Richard K. Cheng

Cyclin A2 Induces Cardiac Regeneration After Myocardial Infarction Through Cytokinesis of Adult Cardiomyocytes

Cyclin A2 mediates cardiac regeneration of infarcted porcine hearts. A Change of Heart After Myocardial Infarction When blood flow is blocked off to the heart, the heart suffers permanent damage in part because cardiomyocytes are terminally differentiated and cannot proliferate. But what if these cells could be stimulated to divide? Some animals—like newts—have the ability to regenerate body parts when they are injured. Others—like zebrafish—can even regenerate heart tissue. Now, Shapiro et al. report that gene therapy can elicit a regenerative response in pig hearts. Cyclin A2 (Ccna2) has been shown to induce cardiac repair in small-animal models after myocardial infarction (MI). The authors have extended these studies by looking in the more translationally relevant pig model of MI. They found that Ccna2 delivered by an adenovirus improved heart function when compared with an adenoviral control. Cardiomyocytes in the pigs showed evidence of increased proliferation. If these data hold true in human studies, patients with MI can take heart. Cyclin A2 (Ccna2), normally silenced after birth in the mammalian heart, can induce cardiac repair in small-animal models of myocardial infarction. We report that delivery of the Ccna2 gene to infarcted porcine hearts invokes a regenerative response. We used a catheter-based approach to occlude the left anterior descending artery in swine, which resulted in substantial myocardial infarction. A week later, we performed left lateral thoracotomy and injected adenovirus carrying complementary DNA encoding CCNA2 or null adenovirus into peri-infarct myocardium. Six weeks after treatment, we assessed cardiac contractile function using multimodality imaging including magnetic resonance imaging, which demonstrated ~18% increase in ejection fraction of Ccna2-treated pigs and ~4% decrease in control pigs. Histologic studies demonstrate in vivo evidence of increased cardiomyocyte mitoses, increased cardiomyocyte number, and decreased fibrosis in the experimental pigs. Using time-lapse microscopic imaging of cultured adult porcine cardiomyocytes, we also show that Ccna2 elicits cytokinesis of adult porcine cardiomyocytes with preservation of sarcomeric structure. These data provide a compelling framework for the design and development of cardiac regenerative therapies based on cardiomyocyte cell cycle regulation.

Systematic donor selection review process improves cardiac transplant volumes and outcomes

BACKGROUNDnHeart 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.nnnMETHODSnWe 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.nnnRESULTSnEach 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.nnnCONCLUSIONSnThe 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.

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.

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

OBJECTIVEnThis study investigates the relationship of periportal fibrosis on postoperative outcomes after ventricular assist device (VAD) implantation.nnnMETHODSnBetween 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.nnnRESULTSnFourteen 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.nnnCONCLUSIONSnThe 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

BACKGROUNDnAllocation 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.nnnMETHODSnWe 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).nnnRESULTSnMedian 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).nnnCONCLUSIONSnThere 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

BACKGROUNDnThe 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.nnnMETHODS AND RESULTSnA 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).nnnCONCLUSIONSnDelaying 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.

Effect of regional competition on heart transplant waiting list outcomes

BACKGROUNDnHeterogeneity of risk within heart transplant urgency designations is undesirable. Regional competition for donor hearts may contribute to this variation in risk. In this study we assessed whether an association exists between center competition and variation in event rates within status designations on the waiting list.nnnMETHODSnOur study sample included 20,237 adult transplant registrants initially listed between July 1, 2006 and July 1, 2013. Market competition was quantified using the Herfindahl-Hirshman Index (HHI) and number of centers within a donor service area (DSA) per 1 million people. A Cox model was used to assess for variation in waiting list outcomes within status designation by both HHI and DSA density. The primary outcome was death or delisting as too ill.nnnRESULTSnOutcome rates within status designations differed significantly between centers: Status 1A, center p < 0.0001; Status 1B, center p < 0.0001; and Status 2, center p < 0.0001. Market competition (decreasing HHI) was associated with differential outcome rates within higher urgency status designation [Status 1A hazard ratio (HR) 0.94, p = 0.012; Status 1B HR 0.95, p = 0.010; and Status 2 HR 1.02, p = 0.360]. Center density within the DSA was not associated with outcome rates within each status designation (Status 1A HR 0.99, p = 0.961; Status 1B HR 1.03, p = 0.901; and Status 2 HR 1.20, p = 0.399).nnnCONCLUSIONSnThe rate of death or delisting as too ill within urgency designations varies between transplant centers and is partially explained by competition between transplant programs. Further methods of normalizing risk within status designations are necessary.

Developing and implementing a heart failure data mart for research and quality improvement

ABSTRACT Objective: The purpose of this project was to build and formatively evaluate a near-real time heart failure (HF) data mart. Heart Failure (HF) is a leading cause of hospital readmissions. Increased efforts to use data meaningfully may enable healthcare organizations to better evaluate effectiveness of care pathways and quality improvements, and to prospectively identify risk among HF patients. Methods and procedures: We followed a modified version of the Systems Development Life Cycle: 1) Conceptualization, 2) Requirements Analysis, 3) Iterative Development, and 4) Application Release. This foundational work reflects the first of a two-phase project. Phase two (in process) involves the implementation and evaluation of predictive analytics for clinical decision support. Results: We engaged stakeholders to build working definitions and established automated processes for creating an HF data mart containing actionable information for diverse audiences. As of December 2017, the data mart contains information from over 175,000 distinct patients and >100 variables from each of their nearly 300,000 visits. Conclusion: The HF data mart will be used to enhance care, assist in clinical decision-making, and improve overall quality of care. This model holds the potential to be scaled and generalized beyond the initial focus and setting.

EFFECT OF REGIONAL VARIATION OF CENTER DENSITY ON HEART TRANSPLANT RISK STRATIFICATION

Variation in mortality risk between transplant listing centers should ideally be minimal. However, lack of standardized physiologic metrics for status designations may lead to significant inter-center variation within a given designation. Local competition for donor hearts may be an additional

POST-DISCHARGE MORTALITY AND READMISSION IN HEART FAILURE PATIENTS WITH PRESERVED, BORDERLINE, AND REDUCED LEFT VENTRICULAR EJECTION FRACTION

Outcomes among hospitalized heart failure (HF) patients with preserved (pEF), borderline (bEF), and reduced (rEF) ejection fraction have not been well studied. We sought to characterize post-discharge mortality and readmission in HF patients by EF group in the modern era.nnGet With The Guidelines-HF