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Many anticancer therapies cause serious cardiovascular complications that degrade quality of life and cause early mortality in treated patients. Specifically, doxorubicin is known as an effective anticancer agent that causes cardiomyopathy in treated patients. There has been growing interest in defining the role of endothelial cells in cardiac damage by doxorubicin. We have shown in the present study that endothelial nuclei accumulate more intravenously administered doxorubicin than other cardiac cell types. Doxorubicin enhanced cardiac production of the transforming growth factor-β (TGF-β) ligands and nuclear translocation of phospho-Smad3 in both cultured and in vivo cardiac endothelial cells. To examine the role of the TGF-β/mothers against decapentaplegic homolog 3 (Smad3) pathway in cardiac damage by doxorubicin, we used both

The persistence of hepatotoxicity induced by N-acetyl-para-aminophenol (Acetaminophen or Paracetamol, abbreviated as APAP) as the most common cause of acute liver failure in the United States, despite the availability of N-acetylcysteine, illustrates the clinical relevance of additional therapeutic approaches. While human mesenchymal stem cells (MSCs) have shown protection in mouse models of liver injury, the MSCs used are generally not cleared for human use and it is unclear whether these effects are due to xenotransplantation. Here we evaluated GMP manufactured clinical grade human Wharton's Jelly mesenchymal stem cells (WJMSCs), which are currently being investigated in human clinical trials, in a mouse model of APAP hepatotoxicity in comparison to human dermal fibroblasts (HDFs) to address these issues. C57BL6J mice were treated with a moderate APAP overdose (300 mg/kg) and WJMSCs were administered 90 min later. Liver injury was evaluated at 6 and 24 h after APAP. WJMSCs treatment reduced APAP-induced liver injury at both time points unlike HDFs, which showed no protection. APAP-induced JNK activation as well as AIF and Smac release from mitochondria were prevented by WJMSCs treatment without influencing APAP bioactivation. Mechanistically, WJMSCs treatment upregulated expression of Gclc and Gclm to enhance recovery of liver GSH levels to attenuate mitochondrial dysfunction and accelerated recovery of pericentral hepatocytes to re-establish liver zonation and promote liver homeostasis. Notably, preventing GSH resynthesis with buthionine sulfoximine prevented the protective effects of WJMSCs. These data indicate that these GMP-manufactured WJMCs could be a clinically relevant therapeutic approach in the management of APAP hepatotoxicity in humans.

Cardiovascular (CV) outcomes can be improved with commonality between provider and patient regarding gender and race/ethnicity. Slow growth in CV care provider diversity is an obstacle for women and underrepresented groups. The hope for more equitable outcomes is unlikely to be realized unless trends change in selection of CV fellows and program directors (PDs). We investigate longitudinal trends of gender and racial/ethnic composition of CV FITs. De-identified demographic data were compiled in a descriptive cross-sectional study from AAMC of internal medicine (IM) residents and CV FITs from 2011 through 2021 to evaluate gender and race/ethnicity trends among CV trainees. Trends of CV fellows who later became program directors were analyzed. In the US between 2011 and 2021, 53% of IM residents were male while 40% female (7% unreported). Among CV FITs, 78% were male and 21% female. Races/ethnicities among CV FITs consisted of 36% non-Hispanic white, 28% non-Hispanic Asian, 5% Hispanic, 4%Black, and 25% were classified within other race/ethnicity categories. The proportion who became CV program directors followed similarly: 79% of PDs were male and 21% female. Demographic profiles for CV FITs have not significantly changed over the past decade despite increased diversity among IM residents. Efforts to improve diversity of CV FITs and PDs need to be analyzed. Slow growth of diversity in CV FITs is outpaced by rising patient diversity, leading to disparities in care and poorer CV outcomes for women and underrepresented minorities. Recruiting, training, and retaining diverse CV FITs is necessary.

Histone modifying enzymes regulate chromatin architecture through covalent modifications and ultimately control multiple aspects of cellular function. Disruption of histone modification leads to changes in gene expression profiles and may lead to disease. Both small molecule inhibitors and intermediary metabolites have been shown to modulate histone modifying enzyme activity although our ability to identify successful drug candidates or novel metabolic regulators of these enzymes has been limited. Using a combination of large scale in silico screens and in vivo phenotypic analysis, we identified several small molecules and intermediary metabolites with distinctive HME activity. Our approach using unsupervised learning identifies the chemical fingerprints of both small molecules and metabolites that facilitate recognition by the enzymes active sites which can be used as a blueprint to design novel inhibitors. Furthermore, this work supports the idea that histone modifying enzymes sense intermediary metabolites integrating genes, environment and cellular physiology.

BACKGROUND: Because of their well-described immunosuppressive properties, allogeneic adult human mesenchymal stromal cells (MSC) derived from bone marrow have demonstrated safety and efficacy in steroid refractory acute graft versus host disease (SR aGVHD). Clinical trials have resulted in variable success and an optimal source of MSC has yet to be defined. Based on the importance of maternal-fetal interface immune tolerance, extraembryonic fetal tissues, such as the umbilical cord, may provide an superior tissue source of MSC to mediate immunomodulation in aGVHD. METHODS: A two-dose cohort trial allogeneic Wharton’s Jelly-derived mesenchymal stromal cells (WJMSC, referred to as MSCTC-0010, here) were tested in 10 patients with de novo high risk (HR) or SR aGVHD post allogeneic hematopoietic stem cell transplantation (allo-HCT). Following Good Manufacturing Practices isolation, expansion and cryostorage, WJMSC were thawed and administered via intravenous infusions on days 0 and 7 at one of two doses (low dose cohort, 2×10(6)/kg, n=5; high dose cohort, 10×10(6)/kg, n=5). To evaluate safety, patients were monitored for infusion related toxicity, Treatment Related Adverse Events (TRAE) til day 42, or ectopic tissue formation at day 90. Clinical responses were monitored at time points up to 180 days post infusion. Serum biomarkers ST2 and REG3α were acquired 1 day prior to first MSCTC-0010 infusion and on day 14. RESULTS: Safety was indicated, e.g., no infusion-related toxicity, no development of TRAE, nor ectopic tissue formation in either low or high dose cohort was observed. Clinical response was suggested at day 28: the overall response rate (ORR) was 70%, 4 of 10 patients had a complete response (CR) and 3 had a partial response (PR). By study day 90, the addition of escalated immunosuppressive therapy was necessary in 2 of 9 surviving patients. Day 100 and 180 post infusion survival was 90% and 60%, respectively. Serum biomarker REG3α decreased, particularly in the high dose cohort, and with REG3α decrease correlated with clinical response. CONCLUSIONS: Treatment of patients with de novo HR or SR aGVHD with low or high dose MSCTC-0010 was safe: the infusion was well-tolerated, and no TRAEs or ectopic tissue formation was observed. A clinical improvement was seen in about 70% patients, with 4 of 10 showing a complete response that may have been attributable to MSCTC-0010 infusions. These observations indicate safety of two different doses of MSCTC-0010, and suggest that the 10 × 10(6) cells/kg dose be tested in an expanded randomized, controlled Phase 2 trial.

Rationale: Human umbilical cord blood (hUCB) contains diverse populations of stem/progenitor cells. Whether hUCB-derived nonhematopoietic cells would induce cardiac repair remains unknown. Objective: To examine whether intramyocardial transplantation of hUCB-derived CD45 − Lin − nonhematopoietic cellular fraction after a reperfused myocardial infarction in nonimmunosuppressed rats would improve cardiac function and ameliorate ventricular remodeling. Methods and Results: Nonhematopoietic CD45 − Lin − cells were isolated from hUCB. Flow cytometry and quantitative polymerase chain reaction were used to characterize this subpopulation. Age-matched male Fischer 344 rats underwent a 30-minute coronary occlusion followed by reperfusion and 48 hours later received intramyocardial injection of vehicle or hUCB CD45 − Lin − cells. After 35 days, compared with vehicle-treated rats, CD45 − Lin − cell–treated rats exhibited improved left ventricular function, blunted left ventricular hypertrophy, greater preservation of viable myocardium in the infarct zone, and superior left ventricular remodeling. Mechanistically, hUCB CD45 − Lin − cell injection favorably modulated molecular pathways regulating myocardial fibrosis, cardiomyocyte apoptosis, angiogenesis, and inflammation in postinfarct ventricular myocardium. Rare persistent transplanted human cells could be detected at both 4 and 35 days after myocardial infarction. Conclusions: Transplantation of hUCB-derived CD45 − Lin − nonhematopoietic cellular subfraction after a reperfused myocardial infarction in nonimmunosuppressed rats ameliorates left ventricular dysfunction and improves remodeling via favorable paracrine modulation of molecular pathways. These findings with human cells in a clinically relevant model of myocardial ischemia/reperfusion in immunocompetent animals may have significant translational implications.Visual Overview: An online visual overview is available for this article.

Summary Although vitamin D3 (VitD3) prevents angiogenesis in cancer, VitD3 deficiency is associated with greater incidence of cardiovascular events in patients. We examined the influence of VitD3 on the angiogenic potential of mesenchymal stem cells (MSCs). VitD3 treatment increased the expression of proangiogenic molecules in MSCs, which exhibited an endothelial cell-like phenotype and promoted vascularization in vitro and in vivo. VitD3 activated the IGF-1 promoter and boosted IGF-1 receptor (IGF-1R) signaling, which was essential for the mesenchymal-to-endothelial transition (MEndoT) of MSCs. VitD3-treated MSCs created a proangiogenic microenvironment for co-cultured arterial endothelial cells, as well as aortic rings. The induction of MEndoT and angiogenesis promotion by VitD3-stimulated MSCs was attenuated by IGF-1R inhibitor picropodophyllin. We conclude that VitD3 promotes MEndoT in MSCs, and VitD3-treated MSCs augment vascularization by producing a proangiogenic niche through continued IGF-1 secretion. These results suggest a potential therapeutic role of VitD3 toward enhancing MSC-induced angiogenesis., Graphical abstract, Highlights • Vitamin D3 (VitD3) treatment induces IGF-1 in mesenchymal stem cells (MSCs) • VitD3 promotes mesenchymal-to-endothelial transition in MSCs via IGF-1 signaling • Continued IGF-1 secretion by VitD3-treated MSCs creates a proangiogenic niche • VitD3 may enhance MSC-induced angiogenesis through dual mechanisms, Biological Sciences; Physiology; Molecular Biology; Cell Biology

Both mesenchymal stem cells (MSCs) and their corresponding small extracellular vesicles (sEVs, commonly referred to as exosomes) share similar immunomodulatory properties that are potentially beneficial for the treatment of acute graft versus host disease (aGvHD). We report that clinical grade Wharton's Jelly‐derived MSCs (WJMSCs) secrete sEVs enriched in programmed death‐ligand 1 (PD‐L1), an essential ligand for an inhibitory immune checkpoint. A rapid increase in circulating sEV‐associated PD‐L1 was observed in patients with aGvHD and was directly associated with the infusion time of clinical grade WJMSCs. In addition, in vitro inhibitory antibody mediated blocking of sEV‐associated PD‐L1 restored T cell activation (TCA), suggesting a functional inhibitory role of sEVs‐PD‐L1. PD‐L1‐deficient sEVs isolated from WJMSCs following CRISPR‐Cas9 gene editing fail to inhibit TCA. Furthermore, we found that PD‐L1 is essential for WJMSC‐derived sEVs to modulate T cell receptors (TCRs). Our study reveals an important mechanism by which therapeutic WJMSCs modulate TCR‐mediated TCA through sEVs or sEV‐carried immune checkpoints. In addition, our clinical data suggest that sEV‐associated PD‐L1 may be not only useful in predicting the outcomes from WJMSC clinical administration, but also in developing cell‐independent therapy for aGvHD patients.

Introduction: The effects of bone marrow cell (BMC) therapy in patients with chronic ischemic heart disease (CIHD) remain controversial. Hypothesis: We hypothesized that injection of BMCs in patients with CIHD would improve left ventricular (LV) structure and function. We also hypothesized that BMC therapy would improve clinical outcomes in CIHD patients. Methods: We performed a systemic review and meta-analysis of pooled data from published randomized controlled trials (RCTs) that evaluated the efficacy of BMC administration in patients with CIHD. The effects of BMC injection on LV ejection fraction (LVEF), LV end-systolic volume (LVESV), LV end-diastolic volume (LVEDV), infarct size, and patient outcomes were analyzed using random-effects meta-analysis. Results: The literature search yielded 30 RCTs enrolling 1,548 patients. Transplantation of BMCs resulted in an improvement in LVEF in cell-treated patients compared with controls (2.89%; 95% confidence interval (CI): 1.80 to 3.97; P P = 0.14) and LVEDV (-5.95 ml; 95% CI: -12.09 to 0.18 ml; P =0.06). The improvement in LVEDV was more pronounced (-7.42 ml; 95% CI: -13.68 to -1.17ml; P =0.02) in patients with baseline LVEF Conclusions: BMC injection improves cardiac function and remodeling in patients with CIHD. These benefits are more pronounced in patients with LVEF

Background The ACC/AHA guidelines recommend low-dose dobutamine challenge for hemodynamic assessment of the severity of AS in patients with low flow, low gradient aortic stenosis with reduced ejection fraction (EF) (LFLG-AS; stage D2). Inherent pitfalls of echocardiography could result in inaccurate aortic valve areas (AVA), which have downstream prognostic implications. Data on the safety and efficacy of coronary pressure wire and fluid-filled catheter use for low dose dobutamine infusion is sparse. Methods We retrospectively analyzed 39 consecutive patients with EF on echocardiography who underwent simultaneous right and left heart catheterization . Hemodynamic assessments were performed at baseline and at every increment in the dobutamine infusion rate (The infusion was continued until maximal dose of dobutamine or a mean AV gradient > 40 mm Hg was attained. The occurrence of sustained ventricular arrhythmias , symptomatic hypotension or intolerable symptoms leading to cessation of infusion was recorded. Transient ischemic attacks (TIAs) or clinically apparent strokes periprocedurally or up to 30 days after the procedure were recorded. Results Dobutamine challenge confirmed true AS in 26 patients (67%) and pseudosevere AS in 34%. No sustained arrhythmias, hypotension or cessation of infusion from intolerable symptoms were observed. No clinical strokes or TIAs were observed up to 30 days after procedure in any of these patients. Conclusions Hemodynamic assessment of AS using a pressure wire with dobutamine challenge is a safe and effective tool in identifying truly severe AS in patients with LFLG-AS with reduced EF.

Induced pluripotent stem cell (iPSC)-based cardiac regenerative medicine requires the efficient generation, structural soundness and proper functioning of mature cardiomyocytes, derived from the patient's somatic cells. The most important functional property of cardiomyocytes is the ability to contract. Currently available methods routinely used to test and quantify cardiomyocyte function involve techniques that are labor-intensive, invasive, require sophisticated instruments or can adversely affect cell vitality. We recently developed optical flow imaging method analyses and quantified cardiomyocyte contractile kinetics from video microscopic recordings without compromising cell quality. Specifically, our automated particle image velocimetry (PIV) analysis of phase-contrast video images captured at a high frame rate yields statistical measures characterizing the beating frequency, amplitude, average waveform and beat-to-beat variations. Thus, it can be a powerful assessment tool to monitor cardiomyocyte quality and maturity. Here we demonstrate the ability of our analysis to characterize the chronotropic responses of human iPSC-derived cardiomyocytes to a panel of ion channel modulators and also to doxorubicin, a chemotherapy agent with known cardiotoxic side effects. We conclude that the PIV-derived beat patterns can identify the elongation or shortening of specific phases in the contractility cycle, and the obtained chronotropic responses are in accord with known clinical outcomes. Hence, this system can serve as a powerful tool to screen the new and currently available pharmacological compounds for cardiotoxic effects.

Small nucleolar RNAs (snoRNAs) are a group of noncoding RNAs that perform various biological functions, including biochemical modifications of other RNAs, precursors of miRNA, splicing, and telomerase activity. The small Cajal body-associated RNAs (scaRNAs) are a subset of the snoRNA family and collect in the Cajal body where they perform their canonical function to biochemically modify spliceosomal RNAs prior to maturation. Failure of sno/scaRNAs have been implicated in pathology such as congenital heart anomalies, neuromuscular disorders, and various malignancies. Thus, understanding of sno/scaRNAs demonstrates the clinical value.

Cocaine use causes significant cardiovascular morbidity from its hemodynamic effects. It is less clear whether cocaine promotes atherosclerosis. Vascular inflammation is one of the earliest steps in the pathophysiology of atherosclerosis. We hypothesized that cocaine results in an increase in inflammatory markers. Study objective was to measure the acute effects of intravenous cocaine on biomarkers of vascular inflammation. Eleven chronic cocaine users were enrolled. After a drug-free period, they received intravenous cocaine at 0.36 mg/kg dose in an in-hospital controlled environment. Serum levels of soluble CD40 ligand, monocyte chemoattractant protein-1, interleukin 6, and soluble intercellular adhesion molecule-1 were measured at baseline, 6 h, 24 h, and 6 days after cocaine challenge and at baseline for controls. After cocaine challenge, sCD40 ligand levels decreased in subjects and were significantly lower at 24 h. MCP-1 levels decreased and were significantly lower at the 6-day time point. No significant changes in IL-6 or sICAM-1 level were found. In conclusion, intravenous cocaine did not result in an increase in levels of inflammatory markers. Levels of MCP-1 and sCD40L decreased significantly. This unexpected finding suggests that chronic effects of cocaine on inflammation may be different from acute effects or that higher dosing may have differential effects as compared to lower dose used here.

Background The impact of left atrial appendage (LAA) exclusion, comparing an epicardial LAA or an endocardial LAA device, on systemic homeostasis remains unknown. Objectives This study compared the effects of epicardial or endocardial LAA devices on the neurohormonal profiles of patients, emphasizing the roles of the renin-angiotensin-aldosterone system and the autonomic nervous system. Methods This is a prospective, single-center, observational study including 77 patients who underwent LAA closure by an epicardial (n = 38) or endocardial (n = 39) device. Key hormones involved in the adrenergic system (adrenaline, noradrenaline), renin-angiotensin-aldosterone system (aldosterone, renin), metabolic system (adiponectin, free fatty acids, insulin, β-hydroxybutyrate, and free glycerols), and natriuresis (atrial and B-type natriuretic peptides) were assessed immediately before the procedure, immediately after device deployment, at 24 h, and at 3 months follow-up. Results In the epicardial LAA device group, when compared with baseline blood adrenaline, noradrenaline and aldosterone were significantly lower at 24 h and 3 months (p Conclusions There are substantial differences in hemodynamics and neurohormonal effects of LAA exclusion with epicardial and endocardial devices. Further studies are required to elucidate the underlying mechanism of these physiological changes.

Extracellular vesicles (EVs) comprise apoptotic bodies, microvesicles and exosomes, and they perform as key regulators in cell-to-cell communication in normal as well as diseased states. EVs contain natural cargo molecules, such as miRNA, mRNA and proteins, and transfer these functional cargos to neighboring cells or more distant cells through circulation. These functionally active molecules then affect distinct signaling cascades. The message conveyed to the recipient cells is dependent upon the composition of the EV, which is determined by the parent cell and the EV biogenesis. Because of their properties such as increased stability in circulation, biocompatibility, low immunogenicity and toxicity, EVs have drawn attention as attractive delivery systems for therapeutics. This review focuses on the functional use of exosomes in therapy and the potential advantages and challenges in using exosomes for therapeutic purposes.

Objectives There is paucity of information regarding critical limb ischemia-related readmission rates in patients admitted with critical limb ischemia. We studied 30-day critical limb ischemia-related readmission rate, its predictors, and clinical outcomes using a nationwide real-world dataset. Methods We did a secondary analysis of the 2013 Nationwide Readmissions Database. We included all patients with a primary diagnosis of extremity rest pain, ulceration, and gangrene secondary to peripheral arterial disease. From this group, all patients readmitted with similar diagnosis within 30 days were recorded. Results Of the total 25,111 index hospitalization for critical limb ischemia, 1270 (5%) were readmitted with a primary diagnosis of critical limb ischemia within 30 days. The readmission rate was highest (9.5%) for the group that did not have any intervention (revascularization or major amputation) and was lowest for surgical revascularization and major amputation groups (2.6% and 1.3%, P value Conclusions In patients with primary diagnosis of critical limb ischemia, 30-day critical limb ischemia-related readmission rate was affected by initial management strategy and the severity of critical limb ischemia. Readmission was associated with a significantly higher rate of amputation, increased length of stay, and a more frequent discharge to an alternate care facility than index admission and thus may serve as a useful quality of care metric in critical limb ischemia patients.

A small percentage of patients with asymptomatic carotid artery stenosis (ACAS) who are on optimal medical management do go on to develop ischemic stroke or transient ischemic attacks (IS/TIA). Several diagnostic tools have been studied to identify those patients who are at increased risk. However, most of these diagnostic tools are not available for routine clinical use or are resource intensive. We performed a retrospective study to assess the incremental value of external carotid artery stenosis progression (ECASP) along with internal carotid artery stenosis progression (ICASP) in predicting risk of ipsilateral IS/TIA in a cohort of patients with ACAS. We conducted a retrospective analysis of patients with ACAS who had at least two serial duplex ultrasounds (DUS) at our center. A total of 356 patients (712 carotid arteries) were included in the study (mean age 74.7±9 years, 49.2% male) with a mean follow-up of 60.7±32.7 months. In univariate analysis, concurrent progression of ICA and ECA stenosis on the same side arteries was associated with a very significant increased risk of ipsilateral IS/TIA (14.7% vs 4.6%, p

Both QT interval and body mass index (BMI) are independently associated with mortality. Those with higher BMI have longer QT, although evidence is inconsistent. The joint association of QT and BMI with mortality merits investigation.To examine the association of QT with BMI, and to examine the joint association of QT and BMI with all-cause and cardiovascular mortality.We followed 4036 participants from NHANES III for a median of 14.7 years. Weighted sample was divided into 4 categories by BMI as: 18.5-24.9, 25-29.9, 30-34.9 and ≥35, and 2 categories by corrected QT interval (QTc) as: normal (450ms in males,460ms in females) or prolonged. Cox proportional hazards models were used with adjustment for demographic characteristics and cardiovascular risk factors.QTc was longer among those with higher BMI (mean QTc: 424.7, 425.8, 430.9 and 437.8 respectively for BMI 18.5-24.9, 25-29.9, 30-34.9 and ≥35, p-trend:0.001). Overall, longer QTc or higher BMI were associated with increased all-cause and cardiovascular mortality risk compared to mean QTc or mean BMI, respectively. When combined, cardiovascular mortality was significantly increased among obese individuals with prolonged QTc [hazard ratio (95% CI): 3.1 (1.2-8.0) and 4.8 (1.2-19.9) but not when QTc was normal [1.0 (0.5-2.0) and 1.4 (0.8-2.8)] for BMI 30-34.9 and ≥35, respectively compared to BMI 18.5-24.9 and normal QTc. Similar (although not statistically significant) findings were observed for all-cause mortality. Risk prediction for both all-cause and cardiovascular mortality improved when QTc was added to the adjusted model with BMI (net reclassification index 0.14, p=0.01 and 0.14, p0.0001 for all-cause and cardiovascular mortality, respectively).Individuals with higher BMI have a significantly longer QTc. BMI is associated with increased all-cause and cardiovascular mortality risk when QTc is prolonged but not when QTc is normal. These novel observations suggest that QTc should be factored into risk stratification of obese individuals with a screening electrocardiogram. This may help stratify individuals into lower risk categories when QTc is normal.

Rationale: Acute kidney injury (AKI) is common during high-risk percutaneous coronary intervention (PCI), particularly in those with severely reduced left ventricular ejection fraction. The impact of partial hemodynamic support with a microaxial percutaneous left ventricular assist device (pLVAD) on renal function after high-risk PCI remains unknown. Objective: We tested the hypothesis that partial hemodynamic support with the Impella 2.5 microaxial pLVAD during high-risk PCI protected against AKI. Methods and Results: In this retrospective, single-center study, we analyzed data from 230 patients (115 consecutive pLVAD-supported and 115 unsupported matched-controls) undergoing high-risk PCI with ejection fraction ≤35%. The primary outcome was incidence of in-hospital AKI according to AKI network criteria. Logistic regression analysis determined the predictors of AKI. Overall, 5.2% (6) of pLVAD-supported patients versus 27.8% (32) of unsupported control patients developed AKI ( P P P P =0.04 and adjusted odds ratio, 0.16; 95% confidence intervals, 0.12–0.28; P Conclusions: Impella 2.5 (pLVAD) support protected against AKI during high-risk PCI. This renal protective effect persisted despite the presence of underlying CKD and decreasing ejection fraction.

BACKGROUND Implantation of cardiac implanted electronic device (CIED) has surged lately. This resulted in a rise in cardiac device-related infections (CDI) and inevitably, lead extractions. We examined the recent national trend in the incidence of CIED infections and lead extractions in hospitalized patients and associated mortality. METHODS Using the Nationwide Inpatient Sample for the years 2003-2011 we identified patients diagnosed with a CDI-associated infection as determined by discharge ICD-9 diagnostic codes. We examined the trend of device-related infections overall and in different subgroups. We studied mortality associated with device infections, lead extractions, associated costs, and length of stay. RESULTS There is a significant increase in the number of hospitalizations due to CDI from 5,308 in the year 2003 to 9,948 in 2011. Males (68%), Caucasians (77%), and age group 65-84 years (56.4%) accounted for majority of CDI. The mortality associated with CDI was 4.5 %, and was worse in higher age groups (2.5% in 18-44 years compared to 5.3% in 85+ years, P < 0.001). Average length of stay was unchanged over the years remaining at 13.6 days; however, mean hospitalization charges increased from $91,348 in 2003 to $173,211 in 2011 (P < 0.001). Among all lead extraction procedures, the percentage of patients undergoing lead extraction secondary to CDI also increased from 2003 (59.1%) to 2011 (76.7%), P-value < 0.001. CONCLUSIONS Healthcare burden associated with CDI infections and associated lead extractions has significantly increased in the recent years. Despite an increase in cost associated with CIED infections, mortality remains the same, and is higher in older patients.

Even though the discovery of the term 'epigenetics' was in the 1940s, it has recently become one of the most promising and expanding fields to unravel the gene expression pattern in several diseases. The most well studied example is cancer, but other diseases like metabolic disorders, autism, or inflammation-associated diseases such as lung injury, autoimmune disease, asthma, and type-2 diabetes display aberrant gene expression and epigenetic regulation during their occurrence. The change in the epigenetic pattern of a gene may also alter gene function because of a change in the DNA status. Constant environmental pressure, lifestyle, as well as food habits are the other important parameters responsible for transgenerational inheritance of epigenetic traits. Discovery of epigenetic modifiers targeting DNA methylation and histone deacetylation enzymes could be an alternative source to treat or manipulate the pathogenesis of diseases. Particularly, the combination of epigenetic drugs such as 5-aza-2-deoxycytidine (Aza) and trichostatin A (TSA) are well studied to reduce inflammation in an acute lung injury model. It is important to understand the epigenetic machinery and the function of its components in specific diseases to develop targeted epigenetic therapy. Moreover, it is equally critical to know the specific inhibitors other than the widely used pan inhibitors in clinical trials and explore their roles in regulating specific genes in a more defined way during infection.

Background and Purpose: To assess the effect of optimal medical management including atherosclerotic risk factor control on ischemic stroke (IS), transient ischemic attack (TIA), carotid revascularization (CRV), and progression of severity of carotid stenosis (PSCS) in patients with asymptomatic carotid artery stenosis (ACAS). Methods: We conducted a retrospective analysis of patients with ACAS (who had at least 3 serial carotid duplex ultrasounds) for incidence of IS, TIA, and PSCS. Results: Eight hundred sixty-four patients with a mean follow-up duration of 79 ± 36 months were included. IS/TIA and CRV occurred in 12.2% of the patients and PCSS was observed in 21.5% vessels. On univariate analysis it was found that low-density lipoprotein (LDL) levels >100 mg/dL, no statin or low-potency statins, average systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg and history of smoking were predictors of the combined endpoint of IS/TIA/CRV and PSCS. On multivariate analysis, it was found that LDL >100 mg/dL, no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, and Hx of smoking were independent predictors of PSCS. Similarly no statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, Hx of atrial fibrillation/flutter, Hx of chronic kidney disease, and PSCS were independent predictors of IS/TIA. No statin or low-potency statin, SBP ≥140 mm Hg and/or DBP ≥90 mm Hg, diabetes mellitus, baseline carotid artery stenosis ≥70%, and PSCS were found to be independent predictors of combined endpoint IS/TIA and CRV. Conclusion: Intensive medical therapy in the patients with ACAS results in lower incidence of IS/TIA, CRV, and PSCS with a significant incremental beneficial effect.

Objective: The aim of this paper was to study the association between body mass index (BMI) and coronary sinus (CS) brain natriuretic peptide (BNP) levels in patients with heart failure and reduced systolic function (HFrEF). Background: There is an inverse relationship between systemic venous BNP (V-BNP) levels and BMI in patients with HFrEF. It is unclear whether this finding is due to decreased production or due to an increased metabolism of BNP. Since CS-BNP levels reflect BNP production, we hypothesized that assessing the correlation of CS-BNP levels with BMI would provide insight into the mechanism of this inverse relationship of V-BNP and BMI. Methods: We prospectively enrolled 54 subjects with HFrEF who were to undergo cardiac resynchronization device implantation. CS-BNP, V-BNP, and arterial BNP (A-BNP) levels were measured during the implant procedure. Subjects were divided into 2 groups based on their BMI (group 1: BMI Results: The mean age of the overall study group was 64 ± 10 years. Average BMI for group 1 was 25.8 ± 2.8 and 36.8 ± 4.6 for group 2 (p < 0.03). A history of hypertension was present in 55% (n = 26) of the subjects, while diabetes was reported in 31% (n = 15). Serum creatinine was 1.0 ± 0.2 mg/dL and TSH 2.1 ± 1.4 mIU/L. 79% of the subjects were receiving β-blockers, while 94% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. The mean CS-BNP, V-BNP, and A-BNP levels in group 2 were significantly lower than in group 1 (286.2 ± 170.5 vs. 417.5 ± 247.5 pg/mL, p = 0.04; 126.6 ± 32.5 vs. 228 ± 96.4 pg/mL, p = 0.01; and 151.9 ± 28.6 vs. 242 ± 88.8 pg/mL, p = 0.04, respectively). Univariate analysis and multivariate regression adjusted for age, diabetes mellitus, sex, glomerular filtration rate, and left atrial size confirmed BMI as an independent predictor of CS-BNP levels (β = -0.372, p = 0. 03) in our study. Conclusions: In this study, we demonstrate an inverse relationship between CS-BNP levels and BMI in patients with HFrEF. These findings suggest that the previously established inverse relationship between V-BNP and BMI is due to a decreased cardiac production of BNP in obese patients rather than from increased peripheral metabolism.

Background & Aim Allogeneic hematopoietic stem cell transplantation used to manage hematologic malignancies, is frequently complicated by graft versus host disease (GvHD) leading to poor outcomes with increased non-relapse morbidity and mortality. Traditional immunosuppressive therapy has many side effects, thus, necessitating alternative therapies to treat GvHD. Based on their immunomodulation and immunosuppression properties, mesenchymal stem cells (MSCs) are being explored to treat acute GvHD. Currently, there are no cellular products approved in the United States to treat steroid refractory aGvHD. MSCTC-0010, manufactured at the Midwest Stem Cell Therapy Center's GMP facility, is an investigational product consisting of tissue-derived allogeneic, Wharton's Jelly MSCs. We investigated MSCTC-0010 for the treatment of de novo high-risk acute or steroid refractory GvHD in a Phase I, safety clinical trial (IND#17672). The MSCTC-0010 is manufactured by explantation, ex-vivo culture and expansion, and cryopreservation and is tested for identity, potency, sterility, and stability. Methods, Results & Conclusion Method MSCTC-0010 was delivered intravenously twice at a dose of 2 × 106cells/kg in the first cohort and 10 × 106cells/kg in the second cohort on day 0 and 7. GvHD was graded by organ (skin, liver, and gastrointestinal) involvement. The primary endpoint was to evaluate the safety of MSCTC-0010 in patients who experienced a treatment related adverse event. The secondary endpoints include achievement of complete response of aGvHD by day 42 and improvement of GvHD in 1 or more organs involved. Samples were drawn at regular intervals to explore biomarkers that correlate with biological response. Results The study enrolled 10 patients (ages 18-75). Safety of the MSCTC-0010 was demonstrated as there was no infusion related toxicity and no increased incidence of infections. The study showed aGvHD response in 7 of the 10 patients at day 28 (refer to table). A biomarker panel consisting of Reg 3-α and ST-2 was analyzed. Analysis of these two biomarkers showed a reduction from day 0 to day 42. Subjects who received the higher dose of MSCTC-0010 had a statistically significant decline in the Reg-3 α levels on day 7, 14, 21, and 28. The drop in levels correlated with the clinical response. ST-2 levels showed a significant decrease on day 28 and 42. Conclusion This Phase 1 trial with MSCTC-0010 successfully met its primary endpoint of safety. Treatment with MSCTC-0010 shows promise in patients with high risk aGvHD.

This was a prospective, single-center study evaluating the efficacy and cost-effectiveness of early ambulation (within 30 min) following femoral artery closure with the ProGlide® suture-mediated vascular closure device (PD) in patients undergoing diagnostic cardiac catheterization compared with manual compression. It is unclear whether early ambulation with ProGlide is safe or is associated with patient satisfaction and cost savings as compared with manual compression (MC). Inclusion criteria were met in 170 patients (85 PD and 85 MC patients). Patients ambulated 20 ft. within 30 min (PD) or after the requisite 4 h recumbent time (MC) if feasible. Primary endpoint was time-to-ambulation (TTA) following device closure. We also directly compared the safety of closure, times-to-hemostasis (TTH), -ambulation (TTA) and -discharge (TTD) with MC and, using a fully allocated cost model, performed cost analysis for both strategies. Multivariate analysis was used to determine predictors of patient satisfaction. The primary endpoint of safe, early ambulation was achieved following closure (mean of 27.1 ± 14.9 min, 95% confidence interval [CI] 25.2–30.2). Predictors of patient satisfaction in the PD group were absence of pain during closure, decreased TTA, and drastic reductions in TTD, the latter contributed indirectly to significant cost savings in the PD group (1250.3 ± 146.4 vs. 2248.1 ± 910.2 dollars, respectively, P < 0.001) and incremental cost savings by strategy also favored closure over MC ($84, 807). ProGlide is safe and effective for femoral artery closure in patients who ambulate within 30 min after cardiac catheterization, translating into improved patient satisfaction and substantial cost savings.

Objective This was a prospective, single-center study evaluating the efficacy and cost-effectiveness of early ambulation (within 30 min) following femoral artery closure with the ProGlide® suture-mediated vascular closure device (PD) in patients undergoing diagnostic cardiac catheterization compared with manual compression. Background It is unclear whether early ambulation with ProGlide is safe or is associated with patient satisfaction and cost savings as compared with manual compression (MC). Methods and results Inclusion criteria were met in 170 patients (85 PD and 85 MC patients). Patients ambulated 20 ft. within 30 min (PD) or after the requisite 4 h recumbent time (MC) if feasible. Primary endpoint was time-to-ambulation (TTA) following device closure. We also directly compared the safety of closure, times-to-hemostasis (TTH), -ambulation (TTA) and -discharge (TTD) with MC and, using a fully allocated cost model, performed cost analysis for both strategies. Multivariate analysis was used to determine predictors of patient satisfaction. The primary endpoint of safe, early ambulation was achieved following closure (mean of 27.1 ± 14.9 min; 95% confidence interval [CI] 25.2–30.2). Predictors of patient satisfaction in the PD group were absence of pain during closure, decreased TTA, and drastic reductions in TTD; the latter contributed indirectly to significant cost savings in the PD group (1250.3 ± 146.4 vs. 2248.1 ± 910.2 dollars, respectively; P

Background: Pocket hematoma is one of the most common complications following cardiac device implantation. This study examined the impact of this complication on in-hospital outcomes following Implantable Cardioverter Defibrillator (ICD) implantation. Methods: Data from Nationwide Inpatient Sample (NIS) 2010 was queried to identify all primary implantations of ICDs and Cardiac Resynchronization Therapy Defibrillators (CRT-D) during the year 2010 using ICD-9 codes. We then identified the patients who experienced a procedure related hematoma during the hospital stay. We compared the outcomes of the patients with and without a hematoma complication. All analyses were performed using SPSS 20 complex samples using appropriate weights to adjust for the complex sampling design of the national database. Results: Out of a total of 85,276 primary ICD implantations in the year 2010, 2233 (2.6% of the implantations) were complicated by a hematoma. Increased age (p

Background Testosterone replacement therapy (TRT) prescriptions have increased several-fold in the last decade. There have been concerns regarding a possible increased incidence of DVT and pulmonary embolism (PE) with TRT. Few data support the association between TRT and DVT/PE. We evaluated the incidence of DVT and PE in men who were prescribed TRT for low serum total testosterone (sTT) levels. Methods This is a retrospective cohort study, conducted using data obtained from the Veterans Affairs Informatics and Computing Infrastructure. We compared the incidence of DVT/PE between those who received TRT and subsequently had normal on-treatment sTT levels (Gp1), those who received TRT but continued to have low on-treatment sTT (Gp2), and those who did not receive TRT (Gp3). Those with prior history of DVT/PE, cancer, hypercoagulable state, and chronic anticoagulation were excluded. Results The final cohort consisted of 71,407 subjects with low baseline sTT. Of these, 10,854 did not receive TRT (Gp3) and 60,553 received TRT. Of those who received TRT, 38,362 achieved normal sTT (Gp1) while 22,191 continued to have low sTT (Gp2). The incidence of DVT/PE was 0.5%, 0.4%, and 0.4% in Gp1, Gp2, and Gp3, respectively. Univariate, multivariate, and stabilized inverse probability of treatment weights analyses showed no statistically significant difference in DVT/PE-free survival between the various groups. Conclusions This study did not detect a significant association between testosterone replacement therapy and risk of DVT/PE in adult men with low sTT who were at low to moderate baseline risk of DVT/PE.

Background The goal of this study is to assess the effect of cardiac resynchronization therapy (CRT) over time on renal function and its impact on mortality. The effect of CRT on renal function in patients with heart failure is not well understood. Methods All patients who underwent CRT implantation at University of Kansas between year 2000 and 2009 were reviewed and patients who had pre and post CRT renal function studied were included in our study. Stages of chronic kidney disease (CKD) were defined based on Kidney Disease Outcome Quality Initiative (KDOQI) guidelines. The effect of CRT on renal and cardiac function were studied at short term (≤6 months post implantation) and long term (>6 months). Results A total of 588 patients with mean age of 67 ± 12 yrs were included in the study. CRT responders (defined by increase in LVEF ≥ 5%) were 54% during short term follow-up and 65% on long term follow-up. When compared to baseline, there was no significant deterioration in mean Glomerular Filtration Rate (GFR) during follow up. When analyzed based on the stages of CKD, there was significant improvement of renal function in patients with advanced kidney disease. Multivariate logistic regression analysis showed that stable GFR or an improvement in GFR independently predicted mortality after adjusting for co-morbidities. Conclusions CRT was associated with stabilization of renal function in patients with severe LV dysfunction and improvement in stage 4 and 5 CKD. Improved renal function was associated with a lower mortality.

Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery: the ERICCA Trial Hausenloy et al N Engl J Med . 2015;373:1408–1417. A multi-center trial of remote ischemic preconditioning for heart surgery Meybohm et al N Engl J Med. 2015;373:1397–1407. Ever since its discovery more than 2 decades ago, remote ischemic preconditioning (RIPC) has generated tremendous interest among scientists and clinicians alike. However, two recent large, well-conducted, randomized controlled trials (RCTs) have failed to identify any significant benefit of RIPC during cardiac surgery. A reconciliatory yet objective review of cumulative evidence with regard to cardiac surgery reveals that RIPC in preclinical studies reduced infarct size after experimental myocardial infarction (MI), which is different from cardiac surgery; improved release of biomarkers, but not hard clinical end points, in proof-of-concept clinical trials with discordant results; and failed to produce significant improvement in outcomes in meta-analyses. This difficult journey of RIPC across the valley of death underscores the importance of scientific rigor and exercise of caution in interpreting data at every step of the way until efficacy of a purported therapy is proven conclusively in large RCTs . RIPC is a phenomenon, whereby brief episodes of ischemia in a distant vascular bed protect other organs in the body from subsequent ischemic injury. The concept that a noninvasive and simple procedure can protect organs during elective ischemic episodes has continued to generate tremendous interest among clinicians and scientists. Promising results from numerous basic studies led to many smaller clinical trials and meta-analyses, and then to two large, well-conducted RCTs. The recent results from Effect of Remote Ischaemic Preconditioning on Clinical Outcomes in CABG Surgery (ERICCA) and RIPHeart, however, have failed to identify any significant benefit of RIPC on hard clinical end points or surrogate markers of organ protection. …

Objective: To examine the effect of cigarette smoking (CS) status and total testosterone (TT) levels after testosterone replacement therapy (TRT) on all-cause mortality, myocardial infarction (MI), and stroke in male smokers and nonsmokers without history of MI and stroke. Participants and Methods: Data from 18,055 males with known CS status and low TT levels who received TRT at the Veterans Health Administration between December 1, 1999, and May 31, 2014, were grouped into (1) current smokers with normalized TT, (2) current smokers with nonnormalized TT, (3) nonsmokers with normalized TT, and (4) nonsmokers with nonnormalized TT. Combined effect of CS status and TT level normalization after TRT on all-cause mortality, MI, and stroke was compared using propensity score–weighted Cox proportional hazard models. Results: Normalization of serum TT levels in nonsmokers was associated with a significant decrease in all-cause mortality (hazard ratio [HR]=0.526; 95% CI, 0.477-0.581; P