Nahush A. Mokadam

Predictive value of the Seattle Heart Failure Model in patients undergoing left ventricular assist device placement

BACKGROUND Left ventricular assist devices (LVADs) are increasingly used in advanced heart failure patients. Despite proven efficacy, optimal timing of LVAD implantation is not well defined. METHODS Patients receiving an LVAD were prospectively recorded. Laboratory and clinical data were extracted and used to calculate the predicted survival with medical therapy using the Seattle Heart Failure Model (SHFM). This was compared with observed survival, hospital length of stay and timeliness of discharge. RESULTS We identified 104 patients. Survival with an LVAD vs SHFM predicted survival was 69% vs 11% at 1 year, corresponding to a hazard ratio of 0.17 (p < 0.0001). SHFM-estimated 1-year survival with medical therapy increased from 4% in 1997 to 2004 to 25% in 2007-2008 (p < 0.0001). Subgroup analysis of higher vs lower risk LVAD patients showed observed 1-year survival of 83% vs 57% (p = 0.04). The lower risk group had a shorter length of stay (46 vs 75 days, p = 0.03), along with higher rates of discharge prior to transplant (88% vs 61%, p = 0.01) and discharge within 60 days of LVAD placement (77% vs 52%, p = 0.03). CONCLUSIONS The SHFM allows prediction of important features of a patients hospital course post-operatively, including length of stay and 1-year survival. Given evidence of improved survival and shorter hospital stay in lower risk patients, earlier LVAD placement based on a prediction model like the SHFM should be considered in advanced heart failure patients. The SHFM may have utility as a virtual control arm for single-arm LVAD trials.

Transplant Registrants With Implanted Left Ventricular Assist Devices Have Insufficient Risk to Justify Elective Organ Procurement and Transplantation Network Status 1A Time

OBJECTIVES The goal of this research was to identify disparities in risk within heart transplant urgency designations. BACKGROUND Patients with left ventricular assist devices (LVADs) are given 30 days of elective status 1A time. This allowance may create competition for organs between stable LVAD-supported registrants and less stable registrants listed status 1A or 1B. METHODS The Scientific Registry of Transplant Recipients database was analyzed for all status 1A and 1B listings between 2005 and 2010. Cox models were used to estimate the relative and absolute risk of adverse events (death or delisting as too ill) during status 1A or 1B listing. RESULTS Status 1A registrants supported with dual inotropes and right heart monitoring had a higher risk of adverse events compared to those supported with implanted LVADs using elective 1A time (hazard ratio: 3.2; 95% confidence interval: 1.8 to 5.7). The 30-day risk of events was 1% (95% confidence interval: 0.1% to 3%) for implanted LVADs using elective 1A time and 6% (95% confidence interval: 4% to 8%) for dual inotrope support. Registrants listed with paracorporeal ventricular assist devices had a higher risk of adverse events (hazard ratio: 9.1; p < 0.0001) compared with registrants with implanted LVADs using elective 1A time. The odds of transplant were higher for implanted LVADs (odds ratio: 1.5; p < 0.0001) compared with dual-inotrope and intra-aortic balloon pump support. CONCLUSIONS The historic allowance for 30 days of elective status 1A time for implanted LVADs creates disparities in risk among status 1A registrants. The allowance of 30 days of elective status 1A time should not be allocated to stable registrants with implanted LVADs. Registrants supported with paracorporeal ventricular assist devices should be listed status 1A indefinitely.

Scan, plan, print, practice, perform: Development and use of a patient-specific 3-dimensional printed model in adult cardiac surgery

Objective: Static 3‐dimensional printing is used for operative planning in cases that involve difficult anatomy. An interactive 3D print allowing deliberate surgical practice would represent an advance. Methods: Two patients with hypertrophic cardiomyopathy had 3‐dimensional prints constructed preoperatively. Stereolithography files were generated by segmentation of chest computed tomographic scans. Prints were made with hydrogel material, yielding tissue‐like models that can be surgically manipulated. Septal myectomy of the print was performed preoperatively in the simulation laboratory. Volumetric measures of print and patient resected specimens were compared. An assessment tool was developed and used to rate the utility of this process. Clinical and echocardiographic data were reviewed. Results: There was congruence between volumes of print and patient resection specimens (patient 1, 3.5 cm3 and 3.0 cm3, respectively; patient 2, 4.0 cm3 and 4.0 cm3, respectively). The prints were rated useful (3.5 and 3.6 on a 5‐point Likert scale) for preoperative visualization, planning, and practice. Intraoperative echocardiographic assessment showed adequate relief of left ventricular outflow tract obstruction (patient 1, 80 mm Hg to 18 mm Hg; patient 2, 96 mm Hg to 9 mm Hg). Both patients reported symptomatic improvement (New York Heart Association functional class III to class I). Conclusions: Three‐dimensional printing of interactive hypertrophic cardiomyopathy heart models allows for patient‐specific preoperative simulation. Resection volume relationships were congruous on both specimens and suggest evidence of construct validity. This model also holds educational promise for simulation of a low‐volume, high‐risk operation that is traditionally difficult to teach.

Activity, Inhibition, and Induction of Cytochrome P450 2J2 in Adult Human Primary Cardiomyocytes

Cytochrome P450 2J2 plays a significant role in the epoxidation of arachidonic acid to signaling molecules important in cardiovascular events. CYP2J2 also contributes to drug metabolism and is responsible for the intestinal clearance of ebastine. However, the interaction between arachidonic acid metabolism and drug metabolism in cardiac tissue, the main expression site of CYP2J2, has not been examined. Here we investigate an adult-derived human primary cardiac cell line as a suitable model to study metabolic drug interactions (inhibition and induction) of CYP2J2 in cardiac tissue. The primary human cardiomyocyte cell line demonstrated similar mRNA-expression profiles of P450 enzymes to adult human ventricular tissue. CYP2J2 was the dominant isozyme with minor contributions from CYP2D6 and CYP2E1. Both terfenadine and astemizole oxidation were observed in this cell line, whereas midazolam was not metabolized suggesting lack of CYP3A activity. Compared with recombinant CYP2J2, terfenadine was hydroxylated in cardiomyocytes at a similar Km value of 1.5 μM. The Vmax of terfenadine hydroxylation in recombinant enzyme was found to be 29.4 pmol/pmol P450 per minute and in the cells 6.0 pmol/pmol P450 per minute. CYP2J2 activity in the cell line was inhibited by danazol, astemizole, and ketoconazole in submicromolar range, but also by xenobiotics known to cause cardiac adverse effects. Of the 14 compounds tested for CYP2J2 induction, only rosiglitazone increased mRNA expression, by 1.8-fold. This cell model can be a useful in vitro model to investigate the role of CYP2J2-mediated drug metabolism, arachidonic acid metabolism, and their association to drug induced cardiotoxicity.

Experience With the Cardiac Surgery Simulation Curriculum: Results of the Resident and Faculty Survey

BACKGROUND The Cardiac Surgery Simulation Curriculum was developed at 8 institutions from 2010 to 2013. A total of 27 residents were trained by 18 faculty members. A survey was conducted to gain insight into the initial experience. METHODS Residents and faculty were sent a 72- and 68-question survey, respectively. In addition to demographic information, participants reported their view of the overall impact of the curriculum. Focused investigation into each of the 6 modules was obtained. Participants evaluated the value of the specific simulators used. Institutional biases regarding implementation of the curriculum were evaluated. RESULTS Twenty (74%) residents and 14 (78%) faculty responded. The majority (70%) of residents completed this training in their first and second year of traditional-track programs. The modules were well regarded with no respondents having an unfavorable view. Both residents and faculty found low, moderate, and high fidelity simulators to be extremely useful, with particular emphasis on utility of high fidelity components. The vast majority of residents (85%) and faculty (100%) felt more comfortable in the resident skill set and performance in the operating room. Simulation of rare adverse events allowed for development of multidisciplinary teams to address them. At most institutions, the conduct of this curriculum took precedence over clinical obligations (64%). CONCLUSIONS The Cardiac Surgery Simulation Curriculum was implemented with robust adoption among the investigating centers. Both residents and faculty viewed the modules favorably. Using this curriculum, participants indicated an improvement in resident technical skills and were enthusiastic about training in adverse events and crisis management.

Systematic donor selection review process improves cardiac transplant volumes and outcomes

BACKGROUND Heart transplant remains the definitive therapy for advanced heart failure patients but is limited by organ availability. We identified a large number of donor hearts from our organ procurement organization (OPO) being exported to other regions. METHODS We engaged a multidisciplinary team including transplant surgeons, cardiologists, and our OPO colleagues to identify opportunities to improve our center-specific organ utilization rate. We performed a retrospective analysis of donor offers before and after institution of a novel review process. RESULTS Each donor offer made to our program was reviewed on a monthly basis from July 2013 to June 2014 and compared with the previous year. This review process resulted in a transplant utilization rate of 28% for period 1 versus 49% for period 2 (P = .007). Limiting the analysis to offers from our local OPO changed our utilization rate from 46% to 75% (P = .02). Transplant volume increased from 22 to 35 between the 2 study periods. Thirty-day and 1-year mortality were unchanged over the 2 periods. A total of 58 hearts were refused by our center and transplanted at other centers. During period 1, the 30-day and 1-year survival rates for recipients of those organs were 98% and 90%, respectively, comparable with our historical survival data. CONCLUSIONS The simple process of systematically reviewing donor turndown events as a group tended to reduce variability, increase confidence in expanded criteria for donors, and resulted in improved donor organ utilization and transplant volumes.

Mechanisms of Bone Marrow-Derived Cell Therapy in Ischemic Cardiomyopathy with Left Ventricular Assist Device Bridge to Transplant

BACKGROUND Clinical trials report improvements in function and perfusion with direct injection of bone marrow cells into the hearts of patients with ischemic cardiomyopathy. Preclinical data suggest these cells improve vascular density, which would be expected to decrease fibrosis and inflammation. OBJECTIVES The goal of this study was to test the hypothesis that bone marrow stem cells (CD34+) will improve histological measurements of vascularity, fibrosis, and inflammation in human subjects undergoing left ventricular assist device (LVAD) placement as a bridge to cardiac transplantation. METHODS Subjects with ischemic cardiomyopathy who were scheduled for placement of an LVAD as a bridge to transplantation underwent bone marrow aspiration the day before surgery; the bone marrow was processed into cell fractions (bone marrow mononuclear cells, CD34+, and CD34-). At LVAD implantation, all fractions and a saline control were injected epicardially into predetermined areas and each injection site marked. At the time of transplantation, injected areas were collected. Data were analyzed by paired Student t test comparing the effect of cell fractions injected within each subject. RESULTS Six subjects completed the study. There were no statistically significant differences in complications with the procedure versus control subjects. Histological analysis indicated that myocardium injected with CD34+ cells had decreased density of endothelial cells compared to saline-injected myocardium. There were no significant differences in fibrosis or inflammation between groups; however, density of activated fibroblasts was decreased in both CD34+ and CD34- injected areas. CONCLUSIONS Tissue analysis does not support the hypothesis that bone marrow-derived CD34+ cells promote increased vascular tissue in humans with ischemic cardiomyopathy via direct injection.

Prevalence of birefringent crystals in cardiac and prostatic tissues, an observational study

Introduction The prevalence of urate crystals in residual tissue samples from coronary arteries, aortic valves and prostate glands was assessed. Methods Alcohol-fixed coronary arteries from 55 explanted hearts, alcohol-fixed aortic valves collected from 75 valve replacement surgeries and 40 frozen, unfixed prostate specimens resected during cancer surgery were examined for birefringent crystals with polarising microscopy. Results In the 55 explanted hearts, 6 (10.9%) contained a coronary artery with birefringent crystals. One of the 75 aortic valves (1.4%) contained negatively and positively birefringent crystals. Nineteen of the 40 (47.5%) prostates contained birefringent crystals. Conclusions We found that a remarkable percentage of coronary arteries and prostate specimens contained birefringent crystals. Crystal presence is an obvious prerequisite for possible crystal induced-inflammation in these tissues, just as similar crystals elicit a gouty inflammatory cascade in synovial joints. Further studies are necessary to determine whether urate crystals may play this role in these tissues and, if so, to establish whether urate-lowering therapy may be beneficial in prostatitis and coronary disease.

The Joint Council on Thoracic Surgery Education Coronary Artery Assessment Tool Has High Interrater Reliability

BACKGROUND Barriers to incorporation of simulation in cardiothoracic surgery training include lack of standardized, validated objective assessment tools. Our aim was to measure interrater reliability and internal consistency reliability of a coronary anastomosis assessment tool created by the Joint Council on Thoracic Surgery Education. METHODS Ten attending surgeons from different cardiothoracic residency programs evaluated nine video recordings of 5 individuals (1 medical student, 1 resident, 1 fellow, 2 attendings) performing coronary anastomoses on two simulation models, including synthetic graft task station (low fidelity) and porcine explant (high fidelity), as well as in the operative setting. All raters, blinded to operator identity, scored 13 assessment items on a 1 to 5 (low to high) scale. Each performance also received an overall pass/fail determination. Interrater reliability and internal consistency were assessed as intraclass correlation coefficients and Cronbachs α, respectively. RESULTS Both interrater reliability and internal consistency were high for all three models (intraclass correlation coefficients = 0.98, 0.99, and 0.94, and Cronbachs α = 0.99, 0.98, and 0.97 for low fidelity, high fidelity, and operative setting, respectively). Interrater reliability for overall pass/fail determination using κ were 0.54, 0.86, 0.15 for low fidelity, high fidelity, and operative setting, respectively. CONCLUSIONS Even without instruction on the assessment tool, experienced surgeons achieved high interrater reliability. Future resident training and evaluation may benefit from utilization of this tool for formative feedback in the simulated and operative environments. However, summative assessment in the operative setting will require further standardization and anchoring.

LVAD Outflow Graft Angle and Thrombosis Risk.

This study quantifies thrombogenic potential (TP) of a wide range of left ventricular assist device (LVAD) outflow graft anastomosis angles through state-of-the-art techniques: 3D imaged-based patient-specific models created via virtual surgery and unsteady computational fluid dynamics with Lagrangian particle tracking. This study aims at clarifying the influence of a single parameter (outflow graft angle) on the thrombogenesis associated with flow patterns in the aortic root after LVAD implantation. This is an important and poorly-understood aspect of LVAD therapy, because several studies have shown strong inter and intrapatient thrombogenic variability and current LVAD implantation strategies do not incorporate outflow graft angle optimization. Accurate platelet-level investigation, enabled by statistical treatment of outliers in Lagrangian particle tracking, demonstrates a strong influence of outflow graft anastomoses angle on thrombogenicity (platelet residence times and activation state characterized by shear stress accumulation) with significantly reduced TP for acutely-angled anastomosed outflow grafts. The methodology presented in this study provides a device-neutral platform for conducting comprehensive thrombogenicity evaluation of LVAD surgical configurations, empowering optimal patient-focused surgical strategies for long-term treatment and care for advanced heart failure patients.