Clinical impact of high platelet reactivity in patients with atrial fibrillation and concomitant percutaneous coronary intervention on dual or triple antithrombotic therapy.

High platelet reactivity (HPR) on clopidogrel is an established thrombotic risk factor after percutaneous coronary intervention (PCI). The introduction of more potent antiplatelet drugs has partially surpassed this issue. However, in the setting of concomitant atrial fibrillation (AF) and PCI clopidogrel is still the most adopted P2Y12 inhibitor. In the present study all consecutive patients with history of AF discharged from our cardiology ward with dual (DAT) or triple (TAT) antithrombotic therapy after a PCI from April 2018 to March 2021 were enrolled in an observational registry. For all subjects, blood serum samples were collected and tested for platelet reactivity by arachidonic acid and ADP (VerifyNow system) and genotyping of the CYP2C19*2 loss-of-function polymorphism. We recorded at 3 and 12-months follow-up: (1) major adverse cardiac and cerebrovascular events (MACCE), (2) major hemorrhagic or clinically relevant non-major bleeding and (3) all-cause mortality. A total of 147 patients were included (91, 62% on TAT). In 93.4% of patients, clopidogrel was chosen as P2Y12 inhibitor. P2Y12 dependent HPR resulted an independent predictor of MACCE both at 3 and 12 months (HR 2.93, 95% C.I. 1.03 to 7.56, p = 0.027 and HR 1.67, 95% C.I. 1.20 to 2.34, p = 0.003, respectively). At 3-months follow-up the presence of CYP2C19*2 polymorphism was independently associated with MACCE (HR 5.21, 95% C.I. 1.03 to 26.28, p = 0.045). In conclusion, in a real-world unselected population on TAT or DAT, the entity of platelet inhibition on P2Y12 inhibitor is a potent predictor of thrombotic risk, suggesting the clinical utility of this laboratory evaluation for a tailored antithrombotic therapy in this high-risk clinical scenario. The present analysis was performed in patients with AF undergoing PCI on dual or triple antithrombotic therapy. At 1 year follow-up MACCE incidence was consistent, and it was not different in different antithrombotic pattern groups. P2Y12 dependent HPR was a potent independent predictor of MACCE both at 3- and 12-months follow-up. In the first 3 months after stenting the carriage of CYP2C19*2 allele was similarly associated with MACCE. Abbreviation: DAT, dual antithrombotic therapy; HPR, high platelet reactivity; MACCE, major adverse cardiac and cerebrovascular events; PRU, P2Y12 reactive unit; TAT, triple antithrombotic therapy. Created with BioRender.com.

Deterministic and time resolved thermo-magnetic switching in a nickel nanowire.

Heating a ferromagnetic material is often perceived as detrimental for most applications. This is indeed the case for modern nano-scaled spintronic devices which are operated solely (at least ideally) by an electric current. Heat is a by-product of the current-driven operation and it deteriorates many functionalities of the device. A large scientific and technological effort is devoted these days to avoid heat in modern magnetic nano devices. Here we show that heat can be used to provide an additional and useful degree of freedom in the control of the local magnetization at the nanoscale. In a ferromagnetic nanowire, temperature is used to induce a magnetic switching through a perfectly deterministic mechanism. The nucleation of the magnetic domain walls that triggers the switching can be achieved at a field considerably smaller than the nucleation field and, importantly, the exact moment of the magnetic switching can be pre-determined with nanosecond precision by controlling the power delivered locally to the switching area. With the help of micromagnetic simulations and a theoretical model, we provide an accurate explanation of how this deterministic thermo-magnetic switching operates. The concepts described in this work may lead to an increased functionality in magnetic nano-devices based on magnetic domain walls.

JUNO/JIRAM's view of Jupiter's H3+ emissions.

The instrument JIRAM (Jovian Infrared Auroral Mapper), on board the NASA spacecraft Juno, is both an imager and a spectrometer. Two distinct detectors are used for imaging and spectroscopy. The imager acquires Jupiter images in two bands, one of which (L band, 3.3-3.6 µm) is devoted to monitor the H3+ emission. The spectrometer covers the spectral region from 2 to 5 µm (average spectral resolution 9 nm) with a 256 pixels slit that can observe the same scene of the L band imager with some delay. JIRAM scientific goals are the exploration of the Jovian aurorae and the planet's atmospheric structure, dynamics and composition. Starting early July 2016 Juno is orbiting around Jupiter. Since then, JIRAM has provided an unprecedented amount of measurements, monitoring both Jupiter's atmosphere and aurorae. In particular, the camera has monitored Jupiter's poles with very high spatial resolution, providing new insights in both its aurorae and the polar dynamic. The main findings obtained by the L imager are detailed pictures of Jupiter's aurorae showing an extremely complex morphology of the H3+ distribution in the main oval and in the moon's footprints. The spectrometer has enabled the measure the distribution of both H3+ concentration and temperature. The analysis of the north auroral region limb observations shows that the peak density of H3+ is above 750 km and that often it is anticorrelated to the temperature, confirming the infrared cooling effect of H3+. This article is part of a discussion meeting issue 'Advances in hydrogen molecular ions: H3+, H5+ and beyond'.

Juno observations of spot structures and a split tail in Io-induced aurorae on Jupiter.

Jupiter's aurorae are produced in its upper atmosphere when incoming high-energy electrons precipitate along the planet's magnetic field lines. A northern and a southern main auroral oval are visible, surrounded by small emission features associated with the Galilean moons. We present infrared observations, obtained with the Juno spacecraft, showing that in the case of Io, this emission exhibits a swirling pattern that is similar in appearance to a von Kármán vortex street. Well downstream of the main auroral spots, the extended tail is split in two. Both of Ganymede's footprints also appear as a pair of emission features, which may provide a remote measure of Ganymede's magnetosphere. These features suggest that the magnetohydrodynamic interaction between Jupiter and its moon is more complex than previously anticipated.

Clusters of cyclones encircling Jupiter's poles.

The familiar axisymmetric zones and belts that characterize Jupiter's weather system at lower latitudes give way to pervasive cyclonic activity at higher latitudes. Two-dimensional turbulence in combination with the Coriolis ß-effect (that is, the large meridionally varying Coriolis force on the giant planets of the Solar System) produces alternating zonal flows. The zonal flows weaken with rising latitude so that a transition between equatorial jets and polar turbulence on Jupiter can occur. Simulations with shallow-water models of giant planets support this transition by producing both alternating flows near the equator and circumpolar cyclones near the poles. Jovian polar regions are not visible from Earth owing to Jupiter's low axial tilt, and were poorly characterized by previous missions because the trajectories of these missions did not venture far from Jupiter's equatorial plane. Here we report that visible and infrared images obtained from above each pole by the Juno spacecraft during its first five orbits reveal persistent polygonal patterns of large cyclones. In the north, eight circumpolar cyclones are observed about a single polar cyclone; in the south, one polar cyclone is encircled by five circumpolar cyclones. Cyclonic circulation is established via time-lapse imagery obtained over intervals ranging from 20 minutes to 4 hours. Although migration of cyclones towards the pole might be expected as a consequence of the Coriolis ß-effect, by which cyclonic vortices naturally drift towards the rotational pole, the configuration of the cyclones is without precedent on other planets (including Saturn's polar hexagonal features). The manner in which the cyclones persist without merging and the process by which they evolve to their current configuration are unknown.

Spontaneous exchange bias formation driven by a structural phase transition in the antiferromagnetic material.

Most of the magnetic devices in advanced electronics rely on the exchange bias effect, a magnetic interaction that couples a ferromagnetic and an antiferromagnetic material, resulting in a unidirectional displacement of the ferromagnetic hysteresis loop by an amount called the 'exchange bias field'. Setting and optimizing exchange bias involves cooling through the Néel temperature of the antiferromagnetic material in the presence of a magnetic field. Here we demonstrate an alternative process for the generation of exchange bias. In IrMn/FeCo bilayers, a structural phase transition in the IrMn layer develops at room temperature, exchange biasing the FeCo layer as it propagates. Once the process is completed, the IrMn layer contains very large single-crystal grains, with a large density of structural defects within each grain, which are promoted by the FeCo layer. The magnetic characterization indicates that these structural defects in the antiferromagnetic layer are behind the resulting large value of the exchange bias field and its good thermal stability. This mechanism for establishing the exchange bias in such a system can contribute towards the clarification of fundamental aspects of this exchange interaction.

Seasonal exposure of carbon dioxide ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Carbon dioxide (CO2) is one of the most abundant species in cometary nuclei, but because of its high volatility, CO2 ice is generally only found beneath the surface. We report the infrared spectroscopic identification of a CO2 ice-rich surface area located in the Anhur region of comet 67P/Churyumov-Gerasimenko. Spectral modeling shows that about 0.1% of the 80- by 60-meter area is CO2 ice. This exposed ice was observed a short time after the comet exited local winter; following the increased illumination, the CO2 ice completely disappeared over about 3 weeks. We estimate the mass of the sublimated CO2 ice and the depth of the eroded surface layer. We interpret the presence of CO2 ice as the result of the extreme seasonal changes induced by the rotation and orbit of the comet.

Exposed water ice on the nucleus of comet 67P/Churyumov-Gerasimenko.

Although water vapour is the main species observed in the coma of comet 67P/Churyumov-Gerasimenko and water is the major constituent of cometary nuclei, limited evidence for exposed water-ice regions on the surface of the nucleus has been found so far. The absence of large regions of exposed water ice seems a common finding on the surfaces of many of the comets observed so far. The nucleus of 67P/Churyumov-Gerasimenko appears to be fairly uniformly coated with dark, dehydrated, refractory and organic-rich material. Here we report the identification at infrared wavelengths of water ice on two debris falls in the Imhotep region of the nucleus. The ice has been exposed on the walls of elevated structures and at the base of the walls. A quantitative derivation of the abundance of ice in these regions indicates the presence of millimetre-sized pure water-ice grains, considerably larger than in all previous observations. Although micrometre-sized water-ice grains are the usual result of vapour recondensation in ice-free layers, the occurrence of millimetre-sized grains of pure ice as observed in the Imhotep debris falls is best explained by grain growth by vapour diffusion in ice-rich layers, or by sintering. As a consequence of these processes, the nucleus can develop an extended and complex coating in which the outer dehydrated crust is superimposed on layers enriched in water ice. The stratigraphy observed on 67P/Churyumov-Gerasimenko is therefore the result of evolutionary processes affecting the uppermost metres of the nucleus and does not necessarily require a global layering to have occurred at the time of the comet's formation.

Primary PCI for the treatment of ectatic infarct-related coronary artery.

AIM: There is lack of information on the outcome of patients treated with primary angioplasty for lesions located in an ectatic coronary artery segment in the setting of acute myocardial infarction. The aim of this study was to analyse the 2-year follow-up of this specific patient population. METHODS: By means of a systematic review of the databases and cine-films of 5912 primary angioplasties performed in eight Italian cardiac centers we identified 101 patients with infarct-related coronary artery ectasia. Ectasia was defined as a dilatation exceeding the 1.5-fold of normal adjacent segment and was classified according to its severity. The primary end point was the composite rate of cardiac death, recurrence of acute myocardial infarction and a new revascularisation at 2-year. RESULTS: The procedure was successful in 70.3% of cases, unsuccessful or complicated in 29.7%. The primary endpoint was met in 6.9% of cases during hospitalization (95% CI: 2.0-11.8), in 17.8% (95% CI: 10.3-25.3) at 1 year, and in 38.5% (95% CI: 29.0-48.0) at 2 years. Nine patients had a stent thrombosis: 3 acute and 6 sub-acute. A statistically significant correlation between the dimensions of the stent and stent thrombosis was observed (P=0.005). CONCLUSION: In subjects undergoing primary angioplasty for acute myocardial infarction the rate of patients treated on lesions located in an ectatic coronary artery segment is very small (1.7%). The procedural success was low, whereas the rate of events at follow-up was quit high reflecting the complexity of this disease.

Time course of serum collagen types I and III metabolism products after reperfused acute myocardial infarction in patients with and without systemic hypertension.

We examined 55 consecutive patients successfully treated with primary percutaneous coronary intervention (PCI) for a first acute myocardial infarction with left ventricular (LV) systolic dysfunction. In all patients we performed echocardiographic examination, dosage of plasma brain natriuretic peptide, serum carboxy-terminal propeptide and telopeptide of procollagen type I and amino-terminal propeptide of procollagen type III at days 1 and 3, and at 1 and 6 months after index infarction. The hypertensive patients (group 1; n=30) differed for higher baseline blood pressure (133+/-4 mm Hg vs 118+/-4 mm Hg; P=0.03), greater LV mass index (108+/-5 vs 94+/-4 g m(-2), P=0.03) and lower mitral E/A wave peak (0.8+/-0.06 vs 1.1+/-0.12, P=0.02) with respect to non-hypertensive patients (group 2; n=25). From day 1 to month 6 carboxy-terminal propeptide of procollagen type I and amino-terminal propeptide of procollagen type III increased (P<0.005 and P<0.05, respectively) in both groups, whereas carboxy-terminal telopeptide of procollagen type I increased from day 1 to day 3 (P<0.01 in both groups, respectively) and then decreased from day 3 to month 6 (P<0.01 and P<0.05 in both groups, respectively). From day 1, brain natriuretic peptide decreased in both groups (P<0.005). There was no significant difference between the two groups in values of procollagens and natriuretic peptide. Finally, LV diastolic volume and function at 6 months were similar in the two groups. Thus, in patients with reperfused acute myocardial infarction and LV dysfunction, antecedent hypertension was not associated with a different pattern of serum procollagen release and ventricular remodelling at 6 months of follow-up.

Five year outcome after primary coronary intervention for acute ST elevation myocardial infarction: results from a single centre experience.

OBJECTIVES: To analyse the five year outcome of unselected patients with acute myocardial infarction (AMI) treated by primary percutaneous coronary intervention (PCI). SETTING: High volume PCI tertiary centre. DESIGN AND RESULTS: The study was based on a sample of 1009 consecutive patients with ST elevation AMI treated by primary PCI. The mean (SD) clinical follow up was 51 (21) months and the follow up rate was 97.8%. The overall mortality was 20% and cardiac mortality was 16%. Non-fatal reinfarction rate was 5% and additional revascularisation procedure rate was 19%. Hospitalisation for heart failure was needed by 42 patients (4%). The variables related to mortality in multivariate Cox analysis were age (hazard ratio (HR) 1.054, 95% confidence interval (CI) 1.039 to 1.069, p < 0.0001), cardiogenic shock (HR 2.985, 95% CI 2.157 to 4.129, p < 0.0001), previous myocardial infarction (HR 1.696, 95% CI 1.199 to 2.398, p = 0.0003), and the presence of multivessel coronary artery disease (HR 1.820, 95% CI 1.317 to 2.514, p = 0.0003). Each additional high risk feature was associated with a relative risk for five year death of 2.328 (95% CI 2.048 to 2.646, p < 0.0001). CONCLUSIONS: The satisfactory results of routine mechanical revascularisation strategy in AMI were maintained during several years of follow up. Patients at risk of death during long term follow up may be identified by simple clinical and angiographic characteristics, such as old age, cardiogenic shock, previous myocardial infarction, and multivessel coronary artery disease. The risk of death progressively increases with the number of these high risk features.

Clinical and angiographic outcomes following elective implantation of the Carbostent in patients at high risk of restenosis and target vessel failure.

The Carbostent is a new balloon-expandable, stainless steel, tubular stent with innovative multicellular design and unique turbostratic carbon coating. The aim of this study was to assess clinical and angiographic outcomes after Carbostent implantation in 112 patients poorly suitable for an effective treatment with stenting because of the high risk of thrombosis, late restenosis, and clinical target vessel failure. The inclusion criteria were age > 75 years, diabetes mellitus, a lesion length > 10 mm, a reference vessel diameter < 3.0 mm, an ostial location of the target lesion, and chronic total occlusion. Overall, a total of 175 stents ranging from 9 to 25 mm in length were placed in 147 lesions. There were no stenting attempt failures. The acute gain after stent implantation was 2.46 +/- 0.51 mm, and the residual stenosis 0 +/- 4%. No stent thrombosis occurred, nor myocardial infarction. The 6-month event-free survival rate was 74% +/- 5%. The 6-month angiographic follow-up showed a late loss of 0.81 +/- 0.88 mm and a binary (> or = 50%) restenosis rate of 25%. The results of this study suggest that the Carbostent may be highly effective in patients at high risk of restenosis and target vessel failure.

Early detection of myocardial ischaemia in the emergency department by rest or exercise (99m)Tc tracer myocardial SPET in patients with chest pain and non-diagnostic ECG.

Chest pain (CP) represents a frequent reason for presentation at the emergency department (ED). A large proportion of patients have non-diagnostic ECG on presentation, and in many cases several hours have elapsed since onset of symptoms. Acute rest myocardial scintigraphy (rest SPET) has been shown to have a relevant role in the detection of patients at risk for coronary events, but its sensitivity and negative predictive value are optimal only within the first 3 h following onset of symptoms. In those with delayed presentation, exercise SPET alone, as a screening approach, appears more promising, but its feasibility and diagnostic role in the ED are still unresolved. A total of 231 consecutive patients with a recent-onset (<24 h) first episode of CP had a negative first-line work-up including ECG, troponins, creatine kinase-MB and echocardiography. These patients were considered at low risk for short-term coronary events. Patients were studied with rest SPET if they presented <3 h after onset of CP and exercise SPET if they presented after > or =3 h. The end-points of the study were detection of significant coronary artery disease (CAD) by angiography and major coronary events or cardiac death at 6 months. Eighty patients (35%) underwent rest SPET, while 151 (65%) underwent exercise SPET. Two of the 159 patients with negative SPET had evidence of critical CAD at 6-month follow-up (one patient in the rest SPET group and one in the exercise SPET group; P=NS). Of the 72 patients (31%) with a positive scan, 34 (15%) had documented CAD (16 patients in the rest SPET group and 18 in the exercise SPET group; P=NS). Sensitivity, specificity, accuracy and predictive value were not statistically different between the two groups. In conclusion, the accuracy of exercise SPET in patients with CP and delayed presentation to the ED is comparable to that of validated rest SPET in patients with early presentation. Owing to the high negative predictive value (99%), exercise SPET is especially valuable as a screening tool for the exclusion of CAD in low-risk patients and implementation of early discharge.

Direct infarct artery stenting without predilation and no-reflow in patients with acute myocardial infarction.

BACKGROUND: In patients with acute myocardial infarction (AMI), the rate of microvascular embolization and no-reflow promoted by coronary stenting with the use of conventional techniques (CS) appears to be greater than the one that occurs with balloon angioplasty. The minor invasiveness of direct stenting (DS) of the infarct artery without predilation could be expected to reduce embolization in the coronary microvasculature and no-reflow in patients with AMI. METHODS: In a cohort of 423 consecutive patients with AMI who underwent infarct-artery stenting, we compared CS and DS in terms of angiographic no-reflow rate and 1-month clinical outcome. RESULTS: At baseline patients who underwent DS (n = 110) had a better risk profile compared with the use of CS (n = 313). The incidence of angiographic no-reflow was 12% in the CS group and 5.5% in the DS group (P =.040). The 1-month mortality rate was 8% in the CS group and 1% in the DS group (P =.008). The mortality rate was 11% in patients with no-reflow and 5.6% in patients with a normal flow. Multivariate analysis showed that age, preprocedure patent infarct artery, and lesion length were related to the risk of no-reflow. In the subset of patients with a target lesion length

Sex-based differences in clinical and angiographic outcomes after primary angioplasty or stenting for acute myocardial infarction.

A paucity of data exists on the importance of gender in contributing to the mortality rate after primary angioplasty, although it is has been shown that women with acute myocardial infarction (AMI) are less likely than men to undergo reperfusion treatments. This study analyzes gender-related differences in 6-month clinical and angiographic outcomes in nonselected patients with AMI who underwent primary angioplasty or stenting. We compared clinical and angiographic outcomes of 230 women and 789 men who underwent primary angioplasty or stenting from January 1995 to August 1999. The women were older than the men, and had a greater incidence of diabetes and cardiogenic shock. The 6-month mortality rate was 12% in women and 7% in men (p = 0.028). Nonfatal reinfarction occurred in 3% of the women and in 1% of the men (p = 0.010). There were no differences in repeat target vessel revascularization rates. After multivariate analysis, gender did not emerge as a significant variable in relation to 6-month mortality or to the combined end point of death, reinfarction, and repeat target vessel revascularization. Both women and men with stented infarct arteries had lower restenosis rates (29% and 26%, respectively) than patients without stents (52% and 39%, repectively). The results of outcome analysis in nonselected patients suggest that sex is not an independent predictor of mortality after primary angioplasty for AMI, and that the benefit of primary stenting is similar in men and women.

Primary stenting in nonselected patients with acute myocardial infarction: the Multilink Duet in Acute Myocardial Infarction (MIAMI) trial.

Most randomized trials comparing primary stenting with primary coronary angioplasty (PTCA) excluded patients at high risk from enrollment, thus arising the important question about the generalizability of the randomized trial results to all patients with AMI. The aim of this study was to assess the feasibility and effectiveness of a primary infarct-related artery (IRA) stenting strategy using a second-generation tubular stent in nonselected patients with acute myocardial infarction (AMI). All patients with AMI were considered eligible for primary IRA stenting. No restriction was made based on age or clinical status on presentation, or coronary anatomy, except in cases of a reference IRA diameter < 2.5 mm. The primary endpoint of the study was clinical target vessel failure defined as death, reinfarction, or repeat TVR due to restenosis or reocclusion of the IRA. Between June 1998 and March 1999, 201 consecutive patients with AMI underwent mechanical recanalization of the IRA. The mean age was 64 +/- 12, and 16% of patients were aged 75 years or over. The incidence of shock was 9%. Primary IRA stenting was performed in 89% of the patients. Patients who underwent PTCA alone had a smaller IRA diameter as compared to patients with a stented IRA (2.48 +/- 0.46 mm vs. 3.15 +/- 0.37 mm; P < 0.001). There were no stent deployment failures. The 6-month primary endpoint rate was 15% (2 deaths, 27 repeat TVR, 0 reinfarctions), while the 6-month angiographic restenosis rate was 22%. Primary IRA stenting in nonselected patients with AMI is highly feasible and associated with favorable clinical and angiographic outcomes. Cathet. Cardiovasc. Intervent. 51:273-279, 2000.

Cardiac growth factors in human hypertrophy. Relations with myocardial contractility and wall stress.

The aim of the present study was to investigate whether and which cardiac growth factors are involved in human hypertrophy, whether growth factor synthesis is influenced by overload type and/or by the adequacy of the hypertrophy, and the relationships between cardiac growth factor formation and ventricular function. Cardiac growth factor formation was assessed by measuring aorta-coronary sinus concentration gradient in patients with isolated aortic stenosis (n=26) or regurgitation (n=15) and controls (n=12). Gene expression and cellular localization was investigated in ventricular biopsies using reverse transcriptase-polymerase chain reaction and in situ hybridization. Cardiac hypertrophy with end-systolic wall stress <90 kdyne/cm2 was associated with a selective increased formation of insulin-like growth factor (IGF)-I in aortic regurgitation and of IGF-I and endothelin (ET)-1 in aortic stenosis. mRNA levels for IGF-I and preproET-1 were elevated and mainly expressed in cardiomyocytes. At stepwise analysis, IGF-I formation was correlated to the mean velocity of circumferential fiber shortening (r=0.86, P<0.001) and ET-1 formation to relative wall thickness (r=0.82, P<0. 001). When end-systolic wall stress was >90 kdyne/cm2, IGF-I and ET-1 synthesis by cardiomyocytes was no longer detectable, and only angiotensin (Ang) II was generated, regardless of the type of overload. The mRNA level for angiotensinogen was high, and the mRNA was exclusively expressed in the interstitial cells. Ang II formation was positively correlated to end-systolic stress (r=0.89, P<0.001) and end-diastolic stress (r=0.84, P<0.001). Multivariate stepwise analysis selected end-systolic stress as the most predictive variable and left ventricular end-diastolic pressure as the independent variable for Ang II formation (r=0.93, P<0.001). In conclusion, the present results indicate that the course of human left ventricular hypertrophy is characterized by the participation of different cardiac growth factors that are selectively related both to the type of hemodynamic overload and to ventricular function.

Increased renal endothelin formation is associated with sodium retention and increased free water clearance.

To investigate whether renal endothelin (ET)-1 participates in water and sodium handling, we investigated the influence of different sodium intakes on renal production of ET-1 in eight healthy subjects. The functional relationship with the renin-angiotensin system was also studied. Renal ET-1 formation is affected by sodium intake, because 1 wk of high sodium decreased urinary ET-1 excretion (-34%, P < 0.05), whereas a low-sodium diet increased ET-1 excretion (66%, P < 0.05) and mRNA expression for preproendothelin-1 in epithelial cells of medullary collecting ducts and endothelial cells of the peritubular capillary network. Increased ET-1 renal synthesis was associated with sodium retention and increased free water clearance. Urinary ET-1 excretion changes from normal to low-sodium diet were negatively related to contemporary changes in sodium excretion (r = 0.97, P < 0.05) and were positively correlated with free water clearance (r = 0.97, P < 0.05). These correlations were maintained during angiotensin-converting enzyme inhibition, which only partially reduced ET-1 renal excretion. These results indicate that renal ET-1 production is indeed modulated by varying sodium intakes and may exert a role in sodium and water handling.