BMI-Stratified Exploration of the 'Obesity Paradox': Heart Failure Perspectives from a Large German Insurance Database.

Background: The global rise of obesity and its association with cardiovascular risk factors (CVRF) have highlighted its connection to chronic heart failure (CHF). Paradoxically, obese CHF patients often experience better outcomes, a phenomenon known as the 'obesity paradox'. This study evaluated the 'obesity paradox' within a large cohort in Germany and explored how varying degrees of obesity affect HF outcome. Methods: Anonymized health claims data from the largest German insurer (AOK) for the years 2014-2015 were utilized to analyze 88,247 patients hospitalized for myocardial infarction. This analysis encompassed baseline characteristics, comorbidities, interventions, complications, and long-term outcomes, including overall survival, freedom from CHF, and CHF-related rehospitalization. Patients were categorized based on body mass index. Results: Obese patients encompassed 21.3% of our cohort (median age 68.69 years); they exhibited a higher prevalence of CVRF (p < 0.001) and comorbidities than non-obese patients (median age 70.69 years). Short-term outcomes revealed lower complication rates and mortality (p < 0.001) in obese compared to non-obese patients. Kaplan-Meier estimations for long-term analysis illustrated increased incidences of CHF and rehospitalization rates among the obese, yet with lower overall mortality. Multivariable Cox regression analysis indicated that obese individuals faced a higher risk of developing CHF and being rehospitalized due to CHF but demonstrated better overall survival for those classified as having low-level obesity (p < 0.001). Conclusions: This study underscores favorable short-term outcomes among obese individuals. The 'obesity paradox' was confirmed, with more frequent CHF cases and rehospitalizations in the long term, alongside better overall survival for certain degrees of obesity.

Tricuspid Valve Surgery in Patients Receiving Left Ventricular Assist Devices.

BACKGROUND: Tricuspid regurgitation (TR) is common and related to poor prognosis in patients after left ventricular assist device (LVAD) implantation. The concomitant tricuspid valve surgery (TVS) at the time of LVAD implantation on short and long-term outcomes are controversial in current evidence. METHODS: This is a single-center, observational, retrospective study. We enrolled patients with moderate-to-severe TR who received LVAD implantations from 2009 to 2020. Postoperative right ventricular failure (RVF), right ventricular assist device (RVAD) use, hospital mortality, new-onset renal replacement therapy (RRT), and acute kidney injury (AKI) were evaluated retrospectively. RESULTS: Sixty-eight patients were included, 36 with and 32 without concomitant TVS. Baseline characteristics did not differ between the two groups. Patients receiving TVS had significantly increased incidences of postoperative RVF (52.8 vs. 25.0%, p = 0.019), RVAD implantation (41.7 vs. 18.8%, p = 0.041), and new-onset RRT (22.2 vs. 0%, p = 0.004). No difference in the incidence of AKI and hospital mortality was detected. Besides, these associations remained consistent in patients who underwent LVAD implantation via median sternotomy. During a median follow-up of 2.76 years, Kaplan-Meier analysis and competing-risk analysis showed that TVS was not associated with better overall survival in patients after LVAD implantation compared with the no-TVS group. CONCLUSION: Our study suggests that concomitant TVS failed to show benefits in patients receiving LVAD implantation. Even worse, concomitant TVS is associated with significantly increased incidences of RVF, RVAD use, and new-onset of RRT. Considering the small sample size and short follow-up, these findings warrant further study.

An external validation study of the Utah Bleeding Risk Score.

OBJECTIVES: Gastrointestinal bleeding in patients with continuous-flow left ventricular assist devices (CF-LVAD) impairs quality of life and increases hospitalization rate. The Utah Bleeding Risk Score (UBRS) has been created to predict gastrointestinal bleeding (GIB) in patients on left ventricular assist device. We here aimed to externally validate UBRS on our cohort of CF-LVAD patients. METHODS: Utah Bleeding Risk Score was calculated, GIB events summarized on follow-up and patients stratified into 3 risk groups. Predictive ability of UBRS was examined at 3 years and during whole support time and person time incidence rates correlated to UBRS. In a sub-analysis, single effects of UBRS variables on freedom from GIB were assessed. RESULTS: A total of 111 CF-LVAD patients were included. The median UBRS was 2 (3-1). Receiver operating characteristic curve analysis showed an area under the curve of 0.519 (P = 0.758, 95% confidence interval = 0.422-0.615) at 3 years and an area under the curve of 0.515 (P = 0.797, 95% confidence interval = 0.418-0.611) during whole support time. No significant difference was observed in UBRS between bleeders and non-bleeders (P = 0.80). No significant difference in freedom from GIB was observed (P3 years = 0.7; Psupport-time = 0.816) and no independent significance regarding the freedom from bleeding at 3 years for any variable was observed. Coronary artery disease was associated with higher risk of GIB beyond the 3rd year (P = 0.048). CONCLUSIONS: UBRS was not able to predict GIB and therefore not applicable in our cohort of patients. Coronary artery disease could lead to a higher risk for GIB during support time. An additional validation in a larger cohort is advisable.

Efficacy and safety of sacubitril/valsartan in an outpatient setting: A single-center real-world retrospective study in HFrEF patients with focus on possible predictors of clinical outcome.

BACKGROUND: Currently, data on sacubitril/valsartan therapy from the real-world settings are scarce and the predictors of a good clinical responsiveness to this drug are unknown. OBJECTIVES: To assess efficacy and safety profile of sacubitril/valsartan and to identify predictors for a better clinical outcome. MATERIAL AND METHODS: Clinical, laboratory and echocardiographic data of 95 chronic heart failure (CHF) patients with reduced ejection fraction (HFrEF) were retrospectively analyzed. A good efficacy of sacubitril/valsartan was defined as the fulfilment of at least 2 of the following criteria: improvement of left ventricular ejection fraction (LVEF) or functional status, and reduction of N-terminal pro-brain natriuretic peptide (NT-proBNP) levels or hospitalization rates. RESULTS: Under sacubitril/valsartan, major improvements were observed in LVEF, the New York Heart Association (NYHA) class, NT-proBNP levels, and hospitalization rates. Patients with a good efficacy of sacubitril/valsartan were characterized by initially worse LVEF (median (interquartile range (IQR)): 29.0% (23.0-33.0%) compared to 32.0% (28.5-38.0%) with more frequent nonischemic etiology (65.4% compared to 41.9%) and hospitalizations for CHF/month (0.016 (0.004-0.057) compared to 0.000 (0.000-0.012)), lower cholesterol (42.3% compared to 65.1%), higher C-reactive protein (CRP) levels at baseline (0.5 mg/L (0.5-1.0 mg/L) compared to 0.5 mg/L (0.5-0.5 mg/L)), and a shorter timespan between CHF diagnosis and the start of sacubitril/valsartan treatment (66.0 (11.0-127.0) compared to 111 (73.0-211.0) months) (p < 0.05 each). In a multivariate Cox analysis, only the last 2 parameters were shown to be independent predictors of good clinical responsiveness to sacubitril/valsartan (hazard ratio (HR) = 1.263, 95% confidence interval (95% CI) = [1.048; 1.521]; HR = 0.992, 95% CI = [0.987; 0.997], p < 0.05, respectively). CONCLUSIONS: Sacubitril/valsartan improved LVEF, NYHA class, NT-proBNP levels, and hospitalization rates, mostly without relevant side effects. The independent predictors of a good clinical efficacy were higher CRP levels at baseline and a shorter delay between CHF diagnosis and the initialization of sacubitril/valsartan therapy.

Inpatient Cardiac Rehabilitation of LVAD Patients-Updated Recommendations from the Working Group of the German Society for Prevention and Rehabilitation of Cardiovascular Diseases.

Cardiac rehabilitation physicians are faced to an increasing number of heart failure patients supported by left ventricular assist devices (LVAD). Many of these patients have complex medical issues and prolonged hospitalizations and therefore need special cardiac rehabilitation strategies including psychological, social, and educational support which are actually poorly implemented.Cardiac rehabilitation with clear guidance and more evidence should be considered as an essential component of the patient care plan especially regarding the increasing number of destination patients and their long-term follow-up.In this article the working group for postimplant treatment and rehabilitation of LVAD patients of the German Society for Prevention and Rehabilitation of Cardiovascular Diseases has summarized and updated the recommendations for the cardiac rehabilitation of LVAD patients considering the latest literature.

Improved aftercare in LVAD patients: Development and feasibility of a smartphone application as a first step for telemonitoring.

For the success of the treatment with a left ventricular assist device (LVAD), both adequate self-management by the patient and an optimum level of support from the implanting hospital are crucial. A smartphone application has recently been developed within the framework of a European research project for the close monitoring of LVAD patients in order to improve upon their current aftercare situation. Using this new tool, different relevant parameters (eg, weight, international normalized ratio [INR], medication, LVAD parameters, symptoms, and photos of the driveline exit) can be sent daily or as required to a corresponding clinical application at the hospital for evaluation. The objective of this study was to monitor the functionality, acceptance, and usability of this smartphone application in LVAD patients. Prospective single-center study: in total, 13 patients (60 ± 7 years, 92% male, 1027 ± 653 days after LVAD implantation) were requested to test the application for approx. 4 weeks. At the end of the study, all entered data were evaluated and the patients were questioned regarding the acceptance and the usability. During the study period of mean 34 ± 8 days, a total of 453 data records (mean 35 ± 7 per patient) arrived at the hospital. In addition, a total of 19 photos of the driveline exit site were also sent via smartphone. The clinical application registered a total of 160 conspicuities. These comprised 126 INR deviations (target range 2.3-2.8) and 34 symptoms (mainly nosebleeds). The smartphone application functioned reliably, was well received by the patients and was graded highly for acceptance and usability. The results show that smartphone applications can definitely be used to improve aftercare in LVAD therapy in selected patients. Long-term studies are now needed to investigate the extent to which complications can be prevented, healthcare costs reduced, and quality of life increased.

Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography for improving diagnosis of infection in patients on CF-LVAD: longing for more 'insights'.

Aim: Presence and consequent extent of infection in patients on continuous-flow left ventricular assist devices (CF-LVADs) can be challenging with the current diagnostic tools. The present study sought to demonstrate the diagnostic power of 18F-Fluorodeoxyglucose-Positron-Emission Tomography/Computed Tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Background: The present study sought to demonstrate the diagnostic power of 18F-fluorodeoxyglucose-positron-emission tomography/computed tomography (18F-FDG PET/CT) in detecting infection in patients supported with CF-LVAD. Methods and results: Between July 2009 and April 2016, 61 PET/CT examinations were performed in 47 patients (median age 64.13 years, IQR 18.77) supported with a CF-LVAD. PET/CT assessments were performed qualitatively and quantitatively at three different levels: at the piercing site of driveline (first level), along the intracorporeal course of driveline (second level), and around the device (third level). Final diagnosis of LVAD infection was prospectively performed and was based upon microbiological samples taken at hospital admission, during the surgical revision/transplantation and recurrence of symptoms on long-term follow-up. At last follow-up a total of 40 (65.57%) final diagnoses of LVAD-infection could be ascertained. Matching the final diagnosis with the PET/CT assessments the sensitivity, specificity, and positive and negative predictive value were 90.0, 71.4, 85.71, and 78.94%, respectively. Level sub-analyses of SUV max showed an optimal discriminator power for levels 1 and 2 (AUC of level 1-0.824, P < 0.001; AUC of level 2-0.849, P < 0.001, respectively). At the third level semi-quantitative analysis showed poor discriminator power (AUC 0.589, P = 0.33). Qualitative visual analysis instead indicated a trend toward significance (P = 0.07). Conclusions: Quantitative 18F-FDG PET/CT is an optimal diagnostic tool in detecting superficial and deep driveline infections. However, diagnostic accuracy with regard to the diagnosis of pump housing infection is limited. Here, clinical and qualitative PET/CT analyses must be better considered.

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.

Metabolic volume performs better than SUVmax in the detection of left ventricular assist device driveline infection.

PURPOSE: A continuous-flow left ventricular assist device (LVAD) is a new and highly promising therapy in supporting end-stage heart failure patients, either bridging them to heart transplantation or as a destination therapy. Infection is one of the major complications associated with LVAD implants. 18F-FDG PET/CT has already been shown to be useful in the detection of LVAD infection. The goal of this study was to compare the diagnostic accuracy of different PET analysis techniques (visual grading versus SUVmax and metabolic volume). METHODS: We retrospectively analyzed 48 patients with implanted LVAD who underwent an 18F-FDG PET/CT that were either suspected to have a driveline or device infection or inflammation of unknown origin. PET/CT was analyzed qualitatively (visual grading) and quantitatively (SUVmax and metabolic volume) and matched to the final clinical diagnosis concerning driveline infection. The final diagnosis (standard of reference) was made at the end of clinically recorded follow-up or transplantation and included microbiological cultures of the driveline exit site and/or surgical samples, and clinical signs of infection despite negative cultures as well as recurrence of symptoms. RESULTS: Sensitivity, specificity, positive and negative predictive value were 87.5%, 79%, 81% and 86% for visual score, 87.5%, 87.5%, 87.5% and 87.5% for SUVmax and 96%, 87.5%, 88.5%, 95.5% for metabolic volume, respectively. ROC analysis revealed an AUC of .929 for SUVmax and .969 for metabolic volume. Both SUVmax and metabolic volume had a high detection rate of patients with driveline infection (21/24 = 91.5% true positive vs. 23/26 = 88.5% true positive, respectively). However, metabolic volume detected more patients without any infection correctly (1/22 = 4.5% false negative vs. 3/24 = 12.5% false negative). CONCLUSIONS: 18F-FDG PET/CT is a valuable tool for the diagnosis of LVAD driveline infection with high diagnostic accuracy. Particularly the use of the metabolic volume yields very high accuracy and performs slightly better than SUVmax.

Supporting imaging modalities for improving diagnosis of prosthesis endocarditis: preliminary results of a single-center experience with 18F-FDG-PET/CT.

BACKGROUND: The aim of the current study was to evaluate the role of PET-CT in the diagnosis of prosthetic valve endocarditis (PVE). METHODS: This is a single-center study including 13 PET/CT examinations performed between February 2009 and March 2016 in 13 patients (76.9% men, mean age 68.1 years, IQR 11.1) because of suspect of PVE. Median interval time between first operation and PET/CT examination was 19.02 months (IQR 85.5). Final diagnosis was made according to pathological criteria (histological and microbiological) of the Duke classification. RESULTS: Eleven patients (84.6%) presented at the hospital admission positive blood cultures. Eight patients (61.5%) had inconclusive transesophageal echocardiography (TEE). Abnormal 18F-FDG uptake suggestive of active PVE was observed in 10 patients (76.9%), whereas in 3 patients (23.1%) PET/CT did not show any pathological tracer uptake at the level of the previous implanted prostheses. PET/CT revealed 15 (115.4%) new extracardiac findings and one (7.7%) new cardiac focus not previously detected in TEE. All patients underwent redo surgery. Matching the intraoperative findings with those of PET/CT, a total of 10 true positives, 2 true negatives, no false positive and 1 false negative finding was reported. Sensitivity, specificity, and positive and negative predictive values of PET/CT were 90.9%, 100%, 100% and 50% whereas for TEE they were 81.82%, 50%, 81.82%, and 50% respectively. In 61.63% of patients (N. 8) PET/CT and echo findings were concordant. In those cases the diagnosis of endocarditis was confirmed in all. CONCLUSIONS: This study highlights the potential advantages of PET-CT in patients with suspected prosthesis endocarditis. Further prospective evaluations are needed to confirm those preliminary results.

Can Perioperative Right Ventricular Support Prevent Postoperative Right Heart Failure in Patients With Biventricular Dysfunction Undergoing Left Ventricular Assist Device Implantation?

OBJECTIVES: Depending on the pre-existing condition of the right ventricle (RV), left ventricular assist device (LVAD) implantation may have a detrimental effect on RV function, subsequently leading to right heart failure. This study details the authors' experience with perioperative mechanical RV support in patients with biventricular impairment but primarily scheduled for isolated LVAD implantation. DESIGN: Retrospective study. SETTING: Two center study, university hospital. PARTICIPANTS: This study included LVAD recipients with preoperative biventricular impairment who received an additional right ventricular assist device (RVAD) after a failed weaning attempt from cardiopulmonary bypass due to acute RV failure. INTERVENTIONS: Outcomes of 25 patients who underwent LVAD and unplanned temporary RVAD implantation were analyzed. MEASUREMENTS AND MAIN RESULTS: All patients experienced significant preoperative RV impairment (tricuspid annular plane systolic excursion: 10.2±26.3 mm; right atrium pressure: 17.9±10.4 mmHg) and pulmonary hypertension (pulmonary artery pressure: 54.8±25.7 mmHg). In 15 patients, additional tricuspid valve annuloplasty was performed. Mean duration of temporary RVAD support was 11.1±7.2 days. In 23 patients (92%), the RVAD was removed successfully. None of the patients developed RV failure after RVAD removal. Hospital survival and the 1-year survival rate of the study group were 68% and 56%, respectively. CONCLUSIONS: The results of perioperative RVAD support in LVAD recipients with biventricular dysfunction are encouraging. Temporary RVAD support allows an already compromised RV to become attuned to the hemodynamic conditions after LVAD implantation. This strategy provides patients with preoperative impaired RV function a high likelihood to permanently undergo LVAD support only.

Left Ventricular Assist Devices as Bridge to Cardiac Recovery in Nonischemic Heart Failure: Keeping Weaning from the Device in Mind.

A minority of patients on left ventricular assist devices (LVADs) display myocardial recovery raising the question of device explantation. We report a series of seven LVAD patients with nonischemic cardiomyopathy allowing explantation of the VAD. In case of four patients we overview follow-up periods of 4 to 10 years. Remarkably, in three cases device explantation was considered beyond 1 year of LVAD support. Explantation was finally performed after 20 months and more on the device. In light of the scarcity of donor organs we conclude that patients on LVAD support should be evaluated for possible weaning from the device on a regular basis.

Pulmonary Bleeding During Right Ventricular Support After Left Ventricular Assist Device Implantation.

OBJECTIVES: Right heart failure still occurs in up to 20% of patients after implantation of a left ventricular assist device (LVAD). One treatment option for these patients is the implantation of a temporary right ventricular assist device (RVAD). Experimental data suggest that non-pulsatile perfusion of the lungs is associated with an increased rate of pulmonary hemorrhage. The aim of this study was to determine the incidence of pulmonary bleeding complications in these patients. DESIGN: Observational study. SETTING: Single center, university hospital. PARTICIPANTS: This study included patients undergoing LVAD implantation for end-stage heart failure and subsequent implantation of a temporary right ventricular support system. INTERVENTIONS: In this study, 25 patients who underwent LVAD and additional temporary RVAD implantation were screened for pulmonary bleeding complications. MEASUREMENTS AND MAIN RESULTS: The mean Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) level at the time of LVAD implantation was 2.84. All patients experienced severe right ventricular failure (tricuspid annular plane systolic excursion [TAPSE], 10.16±26.3 mm) and severe pulmonary hypertension (right atrial [RA] pressure, 56.21±15.58 mmHg). Average duration of right ventricular support was 11.12±7.20 days, with right ventricular support being administered to 14 patients for more than 7 days. Seventeen patients were weaned successfully from right ventricular support after a mean support duration of 5 days. Five patients developed pulmonary bleeding complications, diagnosed using computed tomography scan and bronchoscopy. All bleeding occurred after postoperative day 7 and was associated with RVAD flow of more than 4 L/min within 24 hours before bleeding occurred. CONCLUSIONS: The data presented in this study suggested that right ventricular support for more than 7 days and a blood flow greater than 4 L/min were associated with pulmonary bleeding complications. This should be taken into consideration when temporary right ventricular support after LVAD implantation is planned.

Contributory Role of Fluorine 18-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in the Diagnosis and Clinical Management of Infections in Patients Supported With a Continuous-Flow Left Ventricular Assist Device.

BACKGROUND: The current study sought to demonstrate the advantages offered by fluorine 18-fluorodeoxyglucose ((18)F-FDG) positron emission tomography/computed tomography (PET/CT) in patients supported with continuous-flow left ventricular assist devices (CF-LVADs) in detecting infection and the consequent effect on clinical decisions. METHODS: Between April 2009 and September 2013, 40 PET examinations were performed in 31 patients (78.1% men; mean age, 51.0 ± 14.9 years) supported with a CF-LVAD. In group A (19 examinations in 14 patients), PET/CT was performed to detect infectious focus in patients without external signs of driveline involvement but with at least two of the following infection signs: recurrent fever, positive blood culture, or elevated infectious indicators. In group B (21 examinations in 17 patients), PET/CT aimed to assess the internal extension of infection in patients with external signs of driveline infection. RESULTS: In 50% of the cases of the patients in group A, abnormal (18)F-FDG uptake (9 patients) was related to VAD components. Matching the results with the final diagnosis, we reported 9 true-positive, 8 true-negative, no false-negative, and 2 false-positive findings. New information unrelated to VAD was found in 9 patients (50%): pneumonia in 3, colon diverticulitis in 3, sternal dehiscence in 1, paravertebral abscess in 1, and erysipelas in 1. In group B, superficial abnormal (18)F-FDG uptake was found at the piercing site of the driveline in 2 patients, deeper extension of infection along the driveline in 10, initial involvement of the pump housing in 2, and full involvement of the device in 4. These findings contributed to changing the clinical management in 84.2% of group A patients and in 85.7% of group B patients: 16 patients were scheduled for urgent transplantation, 2 underwent surgical revision of the driveline, 7 required prolonged antibiotic therapy, and 3 underwent colonoscopy. CONCLUSIONS: This single-center experience highlights the diagnostic value of PET/CT in detecting the localization and internal extension of infection to internal VAD components. Moreover, this information notably influences the therapeutic management.

Is Implantation of a Left Ventricular Assist Device in Patients With Critical or Impending Cardiogenic Shock an Absolute Contraindication? Looking Back at Our Past Experience Trying to Identify Contraindicative Risk Factors.

Poor survival has been demonstrated after ventricular assist device (VAD) implantation for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 and 2 patients compared with more stable levels. However, risk factors within this high-risk cohort have not been determined so far. The aim of the present study was to identify risk factors associated with this very high mortality rate. Between February 1993 and January 2013, 298 patients underwent VAD implantation in our institution. One hundred nine patients were in INTERMACS level 1 and 49 patients were in INTERMACS level 2 and were therefore defined as hemodynamically critical (overall 158 patients). Assist devices implanted were: HVAD HeartWare n = 18; Incor n = 11; VentrAssist n = 2; DeBakey n = 22; and pulsatile systems n = 105. After cumulative support duration of 815.35 months, Kaplan-Meier analysis revealed a survival of 63.9, 48.8, and 40.3% at 1, 6, and 12 months, respectively. Cox regression analyses identified age > 50 (P = 0.001, odds ratio [OR] 2.48), white blood cell count > 13.000/µL (P = 0.01, OR 2.06), preoperative renal replacement therapy (P = 0.001, OR 2.63), and postcardiotomy failure (P < 0.001, OR 2.79) as independent predictors of mortality. Of note, last generation VADs were not associated with significantly better 6-month survival (P = 0.59). Patients without the aforementioned risk factors could yield a survival of 79.2% at 6 months. This single-center experience shows that VAD implantation in hemodynamically unstable patients generally results in poor early outcome, even in third-generation pumps. However, avoiding the aforementioned risk factors could result in improved outcome.

A recurrent activating PLCG1 mutation in cardiac angiosarcomas increases apoptosis resistance and invasiveness of endothelial cells.

Primary cardiac angiosarcomas are rare tumors with unfavorable prognosis. Pathogenic driver mutations are largely unknown. We therefore analyzed a collection of cases for genomic aberrations using SNP arrays and targeted next-generation sequencing (tNGS) of oncogenes and tumor-suppressor genes. Recurrent gains of chromosome 1q and a small region of chromosome 4 encompassing KDR and KIT were identified by SNP array analysis. Repeatedly mutated genes identified by tNGS were KDR with different nonsynonymous mutations, MLL2 with different nonsense mutations, and PLCG1 with a recurrent nonsynonymous mutation (R707Q) in the highly conserved autoinhibitory SH2 domain in three of 10 cases. PLCγ1 is usually activated by Y783 phosphorylation and activates protein kinase C and Ca(2+)-dependent second messengers, with effects on cellular proliferation, migration, and invasiveness. Ectopic expression of the PLCγ1-R707Q mutant in endothelial cells revealed reduced PLCγ1-Y783 phosphorylation with concomitant increased c-RAF/MEK/ERK1/2 phosphorylation, increased IP3 amounts, and increased Ca(2+)-dependent calcineurin activation compared with ectopic expressed PLCγ1-wild-type. Furthermore, cofilin, whose activation is associated with actin skeleton reorganization, showed decreased phosphorylation, and thus activation after expression of PLCγ1-R707Q compared with PLCγ1-wild-type. At the cellular level, expression of PLCγ1-R707Q in endothelial cells had no influence on proliferation rate, but increased apoptosis resistance and migration and invasiveness in in vitro assays. Together, these findings indicate that the PLCγ1-R707Q mutation causes constitutive activation of PLCγ1 and may represent an alternative way of activation of KDR/PLCγ1 signaling besides KDR activation in angiosarcomas, with implications for VEGF/KDR targeted therapies.