Jennifer Chyu

Four-Variable Risk Model in Men and Women With Heart Failure

Background— Risk stratification is an integral component of clinical decision making in heart failure (HF). Women with HF have unique characteristics compared with men, and it is unknown whether common prognostic factors are equally useful in both populations. We aimed to investigate whether sex-specific risk models are more accurate for risk prediction in patients with advanced HF. Methods and Results— Patients with advanced HF referred to University of California, Los Angeles (UCLA; n=2255), were stratified by sex into derivation (referred in 2000–2007) and validation (referred in 2008–2011) cohorts. Cox regression analysis was used to ascertain key variables predictive of the primary end point of death/urgent transplantation/ventricular assist device in the derivation cohorts and confirmed in the validation cohorts in men, women, and the total population. Women were younger, with higher ejection fraction and better event-free survival. Despite differences in baseline characteristics, the 4 strongest predictors of outcome in both women and men, as well as in the total cohort, were B-type natriuretic peptide, peak oxygen consumption by cardiopulmonary exercise testing (pkVO2), New York Heart Association (NYHA) classification, and use of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. In addition, the UCLA model performed better than the Seattle Heart Failure Model (SHFM) and the Heart Failure Survival Score (HFSS) in our cohort (c-indices of 0.791[UCLA] versus 0.758 [SHFM], 0.607 [noninvasive HFSS], and 0.625 [invasive HFSS]). Conclusions— A simple risk model assessing 4 clinical variables—B-type natriuretic peptide, pkVO2, NYHA, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use—is well suited to provide prognostic information in both men and women with advanced HF.

Characterization and therapeutic potential of induced pluripotent stem cell-derived cardiovascular progenitor cells.

Background Cardiovascular progenitor cells (CPCs) have been identified within the developing mouse heart and differentiating pluripotent stem cells by intracellular transcription factors Nkx2.5 and Islet 1 (Isl1). Study of endogenous and induced pluripotent stem cell (iPSC)-derived CPCs has been limited due to the lack of specific cell surface markers to isolate them and conditions for their in vitro expansion that maintain their multipotency. Methodology/Principal Findings We sought to identify specific cell surface markers that label endogenous embryonic CPCs and validated these markers in iPSC-derived Isl1+/Nkx2.5+ CPCs. We developed conditions that allow propagation and characterization of endogenous and iPSC-derived Isl1+/Nkx2.5+ CPCs and protocols for their clonal expansion in vitro and transplantation in vivo. Transcriptome analysis of CPCs from differentiating mouse embryonic stem cells identified a panel of surface markers. Comparison of these markers as well as previously described surface markers revealed the combination of Flt1+/Flt4+ best identified and facilitated enrichment for Isl1+/Nkx2.5+ CPCs from embryonic hearts and differentiating iPSCs. Endogenous mouse and iPSC-derived Flt1+/Flt4+ CPCs differentiated into all three cardiovascular lineages in vitro. Flt1+/Flt4+ CPCs transplanted into left ventricles demonstrated robust engraftment and differentiation into mature cardiomyocytes (CMs). Conclusion/Significance The cell surface marker combination of Flt1 and Flt4 specifically identify and enrich for an endogenous and iPSC-derived Isl1+/Nkx2.5+ CPC with trilineage cardiovascular potential in vitro and robust ability for engraftment and differentiation into morphologically and electrophysiologically mature adult CMs in vivo post transplantation into adult hearts.

Microenvironment influences vascular differentiation of murine cardiovascular progenitor cells

We examined the effects of the microenvironment on vascular differentiation of murine cardiovascular progenitor cells (CPCs). We isolated CPCs and seeded them in culture exposed to the various extracellular matrix (ECM) proteins in both two-dimensional (2D) and 3D culture systems. To better understand the contribution of the microenvironment to vascular differentiation, we analyzed endothelial and smooth muscle cell differentiation at both day 7 and day 14. We found that laminin and vitronectin enhanced vascular endothelial cell differentiation while fibronectin enhanced vascular smooth muscle cell differentiation. We also observed that the effects of the 3D electrospun scaffolds were delayed and not noticeable until the later time point (day 14), which may be due to the amount of time necessary for the cells to migrate to the interior of the scaffold. The study characterized the contributions of both ECM proteins and the addition of a 3D culture system to continued vascular differentiation. Additionally, we demonstrated the capability bioengineer a CPC-derived vascular graft.

Treatment Outcomes of Rathke's Cleft Cysts Managed with Marsupialization.

Objectives Rathkes cleft cysts (RCC) are benign cystic lesions of the sella resulting from incomplete obliteration of Rathkes cleft. Symptomatic lesions often require surgical decompression, which is often amenable to a transnasal, transsphenoidal (TNTS) approach. We report our experience with marsupialization of RCC and describe a novel technique to promote re‐epithelization of the cyst cavity. Design Retrospective review. Setting Tertiary academic medical center. Participants Patients who underwent TNTS for RCC between 2007 and 2015. Main Outcome Measures Demographics, lesion characteristics, and reconstruction and treatment outcomes. Results In total, 52 patients were identified. The mean age was 41 ± 18 years. The mean RCC size was 13 ± 5 mm. Intraoperative cerebrospinal fluid (CSF) leak was encountered in 14 (27%) patients; all were repaired. There were six complications (12%) and no deaths. Mean follow‐up was 20 ± 18 months, with five (10%) recurrences. RCC size was associated with intraoperative CSF leak (p = 0.04). In 12 patients, the marsupialized cyst cavity was lined with a free mucosal graft (FMG) to promote healing and re‐epithelialization. Conclusions The TNTS approach is safe and effective in surgical decompression of RCC. Lining the exposed cyst cavity with an FMG is a simple intervention without added morbidity that may promote formation of an epithelialized tract. Level of Evidence Not applicable.

Laser prostate ablation and enucleation: Analysis of a national cohort

To compare characteristics and outcomes of benign prostatic hyperplasia patients undergoing prostate laser ablation with those undergoing laser enucleation using a nationwide cohort.

Response to Letter Regarding Article, “Four-Variable Risk Model in Men and Women With Heart Failure”

We appreciated reading the letter to the editor by Petretta and Cuocolo regarding our article “Four-Variable Risk Model in Men and Women With Heart Failure.”1 In an answer to their query on the exponential equation we provided (Survival( t ) = e(−0.00221 t *e^(score))), this equation predicts survival free from all-cause …

Hyaluronan-Based Three-Dimensional Microenvironment Potently Induces Cardiovascular Progenitor Cell Populations

The relationship between stem cell niches in vivo and their surrounding microenvironment is still relatively unknown. Recent advances have indicated that extrinsic factors within the cardiovascular progenitor cell niche influence maintenance of a multipotent state as well as drive cell-fate decisions. We have previously shown the direct effects of extracellular matrix (ECM) proteins and have now investigated the effects of dimension on the induction of a cardiovascular progenitor cell (CPC) population. We have shown here that the three-dimensionality of a hyaluronan-based hydrogel greatly induces a CPC population, as marked by Flk-1. We have compared the effects of a 3D microenvironment to those of conventional 2D cell culture practices and have found that the 3D microenvironment potently induces a progenitor cell state.