-pregnancy BMI) consecutively recruited at 10+/-2 weeks of pregnancy in the space of 2 years (1999-2000). They were all normotensive (<130/80 mm Hg) and normoalbuminuric (AER<20 microg/min) at entry to the study. STATISTICS: Analysis of variance (ANOVA) and simple regression and chi(2) were applied as appropriate by an Apple software program (Stat View). RESULTS: In diabetic women, we recorded higher levels of diastolic BP (even if within a normal range) at each time point; diabetic vs. nondiabetic women: first trim daytime diastolic BP: 71.35+/-8.75 vs. 67.7+/-9.7, P=.01; second trim nighttime diastolic BP: 62.15+/-6.45 vs. 58.05+/-6.7, P=.05; third trim nighttime diastolic BP: 66.03+/-8.72 vs. 60.7+/-6.5, P=.01. Among diabetics, those who later developed pregnancy-induced hypertension (36.6%) showed significantly higher values of BP at the first and third trimester compared to those who remained normotensive. In the two groups, there were no differences in age and pre-pregnancy BMI by contrast of diabetes duration (hypertensive vs. normotensive, 19.18+/-7.3 vs. 14.35+/-9.1 years, P=.03) and age of diagnosis (hypertensive vs. normotensive, 9.6+/-5.5 vs. 14.7+/-8.6 years, P=.01). Positive correlation was found between fasting blood glucose and diastolic BP at each trimester of pregnancy.     

Neurohormonal effects of furosemide withdrawal in elderly heart failure patients with normal systolic function

BACKGROUND: In heart failure patients, diuretics cause renin-angiotensin-aldosterone system (RAS) activation, which may lead to increased morbidity and mortality despite short-term symptomatic improvement. AIM: To determine changes in RAS activation and clinical correlates following furosemide withdrawal in elderly heart failure patients without left ventricular systolic dysfunction. METHODS AND RESULTS: We performed clinical assessments and laboratory determinations of aldosterone, plasma renin activity (PRA), atrial natriuretic peptide (ANP), norepinephrine, and endothelin in 29 heart failure patients [aged 75.1+/-0.7 (mean+/-S.E.M.) years], before, 1 and 3 months after placebo-controlled furosemide withdrawal. Recurrent congestion occurred in 2 of 19 patients withdrawn, and in 1 of 10 patients continuing on furosemide. Three months after withdrawal, PRA had decreased -1.61+/-0.71 nmol/l/h (P<0.05). Decreases in aldosterone levels did not reach significance (-0.17+/-0.38 nmol/l). The decreases in PRA after withdrawal correlated with decreases in systolic (r(s)=0.61, P=0.020) and diastolic blood pressure (r(s)=0.80, P=0.01). Successful withdrawal was associated with increases in norepinephrine (+0.58+/-0.22 nmol/l) and ANP (+3.5+/-1.3 pmol/l) (P<0.05) after 1 month, but these changes did not persist after 3 months. Endothelin levels did not change in both groups. CONCLUSION: Successful furosemide withdrawal in elderly heart failure patients causes persistent decreases in RAS activation.     

Determinants of exaggerated difference in morning and evening blood pressure measured by self-measured blood pressure monitoring in medicated hypertensive patients: Jichi Morning Hypertension Research (J-MORE) Study

BACKGROUND: Morning blood pressure (BP) surge in ambulatory BP monitoring was a risk factor for stroke in our previous study. We studied the determinants of the morning minus evening systolic BP difference (ME difference) in self-measured BP monitoring, as a possible risk factor for stroke in medicated hypertensive patients. METHODS: Nine hundred sixty-nine hypertensive outpatients receiving stable antihypertensive drug treatment were studied using self-measured BP monitoring in the morning and evening. RESULTS: The ME difference ranged from -37.3 to 53.3 mm Hg (mean 7.9 mm Hg). The highest quartile (Q4) of the ME difference group (>15.0 mm Hg) had older age (68.0+/-9.8 years v 66.2+/-10.3 years, P=.01) and higher prevalence of men (48.3% v 39.9%, P=.02), regular alcohol drinkers (34.7% v 26.0%, P=.01) and beta-blocker use (26.9% v 19.9%, P=.03) than the other quartile groups (Q1 to Q3), whereas there was no significant difference in the average of morning and evening (ME average) BP. In logistic regression analysis controlling for ME average and other confounding factors, independent risks for Q4 of ME difference were older age (10 years older: odds ratio [OR] 1.21, P=.01, 95% confidence interval (CI) 1.04-1.42), regular alcohol drinker (OR 1.51, P=.04, 95% CI 1.01-2.26), and beta-blocker use (OR 1.50, P=.02, 95% CI 1.06-2.12). CONCLUSIONS: Older age, beta-blocker use, and regular alcohol drinking were significant determinants of the exaggerated ME difference in medicated hypertensive patients.     

Efficacy of the combination of amlodipine and valsartan in patients with hypertension uncontrolled with previous monotherapy: the Exforge in Failure after Single Therapy (EX-FAST) study

In this randomized, double-blind, multicenter study, patients whose blood pressure (BP) was uncontrolled by monotherapy were switched directly to amlodipine/valsartan 5/160 mg (n=443) or 10/160 mg (n=451). After 16 weeks, BP control (levels <140/90 mm Hg or <130/80 mm Hg for diabetics) was achieved in 72.7% (95% confidence interval [CI], 68.6-76.9) of patients receiving amlodipine/valsartan 5/160 mg and in 74.8% (95% CI, 70.8-78.9) receiving amlodipine/valsartan 10/160 mg. Incremental reductions from baseline in mean sitting systolic and diastolic BP were significantly greater with the higher dose (20.0+/-0.7 vs 17.5+/-0.7 mm Hg; P=.0003 and 11.6+/-0.4 vs 10.4+/-0.4 mm Hg; P=.0046). Incremental BP reductions were also achieved with both regimens irrespective of previous monotherapy, hypertension severity, diabetic status, body mass index, and age. Peripheral edema was the most frequent adverse event. These results provide support for the BP-lowering benefits of complementary antihypertensive therapy with amlodipine and valsartan in patients with hypertension uncontrolled by previous monotherapy.     

Blunted hemodynamic response and reduced oxygen delivery with exercise in anemic heart failure patients with systolic dysfunction

Anemic heart failure patients with systolic dysfunction are known to have reduced exercise capacity. Whether this is related to poor hemodynamic adaptation to anemia is not known. Peak exercise oxygen consumption (VO2) and hemodynamics at rest and peak exercise were assessed among 209 patients and compared among those who were (n=90) and were not (n=119) anemic. Peak VO2 was significantly lower among anemic patients (11.7+/-3.3 mL/min/kg vs 13.4+/-3.1 mL/min/kg; P=.01). At rest, right atrial pressure was higher (10+/-5 mm Hg vs 8+/-4 mm Hg; P=.02) and venous oxygen saturation lower (62%+/-8% vs 58%+/-10%; P<.01) among anemic patients. At peak exercise, anemic patients had a higher wedge pressure (27+/-9 mm Hg vs 24+/-10 mm Hg; P=.04). No significant differences in stroke volume, cardiac index, systemic vascular resistance, or oxygen saturation were noted between the 2 groups. In conclusion, the relative hemodynamic response to exercise among anemic heart failure patients appears blunted and may contribute to worse exercise tolerance.     

Prolonged treatment with the AT1 receptor blocker,valsartan, increases small and large artery compliance in uncomplicated essential hypertension

BACKGROUND: Decreased arterial compliance (AC) is considered an early marker of vascular wall damage. Hypertension gradually decreases arterial compliance. We studied whether treatment with the angiotensin type 1 (AT(1)) antagonist valsartan will affect AC in patients with essential hypertension (EH). METHODS: Twenty-two patients with EH, 6 men and 16 women, mean age 58.7 +/- 4.1 years, without overt target organ damage were included. Antihypertensive medications were withdrawn for 3 weeks, Valsartan was given at 80- and 160-mg doses. The AC, blood pressure (BP), blood, and urine were measured monthly. Large (C1) and small (C2) AC were derived from radial artery waveforms, obtained using a calibrated tonometer (model CR-2000, HDI Inc., Eagan, MN). RESULTS: After 3 months, systolic BP decreased from 172 +/- 17 to 142 +/- 13 mm Hg (P <.0001) and diastolic BP from 95 +/- 9 to 82 +/- 8 mm Hg (P <.0001). The decrease in BP was significant within 1 month and improved further on. The C1 increased by 22%, from 8.0 +/- 3.1 to 9.7 +/- 2.3 mL/mm Hg x 10 (P <.01). The C2 increased by 35%, from 2.9 +/- 1.3 to 3.9 +/- 1.9 mL/mm Hg x 100 (P <.01). Both C1 and C2 reached statistical significance only after 3 months. Systemic vascular resistance (SVR) decreased by 15% from 2,140 +/- 376 to 1,817 +/- 262 dynes/sec/cm(-5) (P <.0001). CONCLUSIONS: Treatment with valsartan in patients with EH improves small and large AC. The improvement in AC was significant only after 3 months of treatment, whereas systolic BP, diastolic BP, and SVR decreased earlier. The AT(1) receptor blockade with valsartan seems to be an effective means of not only lowering BP but of reversal of vascular wall damage, which predisposes to cardiovascular events.