Claudius Mahr

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.

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.

Impact of LVAD Implantation Site on Ventricular Blood Stagnation.

Treatment of end-stage heart failure includes cardiac transplantation or ventricular assist device (VAD) therapy. Although increasingly prevalent, current VAD therapy has inherent complications, including thrombosis. Studies have demonstrated that VAD implantation alters intracardiac blood flow, creating areas of stagnation that predispose to thrombus formation. Two potential surgical configurations exist for VAD implantation: through the apical or diaphragmatic surfaces of the heart. We hypothesized that diaphragmatic implantation causes more stagnation than apical implantation. We also hypothesized that intermittent aortic valve (AV) opening reduces stagnation of blood inside the left ventricle (LV) when compared with a closed AV. To test these hypotheses, a human LV geometry was recreated in silico and a VAD inflow cannula was virtually implanted in each configuration. A computational indicator-dilution study was conducted where “virtually dyed blood” was washed out of the LV by injecting blood with no dye. Simulations demonstrated a substantial reduction in stagnation with intermittent AV opening. In addition, virtual dye was cleared slightly faster in the apical configuration. Simulations from our study demonstrate the clinical importance of VAD management to allow intermittent opening of the AV to prevent subvalvular stagnation, and also suggests that apical configuration might be more hemodynamically favorable.

Durable mechanical circulatory support in teenagers and adults with congenital heart disease: A systematic review

BACKGROUND Heart failure is the leading cause of morbidity and mortality for adults with congenital heart disease (ACHD). Many patients are ineligible for transplantation, and those who are eligible often face long wait times with high wait-list morbidity. Durable mechanical circulatory support (MCS) may be an option for many patients. This systematic review evaluates the published literature on the use of durable MCS in teenagers and adults with congenital heart disease. METHODS A comprehensive search of MEDLINE (PubMed), EMBASE, and the Cochrane Library was performed electronically in July 2015 and updated in March 2016, guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. RESULTS Individual case reports and several case series identified 66 patients with ACHD treated with durable MCS. More than half were INTERMACS 1 or 2 at the time of implantation. Patients with Fontan repairs were more frequently classified as INTERMACS 1 or 2 (89% compared to 59% or less among other groups). Cases published after 2010 showed a trend toward less severe INTERMACS status, and patients were less likely to have received transplants by the time of reporting (31% compared to 61% prior). Durable MCS was implanted as bridge-to-transplant in 77%. Patients with Fontan repair accounted for 14% of cases. CONCLUSION Reports of durable MCS utilization in patients with ACHD are becoming more frequent and devices are being implanted in more stable patients. Reports are mostly case reports or small case series so reporting bias is likely and prospective protocoled reporting is needed.

Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study

Background— The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. Methods— On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity–ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. Conclusions— We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

Biventricular Support With Intracorporeal, Continuous Flow, Centrifugal Ventricular Assist Devices

BACKGROUND The incidence of right ventricular dysfunction requiring right ventricular assist device after left ventricular assist device placement has been reported between 10% to 30%. The mortality rate is higher compared with patients who require left ventricular assist device only; the most effective and safest biventricular assist device remains unknown. We aimed to determine the survival outcomes and frequency of adverse events in patients with two durable, intracorporeal, continuous flow centrifugal pumps for support. METHODS Between November 2012 and June 2015, 38 patients were identified from INTERMACS received durable, intracorporeal continuous flow centrifugal pumps for biventricular support. Pediatric patients were excluded. Mean age was 47 years, and 74% of patients were male. The common primary diagnoses in this cohort were dilated myopathy, idiopathic (37%) and ischemic (16%). RESULTS Nineteen participating centers implanted devices in 38 patients; 11 patients died with device in place, 9 patients received a heart transplant, and 18 were alive on support with the right ventricular assist device in place. Survival outcomes were 68% at 6 months and 62% at 12 months. The left ventricular assist device was placed in the left ventricle apex in 91% of cases, and in 9%, the location was not specified. The right ventricular assist device was placed in the right ventricle in 50%, right atrium in 37%, and not specified in 13%. The adverse events included infection 50%, bleeding 44%, respiratory failure 31.6%, and malfunction 26.3%; neurologic dysfunction 26.3%; renal dysfunction 18.4%; and arrhythmia 18.4%. CONCLUSIONS The use of durable, intracorporeal, continuous flow centrifugal pumps for management of advanced biventricular heart failure is associated with high morbidity and mortality. Further investigation of this device configuration is warranted.

Intermittent Aortic Valve Opening and Risk of Thrombosis in Ventricular Assist Device Patients

The current study evaluates quantitatively the impact that intermittent aortic valve (AV) opening has on the thrombogenicity in the aortic arch region for patients under left ventricular assist device (LVAD) therapy. The influence of flow through the AV, opening once every five cardiac cycles, on the flow patterns in the ascending aortic is measured in a patient-derived computed tomography image-based model, after LVAD implantation. The mechanical environment of flowing platelets is investigated, by statistical treatment of outliers in Lagrangian particle tracking, and thrombogenesis metrics (platelet residence times and activation state characterized by shear stress accumulation) are compared for the cases of closed AV versus intermittent AV opening. All hemodynamics metrics are improved by AV opening, even at a reduced frequency and flow rate. Residence times of platelets or microthrombi are reduced significantly by transvalvular flow, as are the shear stress history experienced and the shear stress magnitude and gradients on the aortic root endothelium. The findings of this device-neutral study support the multiple advantages of management that enables AV opening, providing a rationale for establishing this as a standard in long-term treatment and care for advanced heart failure patients.

Periportal fibrosis without cirrhosis does not affect outcomes after continuous flow ventricular assist device implantation.

OBJECTIVE This study investigates the relationship of periportal fibrosis on postoperative outcomes after ventricular assist device (VAD) implantation. METHODS Between July 2005 and August 2014, a total of 233 patients were implanted with continuous flow VADs. Liver biopsy was performed on 16 patients with concern for liver disease. Survival was evaluated using the Kaplan-Meier method. The effect of fibrosis on length of stay (LOS) in the intensive care unit was modeled using Poisson regression. Adjustments were made for age, profile from the Interagency Registry for Mechanically Assisted Circulatory Support, biopsy, and model for end-stage liver disease score. RESULTS Fourteen of the 16 patients who underwent biopsy had periportal fibrosis without cirrhosis. One-year survival for the groups with and without biopsy-proven fibrosis was 93% ± 7% and 86% ± 2% (P = .97), respectively. The intensive care unit LOS was not different for those with (median, 7 days; interquartile range: 3-14 days) versus without fibrosis (median, 6 days; interquartile range 4-10 days; P = .65). Fibrosis (P = .42), age (0.95), model for end-stage liver disease excluding internal normalized ratio-XI score (P = .64), performance of a biopsy (P = .28), and Interagency Registry for Mechanically Assisted Circulatory Support class (P = .70) were not associated with intensive care unit LOS. Risk was increased of gastrointestinal bleeding (14% vs 4%; P = .026) in the first year among patients with fibrosis. CONCLUSIONS The presence of periportal fibrosis did not affect survival or outcomes in patients undergoing VAD implantation. These findings suggest that carefully selected patients with advanced heart failure and hepatic fibrosis without cirrhosis may achieve acceptable outcomes with VAD implantation.

Agreement between risk and priority for heart transplant: Effects of the geographic allocation rule and status assignment

BACKGROUND Allocation of donor hearts in the United States is accomplished by an algorithm based on status, time waited, and geographic boundaries. Although not designed to always transplant the highest acuity candidates, the ability of current United Network for Organ Sharing policies to prioritize highest acuity candidates is unknown. METHODS We analyzed 32,866 adult match runs generated from 2007 to 2014. Each candidates sequence number within a match run was compared with the candidates risk of mortality using Kendalls tau-b-a measure of rank correlation. Two primary methods of evaluating risk of mortality were used: status designation-based risk (i.e., status 1A risk > status 1B > status 2) and status justification-based risk (e.g., status 1A justified by presence of a complication). RESULTS Median sequence number for transplanted candidates was 3 (interquartile range [IQR]: 1, 9). Median correlation among match runs for status-based risk was 0.57 (IQR: 0.47, 0.66) and for justification-based risk was 0.51 (IQR: 0.39, 0.60). Sensitivity to status 2 candidates was evident when status 2 candidates were removed from the sample (status-based tau-b = 0.31, justification-based tau-b = 0.1) and with restriction of the data set to only the first 20 candidates (status-based tau-b = 0.35, justification-based tau-b = 0.15). CONCLUSIONS There is only mild correlation between status and priority under the current allocation algorithm and poor concordance when more detailed risks are considered. The geographic allocation rule is responsible for most of the measured discordance.

Adverse Effects of Delayed Transplant Listing Among Patients With Implantable Left Ventricular Assist Devices

BACKGROUND The timing of transplant listing after implantation of a left ventricular assist device (LVAD) remains uncertain, given high device complication rates and apparent stability of some LVAD-supported patients. This investigation quantifies the effect of delayed transplant listing and transplantation rates on medium-term survival and LVAD complications. METHODS AND RESULTS A Markov model was used to simulate the effects of delaying initial transplant listing after LVAD implantation. Modeled parameters were derived from the Standard Transplant Analysis and Research file. When transplant listing was delayed and 5-year results were examined, fewer persons underwent transplantation (53% in base model vs 51% in 180-day-delay model) and the fraction of deaths while waiting increased (17% in base model vs 21% in 180-day delay model). Life expectancy changed minimally from the base model (3.50 y) when initial listing was delayed by 180 days (3.51 y). CONCLUSIONS Delaying initial transplant listing increased the likelihood of death while waiting for a transplant and decreased the likelihood of transplantation. In aggregate, life expectancy was unchanged by delays in listing. This study suggests that delaying transplant listing with the expectation of providing additional life expectancy is not likely with current LVAD technology.