Brain Natriuretic Peptide Counteracting the Renin-angiotensin-aldosterone System in Accelerated Malignant Hypertension.

We describe 2 patients, a 52-year-old woman and a 57-year-old man, with rapidly progressive hypertension and marked elevation of brain natriuretic peptide who exhibited polyuria, natriuresis, hypokalemia, posterior reversible encephalopathy syndrome and left ventricular dysfunction together with retinopathy and nephropathy, which were attenuated in a short time span of 1-2 months with normalization of blood pressure after the antihypertensive treatment. The possible role of brain natriuretic peptide in the pathophysiology of accelerated malignant hypertension was discussed and a review of the literature was completed.

CD4(+)CD25(+) T Cells in primary malignant hypertension related kidney injury.

CD4(+)CD25(+) T cells are critical for maintenance of immunologic self-tolerance. We measured the number of CD4(+)CD25(+) cells in the patients with primary malignant hypertension related kidney injury, to explore the molecular pathogenesis of this disease. We selected 30 patients with primary malignant hypertension related kidney injury and 30 healthy volunteers. Information on clinical characteristics and laboratory tests was obtained from each subject. The number of CD4(+)CD25(+) cells and glomerular injury were assessed by flow cytometry and histopathology, respectively. Both serum IL-2, IL-4, and IL-6 and endothelial cell markers were analyzed by ELISA. ADAMTS13 antibody was detected by Western blotting. CD4(+)CD25(+) cells were significantly reduced in patients with primary malignant hypertension related kidney injury compared to controls (P < 0.05). The number of CD4(+)CD25(+) cells was negatively related to blood urea nitrogen, serum uric acid, proteinuria, and supernatant IL-4; whereas positively associated with estimated glomerular filtration rate in patients. Gradually decreasing CD4(+)CD25(+) cells were also found as increasing renal injury. Additionally, patients exhibited increasing supernatant IL-4, serum IL-2 and IL-6, endothelial cell markers, and anti-ADAMTS13 antibody compared with controls (all P < 0.05). CD4(+)CD25(+) cells may play a key role in the pathogenesis of primary malignant hypertension related kidney injury.

Impact of a novel mutation in the 5'-flanking region of natriuretic peptide precursor B gene on the antihypertensive effects of sodium nitroprusside in patients with hypertension.

Our aim was to identify the possible mutations of the natriuretic peptide precursor B (NPPB) gene in a family with hereditary hypertension, and determine whether the mutations are associated with the antihypertensive effect of sodium nitroprusside. The subjects included one family with hereditary hypertension, 36 cases of sporadic hypertension and 120 healthy controls. The 5'-flanking sequence of NPPB was amplified with PCR, and the presence of mutations was analyzed by direct sequencing. Patients with hypertension were treated with sodium nitroprusside and blood pressure data and serum B-type natriuretic peptide (BNP) levels were measured. A novel complex mutation in 5'-flanking sequence of the NPPB gene was detected in three patients (II 2, III 2, and III 5) of the hypertension family, which included c.-1195_ -1176 insert 5'-CCTTCTTTCTTTCTTTCTTT-3', c.-1208 T>A, c.-1214 T>C, and c.-1216 T>A. Patients with this mutation were less sensitive to sodium nitroprusside treatment. Sporadic hypertension patients (without NPPB gene mutation) and patients with the c.-1181 T>A point mutation were sensitive to sodium nitroprusside treatment. BNP levels of patients with the complex mutation were significantly lower than that of sporadic hypertension patients and c.-1181 T>A mutation patients before and during the early stage of sodium nitroprusside treatment. The complex mutation of the NPPB gene might be an etiological factor of hereditary malignant hypertension, and it is associated with low sensitivity to the antihypertensive effect of sodium nitroprusside.

Hemolytic-uremic syndrome, malignant hypertension and IgA nephropathy: successful treatment with plasma exchange therapy.

A young patient with hemolytic-uremic syndrome and malignant hypertension with serious deterioration of renal function is described whose biopsy specimen showed additional IgA mesangial deposits. The patient responded to steroid treatment and to plasma exchange therapy without the need of hemodialysis sessions. In the following years, he achieved clinical remission and his blood pressure was in normal ranges without any further complications. IgA glomerulonephritis is rarely associated to hemolytic-uremic syndrome and malignant hypertension, with only a few previously described cases. We present an overview of potential pathophysiological connections between these diseases.

Clinical features of malignant hypertension with thrombotic microangiopathy.

Thrombocytopenia, microangiopathic hemolytic anemia, and elevated serum lactate dehydrogenase (LDH) clinically characterize thrombotic microangiopathy (TMA), which is frequently recognized among patients with malignant hypertension (MH). Sixteen consecutive patients with MH were retrospectively investigated over a 7-year period and clinical features of the subjects with TMA were evaluated. We confirmed TMA relevant to MH by the normalization of the platelet count and LDH after adequate blood pressure (BP) control was achieved. Thrombotic microangiopathy was found in 7 (44%) of 16 patients. All 7 patients had an elevated plasma renin activity (PRA). Although no significant differences were observed in PRA, the patients with TMA had a significantly higher plasma aldosterone (ALDO) (median: 403 pg/ml; IR: 305 to 568) in comparison to those without TMA (median: 220 pg/ml; IR: 147 to 287; p = 0.013). Overall, ALDO correlated with LDH (r = 0.634, p = 0.0095). However, no significant association was observed between PRA and LDH (r = 0.336, p = 0.2263). The median platelet count nadir of the patients with TMA was 8.4 × 10(4) per µl (IR: 7.15 to 9.95). Thrombocytopenia and elevated LDH were normalized, along with a gradual improvement of BP within an average of 5 days and 21.7 days, respectively. These results suggest that ALDO, but not PRA, may act as a potent indicator of the magnitude of vascular and organ damage related to TMA among patients with malignant hypertension (MH).

Increased sympathetic activity in normotensive offspring of malignant hypertensive parents compared to offspring of normotensive parents.

Malignant hypertension seems to be the consequence of very high blood pressure. Furthermore, an increase in sympathetic and renin-angiotensin system activity is considered to be the main mechanisms producing malignant hypertension. In the present study, 10 offspring of malignant hypertensive (OMH) parents (age 28 +/- 5 years, 7 males, 3 females, 2 white and 8 non-white) and 10 offspring of normotensive (ONT) parents (age 28 +/- 6 years, 2 males, 8 females, 3 white and 7 non-white) were evaluated. The OMH group had significantly higher (P < 0.05) casual blood pressure (125 +/- 10/81 +/- 5 mmHg) compared with ONT (99 +/- 13/67 +/- 5 mmHg). The increase in blood pressure was greater in OMH (Delta SBP = 17 +/- 2 vs Delta SBP = 9 +/- 1 mmHg in ONT) during cold pressor testing, but they had a lower increase in heart rate (Delta HR = 13 +/- 2 vs Delta HR = 20 +/- 3 bpm in ONT) during isometric exercise(handgrip test). Sympathetic activity, measured by microneurography, was significantly higher (P < 0.05) before exercise in OMH (17 +/- 6 vs 11 +/- 4 burst/min in ONT) and exhibited a greater increase (Delta = 18 +/- 10 vs Delta = 8 +/- 3 burst/min in ONT) during isometric exercise. This study showed increased sympathetic activity in OMH before exercise and a greater response during isometric exercise, suggesting an autonomic abnormality before exercise and a greater sympathetic response to physical stress in OMH compared to ONT.

Increased sympathetic activity in normotensive offspring of malignant hypertensive parents compared to offspring of normotensive parents

Malignant hypertension seems to be the consequence of very high blood pressure. Furthermore, an increase in sympathetic and renin-angiotensin system activity is considered to be the main mechanisms producing malignant hypertension. In the present study, 10 offspring of malignant hypertensive (OMH) parents (age 28 ± 5 years, 7 males, 3 females, 2 white and 8 non-white) and 10 offspring of normotensive (ONT) parents (age 28 ± 6 years, 2 males, 8 females, 3 white and 7 non-white) were evaluated. The OMH group had significantly higher (P < 0.05) casual blood pressure (125 ± 10/81 ± 5 mmHg) compared with ONT (99 ± 13/67 ± 5 mmHg). The increase in blood pressure was greater in OMH (Ä SBP = 17 ± 2 vs Ä SBP = 9 ± 1 mmHg in ONT) during cold pressor testing, but they had a lower increase in heart rate (Ä HR = 13 ± 2 vs Ä HR = 20 ± 3 bpm in ONT) during isometric exercise (handgrip test). Sympathetic activity, measured by microneurography, was significantly higher (P < 0.05) before exercise in OMH (17 ± 6 vs 11 ± 4 burst/min in ONT) and exhibited a greater increase (Ä = 18 ± 10 vs Ä = 8 ± 3 burst/min in ONT) during isometric exercise. This study showed increased sympathetic activity in OMH before exercise and a greater response during isometric exercise, suggesting an autonomic abnormality before exercise and a greater sympathetic response to physical stress in OMH compared to ONT.

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.

Adrenalectomy for bilateral and recurrent pheochromocytoma: increased intraoperative risk?

Adrenalectomy for pheochromocytoma is per se associated with a specific intraoperative cardiovascular risk caused by catecholamine secretion during manipulation of the tumor. Bilateral or multiple, and recurrent chromaffine tumors are special subentities with a potentially more intensified and longer surgical preparation. The aim of our study was to examine these effects on hemodynamic changes compared with those observed for primary, solitary tumors. Of the 82 studied interventions between February 1992 and May 2005, 58 were seen to involve primary, unilateral tumors, 17 involved bilateral (1 trilateral) findings, and there were 7 cases of recurrency. The hemodynamic changes related to primary, solitary pheochromocytomas revealed a higher frequency of intraoperative blood pressure crises (37%) compared with the comparative groups (11.8% in bilateral and 0% in recurrent tumors), as well as higher maximum pCO2 values noted. The intraoperative blood loss was more pronounced in interventions involving recurrencies. Aside from an appropriate preliminary therapy using an alpha-blocker and the careful surgical preparation of the adrenal gland, the different hemodynamic changes possibly may be related to the presence of smaller tumors in bilateral pheochromocytoma, as well as being based upon the already existent ligature of the draining vein in the event of recurrent procedures. The extent to which the adrenergic effect of the increased maximum pCO2 value plays a role on the development of higher maximum blood pressure values and more frequent intraoperative blood pressure crises continues to remain unclear.

Plasma adrenomedullin concentrations in patients with renovascular or malignant hypertension.

AIM: The aim of the present study was to investigate the behaviour of plasma adrenomedullin (AM), a hypotensive peptide, in patients with malignant (MHT) and renovascular hypertension (RVH), 2 pathologic conditions in which renin-angiotensin system (RAS) is activated and to compare them with those in essential hypertensive patients (EHT) and normotensive subjects (NS). METHODS: Three groups of hypertensive patients have been studied: group 1 (4 patients with MHT), group 2 (10 patients with RVH), group 3 (24 patients with EHT) and 21 patients NS were enrolled as controls. In all patients, 10 ml vein blood samples were collected and AM was measured with specific radioimmunoassay. RESULTS: As expected, the plasma renin activity (PRA) levels in the RVH and MHT patients were significantly higher (p<0.0001) respect to NS and EHT. The mean plasma AM (+/-SD) concentrations in EHT (22.5+/-9.1 pg/ml) and RVH (46.8+/-19.4 pg/ml) were significantly (p<0.0001) higher than those in NS (13.7+/-6.1 pg/ml). The plasma AM concentrations were further elevated in MHT patients (107+/-12.3 pg/ml) and were significantly higher (p<0.0001) than those in EHT and RVH patients. In the MHT patients the elevated plasma AM levels, similarly to blood pressure and PRA values, declined after antihypertensive treatment (36.8+/-5.7 pg/ml; p<0.01). CONCLUSION: In conclusion, the findings demonstrated that the plasma AM concentrations were increased in proportion to the severity of arterial hypertension. RAS was activated in patients with MHT and RVH suggesting that activation of this system may contribute to increased in the plasma levels of AM.

Role of increased circulating and renal adrenomedullin in rats with malignant hypertension.

Although it has been reported that the circulating adrenomedullin (AM) level is elevated in hypertension and renal failure, the pathophysiological significance of circulating and intrarenal AM in malignant hypertension remains unknown. We investigated the circulating and intrarenal AM system in rats with malignant hypertension by measuring the plasma level, renal tissue level, and mRNA abundance of AM and the mRNA abundance of AM receptor. We also investigated the effects of intravenously infused calcitonin gene-related peptide (CGRP)-(8-37), an antagonist of AM, on the hemodynamics and renal tubular function. We studied the following four groups: control Wistar-Kyoto rats (WKY), control spontaneously hypertensive rats (C-SHR), salt-loaded SHR (S-SHR), and DOCA-salt SHR (D-SHR). After 3 wk of DOCA treatment, D-SHR developed malignant hypertension. D-SHR were characterized by higher blood pressure, kidney weight, urinary protein excretion and blood urea nitrogen, and lower creatinine clearance compared with the other three groups. The plasma AM level and urinary excretion of AM were markedly higher in D-SHR than in the other three groups. In the kidney, the tissue AM level and the expression of AM mRNA in the renal medulla were significantly increased in D-SHR compared with the other three groups, whereas there were no significant differences in these levels in the renal cortex among the four groups. In the renal AM receptor system, the expression of the gene for receptor activity modifying protein 3 was significantly increased in the renal medulla in D-SHR compared with the other three groups. An immunohistochemical study revealed that AM immunostaining in renal collecting duct cells and distal tubules was more intense in D-SHR than in the other three groups. After CGRP-(8-37) infusion, blood pressure increased significantly and urinary sodium excretion and urine flow decreased significantly only in D-SHR. These results suggest that the increased circulating AM and renal AM and the increased expression of the mRNA for AM and its receptor may at least partly compensate for the malignant hypertensive state in certain forms of malignant hypertension via the hypotensive, natriuretic, and diuretic actions of AM.

Humoral mechanisms in the pathogenesis of postprandial hypotension in patients with essential hypertension.

OBJECTIVE: To examine the role of catecholamines and insulin in the development of postprandial hypotension (PPH) in hypertensive patients. PATIENTS: Forty patients with essential hypertension (25 men, 15 women, mean age 68 +/- 2 years). METHOD: Blood pressure and heart rate were recorded in all subjects immediately after a 1903 kJ test meal and at 15-minute intervals for up to 1 hour after the meal. At these time points, circulating levels of norepinephrine, epinephrine, dopamine and C-peptide were measured. RESULTS: Twenty-three patients (58%) had PPH. By 15 minutes norepinephrine had significantly increased in PPH-negative subjects while it rose more slowly in PPH-positive patients and peaked by 45 minutes after the meal. Norepinephrine levels in 15 minutes were lower in PPH-positive than in PPH-negative ones (159.8 +/- 9.7 vs. 212.3 +/- 21.1 pg/ml, p = 0.01). Epinephrine levels rose only in PPH-negative subjects and did not differ significantly at the different time points. However, the area under curve analysis showed significantly lower epinephrine values in PPH-positive subjects (2903 + 247 pg.min.ml-1 vs. 3710 + 284 pg.min.ml-1, p = 0.03). Dopamine increased in both groups, although it was lower in subjects with PPH during the entire study (15 minutes: 68.6 +/- 3.7 vs. 93.7 +/- 11.7 pg/ml, p = 0.02; 30 minutes: 68.8 +/- 3.7 vs. 86.1 +/- 7.7 pg/ml, p = 0.03; 45 minutes: 60.5 +/- 4.2 vs. 79.7 +/- 5.2 pg/ml, p = 0.006). The postprandial C-peptide response did not differ between patients with PPH and those without PPH. CONCLUSIONS: In patients with essential hypertension, a marked decline in postprandial systolic blood pressure is associated with lower postprandial levels of norepinephrine, epinephrine and dopamine as compared to subjects without postprandial hypotension. This indicates that impaired sympatho-adrenal activation after ingestion of a meal may contribute to the development of PPH. Insulin appears not to be involved in the pathogenesis of postprandial hypotension.

Dyslipidaemia in patients with malignant-phase hypertension.

Low-density lipoprotein (LDL) consists of a heterogeneous group of particles of differing size, density and electrophoretic mobility, smaller particles being more atherogenic. A high proportion of small LDL particles is an independent risk factor for cardiovascular disease. We hypothesized that patients with malignant phase hypertension (MHT), the most severe form of hypertension, would demonstrate a more atherogenic LDL subfraction profile than either non-malignant hypertension (NMHT) or normotensive controls. We compared 16 patients with MHT to 41 patients with untreated NMHT and 45 normotensive controls. LDL subfraction profile was measured by disc polyacrylamide gel electrophoresis using a validated scoring system to calculate the mean size (locus) and heterogeneity (spread) of LDL subfraction mobilities. A higher LDL locus indicates a greater proportion of small LDL subfractions. LDL cholesterol levels were similar in all three groups (p=0.23). High-density lipoprotein cholesterol (HDL-C) levels were significantly lower (p<0.001) and serum triglyceride concentrations significantly higher (p=0.02) in the MHT group, compared to normotensive controls. LDL locus was greater in the NMHT group than in the normotensive controls and intermediate in the MHT group (p=0.008). There was no significant difference in LDL spread (p=0.26). Serum triglyceride concentrations were not significantly higher after adjusting for confounding variables. MHT is associated with an abnormal lipid profile, characterized by low HDL-cholesterol concentration. This dyslipidaemia may be partly responsible for the vascular complications and the poor prognosis of these patients.

Hipertensión arterial maligna y síndrome urémico hemolítico / Malignant arterial hypertension and hemolytic uremic syndrome

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Failure of L-arginine to induce hypotension in patients with a history of accelerated-malignant hypertension.

A profound elevation of blood pressure on exercises or after withdrawal of antihypertensive drugs has been reported in patients with a history of accelerated-malignant hypertension. We tested the hypothesis that severe endothelial dysfunction is responsible for the profound hypertensive response in these patients. Responses of blood pressure, heart rate and plasma cyclic guanosine monophosphate to intravenously infused L-arginine, a precursor of nitric oxide, was investigated in hypertensive patients with (group A) or without any history of accelerated-malignant hypertension (group B) in order to evaluate endothelial function. Casual blood pressure or severity of hypertension was not different between group A and B. Infusion of L-arginine decreased mean blood pressure in group B (97.4 +/- 8.7 to 81.7 +/- 6.9 mm Hg), but not in group A (99.0 +/- 10.2 to 101.5 +/- 8.7 mm Hg). Plasma levels of cyclic guanosine monophosphate were increased after infusion of L-arginine in group B (5.4 +/- 2.0 to 7. 7 +/- 1.7 pmol/ml, P< 0.01), while no significant changes were observed in group A (5.4 +/- 2.1 to 5.9 +/- 2.1 pmol/ml). There was a significant correlation between decrease in mean blood pressure and increase in plasma levels of cyclic guanosine monophosphate (r = 0.83, P < 0.001). The results indicated that much more severe endothelial dysfunction is present in hypertensive patients with a history of accelerated-malignant hypertension as compared to those without the history. The difference in the endothelial function may account for the different pressor responses to exercises or other stimuli observed in hypertensive patients with and without a history of accelerated-malignant hypertension. Journal of Human Hypertension (2000) 14, 485-488

Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.

Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.

Serum urate is associated with baseline renal dysfunction but not survival or deterioration in renal function in malignant phase hypertension.

BACKGROUND: There has been speculation whether serum uric acid levels are an independent prognostic factor in patients with hypertension. OBJECTIVE: To investigate the clinical associations and prognostic value of serum urate in patients with malignant phase hypertension (MHT), by comparing clinical features in patients with serum urate levels above and below the median levels for this population, and secondly, by performing a survival analysis in these patients. PATIENTS AND METHODS: Review of the data on 153 patients (98 males; mean age 50.3 years, SD 13.5) with MHT on the west Birmingham MHT register. Median uric acid levels in this population was 0.41 mmol/l (6.9 mg/dl), with an interquartile range of 0.34-0.50 mmol/l (5.7-8.4 mg/dl). Clinical characteristics of patients with a serum urate <0.41mmol/1 (group 1) were compared to those with levels above the median (0.41 mmol/l, group 2). RESULTS: Mean duration of follow-up was similar in both groups. The mean diastolic blood pressure at presentation and both mean systolic and diastolic blood pressures at follow-up were significantly higher in group 2 (that is, those with high serum urate levels) (unpaired t test, P= 0.039). There was also more renal dysfunction in group 2 patients with MHT, with higher mean serum urea and creatinine levels, both at presentation and at follow-up (unpaired t test, P< 0.01). The commonest causes of death were myocardial infarction (n = 7), heart failure (n = 4), stroke (n = 10) and renal failure (n = 5). There was no difference in mean survival duration between groups 1 and 2 (Kaplan-Meier, 64.6 versus 66.8 months; log-rank test, P= 0.519). Serum urate levels also did not predict the rise in serum creatinine levels (log-rank test, P= 0.84) or urea (P= 0.4033) amongst these patients. Using a multivariate Cox proportional hazards analysis, the only independent predictors of outcomes (death or the need for dialysis) were age (P = 0.007) and serum creatinine levels at presentation (P = 0.0046). CONCLUSION: Our analysis of a large series of patients with MHT shows that those with high urate levels had higher diastolic blood pressures and greater renal impairment at baseline. At follow-up, patients with median serum urate >0.41 mmol/l showed a greater deterioration in renal function and higher blood pressures, but no significant difference in survival. Serum urate levels also do not appear to be predictive of the deterioration in renal function or overall survival in patients with MHT.