Prevalence and clinical correlates of pulmonary arterial hypertension in progressive systemic sclerosis

Forty-nine patients with progressive systemic sclerosis who had undergone extensive studies including pulmonary artery catheterization as part of an ongoing prospective study of the natural course of progressive systemic sclerosis were evaluated. The overall prevalence of pulmonary arterial hypertension in this population of patients with progressive systemic sclerosis was 33 percent, and among 10 subjects with the CREST syndrome the prevalence of pulmonary hypertension was 50 percent. The relation between pulmonary arterial hypertension documented at catheterization and abnormal results of noninvasive studies suggesting pulmonary hypertension, including physical examination, chest x-ray, electrocardiography, echocardiography, single-breath diffusing capacity, and vital capacity, was studied. Diffusing capacity was significantly lower in those patients with definite pulmonary hypertension (mean pulmonary artery pressure of 22 mg Hg or more) compared with those with a normal mean pulmonary artery pressure, and a diffusing capacity below 43 percent of predicted showed the greatest sensitivity (67 percent) of any single diagnostic test in detecting definite pulmonary hypertension. Chest x-ray suggesting pulmonary hypertension was the least sensitive of the tests evaluated, but showed the greatest specificity (100 percent) in identifying patients with pulmonary hypertension. A classification matrix based on discriminant function analysis utilizing the combination of diffusing capacity below 43 percent of predicted and chest x-ray and electrocardiographic findings correctly identified 75 percent of patients with definite pulmonary hypertension and 97 percent of patients with a normal pulmonary artery pressure, but failed to identify correctly patients with mild pulmonary hypertension (mean pulmonary artery pressure of 20 mm Hg). These findings indicate that specific noninvasive studies are helpful in assessing the likelihood of normal or definitely elevated pulmonary artery pressures in patients with progressive systemic sclerosis, but patients with mild pulmonary hypertension are not likely to be identified by these noninvasive studies.     

Ultrastructural changes in renal arterioles and juxtaglomerular cells in hypertension

The ultrastructural appearance of socalled arteriolar hyalinosis was qualitatively indistinguishable in renal biopsies from patients with essential hypertension with or without diabetes mellitus, renovascular hypertension (the unimpaired member), hypertension associated with progressive systemic sclerosis and gout, normotensive aging (greater than 50 years), persons without renal disease, and a high percentage of adolescent normotensive diabetic individuals. These findings provide further evidence identifying the hypertension observed in patients with gout and progressive systemic sclerosis with that of the essential type.     

Autologous and allogeneic mixed lymphocyte reactions in progressive systemic sclerosis

The autologous and allogeneic mixed lymphocyte reactions (MLR), observed when peripheral blood mononuclear cells from 20 patients with progressive systemic sclerosis were used, were compared with those of age-, sex-, and race-matched normal controls. Such cells were separated by gradient centrifugation of sheep red blood cell (E) rosettes into stimulator (E- or non-T cell) and responder (E + or T cell) populations. The autologous MLR of both the progressive systemic sclerosis and normal peripheral blood mononuclear cells varied widely but there was no statistical difference between the means of each group. In the allogeneic MLR, proliferation between progressive systemic sclerosis non-T cells and normal T cells was significantly less than that of normal non-T cells and progressive systemic sclerosis T cells (P = 0.001). A decreased autologous MLR, while noted with other autoimmune diseases, was lacking in progressive systemic sclerosis. This suggests a different defect. The differences in the allogeneic MLR also suggest that either progressive systemic sclerosis non-T cells were poor stimulators or T cells associated with this disease were better responders when compared with similarly prepared cell populations from normal individuals. The MLR differences could have also resulted from compositional subset alterations or the sharing of a common antigen. HLA-DR5 was found in 9 of the 17 white patients with progressive systemic sclerosis. Although these individuals were evenly distributed as low, medium, and high responders, this finding showed that some progressive systemic sclerosis non-T cells shared a common antigen.     

Increased pulmonary artery pressure in association with Raynaud's phenomenon

Pulmonary artery vasospasm is a hypothesized antecedent and etiologic factor in the pulmonary hypertension associated with progressive systemic sclerosis. Recent clinical data refute the existence of pulmonary vasospasm in a cohort of patients with scleroderma and normal baseline pulmonary artery pressure. A case of episodic pulmonary hypertension associated with a digital Raynaud's response is reported, and a cardiac mechanism is hypothesized.     

Changes in the excretion of catecholamines and their metabolites in patients with essential hypertension during sodium intake restriction

Excretion of noradrenaline (NA), adrenaline (A), dopamine (DA) and their metabolites vanillylmandelic acid (VMA), methoxycatecholamines (MNA + MA) as well as 3-methoxy-4-hydroxy-phenylglycol (MHPG) was studied in 95 patients with essential hypertension and in 25 normal subjects on normal and low sodium diets. The patients were divided into 3 groups according to NA excretion under basal conditions. NA excretion was increased during sodium intake restriction, the highest values of this increase being found in patients whose basal NA excretion was diminished. At low sodium intake the high and the low NA excretors responded with significant increases of DA excretion. The mean excretion of VMA increased significantly on low sodium diet in all 3 groups of patients. The MNA + MA excretion decreased significantly during sodium intake restriction in patients with normal NA excretion. At low sodium intake the excretion of MHPG was highest in patients with low basal NA excretion. These data suggest that in patients with essential hypertension subjected to sodium restriction the excretion and metabolism of catecholamines are related to basal sympathetic activity.     

Interrelations among blood pressure,blood volume,plasma renin activity and urinary catecholamines in benign essential hypertension

Interrelations among blood pressure, circulatory volume, plasma renin activity (PRA) and urinary catecholamine excretion rates were studied in normal subjects and in patients with benign essential hypertension. Mean plasma or blood volumes related to lean body mass, products of blood volume and the logarithm of PRA, and catecholamine excretion rates did not differ significantly between normal and hypertensive subjects. In both normal subjects and hypertensive patients, blood pressure levels correlated positively with the noradrenaline excretion rate (r = 0.40 and 0.36, respectively; p < 0.025) but not with adrenaline excretion, circulatory volume or the volume-renin product. The logarithm of PRA correlated inversely with mean Mood pressure in normal subjects (r = −0.40; p < 0.001) but not in hypertensive patients; however, there was no convincing evidence for an inappropriate blood pressure-PRA relationship as a prominent feature in the hypertensive patients. PRA did not correlate with blood volume. Patients with low PRA relative to sodium excretion (21 per cent of hypertensive population) were consistently normovolemic, but they tended to be older and excreted less (p < 0.025) adrenaline than patients with normal or high PRA. The patient subgroup with high PRA relative to sodium excretion (11 per cent of population) was hypovolemic (p < 0.02); despite this, urinary sodium output was high (172 ± 64 meq/24 hours). These data reveal no evidence for major roles of PRA, circulatory volume and free peripheral catecholamines in the maintenance of benign essential hypertension. Essential hypertension with low PRA is usually not a hypervolemic state, but it may reflect diminished adrenergic activity, factors associated with aging and effects of a high systemic pressure. High PRA in benign essential hypertension may be at least partly a consequence of hypovolemia resulting from high blood pressure-induced sodium diuresis.     

Exocrine pancreatic function in patients with progressive systemic sclerosis

The exocrine pancreatic function was investigated in 16 patients with progressive systemic sclerosis by means of a meal test (Lundh test) and in 9 of the patients by the secretin-cholecystokinin test as well. Gastrointestinal involvement with progressive systemic sclerosis was evaluated by esophageal manometry and by routine roentgenographic series of the small bowel. Fecal fat excretion measurement, the D-xylose absorption test, and a small-intestinal biopsy procedure were carried out. Duodenal juice was cultured and bacterial counts were estimated. One-third of the patients had reduced exocrine pancreatic function, but only four patients had unequivocally a reduction that could be of clinical importance. The results obtained with the meal test were in accordance with the secretin-cholecystokinin test, indicating a preserved capacity for endogenous stimulation.     

Urinary sodium excretion in women with hypertension and various indicators of hemodynamics and pressor hormone levels

Urinary sodium excretion was assessed in women with essential hypertension as an indicator of dietary sodium consumption. Groups of individuals with low (below 120 mmol/day), medium and high (above 180 mmol/day) excretion were identified. Patients with high sodium excretion levels showed slower withdrawal rates, as well as high total peripheral resistance and low cardiac output values. At the labile hypertension stage, these patients demonstrated an increase in total metabolic sodium owing to its growing residual fraction, and expanded interstitial fluid volume. Changes in renin-angiotensin-aldosterone activity showed close correlation with changes in sodium balance. Urinary adrenaline and noradrenaline excretion decreased in patients with labile hypertension who had the highest sodium excretion levels, and increased considerably in stable hypertension. Hypertension was particularly severe in patients who excreted over 180 mmol sodium daily whereas patients who excreted less than 120 mmol in the presence of stable hypertension had normal values of total metabolic sodium and cardiac output, and moderately elevated peripheral vascular resistance.     

Plasma endothelin-1 levels in patients with systemic sclerosis: influence of pulmonary or systemic arterial hypertension.

OBJECTIVES--To investigate the behaviour of circulating endothelin-1 (ET-1) in patients affected by systemic sclerosis and to elucidate the relationship between systemic and pulmonary plasma peptide and arterial pressure levels. METHODS--Plasma ET-1 concentrations were determined in 48 patients affected by systemic sclerosis (41 women, seven men; mean age 47.2 (SD 5.5) years) with or without systemic or pulmonary hypertension (or both). A group of 18 normal volunteers served as controls (15 women, three men; mean age 45.0 (10.1) years). RESULTS--Plasma ET-1 levels were significantly greater in patients affected by systemic sclerosis (1.65 (0.29) pg/ml) than in controls (0.63 (0.19) pg/ml) (p < 0.0001). Pulmonary artery systolic hypertension alone was present in 14 patients with systemic sclerosis (50.5 (8.49) mm Hg, range 37-67 mm Hg), and systemic hypertension alone (160.7 (5.9)/100.6 (3.2) mm Hg) was present in 11 patients. Both conditions were present in 12 patients, while 11 patients had systemic hypertension. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension alone (1.62 (0.21) pg/ml) and those with systemic hypertension alone (1.65 (0.43) pg/ml). In particular, patients with normal pulmonary artery and systemic pressures (n = 11) had plasma ET-1 concentrations identical to those found in patients (n = 12) with both pulmonary and systemic hypertension (1.70 (0.15) v 1.64 (0.35) pg/ml, respectively). No correlations were observed between plasma ET-1 and either pulmonary or systemic pressures. CONCLUSION--Systemic sclerosis is characterised by increased plasma ET-1 levels, but neither pulmonary nor systemic hypertension are accompanied by further increase in plasma peptide levels.     

The pattern of electrolyte excretion in normal and hypertensive subjects before and after saline infusions A simple electrolyte formula for the diagnosis of primary aldosteronism

Electrolyte excretion and serum electrolytes were studied in 99 subjects—19 normal subjects, 62 patients with essential hypertension, 10 with hypertension and renal disease, and 8 patients with primary aldosteronism—during administration of a low sodium diet and during 2 days of intravenous sodium loading. With saline infusions patients with primary aldosteronism gained significantly less weight, excreted significantly more potassium on each day of infusion, and excreted significantly more sodium on the first day of infusion only, than the other groups studied. Mean serum potassium levels fell significantly with saline infusions in patients with primary aldosteronism but remained unchanged in the other groups.

From these observations a diagnostic formula based on potassium clearance corrected for sodium excretion was derived by which patients with primary aldosteronism could be separated completely from the other groups, with the exception of 1 patient with renal disease.

Although patients with primary aldosteronism tended to have lower salivary sodium/potassium ratios than patients with essential hypertension, the difference was not significant.     

Solid-phase radionuclide esophageal transit in progressive systemic sclerosis

BACKGROUND/AIMS: In most patients with progressive systemic sclerosis the esophagus is affected. Reflux symptoms are most frequent whilst dysphagia also occurs. The radionuclide esophageal transit study is a sensitive screening test for esophageal dysfunction. In this study, we evaluated the esophageal motility of patients with progressive systemic sclerosis using a solid-phase radionuclide esophageal study. METHODOLOGY: Thirty-two patients with progressive systemic sclerosis and 30 normal volunteers were studied with solid-phase radionuclide esophageal study. Each subject was placed in a supine position above a gamma camera linked to a computer and was given a 4-mL bolus of solid gelatin containing 1 mCi of Tc-99m phytate. Data were acquired in the list mode. RESULTS: Twenty-nine of the 32 patients (91%) had abnormal findings from the study. CONCLUSIONS: The radionuclide esophageal transit study can be regarded as a useful tool for evaluating the esophageal function in patients with progressive systemic sclerosis and in the follow-up of treatment.     

Systemic hemodynamics and renal function in cirrhotic patients during plasma volume expansion

Systemic hemodynamic impairment (hepatocirculatory failure) has been suggested as one of the possible factors which may explain the renal hemodynamic alterations found in the late stage of liver cirrhosis, typical of the hepatorenal syndrome. 20 patients, divided into two groups of 10 sodium retainers and 10 sodium excretors, affected by liver cirrhosis with portal hypertension and ascites, were studied. Renal functional parameters (diuresis, urinary and plasma electrolytes, urine to plasma osmolality and creatinine ratios and creatinine clearance) were evaluated before and after acute volume expansion with 1,000 ml of 10% dextran in saline, infused through a catheter located in the right atrium. Hemodynamic tests (cardiac index, systemic vascular resistance, right atrial pressure and capillary wedge pressure) were performed before, during and after expansion. Cardiac index decreased in 6 patients (sodium excretors) after a 500-ml infusion and rose again after 1,000 ml in 5 of them. The remaining 14 patients showed a progressive and significant increase of cardiac index. A strong inverse relationship between cardiac index and systemic vascular resistance was observed (r = -0.87; p less than 0.001). The mean left-ventricular function curve showed a slow response in most sodium excretors and a normal response in the sodium-retaining group, without significant difference between the two groups. Sodium excretion significantly improved after expansion in both groups of patients. No relationship was found between hemodynamic response and renal function. These data show that cardiocirculatory function is normal, even in sodium-retaining cirrhotics.     

Sjögren's syndrome in progressive systemic sclerosis (scleroderma)

Sicca features of Sjögren's syndrome were investigated in 25 consecutive patients with progressive systemic sclerosis by means of clinical examination, Schirmer's tests, rose bengal staining tests, secretory parotid sialographies, scintillation scanning of salivary glands with ^99-mTc pertechnetate, radionuclide salivary excretion studies and lip biopsies for study of minor salivary glands.All 25 patients had at least one abnormal test and all but 3 patients had more than two abnormal tests.Pathologic findings in minor salivary glands included both lymphocytic infiltration and duct cell proliferation characteristic of Sjögren's syndrome, as well as collagen infiltration and disruption attributable to scleroderma. However, the finding of lacrimal and major salivary gland involvement indicates that Sjögren's syndrome does occur in the majority of patients with progressive systemic sclerosis. Because Sjögren's syndrome coexists almost exclusively with autoimmune disorders, our findings support the contention that progressive systemic sclerosis is related to autoimmunity.     

Abnormalities of esophageal and gastric emptying in progressive systemic sclerosis

Gastric and esophageal emptying were assessed using scintigraphic techniques in 12 patients with progressive systemic sclerosis and 22 normal volunteers. Esophageal emptying was significantly delayed in the patient group, with 7 of the 12 patients beyond the normal range. Gastric emptying was slower in patients than in controls, with 9 patients being outside the normal range for solid emptying and 7 patients outside the normal range for liquid emptying. Findings from gastric and esophageal emptying tests generally correlated well with symptoms of dysphagia and gastroesophageal reflux. However, 2 patients with normal emptying studies had symptomatic heartburn, and 2 patients with delay of both solid and liquid gastric emptying gave no history of gastroesophageal reflux. Delayed gastric emptying may be an important factor in the development of upper gastrointestinal symptoms in patients with progressive systemic sclerosis.     

Non-cirrhotic portal fibrosis in a patient with rheumatoid arthritis.

A 53-year-old man suffering from rheumatoid arthritis for 15 years presented with bleeding esophageal varices, hepatosplenomegaly and normal splenoportal venous axis. Liver biopsy revealed mild fibrosis, suggestive of non-cirrhotic portal fibrosis (NCPF). There are reports of the association of idiopathic portal hypertension, a condition similar to NCPF, with progressive systemic sclerosis, Hashimoto's thyroiditis and systemic lupus erythematosus.     

Enterocyte function in progressive systemic sclerosis as estimated by the deconjugation of pteroyltriglutamate to folic acid.

As a measure of enterocyte function, the deconjugation of pteroyl-L-glutamyl-gamma-L-glutamyl-gamma-L-glutamic acid to folic acid and subsequent active absorption was measured in 19 patients with progressive systemic sclerosis and compared with 14 controls. The absorption step of folic acid was identical in the two groups, while deconjugation of pteroyl-L-glutamyl-gamma-L-glutamyl-gamma-L-glutamic acid was significantly decreased in the patients with progressive systemic sclerosis. This observation suggests a primary epithelial defect of the small intestine in patients with progressive systemic sclerosis.     

Transcapillary escape rate of albumin in hypertensive patients with Type 1 (insulin-dependent) diabetes mellitus

Summary Diabetic patients with elevated urinary albumin excretion rate (incipient or clinical nephropathy) also have an increased transcapillary escape rate of albumin. This study was designed to clarify whether this is caused by a general vascular dysfunction or by elevated systemic blood pressure. The systemic blood pressure and the transcapillary escape rate of albumin were measured in the following groups after 4 weeks without antihypertensive treatment: Group 1 — eleven healthy control subjects. Group 2 — ten Type 1 (insulin-dependent) diabetic patients with incipient nephropathy (urinary albumin excretion rate: 30–300 mg/24 h) and normal blood pressure. Group 3 — eleven non-diabetic patients with essential hypertension. Group 4 — nine Type 1 diabetic patients with hypertension but normal urinary albumin excretion (<30 mg/24 h). Group 5 — eleven Type 1 diabetic patients with nephropathy (urinary albumin excretion rate > 300 mg/24 h) and hypertension. Systolic and diastolic blood pressure were similar in the three hypertensive groups: group 3, 148±8/95±6; group 4, 150±12/94±8 and group 5; 152±12/92±7mmHg, but significantly elevated (p<0.001) compared to control group 1,117±12/74±9 and group 2, 128±7/82±4 mm Hg. The transcapillary escape rate of albumin was similar in the control subjects (5.2±2.7%) and the subjects in the normoalbuminuric groups 3 and 4 (6.2±1.9 and 5.1±1.4 %, respectively) and significantly lower (p<0.001) than in patients with elevated urinary albumin excretion without or with hypertension group 2, 10.1±2.8 and group 5, 11.4±5.7 %. The increased transcapillary escape rate of albumin in patients with elevated urinary albumin excretion is unrelated to moderate systemic hypertension and may therefore be caused by alterations in the properties of the capillary walls.     

Microalbuminuria in systemic sclerosis.

A prospective study was performed to determine urinary albumin excretion in a group of 28 patients with systemic sclerosis. At the initial screen one patient had proteinuria and three had microalbuminuria. One year later these abnormalities persisted and in two of of the patients serum creatinine had significantly increased. In addition, a further three patients had developed microalbuminuria. In a control group of 10 patients with primary Raynaud's disease none had microalbuminuria. In a second control group of 16 patients with unrelated skin diseases one patient had microalbuminuria and one proteinuria, but both these patients had a history of hypertension. It is concluded that microalbuminuria is more common in patients with systemic sclerosis than in patients of equivalent age with other dermatological conditions but no vascular disease.     

The role of the renal kallikrein-kinin system in sodium metabolism in normal and low renin essential hypertension

In order to investigate the pathophysiological role of the renal kallikrein-kinin system in renin subgroups of essential hypertension, the quantity and activity of urinary kallikrein, urinary kinin excretion, and correlations of kallikrein and kinin excretions with renal sodium handling in the renal tubules were studied in 17 normal subjects, 23 patients with normal renin and 12 patients with low renin essential hypertension. Urine samples were collected by the 2-hour clearance method in the early morning. The quantity and activity of urinary kallikrein, and the urinary excretion of kinin were significantly lower in both low and normal renin patients than in normal subjects. Comparing the normal renin and the low renin group, no significant difference was found in the quantity of urinary kallikrein, while the activity of urinary kallikrein and urinary kinin excretion were significantly lower in low renin patients than in normal renin ones. Fractional excretions of sodium (FENa) and inorganic phosphorus (FEP), which reflect renal tubular and proximal tubular sodium reabsorption, respectively, were significantly lower in the low renin patients than in the normal renin ones. A significantly positive correlation was observed between the urinary kallikrein activity or urinary kinin excretion and FENa or FEP in both normal subjects and normal renin patients, but not in low renin patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Studies of endogenous catecholamines in patients with Raynaud's phenomenon secondary to progressive systemic sclerosis (scleroderma)

Studies of the resting venous plasma catecholamine concentration and the urinary catecholamine excretion patterns of patients with Raynaud's phenomenon secondary to progressive systemic sclerosis (scleroderma) failed to support the hypothesis that norepinephrine and/or epinephrine are neurohumors of excess in this particular form of Raynaud's phenomenon.