Signaling mechanisms inducing hyporesponsiveness of phagocytes during systemic inflammation.

The inflammatory responsiveness of phagocytes to exogenous and endogenous stimuli is tightly regulated. This regulation plays an important role in systemic inflammatory response syndromes (SIRSs). In SIRSs, phagocytes initially develop a hyperinflammatory response, followed by a secondary state of hyporesponsiveness, a so-called "tolerance." This hyporesponsiveness can be induced by endotoxin stimulation of Toll-like receptor 4 (TLR4), resulting in an ameliorated response after subsequent restimulation. This modification of inflammatory response patterns has been described as innate immune memory. Interestingly, tolerance can also be triggered by endogenous TLR4 ligands, such as the alarmins myeloid-related protein 8 (MRP8, S100A8) and MRP14 (S100A9), under sterile conditions. However, signaling pathways that trigger hyporesponsiveness of phagocytes in clinically relevant diseases are only barely understood. Through our work, we have now identified 2 main signaling cascades that are activated during MRP-induced tolerance of phagocytes. We demonstrate that the phosphatidylinositol 3-kinase/AKT/GSK-3ß pathway interferes with NF-κB-driven gene expression and that inhibition of GSK-3ß mimics tolerance in vivo. Moreover, we identified interleukin-10-triggered activation of transcription factors STAT3 and BCL-3 as master regulators of MRP-induced tolerance. Accordingly, patients with dominant-negative STAT3 mutations show no tolerance development. In a clinically relevant condition of systemic sterile stress, cardiopulmonary bypass surgery, we confirmed the initial induction of MRP expression and the tolerance induction of monocytes associated with nuclear translocation of STAT3 and BCL-3 as relevant mechanisms. Our data indicate that the use of pharmacological JAK-STAT inhibitors may be promising targets for future therapeutic approaches to prevent complications associated with secondary hyporesponsiveness during SIRS.

FDG-PET proves to be reliable in the diagnostic workup of a rare cardiac hemangioma.

The noninvasive characterization of cardiac tumors is of clinical importance for surgical resection planning. Conventional radiological examinations like cardiac computed tomography (CT) or magnetic resonance imaging (MRI) may be misleading as benign cardiac lesions can present features suspicious for malignancy. Moreover, the low prevalence of cardiac tumors may additionally hamper a sound diagnosis. However, fluorodeoxyglucose-positron emission tomography (FDG-PET) has proven to be a reliable tool for cardiac tumor characterization. Here, FDG-PET/CT imaging of a 50-year-old man suffering from a cardiac tumor is presented. Despite CT and MRI signs of malignancy, FDG-PET characterized the tumor as benign. Histology confirmed the FDG-PET prediction and revealed a pericardial capillary hemangioma. Thereby, it seems important to integrate FDG-PET in the diagnostic workup of cardiac tumors.

Postoperative Complications and Long-Term Results after Primary Cardiac Sarcoma Resection.

BACKGROUND: Primary malignant cardiac tumors rarely occur in clinical care. Little is known about the impact of a parameter on postoperative survival. METHODS: From May 1991 to May 2014, a total of 24 patients underwent surgical treatment of a primary cardiac sarcoma in our center. We analyzed our clinical database retrospectively for information on patient characteristics and treatment data. The follow-up could be completed to 91.7%. RESULTS: Angiosarcoma and non-otherwise-specified sarcoma were the most common tumor entities. R0 resection was achieved in most cases. Postoperative mortality within the first 30 days was 20.8% (n = 5). In four of these five cases, postoperative low-output cardiac failure was the leading cause of death. The cumulative survival rate was 77.3% after 30 days, 68.2% after 3 months, 50.0% after 6 months, 45.0% after 12 months, and 18.0% after 24 months. The mean survival time in the whole group was 47.0 months. A low tumor differentiation was associated with low mean survival, but this was not statistically significant. Mean survival of sarcoma was higher after R0 resection. There was no significant rate of survival difference regarding the adjuvant therapy concept. CONCLUSION: Extended surgery alone or in combination with chemo- and/or radiotherapy may be successful in certain cases and may offer a satisfactory quality of life. The establishment of a multicenter heart tumor register in Germany is necessary to increase the number of cases in studies, get more remarkable study results, and standardize the diagnosis and therapy.

Minimally Invasive Implantation of HeartWare Assist Device and Simultaneous Tricuspid Valve Reconstruction Through Partial Upper Sternotomy.

Left ventricular assist device (LVAD) implantation is a well-established therapy to support patients with end-stage heart failure. However, the operative procedure is associated with severe trauma. Third generation LVADs like the HeartWare assist device (HeartWare, Inc., Framingham, MA, USA) are characterized by enhanced technology despite smaller size. These devices offer new minimally invasive surgical options. Tricuspid regurgitation requiring valve repair is frequent in patients with the need for mechanical circulatory support as it is strongly associated with ischemic and nonischemic cardiomyopathy. We report on HeartWare LVAD implantation and simultaneous tricuspid valve reconstruction through minimally invasive access by partial upper sternotomy to the fifth left intercostal space. Four male patients (mean age 51.72 ± 11.95 years) suffering from chronic heart failure due to dilative (three patients) and ischemic (one patient) cardiomyopathy and also exhibiting concomitant tricuspid valve insufficiency due to annular dilation underwent VAD implantation and tricuspid valve annuloplasty. Extracorporeal circulation was established via the ascending aorta, superior vena cava, and right atrium. In all four cases the LVAD implantation and tricuspid valve repair via partial median sternotomy was successful. During the operative procedure, no conversion to full sternotomy was necessary. One patient needed postoperative re-exploration because of pericardial effusion. No postoperative focal neurologic injury was observed. New generation VADs are advantageous because of the possibility of minimally invasive implantation procedure which can therefore minimize surgical trauma. Concomitant tricuspid valve reconstruction can also be performed simultaneously through partial upper sternotomy. Nevertheless, minimally invasive LVAD implantation is a challenging operative technique.

Economic aspects of long-term left ventricular assist device treatment for chronic heart failure.

AIMS: Technological advances and the current shortage of donor organs have contributed to an increase in the number of left ventricular assist device (LVAD) implantations in patients with end-stage heart failure. Demographic change and medical progress might raise the number of these patients, resulting in a further increase in the number of LVAD implantations. The aim of this study was to evaluate the long-term costs of LVAD therapy and identify diagnoses resulting in expensive stays. METHODS AND RESULTS: In this retrospective analysis of prospectively collected data, all patients after implantation of a second- or third-generation LVAD by 31 March 2022 were included. In addition to demographic and survival data, revenues and case mix points were determined for each patient. Of the 163 patients included, 75.5% were male. The mean age at LVAD implantation was 52 ± 14 years. The mean survival was 1458 ± 127 days. During follow-up, the total inpatient treatment time per patient was 70 ± 87 days. The average duration of outpatient treatment was 55.1%, based on the total duration of support. The average revenue per patient for the implant stay was $193 192.35 ± $111 801.29, for inpatient readmissions $52 068.96 ± $116 630.00, and for outpatient care $53 195.94 ± $62 363.53. CONCLUSIONS: LVAD implantation in patients with end-stage heart failure leads to improved survival but a significant increase in treatment costs. Further multi-centre studies are necessary in order to be able to assess the effects of long-term LVAD treatment on the healthcare system.

Heart transplantation surgery in children and young adults with congenital heart disease.

BACKGROUND: Pediatric cardiac transplantation remains a surgical challenge as a variety of cardiac and vessel malformation are present in patients with congenital heart disease (CHD). Despite limited availability and acceptability of donor hearts, the number of heart transplantations remains on a stable level with improved survival and quality of life. OBSERVATION: As treatment options for CHD continue to improve and the chances of survival increase, more adult CHD patients are listed for transplantation. This review focuses on the clinical challenges and modified techniques of pediatric heart transplantations. CONCLUSION: Not only knowledge of the exact anatomy, but above all careful planning, interdisciplinary cooperation and surgical experience are prerequisites for surgical success.

Do the age of patients with tetralogy of fallot at the time of surgery and the applied surgical technique influence the reoperation rate? a single-center experience.

BACKGROUND AND PURPOSE: Primary repair of tetralogy of Fallot (TOF) has been favored in many centers for years now and results and advantages of this management seem to verify this procedure. The authors wanted to know, if the age at the time of surgery and the surgical techniques had an influence on the long-term results. PATIENTS AND METHODS: Between 1992 and 2003, 124 patients underwent complete repair of TOF at the University Hospital Münster, Germany. Patients were subdivided into two groups based on their age (< 1 year and > 1 year of age). Patients in whom a transannular patch (TAP) was used were compared with those without (NTAP), or in whom a conduit was used. RESULTS: Overall mortality was 8%, with an average age of death of 9.53 years (range 0.06-19.77 years). The patients' age at the time of surgery affected their survival as only two cases of death were reported among the group of children < 1 year of age (3.2%) whereas eight patients were older (12.9%; p = 0.0483). Six patients died within the first 30 days post surgery. Reoperation had to be performed in 21 cases, 13 (61.9%) of these patients were < 1 year of age at the time of surgery, eight were older (38.1%). A TAP, NTAP or conduit treatment did not show significant differences in long-term survival or freedom from reoperation. CONCLUSION: Early repair of TOF within the 1st year of life can be recommended, because mortality is lower than in patients treated at a higher age. There seems no significant difference in the reintervention rate between patients treated within the 1st year of life or later.

The Transcription Factor ATF4 Promotes Expression of Cell Stress Genes and Cardiomyocyte Death in a Cellular Model of Atrial Fibrillation.

INTRODUCTION: Cardiomyocyte remodelling in atrial fibrillation (AF) has been associated with both oxidative stress and endoplasmic reticulum (ER) stress and is accompanied by a complex transcriptional regulation. Here, we investigated the role the oxidative stress and ER stress responsive bZIP transcription factor ATF4 plays in atrial cardiomyocyte viability and AF induced gene expression. METHODS: HL-1 cardiomyocytes were subjected to rapid field stimulation. Forced expression of ATF4 was achieved by adenoviral gene transfer. Using global gene expression analysis and chromatin immunoprecipitation, ATF4 dependent transcriptional regulation was studied, and tissue specimen of AF patients was analysed by immunohistochemistry. RESULTS: Oxidative stress and ER stress caused a significant reduction in cardiomyocyte viability and were associated with an induction of ATF4. Accordingly, ATF4 was also induced by rapid field stimulation mimicking AF. Forced expression of wild type ATF4 promoted cardiomyocyte death. ATF4 was demonstrated to bind to the promoters of several cell stress genes and to induce the expression of a number of ATF4 dependent stress responsive genes. Moreover, immunohistochemical analyses showed that ATF4 is expressed in the nuclei of cardiomyocytes of tissue specimen obtained from AF patients. CONCLUSION: ATF4 is expressed in human atrial cardiomyocytes and is induced in response to different types of cell stress. High rate electrical field stimulation seems to result in ATF4 induction, and forced expression of ATF4 reduces cardiomyocyte viability.

Intraindividual comparison of 3D coronary MR angiography and coronary CT angiography.

RATIONALE AND OBJECTIVES: To compare the diagnostic value of magnetic resonance (MR) and computed tomography (CT) for the detection of coronary artery disease (CAD) with special regard to calcifications. MATERIALS AND METHODS: Twenty-seven patients with known CAD were examined with a targeted, navigator-gated, free-breathing, steady-state free precession MR angiography sequence (repetition time = 5.6 milliseconds, echo time = 2.8 milliseconds, flip angle 110 degrees ) and 16-slice coronary CT angiography. Segment-based sensitivity, specificity, and accuracy for the detection of stenoses larger than 50% were determined as defined by the gold standard catheter coronary angiography along with the subjective image quality (Grade 1-4). The degree of calcifications in each segment was quantified using a standard calcium scoring tool. RESULTS: Of 115 possible segments, 7% had to be excluded in MR imaging because of poor image quality. In CT, 3% were nondiagnostic because of image quality and 15% were not evaluable because of calcifications. Values for the detection of relevant coronary artery stenoses in the evaluated segments were: sensitivity: MR imaging 85% versus CT 96%; specificity: 88% versus 96%; accuracy: 87% versus. 96%. Average subjective image quality was 1.8 for MR imaging and 1.6 for CT. Of the 15% of segments that had to be excluded from CT evaluation because of calcifications, MR imaging provided the correct diagnosis segments in 67%. CONCLUSIONS: CT provided a better image quality with superior accuracy for the detection of CAD. Despite its overall inferiority, MR imaging proved to be helpful method in interpreting coronary stenosis in severely calcified segments.

Giant Left Atrial Myxoma: Cause for Position-Dependent Nocturnal Dyspnea and Cardiac Murmur.

Primary tumors of the heart are rare. The majority of them are benign, the left atrial myxoma being the most frequent one. Clinical appearance varies from unapparent to life-threatening complications such as stroke, acute heart failure, or even sudden death. Diagnosis and consecutive surgical treatment strongly depend on the clinical symptoms, but their extent does not correlate with the risk for serious complications. Therefore, patients with variable clinical presentation can be especially endangered. Consequent diagnostic and immediate operative therapy is essential.

Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the PrevAKI randomized controlled trial.

PURPOSE: Care bundles are recommended in patients at high risk for acute kidney injury (AKI), although they have not been proven to improve outcomes. We sought to establish the efficacy of an implementation of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines to prevent cardiac surgery-associated AKI in high risk patients defined by renal biomarkers. METHODS: In this single-center trial, we examined the effect of a "KDIGO bundle" consisting of optimization of volume status and hemodynamics, avoidance of nephrotoxic drugs, and preventing hyperglycemia in high risk patients defined as urinary [TIMP-2]·[IGFBP7] > 0.3 undergoing cardiac surgery. The primary endpoint was the rate of AKI defined by KDIGO criteria within the first 72 h after surgery. Secondary endpoints included AKI severity, need for dialysis, length of stay, and major adverse kidney events (MAKE) at days 30, 60, and 90. RESULTS: AKI was significantly reduced with the intervention compared to controls [55.1 vs. 71.7%; ARR 16.6% (95 CI 5.5-27.9%); p = 0.004]. The implementation of the bundle resulted in significantly improved hemodynamic parameters at different time points (p < 0.05), less hyperglycemia (p < 0.001) and use of ACEi/ARBs (p < 0.001) compared to controls. Rates of moderate to severe AKI were also significantly reduced by the intervention compared to controls. There were no significant effects on other secondary outcomes. CONCLUSION: An implementation of the KDIGO guidelines compared with standard care reduced the frequency and severity of AKI after cardiac surgery in high risk patients. Adequately powered multicenter trials are warranted to examine mortality and long-term renal outcomes.

Outcome of patients with reduced ankle brachial index undergoing open heart surgery with cardiopulmonary bypass.

OBJECTIVES: In open heart surgery using cardiopulmonary bypass, perfusion of the lower extremities is markedly reduced which may induce critical ischaemia in patients with pre-existing peripheral artery disease. Whether these patients have an increased risk for amputation and should better undergo peripheral revascularization prior to surgery remains unclear. METHODS: From 1 January 2009 to 31 December 2010, 785 consecutive patients undergoing open heart surgery were retrospectively included. In 443 of these patients, preoperative ankle brachial index (ABI) measurements were available. The cohort was divided into four groups: (i) ABI < 0.5, (ii) ABI 0.5-0.69, (iii) ABI 0.7-0.89 or (iv) ABI ≥ 0.9. Follow-up data of 413 (93.2%) patients were analysed with regard to mortality and amputations. RESULTS: The groups differed significantly in terms of age, cardiac risk factors, performed cardiac surgery and renal function. Postoperative delayed wound healing was significantly associated with lower ABI (25.9, 15.2, 27.0 and 9.6% in Groups I-IV, respectively, P = 0.003), whereas 30-day mortality was not significantly higher in patients with lower ABI (0, 4.3, 8.1 and 3.9%, respectively, P = 0.4). Kaplan-Meier models showed a significantly lower long-term survival over 4 years in patients with reduced ABI (P = 0.001, long-rank test) while amputations occurred rarely with only one minor amputation in Group II (P = 0.023). CONCLUSIONS: Patients with reduced ABIs undergoing heart surgery showed more wound-healing disturbances, and higher long-term mortality compared with those with normal ABIs. However, no perioperative ischaemia requiring amputation occurred. Thus, reduced ABIs were not associated with increased peripheral risks in open heart surgery but ABI may be helpful in selecting the site for saphenectomy to potentially avoid delayed healing of related wounds in legs with severely impaired arterial perfusion.

Aminoterminal pro type B natriuretic peptide as a predictive and prognostic marker in patients with chronic heart failure.

BACKGROUND: B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall tension. We studied the relation of NT-proBNP to Heart Failure Survival Score (HFSS) and New York Heart Association (NYHA) class in patients with chronic heart failure (CHF). We also studied the impact for recipient selection for cardiac transplant and assessed it as a predictive and prognostic marker of CHF. METHODS: A total of 550 patients with dilative cardiomyopathy (n = 323), and coronary artery disease (n = 227) were prospectively examined. All patients underwent spiroergometry, echocardiography, right heart catheterization, and electrocardiogram. Routine blood levels and NT-proBNP were measured. The clinical selection for cardiac transplant candidates was adjudicated by 2 independent cardiologists who were blinded to the results of NT-proBNP assays. Clinical outcome and predictive power of NT-proBNP were analyzed. RESULTS: NT-proBNP levels in patients clinically considered for cardiac transplantation were significantly higher (2293 ng/ml vs 493 ng/ml; p < 0.001). The receiver operating characteristic (ROC) analysis regarding transplant candidacy showed an area under the ROC curve (AUC) of 0.84 +/- 0.01 for HFSS, 0.86 +/- 0.001 for NYHA, and 0.96 +/- 0.01 for NT-proBNP. Patients with increasing NT-proBNP levels or remaining elevated levels despite adequate heart insufficiency treatment were maintained with left ventricular assist device implantation (n = 10) or urgent heart transplantation (n = 2). Patients with NT-proBNP levels above 5000 pg/ml had a mortality rate of 28.4% per year. Twenty-eight patients died during the observation period; all these patients were within NYHA Classes 3 and 4 (NT-proBNP 5423 +/- 423 ng/ml). CONCLUSIONS: NT-proBNP discriminates patients at high likelihood of being a candidate for transplantation and provides prognostic informations in patients with CHF. NT-proBNP levels above 5000 pg/ml at admission were associated with death, and these levels markedly discriminated candidates for left ventricular assist devices or urgent transplantation.

Skeletonization versus pedicle preparation of the radial artery with and without the ultrasonic scalpel.

BACKGROUND: The radial artery (RA) is increasingly used for myocardial revascularization because of its presumed advantageous long-term patency rates. The vessel can be harvested as a pedicle or skeletonized. The aim of this study was to compare the skeletonization technique with pedicle preparation using either an ultrasonic scalpel or scissors. METHODS: Forty consecutive patients with coronary artery disease undergoing complete arterial revascularization were included in the study. In 20 patients the RAs were prepared using scissors and clips (group 1: skeletonization; group 2: pedicle). In another 20 patients the arteries harvested were prepared using an ultrasonic scalpel (group 3: skeletonization; group 4: pedicle). The RA was treated with papaverine to prevent spasm of the vessel during and after harvesting. Tissue specimens of each RA were taken to analyze endothelial morphology by scanning electron microscopy. After implantation of the RA, graft perfusion was measured with a flow probe. RESULTS: Harvesting the RA as a skeletonized vessel took more time as compared with pedicle preparation (group 1 vs group 2: 37.1 +/- 3.5 minutes vs 24.4 +/- 3.9 minutes; p < 0.001 and group 3 vs group 4: 31.1 +/- 3.5 minutes vs 25.6 +/- 3.7 minutes; p < 0.01). The number of hemostatic titanium clips was similarly higher in group 1 as opposed to group 2 (58.7 +/- 7.1 vs 38.7 +/- 7.1; p < 0.01). However, there was no difference between groups 3 and 4 (p = 0.086). The length of the RA after skeletonization with scissors and clips was 20.8 +/- 1.5 cm in contrast with 19.1 +/- 0.9 cm (p < 0.01) after dissection as a pedicle. In the groups using the ultrasonic scalpel, there was no difference in graft length (p = 0.062). Mean blood flow through the graft after establishing the proximal anastomosis was similar among all groups (groups 1, 2, 3, and 4: 50 +/- 20.1 mL/min, 53.8 +/- 24.3 mL/min, 56.3 +/- 25.1 mL/min, and 51.8 +/- 23 mL/min, respectively). Scanning electron microscopy demonstrated endothelial damage in all patients in groups 1, 2, and 3 and in 7 patients of group 4. Most endothelial lesions were minor except in group 3 in which 1 of 5 endothelial lesions were severe. Statistically significant differences was found between groups 1 and 2, and 3 and 4 with respect to the degree of endothelial damage (p < 0.01). CONCLUSIONS: Skeletonization using scissors and clips is more time consuming and technically more difficult, but yield significantly longer grafts. Skeletonization with an ultrasonic scalpel did not result in additional length and was more frequently associated with severe endothelial damage. Pedicle preparation using scissors or an ultrasonic scalpel is much simpler and faster, and does not jeopardize endothelial integrity.

Resolved hypersensitivity myocarditis after ventricular circulatory assist.

Hypersensitivity myocarditis is known to be a cardiac manifestation of a delayed-type hypersensitivity response caused by drug treatment. In heart transplantation candidates the incidence is elevated. We report the case of a patient with end-stage heart failure who underwent implantation of a left ventricular assist device as a bridge to transplantation. The histologic investigation of the left ventricular specimen obtained during device implantation revealed the diagnosis of a hypersensitivity myocarditis. Ten months later this lesion showed complete reversibility within specimens of the explanted heart, maybe as a result of the termination of inotropic therapy after implantation of the left ventricular assist device.

Cardiac tumors--diagnosis and surgical treatment.

BACKGROUND: Primary tumors of the heart are rare even in major cardiac surgery centers. Because of the low case numbers, there is an insufficient evidence base to determine the optimal treatment, particularly for malignant tumors. METHOD: The authors review the pertinent literature retrieved by a selective PubMed search on the terms "cardiac tumor," "heart tumor," "cardiac myxoma," and "cardiac sarcoma." They also present operative techniques and their own long-term results in 181 patients with cardiac tumors. RESULTS: Patients with cardiac tumors generally have nonspecific symptoms depending on the site of the tumor and the extent of infiltration into the neighboring tissue. The diagnosis is based on the clinical history, echocardiography (in most cases), and, sometimes, computerized tomography and magnetic resonance imaging. Autopsy studies reveal a 0.02% prevalence of cardiac tumors, of which 75% are benign and 25% malignant. Myxoma is the most common benign tumor (50-70%); angiosarcoma is the most common malignant one (30%), followed by rhabdomyosarcoma (20%). About 10% of all tumor patients develop cardiac metastases, but these are only rarely clinically manifest. From 1989 to 2012, 181 patients underwent surgery for cardiac tumors in the authors' institution. The 5-year survival rates were 83% for benign tumors (139 patients), 30% for malignant tumors (26 patients), and 26% for cardiac metastases (16 patients). CONCLUSION: Patients with cardiac tumors should undergo surgery in a timely fashion in a specialized center. This holds for both malignant and benign tumors, particularly for atrial myxoma, which can cause serious secondary complications by embolization.