Mast-cell expressed membrane protein-1 is expressed in classical monocytes and alveolar macrophages in idiopathic pulmonary fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFß-dependent manner.

Mast-cell expressed membrane protein-1 (MCEMP1) is higher in patients with idiopathic pulmonary fibrosis (IPF) with an increased risk of death. Here we aimed to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared with controls. MCEMP1 is upregulated by transforming growth factor beta (TGFß) at the mRNA and protein levels in monocytic leukemia THP-1 cells. TGFß-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis-regulatory elements within the MCEMP1 promoter. We also found that MCEMP1 regulates TGFß-mediated monocyte chemotaxis, adhesion, and migration. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.NEW & NOTEWORTHY MCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF, is regulated by TGFß, and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFß in RHO activity.

Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is expressed in classical monocytes and alveolar macrophages in Idiopathic Pulmonary Fibrosis and regulates cell chemotaxis, adhesion, and migration in a TGFß dependent manner.

Background: Mast-Cell Expressed Membrane Protein-1 (MCEMP1) is higher in Idiopathic Pulmonary Fibrosis (IPF) patients with increased risk of death and poor outcomes. Here we seek to establish the mechanistic role of MCEMP1 in pulmonary fibrosis. Methods: MCEMP1 expression was analyzed by single-cell RNA sequencing, immunofluorescence in Peripheral Blood Mononuclear Cells (PBMC) as well as in lung tissues from IPF patients and controls. Chromatin Immunoprecipitation (ChiP) and Proximity Ligation Assay (PLA) were used to study the transcriptional regulation of MCEMP1 . Transient RNA interference and lentivirus transduction were used to knockdown and knock-in MCEMP1 in THP-1 cells to study chemotaxis, adhesion, and migration. Bulk RNA sequencing was used to identify the mechanisms by which MCEMP1 participates in monocyte function. Active RHO pull-down assay was used to validate bulk RNA sequencing results. Results: We identified increased MCEMP1 expression in classical monocytes and alveolar macrophages in IPF compared to controls. MCEMP1 was upregulated by TGFß at the mRNA and protein levels in THP-1. TGFß-mediated MCEMP1 upregulation results from the cooperation of SMAD3 and SP1 via concomitant binding to SMAD3/SP1 cis -regulatory elements within the MCEMP1 promoter. In terms of its function, we found that MCEMP1 regulates TGFß-mediated monocyte chemotaxis, adhesion, and migration. 400 differentially expressed genes were found to increase after TGFß stimulation of THP-1, further increased in MCEMP1 knock-in cells treated with TGFß and decreased in MCEMP1 knockdown cells treated with TGFß. GO annotation analysis of these genes showed enrichment for positive regulation of RHO GTPase activity and signal transduction. While TGFß enhanced RHO GTPase activity in THP-1 cells, this effect was attenuated following MCEMP1 knockdown. Conclusion: MCEMP1 is highly expressed in circulating classical monocytes and alveolar macrophages in IPF. MCEMP1 is regulated by TGFß and participates in the chemotaxis, adhesion, and migration of circulating monocytes by modulating the effect of TGFß in RHO activity. Our results suggest that MCEMP1 may regulate the migration and transition of monocytes to monocyte-derived alveolar macrophages during pulmonary fibrosis development and progression.

Use of Organ Care System Lung for Single-Lung Transplantation.

The Organ Care System-Lung allows for normothermic lung preservation in double-lung transplantation. Deterioration of the lung bloc may due to a single nonfunctional side, and surgeons need to be aware of this scenario in hopes of preserving the functional side for transplantation.

Coronary artery bypass graft markers: history, usage, and effects.

Coronary artery bypass grafting (CABG) is one of the most common procedures in the United States as many Americans suffer from coronary heart disease and undergo CABG each year. While CABG has been performed for decades, questions remain regarding the benefits graft marker placement provides for patient therapy and outcomes. Markers at the proximal graft anastomosis aim to improve the efficiency and reduce the risks of subsequent, post-coronary artery bypass grafting coronary angiography by decreasing fluoroscopy time and contrast volume used. Graft markers have been shown to reduce fluoroscopy time and contrast volume, but concerns exist regarding their potentially negative impact on patient outcomes by increasing procedural time and possibly affecting graft patency. The relationship between graft markers and graft patency has not been studied in depth, and there is little evidence to show that graft patency is determined by graft marker placement. Because of the potential benefits to patients and the limited risks, it is important to continue studying graft marker usage and their effects on long-term outcomes.

Heart Transplantation Outcomes in Patients With Hepatitis C Virus Infection: Potential Impact of Newer Antiviral Treatments After Transplantation.

This study found significant improvements in heart transplant outcomes and survival in patients with hepatitis C virus.

Impact of INTERMACS Profile on Clinical Outcomes for Patients Supported With the Total Artificial Heart.

BACKGROUND: Insufficient data delineate outcomes for Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 patients with the total artificial heart (TAH). METHODS: We studied 66 consecutive patients implanted with the TAH at our institution from 2006 through 2012 and compared outcome by INTERMACS profile. INTERMACS profiles were adjudicated retrospectively by a reviewer blinded to clinical outcomes. RESULTS: Survival after TAH implantation at 6 and 12 months was 76% and 71%, respectively. INTERMACS profile 1 patients had decreased 6-month survival on the device compared with those in profiles 2-4 (74% vs 95%, log rank: P = .015). For the 50 patients surviving to heart transplantation, the 1-year posttransplant survival was 82%. There was no difference in 1-year survival when comparing patients in the INTERMACS 1 profile with less severe profiles (79% vs 84%; log rank test P = .7; hazard ratio [confidence interval] 1.3 [0.3-4.8]). CONCLUSIONS: Patients implanted with the TAH as INTERMACS profile 1 had reduced survival to transplantation compared with less sick profiles. INTERMACS profile at the time of TAH implantation did not affect 1-year survival after heart transplantation.

Renal Function Recovery with Total Artificial Heart Support.

Heart failure patients requiring total artificial heart (TAH) support often have concomitant renal insufficiency (RI). We sought to quantify renal function recovery in patients supported with TAH at our institution. Renal function data at 30, 90, and 180 days after TAH implantation were analyzed for patients with RI, defined as hemodialysis supported or an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m. Between January 2008 and December 2013, 20 of the 46 (43.5%) TAH recipients (age 51 ± 9 years, 85% men) had RI, mean preoperative eGFR of 48 ± 7 ml/min/1.73 m. Renal function recovery was noted at each follow-up interval: increment in eGFR (ml/min/1.73 m) at 30, 90, and 180 days was 21 ± 35 (p = 0.1), 16.5 ± 18 (p = 0.05), and 10 ± 9 (p = 0.1), respectively. Six patients (30%) required preoperative dialysis. Of these, four recovered renal function, one remained on dialysis, and one died. Six patients (30%) required new-onset dialysis. Of these, three recovered renal function and three died. Overall, 75% (15 of 20) of patients' renal function improved with TAH support. Total artificial heart support improved renal function in 75% of patients with pre-existing significant RI, including those who required preoperative dialysis.

Dobutamine induced eosinophilic myocarditis and right heart failure requiring emergent biventricular assist device implantation.

Dobutamine is a rare and unrecognized cause of eosinophilic myocarditis (EM). It is even more unique for it to cause significant clinical deterioration. Patients with end stage cardiomyopathy have very little cardiac reserve and dobutamine induced myocarditis may cause enough harm to require urgent mechanical circulatory support. We describe a man with dilated cardiomyopathy that developed accelerated clinical deterioration from dobutamine induced EM. He had a predominance of right heart failure, requiring an urgent biventricular assist device and acutely responded to withdrawal of dobutamine.

Donor Heart Utilization following Cardiopulmonary Arrest and Resuscitation: Influence of Donor Characteristics and Wait Times in Transplant Regions.

Background. Procurement of hearts from cardiopulmonary arrest and resuscitated (CPR) donors for transplantation is suboptimal. We studied the influences of donor factors and regional wait times on CPR donor heart utilization. Methods. From UNOS database (1998 to 2012), we identified 44,744 heart donors, of which 4,964 (11%) received CPR. Based on procurement of heart for transplantation, CPR donors were divided into hearts procured (HP) and hearts not procured (HNP) groups. Logistic regression analysis was used to identify predictors of heart procurement. Results. Of the 4,964 CPR donors, 1,427 (28.8%) were in the HP group. Donor characteristics that favored heart procurement include younger age (25.5 ± 15 yrs versus 39 ± 18 yrs, P ≤ 0.0001), male gender (34% versus 23%, P ≤ 0.0001), shorter CPR duration (<15 min versus >30 min, P ≤ 0.0001), and head trauma (60% versus 15%). Among the 11 UNOS regions, the highest procurement was in Region 1 (37%) and the lowest in Region 3 (24%). Regional transplant volumes and median waiting times did not influence heart procurement rates. Conclusions. Only 28.8% of CPR donor hearts were procured for transplantation. Factors favoring heart procurement include younger age, male gender, short CPR duration, and traumatic head injury. Heart procurement varied by region but not by transplant volumes or wait times.

Safety analysis of intermittent hemodialysis in patients with continuous flow left ventricular assist devices.

Dialysis centers adopt a cautious approach when it comes to performing intermittent hemodialysis (HD) on patients with continuous flow (CF) left ventricular assist devices (LVADs) because of the potential for volume flux-related complications and absence of pulsatile blood pressure for monitoring. Many patients have to remain hospitalized because of the inability of the dialysis centers to accept them for outpatient dialysis. In this study, the effect of HD was observed in such patients. Between June 2009 and October 2012, 139 patients received LVADs, of which 10 patients (7%) required intermittent HD postoperatively. The mean age of the patients was 53 ± 14 years and 90% were men. A total of 281 dialysis sessions were administered amounting to 1025 hours of dialysis. The mean systolic blood pressure monitored with Doppler device was 97 ± 18 mmHg. Dialysis durations averaged 218 ± 18 minutes. Mean blood flow rate was 334 ± 38 cc/min, and 2.6 ± 1.1 L was ultrafiltrated during each session. Only 15 (5.3%) sessions were interrupted or terminated in six patients. The reasons for termination were symptomatic hypotension--6 (2.1%), asymptomatic hypotension--3 (1%), ventricular tachycardia--1 (0.36%), dialysis machine malfunction--2 (0.7%), low phosphorus--2 (0.7%), and abdominal cramps--1 (0.36%). Volume expansion was necessary on three occasions. Low-flow device alarms were registered during two (0.71%) sessions. The results showed no serious adverse effects or deaths.

Left ventricular assist device and heart transplantation in hemophilia a patient.

We report here a hemophilia patient who was bridged with a left ventricle assist device and later received heart transplantation. Preparation for surgery with factor VIII supplementation, intraoperative conduct of surgery, and challenges of postoperative course are described with a brief literature review.

The safety of preoperative vardenafil in patients undergoing coronary artery bypass graft surgery.

Phosphodiesterase 5 inhibitors are cardioprotective against myocardial reperfusion ischemic injury in animal models but are contraindicated in patients with coronary disease who take nitrates because of a risk for hypotension. We investigated the safety of vardenafil in patients undergoing coronary artery bypass grafting (CABG) surgery. A single dose of vardenafil was given to 10 patients before CABG surgery. The postoperative course of these 10 patients was compared with the postoperative course of 47 patients who did not receive vardenafil before CABG surgery. There were no perioperative deaths and no episodes of hypotension in the group receiving vardenafil. The clinical and operative characteristics of the 2 study groups were similar. There were no significant differences in postoperative serum troponin levels (9.1 ± 8.3 vs 12.5 ± 9.3 ng/mL; P = 0.29, respectively), duration of postoperative intubation (21.4 ± 10.1 vs 27.4 ± 15.2 hours; P = 0.14, respectively), or length of hospital stay (11.1 ± 13.2 vs 10.0 ± 4.7 days; P = 0.8, respectively) between the group receiving vardenafil and the control group. This pilot study of 10 patients suggests that vardenafil use is safe in patients before CABG surgery. A larger study is needed to explore the myocardial protective effect of the drug.

Persistent anemia after implantation of the total artificial heart.

BACKGROUND: The total artificial heart (TAH) replaces the heart with 2 pneumatic pumps and 4 tilting disk mechanical valves. It was hypothesized that patients receiving TAH support have persistent hemolysis that resolves after heart transplantation (HT). METHODS AND RESULTS: Hematocrit (HCT) was compared in patients on TAH to left ventricular assist device (LVAD) support for bridge to HT. Data were compared with t tests. The TAH (n = 36; mean age 47 ± 13 years) and LVAD patients (n = 14; mean age 53 ± 12 years) were supported for a median of 83 (interquartile range [IQR] 43-115) and 106 days (IQR 84-134), respectively. Hematocrit was similar between the TAH and LVAD patients (34 ± 6% vs 37 ± 5%; P = .07) at baseline. After placement, TAH patients had lower HCT at 2 (20 ± 2% vs 24 ± 3%), 4 (22 ± 3% vs 26 ± 3%), 6 (22 ± 4% vs 30 ± 4%), and 8 weeks (23 ± 4% vs 33 ± 5%; P < .001 for all). There were no differences in HCT at 1 (30 ± 4% vs 29 ± 7%; P = .42) and 3 months (35 ± 7% vs 35 ± 4%; P = .98) after removal of the devices for HT. TAH patients had undetectable haptoglobin in 96% of assessments, increased lactate dehydrogenase (1,128 ± 384 units/L), and detectable plasma free hemoglobin in 40% of measurements (21 ± 15 mg/dL). High sensitivity C-reactive protein (52 ± 50 mg/dL) was elevated, and reticulocyte production index was decreased (1.6 ± 0.6). CONCLUSIONS: Patients implanted with a TAH have persistent anemia that resolves only after HT. The association of hemolysis, ineffective erythropoiesis, and inflammation with the TAH warrants further study.

The total artificial heart for biventricular heart failure and beyond.

PURPOSE OF REVIEW: Treatment options for late-stage biventricular heart failure are limited but include medical therapy with intravenous inotropes, biventricular assist devices (Bi-VADs) and the total artificial heart (TAH). In this manuscript, we review the indications, surgical techniques and outcomes for the TAH. RECENT FINDINGS: The TAH offers biventricular replacement, rather than 'assistance', as the device is placed orthotopically after excision of the entire ventricular myocardium and all four native valves. In contrast to patients with Bi-VADs, patients with the TAH have no postoperative inotrope requirements, arrhythmias or inflow/outflow cannulae-related complications. Additionally, patients participate in rehabilitation early after device placement and the development of a portable drive may facilitate hospital discharge in the USA. Furthermore, total heart replacement may be ideal for heart failure associated with unique anatomical and mechanical complications. SUMMARY: The TAH is an effective therapeutic option for the treatment of patients dying of heart failure who may not be suitable candidates for left ventricular assist devices.

Evaluating heart failure after implantation of mechanical circulatory support devices.

The medical community has seen an explosive rise in the utilization of implantable mechanical circulatory support devices for late-stage cardiomyopathy. Care for these complex patients requires a basic understanding of device physiology and potential complications. This review focuses on an algorithm that incorporates a careful clinical history and examination with diagnostic modalities for the evaluation of a patient who is failing therapy with a continuous-flow left ventricular assist device, as well as the general management and optimization of patients implanted with an artificial heart.

Exercise blood pressure response during assisted circulatory support: comparison of the total artificial [corrected] heart with a left ventricular assist device during rehabilitation.

BACKGROUND: The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). METHODS: We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. RESULTS: In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (ß = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: ß = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. CONCLUSIONS: During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Implantable mechanical circulatory support: demystifying patients with ventricular assist devices and artificial hearts.

Engineering advancements have expanded the role for mechanical circulatory support devices in the patient with heart failure. More patients with mechanical circulatory support are being discharged from the implanting institution and will be seen by clinicians outside the immediate surgical or heart-failure team. This review provides a practical understanding of device design and physiology, general troubleshooting, and limitations and complications for implantable left ventricular assist devices (pulsatile-flow and continuous-flow pumps) and the total artificial heart.

Antithrombotic therapy for the CardioWest temporary total artificial heart.

The CardioWest temporary total artificial heart serves as a viable bridge to orthotopic heart transplantation in patients who are experiencing end-stage refractory biventricular heart failure. This device is associated with a low, albeit still substantial, risk of thrombosis. Platelet interactions with artificial surfaces are complex and result in continuous activation of contact proteins despite therapeutic anticoagulation. We searched the medical literature (publication dates, January 1962-October 2009) in order to evaluate means of mitigating adverse events that have occurred after implantation of the CardioWest temporary total artificial heart.We conclude that the use of a multitargeted antithrombotic approach, involving anticoagulation (bivalirudin and warfarin) and antiplatelet therapy (dipyridamole and aspirin), can mitigate the procoagulative effects of mechanical circulatory assist devices, particularly those that are associated with the CardioWest temporary total artificial heart. Careful monitoring with use of a variant multisystem approach, involving efficacy tests (thrombelastography and light transmittance aggregometry), safety tests (laboratory analyses), and warfarin genomics, may maximize the therapeutic actions and minimize the bleeding risks that are associated with the multitargeted antithrombotic approach. The development and monitoring of individualized antithrombotic regimens require that informed health professionals appreciate the complexities and grasp the hazards that are associated with these therapies.

Successful use and dosing of bivalirudin after temporary total artificial heart implantation: a case series.

The temporary total artificial heart (TAH-t) has emerged as an effective bridge to transplantation for individuals with biventricular failure. Implantation of a TAH-t creates a hypercoagulable state requiring a multidrug approach that includes low-dose unfractionated heparin (UFH) in order to minimize thromboembolism. A concern with UFH is the development of heparin-dependent antibodies, which develop in up to 50% of patients receiving the drug as part of cardiopulmonary bypass. If UFH therapy continues postoperatively, the risk of heparin-induced thrombocytopenia approaches 3%. Small investigations have demonstrated that bivalirudin, given as a bolus of 0.75-1 mg/kg followed by an infusion at 1.75-2.5 mg/kg/hour, is an effective alternative to UFH for therapeutic anticoagulation during coronary artery bypass surgery, valve replacement, or both. We describe a series of five adults (age range 24-58 yrs) who received bivalirudin as an alternative to low-dose UFH after TAH-t implantation. None of the patients had documented heparin-induced thrombocytopenia. Treatment was started at the discretion of the treating physician, and adjustments were based principally on the results of thromboelastography. Additional general monitoring included activated partial thromboplastin time, prothrombin time, international normalized ratio, fibrinogen, D-dimer, platelet count, hemoglobin, hematocrit, and platelet aggregation studies. Bivalirudin therapy was continued until successful warfarin implementation. All five patients received bivalirudin in addition to standard antithrombotic therapy. Bivalirudin treatment started at a dosage of 0.005 or 0.01 mg/kg/hour with titration to maintain normocoagulability, which occurred (without concomitant warfarin therapy) within the dosage range of 0.01-0.02 mg/kg/hour. Duration of TAH-t implantation was a mean of 38.8 days (range 25-60 days), and bivalirudin was continued for a mean of 15.2 days (range 7-24 days). No major hemorrhagic events occurred during treatment, and all patients successfully transitioned to warfarin therapy. Low-dose bivalirudin, as an alternative to UFH, maintained normocoagulability after TAH-t implantation. Further investigation is warranted to define the role and dosing of bivalirudin in this situation.