Soluble CD14 inhibits contractile function and insulin action in primary adult rat cardiomyocytes.

Epicardial adipose tissue (EAT) from patients with type 2 diabetes (T2D) is characterized by monocyte infiltrations and displays an elevated release of the monocyte marker soluble cluster of differentiation 14 (sCD14) versus EAT from patients without T2D. We propose that an increased abundance of sCD14 in EAT from patients with T2D may impair the function and insulin sensitivity of the adjacent cardiomyocytes. To examine this, primary adult rat cardiomyocytes were incubated with increasing concentrations of sCD14 in the presence and absence of the co-receptor lipopolysaccharide (LPS), and analyzed for effects on determinants of contractile function, activation of inflammation signalling and insulin action. Exposing cardiomyocytes to sCD14 increased the phosphorylation of the stress kinases p38 and extracellular-signal regulated kinase (ERK). In contrast, insulin-mediated phosphorylation of Akt on Thr308 and Ser473 was inhibited. Furthermore, sCD14 impaired sarcomere shortening and cytosolic Ca2+-fluxes. All responses were concentration-dependent and became significant at 1ng/ml sCD14. LPS, either alone or in complex with sCD14, did not affect contractile function or the activation of stress kinases and insulin signalling pathways. Similar data on protein phosphorylation were obtained when exposing human umbilical vein endothelial cells to sCD14. Finally, pharmacological inhibition of p38 reversed the detrimental effects of sCD14 on contractile function, but not on sCD14-induced insulin resistance. Collectively, these data show that sCD14 impairs the function and insulin sensitivity of cardiomyocytes, suggesting that an enhanced sCD14 release from EAT in patients with T2D may contribute to the pathogenesis of diabetes-related cardiometabolic complications.

An Alternative Approach for Perioperative Extracorporeal Life Support Implantation.

Central veno-arterial extracorporeal membrane oxygenation (ECMO) is traditionally implanted using direct cannulation of the aorta and right atrium. We aim to summarize the outcome of patients who underwent perioperative central ECMO implantation using an alternative surgical approach, which allows sternum closure and does not require resternotomy at the time of explantation. We retrospectively reviewed patients who required veno-arterial ECMO support at our institution between January 2013 and July 2014. Inclusion criteria were patients undergoing central ECMO implantation using the above-mentioned implantation technique. Nine patients (65 ± 14 years) were supported using this technique. Four patients underwent coronary bypass surgery as a primary surgery and the other five patients had combined coronary and valve surgeries. The average duration of ECMO support was 9 ± 7 days (range 1-24 days). The dominant postoperative complication was renal failure, which occurred in eight patients (89%). In four patients (44%), the ECMO was successfully removed. Survival rate to discharge was 22%. In conclusion, this study showed the feasibility of this alternative ECMO implantation technique. No technical issues were encountered. Extended support duration and reducing resternotomy risks may be the main advantages of this technique compared with conventional ECMO implantation methods.

Sexual Concerns of Patients With Implantable Left Ventricular Assist Devices.

The growing field of implantable left ventricular assist devices (LVADs) lacks studies that evaluate the sexual and psychosocial concerns of LVAD patients. The aim of this prospective study was to determine the sexual and psychosocial behaviors of these patients. A sexual and psychosocial survey was conducted in patients who underwent the implantation of LVAD. Inclusion criteria were patients who were discharged home. The survey consisted of 17 questions with main focus on the sexual life and activities. The survey was sent to 38 patients. Twelve patients had either no partners or did not respond to the survey. Data of the remaining 26 patients with a mean age of 54 ± 13 years old were analyzed. The mean time between LVAD implantation and the first sexual activity was 16 ± 13 weeks (6-42 weeks). Following LVAD implantation, there was a steady improvement in the physical condition and quality of life. However, a remarkable decrease in the degree of satisfaction with sexual life following LVAD implantation (5.5 ± 2.2 vs. 4.1 ± 2.5) was observed (P = 0.05) (a scale of 1-7, with 7 being very satisfied and 1 not satisfied). Decreasing sexual activities after LVAD implantation was mainly to avoid partner disappointment, sudden cardiac arrest, and LVAD failure. There is a notable reduction in the degree of satisfaction with sexual life after LVAD implantation. The majority of the patients avoid discussing this issue with their physicians. Psychological and psychosocial support of LVAD patients is mandatory to improve their life quality.

Survival predictors in ventricular assist device patients with prior extracorporeal life support: selecting appropriate candidates.

Several centers turn patients down for long-term ventricular assist devices (VADs) once they have received extracorporeal life support (ECLS) due to the expected poor outcome in these patients. The aim of this study was to identify survival predictors in this cohort of patients. Data of patients undergoing VAD support between January 2010 and November 2013 were retrospectively reviewed. Patients on ECLS support before implantation were considered eligible for inclusion. Outcome in survivors following long-term VAD support was compared with outcomes in nonsurvivors. Student's t-test and χ(2)-test were used as applicable. A total of 65 long-term VADs were implanted. The inclusion criteria were met by 24 patients. Eight patients did not survive the first 30 days. All preoperative characteristics were comparable between the two groups except for statistically higher Model for End-stage Liver Disease (MELD) score, bilirubin, white blood cell count, and blood urea nitrogen in nonsurvivors (P = 0.002, 0.01, 0.01, and 0.003, respectively). Stepwise discriminant analysis revealed MELD score as the most important survival predictor. Based on this analysis, an outcome predictor formula was generated. The 30-day and 1-year survival rates were 67% and 54%, respectively. In this study, we were able to determine survival predictors in VAD patients with prior ECLS support. The outcome in these patients is limited and associated with higher postoperative complications, particularly right ventricular and respiratory failure. The pre-VAD MELD score is an important predictor of poor outcome.

Femoro-femoral versus atrio-aortic extracorporeal membrane oxygenation: selecting the ideal cannulation technique.

Veno-arterial extracorporeal membrane oxygenation (ECMO) may be implanted using peripheral ECMO (pECMO) or central ECMO (cECMO) cannulation techniques. The aim of this study was to compare the outcome between these two cannulation techniques. A retrospective study was performed at Düsseldorf University Hospital from October 2009 through June 2011. Inclusion criteria were patients with veno-arterial ECMO support ≥24 h. Various pre- and postimplantation variables were investigated including postimplantation hemodynamic and ECMO parameters, oxygenation/ventilation parameters at 3, 6, 12, 24, 48, 72 h, as well as renal and liver function tests at first and third postoperative days following implantation. Outcome data of patients receiving pECMO were compared with those who received cECMO. The inclusion criteria were met by 37 patients (25 pECMO and 12 cECMO). There were no significant differences in baseline characteristics between these two groups except for younger age in pECMO patients (P=0.005). All postimplantation variables were comparable between the two groups except for higher PO2 and lower PCO2 values at the 3rd hour postimplantation in patients with pECMO (P=0.007 and 0.01, respectively). Eleven (44%) of the pECMO patients required re-exploration for bleeding versus 100% of patients with cECMO (P=0.01). Ischemic leg complication was observed in four pECMO and three cECMO patients. Thirty-day mortality in patients with pECMO and cECMO was 60% versus 67%, respectively (P=1.00). In this study, no particular oxygenation/ventilation, hemodymanic, or end-organ function advantage was observed with either cannulation technique. However, more bleeding and resternotomy complications were observed in cECMO patients.

Secretory products from epicardial adipose tissue of patients with type 2 diabetes mellitus induce cardiomyocyte dysfunction.

BACKGROUND: Secreted factors from epicardial adipose tissue (EAT) have been implicated in the development of cardiomyocyte dysfunction. This study aimed to assess whether alterations in the secretory profile of EAT in patients with type 2 diabetes mellitus (DM2) affect contractile function and insulin action in cardiomyocytes. METHODS AND RESULTS: Contractile function and insulin action were analyzed in primary adult rat cardiomyocytes incubated with conditioned media (CM) generated from explants of EAT biopsies obtained from patients without and with DM2. CM from subcutaneous and pericardial adipose tissue biopsies from the same patients served as the control. Cardiomyocytes treated with CM (EAT) from DM2 patients showed reductions in sarcomere shortening, cytosolic Ca(2+) fluxes, expression of sarcoplasmic endoplasmic reticulum ATPase 2a, and decreased insulin-mediated Akt-Ser473-phosphorylation as compared with CM from the other groups. Profiling of the CM showed that activin A, angiopoietin-2, and CD14 selectively accumulated in CM-EAT-DM2 versus CM-EAT in patients without DM2 and CM from the other fat depots. Accordingly, EAT biopsies from DM2 patients were characterized by clusters of CD14-positive monocytes. Furthermore, SMAD2-phosphorylation, a downstream target of activin A signaling, was elevated in cardiomyocytes treated with CM (EAT) from DM2 patients, and the detrimental effects of CM (EAT) from DM2 patients were partially abolished in cardiomyocytes pretreated with a neutralizing antibody against activin A. Finally, both recombinant activin A and angiopoietin-2 reduced cardiomyocyte contractile function, but only activin A reduced the expression of sarcoplasmic endoplasmic reticulum ATPase 2a. CONCLUSIONS: Collectively, our data implicate DM2-related alterations in the secretory profile of EAT in the pathogenesis of diabetes mellitus-related heart disease.

VEGF in the crosstalk between human adipocytes and smooth muscle cells: depot-specific release from visceral and perivascular adipose tissue.

Adipose tissue secrets adipokines and fatty acids, which may contribute to obesity-associated vascular dysfunction and cardiovascular risk. This study investigated which factors are responsible for the synergistic effect of adipokine and oleic acid- (OA-) induced proliferation of human vascular smooth muscle cells (VSMC). Adipocyte-conditioned medium (CM) from human adipocytes induces proliferation of VSMC in correlation to its vascular endothelial growth factor (VEGF) content. CM increases VEGF-receptor (VEGF-R) 1 and 2 expression and VEGF secretion of VSMC, while OA only stimulates VEGF secretion. VEGF neutralization abrogates CM- and OA-induced proliferation and considerably reduces proliferation induced by CM and OA in combination. VEGF release is higher from visceral adipose tissue (VAT) of obese subjects compared to subcutaneous adipose tissue (SAT) and VAT from lean controls. Furthermore, VEGF release from VAT correlates with its proliferative effect. Perivascular adipose tissue (PAT) from type 2 diabetic patients releases significantly higher amounts of VEGF and induces stronger proliferation of VSMC as compared to SAT and SAT/PAT of nondiabetics. In conclusion, VEGF is mediating CM-induced proliferation of VSMC. As this adipokine is released in high amounts from VAT of obese patients and PAT of diabetic patients, VEGF might link adipose tissue inflammation to increased VSMC proliferation.

Five days of no anticoagulation or antiplatelet therapy and NovoSeven administration in a HeartWare HVAD patient.

Postoperative bleeding is the most common complication following the implantation of ventricular assist devices. This is a case report of a HeartWare HVAD patient with intractable bleeding following chest tube insertion necessitating massive blood transfusion and multiple thoracotomies. Anticoagulation and antiplatelet therapy were discontinued and intravenous NovoSeven was administered as last resort. Bleeding ceased immediately and no pump-related issues were observed. However, thrombus formation in the right atrium and superior vena cava was detected.

Gastrointestinal Bleeding in Patients with HeartWare Ventricular Assist Device: Does the Activation of the Lavare Cycle Make a Difference?

We aimed to investigate the prevalence of gastrointestinal bleeding (GIB) events in patients supported with HeartWare ventricular assist device (VAD) and activated lavare cycle. Thirty-two GIB events were documented in 22 patients (21%) after median support duration of 22 days (IQR: 11-157 days). There were 13 patients with early episodes of GIB. Meanwhile, 17 GIB events were documented in 9 patients after a median support duration of 174 days (IQR 25-736 days) (late bleeders), accounting for 0.18 events per patient's years. The GIB events appear to be a frequent complication in patients with HeartWare VAD regardless of the lavare cycle.

Conservative approaches for HeartWare ventricular assist device pump thrombosis may improve the outcome compared with immediate surgical approaches.

PURPOSE: Left ventricular assist device (LVAD) pump thrombosis is one of the devastating complications following mechanical circulatory support implantation. Surgical pump exchange is a known high-risk surgery with a high perioperative mortality rate. We aim to summarize our experience with several other alternative approaches in patients with suspected HeartWare HVAD (HeartWare, Framingham, MA, USA) pump thrombosis. METHODS: The outcome of HeartWare HVAD implantations performed at single institution from January 2010 to September 2015 was studied. Inclusion criteria were patients with suspected HeartWare HVAD pump thrombosis. Patients' preoperative characteristics and outcome following various interventions were reviewed. RESULTS: A total of 94 HeartWare HVAD pumps were implanted in 91 patients. The inclusion criteria were met by 13 patients (14%) with a mean age of 55 ± 14 years old and a median total pump support duration of 467 days (11-937 days). A conservative approach using systemic thrombolysis (recombinant tissue plasminogen activator) + heparin was used in the majority of the patients (15 events = 65%). Heart transplantation was performed in 4 patients and device explantation in 2 patients. Other approaches were used in the rest of patients. Considering thrombolysis-related complications, 1 patient required resternotomy for bleeding after thrombolysis, which was necessary a few days after LVAD implant surgery and 2 patients developed minor intracranial bleeding after thrombolysis. One-year survival after the latest intervention was 69%. CONCLUSIONS: This report showed the feasibility of several alternative conservative approaches combining medications, minimally invasive and interventional methods for patients with HeartWare pump thrombosis. The outcome may be better than immediate surgical pump exchange.

Implanting permanent left ventricular assist devices in patients on veno-arterial extracorporeal membrane oxygenation support.

Selected patients who fail to be weaned off temporary veno-arterial extracorporeal membrane oxygenation support may be considered for long-term left ventricular assist devices.  We describe here a left ventricular assist device implantation technique in patients with prior veno-arterial extracorporeal membrane oxygenation support without the use of a cardiopulmonary bypass machine, which minimizes the intraoperative trauma and blood loss while still meeting all the goals of the standard procedure.

Implanting permanent left ventricular assist devices in patients on veno-arterial extracorporeal membrane oxygenation support: do we really need a cardiopulmonary bypass machine?

OBJECTIVES: Selected patients who failed to be weaned off temporary veno-arterial extracorporeal membrane oxygenation (VA-ECMO) support may be considered for long-term left ventricular assist devices (LVADs). Activation of the systemic inflammatory response due to the cardiopulmonary bypass (CPB) machine and its associated deleterious effects on the coagulation system have been well documented. The aim of the study was to compare the outcome of patients receiving VAD on VA-ECMO with patients who were converted to CPB at the time of VAD implantation. METHODS: Data of patients undergoing LVAD implantation between January 2010 and September 2015 were retrospectively reviewed. Inclusion criteria were patients with prior VA-ECMO. Perioperative characteristics and postoperative outcome of patients who received LVAD after VA-ECMO with (CPB group) or without CPB (no-CPB group) were compared. RESULTS: A total of 110 permanent VADs were implanted during this time frame. Forty patients had VA-ECMO prior to VAD implantation and met the inclusion criteria. The CPB was used in 23 patients and 17 patients received VAD on VA-ECMO without using CPB. The preoperative characteristics of the patients were comparable except for lower body mass index, higher international normalized ratio (INR) and higher rate of preoperative intra-aortic balloon pump usage in the CPB group (P = 0.035, 0.008 and 0.003, respectively). The incidence of postoperative right VAD implantation and survival rate was comparable between both groups. However, the chest tube blood loss and amount of blood product usage was higher in the CPB group. The total blood loss in the first 24 h after surgery (2469 ± 2067 vs 1080 ± 941 ml, P= 0.05) and number of units of intraoperative fresh frozen plasma administered (4 ± 3 vs 1 ± 2, P= 0.02) remained higher in the CPB group even after adjustment for differences in preoperative INR value by propensity score matching. CONCLUSIONS: This study demonstrates that the CPB machine can be safely omitted when a long-term VAD is implanted on VA-ECMO support. Blood loss in the first 24 h after surgery was less and a significantly lower number of blood products were necessary in these patients compared with patients in whom the CPB machine was used. However, similar survival rates between these two groups were observed.

Prevalence of De Novo Aortic Valve Insufficiency in Patients After HeartWare VAD Implantation with an Intermittent Low-Speed Algorithm.

De novo aortic valve insufficiency (AI) is a frequent occurrence in patients supported with left ventricular assist device (LVAD). The European version of the HeartWare LVAD has intermittent low-speed software (lavare cycle) to facilitate intermittent aortic valve opening. We examined aortic valve opening status and prevalence of AI in patients supported with HeartWare LVAD and activated lavare cycle. HeartWare LVAD patients were prospectively monitored using serial echocardiograms at different time points after the LVAD implantation. Inclusion criteria were patients with no > mild AI and/or no aortic valve surgery at the time of LVAD implantation and at least 60 days of support. Three of 37 patients had aortic valve surgery and were excluded from the analysis. A total of 34 patients with mean age of 57 ± 12 years met the inclusion criteria. After median support duration of 408 days (77-1250 days), eight patients had trace/mild AI (24%) and one patient developed moderate AI (3%). An average pump flow, speed, and mean arterial pressure of 4.4 ± 0.6 L/min, 2,585 ± 147 rpm, and 88 ± 11 mmHg were documented, respectively. Aortic valve opening was persistently seen in 22 patients (65%). Aortic valve opening is frequent, and the development of > mild AI seems to be rare in patients supported with HeartWare LVAD.

Alternative right ventricular assist device implantation technique for patients with perioperative right ventricular failure.

OBJECTIVES: Temporary right ventricular assist devices (RVADs) may be required to support patients with perioperative refractory right ventricular failure (RVF). We report on our experience using a different technique of RVAD implantation that does not necessitate resternotomy at the time of RVAD removal. METHODS: Patients with perioperative RVF who underwent temporary RVAD implantation between January 2010 and February 2014 were reviewed. A dacron graft was attached to the pulmonary artery and passed through a subxiphoid exit, where the RVAD outflow cannula was inserted. The inflow cannula was percutaneously cannulated in the femoral vein, and the sternum was primarily closed. On the day of RVAD explantation, the outflow graft of the RVAD was pulled and ligated, and the insertion site was secondarily closed. The RVAD inflow cannula was removed, and direct pressure was applied. RESULTS: Twenty-one patients (age 58 ± 14 years) were supported. Seventeen patients (81%) had RVF after left ventricular assist device implantation, and 4 patients developed postcardiotomy RVF. The median duration of RVAD support was 9 days (range: 2-88 days). Eleven patients (52%) were successfully weaned from the RVAD. Two patients were bridged to transplantation. Eight patients died on left ventricular assist device and/or RVAD support. The survival rates to discharge or heart transplantation, and to 1-year, were 62% and 52%, respectively. CONCLUSIONS: No technical issues were encountered in this large series of RVAD implantations using the described technique for various forms of postoperative RVF. Extended support duration and reduction of resternotomy risks may be the main advantages of this technique compared with conventional RVAD implantation methods.

Minimally Invasive Right Ventricular Assist Device Implantation in a Patient with HeartWare left ventricular Assist Device.

Many centers reported positive outcome after left ventricular assist devices (LVADs) implantation using a minimally invasive approach. The main drawback of this minimally invasive approach is the feasibility of right ventricular assist device (RVAD) implantation with direct cannulation of the pulmonary artery in cases of perioperative right ventricular failure (RVF). We report our experience with a 41-year-old male patient who was supported with a temporary RVAD using J-sternotomy approach for RVF after LVAD implantation. No technical issue was encountered, and the patient's condition stabilized immediately after RVAD implantation. However, several days later, the patient developed severe septic shock caused by pneumonia and died on the postoperative day 15 after RVAD implantation.

Intraventricular pledgetted sutures to prevent suction events in patients with the heartware left ventricular assist device.

Suction events are among the frequently encountered issues after the implantation of a left ventricular assist device and may induce malignant arrhythmias. Several factors may play a role in inducing these suction events. A proper inflow cannula insertion site at the time of surgery, particularly in hypertrophic left ventricles, plays a significant role in the prevention of these events. We describe a novel technique that helps avoid future suction events through the application of several intraventricular pledgetted sutures that displace the intraventricular muscle away from the inflow cannula, change the left ventricular geometry, and provide more room around the inflow cannula.

Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143.

AIMS: Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression. METHODS AND RESULTS: Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC. CONCLUSION: Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.

Cardioprotective properties of omentin-1 in type 2 diabetes: evidence from clinical and in vitro studies.

CONTEXT: Adipokines are linked to the development of cardiovascular dysfunction in type 2 diabetes (DM2). In DM2-patients, circulating levels of omentin-1, an adipokine preferentially expressed in epicardial adipose tissue, are decreased. This study investigated whether omentin-1 has a cardioprotective function. METHODS: Omentin-1 levels in plasma and cardiac fat depots were determined in DM2-patients versus controls. Moreover, the relation between omentin-1 levels and cardiac function was examined in men with uncomplicated DM2. Finally, we determined whether omentin-1 could reverse the induction of cardiomyocyte dysfunction by conditioned media derived from epicardial adipose tissue from patients with DM2. RESULTS: Omentin-1 was highly expressed and secreted by epicardial adipose tissue, and reduced in DM2. Circulating omentin-1 levels were lower in DM2 versus controls, and positively correlated with the diastolic parameters early peak filling rate, early deceleration peak and early deceleration mean (all P<0.05). The improved diastolic function following pioglitazone treatment associated with increases in omentin-1 levels (P<0.05). In vitro, exposure of cardiomyocytes to conditioned media derived from epicardial adipose tissue from patients with DM2 induced contractile dysfunction and insulin resistance, which was prevented by the addition of recombinant omentin. CONCLUSION: These data identify omentin-1 as a cardioprotective adipokine, and indicate that decreases in omentin-1 levels could contribute to the induction of cardiovascular dysfunction in DM2.