Cesare Bellini

Plasma endothelin-1 levels, pulmonary hypertension, and lung fibrosis in patients with systemic sclerosis

PURPOSE To investigate the behavior of circulating endothelin (ET)-1 concentrations in patients affected by systemic sclerosis, and to elucidate the possible relationships existing in this disease among plasma peptide levels, pulmonary hypertension, and lung fibrosis. PATIENTS AND METHODS Circulating ET-1 levels were determined by reverse-phase, high-pressure liquid chromatography followed by sensitive radioimmunoassay in 20 patients affected by systemic sclerosis (18 women and 2 men, mean age 48.1 +/- 13.7 years) with or without pulmonary hypertension as evaluated by Doppler echocardiography, or lung fibrosis as measured by a score method based on lung examination by high-resolution computed tomography (HRCT). A group of 18 normal volunteers served as controls (15 women and 3 men, mean age 45.0 +/- 10.1 years). RESULTS Plasma ET-1 levels were significantly higher (P < 0.001) in patients with systemic sclerosis (1.72 +/- 0.28 pg/mL) than in control subjects (0.63 +/- 0.06 pg/mL). Pulmonary artery systolic hypertension was detected in 10 patients (50%) with systemic sclerosis (56.2 +/- 18.0 mm Hg, range 37 to 97) versus none of the control subjects (30.2 +/- 2.2 mm Hg, P < 0.0001). Lung fibrosis was present in 12 patients (60%), with an HRCT overall score of 9.0 +/- 4.6. There were no significant differences in plasma ET-1 levels between patients with pulmonary hypertension (1.58 +/- 0.20 pg/mL) or without it (1.76 +/- 0.39 pg/mL, P = 0.188, not significant [NS]); or between patients with lung fibrosis (1.65 +/- 0.14 pg/mL) or without fibrosis (1.78 +/- 0.37 pg/mL, P = 0.290, NS). In particular, 6 patients had neither pulmonary hypertension nor lung fibrosis. In these patients, plasma ET-1 levels were similar compared with the others (1.85 +/- 0.49 versus 1.66 +/- 0.13, respectively; P = 0.180, NS). No correlations were observed between ET-1 levels and either pulmonary pressure levels or HRCT overall scores. CONCLUSIONS The use of a sensitive assay, highly selective for ET-1, showed higher levels of circulating peptide in patients affected by systemic sclerosis than in control subjects. Neither pulmonary hypertension nor lung fibrosis was accompanied by a further rise in plasma ET-1 concentrations.

Circulating endothelin-1 levels in lean non-insulin-dependent diabetic patients: Influence of ACE inhibition

To evaluate the effect of captopril on plasma endothelin-1 (ET-1) levels and insulin sensitivity, 15 lean normotensive men (51.6 +/- 3.8 years) affected by non-insulin-dependent diabetes mellitus (NIDDM) underwent 2-h euglycemic hyperinsulinemic clamp. Each patient was then assigned to receive either captopril (25 mg twice daily for 1 week) or placebo, in a double-blind randomized fashion, before repeating clamp. At baseline, plasma ET-1 levels were 0.77 +/- 0.25 pg/mL in captopril (n = 10) and 0.83 +/- 0.3 pg/mL in placebo patients (n = 5). A twofold increase in plasma ET-1 levels occurred during the 2-h insulin infusion in both groups (P < .05 after 60 and 120 min), with a rapid return to baseline after 30 min from insulin withdrawal. After 1 week of therapy, total glucose uptake significantly increased in captopril (from 3.71 +/- 1.70 mg/kg/min to 4.24 +/- 1.72 mg/kg/min, P < .03) but not in placebo patients. Plasma ET-1 levels significantly decreased after captopril therapy (0.48 +/- 0.25 pg/mL at time 0, P < .03 v pretreatment levels), but were unaffected by placebo. Moreover, captopril slightly reduced the magnitude of ET-1 increment during insulin infusion (0.65 +/- 0.28 pg/mL and 0.88 +/- 0.48 pg/mL at 60 and 120 min, respectively, P < .05 v time 0). As a consequence, during the second insulin infusion circulating ET-1 levels were significantly lower in captopril- than in placebo-treated patients at time 0 (P < .02), 60 (P < .002), 120 (P < .004), and 150 min (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of salt sensitivity on the blood pressure response to exogenous kallikrein in essential hypertensive patients

In order to verify the influence of salt sensitivity on the blood pressure response to orally administered kallikrein, we evaluated the efficacy of glandular kallikrein (derived from porcine pancreas) in 28 essential hypertensives (21 males and 9 females) aged between 40 and 62 years. After a placebo run-in period, the patients were assigned to receive oral kallikrein therapy (150 IU 3 times a day; n = 18 patients) or placebo (n = 10 patients) over a period of 8 days in a random double-blind fashion. In the salt-resistant patients (n = 8), kallikrein administration did not modify blood pressure levels. In the same group, natriuresis increased significantly after the treatment [from 94.51 +/- 10.76 to 111.65 +/- 23.19 mEq/24 h (mmol/24 h), p < 0.039]. In the salt-sensitive patients (n = 10), blood pressure decreased with the kallikrein therapy (systolic: from 158.50 +/- 9.20 to 144.50 +/- 10.12 mm Hg, p < 0.005; diastolic: from 99.50 +/- 2.16 to 90.0 +/- 3.67 mm Hg, p < 0.024). In the same patients, urinary Na+ excretion increased considerably after the kallikrein treatment (from 101.07 +/- 18.36 to 134.34 +/- 18.27 mEq/24 h, p < 0.0001). Therefore, our data indicate that the oral kallikrein administration reduces blood pressure levels only in the salt-sensitive hypertensives. In both the salt-sensitive and the salt-resistant groups a marked increase in the 24-hour urinary excretion of sodium was observed after the kallikrein treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormal atrial natriuretic peptide and renal responses to saline infusion in nonmodulating essential hypertensive patients.

BackgroundNonmodulation seems to represent an inheritable trait characterized by abnormal angiotensin-mediated control of aldosterone release and renal blood supply and salt-sensitive hypertension. Recently, we demonstrated that atrial natriuretic peptide (ANP) response to angiotensin II also is altered in nonmodulators. Moreover, an abnormal ANP response to acute volume expansion has been shown by others in hypertensive patients displaying some features of nonmodulators. These data induced us to hypothesize that nonmodulators. These data induced us to hypothesize that nonmodulation could be characterized by an abnormal ANP response to saline load. Methods and ResultsForty-three essential hypertensive men were subdivided into low-renin patients (n = 12), nonmodulators (n = 15), and modulators (n = 16) according to their renin profile and ability to modulate aldosterone and p-aminohippurate clearance responses to a graded angiotensin II infusion (1.0 ng.kg-1·min−1 and 3.0 ng·kg−1.min−1 for 30 minutes each) on both a low- (10 mmol Na+ per day) and a high- (210 mmol Na+ per day) Na+ intake. The intravenous saline load (0.25 mL.kg−1−min−1 for 2 hours) performed on a low-Na+ diet increased plasma ANP levels in low-renin (from 14.30 ± 4.68 to 23.30 ± 7.52 fmol/mL at 120 minutes, P < .05) and modulating patients (from 10.95 ± 3.55 to 18.21 ± 5.42 fmol/mL at 120 minutes, P < .05), whereas it did not change the hormone levels in nonmodulators (from 10.77 ± 3.25 to 13.83 ± 5.70 fmol/mL at 120 minutes, P = NS). When patients switched from a low- to a high-NaCl diet, plasma ANP levels increased significantly in all groups. However, when the saline load was repeated on a high-NaCl intake, ANP levels increased in both low-renin and modulating patients (P < .05), whereas it failed to increase in nonmodulators. ConclusionsNonmodulating hypertensive patients showed a reduced ANP response to saline infusion in the presence of a normal increase of plasma ANP with dietary NaCl load. The impaired ANP response to saline infusion could be due to a different distribution of volume load and contribute to determining the reduced ability to excrete sodium that is commonly described in nonmodulators.

Salt-sensitivity is associated with a hyperinsulinaemic and hyperglycaemic response to atrial natriuretic peptide infusion in human essential hypertension

SummaryTo evaluate the influence of salt-sensitivity on the plasma insulin and glucose response to infusion of ANP, we studied 22 men with essential hypertension, who were between 40 and 60 years old. After 1 month under normal Na+ intake (120 mmol Na+ per day), patients were randomly assigned to receive either ANP (0.04 μg · kg−1 · min−1) (n=15) or vehicle (50 ml saline) (n=7) over a 60-min period, while in the supine position. Plasma insulin and glucose were measured at time −60, 0, 20, 40, 60, 120, 180, 240 min. Ten days after ANP infusion, blood pressure sensitivity to changes in di etary salt intake was assessed according to a randomized double-blind crossover protocol. Patients were classified into two groups either salt-sensitive (n=8) or salt-resistant (n=7). Our results showed that plasma insulin and glucose did not change during ANP infusion in both groups. However, both plasma insulin (from 75.6 ± 45.1 pmol/l at 60 min to 121.2 ± 48.6 pmol/l at 240 min, p <0.05 vs time 0) and glucose levels (from 4.86 ± 0.73 mmol/l at 60 min to 6.56 ± 1.03 mmol/l at 240 min, p <0.01 vs time 0) rose after discontinuation of ANP in salt-sensitive patients, but did not change at all in salt-resistant patients. In conclusion, this randomized vehicle-controlled study demonstrates that plasma insulin and glucose levels increase in salt-sensitive hypertensive patients after the infusion of ANP. The increase of plasma insulin levels observed after ANP discontinuation, if occurring under physiologic conditions, could influence the blood pressure sensitivity to dietary Na+ intake.

Oxygen Administration Increases Plasma Digoxin-Like Substance and Renal Sodium Excretion in Chronic Hypoxic Patients

Despite the absence of cardiac or renal pathologies, edema and mild hyponatremia may often occur in patients affected by chronic obstructive pulmonary disease (COPD). Therefore, it has been suggested that hypoxia may influence the release of different hormones regulating renal sodium handling. To evaluate the effect of hyperoxia and O2 removal on plasma digitalis-like substance (DLS) levels, 9 patients affected by COPD and 7 normal subjects were studied. After 1 h in supine position, O2 was administered for 3 h by a tight-fitting face-mask. Blood samples for plasma DLS were taken at time 0, 60, 180 min and then for 3 h after O2 removal. In normal subjects, plasma DLS did not vary after O2 administration (from basal values of 162.25 +/- 8.59 to 107.75 +/- 6.65 pg/ml at 180 min; NS), and O2 removal (143.7 +/- 16.87 pg/ml after 3 h from O2 removal; NS). On the contrary, in patients affected by COPD, plasma DLS levels increased during O2 administration (from basal values of 138.98 +/- 8.31 to 202.14 +/- 8.21 pg/ml at 180 min; p < 0.05), and returned to baseline levels (142.59 +/- 8.28 pg/ml) 3 h after O2 removal. In the same patients, DLS increase was accompanied by a rise in Na+ excretion (from 0.08 +/- 0.01 at time 0 to 0.16 +/- 0.02 mEq/min after 3 h of O2 administration; p < 0.05). In conclusion, our findings showed an oxygen-related increase in plasma DLS levels and in urinary Na+ excretion in patients affected by COPD. This phenomenon could promote Na+ urinary loss during prolonged O2 therapy in these patients and should be taken into account in their management.

Catheter ablation of idiopathic ventricular tachycardia without the use of fluoroscopy.

BACKGROUND Catheter ablation is the treatment of choice for many patients with idiopathic ventricular tachycardia (VT). Unfortunately, conventional catheter ablation is guided by fluoroscopy, which is associated with a small but definite radiation risk for patients and laboratory personnel. The aim of our study is to assess feasibility, success rate and safety of idiopathic VT ablation procedure performed without the use of fluoroscopy. METHODS Nineteen consecutive patients undergoing idiopathic VT ablation at our institution have been included. The ablation procedures were performed under the guidance of electroanatomical mapping (EAM) system and intracardiac echocardiography (ICE). RESULTS Nineteen patients (mean age 38.7 years) underwent ablation procedure for idiopathic VT. Twelve (63%) had outflow tract VT, 3 (18%) fascicular tachycardia, 2 (11%) peri-tricuspidal VT, 1 (5%) peri-mitral VT, and 1 (5%) lateral left free-wall VT. The mean procedural time was 170.2 ± 45.7 min. No fluoroscopy was used in any procedural phase. Acute success rate was 100%. No complication was documented in any patients. After a mean follow up of 18 ± 4 months, recurrences occurred in 2 patients. CONCLUSIONS In our preliminary experience idiopathic VT ablation without the use of fluoroscopy was feasible and safe, using a combination of EAM and ICE. Success rate was excellent with no complication.

Hormonal and renal responses to atrial natriuretic peptide infusion in low-renin hypertension

Although atrial natriuretic peptide (ANP) levels are often elevated in low-renin hypertensives, the renal and hormonal effects of ANP infusion have never been evaluated in these patients. To address this topic, 27 lean nondiabetic men affected by uncomplicated essential hypertension were studied. Low-renin patients (n = 9, age 42 +/- 3 years) were defined as those individuals in balance on a low NaCl intake (10 mmol NaCl/day for 1 week) who had a plasma renin activity <0.30 ng angiotensin I/l/s, in both the supine and the upright positions. The remaining hypertensives (n = 18, age 41 +/- 4 years) were classified into the normal-renin group. Six age-matched healthy men (age 40 +/- 2 years) served as controls. After plasma renin activity determinations, both patients and controls were replaced on a normal NaCl intake (120 mmol NaCl/day). After 1 week, either ANP (99-126), at a dose (0.7 pmol/kg/min for 3 h) which is known to induce changes in plasma ANP confined to the range of normality, or its vehicle were infused at 1-week intervals, according to a randomized double-blind crossover design. At time 0, low-renin patients had significantly higher (p < 0.05) levels of plasma ANP (12.4 +/- 2.5 fmol/ml) than normal-renin patients (7.2 +/- 2.4 fmol/ ml) and normotensives (7.4 +/- 3.3 fmol/ml).(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma endothelin-1 levels during transient acute myocardial ischaemia in men : effects of coronary revascularization

The endothelium‐derived peptide endothelin‐1 (ET‐1) was evaluated in 14 male patients [mean age 52.74 years (SEM 1.10)] affected by coronary artery disease during a bicycle electrocardiographic stress test and dipyridamole echocardiogram. Both tests were performed before and after coronary revascularization. Fourteen healthy male subjects served as controls [mean age 53.21 years (SEM 1.63)]. Baseline plasma endothelin‐1 levels were higher (P < 0.0001) in ischaemic patients [1.81 pg mL−1 (0.15, n = 14)] than in control subjects [0.61 pg mL−1 (0.03, n = 14)], but did not increase with exercise in both groups. Similar results were obtained with dipyridamole infusion. Endothelin‐1 levels significantly decreased after coronary revascularization [before: mean 1.81 pg mL−1 (SEM 0.15, n = 14); after: mean 1.16 pg mL−1 (SEM 0.11), P < 0.002], without changes in the peptide response to both tests. In conclusion, elevated plasma endothelin‐1 concentrations were found in patients with stable angina compared with non‐ischaemic subjects. No changes were observed during exercise or dipyridamole infusion in both groups. Coronary revascularization was followed by a significant decrease in plasma endothelin‐1 levels.

Effect of aprotinin on insulin sensitivity in non-insulin-dependent diabetes mellitus

It has been suggested that kallikrein‐kinin system may influence carbohydrate metabolism via a kinin‐mediated increment of insulin‐mediated glucose uptake. To evaluate the effect of acute inhibition of the kallikrein‐kinin system on insulin sensitivity, a randomized, placebo‐controlled, double‐blind study was performed in 15 male non‐insulin‐dependent diabetic patients. After basal evaluation of insulin sensitivity with a 2‐h euglycaemic hyperinsulinaemic clamp (40 mU m−2 min−1), patients were infused either with aprotinin (200 000 U.I.C. as intravenous bolus injection) or placebo (10 ml isotonic saline) in a cross‐over fashion, at 1 week intervals. After both saline and aprotinin infusions, insulin sensitivity was reassessed by continuing the euglycaemic hyperinsulinaemic clamp for a further 1 h. Resulting data showed that aprotinin significantly improved total glucose uptake (from 16.2 ± 2.9 μmol kg min−1 to 20.6 ± 4.9 μmol kg min−1, p<0.01), and decreased metabolic clearance rate of insulin (from 586 ± 57 ml m−2 min−1 to 442 ± 155 ml m−2 min−1, p<0.05). Thus, in spite of the suggested positive effects of kinins on insulin‐mediated glucose uptake, acute inhibition of the kallikrein‐kinin system resulted in a paradoxical increment of insulin sensitivity, which was probably mediated by the reduced metabolic clearance rate of insulin.