Circulating platelet aggregates damage endothelial cells in culture.

BACKGROUND: Presence of circulating endothelial cells (CECs) in systemic circulation may be an indicator of endothelial damage and/or denudation, and the body's response to repair and revascularization. Thus, we hypothesized that aggregated platelets (AgPlts) can disrupt/denude the endothelium and contribute to the presence of CEC and EC-derived particles (ECDP). METHODS: Endothelial cells were grown in glass tubes and tagged with/without 0.5 µm fluorescent beads. These glass tubes were connected to a mini-pump variable-flow system to study the effect of circulating AgPlts on the endothelium. ECs in glass tube were exposed to medium alone, nonaggregated platelets (NAgPlts), AgPlts, and 90 micron polystyrene beads at a flow rate of 20 mL/min for various intervals. Collected effluents were cultured for 72 h to analyze the growth potential of dislodged but intact ECs. Endothelial damage was assessed by real time polymerase chain reaction (RT-PCR) for inflammatory genes and Western blot analysis for von Willebrand factor. RESULTS AND CONCLUSION: No ECs and ECDP were observed in effluents collected after injecting medium alone and NAgPlts, whereas AgPlts and Polybeads drastically dislodged ECs, releasing ECs and ECDP in effluents as the time increased. Effluents collected when endothelial cell damage was seen showed increased presence of von Willebrand factor as compared to control effluents. Furthermore, we analyzed the presence of ECs and ECDPs in heart failure subjects, as well as animal plasma samples. Our study demonstrates that circulating AgPlts denude the endothelium and release ECs and ECDP. Direct mechanical disruption and shear stress caused by circulating AgPlts could be the underlying mechanism of the observed endothelium damage.

Lung transplantation with lungs from older donors: an analysis of survival in elderly recipients.

BACKGROUND: The average ages of lung transplant (LTx) recipients and donors are increasing. With older recipients considered to be especially at high risk of posttransplant mortality, we sought to determine whether the use of allografts from older donors affects survival among older patients undergoing LTx. METHODS: The United Network for Organ Sharing registry was used to identify patients aged 65-80 y receiving a first-time LTx between 1987 and 2013. Survival analysis examined implications of a donor-recipient age difference >10 y using Cox proportional hazards regression. RESULTS: The cohort selected for analysis included 3227 elderly LTx recipients, of whom 263 (8.15%) had donors within 10 y of their age at transplantation. Univariate Cox models found no differences with LTx involving donors at least 10 y younger than the recipient with respect to overall survival (hazard ratio = 0.979; 95% confidence interval [CI] = 0.807-1.188; P = 0.831) or conditional survival past 1 y (hazard ratio = 1.067; 95% CI = 0.819-1.391; P = 0.629) relative to LTx involving donors within 10 y of an elderly recipient's age. These findings were substantiated in multivariate analysis adjusting for potential confounders. CONCLUSIONS: In elderly LTx recipients aged 65-80 y at transplantation, intermediate-term survival was not influenced by donor age. For the viable elderly LTx candidate, a carefully selected older donor should be considered to increase donor availability.

Impact of induction immunosuppression on survival in heart transplant recipients: a contemporary analysis of agents.

INTRODUCTION: The impact of induction immunosuppression on long-term survival in heart transplant recipients is unclear. Over the past three decades, practices have varied as induction agents have changed and experiences grew. We sought to evaluate the effect of contemporary induction immunosuppression agents in heart transplant recipients with the primary endpoint of survival, utilizing national registry data. METHODS: We queried the United Network for Organ Sharing (UNOS) data registry for all heart transplants from 1987 to 2012. We restricted our analysis to adult (≥18 yr) recipients performed from 2001-2011 (to allow for the potential for a minimum of 12 months post-transplant follow-up) who received either: no antibody based induction (NONE) or the contemporary agents (INDUCED) of either: basiliximab/daclizumab (IL-2Rab), alemtuzumab, or ATG/ALG/thymoglobulin. Kaplan-Meier estimates of the survival function as well as Cox proportional hazards models were utilized. RESULTS: Of the 17 857 heart transplants that met the inclusion criteria, there were 4635 (26%) reported deaths during the follow-up period. There were 8216 (46%) patients who were INDUCED. Of the INDUCED agents, 55% were IL-2Rab, 4% alemtuzumab, and 40% ALG/ATG/thymoglobulin. Donor and recipient characteristics were evaluated. Overall, being INDUCED did not significantly affect survival in univariable (p = 0.522) and multivariable (p = 0.130) Cox models as well as a propensity score adjusted model (p = 0.733). Among those induced, ATG/ALG/thymoglobulin appeared to have superior survival as compared with IL-2Rab (log-rank p = 0.007, univariable hazard ratio [HR] = 0.886; 95% CI: 0.811-0.968; p = 0.522). However, in a multivariable Cox model that adjusted for recipient age, VAD, BMI, steroid use, CMV match, and ischemic time, the hazard ratio for ALG/ATG/thymoglobulin vs. IL-2Rab was no longer statistically significant (HR = 0.948; 95% CI: 0.850-1.058; p = 0.341). CONCLUSION: In a contemporary analysis of heart transplant recipients, an overall analysis of induction agents does not appear to impact survival, as compared to no induction immunosuppression. While ALG/ATG/thymoglobulin appeared to have a beneficial effect on survival compared to IL-2Rab in the univariable model, this difference was no longer statistically significant once we adjusted for clinically relevant covariates.

Endovascular abdominal aortic aneurysm repair in patients with ventricular assist devices.

Long-term mechanical circulatory support devices are currently an established therapy for the management of end-stage heart failure, and current evidence supports their superiority in comparison to maximal medical therapy in these patients. Screening for peripheral arterial disease and abdominal aortic aneurysm (AAA) before left ventricular assist device (LVAD) implantation is recommended. Although repair of AAA before or during LVAD placement has been reported, management of patients with AAA after LVAD implantation needs to be further investigated. We describe our management and operative strategies in 2 patients on destination LVAD therapy who underwent successful endovascular AAA repair.

Regional disparities in heart transplant mortality in the United States.

BACKGROUND: Mortality after heart transplantation can be influenced by multiple factors. This study analyzed its variation across 4 regions of the United States. OBJECTIVE: Analyze the differences in mortality among patients receiving a heart transplant across 4 regions of the United States. METHODS: Organ Procurement and Transplantation Network (OPTN)/United Network for Organ Sharing (UNOS) registry was analyzed for adult heart transplant recipients from 1987-2023. They were divided into 4 regions according to heart transplant recipients' residence: the Northeast, Midwest, South, and West. The endpoint was all-cause mortality. RESULTS: A total of 33,482 heart transplant recipients were included in the analysis. Baseline characteristics differed by region. The median survival (years) was lower in the South [Northeast 12.9 (6.1-17.9), Midwest 13.1 (6.5-18.1), South 11.6 (5.3-16.8), West 13.6 (7.0-18.6); p<0.0001]. Mortality incidence rate was greater in the South. When compared to the Northeast, in the unadjusted analysis, mortality was higher in the South [HR 1.13 (95%CI 1.07-1.19), p<0.001] and lower in the West [HR 0.89 (95%CI 0.83-0.94), p<0.001]. After adjusting for demographic and clinical variables, only the South retained significant differences [HR 1.17 (95%CI 1.10-1.24), p<0.001]. Mortality significantly increased in all regions after 2018. CONCLUSION: Mortality of heart transplant recipients varies across region of residence in the United States. A significant increase in adjusted mortality was observed in the South. These findings suggest that there are regional disparities in the mortality rates of heart transplant recipients.

Relationship between donor ejection fraction, left ventricular wall thickness and mortality in heart transplants recipients.

This study explored the impact of donor left ventricular ejection fraction (EF) and left ventricular wall thickness (LVWT) on mortality among heart transplant (HTx) recipients. Utilizing data from the United Network for Organ Sharing (UNOS) registry, adult HTx recipients between 2006-2022 were analyzed. Patients were categorized into four groups based on donor EF(>50 % or ≤50 %) and LVWT(<1.4 cm or ≥1.4 cm). 21,012 patients were included. There were significant differences in baseline characteristics among the groups. Unadjusted mortality was 6.3 %, 6.0 %, 6.0 %, and 2.4 %(p=0.86) at 30-days; 16.2 %, 13.5 %, 16.8 %, and 7.3 %(p=0.08) at 1-year; and 32.2 %, 29.2 %, 35.4 %, and 29.0 %(p=0.18) at 5-years, respectively. In addition, adjusted mortality did not differ across the groups. There were no significant differences in recipient mortality in groups based on donor EF and LVWT. Expanding the donor selection criteria would allow for increase in the donor pool and assist in decreasing the mortality, while on the waitlist for HTx.

Preoperative hyponatremia predicts outcomes after cardiac surgery.

OBJECTIVE: To study the effect of preoperative hyponatremia (Na <135 mEq/L) on outcomes after cardiac surgery. METHODS: From 2002 to 2008, 4370 patients had cardiac surgery at our institution (CABG in 2238, valve in 597, CABG valve in 537, other in 998). The institution electronic medical records, STS database, and Social Security death index data were analyzed. The association of hyponatremia with mortality, hospital length of stay (LOS), and complications was analyzed using regression analysis. RESULTS: Prevalence of hyponatremia was 21%. Patients with preoperative hyponatremia had lower left ventricular ejection fraction (39% ± 17% versus 46% ± 14%, P < 0.001) and glomerular filtration rate (69 ± 32 mg/min/1.73 m(2)versus 74 ± 27 mg/min/1.73 m(2), P < 0.001) and higher median EuroSCORE (19% versus 9%, P < 0.001), NYHA class 3-4 (77% versus 65%, P < 0.001), prevalence of chronic obstructive pulmonary disease (25% versus 18%, P < 0.001), and arteriopathy (20% versus 13%, P < 0.001). Hyponatremia was associated with increased early mortality (9% versus 4%, P < 0.001), late mortality (24% versus 16%, P < 0.001), and LOS (13 versus 8 d, P < 0.001). Mortality increased with the severity of hyponatremia. After adjusting for baseline and operative variables, hyponatremia was associated with increased hazard of mortality (hazard ratio [HR] 1.31, 95% confidence interval [CI] 1.14-1.52, P < 0.001), risk of early mortality (odds ratio [OR] 1.52, 95% CI 1.09-2.12, P < 0.001), late mortality (HR 1.37, 95% CI 1.16-1.62, P < 0.001), LOS (multiplier 1.26, 95% CI 1.15-1.39, P < 0.001), operative complications (OR 1.30, 95% CI 1.00-1.69, P = 0.051), and dialysis (OR 1.64, 95% CI 1.11-2.44, P = 0.013). CONCLUSIONS: Preoperative hyponatremia is common, especially in high-risk patients. It is an independent risk factor for mortality, prolonged hospitalization, and complications after cardiac surgery.

Incidental detection of pheochromocytoma during workup for symptomatic aortic stenosis: A case report and management discussion.

Pheochromocytoma patients with high levels of circulating catecholamines are at risk of cardiovascular complications related to hypertensive emergencies and subsequent organ damage. A patient with concomitant aortic stenosis and pheochromocytoma has compounded risk of cardiovascular complications, especially during surgery, which complicates medical decision-making. We report a patient with Turner syndrome and congenital heart defects (CHDs) who was incidentally discovered to have a pheochromocytoma during workup of symptomatic severe bioprosthetic aortic stenosis. Management included laparoscopic adrenalectomy followed by Transcatheter Aortic Valve Replacement (TAVR). We describe considerations for multidisciplinary management in this complex clinical case.

Induction of brain natriuretic peptide and monocyte chemotactic protein-1 gene expression by oxidized low-density lipoprotein: relevance to ischemic heart failure.

Brain natriuretic peptide (BNP) and monocyte chemotactic protein-1 (MCP-1) are biomarkers of heart failure (HF). The aim of the present study was to determine the role of oxidized low-density lipoprotein (Ox-LDL) in the induction of these biomarkers and the signaling pathways involved in vitro. Incubation of HL-1 cardiomyocytes and human myocytes with Ox-LDL induced the expression of BNP and MCP-1 genes, while native LDL had no effect. When peroxides associated with Ox-LDL were reduced to hydroxides, the ability to induce BNP and MCP-1 gene expression was abolished. Furthermore, exposure of HL-1 cells to ischemic conditions alone had no effect on BNP gene expression, while ischemia followed by reperfusion resulted in increased expression of BNP gene. Inhibitors of ERK and JNK inhibited the induction of BNP. Signaling array results suggested that the induction of both MAPK and NF-κB pathways is involved in the induction of BNP by Ox-LDL. These results suggest that Ox-LDL or peroxidized lipids formed in oxidatively stressed myocytes during ischemia-reperfusion injury may play a role in the induction of BNP and MCP-1.

Shortness of breath: pulmonary embolism, ischemic heart failure, or both? The role of concomitant surgery.

We present a case of a patient who underwent successful concomitant surgical management of his massive pulmonary embolism and severe multivessel coronary disease. His presentation with shortness of breath prompted a comprehensive evaluation, which revealed both problems. This experience emphasizes the importance of considering both problems, because treating one but not the other could be catastrophic.

Cardiopulmonary Injury in the Syrian Hamster Model of COVID-19.

The Syrian hamster has proved useful in the evaluation of therapeutics and vaccines for severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). To advance the model for preclinical studies, we conducted serial sacrifice of lungs, large pulmonary vessels, and hearts from male and female Syrian hamsters for days 1-4, and 8 post-infection (dpi) following infection with a high dose of SARS-CoV-2. Evaluation of microscopic lung histopathology scores suggests 4 and 8 dpi as prime indicators in the evaluation of moderate pathology with bronchial hyperplasia, alveolar involvement and bronchiolization being key assessments of lung disease and recovery, respectively. In addition, neutrophil levels, red blood cell count and hematocrit showed significant increases during early infection. We present histological evidence of severe damage to the pulmonary vasculature with extensive leukocyte transmigration and the loss of endothelial cells and tunica media. Our evidence of endothelial and inflammatory cell death in the pulmonary vessels suggests endothelialitis secondary to SARS-CoV-2 epithelial cell infection as a possible determinant of the pathological findings along with the host inflammatory response. Lastly, pathological examination of the heart revealed evidence for intracardiac platelet/fibrin aggregates in male and female hamsters on 8 dpi, which might be indicative of a hypercoagulative state in these animals.

Anterior wall viability and low ejection fraction predict functional improvement after CABG.

BACKGROUND: Absence of myocardial hyperenhancement on cardiac magnetic resonance imaging (CMR) predicts functional improvement after coronary artery bypass graft surgery (CABG). However, not all patients with absence of hyperenhancement improve their left ventricular ejection fraction (LVEF) after CABG. We sought to identify other characteristics associated with improvement in LVEF after CABG. METHODS: Preoperative CMR was obtained in 95 patients who underwent CABG from 2003 to 2007 at The Ohio State University Medical Center. Follow-up LVEF was assessed by echocardiogram between 3 wk and 2 y postoperatively (mean: 7±0.5 mo). Improvement in LVEF was defined as a postoperative increase in LVEF≥10%. CMR and clinical factors were analyzed for predictors of functional improvement. RESULTS: Mean age was 61±1 y with 79 males. LVEF improved from 28%±2% preoperatively, to 38%±2% postoperatively (P<0.0001). Forty-three patients improved their LVEF. Patients who improved their LVEF had a lower preoperative LVEF (P=0.0001) and higher anterior wall viability (P=0.03). Preoperative LVEF (odds ratio 0.89, 95% CI 0.83-0.95, P=0.001) and left ventricular end systolic volume index (odds ratio 0.97, 95% CI 0.95-0.99, P=0.015) were predictors of improvement in LVEF by multivariable logistic regression analysis. CONCLUSIONS: Recruitment of viable non functioning myocardium of the anterior wall is responsible for the improvement in ejection fraction. Low LVEF, non-remodeled left ventricle, and anterior wall viability predict improvement in ejection fraction after CABG. These criteria may help clinicians select patients who would benefit from surgical revascularization.

PTEN as a Therapeutic Target in Pulmonary Hypertension Secondary to Left-heart Failure: Effect of HO-3867 and Supplemental Oxygenation.

Pulmonary hypertension (PH) is a condition when the pressure in the lung blood vessels is elevated. This leads to increase in thickness of the blood vessels and increases the workload of the heart and lungs. The incidence and prevalence of PH has been on the increase in the last decade. It is estimated that PH affects about 1% of the global population and about 10% of individuals >65 years of age. Of the various types, Group 2 PH is the most common type seen in the elderly population. Fixed PH or PH refractive to therapies is considered a contraindication for heart transplantation; the 30-day mortality in heart transplant recipients is significantly increased in the subset of this population. In general, the pathobiology of PH involves multiple factors including hypoxia, oxidative stress, growth factor receptors, vascular stress, etc. Hence, it is challenging and important to identify specific mechanisms, diagnosis and develop effective therapeutic strategies. The focus of this manuscript is to review some of the important pathobiological processes and mechanisms in the development of PH. Results from our previously reported studies, including targeted treatments along with some new data on PH secondary to left-heart failure, are presented.

The use of extracorporeal membrane oxygenation in severe necrotizing soft tissue infections complicated by septic shock.

Necrotizing soft tissue infections remain a challenging clinical problem. Delays in diagnosis, incomplete débridement of necrotic tissues, and the hemodynamic instability and end-organ failure associated with overwhelming sepsis all contribute to significant mortality. Extracorporeal support is a well-established tool to support profound cardiopulmonary failure. To broaden the indications for use, we present two cases of young adults with necrotizing soft tissue infections who sustained sepsis-induced hemodynamic collapse and required extracorporeal support to facilitate adequate tissue débridement as a bridge to recovery.

Medial necrosis in aortic root aneurysm after repair of tetralogy of Fallot.

Aneurysmal dilatation of the aortic root occurs in some patients with tetralogy of Fallot (TOF) late after repair. It can lead to aortic valve insufficiency and rarely to aortic rupture or dissection. Aortic valve or aortic surgery is rarely performed in this group of patients. We present a case of aneurysmal dilatation of the ascending aorta treated with aortic valve sparing root replacement 43 years after the TOF repair. Histological examination of the aortic wall revealed medial necrosis. The implications of those finding and the timing of surgery are discussed.

Development of a novel large animal model of ischemic heart failure using autologous platelet aggregates.

BACKGROUND: Current animal models of heart failure lack the biomass of thrombus that occurs in patients undergoing myocardial infarction. We propose a novel animal model of ischemic cardiomyopathy developed by sequential direct injections of autologous platelet aggregates into the coronary circulation resulting in development of ischemic cardiac insufficiency. METHODS: Autologous platelets from adult sheep were isolated and aggregated. Aggregated platelets were then injected into the coronary circulation of anesthetized animals under fluoroscopic guidance. Troponin I levels were monitored for first three days after embolization to validate cardiac tissue injury. Progression of heart failure was corroborated by monitoring changes in echo-based assessment of ejection fraction and left ventricular end-systolic and end-diastolic dimensions. Thrombus-based obstruction of coronary artery was confirmed with histopathology review by mepacrine labeling of pre-aggregated platelets. RESULTS: All experimental animals developed heart failure-like cardiac insufficiency confirmed by elevated levels of troponin I and associated with significant drop in the ejection fraction. CONCLUSIONS: Sequential injections of aggregated platelets into coronary circulation lead to progressive development of ischemic cardiac insufficiency. This phenomenon seems to mimic development of ischemic heart failure seen in human patients and opens multiple research opportunities to fill the existing gap between basic research and clinical practice.

Long-term mechanical support for complex left ventricular postinfarct pseudoaneurysms.

Left ventricular free wall rupture can be a catastrophic problem. Although small lacerations can be managed with various techniques of primary closure, larger and more complex defects can be difficult to treat. We present and discuss 2 cases of chronic, complex ventricular pseudoaneurysms managed successfully with long-term mechanical support.

Targeting ticagrelor: a novel therapy for emergency reversal.

Newer P2Y12 inhibitors are prescribed in place of clopidogrel for patients with acute coronary syndrome (ACS) and are associated with significant bleeding risks. Currently, limited options exist for the management of life-threatening bleeding or acute reversal for patients on P2Y12 inhibitor therapy, specifically ticagrelor. Various interventions, including platelet transfusion and desmopressin, have been studied for ticagrelor reversal demonstrating limited success. PB2452 is a novel monoclonal antibody which binds to both ticagrelor and its active metabolite resulting in a rapid return of platelet aggregation. PB2452 has been studied in animal models and, most recently, in a Phase I trial in healthy volunteers. In animal models, PB2452 displayed rapid reversal of ticagrelor and its metabolites and return to near normal levels of platelet aggregation within 60 min. In healthy human volunteers, cohorts that received higher dose bolus and infusions of PB2452 over 12-16 h resulted in maximal and sustained reversal of ticagrelor inhibition of platelet aggregation. While it is currently not US Food and Drug Administration approved, future Phase 2 and 3 studies are currently underway that may lead to new directions for patients on ticagrelor therapy who require urgent reversal.

Does recipient work status pre-transplant affect post-heart transplant survival? A United Network for Organ Sharing database review.

BACKGROUND: Recipient-related factors, such as education level and type of health insurance, are known to affect heart transplantation outcomes. Pre-operative employment status has shown an association with survival in abdominal organ transplant patients. We sought to evaluate the effect of work status of heart transplant (HTx) recipients at the time of listing and at the time of transplantation on short- and long-term survival. METHODS: We evaluated the United Network for Organ Sharing (UNOS) registry for all adult HTx recipients from 2001 to 2014. Recipients were grouped based on their work status at listing and at heart transplantation. Kaplan-Meier estimates illustrated 30-day, 1-year, 5-year, and 10-year survival comparing working with non-working groups. The Cox proportional hazards regression model was applied to adjust for covariates that could potentially confound the post-transplantation survival analysis. RESULTS: Working at listing for HTx was not significantly associated with 30-day and 1-year survival. However, 5- and 10-year mortality were 14.5% working vs 19.8% not working (p < 0.0001) and 16% working vs 26% not working (p < 0.0001), respectively. Working at HTx appeared to be associated with a survival benefit at every time interval, with a trend toward improved survival at 30 days and 1 year and a significant association at 5 and 10 years. Kaplan-Meier analysis demonstrated a 5% and 10% decrease in 5- and 10-year mortality, respectively, for the working group compared with the group not working at transplantation. The Cox proportional hazards regression model showed that working at listing and working at transplantation were each associated with decreased mortality (hazard ratio [HR] = 0.8, 95% confidence interval [CI] 0.71 to 0.91; and HR = 0.76, 95% CI 0.65 to 0.89, respectively). CONCLUSIONS: This study is the first analysis of UNOS STAR data on recipient work status pre-HTx demonstrating: (1) an improvement in post-transplant survival for working HTx candidates; and (2) an association between working pre-HTx and longer post-HTx survival. Given that work status before HTx may be a modifiable risk factor for better outcomes after HTx, we strongly recommend that UNOS consider these important findings for moving forward this patient-centered research on work status. Working at listing and working at HTx are associated with long-term survival benefits. The association may be reciprocal, where working identifies less ill patients and also improves well-being. Consideration should be given to giving additional weight to work status during organ allocation. Work status may also be a modifiable factor associated with better post-HTx outcomes.