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.

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.

Treatment Outcomes for Right-Sided Endocarditis in Intravenous Drug Users: A Systematic Review and Analysis of Outcomes in a Tertiary Centre.

BACKGROUND: The increasing prevalence of intravenous drug users (IVDU) has resulted in higher incidence of right-sided infective endocarditis (RSIE). However, treatment guidelines for RSIE in IVDU are not well defined. The aim is to evaluate efficacy of different treatment strategies in reducing mortality and to describe treatment outcomes. METHODS: We systematically reviewed the literature using PubMed, Cochrane, CENTRAL, OvidEMBASE, Web of Science, and Medline databases to include prospective studies that compare mortality rates among IVDU with RSIE receiving isolated medical treatment versus those receiving medical-surgical treatment. In conjunction, analysis of 27 RSIE patients (including IVDU) treated at authors' institution was done to supplement the findings. Kaplan-Meier survival rates following hospital admission and cumulative incidence estimates for hospital re-admission were obtained. RESULTS: A total of nine studies (all with low or marginal risk of bias) met inclusion criteria. The prevalence of RSIE among IVDU with infective endocarditis varied from 34% to 100%. Seven studies compared medical versus medical-surgical therapy with less than 30% needing surgery. Mortality was higher in patients receiving surgical therapy. There were 27 RSIE (16 non-IVDU and 11 IVDU) analyzed at the authors' institution. Survival at 30 days, 1 year, and 3 years were 89%, 82%, and 78%, respectively, and repeat hospitalization for recurrent endocarditis were 8%, 17%, and 23%, respectively. CONCLUSIONS: There is paucity around optimal RSIE management strategy for IVDU that can decrease mortality. Surgical management of RSIE may be associated with increased mortality over medical management mainly due to advanced surgical indications.

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.

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.

Recurrent Seizures Following Cardiac Surgery: Risk Factors and Outcomes in a Historical Cohort Study.

OBJECTIVES: To determine the risk factors for and outcomes after recurrent seizures (RS) in patients following cardiac surgery. DESIGN: A historical cohort study. SETTING: A single-center university teaching hospital. PARTICIPANTS: Cardiac surgery patients from April 2003 to September 2010 experiencing postoperative seizures. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were divided into an isolated seizure group and an RS group. Risk factors for RS were determined using logistic regression. Intermediate-term follow-up was conducted by phone. Of 7,280 consecutive patients undergoing cardiac surgery, 61 (0.8%) experienced postoperative seizure and 36 (59%) of those experienced at least 1 recurrence. Of these, 32 (89%) experienced RS within 24 hours of the first seizure, and 29 (81%) had grand mal seizures. Preoperative creatinine ≥120 µmol/L (p = 0.02), time until first seizure occurred (≤4 hours; p = 0.01), and procedures involving the thoracic aorta were associated with RS (R(2) = 0.53, p<0.05). Patients with RS had longer intensive care unit stays (5.3 v 2.9 days, p = 0.03) and longer mechanical ventilation duration (53.3 v 15.0 hours, p = 0.01). At a median follow-up of 21 months for the RS group and 16 months for the isolated seizure group, restrictions, anticonvulsant use, morbidity, and mortality were similar between patients with isolated versus recurrent seizures. CONCLUSIONS: Higher preoperative creatinine, thoracic aortic surgery, and early seizure onset were associated with RS after cardiac surgery. When compared to isolated seizures, recurrence per se was not associated with significantly increased long-term morbidity or mortality.

The benefits of 24/7 in-house intensivist coverage for prolonged-stay cardiac surgery patients.

OBJECTIVE: The objective of our study was to evaluate the efficacy of 24/7 in-house intensivist care for patients requiring prolonged intensive care unit (ICU) stay following cardiac surgery. METHODS: A propensity-matched retrospective before-and-after observational study comparing 2 models of ICU physician staffing was undertaken. Previously, residents (with intensivist backup) provided care for patients after cardiac surgery (surgical ICU cohort). ICU physician staffing was modified with the implementation of 24/7 in-house board-certified intensivist coverage in a cardiac surgery ICU (cardiac surgery ICU cohort) for postoperative care. Patients with a prolonged ICU stay (ie, >48 hours) were identified and their outcomes analyzed for both models of care. RESULTS: Propensity matching between cohorts was successful for 271 patients (75.7%), with matched patients being used for comparison. There was no difference in ICU or 30-day mortality. There was also no difference in ICU length of stay (LOS); however, the median hospital LOS was significantly shorter in the cardiac surgery ICU cohort (12.3 vs 11.0 days; P < .01). There was a decrease in the proportion of patients receiving transfused red blood cells in the cardiac surgery ICU cohort (80.8% vs 65.7%; P < .001). The cardiac surgery ICU cohort had reduced complications relating to sepsis (4.7% vs 0.7%; P < .01) and renal failure (22.5% vs 12.5%; P < .01); however, the identification of neurologic dysfunction was significantly higher (11.1% vs 20.7%; P < .01). CONCLUSIONS: For patients requiring a prolonged ICU stay, our model of 24/7 in-house intensivist coverage was not associated with changes in ICU LOS, nor ICU and 30-day mortality. However a reduction in blood product use, ICU complications, and total hospital LOS was observed.