Readmissions After Surgical Aortic Valve Replacement: Influence of Prosthesis Type.

INTRODUCTION: Prosthesis choice during aortic valve replacement (AVR) weighs lifelong anticoagulation with mechanical valves (M-AVR) against structural valve degeneration in bioprosthetic valves (B-AVR). METHODS: The Nationwide Readmissions Database was queried to identify patients who underwent isolated surgical AVR between January 1, 2016 and December 31, 2018, stratifying by prothesis type. Propensity score matching was used to compare risk-adjusted outcomes. Readmission at 1 y was estimated with Kaplan-Meier (KM) analysis. RESULTS: Patients (n = 109,744) who underwent AVR (90,574 B-AVR and 19,170 M-AVR) were included. B-AVR patients were older (median 68 versus 57 y; P < 0.001) and had more comorbidities (mean Elixhauser score: 11.8 versus 10.7; P < 0.001) compared to M-AVR patients. After matching (n = 36,951), there was no difference in age (58 versus 57 y; P = 0.6) and Elixhauser score (11.0 versus 10.8; P = 0.3). B-AVR patients had similar in-hospital mortality (2.3% versus 2.3%; P = 0.9) and cost (mean: $50,958 versus $51,200; P = 0.4) compared with M-AVR patients. However, B-AVR patients had shorter length of stay (8.3 versus 8.7 d; P < 0.001) and fewer readmissions at 30 d (10.3% versus 12.6%; P < 0.001) and 90 d (14.8% versus 17.8%; P < 0.001), and 1 y (P < 0.001, KM analysis). Patients undergoing B-AVR were less likely to be readmitted for bleeding or coagulopathy (5.7% versus 9.9%; P < 0.001) and effusions (9.1% versus 11.9%; P < 0.001). CONCLUSIONS: B-AVR patients had similar early outcomes compared to M-AVR patients, but lower rates of readmission. Bleeding, coagulopathy, and effusions are drivers of excess readmissions in M-AVR patients. Readmission reduction strategies targeting bleeding and improved anticoagulation management are warranted in the first year following AVR.

Considerations for Left Atrial Appendage Occlusion During Cardiac Surgery.

Atrial fibrillation is associated with an increased risk of stroke secondary to thrombus formation in the left atrial appendage. Left atrial appendage occlusion (LAAO) is an effective method of reducing the risk of stroke in patients with atrial fibrillation. Although LAAO does not remove the requirement for anticoagulation, it reduces the risk of stroke when compared to anticoagulation alone. We critically analyze the data on LAAO in cardiac surgery. We also discuss the methods of LAAO, the risks of LAAO, and patient populations that could benefit from LAAO. We discuss high-level evidence that LAAO at the time of cardiac surgery reduces the risk of stroke in patients with a history of atrial fibrillation. In patients without a history of atrial fibrillation undergoing cardiac surgery, we suggest that LAAO should be considered in select patients at high risk of atrial fibrillation and stroke, when technically feasible.

Outcomes after bioprosthetic versus mechanical mitral valve replacement for infective endocarditis in the United States.

Objective: In patients who underwent mitral valve replacement for infectious endocarditis, we evaluated the association of prosthesis choice with readmission rates and causes (the primary outcomes), as well as with in-hospital mortality, cost, and length of stay (the secondary outcomes). Methods: Patients with infectious endocarditis who underwent isolated mitral valve replacement from January 2016 to December 2018 were identified in the United States Nationwide Readmissions Database and stratified by valve type. Propensity score matching was used to compare adjusted outcomes. Results: A weighted total of 4206 patients with infectious endocarditis underwent bioprosthetic mitral valve replacement (n = 3132) and mechanical mitral valve replacement (n = 1074) during the study period. Patients in the bioprosthetic mitral valve replacement group were older than those in the mechanical mitral valve replacement group (median 57 vs 46 y, P < .001). After propensity matching, the bioprosthetic mitral valve replacement group (n = 1068) had similar in-hospital mortality, length of stay, and costs compared with the mechanical mitral valve replacement group (n = 1056). Overall, 90-day readmission rates were high (28.9%) and comparable for bioprosthetic mitral valve replacement (30.5%) and mechanical mitral valve replacement (27.5%, P = .4). Likewise, there was no difference in readmissions over a calendar year by prosthesis type. Readmissions for infection and bleeding were common for both bioprosthetic mitral valve replacement and mechanical mitral valve replacement groups. Conclusions: Outcomes and readmission rates were similar for mechanical mitral valve replacement and bioprosthetic mitral valve replacement in infectious endocarditis, suggesting that valve choice should not be determined by endocarditis status. Additionally, strategies to mitigate readmission for infection and bleeding are needed for both groups.

Impact of frailty on outcomes and readmissions after transcatheter and surgical aortic valve replacement in a national cohort.

Objective: We examined the effect of frailty on in-hospital mortality, readmission rates, and hospitalization costs after transcatheter and surgical aortic valve replacement in a population-level cohort. Methods: The Nationwide Readmissions Database was queried for patients who underwent transcatheter or surgical aortic valve replacement during 2016-2018. Multivariate logistic regression was used to discern independent effects of frailty on outcomes. Kaplan-Meier time-to-event analysis was used to evaluate the effect of frailty on freedom from readmission. Results: A total of 243,619 patients underwent aortic valve replacement: 142,786 (58.6%) transcatheter aortic valve replacements and 100,833 (41.4%) surgical aortic valve replacements. Frail patients constituted 16,388 (11.5%) and 7251 (7.2%) in the transcatheter aortic valve replacement and surgical aortic valve replacement cohorts, respectively. Compared with nonfrail patients, frail patients had greater in-hospital mortality (transcatheter aortic valve replacement: 3.2% vs 1.1%; surgical aortic valve replacement: 6.1% vs 2.0%; both P < .001), longer length of stay (transcatheter aortic valve replacement: 4 vs 2 days; surgical aortic valve replacement: 13 vs 6 days; P < .001), and greater cost (transcatheter aortic valve replacement: $51,654 vs $44,401; surgical aortic valve replacement: $60,782 vs $40,544; P < .001). Time-to-event analysis showed that frail patients had higher rates of readmission over the calendar year in both transcatheter aortic valve replacement (P < .001) and surgical aortic valve replacement (P < .001) cohorts. This association persisted on adjusted multivariate regression for mortality (transcatheter aortic valve replacement odds ratio [95% CI] 1.98 [1.65-2.37], surgical aortic valve replacement 1.96 [1.60-2.41]), 30-day readmission (transcatheter aortic valve replacement 1.38 [1.27-1.49], surgical aortic valve replacement 1.47 [1.30-1.65]), and 90-day readmission (transcatheter aortic valve replacement 1.41 [1.31-1.52], surgical aortic valve replacement 1.60 [1.43-1.79]) (P < .001 for all). Conclusions: For patients undergoing transcatheter or surgical aortic valve replacement, frailty is associated with in-hospital mortality, readmission, and higher costs. Further efforts to optimize outcomes for frail patients are warranted.

Safety of Early Discharge After Coronary Artery Bypass Grafting: A Nationwide Readmissions Analysis.

BACKGROUND: We determined the safety of early discharge after coronary artery bypass grafting (CABG) in patients with uncomplicated postoperative courses and compared outcomes with routine discharge in a national cohort. We identified preoperative factors associated with readmission after early discharge after CABG. METHODS: The Nationwide Readmissions Database was queried to identify patients undergoing CABG from January 2016 to December 2018. Patients were stratified based on length of stay (LOS) as early (≤4 days) vs routine (5-10 days) discharge. Patients were excluded with hospital courses indicative of complicated stays (emergent procedures, LOS >10 days, discharge to extended care facility or with home health, index hospitalization mortality). Propensity score matching was performed to compare outcomes between cohorts. Multivariable logistic regression models were used to identify factors associated with readmission after early discharge. RESULTS: During the study period, 91,861 patients underwent CABG with an uncomplicated postoperative course (∼20% of CABG population). Of these, 31% (28,790 of 91,861) were discharged early, and 69% (63,071 of 91,861) were routinely discharged. After propensity score matching, patients discharged early had lower readmission rates at 30 days, 90 days, and up to 1 year (P < .001 for all). The index hospitalization cost was lower with early discharge ($26,676 vs $32,859; P < .001). Early discharge was associated with a lower incidence of nosocomial infection at the index hospitalization (0.17% vs 0.81%, P < .001) and readmission from infection (14.5% vs 18%, P = .016). CONCLUSIONS: Early discharge after uncomplicated CABG can be considered in a highly selective patient population. Early-discharge patients are readmitted less frequently than matched routine-discharge patients, with a lower incidence of readmission from infection. Appropriate postdischarge processes to facilitate early discharge after CABG should be further pursued.

Dantrolene inhibits lysophosphatidylcholine-induced valve interstitial cell calcific nodule formation via blockade of the ryanodine receptor.

Calcific aortic valve disease (CAVD), a fibrocalcific thickening of the aortic valve leaflets causing obstruction of the left ventricular outflow tract, affects nearly 10 million people worldwide. For those who reach end-stage CAVD, the only treatment is highly invasive valve replacement. The development of pharmaceutical treatments that can slow or reverse the progression in those affected by CAVD would greatly advance the treatment of this disease. The principal cell type responsible for the fibrocalcific thickening of the valve leaflets in CAVD is valvular interstitial cells (VICs). The cellular processes mediating this calcification are complex, but calcium second messenger signaling, regulated in part by the ryanodine receptor (RyR), has been shown to play a role in a number of other fibrocalcific diseases. We sought to determine if the blockade of calcium signaling in VICs could ameliorate calcification in an in vitro model. We previously found that VICs express RyR isotype 3 and that its modulation could prevent VIC calcific nodule formation in vitro. We sought to expand upon these results by further investigating the effects of calcium signaling blockade on VIC gene expression and behavior using dantrolene, an FDA-approved pan-RyR inhibitor. We found that dantrolene also prevented calcific nodule formation in VICs due to cholesterol-derived lysophosphatidylcholine (LPC). This protective effect corresponded with decreases in intracellular calcium flux, apoptosis, and ACTA2 expression but not reactive oxygen species formation caused by LPC. Interestingly, dantrolene increased the expression of the regulator genes RUNX2 and SOX9, indicating complex gene regulation changes. Further investigation via RNA sequencing revealed that dantrolene induced several cytoprotective genes that are likely also responsible for its attenuation of LPC-induced calcification. These results suggest that RyR3 is a viable therapeutic target for the treatment of CAVD. Further studies of the effects of RyR3 inhibition on CAVD are warranted.

Coronary artery bypass grafting at safety-net versus non-safety-net hospitals.

Objectives: Safety-net hospitals (SNHs) provide essential services to predominantly underserved patients regardless of their ability to pay. We hypothesized that patients who underwent coronary artery bypass grafting (CABG) would have inferior observed outcomes at SNHs compared with non-SNHs but that matched cohorts would have comparable outcomes. Methods: We queried the Nationwide Readmissions Database for patients who underwent isolated CABG from 2016 to 2018. We ranked hospitals by the percentage of all admissions in which the patient was uninsured or insured with Medicaid; hospitals in the top quartile were designated as SNHs. We used propensity-score matching to mitigate the effect of confounding factors and compare outcomes between SNHs and non-SNHs. Results: A total of 525,179 patients underwent CABG, including 96,133 (18.3%) at SNHs, who had a greater burden of baseline comorbidities (median Elixhauser score 8 vs 7; P = .04) and more frequently required urgent surgery (57.1% vs 52.8%; P < .001). Observed in-hospital mortality (2.1% vs 1.8%; P = .004) and major morbidity, length of stay (9 vs 8 days; P < .001), cost ($46,999 vs $38,417; P < .001), and readmission rate at 30 (12.4% vs 11.3%) and 90 days (19.0% vs 17.7%) were greater at SNHs (both P < .001). After matching, none of these differences persisted except length of stay (9 vs 8 days) and cost ($46,977 vs $39,343) (both P < .001). Conclusions: After matching, early outcomes after CABG were comparable at SNHs and non-SNHs. Improved discharge resources could reduce length of stay and curtail cost, improving the value of CABG at SNHs.

Socioeconomic disparities in procedural choice and outcomes after aortic valve replacement.

Objective: To identify potential socioeconomic disparities in the procedural choice of patients undergoing surgical aortic valve replacement (SAVR) versus transcatheter aortic valve replacement (TAVR) and in readmission outcomes after SAVR or TAVR. Methods: The Nationwide Readmissions Database was queried to identify a total of 243,691 patients who underwent isolated SAVR and TAVR between January 2016 and December 2018. Patients were stratified according to a tiered socioeconomic status (SES) metric comprising patient factors including education, literacy, housing, employment, insurance status, and neighborhood median income. Multivariable analyses were used to assess the effect of SES on procedural choice and risk-adjusted readmission outcomes. Results: SAVR (41.4%; 100,833 of 243,619) was performed less frequently than TAVR (58.6%; 142,786 of 243,619). Lower SES was more frequent among patients undergoing SAVR (20.2% [20,379 of 100,833] vs 19.4% [27,791 of 142,786]; P < .001). Along with such variables as small hospital size, drug abuse, arrhythmia, and obesity, lower SES was independently associated with SAVR relative to TAVR (adjusted odds ratio [aOR], 1.17; 95% confidence interval [CI], 1.11 to 1.24). After SAVR, but not after TAVR, lower SES was independently associated with increased readmission at 30 days (aOR, 1.19; 95% CI, 1.07-1.32), 90 days (aOR, 1.27; 95% CI, 1.15-1.41), and 1 year (adjusted hazard ratio, 1.19; 95% CI, 1.11 to 1.28; P < .05 for all). Conclusions: Our study findings indicate that socioeconomic disparities exist in the procedural choice for patients undergoing AVR. Patients with lower SES had increased odds of undergoing SAVR, as well as increased odds of readmission after SAVR, but not after TAVR, supporting that health inequities exist in the surgical care of socioeconomically disadvantaged patients.

Influence of concomitant ablation of nonparoxysmal atrial fibrillation during coronary artery bypass grafting on mortality and readmissions.

Objective: We determined the utilization rate of surgical ablation (SA) during coronary artery bypass grafting (CABG) and compared outcomes between CABG with or without SA in a national cohort. Methods: The January 2016 to December 2018 Nationwide Readmissions Database was searched for all patients undergoing isolated CABG with preoperative persistent or chronic atrial fibrillation by using the International Classification of Diseases, 10th Revision classification. Propensity score matching and multivariate logistic regressions were performed to compare outcomes, and Cox proportional hazards model was used to assess risk factors for 1-year readmission. Results: Of 18,899 patients undergoing CABG with nonparoxysmal atrial fibrillation, 78% (n = 14,776) underwent CABG alone and 22% (n = 4123) underwent CABG with SA. In the propensity score-matched cohort (n = 8116), CABG with SA (n = 4054) (vs CABG alone [n = 4112]) was not associated with increased in-hospital mortality (3.4% [139 out of 4112] vs 3.9% [159 ut of 4054]; P = .4), index-hospitalization length of stay (10 days vs 10 days; P = .3), 30-day readmission (19.1% [693 out of 3362] vs 17.2% [609 out of 3537]; P = .2), or 90-day readmission (28.9% [840 out of 2911] vs 26.2% [752 out of 2875]; P = .1). Index hospitalization costs were significantly higher for those undergoing SA ($52,556 vs $47,433; P < .001). Rates of readmission at 300 days were similar between patients receiving SA (43.8%) and no SA (42.8%; log-rank P = .3). The 3 most common causes of readmission were not different between groups and included heart failure (24.3% [594 out of 2444]; P = .6), infection (16.8% [411 out of 2444]; P = .5), and arrhythmia (11.7% [286 out of 2444]; P = .2). Conclusions: In patients with nonparoxysmal atrial fibrillation, utilization of SA during CABG remains low. SA during CABG did not adversely influence mortality or short-term readmissions. These findings support increased use of SA during CABG.

Chronic kidney disease, risk of readmission, and progression to end-stage renal disease in 519,387 patients undergoing coronary artery bypass grafting.

Objective: The association between chronic kidney disease and adverse outcomes after coronary artery bypass grafting is well established; in contrast, the association between chronic kidney disease and readmission has been less thoroughly investigated. We hypothesized that patients at higher chronic kidney disease stages have greater risk of readmission, poorer operative outcomes, and greater hospitalization cost. Methods: Using the 2016-2018 Nationwide Readmissions Database, we identified 519,387 patients who underwent isolated coronary artery bypass grafting. Patients were stratified by chronic kidney disease stage based on International Classification of Diseases 10th Revision classification. Multivariable logistic regression was used to assess risk factors for in-hospital mortality and 90-day readmission. Results: Hospital readmission, in-hospital mortality, and cost progressively increased with worsening chronic kidney disease stage; patients with end-stage renal disease had the highest in-hospital mortality rate (7.2%), hospitalization costs ($59,616) (P < .001), and 90-day readmission rate (40%) (P < .001). Chronic kidney disease stage greater than 3 was associated with in-hospital mortality (odds ratio, 1.56, 95% confidence interval, 1.40-1.73; P < .001) and 90-day readmission (odds ratio, 1.66, 95% confidence interval, 1.56-1.76; P < .001). At 30 days after discharge, new-onset dialysis dependence was more frequent in patients readmitted with chronic kidney disease 4 to 5 (8.9%; n = 1495) than in patients with chronic kidney disease 1 to 3 (1.4%; n = 8623) and patients without chronic kidney disease (0.3%; n = 38,885). At 90 days after discharge, dialysis dependence increased to 11.1% (n = 1916) in readmitted patients with chronic kidney disease 4 to 5 but remained stable for patients with chronic kidney disease 1 to 3 (1.4%; n = 10,907) and patients without chronic kidney disease (0.3%; n = 50,200). Conclusions: Chronic kidney disease stage is strongly associated with mortality, new-onset dialysis dependence, readmission, and higher cost after coronary artery bypass grafting. Patients with chronic kidney disease 4 and 5 and patients with end-stage renal disease are readmitted at the highest rates. Although further research is needed, a targeted approach may reduce costly readmissions and improve outcomes after coronary artery bypass grafting in patients with chronic kidney disease.

Outcomes, Cost, and Readmission After Surgical Aortic or Mitral Valve Replacement at Safety-Net and Non-Safety-Net Hospitals.

BACKGROUND: Safety-net hospitals provide essential services to vulnerable patients with complex medical and socioeconomic circumstances. We hypothesized that matched patients at safety-net hospitals and non-safety-net hospitals would have comparable outcomes, costs, and readmission rates after isolated surgical aortic valve replacement (AVR) or mitral valve replacement (MVR). METHODS: The National Readmissions Database was queried to identify patients who underwent isolated AVR (n = 109 744) or MVR (n = 31 475) from 2016 to 2018. Safety-net burden was defined as the percentage of patients who were uninsured or insured with Medicaid, with hospitals in the top quartile designated as safety-net hospitals. After propensity score matching, outcomes for AVR and MVR at safety-net hospitals vs non-safety-net hospitals were compared. RESULTS: Overall, 17 925 AVRs (16%) and 5516 MVRs (18%) were performed at safety-net hospitals, and these patients had higher comorbidity rates, had lower socioeconomic status, and more frequently required urgent surgery. Observed inhospital mortality was similar between safety-net hospitals and non-safety-net hospitals (AVR 2.2% vs 2.1%, P = .4; MVR 4.8% vs 4.3%, P = .1). After matching, rates of inhospital mortality, major morbidity, and readmission were similar; however, safety-net hospitals had longer length of stay after AVR (7 vs 6 days, P = .001) and higher total cost after AVR ($49 015 vs $42 473, P < .001) and MVR ($59 253 vs $52 392, P < .001). CONCLUSIONS: Isolated surgical AVR and MVR are both performed at safety-net hospitals with outcomes comparable to those at non-safety-net hospitals, supporting efforts to expand access to these procedures for underserved populations. Investment in care coordination resources to reduce length of stay and curtail cost at safety-net hospitals is warranted.

Nationwide database analysis of one-year readmission rates after open surgical or thoracic endovascular repair of Stanford Type B aortic dissection.

Objective: We examined readmissions and resource use during the first postoperative year in patients who underwent thoracic endovascular aortic repair or open surgical repair of Stanford type B aortic dissection. Methods: The Nationwide Readmissions Database (2016-2018) was queried for patients with type B aortic dissection who underwent thoracic endovascular aortic repair or open surgical repair. The primary outcome was readmission during the first postoperative year. Secondary outcomes included 30-day and 90-day readmission rates, in-hospital mortality, length of stay, and cost. A Cox proportional hazards model was used to determine risk factors for readmission. Results: During the study period, type B aortic dissection repair was performed in 6456 patients, of whom 3517 (54.5%) underwent thoracic endovascular aortic repair and 2939 (45.5%) underwent open surgical repair. Patients undergoing thoracic endovascular aortic repair were older (63 vs 59 years; P < .001) with fewer comorbidities (Elixhauser score of 11 vs 17; P < .001) than patients undergoing open surgical repair. Thoracic endovascular aortic repair was performed electively more often than open surgical repair (29% vs 20%; P < .001). In-hospital mortality was 9% overall and lower in the thoracic endovascular aortic repair cohort than in the open surgical repair cohort (5% vs 13%; P < .001). However, the 90-day readmission rate was comparable between the thoracic endovascular aortic repair and open surgical repair cohorts (28% vs 27%; P = .7). Freedom from readmission for up to 1 year was also similar between cohorts (P = .6). Independent predictors of 1-year readmission included length of stay more than 10 days (P = .005) and Elixhauser comorbidity risk index greater than 4 (P = .033). Conclusions: Approximately one-third of all patients with type B aortic dissection were readmitted within 90 days after aortic intervention. Surprisingly, readmission during the first postoperative year was similar in the open surgical repair and thoracic endovascular aortic repair cohorts, despite marked differences in preoperative patient characteristics and interventions.

Readmission After Bioprosthetic vs Mechanical Mitral Valve Replacement in the United States.

BACKGROUND: Choosing between a bioprosthetic and a mechanical mitral valve is an important decision for both patients and surgeons. We compared patient outcomes and readmission rates after bioprosthetic mitral valve replacement (Bio-MVR) vs mechanical mitral valve replacement (Mech-MVR). METHODS: The Nationwide Readmissions Database was queried to identify 31 474 patients who underwent isolated MVR (22 998 Bio-MVR, 8476 Mech-MVR) between January 1, 2016, and December 31, 2018. Propensity score matching by age, sex, elective status, and comorbidities was used to compare outcomes between matched cohorts by prosthesis type. Freedom from readmission within the first calendar year was estimated by Kaplan-Meier analysis and compared between matched cohorts. RESULTS: Bio-MVR patients were older (median age, 69 vs 57 years; P < .001) and had more comorbidities (median Elixhauser score, 14 vs 11; P < .001) compared with Mech-MVR patients. After propensity score matching (n = 15 549), Bio-MVR patients had similar operative mortality (3.5% vs 3.4%; P = .97) and costs ($50 958 vs $49 782; P = .16) but shorter lengths of stay (8 vs 9 days; P < .001) and fewer 30-day (16.0% vs 18.1%; P = .04) and 90-day (23.8% vs 26.8%; P = .01) readmissions compared with Mech-MVR patients. The difference in readmissions persisted at 1 year (P = .045). Readmission for bleeding or coagulopathy complications was less common with Bio-MVR (5.7% vs 10.1%; P < .001). CONCLUSIONS: Readmission was more common after Mech-MVR than after Bio-MVR. Identifying and closely observing patients at high risk for bleeding complications may bridge the readmissions gap between Bio-MVR and Mech-MVR.

Cell-Laden Bioactive Poly(ethylene glycol) Hydrogels for Studying Mesenchymal Stem Cell Behavior in Myocardial Infarct-Stiffness Microenvironments.

PURPOSE: Cellular therapy with mesenchymal stem cells (MSCs) shows promise for restoring function after myocardial infarction (MI). However, cellular therapy has yet to be clinically translated, in part because of difficulty in studying how MSCs interact with the post-MI scar microenvironment. This study aimed to design an in vitro model to study MSC behavior in the post-MI scar stiffness microenvironment. METHODS: Using poly(ethylene glycol)-acrylate (PEG) conjugated to bioactive peptides, rat MSCs were encapsulated in hydrogels of varying stiffnesses and crosslinking densities. Cell viability was assessed through 14 days using calcein and ethidium homodimer staining. To simulate post-MI pro-fibrotic signaling, transforming growth factor-beta (TGFß) was added to selected cultures. Immunofluorescence and qRT-PCR were used to assess changes in cardiac transdifferentiation or paracrine secretion, two proposed methods of MSCs in cellular therapy. RESULTS: Bioactivated PEG hydrogels with stiffnesses between 1.6 and 151.0 kPa were prepared. Rat MSCs demonstrated up to 71.6% viability after 3 days of encapsulated culture, and survived within the hydrogels up to 14 days. Encapsulation decreased MSC expression of cardiac troponin T and most growth factors, except interleukin-6. Meanwhile, TGFß caused increased cardiac troponin T expression but decreased secreted factor expression. Varying hydrogel stiffness did not have an effect on cardiac troponin T or secreted factor expression. CONCLUSIONS: These findings suggest that a 3D microenvironment hinders two key mechanisms by which MSCs could improve cardiac function after post-MI scar formation, namely cardiac transdifferentiation and secreted factor production. Future studies incorporating MSCs other cell types should broaden understanding of the post-MI scar microenvironment.

The Ryanodine Receptor Contributes to the Lysophosphatidylcholine-Induced Mineralization in Valvular Interstitial Cells.

PURPOSE: Fibrocalcific aortic valve disease (CAVD) is caused by the deposition of calcific nodules in the aortic valve leaflets, resulting in progressive loss of function that ultimately requires surgical intervention. This process is actively mediated by the resident valvular interstitial cells (VICs), which, in response to oxidized lipids, transition from a quiescent to an osteoblast-like state. The purpose of this study was to examine if the ryanodine receptor, an intracellular calcium channel, could be therapeutically targeted to prevent this phenotypic conversion. METHODS: The expression of the ryanodine receptor in porcine aortic VICs was characterized by qRT-PCR and immunofluorescence. Next, the VICs were exposed to lysophosphatidylcholine, an oxidized lipid commonly found in low-density lipoprotein, while the activity of the ryanodine receptor was modulated with ryanodine. The cultures were analyzed for markers of cellular mineralization, alkaline phosphatase activity, proliferation, and apoptosis. RESULTS: Porcine aortic VICs predominantly express isoform 3 of the ryanodine receptors, and this protein mediates the cellular response to LPC. Exposure to LPC caused elevated intracellular calcium concentration in VICs, raised levels of alkaline phosphatase activity, and increased calcific nodule formation, but these changes were reversed when the activity of the ryanodine receptor was blocked. CONCLUSIONS: Our findings suggest blocking the activity of the ryanodine receptor can attenuate the valvular mineralization caused by LPC. We conclude that oxidized lipids, such as LPC, play an important role in the development and progression of CAVD and that the ryanodine receptor is a promising target for pharmacological intervention.

Radiation-Induced Cardiovascular Disease: Mechanisms and Importance of Linear Energy Transfer.

Radiation therapy (RT) in the form of photons and protons is a well-established treatment for cancer. More recently, heavy charged particles have been used to treat radioresistant and high-risk cancers. Radiation treatment is known to cause cardiovascular disease (CVD) which can occur acutely during treatment or years afterward in the form of accelerated atherosclerosis. Radiation-induced cardiovascular disease (RICVD) can be a limiting factor in treatment as well as a cause of morbidity and mortality in successfully treated patients. Inflammation plays a key role in both acute and chronic RICVD, but the underling pathophysiology is complex, involving DNA damage, reactive oxygen species, and chronic inflammation. While understanding of the molecular mechanisms of RICVD has increased, the growing number of patients receiving RT warrants further research to identify individuals at risk, plans for prevention, and targets for the treatment of RICVD. Research on RICVD is also relevant to the National Aeronautics and Space Administration (NASA) due to the prevalent space radiation environment encountered by astronauts. NASA's current research on RICVD can both contribute to and benefit from concurrent work with cell and animal studies informing radiotoxicities resulting from cancer therapy. This review summarizes the types of radiation currently in clinical use, models of RICVD, current knowledge of the mechanisms by which they cause CVD, and how this knowledge might apply to those exposed to various types of radiation.

Ceragenin mediated selectivity of antimicrobial silver nanoparticles.

The understanding that common broad-spectrum antimicrobials disrupt natural microbial flora important in acquiring nutrients and preventing infection has resulted in a paradigm shift favoring more selective antimicrobials. This work explores silver nanoparticles conjugated with ceragenin, or cationic antimicrobials (CSA-SNPs), as a potential Gram-positive selective antimicrobial. Herein, CSA-SNPs are characterized using transmission electron microscopy (TEM), dynamic light scattering (DLS), zeta potential, and high-performance liquid chromatography-electrospray time-of-flight mass spectrometry (HPLC-ESI-TOF-MS). The antimicrobial properties are determined through minimum inhibitory concentration/minimum bactericidal concentration (MIC/MBC) and time-kill studies. Spatial selectivity of the conjugate nanoparticle was evaluated using confocal imaging, MATLAB statistical analysis, and video monitored interactions between bacteria and CSA-SNPs via laser trapping techniques. Cytotoxicity was also determined by live/dead staining and flow cytometry. Average particle size, as determined through TEM analysis, and hydrodynamic diameter, as determined via DLS, are 63.5 ± 38.8 and 102.23 ± 2.3 nm, respectively. The zeta potential of the SNP before and after CSA attachment is -18.23 and -8.34 mV, respectively. MIC/MBC data suggest that CSA-SNPs are 8 times more effective against Staphylococcus aureus than SNPs alone. Furthermore, MATLAB analysis of confocal imaging found that 70% of CSA-SNPs are within 2 µm of S. aureus, whereas this percentage falls to below 40% with respect to Escherichia coli. These results are bolstered further by laser trapping experiments demonstrating selective adherence of CSA-SNPs conjugates with bacterial strains. Cytotoxicity studies of CSA-SNPs against 3T3 fibroblasts indicate 50% cell viability at 50 ppm.