Hans Herlitz

Increased sympathetic nerve activity in renovascular hypertension.

BACKGROUND Increased sympathetic nerve activity may contribute to the progression of renovascular hypertension. Because previous results have been inconclusive, we investigated whether renovascular hypertensives show increased total and regional sympathetic nerve activity. METHODS AND RESULTS Sixty-five patients underwent renal angiography and measurements of plasma renin activity and angiotensin II in conjunction with estimation of sympathetic nerve activity by means of radiotracer dilution and intraneural recordings of muscle sympathetic nerve activity (MSNA). Age-matched healthy subjects (n=15) were examined for comparison. Total body norepinephrine (NE) spillover, an index of overall sympathetic nerve activity, was increased by 100% and MSNA by 60% in the hypertensive patients compared with healthy subjects (P<0.01 for both). A subgroup of 24 patients with well-defined renovascular hypertension (cured or improved hypertension after renal angioplasty) showed similar increases in total body NE spillover compared with the group at large. Patients with arterial plasma renin activity and angiotensin II levels above median had higher values for total body NE spillover than patients below median (P<0.01). CONCLUSIONS This study unequivocally demonstrates elevated sympathetic nerve activity in patients with renovascular hypertension. The adrenergic overactivity may contribute to the blood pressure elevation and perhaps also to the high cardiovascular mortality in renovascular hypertension.

Increased cardiovascular mortality in hypertensive patients with renal artery stenosis. Relation to sympathetic activation, renal function and treatment regimens.

BACKGROUND Previous studies in hypertensive patients with renovascular disease have shown both elevated sympathetic nerve activity and increased cardiovascular mortality. OBJECTIVE The aim of the present study was to assess long-term survival in hypertensive patients with renal artery stenosis in relation to sympathetic activation, renal function and treatment regimens. SUBJECTS AND METHODS A total of 169 consecutive patients aged 54 +/- 1 years with hypertension underwent a clinical investigation for renovascular hypertension including renal angiography and measurement of bilateral renal renin secretion. In 107 of these patients, arterial plasma concentrations of noradrenaline were measured. The mean follow-up time was 7.1 +/- 0.3 years and survival data were available in all patients up to May 1997. For comparison, healthy age-matched normotensive controls were examined. RESULTS Arterial noradrenaline concentrations were threefold elevated in hypertensive patients with renal artery stenosis compared to healthy controls (P < 0.01). During the follow-up time, 44 patients died. Cardiovascular mortality accounted for 75% of all deaths. The risk ratio for overall mortality in hypertensive patients with renal artery stenosis compared to the normal population of Sweden, matched for age, was 3.3 (2.4-4.4), whereas the risk ratio for cardiovascular mortality was 5.7 (3.9-8.0). The arterial plasma concentration of noradrenaline was 3.11 +/- 0.30 pmol/ml in patients who died compared to 3.84 +/- 0.26 pmol/ml in survivors. Reduced renal function and age were independent predictors of death. Survival did not differ between patients undergoing intervention with either renal angioplasty or surgical reconstruction for renal artery stenosis and patients not undergoing intervention. CONCLUSIONS Although sympathetic nerve activity is elevated in hypertensive patients with renal artery stenosis, our results do not suggest that this adrenergic over-activity is directly linked to the observed high cardiovascular mortality. Mortality in hypertensive patients with renovascular disease remains high whether an interventional treatment is performed or not, possibly due to the concomitant coronary disease.

MICROALBUMINURIA IN TREATED HYPERTENSIVE MEN AT HIGH RISK OF CORONARY DISEASE. THE RISK FACTOR INTERVENTION STUDY GROUP

Objective: To examine whether microalbuminuria is a marker of cardiovascular disease in treated hypertensive men without diabetes mellitus at high coronary risk and to examine the associations between microalbuminuria and recognized cardiovascular risk factors Design: Cross-sectional study Setting: Outpatient clinic in city hospital Patients: Three hundred and thirty-three treated hypertensive men, aged 50-72 years, either with a serum cholesterol of ≥6.5mmol/l or smokers, or both. The patients were recruited mainly from a population-based sample of hypertensive men. Patients with diabetes mellitus or overnight urinary albumin excretion of > 100mg/12h were excluded from the analyses Main outcome measures: Overnight urinary albumin excretion, prevalence of microalbuminuria (defined as 17-100 mg/12 h) and organ damage (cardiovascular events or major electrocardiogram changes, or both), various well-established risk factor levels, blood glucose and plasma insulin responses to an oral glucose tolerance test. Results: Microalbuminuria was found in 25% of the cohort. Among microalbuminuric patients, organ damage was significantly more common (47.6%) than in the normoalbuminuric group (30.9%). However, the sensitivity and specificity of microalbuminuria as a marker of organ damage were only 34 and 80%, respectively. Microalbuminuria was significantly related to body mass index and waist: hip ratio, age and plasma insulin during oral glucose tolerance testing. These relationships also persisted after adjustment for treatment with thiazides or β-blockers Conclusions: In treated hypertensive men without diabetes mellitus, microalbuminuria was associated with factors known to be related to insulin resistance. It had a low sensitivity as a marker of concomitant cardiovascular disease.

IMMUNOLOGICAL CHANGES IN PATIENTS WITH PREVIOUS MALIGNANT ESSENTIAL HYPERTENSION

Increased T-lymphocyte reactivity against human arterial antigen was significantly more common in a group of 20 patients with previously malignant essential hypertension than in matched control subjects. Serum-levels of IgG and IgM and the prevalence of autoantibodies were also significantly higher in the patients. It is suggested that these changes, whether primary or secondary, may contribute to or aggravate the vascular damage in this condition and are therefore of pathogenetic importance.

Increased cardiac sympathetic drive in renovascular hypertension

Background Patients with renovascular hypertension (RVH) have high cardiovascular mortality and morbidity. In these patients, overall sympathetic nerve activity is increased. It is unknown, however, whether this increase also involves the heart. Objective We tested the hypothesis that cardiac sympathetic activity is increased in patients with hypertension and renal artery stenosis. Methods and results A total of 14 patients with hypertension were studied before angioplasty of angiographically identified renal artery stenosis. Nine out of 14 patients had renovascular hypertension proven at the 1-year follow-up visit. A total of 19 healthy subjects served as a control group. A right heart catheterization, including the positioning of a coronary sinus thermodilution catheter was performed for hemodynamic recordings and blood sampling. Using a radiotracer dilution technique with infusion of tritiated noradrenaline ([3H]NA) and adrenaline ([3H]A), fractional extraction and clearance were calculated. Total body and cardiac NA spillovers were used as indices of systemic and cardiac sympathetic nervous activity. The study group had normal left ventricular ejection fraction and cardiac pressures. Cardiac NA spillover was increased by 127% in the hypertensive patients compared with healthy subjects (200 ± 53 versus 88 ± 10 pmol/min in controls, P < 0.05). Total body NA spillover was similar in both groups. Cardiac fractional extraction of [3H]NA and [3H]A was decreased by 26 and 47%, respectively, compared with normotensive subjects (P < 0.01 for both). Conclusions Patients with renovascular hypertension have altered cardiac sympathetic function with increased sympathetic drive and impaired catecholamine extraction. The increased cardiac sympathetic drive may have adverse long-term effects on prognosis in this patient group with high cardiovascular mortality.

Bone Mineral and Related Biochemical Variables in Patients with Kock Ileal Reservoir or Bricker Conduit for Urinary Diversion

PURPOSE Bone material content was studied with single photon absorptiometry and dual energy x-ray absorptiometry , and the various biochemical parameters related to bone metabolism in patients with Kock reservoirs or Bricker conduits for urinary diversion. MATERIALS AND METHODS We examined 34 patients with Kock ileal reservoirs to the skin (29) or urethra (5) and 14 with Bricker conduits 2 to 17 years after urinary diversion. Bone mineral density was measured in the radius with single photon absorptiometry, and in th femur, lumbar spine and whole body with dual x-ray absorptiometry. Serum concentrations of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, osteocalcin, parathyroid hormone, bone specific alkaline phosphatase and ionized calcium were determined. Arterial blood gases were analyzed. RESULTS The mean values for bone mineral density did not differ from age-matched controls in either group and no signs of decrease were observed with followup. Vitamin D serum concentration values remained within normal limits in all patients. Most patients had normal blood gas values. Mean values for osteocalcin, parathyroid hormone, bone specific alkaline phosphatase and ionized calcium also were within normal limits, although a few patients had elevated osteocalcin values indicating increased bone turnover. CONCLUSION Urinary diversion with a Kock reservoir or Bricker conduit did not cause bone demineralization of significant changes in different markers of bone metabolism in patients examined 2 to 17 years after urinary diversion.

Does microalbuminuria predict cardiovascular events in nondiabetic men with treated hypertension

The aim of this study was to investigate the predictive value of microalbuminuria (overnight urinary albumin excretion rate 17 to 100 mg/12 h) as a risk factor for future major cardiovascular events in nondiabetic patients with treated hypertension in a prospective study with follow-up time of 3.3 years. Overnight urinary albumin excretion was measured in 345 nondiabetic treated hypertensive men, aged 50 to 72 years, either with a serum cholesterol of > or = 6.5 mmol/L or smokers, or both. Cardiovascular morbidity was closely recorded during the follow-up period. At entry, microalbuminuria was found in 84 patients (24.3%) and 12 patients had macroalbuminuria (3.5%). During the follow-up period there were no differences in new cardiovascular events between patients with microalbuminuria and those with normoalbuminuria. However, an increase in the risk of future major cardiovascular events occurred in patients with urinary albumin excretion above 100 mg/12 h (macroalbuminuria). In a Cox regression analysis urinary albumin excretion was not associated with the incidence of future major cardiovascular events unless a more detailed approach was used, showing that this was the case for urinary albumin excretion above 100 mg/12 h (macroalbuminuria). Calculations with an alternative definition of microalbuminuria and mortality as end-point did not change the principal result. In conclusion, microalbuminuria does not seem to be a predictor of future mortality and cardiovascular morbidity in nondiabetic men with treated hypertension and at high risk of coronary heart disease. However, macroalbuminuria was associated with future major cardiovascular events in this group of patients.

Differentiated Response of the Sympathetic Nervous System to Angiotensin-Converting Enzyme Inhibition in Hypertension

Hypertension with renal artery stenosis is associated with both an activated renin-angiotensin system and elevated sympathetic activity. Therefore, in this condition it may be favorable to use a therapeutic modality that does not reflexly increase heart rate, renin secretion, and sympathetic nervous activity. The purpose of the present study was to assess overall, renal, and muscle sympathetic activity after short-term administration of an angiotensin-converting enzyme inhibitor (enalaprilat) and a nonspecific vasodilator (dihydralazine) to hypertensive patients with renal artery stenosis. Forty-eight patients undergoing a clinical investigation for renovascular hypertension were included in the study. An isotope dilution technique for assessing norepinephrine spillover was used to estimate overall and bilateral renal sympathetic nerve activity. In 11 patients simultaneous intraneural recordings of efferent muscle sympathetic nerve activity were performed. Thirty minutes after dihydralazine administration, mean arterial pressure fell by 15%, whereas plasma angiotensin II, muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover increased (P <0.05 for all). In contrast, after enalaprilat administration a fall in arterial pressure similar to that for dihydralazine was followed by decreased angiotensin II levels and unchanged muscle sympathetic nerve activity, heart rate, and total body norepinephrine spillover, whereas renal norepinephrine spillover increased by 44% (P <0.05). Acute blood pressure reduction by an angiotensin-converting enzyme inhibitor provokes a differentiated sympathetic response in patients with hypertension and renal artery stenosis, inasmuch that overall and muscle sympathetic reflex activation are blunted, whereas the reflex renal sympathetic response to blood pressure reduction is preserved.

Relationship between anti‐neutrophil cytoplasmic antibody determined with conventional binding and the capture assay, and long‐term clinical course in vasculitis

Gisslén K, Wieslander J, Westberg G, Herlitz H (Sahlgrenska University Hospital, Göteborg; and Wieslab AB, Lund; Sweden). Relationship between anti‐neutrophil cytoplasmic antibody (ANCA) determined with conventional binding and the capture assay, and long‐term clinical course in vasculitis. J Intern Med 2002; 251: 129–135.

Beneficial effect of captopril on systemic lupus erythematosus-like disease in MRL lpr/lpr mice

MRL lpr/lpr (MRL/l) mice exhibit a disease similar to systemic lupus erythematosus (SLE) in humans. To investigate the influence of antihypertensive treatment on this disease, four groups of MRL/l mice were treated with the angiotensin-converting enzyme inhibitor captopril (n = 25), with the sympathetic blocker bretylium (n = 15), and with cyclophosphamide (n = 10). Thirty-five mice did not receive any treatment and served as controls. Survival rate, blood pressure, incidence of proteinuria and hematuria, renal pathology, lymphoid hyperplasia and dermatitis were studied. The survival at the age of 36 weeks was significantly improved by captopril as compared to controls (60 vs. 25%, p = 0.035). The cyclophosphamide group showed no mortality at that time and the bretylium group did not differ from the control group. Captopril and bretylium reduced systolic blood pressure significantly while cyclophosphamide was without effect. Captopril and cyclophosphamide diminished significantly the glomerular damage with less proliferative changes and a decreased incidence of proteinuria. The bretylium-treated animals also exhibited an improved renal pathology index but they did not differ from the controls with respect to proteinuria and hematuria. Lymphoid hyperplasia and dermatitis were decreased only by captopril and cyclophosphamide. It is concluded that captopril improves survival in SLE disease of MRL/l mice, counteracting lymphoid hyperplasia, renal disease, dermatitis and decreasing arterial blood pressure.