A systemic congestive index (systemic pulse pressure to central venous pressure ratio) predicts adverse outcomes in patients undergoing valvular heart surgery.

BACKGROUND AND AIMS: Invasive hemodynamics may provide a more nuanced assessment of cardiac function and risk phenotyping in patients undergoing cardiac surgery. The systemic pulse pressure (SPP) to central venous pressure (CVP) ratio represents an integrated index of right and left ventricular function and thus may demonstrate an association with valvular heart surgery outcomes. This study hypothesized that a low SPP/CVP ratio would be associated with mortality in valvular surgery patients. METHODS: This retrospective cohort study examined adult valvular surgery patients with preoperative right heart catheterization from 2007 through 2016 at a single tertiary medical center (n = 215). Associations between the SPP/CVP ratio and mortality were investigated with univariate and multivariate analyses. RESULTS: Among 215 patients (age 69.7 ± 12.4 years; 55.8% male), 61 died (28.4%) over a median follow-up of 5.9 years. A SPP/CVP ratio <7.6 was associated with increased mortality (relative risk 1.70, 95% confidence interval [CI] 1.08-2.67, p = .019) and increased length of stay (11.56 ± 13.73 days vs. 7.93 ± 4.92 days, p = .016). It remained an independent predictor of mortality (adjusted odds ratio 3.99, 95% CI 1.47-11.45, p = .008) after adjusting for CVP, mean pulmonary artery pressure, aortic stenosis, tricuspid regurgitation, smoking status, diabetes mellitus, dialysis, and cross-clamp time. CONCLUSIONS: A low SPP/CVP ratio was associated with worse outcomes in patients undergoing valvular heart surgery. This metric has potential utility in preoperative risk stratification to guide patient selection, prognosis, and surgical outcomes.

Markers of Immune Function in Heart Transplantation: Implications for Immunosuppression and Screening for Rejection.

PURPOSE OF REVIEW: Recent developments in high-throughput DNA and RNA sequencing technologies have facilitated the development of noninvasive assays to monitor heart transplant rejection. In this review, we summarize existing assays employed for the surveillance of allograft rejection, as well as promising future directions for such tests in the molecular biology field. RECENT FINDINGS: The AlloMap genome expression profiling assay remains the only noninvasive test for rejection surveillance and is incorporated into the International Society of Heart and Lung Transplantation guidelines. Other efforts have focused on messenger RNA (mRNA), microRNA (miRNA), and donor-derived cell-free DNA (dd-cfDNA) as potential viable biomarkers. Mitochondrial pathways in allograft necroptosis and inflammation signaling may represent a novel direction for future research endeavors. Although endomyocardial biopsy remains the gold standard, several converging areas of molecular biology could soon yield successful alternative methods of heart transplant rejection monitoring, with the distinct advantage of avoiding procedural complications.

MAGGIC, STS, and EuroSCORE II Risk Score Comparison After Aortic and Mitral Valve Surgery.

OBJECTIVES: To compare the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score with the established Society of Thoracic Surgeons (STS) and EuroSCORE II risk prediction models regarding mortality discrimination after aortic and mitral valve surgery. DESIGN: Retrospective cohort study. SETTING: Single tertiary academic medical center. PARTICIPANTS: A total of 259 patients who underwent open aortic valve replacement or open mitral valve repair/replacement from 2009-2014. INTERVENTIONS: Retrospective chart review. MEASUREMENTS AND MAIN RESULTS: MAGGIC, STS, and EuroSCORE II risk scores for each patient were studied using binary logistic regression and receiver operating characteristic analysis for the primary endpoint of one-year mortality and secondary endpoint of 30-day mortality. One-year mortality C-statistics were similar across risk scores (STS 0.709, 95% confidence interval [CI] 0.578-0.841; MAGGIC 0.673, 95% CI 0.547-0.799; EuroSCORE II 0.642, 95% CI 0.521-0.762; p = 0.56 between STS and MAGGIC; p = 0.20 between STS and EuroSCORE II; and p = 0.69 between MAGGIC and EuroSCORE II). Thirty-day mortality C-statistics also were similar between STS (0.797, 95% CI 0.655-0.939; p < 0.0001 v null hypothesis), MAGGIC (0.721, 95% CI 0.581-0.860; p = 0.33 v STS), and EuroSCORE II (0.688, 95% CI 0.557-0.818; p = 0.06 v STS; p = 0.68 v MAGGIC). CONCLUSIONS: The MAGGIC risk score performs similarly to STS and EuroSCORE II risk models in mortality discrimination after aortic and mitral valve surgery, albeit in a small sample size. This finding has important implications in establishing MAGGIC as a viable prognostic model in this population subset, with fewer variables and ease of use representing key advantages over STS and EuroSCORE II.

Tyrosine kinase inhibitor toxicity manifesting as comorbid Moyamoya syndrome and obstructive coronary artery disease: A case report and review of the literature.

Tyrosine kinase inhibitors (TKIs) have assumed an increasingly vital role in treating various hematologic and oncologic malignancies. However, adverse effects with respect to vascular disease have been reported following administration of this class of medications. Here, we present a case report of TKI toxicity, manifesting as comorbid Moyamoya syndrome and obstructive coronary artery disease leading to a type 1 non-ST-elevation myocardial infarction. This patient eventually required percutaneous coronary intervention with drug-eluting stent placement in the right coronary artery. Given the expanding indications of TKI therapy, this case highlights a growing population subset which may require coronary and/or peripheral interventions to treat sequela from otherwise life-prolonging treatment.

Haemodynamically Derived Pulmonary Artery Pulsatility Index Predicts Mortality in Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary artery (PA) pulsitility index (PAPi) is a novel haemodynamic index shown to predict right ventricular failure in acute inferior myocardial infarction and post left ventricular assist device surgery. We hypothesised that PAPi calculated as [PA systolic pressure - PA diastolic pressure]/right atrial pressure (RAP) would be associated with mortality in the National Institutes of Health Registry for Primary Pulmonary Hypertension (NIH-RPPH). METHODS: The impact of PAPi, the Pulmonary Hypertension Connection (PHC) risk score, right ventricular stroke work, pulmonary artery capacitance (PAC), other haemodynamic indices, and demographic characteristics was evaluated in 272 NIH-RPPH patients using multivariable Cox proportional hazards (CPH) regression and receiver operating characteristic (ROC) analysis. RESULTS: In the 272 patients (median age 37.7+/-15.9years, 63% female), the median PAPi was 5.8 (IQR 3.7-9.2). During 5years of follow-up, 51.8% of the patients died. Survival was markedly lower (32.8% during the first 3years) in PAPi quartile 1 compared with the remaining patients (58.5% over 3years in quartiles 2-4; p<0.0001). The best multivariable CPH survival model included PAPi, the PHC-Risk score, PAC, and body mass index (BMI). In this model, the adjusted hazard ratio for death with increasing PAPi was 0.946 (95% CI 0.905-0.989). The independent ROC areas for 5-year survival based on bivariable logistic regression for PAPi, BMI, PHC Risk, and PAC were 0.63, 0.62, 0.64, and 0.65, respectively (p<0.01). The ROC area for 5-year survival for the multivariable logistic model with all four covariates was 0.77 (p<0.0001). CONCLUSIONS: Pulmonary artery pulsatility index was independently associated with survival in PAH, highlighting the utility of PAPi in combination with other key measures for risk stratification in this population.

Preoperative Invasive Hemodynamic Determinants of Survival Among Patients Undergoing Aortic or Mitral Valve Surgery.

OBJECTIVES: To evaluate the association of preoperative invasive hemodynamic parameters with mortality in valvular heart surgery. DESIGN: Retrospective cohort study. SETTING: Single tertiary academic medical center. PARTICIPANTS: A total of 382 patients who underwent preoperative right and/or left heart catheterization before open aortic valve replacement (AVR), open mitral valve repair/replacement (MVR), or combined AVR and MVR, from July 2009 to December 2014. INTERVENTIONS: Retrospective chart review. MEASUREMENTS AND MAIN RESULTS: Common hemodynamic indices derived from direct catheterization measurements were assessed, including pulmonary artery systolic pressure (PASP), pulmonary artery pulse pressure (PPP), mean pulmonary capillary wedge pressure (mPCWP), pulmonary artery pulsatility index, diastolic pressure gradient, left ventricular work index, and right ventricular work index. Bivariable and multivariable associations of these measures with survival were determined using Cox proportional hazards regression. Kaplan-Meier survival curves were generated using the log-rank test. The median age of the cohort was 69 years (interquartile range 60-79 years), and 162 (42.4%) of the patients were female. Elevated PASP (hazard ratio [HR] 1.32 per 10 mmHg, p < 0.0001), elevated PPP (HR 1.48 per 10 mmHg, p < 0.0001), and elevated mPCWP (HR 1.95 per 10 mmHg, p < 0.0001) were all associated with decreased survival, as was decreased diastolic blood pressure (DBP) (p = 0.005). The combination of elevated PPP and decreased DBP was associated with the worst outcomes. CONCLUSIONS: PASP, PPP, mPCWP, and DBP were significantly associated with mortality in valvular heart surgery patients. These hemodynamic parameters may be useful in risk stratification of this population subset.

Identification of KANSARL as the first cancer predisposition fusion gene specific to the population of European ancestry origin.

Gene fusion is one of the hallmarks of cancer. Recent advances in RNA-seq of cancer transcriptomes have facilitated the discovery of fusion transcripts. In this study, we report identification of a surprisingly large number of fusion transcripts, including six KANSARL (KANSL1-ARL17A) transcripts that resulted from the fusion between the KANSL1 and ARL17A genes using a RNA splicingcode model. Five of these six KANSARL fusion transcripts are novel. By systematic analysis of RNA-seq data of glioblastoma, prostate cancer, lung cancer, breast cancer, and lymphoma from different regions of the World, we have found that KANSARL fusion transcripts were rarely detected in the tumors of individuals from Asia or Africa. In contrast, they exist in 30 - 52% of the tumors from North Americans cancer patients. Analysis of CEPH/Utah Pedigree 1463 has revealed that KANSARL is a familially-inherited fusion gene. Further analysis of RNA-seq datasets of the 1000 Genome Project has indicated that KANSARL fusion gene is specific to 28.9% of the population of European ancestry origin. In summary, we demonstrated that KANSARL is the first cancer predisposition fusion gene associated with genetic backgrounds of European ancestry origin.

Plasma Volume and Renal Function Predict Six-Month Survival after Hospitalization for Acute Decompensated Heart Failure.

BACKGROUND: Plasma volume (PV) is contracted in stable patients with heart failure (HF) due to decongestion strategies. On the other hand, increased PV can adversely affect the trajectory of HF. We therefore examined the effects of increased percentage change in PV (%ΔPV), blood urea nitrogen (BUN), and %ΔPV stratified by BUN and glomerular filtration rate (GFR) on survival after discharge in patients hospitalized for acute decompensated HF (ADHF). METHODS: We used the Strauss-Davis-Rosenbaum formula to calculate the %ΔPV between baseline and hospital discharge in a cohort from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial (ESCAPE). Kaplan-Meier curves were constructed for survival over 6 months. Cox proportional hazards regression was used to obtain adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for the associations between survival after discharge and %ΔPV, BUN, and %ΔPV stratified by BUN and GFR. RESULTS: Of the 324 patients included in our study (age 56.1 ± 13.6 years, 26.5% female), those with increased or no %ΔPV at discharge were less likely to survive at 6 months compared with those having reduced %ΔPV (log rank, p = 0.0093). Increased %ΔPV (HR 1.08 per 10% increase; 95% CI: 1.02-1.14) and increased BUN at discharge (HR 1.02 per mg/dL; 95% CI: 1.01-1.03) were independently associated with worse survival. Decreasing %ΔPV had a greater association with improved survival in patients with discharge BUN <31 mg/dL (p = 0.02) and discharge GFR >40 mL/min/1.73 m2 (p = 0.047). CONCLUSIONS: Increased %ΔPV and BUN at discharge predicted worse 6-month survival in patients with ADHF. Decreased %ΔPV with low BUN or high GFR at discharge was associated with improved survival.

Decreased Pulmonary Arterial Proportional Pulse Pressure After Pulmonary Artery Catheter Optimization for Advanced Heart Failure Is Associated With Adverse Clinical Outcomes.

BACKGROUND: This study evaluated the novel index pulmonary arterial proportional pulse pressure (PAPP) in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial. METHODS AND RESULTS: Multivariable Cox proportional hazards and logistical regression were used to model 6-month death; death, transplantation, or left ventricular assist device (DTLVAD); and DTLVAD or heart failure rehospitalization (DTLVADHF) with respect to PAPP. Among 175 patients with final hemodynamic data, 15.5% and 33.9%, respectively, died in optimal PAPP (PAPP >0.50) and nonoptimal PAPP (PAPP ≤0.50) groups (P = .008), and PAPP was independently associated with death, DTLVAD, and DTLVADHF (P < .01 for all outcomes). The hypothesized logistic regression model with pulmonary capillary wedge pressure, creatinine, and nonoptimal PAPP had an area under the curve of 0.818 (P < .0001) for death. Furthermore, PAPP as a continuous variable was the most powerful predictor of DTLVADHF (hazard ratio 0.793 per 0.1 increase in PAPP [95% confidence interval 0.659-0.955], chi square 8.80; P = .01) in the Cox model, with no other clinical, laboratory, or hemodynamic parameters significant after adjustment for PAPP. CONCLUSIONS: PAPP, a novel parameter for right-sided proportional pulse pressure, is an independent and powerful predictor of adverse clinical outcomes in advanced HF. Increased PAPP promises to be a useful therapeutic target in patients with pulmonary arterial pressure assessment.

Effectiveness of integrating delayed computed tomography angiography imaging for left atrial appendage thrombus exclusion into the care of patients undergoing ablation of atrial fibrillation.

BACKGROUND: Computed tomography angiography (CTA) can identify and rule out left atrial appendage (LAA) thrombus when delayed imaging is also performed. OBJECTIVE: In patients referred for CTA to evaluate pulmonary vein anatomy before the ablation of atrial fibrillation (AF) or left atrial flutter (LAFL), we sought to determine the effectiveness of a novel clinical protocol for integrating results of CTA delayed LAA imaging into preprocedure care. METHODS: After making delayed imaging of the LAA part of our routine preablation CTA protocol, we integrated early reporting of preablation CTA LAA imaging results into clinical practice as part of a formal protocol in June 2013. We then analyzed the effectiveness of this protocol by evaluating 320 AF/LAFL ablation patients with CTA imaging during the time period 2012-2014. RESULTS: In CTA patients with delayed LAA imaging, the sensitivity and negative predictive values for LAA thrombus using intracardiac echocardiography or transesophageal echocardiography (TEE) as the reference standard were both 100%. Intracardiac echocardiography during ablation confirmed the absence of thrombus in patients with negative CTA or negative TEE results. No patients with either negative CTA results or equivocal CTA results combined with negative TEE results had strokes or transient ischemic attacks. Overall, the need for TEE procedures decreased from 57.5% to 24.0% during the 3-year period because of the CTA protocol. CONCLUSION: Clinical integration of CTA delayed LAA imaging into the care of patients having catheter ablation of AF or LAFL is feasible, safe, and effective. Such a protocol could be used broadly to improve patient care.

The effects of medial ulnar collateral ligament reconstruction on Major League pitching performance.

BACKGROUND: Medial ulnar collateral ligament (MUCL) reconstruction is commonly performed on Major League Baseball (MLB) pitchers. Previous studies have reported that most pitchers return to presurgical statistical performance levels after MUCL reconstruction. METHODS: Pitching performance data--specifically, earned run average (ERA), walks and hits per inning pitched (WHIP), winning percentage, and innings pitched--were acquired for 168 MLB pitchers who had undergone MUCL reconstruction. These data were averaged over the 3 years before surgery and the 3 years after surgery and also acquired from 178 age-matched, uninjured MLB pitchers. RESULTS: Of the pitchers who had MUCL reconstruction surgery, 87% returned to MLB pitching. However, compared with presurgical data, pitching performance declined in terms of ERA (P = .001), WHIP (P = .011), and innings pitched (P = .026). Pitching performance also declined in the season before the surgery compared with previous years (ERA, P = .014; WHIP, P = .036; innings pitched, P < .001; winning percentage, P = .004). Compared with age-matched control pitchers, the MUCL reconstruction pitchers had significantly more major league experience at the same age (P < .001). CONCLUSION: MUCL reconstruction allows most players to return to pitching at the major league level. However, after MUCL reconstruction, there is a statistically significant decline in pitching performance. There appears to be a statistically significant decline in pitching performance the year before reconstructive surgery, and this decline is also a risk factor for requiring surgery. In addition, there is an increased risk of MUCL reconstruction for pitchers who enter the major leagues at a younger age.

Cell-specific determinants of peroxisome proliferator-activated receptor gamma function in adipocytes and macrophages.

The nuclear receptor peroxisome proliferator activator receptor gamma (PPARgamma) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPARgamma is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPARgamma binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPARgamma cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPARgamma colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPARgamma, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPARgamma function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPARgamma binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation.

PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale.

Peroxisome proliferator-activated receptor gamma(PPARgamma), a nuclear receptor and the target of anti-diabetic thiazolinedione drugs, is known as the master regulator of adipocyte biology. Although it regulates hundreds of adipocyte genes, PPARgamma binding to endogenous genes has rarely been demonstrated. Here, utilizing chromatin immunoprecipitation (ChIP) coupled with whole genome tiling arrays, we identified 5299 genomic regions of PPARgamma binding in mouse 3T3-L1 adipocytes. The consensus PPARgamma/RXRalpha "DR-1"-binding motif was found at most of the sites, and ChIP for RXRalpha showed colocalization at nearly all locations tested. Bioinformatics analysis also revealed CCAAT/enhancer-binding protein (C/EBP)-binding motifs in the vicinity of most PPARgamma-binding sites, and genome-wide analysis of C/EBPalpha binding demonstrated that it localized to 3350 of the locations bound by PPARgamma. Importantly, most genes induced in adipogenesis were bound by both PPARgamma and C/EBPalpha, while very few were PPARgamma-specific. C/EBPbeta also plays a role at many of these genes, such that both C/EBPalpha and beta are required along with PPARgamma for robust adipocyte-specific gene expression. Thus, PPARgamma and C/EBP factors cooperatively orchestrate adipocyte biology by adjacent binding on an unanticipated scale.

DOT1L/KMT4 recruitment and H3K79 methylation are ubiquitously coupled with gene transcription in mammalian cells.

The histone H3 lysine 79 methyltransferase DOT1L/KMT4 can promote an oncogenic pattern of gene expression through binding with several MLL fusion partners found in acute leukemia. However, the normal function of DOT1L in mammalian gene regulation is poorly understood. Here we report that DOT1L recruitment is ubiquitously coupled with active transcription in diverse mammalian cell types. DOT1L preferentially occupies the proximal transcribed region of active genes, correlating with enrichment of H3K79 di- and trimethylation. Furthermore, Dot1l mutant fibroblasts lacked H3K79 di- and trimethylation at all sites examined, indicating that DOT1L is the sole enzyme responsible for these marks. Importantly, we identified chromatin immunoprecipitation (ChIP) assay conditions necessary for reliable H3K79 methylation detection. ChIP-chip tiling arrays revealed that levels of all degrees of genic H3K79 methylation correlate with mRNA abundance and dynamically respond to changes in gene activity. Conversion of H3K79 monomethylation into di- and trimethylation correlated with the transition from low- to high-level gene transcription. We also observed enrichment of H3K79 monomethylation at intergenic regions occupied by DNA-binding transcriptional activators. Our findings highlight several similarities between the patterning of H3K4 methylation and that of H3K79 methylation in mammalian chromatin, suggesting a widespread mechanism for parallel or sequential recruitment of DOT1L and MLL to genes in their normal "on" state.