Pulmonary Endarterectomy Surgery for Chronic Thromboembolic Pulmonary Hypertension: A Small-Volume National Referral Center Experience.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, distinct pulmonary vascular disease, which is caused by chronic obstruction of major pulmonary arteries. CTEPH can be cured by pulmonary endarterectomy (PEA). PEA for CTEPH is a challenging procedure, and patient selection and the perioperative management are complex, requiring significant experience. OBJECTIVES: To describe the establishment of a national CTEPH-PEA center in Israel and present results of surgery. METHODS: In this study, we reviewed the outcomes of PEA in a national referral, multi-disciplinary center for CTEPH-PEA. The center was established by collaborating with a high-volume center in Europe. A multidisciplinary team from our hospital (pulmonary hypertension specialist, cardiac surgeon, cardiac anesthesiologist and cardiac surgery intensivist was trained under the guidance of an experienced team from the European center. RESULTS: A total of 38 PEA procedures were performed between 2008 and 2018. We included 28 cases in this analysis for which long-term follow-up data were available. There were two hospital deaths (7%). At follow-up, median New York Heart Association (NYHA) class improved from III to I (P < 0.0001), median systolic pulmonary pressure decreased from 64 mmHg to 26 mmHg (P < 0.0001), and significant improvements were seen in right ventricular function and exercise capacity. CONCLUSIONS: A national center for performance of a rare and complex surgical procedure can be successfully established by collaboration with a high-volume center and by training a dedicated multidisciplinary team.

Presepsin and Inflammatory Markers Correlate With Occurrence and Severity of Nonocclusive Mesenteric Ischemia After Cardiovascular Surgery.

OBJECTIVES: To prospectively evaluate the relationship of established inflammatory markers and presepsin on nonocclusive mesenteric ischemia and to correlate presepsin levels to the occurrence and severity of nonocclusive mesenteric ischemia. DESIGN: Patients were prospectively enrolled and blood samples taken, followed by a retrospective evaluation of laboratory values and angiographic findings. The study was ethics committee approved. SETTINGS: Patients with clinical suspicion of nonocclusive mesenteric ischemia underwent catheter angiography of the superior mesenteric artery. Images were assessed by two experienced radiologists on consensus basis using a previously published standardized reporting system (Homburg-Nonocclusive Mesenteric Ischemia-Score). Two groups were formed according to the severity of nonocclusive mesenteric ischemia, mild and severe, patients without clinical signs of nonocclusive mesenteric ischemia formed the reference group. These data were correlated to inflammatory blood markers assessed pre- and postoperatively: C-reactive protein, leucocytes, procalcitonin, and presepsin as well as outcome data. PATIENTS: Between January 2010 and March 2011, a total of 839 patients undergoing cardiovascular surgery participated in this study. MEASUREMENTS AND MAIN RESULTS: Mild nonocclusive mesenteric ischemia was diagnosed in 4.5%, and severe nonocclusive mesenteric ischemia in 3.2%. Median postoperative presepsin concentrations were significantly greater in mild and severe nonocclusive mesenteric ischemia than in non-nonocclusive mesenteric ischemia. Statistics showed that postoperative presepsin better discriminated mild and severe nonocclusive mesenteric ischemia than any other tested biomarker. CONCLUSIONS: Elevated postoperative plasma presepsin concentrations are an independent predictor of mild and severe nonocclusive mesenteric ischemia. The established inflammatory blood markers significantly correlate with the development and severity of nonocclusive mesenteric ischemia.

Functional Characterization of Patients with Chronic Thromboembolic Disease.

BACKGROUND: Patients with chronic thromboembolic pulmonary disease (CTED) have persistent pulmonary vascular obstruction and exercise intolerance without pulmonary hypertension at rest and may benefit from pulmonary endarterectomy. However, up to now, CTED has been poorly characterized. OBJECTIVES: This study aimed to analyze the exercise capacity and limiting factors in CTED. METHODS: We compared right heart catheterization and cardiopulmonary exercise test results of patients with CTED [mean pulmonary artery pressure (mPAP) at rest <25 mm Hg, n = 10], chronic thromboembolic pulmonary hypertension (CTEPH, n = 31) and a control group (n = 41) presenting with dyspnea but normal pulmonary vascular imaging and excluded pulmonary hypertension. RESULTS: Subjects with CTED show a reduced oxygen uptake [median 76/interquartile range (IQR) 22% pred.] and work rate (median 76/IQR 21 W). The work rate was significantly lower compared to control subjects (p = 0.04) but not significantly different from CTEPH patients (p = 0.66). Oxygen pulse and breathing reserve were normal. CTED subjects showed decreased end-tidal CO2 at anaerobic threshold (28.4/4.3 mm Hg), an elevated VE/VCO2 slope (42.5/23.5), breathing equivalents (EQO2 32.0/8.7, EQCO2 39.5/8.8), alveolar-capillary oxygen gradient (34.7/15.5 mm Hg) and capillary end-tidal carbon dioxide gradient (8.8/5.7 mm Hg) compared to control subjects (p < 0.001). The degree of limitation was similar to that in CTEPH. CONCLUSIONS: Despite an mPAP of <25 mm Hg, subjects with CTED show objective functional impairment and similar limitations to patients with CTEPH. Functional limitation is characterized by gas exchange disturbance and ineffective ventilation.

A single preoperative FGF23 measurement is a strong predictor of outcome in patients undergoing elective cardiac surgery: a prospective observational study.

INTRODUCTION: Several scoring systems have been developed to predict postoperative mortality and complications in patients undergoing cardiac surgery. However, these computer-based calculations are time- and cost-intensive. A simple but highly predictive test for postoperative risk would be of clinical benefit with respect to increasingly scarce hospital resources. We therefore assessed the predictive power of fibroblast growth factor 23 (FGF23) measurement compared with an established scoring system. METHODS: We conducted a prospective interdisciplinary observational study at the Saarland University Medical Centre that included 859 patients undergoing elective cardiac surgery between January 2010 and March 2011 with a median follow-up after discharge of 822 days. We compared a single preoperative measurement of FGF23 as a prognostic tool with the 18 parameters comprising EuroSCORE II with respect to postoperative mortality, acute kidney injury, non-occlusive mesenteric ischemia, clinical course and long-term outcome. RESULTS: Preoperative FGF23 levels were highly predictive of postoperative outcome and complications. The predictive value of FGF23 for mortality in the receiver operating characteristic curve was greater than the EuroSCORE II (area under the curve: 0.800 versus 0.725). Moreover, preoperative FGF23 independently predicted postoperative acute kidney injury and non-occlusive mesenteric ischemia comparably to the EuroSCORE II. Finally, FGF23 was found to be an independent predictor of clinical course parameters, including duration of surgery, ventilation time and length of stay. CONCLUSIONS: In patients undergoing elective cardiac surgery, a simple preoperative FGF23 measurement is a powerful indicator of surgical mortality, postoperative complications and long-term outcome. Its utility compares to the widely used EuroSCORE II.

Human BIN1 isoforms grow, maintain, and regenerate excitation-contraction couplons in adult rat and human stem cell-derived cardiomyocytes.

AIMS: In ventricular myocytes, transverse-tubules (T-tubules) are instrumental for excitation-contraction (EC)coupling and their disarray is a hallmark of cardiac diseases. BIN1 is a key contributor to their biogenesis. Our study set out to investigate the role of human BIN1 splice variants in the maintenance and regeneration of EC-coupling in rat adult ventricular myocytes and human-induced pluripotent stem cell-derived cardiac myocytes (hiPS-CMs). METHODS AND RESULTS: In heart samples from healthy human donors expression patterns of five BIN1 splice variants were identified. Following viral transduction of human BIN1 splice variants in cellular models of T-tubular disarray, we employed high-speed confocal calcium imaging and CaCLEAN analysis to identify functional EC-coupling sites (couplons) and T-tubular architecture. Adult rat ventricular myocytes were used to investigate the regeneration after loss and maintenance of EC-coupling while we studied the enhancement of EC-coupling in hiPS-CMs. All five human BIN1 splice variants induced de-novo generation of T-tubules in both cell types. Isoforms with the phosphoinositide-binding motif (PI) were most potent in maintenance and regeneration of T-tubules and functional EC-coupling in adult rat myocytes. In hiPSC-CMs, BIN1 variants with PI-motif-induced de novo generation of T-tubules, functional couplons and enhanced calcium handling. CONCLUSION: BIN1 is essential for the maintenance, regeneration, and de novo generation of functional T-tubules. Isoforms with PI-motifs appeared as particulalrly potent. These T-tubules trigger the development of functional couplons resulting in enhanced calcium handling.

Assessment of left ventricular dyssynchrony and function using real-time 3-dimensional echocardiography in patients with congenital right heart disease.

BACKGROUND: Patients after repair of congenital right heart disease (CRHD) may exhibit left ventricular (LV) dyssynchrony (LVD). However, the diagnosis of LVD is difficult and its reliability limited because current methods do not assess LVD of the whole LV simultaneously. The aim of the study was to assess LVD according to a novel global systolic dyssynchrony index (SDI) derived from real-time 3-dimensional echocardiography in patients after repaired CRHD. METHODS: Two-dimensional echocardiography and real-time 3-dimensional echocardiography were performed in 30 patients after CRHD repair and in 30 matched healthy controls. Real-time 3-dimensional echocardiography data sets provided time-volume curves, and 2 global SDIs were derived from the dispersion of time to reach minimal systolic volume according to a 16- or 17-LV segment model. RESULTS: Both SDIs were significantly elevated in the patient as compared with the control group (P < .001). A cutoff value for both SDIs was calculated and LVD defined as one of the SDIs exceeding cutoff. Left ventricular dyssynchrony was present in 5 (100%) of 5 patients with a LV ejection fraction (EF) <50% and 13 (52%) of 25 patients with preserved LVEF, thus being diagnosed in a total of 18 (60%) of 30 patients. Moreover, patients with LVD showed a significantly higher degree of pulmonary regurgitation (P = .01) with elevated right ventricular volumes and altered septal motion. Stepwise multivariate analysis identified LVEF (P = .005) and the degree of pulmonary regurgitation (P = .02) as independent predictors of LVD. CONCLUSIONS: Left ventricular dyssynchrony can be detected in about 60% of patients after CRHD repair and is mainly due to significant pulmonary regurgitation resulting in an altered septal motion and systolic LV function.

18F-FDG PET for mediastinal staging of lung cancer: which SUV threshold makes sense?

UNLABELLED: (18)F-FDG PET is the most accurate noninvasive modality for staging mediastinal lymph nodes in lung cancer. Besides using visual image interpretation, some institutions use standardized uptake value (SUV) measurements in lymph nodes. Mostly, an SUV of 2.5 is used as the cutoff, but this choice was never deduced from respective studies. Receiver operating characteristic (ROC) analyses demonstrated that SUV thresholds of more than 4 resulted in the highest accuracy. But these high cutoffs imply high false-negative rates (FNRs). The aim of our evaluation was to determine an optimal SUV threshold and to compare its diagnostic performance with the results of visual interpretation. METHODS: This retrospective study included 95 patients with suspected lung cancer who underwent mediastinoscopy/mediastinal lymphadenectomy after (18)F-FDG PET (90-150 min after 250 MBq of (18)F-FDG). Maximum SUV was measured in 371 lymph node regions biopsied afterward and visually interpreted using a 6-level score (- - - through + + +). Diagnostic performance was assessed by ROC analysis. FNR and false-positive rate (FPR), the sum of both error rates (FNR + FPR), and diagnostic accuracy were plotted against a hypothetical SUV threshold to determine the optimum SUV threshold. RESULTS: SUVs in metastatic lymph nodes were higher (mean +/- SD, 7.1 +/- 4.5; range, 1.4-26.9; n = 70) than in tumor-free lymph node stations (2.4 +/- 1.7; range, 0.6-14.9; n = 301; P < 0.01). Inflammatory lymph nodes exhibited slightly increased SUVs (2.7 +/- 2.0; range, 0.8-14.9; n = 146). The plot of error rates featured a minimum of the sum FNR + FPR for an SUV of 2.5. With increasing SUV threshold, the FPR decreased most prominently up to that value whereas a continuous rise of FNR was noticed. Highest diagnostic accuracy was achieved with an SUV of 4.5. The areas under the ROC curves demonstrated that visual interpretation tends to be more accurate than SUV quantification (visual, 0.930 +/- 0.022; SUV, 0.899 +/- 0.025; P = 0.241). Using an SUV of 2.5 as the threshold, the resulting sensitivity, specificity, and negative predictive value were 89%, 84%, and 96%, respectively. CONCLUSION: For mediastinal staging, the choice of an SUV of 2.5 as the threshold is justified because FNR + FPR is minimized. The resulting high negative predictive value of 96% allows the omission of mediastinoscopy in patients with negative mediastinal findings on (18)F-FDG PET images. For the experienced observer, visual analysis should be relied on primarily, with calculation of the SUV used, at most, as a secondary aid. For the less experienced observer, the SUV may be of greater value.

Occurrence and severity of non-occlusive mesenteric ischemia (NOMI) after cardiovascular surgery correlate with preoperatively assessed FGF-23 levels.

PURPOSE: To evaluate the value of preoperatively assessed fibroblast growth factor 23 (FGF-23) levels and to correlate FGF-23 with angiographic findings in non-occlusive mesenteric (NOMI) ischemia using a standardized scoring system. MATERIALS AND METHODS: Between 2/2011 and 3/2012 a total of 865 patients (median age: 67 years) underwent cardiovascular surgery during this ethics committee approved, prospective study. 65 of these patients had clinical suspicion of NOMI and consequently underwent catheter angiography of the superior mesenteric artery. Images were assessed using a standardized reporting system (Homburg-NOMI-Score). These data were correlated to following preoperative parameters of kidney function: cystatin C, creatinine, FGF-23 and estimated glomerular filtration rate (eGFR), and outcome data (death, acute renal failure) using linear and logistic regressions, as well as nonparametric tests. RESULTS: Significant correlations were found between FGF-23 and the angiographic appearance of NOMI (p = 0.03). Linear regression analysis showed no significant correlation to the severity of NOMI with creatinine (p = 0.273), cystatin C (p = 0.484), cystatin C eGFR (p = 0.914) and creatinine eGFR (p = 0.380). Logistic regression revealed a significant correlation between death and the Homburg-NOMI-Score (p<0.001), but not between development of NOMI and acute renal failure (p = 0.122). The ROC Analysis yielded an area under the curve of 0.695 (95% CI: 0.627-0.763) with a sensitivity of 0.672 and specificity of 0.658. CONCLUSIONS: FGF-23 significantly correlates with the severity of NOMI, which is in contrast to other renal function parameters. The applied scoring system allows to predict mortality in NOMI patients.

Toward a more complete recognition of immunoreactive antigens in squamous cell lung carcinoma.

There is very limited knowledge about the antibody response against tumor-expressed antigens in lung cancer. To arrive at a more complete picture of lung cancer antigens, we generated 2 cDNA libraries from squamous cell lung carcinoma and isolated 15 immunogenic antigens using autologous sera. Among the antigens most frequently identified were the lymphoid blast crisis oncogene (LBC), an unknown hypothetical protein and the p53-binding protein (TP53 BP), which have already been associated with tumor development. Of the immunogenic antigens, 6 map to chromosomes that are frequently altered in squamous cell lung carcinoma. SEREX database analysis showed that 7 of the identified immunogenic antigens have been associated with the humoral immune response in other human tumors. Screening with heterologous sera of patients with lung carcinoma identified 4 antigens, including human protein kinase C and TP53 BP, which have also been found by autologous screening. Only 1 of the 15 identified antigens reacted with any of the 36 control sera, which were taken from individuals without known disease. Sera from adenocarcinoma and large cell carcinoma of the lung were not reactive for the antigens. In summary, using 2 newly established cDNA libraries, we isolated 15 novel antigens, which were subsequently evaluated for the frequency of their corresponding antibodies in autologous, normal and heterologous sera; their chromosomal localization; and their correlation with survival after surgery.