Parietal cell/oncocytic gastric carcinoma: systematic review and first-time assessment of HER2 status in two new cases.

INTRODUCTION: Parietal cell/oncocytic gastric carcinomas are very rare and various aspects of this group remain unclear. The human epithelial growth factor receptor 2 (HER2) status of these tumours is largely unknown. METHODS: We performed a systematic electronic search of the literature and clinicopathological presentation of two cases including first-time complete assessment of HER2 status. Thirty-two patients with a mean age of 64.3 years, 87.5% of whom were male, were included in this review. FINDINGS: Half of the cases were recorded in Asia. Median follow-up was 24 months. There was no predominant site of development, while underlying histological abnormalities were present in 25%. At initial presentation, lymph node involvement was evident in 46.6% while distant metastatic disease was present in 9.3%. Presentation at stage I occurred in 55.6%. Potentially curative surgical/interventional treatment was intended in 90.6%. Recurrence occurred in 6.6%, while death was recorded in 19.2%, with cancer-related deaths reaching 11.5%. The one- and three-year survival rates were 84.2% and 79%, respectively. Our two cases displayed negative HER2 expression. CONCLUSIONS: This systematic review demonstrates that this group of malignancies is very rare but possibly underdiagnosed. The disease commonly presents at early stage, mainly affecting middle-aged men. The prognosis is generally favourable even in cases of advanced disease. The HER2 expression and its correlation with the outcomes need to be further explored.

QTL mapping of melon fruit quality traits using a high-density GBS-based genetic map.

BACKGROUND: Melon shows a broad diversity in fruit morphology and quality, which is still underexploited in breeding programs. The knowledge of the genetic basis of fruit quality traits is important for identifying new alleles that may be introduced in elite material by highly efficient molecular breeding tools. RESULTS: In order to identify QTLs controlling fruit quality, a recombinant inbred line population was developed using two commercial cultivars as parental lines: "Védrantais", from the cantalupensis group, and "Piel de Sapo", from the inodorus group. Both have desirable quality traits for the market, but their fruits differ in traits such as rind and flesh color, sugar content, ripening behavior, size and shape. We used a genotyping-by-sequencing strategy to construct a dense genetic map, which included around five thousand variants distributed in 824 bins. The RIL population was phenotyped for quality and morphology traits, and we mapped 33 stable QTLs involved in sugar and carotenoid content, fruit and seed morphology and major loci controlling external color of immature fruit and mottled rind. The median confidence interval of the QTLs was 942 kb, suggesting that the high density of the genetic map helped in increasing the mapping resolution. Some of these intervals contained less than a hundred annotated genes, and an integrative strategy combining gene expression and resequencing data enabled identification of candidate genes for some of these traits. CONCLUSION: Several QTLs controlling fruit quality traits in melon were identified and delimited to narrow genomic intervals, using a RIL population and a GBS-based genetic map.

Clinical course after surgical treatment of active isolated native mitral valve endocarditis.

AIM: Isolated mitral valve endocarditis (MVE) forms a particular subgroup within native infective valve endocarditis (NVE). We characterized this particular subgroup and analyzed the course of patients undergoing cardiac surgery. METHODS: Between 1997 and 2011, 474 patients underwent cardiac surgery at our institution for NVE treatment. Of these, 89 patients (18.8%) suffered from MVE. Valve replacement was undertaken in 84.2% and valve repair in 15.8%. Follow-up was completed with 267 patient years. RESULTS: A delay between the onset of first symptoms and surgery of 4.7±1.2 weeks was observed. Hence, most patients were in a critical preoperative state characterized by severe sepsis and destruction of the mitral valve. About 19.4% were emergency procedures. The MVE group presented with a higher prevalence of preoperative stroke, atrial fibrillation, coronary artery disease and chronic obstructive pulmonary disease in comparison with remaining NVE cases. MVE was more likely caused by Staphylococcus aureus; Staphylococcus epidermidis and Staphylococcus viridans were less frequent (P<0.01 each). Early mortality (6.7%) was caused by persistent sepsis. ICU stay >7 days and time on artificial ventilation >40 h led to a higher risk of in-hospital death. Five-year survival was 59.6% and affected by extracardiac comorbidities. CONCLUSION: Isolated MVE was characterized by a long delay before surgery, differences in microbiological findings and a higher prevalence of preoperative strokes in comparison to NVE. Surgery for MVE can be conducted with good clinical results, but mid-term outcome is limited by extracardiac comorbidities.

Coronary surgery for acute coronary syndrome: which determinants of outcome remain?

BACKGROUND: The mortality risk associated with coronary artery bypass grafting (CABG) after acute myocardial infarction remains controversial. The objective of the present study was therefore to analyze the outcome and predictors of in-hospital mortality in patients (pts) referred to CABG with acute coronary syndrome (ACS). PATIENTS AND METHODS: Between January 2003 and May 2005, a total of 3,127 pts underwent primary isolated CABG at our institution, including 220 pts with ACS. Out of these, unstable angina pectoris was present in 88 pts (group I), 97 pts (group II) had non-ST-elevation infarction, whereas 35 pts (group III) had ST-elevation infarction. Clinical data, in-hospital morbidity and mortality were recorded and studied retrospectively. RESULTS: Overall in-hospital mortality was 6.4% (n = 14) in the complete cohort, being 2.2% in group I (n = 2), 9.2% in group II (n = 9) and 8.5% (n = 3) in group III (P < 0.05). Logistic regression and receiver operating characteristic analyses identified age, NYHA, ejection fraction < 45%, catecholamine support, cardiogenic shock, renal disease and the additive EuroSCORE > 10 (P < 0.0001) as significant predictors related to in-hospital mortality. The mean time from the onset of symptoms to revascularization differed significantly between survivors (5.1 +/- 2.7 h) and no survivors (11.4 +/- 3.2 h) (P < 0.0007) in the STEMI group. Preoperative cTnI did not provide any prognostic information. CONCLUSION: CABG in pts with ACS can be performed with good clinical results. The clinical outcome is particular depending on the different groups of ACS. Therefore an individual risk stratification of each pts in ACS is necessary. The time interval of 6 h seems to be crucial as prognostic variable in the STEMI-group.

Coronary artery bypass grafting in octogenarians--outcome with and without extracorporeal circulation.

Octogenarians are increasingly considered for coronary artery bypass grafting (CABG), but still represent a high-risk patient group with increased mortality and morbidity. In recent years off-pump surgery has been successfully established in CABG. The avoidance of extracorporeal circulation (ECC) seems to be of particular benefit for this patient group. We retrospectively analyzed our experience with CABG surgery with and without ECC in octogenarians to define the potential benefit of these different approaches in this high-risk group of patients. We analyzed the outcome after isolated CABG of 344 consecutive patients (219 male, 125 female, age: 82 +/- 2.4 years) who were aged 80 or older. Patients were divided into two groups according to the use of ECC. The on-pump group consisted of 237 patients (151 male, 86 female, 82 +/- 2.8 years) and the off-pump group consisted of 107 patients (68 male, 39 female, 82 +/- 1.9 years). The predicted EuroSCORE and EuroSCORE mortality risk were similar for both patient groups. The overall hospital mortality rate was 5.5 % (n = 17): 14 patients (5.9 %) in the on-pump group (n = 237, 100 %) and five patients (4.6 %) in the off-pump group (n = 107, 100 %). The average number of grafts in the on-pump group was 2.8 +/- 0.4 and it was 2.4 +/- 0.6 in the off-pump group ( P = 0.05). Morbidity was comparable in both groups. Significant variables in multivariate regression were preoperative atrial fibrillation ( P = 0.03; RR = 2.7), COPD ( P = 0.0001; RR = 6.5) and prolonged intubation ( P = 0.005; RR = 4.1). Isolated CABG in octogenarians can be performed with good clinical results, although a substantial mortality remains. The results of coronary surgery in this patient group with and without ECC are comparable with respect to mortality and morbidity.

Coronary surgery in dialysis-dependent patients with end-stage renal failure with and without extracorporeal circulation.

Coronary artery bypass grafting (CABG) in dialysis-dependent patients with end-stage renal failure (ESRF) has become the standard treatment for CAD in this patient group, but is still considered as a risk procedure due to the increased mortality and morbidity. The avoidance of extracorporeal circulation in dialysis-dependent patients seems to be an attractive alternative. This retrospective study analyzed and compared our experience with CABG surgery with and without extracorporeal circulation in dialysis-dependent patients with ESRF. We analyzed the clinical results of isolated CABG in 73 dialysis-dependent patients with ESRF with and without the use of extracorporeal circulation. The on-pump group consisted of 43 patients (7 female and 36 male, 65 +/- 7.3 years) and the off-pump group included 30 patients (4 female and 26 male, 67 +/- 7.2 years). Demographic and preoperative data were comparable in both groups. Overall hospital mortality rate was 4.2 % (n = 3), two patients (4.6 %) in the on-pump group and one patient (3.3 %) in the off-pump group died due to noncardiac reasons. Morbidity was comparable in both groups. The mean number of grafts was 3.1 +/- 0.9 in the on-pump group and 2.9 +/- 0.8 in the off-pump group. During follow-up, 13 patients (30.2 %) in the on-pump group died, nine of these patients (69.2 %) due to cardiac reasons; eight patients (26.7 %) in the off-pump group died, mostly due to cardiac reasons (n = 5, 62.5 %). CABG can be performed in patients with dialysis-dependent ESRF with good clinical results and low morbidity with two different surgical approaches. Midterm results are still affected by cardiac events.

Prosthetic valve endocarditis: importance of surgical treatment.

Surgical therapy of prosthetic valve endocarditis (PVE) is still associated with a high mortality of up to 80 %. Further risk analysis and characterization of clinical features are important for a further improvement of surgical results. The aim of this retrospective study was a risk analysis of clinical features of the pre-, intra-, and postoperative period. Between February 1998 and December 2004, 70 patients (52 male, 18 female, age 62 +/- 11 years) were referred to our institution for surgical therapy of PVE. This cohort included 16 patients with early PVE and 54 patients with late PVE. Preoperative, intraoperative and postoperative features were evaluated with respect to their influence on the early postoperative course and the midterm follow-up. The aortic valve was affected in 41 patients (58.6 %) and the mitral valve in 15 patients (21.4 %). Double valve infection was recorded in 14 patients (20.0 %). Staphylococci (n = 36, 51.4 %), Streptococci (n = 9, 12.9 %) and others (n = 24, 14.5 %) were identified as causative agents in blood cultures. The hospital mortality rate was 20.0 % (n = 14), during follow-up (mean follow up: 3.3 +/- 2.5 years), a further 11 patients (15.7 %) died, resulting in an overall mortality of 35.7 %. The main predictors for hospital mortality were preoperative heart failure ( P = 0.01) and Staphylococci infection ( P = 0.01). Predictors of overall mortality were Staphylococci infection ( P = 0.01), heart failure ( P = 0.02) and abscess formation ( P = 0.02). Surgical therapy of prosthetic valve endocarditis is still associated with quite a high mortality during the early and midterm follow-up. Predictors of outcome particularly include preoperative risk constellations (heart failure, Staphylococci infection).

Malplacement of a pacemaker lead--a rare cause for aortic valve endocarditis.

Infective endocarditis of native valves following pacemaker implantation is rare but can be associated with serious complications, approaching a mortality of up to 25%. Recent publications report a frequency of pacemaker related endocarditis between 0.5 and 7%. Due to anatomical reasons the tricuspid valve is mostly affected in these patients, with involvement of the left heart valves usually secondary. We report an incidence of native aortic valve endocarditis due to a misplaced pacemaker lead into the left heart.

Coronary reoperation with and without cardiopulmonary bypass.

Redo coronary artery bypass grafting (CABG) is still associated with increased morbidity and mortality compared to primary operation. Myocardial protection is one of the key issues in redo on pump CABG and is still a matter of debate. Off pump redo CABG seems to be an attractive alternative as native coronary blood flow remains and cross clamping of the aorta is avoided. The aim of this retrospective study was to compare the outcome of redo CABG with and without CPB. From 1/1998 to 5/2004 redo CABG was performed in 195 patients (pts): 162 male (83.1%) and 33 female (16.9%) pts, age 66 +/- 9 years. In 160 pts, CPB with isolated antegrade myocardial protection was used for redo CABG. Off pump redo CABG was performed in 35 pts (30 male (85.7%) and 5 female (14.3%), age 67 +/- 8 years). Perioperative overall mortality rate was 3.6% (n = 7) and comparable in both groups (on pump 3.8% versus off pump 2.9%; p = 0.90), as well as perioperative myocardial infarction, intraaortic balloon pump implantation rate and secondary morbidity. Complete revascularization was achieved in 139 pts (86.9%) after on pump CABG and in 17 pts (48.6%) of the off pump group (p < 0.01). The average number of grafts was significantly higher in the on pump group (2.8 +/- 0.78 versus 1.6 +/- 0.6; p = 0.04).Furthermore, 20 pts (12.5%) in the on pump group died during follow-up (50 +/- 16 months). Five pts (25.0%) died due to cardiac reasons. In the off pump group 3 pts (8.6%) died during follow-up (44 +/- 13 months), noncardiac related. Overall survival was 83.8% in the on pump group and 88.6% in the off pump group (p = 0.92). On pump redo CABG and off pump redo CABG can be safely performed with low mortality and morbidity. Off pump redo CABG might be limited due to incomplete revascularization.

The subjective image quality of conventional and digital panoramic radiography among 6 to 10 year old children.

OBJECTIVES: To compare the diagnostic quality of orthopantomographs made with the conventional unit Orthophos Siemens and the direct digital unit Planmeca 2000 cc Proline among children 6-10 years old and to investigate possible diferences on image interpretation between oral radiologists and pediatric dentists. METHODS: Study material included two independent groups of panoramic images (50 in each group) made with different panoramic modalities (digital conventional). Eight observers (four pediatric dentists and four oral radiologists) evaluated all images for diagnostic quality in 12 pre-determined areas using a 4-point rating scale. RESULTS: Digital and conventional panoramic radiography performed almost similarly as far as it concerns the specific diagnostic tasks rated with the exception of the interproximal contacts of mandibular molars where digital panoramic radiography was scored significantly higher and the periapical region of anterior mandible and anterior mandibular tooth germs where conventional panoramic radiography was found to be significantly better. Both oral radiologists and pediatric dentists graded similarly digital and conventional radiographs for a variety of diagnostic tasks. CONCLUSIONS: It can be concluded that diagnostic image quality obtained with the digital orthopantomograph unit Planmeca 2000 cc Proline was generally equal to image quality obtained with the conventional orthopantomograph unit Orthophos Plus CD. Image interpretation between oral radiologists and pediatric dentists was not substantially different

Coronary surgery in dialysis-dependent patients with end stage renal failure.

The number of patients with dialysis-dependent end stage renal failure (ESRF) and coronary heart disease (CAD) has increased in recent years. Coronary artery bypass grafting (CABG) has become the standard treatment for CAD in this patient group, but is still considered as a risk procedure due to increased mortality and morbidity. In a retrospective study we analyzed our clinical results of isolated CABG in 40 dialysis-dependent patients with ESRF (5 female and 35 male, mean age 65+/-8.4 years) and the use of extracorporeal circulation. The perioperative control group comprised 51 patients (10 female and 41 male, mean age 67+/-7.3 years) with normal renal function and isolated CABG. Demographic and preoperative data were comparable in both groups. Hospital mortality was 2.5% in patients with ESRF and 0% in patients with normal renal function. Morbidity was comparable in both groups. The mean number of grafts was 3.1+/-0.9 in the dialysis group and 2.9+/-0.8 in the control group. In the follow-up of the dialysis group (34+/-23 months) 8 patients died. CABG in patients with dialysis-dependent ESRF can be performed with good clinical results and morbidity comparable to patients with normal renal function.

[Surgical therapy of traumatic cardiologic intervention]. / Chirurgische Therapie nach traumatischen interventionellen Koronarläsionen.

Coronary perforation and entrapment of catheter materials are rare, but life-threatening complications, which often require emergency cardiosurgical treatment. Surgical options include tamponade drainage, coronary artery bypass grafting, perforation suturing, and removal of catheter materials. Surgical strategies are not standardized but mainly depend on the surgical anatomy. This is in particular true for the removal of the catheter remnants (stent, guidewire). Keeping this in mind, these patients can be treated with good clinical results.

Stimulation of pulmonary big endothelin-1 and endothelin-1 by antithrombin III: a rationale for combined application of antithrombin III and endothelin antagonists in sepsis-related acute respiratory distress syndrome?

OBJECTIVES: Antithrombin (AT) III reduces lung damage in animal models of septic acute respiratory distress syndrome (ARDS), which is generally attributed to stimulation of endothelial prostacyclin synthesis. However, clinical studies have failed so far to demonstrate mortality reduction by application of AT III. We investigated whether AT III stimulates pulmonary prostacyclin release. In addition, we hypothesized that it may promote pulmonary endothelins, thereby mitigating its own protective effect in the course of ARDS. DESIGN: Controlled experiment using isolated organs. SETTING: Experimental laboratory. SUBJECTS: Male Wistar rats. INTERVENTIONS: Isolated lungs were perfused over 120 mins in recirculatory mode in the presence of 50 microg/mL endotoxin (n = 11), 2U/mL AT III (n = 10), 5 U/mL AT III (n = 13), endotoxin plus 2 U/mL AT III (n = 5), or vehicle alone (controls, n = 13), respectively. MEASUREMENTS AND MAIN RESULTS: We determined the effects of AT III on vascular release of thromboxane B2, 6-keto-prostaglandin-F1alpha, big endothelin-1, and endothelin-1. Control lungs released 59+/-23 pg/mL thromboxane B2, 1,480+/-364 pg/mL 6-keto-prostaglandin-F1alpha, 15.2+/-4.5 pg/mL big endothelin-1, and 0.46+/-0.13 pg/mL endothelin-1. Exposure to endotoxin increased thromboxane B2 release 2.9-fold, 6-keto-prostaglandin-F1alpha release 1.6-fold, and endothelin-1 1.6-fold (p < .05 each); levels of big endothelin-1 were unchanged. AT III at 2 U/mL elevated production of big endothelin-1 (1.7-fold) and endothelin-1 (1.2-fold) (p < .05 for both). AT III at 5 U/mL enhanced levels of big endothelin-1 (1.6-fold) and endothelin-1 (1.3-fold) (p < .05 for both). Neither dose of AT III affected thromboxane B2 or 6-keto-prostaglandin-F1alpha concentrations. Application of 2 U/mL AT III plus endotoxin stimulated big endothelin-1 production (2.6-fold) compared with endotoxin or AT III alone (p < .05 for both), but did not further elevate endothelin-1 release. CONCLUSIONS: AT III does not stimulate pulmonary prostacyclin, but promotes pulmonary release of big endothelin-1 and endothelin-1 under basal and, particularly, under septic conditions, which may blunt the AT III-induced lung protection during ARDS. Therefore, we suggest combined application of AT III and endothelin antagonists in animal models of septic ARDS.

Antithrombin increases pulmonary endothelins: inhibition by heparin and Ca2+ channel antagonism.

We investigated the mechanism of antithrombin III-induced vascular release of endothelins in rat isolated lung. The antithrombin III-stimulated release of big endothelin-1 and endothelin-1 (1.7-fold and 1.3-fold over baseline) was abolished by nicardipine (L-type Ca2+ channel blocker), heparin, and N-acetyl heparin (a derivative devoid of antithrombin affinity), whereas staurosporine and genistein (inhibitors of protein kinase C and tyrosine kinase, respectively) were ineffective. Thus, (i) the antithrombin III-induced release of endothelins requires extracellular Ca2+, but not protein kinase C or tyrosine kinase activation, and (ii) heparin binding to antithrombin III is not necessary for its inhibitory effect.

Arrhythmogenic effects induced by coronary conversion of pulmonary big endothelin to endothelin: aggravation of this phenomenon in heritable hyperlipidemia.

OBJECTIVES: We investigated whether endogenous pulmonary big endothelin has arrhythmogenic properties under normal conditions and in heritable hyperlipidemia. BACKGROUND: Endothelin (ET), one of the most potent vasoconstrictors, is known to induce ventricular arrhythmias. It is unclear, however, whether its precursor, big endothelin, released from the lung, contributes to arrhythmogenesis. METHODS: In a lung-heart model in which a Langendorff heart is serially perfused with the effluent from the isolated lung of the same animal, we evaluated arrhythmias in control and in Watanabe heritable hyperlipidemic (WHHL) rabbits. RESULTS: In both controls (n=12) and WHHL (n=8), serial perfusion evoked a decrease in coronary flow (controls, -11+/-3%; WHHL, -25+/-6%) and a fourfold increase of ventricular extrasystoles (VES) (controls, 40.7+/-8; WHHL, 40.2+/-5 VES/40 min, p < 0.05). However, WHHL developed more and longer nonsustained ventricular tachycardias (VT) compared with controls (incidence, 1.38+/-1.1 vs. 0.33+/-0.5 VT/40 min, p < 0.05; length, 14.36+/-3.1 vs. 7.25+/-1.5 beats/VT, p < 0.05). Arrhythmias were not ischemia-induced because corresponding mechanical flow reduction had no arrhythmogenic effect (n=6 in controls and WHHL). Although vasoconstriction disappeared entirely, arrhythmias were only partly suppressed by ET(A) antagonists (BQ-123, 2 micromol/liter; A-127722, 20 micromol/liter). The ET-converting enzyme inhibitor phosphoramidon (50 micromol/liter) completely suppressed arrhythmias and vasoconstriction. The ET(B) antagonists (IRL-1038, 4 micromol/liter; IRL-1025, 5 micromol/liter) had no effect (n=6). CONCLUSIONS: Endogenous pulmonary big ET produces arrhythmogenic effects that are aggravated in heritable hyperlipidemia. These effects, requiring coronary conversion of big ET into ET, are partly ET(A)-mediated and ET(B)-independent.

Coronary constriction and consequent cardiodepression in pulmonary embolism are mediated by pulmonary big endothelin and enhanced in early endothelial dysfunction.

OBJECTIVES: Myocardial ischemia plays a central role in the development of right ventricular failure after acute pulmonary embolism. This study investigates whether pulmonary mediators act specifically on coronary tone and cardiac contractile function in acute pulmonary microembolization and whether such effects are altered in the case of early systemic atherosclerosis. We employ a novel model of serial perfusion in which an isolated rabbit heart is perfused with the effluent of the same animal's isolated lung. DESIGN: Controlled experiment using isolated organs. SETTING: Experimental laboratory. SUBJECTS: Male New Zealand White rabbits (controls). Age-matched, male Watanabe rabbits (hypercholesterolemic, development of accelerated atherosclerosis). INTERVENTIONS: Seven isolated control and seven isolated Watanabe hearts were perfused with the saline effluent of the same animal's isolated lung. After the assessment of the baseline data, the lungs were gradually embolized with glass beads measuring 100 microm in diameter to induce an increase in mean pulmonary arterial pressure from 6 to 8 mm Hg, at baseline, up to 25 mm Hg. MEASUREMENTS AND MAIN RESULTS: Pulmonary embolization to 25 mm Hg evoked a coronary constriction, measured as coronary flow decrease to 89 +/- 7% of the baseline value in controls. In the Watanabe group, coronary constriction was significantly enhanced, compared with controls, with coronary flow decreasing to 76 +/- 6% of the baseline value. In both groups, coronary constriction was followed by a deterioration in cardiac contractile performance. This cardiodepression was significantly deeper in Watanabe hearts with respect to both maximum ventricular pressures and maximum rates of pressure development and decline. Coronary constriction and cardiodepression were prevented by coronary infusion of the nonselective endothelin antagonist PD-145065, the endothelinA antagonists A-127722 and BQ-123, and the endothelin-converting enzyme inhibitor phosphoramidon. Concentration of big endothelin in pulmonary effluent increased from 5.6 +/- 0.3 pmol/L in controls and 5.6 +/- 0.2 pmol/L in the Watanabe group, at baseline, to 8.8 +/- 0.4 pmol/L in controls and 8.9 +/- 0.4 pmol/L in the Watanabe group, at 25 mm Hg pulmonary arterial pressure. Endothelin was not detectable at any time during the experiment in pulmonary effluent. The coronary gradient, calculated as a difference in concentration between coronary and pulmonary effluent, was negative for big endothelin and positive for endothelin in both groups. CONCLUSIONS: We have demonstrated that an increase in pulmonary release of big endothelin occurs during lung embolism, which, in turn, results in coronary constriction and consequent cardiodepression. This action of big endothelin is based on its local coronary conversion into endothelin. In addition, coronary endothelial dysfunction, attributed to early systemic atherosclerosis, was shown to represent a specific risk factor in these events.

Pulmonary big endothelin affects coronary tone and leads to enhanced, ET(A)-mediated coronary constriction in early endothelial dysfunction.

BACKGROUND: Lung tissue produces a variety of mediators; however, little is known regarding how these mediators affect coronary regulation and myocardial contractility. In a novel rabbit lung-heart model, we investigated the possible influence exerted by pulmonary mediators on coronary tone both under normal conditions and in early endothelial dysfunction. METHODS AND RESULTS: In our model, the effluent from the isolated lung is used to serially perfuse the coronary vessels of the isolated heart of the same animal. Compared with the hearts of control rabbits, isolated hearts of Watanabe rabbits revealed pharmacological evidence of endothelial dysfunction and a significant steeper decrease of coronary flow during serial perfusion of the coronary vessels with lung effluent (75+/-6% versus 89+/-3%). This decline in coronary flow was prevented by the nonselective endothelin (ET) antagonist PD-145065, the ET(A) antagonists BQ-123 and A-127722, and the endothelin-converting enzyme inhibitor phosphoramidon. The concentration of big ET in lung effluent ranged from 5.5 to 5.8 pmol/L in both control and Watanabe groups, with levels in corresponding coronary effluent falling to 0.9 to 1.1 pmol/L in controls and to 1.0 to 1.2 pmol/L in the Watanabe group. In either group, ET was not detected in lung effluent, but it rose significantly in coronary effluent during serial perfusion. CONCLUSIONS: Pulmonary big ET, locally converted into ET during coronary passage, causes an ET(A)-mediated elevation in coronary tone under basal conditions as well as an enhanced coronary constriction when early endothelial dysfunction is present.