The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration.

Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-α1,3-galactose (αGal) and N-glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients (n = 1668, 34 ± 43 months of follow-up (0.1-182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in <5% of BHV recipients within 2 years. The levels of both anti-αGal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-αGal IgG levels declined significantly faster in control patients compared to BHV recipients. Neu5Gc, anti-Neu5Gc IgG and complement deposition were found in calcified BHVs at much higher levels than in calcified native aortic valves. Moreover, in mice, anti-Neu5Gc antibodies were unable to promote calcium deposition on subcutaneously implanted BHV tissue engineered to lack αGal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in αGal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability.

Delirium definition influences prediction of functional survival in patients one-year postcardiac surgery.

BACKGROUND: Delirium after cardiac surgery is associated with prolonged intensive care unit (ICU) and hospital length of stay and elevated rates of mortality. The Society of Thoracic Surgery National Database (STS-ND) includes delirium in routine data collection but restricts its definition to hyperactive symptoms. The objective is to determine whether the Confusion Assessment Method for ICU (CAM-ICU), which includes hypo- and hyperactive symptoms, is associated with improved prediction of poor 1-year functional survival following cardiac surgery. METHODS: Clinical and administrative databases were used to determine the influence of postoperative delirium on 1-year poor functional survival, defined as being institutionalized or deceased at 1 year. Patients experiencing postoperative delirium using the STS-ND definition (2007-2009) were compared with patients with delirium identified by the CAM-ICU (2010-2012). A propensity score match was undertaken, and multivariable Cox proportional hazards regression models were generated to determine risk of poor 1-year functional survival. RESULTS: There were 2756 and 2236 patients in the STS-ND and CAM-ICU cohorts, respectively. Propensity matching resulted in a cohort of 1835 patients (82.1% matched). The overall rate of delirium in the matched study population was 7.6% in the STS-ND cohort and 13.0% in the CAM-ICU cohort (P < .001). Delirium in the CAM-ICU cohort was independently associated with poor 1-year functional survival (hazard ratio, 2.58; 95% confidence interval, 1.20-5.54; P = .02); delirium in the STS-ND cohort was not associated with poor 1-year functional survival (hazard ratio, 0.92; 95% confidence interval, 0.49-1.71; P = .79). CONCLUSIONS: A systematic screening tool identifies postoperative delirium with improved prediction of poor 1-year functional survival following cardiac surgery.

Studying Xenograft Rejection of Bioprosthetic Heart Valves.

Millions of patients with valvular heart disease have benefitted from heart valve replacement since the procedure was first introduced in the 1960s; however, there are still many patients who get early structural valve deterioration (SVD) of their bioprosthetic heart valves (BHV). BHV are porcine, bovine, or equine tissues that have been glutaraldehyde fixed to preserve the tissue and presumably make the tissue immunologically inert. These glutaraldehyde-fixed BHV with anti-calcification treatments last long periods of time in older adults but develop early SVD in younger patients. The consensus at present is that the early SVD in younger patients is due to more "wear and tear" of the valves and higher calcium turnover in younger patients. However, as younger patients likely have a more robust immune system than older adults, there is a new hypothesis that BHV xenografts may undergo xenograft rejection, and this may contribute to the early SVD seen in younger patients.At present, the technology to noninvasively study in vivo whether an implanted BHV in a human patient is undergoing rejection is not available. Thus, a small animal discordant xenotransplant model in young rodents (to match the young patient getting a pig/bovine/equine BHV) was developed to study whether the hypothesis that glutaraldehyde-fixed BHV undergo xenograft rejection had any merit. In this chapter, we describe our model and its merits and the results of our investigations. Our work provides clear evidence of xenograft rejection in glutaraldehyde-fixed tissue, and our small animal model offers an opportunity to study this process in detail.

Autoimmune heparin-induced thrombocytopenia and venous limb gangrene after aortic dissection repair: in vitro and in vivo effects of intravenous immunoglobulin.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder characterized by heparin-dependent antibodies that activate platelets (PLTs) via PLT FcγIIa receptors. "Autoimmune" HIT (aHIT) indicates a HIT subset where thrombocytopenia progresses or persists despite stopping heparin; aHIT sera activate PLTs strongly even in the absence of heparin (heparin-independent PLT-activating properties). Affected patients are at risk of severe complications, including dual macro- and microvascular thrombosis leading to venous limb gangrene. High-dose intravenous immunoglobulin (IVIG) offers an approach to interrupt heparin-independent PLT-activating effects of aHIT antibodies. CASE REPORT: A 78-year-old male who underwent cardiopulmonary bypass for aortic dissection developed aHIT, disseminated intravascular coagulation, and deep vein thrombosis; progression to venous limb gangrene occurred during partial thromboplastin time (PTT)-adjusted bivalirudin infusion (underdosing from "PTT confounding"). Thrombocytopenia recovered with high-dose IVIG, although the PLT count increase began only after the third dose of a 5-day IVIG regimen (0.4 g/kg/day × 5 days). We reviewed case reports and case series of IVIG for treating HIT, focusing on various IVIG dosing regimens used. RESULTS: Patient serum-induced PLT activation was inhibited in vitro by IVIG in a dose-dependent fashion; inhibition of PLT activation by IVIG was much more marked in the absence of heparin versus the presence of heparin (0.2 U/mL). Our literature review indicated 1 g/kg × 2 IVIG dosing as most common for treating HIT, usually associated with rapid PLT count recovery. CONCLUSION: Our clinical and laboratory observations support dose-dependent efficacy of IVIG for decreasing PLT activation and thus correcting thrombocytopenia in aHIT. Our case experience and literature review suggests dosing of 1 g/kg IVIG × 2 for patients with severe aHIT.

Long-term non-institutionalized survival and rehospitalization after surgical aortic and mitral valve replacements in a large provincial cardiac surgery centre.

OBJECTIVES: Long-term quality of life following open surgical valve replacement is an increasingly important outcome to patients and their caregivers. This study examines non-institutionalized survival and rehospitalization within our surgical aortic valve replacement (AVR) and mitral valve replacement (MVR) populations. METHODS: A retrospective single-centre study of all consecutive open surgical valve replacements between 1995 and 2014 was undertaken. Clinical data were linked to provincial administrative data for 3219 patients who underwent AVR, MVR or double (aortic and mitral) valve replacement with or without concomitant coronary artery bypass grafting (CABG). Non-institutionalized survival and cumulative incidence of rehospitalization was examined up to 15 years. RESULTS: Follow-up was complete for 96.9% of the 2146 patients who underwent AVR ± CABG (66.7% of the overall cohort), 878 who underwent MVR ± CABG (27.3%) and 195 who underwent double (aortic and mitral) valve replacement ± CABG (6.0%) with a median follow-up time of 5.6 years. Overall non-institutionalized survival was 35.4% at 15 years, and the cumulative incidence of rehospitalization was 34.4%, 63.2% and 87.0% at 1, 5 and 15 years, respectively, without significant differences between valve procedure cohorts. Both non-institutionalized survival and cumulative incidence of rehospitalization improved in more recent eras, despite increasing age and comorbidities. CONCLUSIONS: Non-institutionalized survival and rehospitalization data for up to 15 years suggest good functional outcomes long after surgical AVR and/or MVR. Continued improvements are seen in these metrics over the past 2 decades. This provides a unique insight into the quality of life after surgical valve replacement in the ageing demographics with valvular heart disease.

Outcomes of octogenarians discharged from the hospital after prolonged intensive care unit length of stay after cardiac surgery.

OBJECTIVE: Octogenarians offered complex cardiac surgery frequently experience a prolonged intensive care unit length of stay; however, minimal data exist on the outcomes of these patients. We sought to determine the rates and predictors of 1-year noninstitutionalized survival ("functional survival") and rehospitalization for octogenarian patients with prolonged intensive care unit length of stay after cardiac surgery and who were discharged from hospital. METHODS: The outcomes of discharged patients aged 80 years or more who underwent cardiac surgery with prolonged intensive care unit length of stay (≥5 consecutive days) from January 1, 2000, to December 31, 2011, were examined retrospectively from linked clinical and administrative provincial databases. Regression analysis was used to determine predictors of 1-year functional survival and rehospitalization after discharge from the hospital. RESULTS: A total of 80 of 683 (11.7%) discharged octogenarian patients had prolonged intensive care unit length of stay. Functional survival at 1 year was 92% and 81% for those with nonprolonged and prolonged intensive care unit lengths of stay, respectively (P < .01). Lack of outpatient physician visits within 30 days of discharge (hazard ratio, 5.18; P < .01) was a significant predictor of poor 1-year functional survival. The 1-year rehospitalization rates were 38% and 48% for those with nonprolonged and prolonged intensive care unit lengths of stay, respectively, with 41% of all rehospitalizations occurring within 30 days of initial discharge. A rural residence (hazard ratio, 1.82; P < .01) and nosocomial pneumonia during patients' operative admissions (hazard ratio, 2.74; P < .01) were associated with rehospitalization within 30 days of discharge. CONCLUSIONS: Octogenarians with prolonged intensive care unit length of stay have acceptable functional survival at 1 year but have high rates of early rehospitalization. Access to health services may influence functional survival and early rehospitalizations. These data suggest that close follow-up of these vulnerable patients after hospital discharge is warranted.

Predictors of survival, functional survival, and hospital readmission in octogenarians after surgical aortic valve replacement.

OBJECTIVE: To analyze outcomes and predictors of functional survival (personal care home admission and mortality) and hospital readmission in patients aged ≥80 years who underwent surgical aortic valve replacement (SAVR) in a Manitoba hospital. METHODS: This was a retrospective cohort study of patients aged ≥80 years who underwent SAVR with or without coronary artery bypass grafting in Manitoba between 1995 and 2014. Data from the Manitoba Adult Cardiac Surgery database and the Manitoba Centre for Health Policy were used. Kaplan-Meier estimates of outcomes and Cox multivariate regression analysis of risk factors were performed. Survival was compared with that of age- and sex-matched life expectancy. RESULTS: A total of 1872 patients were aged ≥50 years and 378 were aged ≥80 years, 55% of whom (n = 208) underwent concurrent coronary artery bypass grafting. Compared with younger patients, octogenarians had higher in-hospital mortality (8.5%; P <.001), longer median intensive care unit stay (47.2 hours; P <.001), and longer median in-hospital stay (13 days; P <.001). The median follow-up was 5.2 years. Functional survival was 82.4% at 1 year and 56.5% at 5 years, and freedom from hospital readmission was 61.5% at 1 year and 28.4% at 5 years. Survival approximated the age- and sex-matched life expectancy at 1 year (83.8%) and 5 years (60.8%). Preoperative atrial fibrillation, peripheral vascular disease, female sex, postoperative acute kidney injury, and blood transfusion were associated with adverse outcomes. CONCLUSIONS: In eligible octogenarians, SAVR has acceptable 1- and 5-year functional survival and hospital readmission rates, but significant perioperative mortality and morbidity.

Early Rehospitalization After Prolonged Intensive Care Unit Stay Post Cardiac Surgery: Outcomes and Modifiable Risk Factors.

BACKGROUND: Prolonged intensive care unit length of stay (prICULOS) following cardiac surgery (CS) in older adults is increasingly common but rehospitalization characteristics and outcomes are understudied. We sought to describe the rehospitalization characteristics and subsequent non-institutionalized survival of prICULOS (ICULOS ≥5 days) patients and identify modifiable risk factors to decrease 30-day rehospitalization. METHODS AND RESULTS: Consecutive patients from January 1, 2000 to December 31, 2011 were analyzed utilizing linked clinical and administrative databases. Logistic regression was used to identify risk factors associated with 30-day rehospitalization. Out of 9210 consecutive patients discharged from the hospital alive, 596 (6.5%) experienced prICULOS. Cumulative incidence of rehospitalization for the prICULOS cohort at 30 and 365 days was 17.5% and 45.6% versus 11.4% and 28.1% for non-prICULOS (P<0.01). Over 40% of rehospitalizations for the entire cohort occurred within 30 days of discharge costing over $12 million. The most common reasons for rehospitalization were heart failure (in prICULOS) and infection (in non-prICULOS). Rehospitalization within 30 days was associated with a 2.29-fold risk of poor 1-year noninstitutionalized survival for the entire cohort. Potentially modifiable factors affecting 30-day rehospitalization included lack of physician visits within 30 days of discharge (odds ratio 2.11; P=0.01), and preoperative anxiety diagnosis (odds ratio 2.20; P=0.01). CONCLUSIONS: PrICULOS patients have high rates of rehospitalization that is associated with an increased rate of poor noninstitutionalized survival. Addressing modifiable risk factors including early postdischarge access to physician services, as well as access to mental health services may improve patient outcomes.

Current and Future Status of Extracorporeal Cardiopulmonary Resuscitation for In-Hospital Cardiac Arrest.

Numerous series, propensity-matched trials, and meta-analyses suggest that appropriate use of extracorporeal cardiopulmonary resuscitation (E-CPR) for in-hospital cardiac arrest (IHCA) can be lifesaving. Even with an antecedent cardiopulmonary resuscitation (CPR) duration in excess of 45 minutes, 30-day survival with favourable neurologic outcome using E-CPR is approximately 35%-45%. Survival may be related to age, duration of CPR, or etiology. Associated complications include sepsis, renal failure, limb and neurologic complications, hemorrhage, and thrombosis. However, methodological biases-including small sample size, selection bias, publication bias, and inability to control for confounders-in these series prevent definitive conclusions. As such, the 2015 American Heart Association Advanced Cardiac Life Support guidelines update recommended E-CPR as a Level of Evidence IIb recommendation in appropriate cases. The absence of high-quality evidence presents an opportunity for clinician/scientists to generate practice-defining data through collaborative investigation and prospective trials. A multidisciplinary dialogue is required to standardize the field and promote multicentre investigation of E-CPR with data sharing and the development of a foundation for high-quality trials. The objectives of this review are to (1) provide an overview of the strengths and limitations of currently available studies investigating the use of E-CPR in patients with IHCA and highlight knowledge gaps; (2) create a framework for the standardization of terminology, clinical practice, data collection, and investigation of E-CPR for patients with IHCA that will help ensure congruence in future work in this area; and (3) propose suggestions to guide future research by the cardiovascular community to advance this important field.

Human antibody recognition of xenogeneic antigens (NeuGc and Gal) on porcine heart valves: could genetically modified pig heart valves reduce structural valve deterioration?

BACKGROUND: Glutaraldehyde-fixed bioprosthetic heart valves (GBHVs) derived from wild-type (WT, genetically unmodified) pigs are widely used clinically for heart valve replacement. There is evidence that their failure is related to an immune response. The use of valves from genetically engineered pigs that do not express specific pig antigens may prolong GBHV survival. Our aims were to determine (i) expression of Gal and NeuGc on heart (aortic and pulmonary) valves and pericardium of WT, α1,3-galactosyltransferase gene knockout (GTKO) and GTKO/N-glycolylneuraminic acid gene-knockout (GTKO/NeuGcKO) pigs in comparison with three different commercially available GBHVs and (ii) to determine human antibody binding to these tissues. METHODS: Wild-type, GTKO/CD46, and GTKO/CD46/NeuGcKO pig valves and pericardium were tested (i) fresh and (ii) after fixation with glutaraldehyde (0.02%, 0.2%, 2%). Sections of GBHVs, fresh and fixed valves, and pericardium were stained for Gal and NeuGc expression, and for human IgM and IgG antibody binding. RESULTS: Gal and NeuGc expression was high on all GBHVs and WT pig valves/pericardium, but was absent after antigen-specific-knockout. There was no difference in antigen expression or antibody binding among WT aortic, pulmonary valves, and pericardium as well as GBHVs. Glutaraldehyde fixation did not alter expression of Gal or NeuGc. After incubation with human serum, human IgM and IgG bound to all GBHVs and WT pig valves/pericardium. Valves from GTKO/CD46 pigs and, particularly, GTKO/CD46/NeuGcKO pigs (with/without glutaraldehyde fixation) showed less IgM and IgG binding. CONCLUSION: Compared to WT pigs, GTKO/CD46/NeuGcKO pigs would be preferable sources of GBHVs, because the absence of Gal/NeuGc expression reduces human antibody binding.

Long-Term Outcome and Predictors of Noninstitutionalized Survival Subsequent to Prolonged Intensive Care Unit Stay After Cardiac Surgical Procedures.

BACKGROUND: There are minimal data on long-term functional survival (alive and not institutionalized) in patients undergoing cardiac operations who require a prolonged intensive care unit length of stay (prICULOS). We sought to describe 1- and 5-year functional survival in patients who had a prICULOS (ICULOS ≥ 5 days) and determine predictors of functional survival at 1 year. METHODS: Data were obtained from linked clinical and administrative databases from January 1, 2000 to December 31, 2011 to conduct this retrospective single-region analysis. Logistic regression was used to develop a model predicting functional survival at 1 year for patients who had a prICULOS after cardiac operations. RESULTS: There were 9,545 admissions to the ICU after cardiac operations; of these patients, 728 (7.6%) experienced a prICULOS. There was an increasing trend in patients who had a prICULOS over this study period. The functional survival at 1 and 5 years from the surgical procedure for the non-prICULOS versus the prICULOS cohort was 1 year (94.9% versus 73.9%) and 5 years (84.9% versus 53.8%) (p < 0.001). Factors associated with lower rates of functional survival at 1 year were age 80 years or older, female sex, peripheral vascular disease, preoperative renal dysfunction, cerebrovascular disease, preoperative infection, need for extracorporeal membrane oxygenation/ventricular assist device (ECMO/VAD) after cardiotomy, number of days on mechanical ventilation, and number of days in the ICU beyond 5 days (area under the receiver operating characteristic [ROC] curve = 0.766). CONCLUSIONS: The majority of patients who had a prICULOS experienced successful functional survival up to 5 years after cardiac operations. Identification of risk factors for poor functional survival may be of assistance to clinicians, patients, and families for prognostication and decision making.

Xenograft bioprosthetic heart valves: Past, present and future.

The transplantation (implantation) of xenograft heart valves into humans has been carried out for >50 years. There has been considerable research into making this form of xenotransplantation successful, though it is not perfect yet. We review the understanding of the immune response to xenograft heart valves. Important steps in the history include understanding (i) the importance of glutaraldehyde in decreasing the immune response and (ii) the relationship between calcification (which is the main problem leading to xenograft failure) and the immune response. We subsequently discuss the importance of identifying xenoantigens that are important in leading to xenograft valve failure, and the potential of genetically-engineered pigs to allow the development of the 'ideal' heart valve for clinical valve replacement.