Cecillia Lui

Mutations in Alström protein impair terminal differentiation of cardiomyocytes

Cardiomyocyte cell division and replication in mammals proceed through embryonic development and abruptly decline soon after birth. The process governing cardiomyocyte cell cycle arrest is poorly understood. Here we carry out whole exome sequencing in an infant with evidence of persistent postnatal cardiomyocyte replication to determine the genetic risk factors. We identify compound heterozygous ALMS1 mutations in the proband, and confirm their presence in her affected sibling, one copy inherited from each heterozygous parent. Next, we recognise homozygous or compound heterozygous truncating mutations in ALMS1 in four other children with high levels of postnatal cardiomyocyte proliferation. Alms1 mRNA knockdown increases multiple markers of proliferation in cardiomyocytes, the percentage of cardiomyocytes in G2/M phases, and the number of cardiomyocytes by 10% in cultured cells. Homozygous Alms1-mutant mice have increased cardiomyocyte proliferation at two weeks postnatal compared to wild-type littermates. We conclude that deficiency of Alström protein impairs postnatal cardiomyocyte cell cycle arrest.

A Risk Score to Predict Acute Renal Failure in Adult Patients After Lung Transplantation

BACKGROUND Despite the significant morbidity associated with renal failure after lung transplantation (LTx), no predictive models currently exist. Accordingly, the purpose of this study was to develop a preoperative risk score based on recipient-, donor-, and transplant-specific characteristics to predict postoperative acute renal failure in candidates for transplantation. METHODS The United Network of Organ Sharing (UNOS) database was queried for adult patients (≥ 18 years of age) undergoing LTx between 2005 and 2012. The population was randomly divided into derivation (80%) and validation (20%) cohorts. The primary outcome of interest was new-onset renal failure. Variables predictive of acute renal failure (exploratory p value < 0.2) within the derivation cohort were incorporated into a multivariable logistic regression model. Odds ratios were used to assign values to the independent predictors of postoperative renal failure to construct the risk stratification score (RSS). RESULTS During the study period, 10,963 patients underwent lung transplantation, and the incidence of renal failure was 5.5% (598 patients). Baseline recipient-, donor-, and transplant-related factors were similar between the cohorts. Eighteen covariates were included in the multivariable model, and 10 were assigned values based on their relative odds ratios (ORs). Scores were stratified into 3 groups, with an observed rate of acute renal failure of 3.1%, 5.3%, and 15.6% in the low-, moderate-, and high-risk groups, respectively. The incidence of renal failure was found to be significantly increased in the highest risk group (p < 0.001). Furthermore, the risk models predicted rates of renal failure highly correlated with actual rates observed in the population (r = 0.86). CONCLUSIONS We introduce a novel and simple RSS that is highly predictive of renal failure after LTx.

Coronary Button Pseudoaneurysms After Aortic Root Replacement in a Child With Loeys-Deitz Syndrome

Loeys-Deitz syndrome (LDS) is a connective tissue disorder characterized by aggressive aortopathy with a proclivity for aortic aneurysmal rupture and dissection. Prophylactic surgical intervention is often indicated to ameliorate risk of aneurysm rupture. Aortic root replacement involves excision of the coronary arteries from the aortic root with a button of surrounding aortic tissue and subsequent anastomosis of these buttons to the synthetic aortic graft. We report the case of a 16-year-old girl with LDS who developed pseudoaneurysms at the sites of previous coronary button implantation.

Mechanical Characterization of hiPSC-Derived Cardiac Tissues for Quality Control

Heart disease is one of the leading death causes in developed countries. To facilitate heart rehabilitation, engineered cardiac implantation has emerged as a promising alternative to organ transplantation. Currently there is no quantitative standard to ensure the safety and functionality of the engineered cardiac tissues intended for clinical uses. In anticipation of the clinical application of the engineered cardiac tissues to heart disease patients, a suite of methods is assembled to evaluate the mechanical characteristics critical to cardiac functions, including contractility, viscoelasticity, and dynamic stress distribution. As a proof of concept, 3D bioprinted cardiac tissues derived from human induced pluripotent stem cells are tested. First, the engineered cardiac tissues labeled with particles are recorded and tracked to determine spatially and temporally variable contraction forces. Viscoelastic properties are measured using magnetic tweezers. The results are used to compute 3D force and stress distribution over the engineered tissue by finite element method. In summary, a framework is developed to assess clinical‐grade engineered cardiac tissues and determine the appropriate value ranges suitable for implantation. The results relating contractility, intrinsic mechanical properties, and stress distribution in the engineered tissue, can also inform better design for future fabrication of engineered tissues.