Noncardiovascular Disease and Critical Care Delivery in a Contemporary Cardiac and Medical Intensive Care Unit.

BACKGROUND: Noncardiovascular comorbidities and critical illness are increasing in cardiovascular intensive care units (CICUs). There are limited data comparing critical care delivery, resource utilization, and costs between contemporary CICUs and medical intensive care units (MICUs). METHODS: All CICU (n = 6967; 22 748 patient-days) and MICU (n = 10 892; 39 211 patient-days) admissions to Cedars-Sinai Medical Center, a tertiary care academic medical center, between January 2011 and December 2016 were reviewed. Both the CICU and MICU admitted patients for primary cardiovascular or medical conditions during the study period, but not for postoperative surgical care. RESULTS: Patients admitted to the CICU were more frequently older, male, and had more preexisting cardiac disease ( P < .0001). More than one-fifth (21.4%) of CICU patients had a noncardiovascular primary admission diagnosis, compared to 89.2% of MICU patients. Cardiovascular intensive care unit patients had lower Acute Physiology and Chronic Health Evaluation III scores (51.1 [19.9] vs 61.1 [24.9], P < .0001) and shorter median hospital length of stay ( P < .001), but not in-unit stay, as compared to MICU patients. Mechanical ventilation, vasopressors, inotropes, renal replacement therapy, and/or blood transfusion were required in 35.0% of CICU patients compared with 62.2% of MICU patients ( P < .0001). The unit mortality rate was lower for CICU than MICU patients (4.8% vs 13.0%, P < .0001), as was the hospital mortality rate (9.3% vs 21.6%, P < .0001). The standardized mortality ratio was 0.73 for the CICU and 0.86 for the MICU. There was no difference in the mean direct cost of care per patient-day between the CICU and MICU ($4011 USD [376] vs $3990 USD [214], P = .77). CONCLUSIONS: The burden of noncardiovascular diseases and the requirement for critical care therapies are high in contemporary CICU patients but remain lower compared to the MICU population. Our findings support the growing complexity of care in tertiary CICUs. Further studies are required to explore the association between critical care delivery and outcomes in this evolving population.

CD8(+)CD25(+) T cells reduce atherosclerosis in apoE(-/-) mice.

BACKGROUND: It is increasingly evident that CD8(+) T cells are involved in atherosclerosis but the specific subtypes have yet to be defined. CD8(+)CD25(+) T cells exert suppressive effects on immune signaling and modulate experimental autoimmune disorders but their role in atherosclerosis remains to be determined. The phenotype and functional role of CD8(+)CD25(+) T cells in experimental atherosclerosis were investigated in this study. METHODS AND RESULTS: CD8(+)CD25(+) T cells were observed in atherosclerotic plaques of apoE(-/-) mice fed hypercholesterolemic diet. Characterization by flow cytometric analysis and functional evaluation using a CFSE-based proliferation assays revealed a suppressive phenotype and function of splenic CD8(+)CD25(+) T cells from apoE(-/-) mice. Depletion of CD8(+)CD25(+) from total CD8(+) T cells rendered higher cytolytic activity of the remaining CD8(+)CD25(-) T cells. Adoptive transfer of CD8(+)CD25(+) T cells into apoE(-/-) mice suppressed the proliferation of splenic CD4(+) T cells and significantly reduced atherosclerosis in recipient mice. CONCLUSIONS: Our study has identified an athero-protective role for CD8(+)CD25(+) T cells in experimental atherosclerosis.

A Novel Pathway of Platelet Activation in ACS Mediated by LL-37 Immunoglobulin G Autoantibody Immune Complexes.

The cathelicidin antimicrobial peptide LL-37 is a self-antigen in neutrophil extracellular traps that provokes autoantibody responses in autoimmune/autoinflammatory conditions. LL-37 immunoglobulin (Ig) G autoantibody levels were measured in subjects with and without atherosclerotic cardiovascular disease assessed using the coronary artery calcium score, in patients who had a future myocardial infarction and in a cohort of acute coronary syndrome (ACS) patients. LL-37 IgG levels were not associated with coronary artery calcium score, but future myocardial infarction patients had significantly higher LL-37 IgG at baseline. Reduced LL-37 IgG in ACS was associated with increased LL-37 IgG-immune complex. ACS plasma increased activated CD62P+ platelets from healthy donors mediated in part by LL-37 IgG-immune complexes and platelet Fc gamma receptor 2a.

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome.

Background: LL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients. Methods and results: The activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients. Conclusions: Our report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS.

Immunization using ApoB-100 peptide-linked nanoparticles reduces atherosclerosis.

Active immunization with the apolipoprotein B-100 (ApoB-100) peptide P210 reduces experimental atherosclerosis. To advance this immunization strategy to future clinical testing, we explored the possibility of delivering P210 as an antigen using nanoparticles, given this approach has been used clinically. We first characterized the responses of T cells to P210 using PBMCs from patients with atherosclerotic cardiovascular disease (ASCVD). We then investigated the use of P210 in self-assembling peptide amphiphile micelles (P210-PAMs) as a vaccine formulation to reduce atherosclerosis in B6.129P2-Apoetm1Unc/J (ApoE-/-) mice and P210's potential mechanisms of action. We also generated and characterized a humanized mouse model with chimeric HLA-A*02:01/Kb in ApoE-/- background to test the efficacy of P210-PAM immunization as a bridge to future clinical testing. P210 provoked T cell activation and memory response in PBMCs of patients with ASCVD. Dendritic cell uptake of P210-PAM and its costaining with MHC-I molecules supported its use as a vaccine formulation. In ApoE-/- mice, immunization with P210-PAMs dampened P210-specific CD4+ T cell proliferative response and CD8+ T cell cytolytic response, modulated macrophage phenotype, and significantly reduced aortic atherosclerosis. Potential clinical relevance of P210-PAM immunization was demonstrated by reduced atherosclerosis in the humanized ApoE-/- mouse model. Our data support experimental and translational use of P210-PAM as a potential vaccine candidate against human ASCVD.

Immune responses regulating the response to vascular injury.

PURPOSE OF REVIEW: Immune modulation of neointimal formation after vascular injury has been investigated for several decades but the complexities involved continue to obscure a clearer understanding of the process. The rapidly changing field of immunology makes this knowledge imperative. RECENT FINDINGS: The review discusses immune factors involved in the response to vascular injury. Although innate immune responses play a predominantly detrimental role, the adaptive immune response is more complex. Mechanisms of T-cell activation, recruitment, as well as possible regulation are highlighted. SUMMARY: Progress in understanding the role of the immune system in the response to arterial injury has been impressive. However, recent findings underscore the need to unravel the intricacies involved such as the kinetics and specific pathways of activation, specificity of immune cell involvement, and identification of targets for therapy. This is relevant in light of the increasing reports of immune factors involved in vascular disease and intervention in the clinical setting.

Giant saphenous vein graft aneurysm causing left atrial compression and cardiogenic shock.

Saphenous vein graft aneurysm is a rare complication of coronary artery bypass graft (CABG) surgery that is challenging to manage and is associated with catastrophic consequences. We present the case of a 72-year-old woman with prior CABG surgery who presented with chest pain and was found to have a giant saphenous vein graft pseudoaneurysm. Further evaluation revealed that a vein graft pseudoaneurysm was causing significant compression of the left atrium. The pseudoaneurysm was successfully excluded from the blood flow with a covered stent; however, despite intra-aortic balloon pump and supportive therapy, the patient succumbed to cardiogenic shock and sepsis.

Sex differences in crude mortality rates and predictive value of intensive care unit-based scores when applied to the cardiac intensive care unit.

BACKGROUND: Limited data exists regarding sex differences in outcome and predictive accuracy of intensive care unit-based scoring systems when applied to cardiac intensive care unit patients. METHODS: We reviewed medical records of patients admitted to cardiac intensive care unit from 1 January 2011-31 December 2016. Sex differences in mortality rates and the performance of intensive care unit-based scoring systems in predicting in-hospital mortality were analyzed. Calibration was assessed by the Hosmer-Lemeshow test and locally weighted scatterplot smoothing curves. Discrimination was assessed using the c statistic and receiver-operating characteristic curve. RESULTS: Among 6963 patients, 2713 (39%) were women. Overall in-hospital and cardiac intensive care unit mortality rates were similar in women and men (9.1% vs 9.4%, p=0.67 and 5.9% vs 6%, p=0.88, respectively) and in age and major diagnosis subgroups. Of the scoring systems, Acute Physiology and Chronic Health Evaluation III and Sequential Organ Failure Assessment had poor calibration (Hosmer-Lemeshow p value <0.001), while Simplified Acute Physiology Score II performed better (Hosmer-Lemeshow p value 0.09), in both women and men. All scores had good discrimination (C statistics >0.8). In the subgroups of acute myocardial infarction and heart failure patients, all scores had good calibration (Hosmer-Lemeshow p>0.001) and discrimination (C statistic >0.8) while in diagnosis subgroups with highest mortality, the calibration varied among scores and by sex, and discrimination was poor. CONCLUSIONS: No sex differences in mortality were seen in cardiac intensive care unit patients. The mortality predictive value of intensive care unit-based scores is limited in both sexes and variable among different subgroups of diagnoses.

Sex as a Determinant of Responses to a Coronary Artery Disease Self-Antigen Identified by Immune-Peptidomics.

A significant body of work implicates the adaptive immune response in atherosclerosis, the main underlying cause of coronary artery disease (CAD), yet specific antigens involved remain to be fully identified. The pathobiology of CAD is influenced by sex with many factors that may be involved in the underlying mechanisms. Given the reported sexual dimorphic nature of immune-inflammatory responses, we investigated the influence of sex on potential CAD self-antigens from acute coronary syndrome (ACS) patients using immune-precipitation of soluble HLA Class-I/peptide complexes and mass spectrometry. Relevance of identified self-antigens to atherosclerosis, the major underlying cause of CAD, was tested in the apoE-/- atherosclerotic mouse model. Soluble HLA Class-I complexes from ACS patients and self-reported controls were immune-precipitated and subjected to elution, denaturation and size-exclusion to obtain HLA-bound peptides. Peptides were then subjected to mass spectrometry and patient-unique self-peptides were grouped as common to both female and male, or unique to either sex. Three peptides common to both female and male patients (COL6A1, CDSN, and SAA2), and 2 peptides each unique to female (COL1A1 and COL5A2) or male (SAA1 and KRT 9) patients were selected and mouse homologs of the peptides were screened for self-reactive immune responses in apoE-/- mice. The screening step revealed potential sex-influenced immune responses which was associated with differential immune profiles. Based on the frequency in patient plasma, COL6A1, COL5A2, and KRT 9 peptides were then tested in immunization studies. Neither COL5A2 nor KRT 9 peptide immunization resulted in significant effects on atherosclerosis compared to controls. On the other hand, female mice immunized with COL6A1 peptide had significantly reduced atherosclerosis whereas male mice had significantly increased atherosclerosis, associated with differential immune profiles. Our study identified potential self-antigens involved in atherosclerosis using the immune peptidome of CAD patients. Altering self-reactive immune responses to COL6A1 in apoE-/- mice resulted in differential effects on atherosclerosis burden with sex as a determinant of outcome.

The Role of T Cells Reactive to the Cathelicidin Antimicrobial Peptide LL-37 in Acute Coronary Syndrome and Plaque Calcification.

The human cationic anti-microbial peptide LL-37 is a T cell self-antigen in patients with psoriasis, who have increased risk of cardiovascular events. However, the role of LL-37 as a T cell self-antigen in the context of atherosclerosis remains unclear. The objective of this study was to test for the presence of T cells reactive to LL-37 in patients with acute coronary syndrome (ACS). Furthermore, the role of T cells reactive to LL-37 in atherosclerosis was assessed using apoE-/- mice immunized with the LL-37 mouse ortholog, mCRAMP. Peripheral blood mononuclear cells (PBMCs) from patients with ACS were stimulated with LL-37. PBMCs from stable coronary artery disease (CAD) patients or self-reported subjects served as controls. T cell memory responses were analyzed with flow cytometry. Stimulation of PBMCs with LL-37 reduced CD8+ effector T cell responses in controls and patients with stable CAD but not in ACS and was associated with reduced programmed cell death protein 1 (PDCD1) mRNA expression. For the mouse studies, donor apoE-/- mice were immunized with mCRAMP or adjuvant as controls, then T cells were isolated and adoptively transferred into recipient apoE-/- mice fed a Western diet. Recipient mice were euthanized after 5 weeks. Whole aortas and hearts were collected for analysis of atherosclerotic plaques. Spleens were collected for flow cytometric and mRNA expression analysis. Adoptive transfer experiments in apoE-/- mice showed a 28% reduction in aortic plaque area in mCRAMP T cell recipient mice (P < 0.05). Fifty six percent of adjuvant T cell recipient mice showed calcification in atherosclerotic plaques, compared to none in the mCRAMP T cell recipient mice (Fisher's exact test P = 0.003). Recipients of T cells from mice immunized with mCRAMP had increased IL-10 and IFN-γ expression in CD8+ T cells compared to controls. In conclusion, the persistence of CD8+ effector T cell response in PBMCs from patients with ACS stimulated with LL-37 suggests that LL-37-reactive T cells may be involved in the acute event. Furthermore, studies in apoE-/- mice suggest that T cells reactive to mCRAMP are functionally active in atherosclerosis and may be involved in modulating plaque calcification.

Natural antibodies and complement modulate intimal thickening after arterial injury.

Immune factors are involved in modulating neointimal response to arterial wall injury, but the role of individual immune effectors in this response remains unclear. Using a carotid cuff injury model in mice, we tested the role of immunoglobulin isotypes in modulating intimal thickening by using adoptive transfer of splenocytes from WT mice, or the direct administration of IgG or IgM into immune-deficient Rag-1-/- [Rag-1 knockout (Rag-1KO)] mice. The direct role of complement was also tested by depletion of complement. Splenocytes from WT mice were isolated and adoptively transferred to Rag-1KO mice subjected to carotid cuff arterial injury. Transfer of splenocytes to Rag-1KO mice resulted in increased serum IgM and IgG within 48 h and were comparable to WT levels by 21 days after injury. Splenocyte transfer in Rag-1KO decreased intimal area by 40% compared with Rag-1KO mice without cell transfer. To further differentiate the relative contribution of IgM or IgG in reducing intimal thickening, additional groups of Rag-1KO mice were subjected to injury and given intravenous injections of pooled mouse IgG or IgM. Both IgG and IgM treatment significantly reduced intimal thickening compared with untreated Rag-1KO mice. Immunoglobulin treatments modified serum complement C3 profile and decreased C3 presence in injured arteries. Depletion of C3 using cobra venom factor in Rag-1KO mice significantly decreased intimal thickening. Our results identify the direct role of natural IgG and IgM, and complement in the modulation of neointimal response to arterial injury.

Erythropoiesis stimulating agents in heart failure patients with anemia: a meta-analysis.

BACKGROUND: Anemia is prevalent in patients with heart failure and an independent prognostic sign of poor outcome. The current report is a meta-analysis of published clinical trials assessing the use of erythropoeisis stimulating agents (ESA) in heart failure (HF) patients with anemia. METHODS: Literature and Medline search was performed to identify studies with control groups (case-control, cohort or randomized controlled trials) that examined the effect of ESA therapy in patients with HF and anemia. RESULTS: Seven prospective controlled trials met inclusion criteria (n = 663 subjects). The ESA studied was darbepoetin in 4 trials and erythropoietin in 3 trials. Mean follow up period ranged from 12 to 27 weeks. Compared to placebo ESA therapy was associated with improvement in six cardiovascular parameters assessed by at least three of the analyzed trials, including increase in hemoglobin levels 2.35(95% confidence interval [Cl], 1.76-2.93, P < 0.00001), increase in exercise duration 0.91(95% Cl, 0.08-1.73, P = 0.03), improvement in New York Heart Association functional class -1.46(95% Cl, -2.32 to -0.60, P = 0.0009), improvement in 6-minute walk test 1.42(95% Cl, 0.31-2.54, P = 0.01), decrease in B-type natriuretic peptide -0.54(95% Cl, -1.03 to -0.06, P = 0.03), and improvement in peak oxygen consumption 0.93(95% Cl, 0.52-1.34, P < 0.00001). CONCLUSION: In patients with heart failure and anemia, erythropoiesis stimulating agent therapy appears to have a positive effect on several important cardiovascular parameters, compared to control therapy. Large prospective randomized controlled trials are warranted to comprehensively evaluate the potential effects of erythropoiesis stimulating agents on clinical outcomes in heart failure patients with anemia.

IL-7R blockade reduces post-myocardial infarction-induced atherosclerotic plaque inflammation in ApoE-/- mice.

Modulating inflammation by targeting IL-1ß reduces recurrent athero-thrombotic cardiovascular events without lipid lowering. This presents an opportunity to explore other pathways associated with the IL-1ß signaling cascade to modulate the inflammatory response post-myocardial infarction (MI). IL-7 is a mediator of the inflammatory pathway involved in monocyte trafficking into atherosclerotic plaques and levels of IL-7 have been shown to be elevated in patients with acute MI. Recurrent athero-thrombotic events are believed to be mediated in part by index MI-induced exacerbation of inflammation in atherosclerotic plaques. The objective of the study was to assess the feasibility of IL-7R blockade to modulate atherosclerotic plaque inflammation following acute MI in ApoE-/- mice. Mice were fed Western diet for 12 weeks and then subjected to coronary occlusion to induce an acute MI. IL-7 expression was determined using qRT-PCR and immuno-staining, and IL-7R was assessed using flow cytometry. Plaque inflammation was evaluated using immunohistochemistry. IL-7R blockade was accomplished with monoclonal antibody to IL-7R. IL-7 mRNA expression was significantly increased in the cardiac tissue of mice subjected to MI but not in controls. IL-7 staining was observed in the coronary artery. Plaque macrophage and lipid content were significantly increased after MI. IL-7R antibody treatment but not control IgG significantly reduced macrophage and lipid content in atherosclerotic plaques. The results show that IL-7R antibody treatment reduces monocyte/macrophage and lipid content in the atherosclerotic plaque following MI suggesting a potential new target to mitigate increased plaque inflammation post-MI.

Keratin 8 is a potential self-antigen in the coronary artery disease immunopeptidome: A translational approach.

BACKGROUND: Inflammation is an important risk factor in atherosclerosis, the underlying cause of coronary artery disease (CAD). Unresolved inflammation may result in maladaptive immune responses and lead to immune reactivity to self-antigens. We hypothesized that inflammation in CAD patients would manifest in immune reactivity to self-antigens detectable in soluble HLA-I/peptide complexes in the plasma. METHODS: Soluble HLA-I/peptide complexes were immuno-precipitated from plasma of male acute coronary syndrome (ACS) patients or age-matched controls and eluted peptides were subjected to mass spectrometry to generate the immunopeptidome. Self-peptides were ranked according to frequency and signal intensity, then mouse homologs of selected peptides were used to test immunologic recall in spleens of male apoE-/- mice fed either normal chow or high fat diet. The peptide detected with highest frequency in patient plasma samples and provoked T cell responses in mouse studies was selected for use as a self-antigen to stimulate CAD patient peripheral blood mononuclear cells (PBMCs). RESULTS: The immunopeptidome profile identified self-peptides unique to the CAD patients. The mouse homologs tested showed immune responses in apoE-/- mice. Keratin 8 was selected for further study in patient PBMCs which elicited T Effector cell responses in CAD patients compared to controls, associated with reduced PD-1 mRNA expression. CONCLUSION: An immunopeptidomic strategy to search for self-antigens potentially involved in CAD identified Keratin 8. Self-reactive immune response to Keratin 8 may be an important factor in the inflammatory response in CAD.

Early mobility in frail and non-frail older adults admitted to the cardiovascular intensive care unit.

PURPOSE: Little is known about the effects of early mobilization in older adults in the Cardiovascular Intensive Care Unit (CICU). MATERIALS AND METHODS: We reviewed consecutive patients ≥60 years of age admitted to the CICU at an academic tertiary care center from 2016 to 2017. The level of function (LOF) was assessed prehospital, at CICU admission, and at CICU transfer using a graded scale ranging from LOF 1 (bedbound) to 4 (walk > 50 ft). The prehospital frailty status was assessed using Rockwood's Clinical Frailty Scale. We sought to determine whether the mean change of LOF during CICU admission differed based on frailty status. RESULTS: There were 264 patients in the cohort (77.1 ±â€¯9.3 years old; 40% female; 34% frail). Frail patients were more likely to have lower prehospital, CICU admission, day of transfer LOFs (all P < 0.001). The mean LOF improvement during CICU stay was 0.5 ±â€¯0.8 and did not differ based on frailty status. Frailty was not predictive of EM responsiveness in the adjusted analysis. CONCLUSIONS: EM is feasible in older adults admitted to the CICU. Functional status improved in both frail and non-frail older adults during CICU admission. Prospective studies are needed to determine whether frail older adults may benefit from EM.

Systematic review and directors survey of quality indicators for the cardiovascular intensive care unit.

BACKGROUND: Quality indicators (QIs) are increasingly used in cardiovascular care as measures of performance but there is currently no consensus on indicators for the cardiovascular intensive care unit (CICU). METHODS: We searched Medline, CINAHL, EMBASE, and COCHRANE databases from inception until October 2016 and websites for organizations involved in quality measurement for QIs relevant to cardiovascular disease in an intensive or critical care setting. We surveyed 14 expert cardiac intensivist-administrators (7 European; 7 North American) on the importance and relevance of each indicator as a measure of CICU care quality using a scale of 1 (=lowest) to 10 (=highest). Indicators with a mean score ≥8/10 for both importance and relevance were included in the final set. RESULTS: Overall, 108 QIs (70 process, 18 structural, 18 outcome, 1 patient engagement, and 1 covering multiple domains) were identified in 30 articles representing 23 agencies, organizations, and societies. Disease-specific QIs included myocardial infarction (n = 37), heart failure (n = 31), atrial fibrillation (n = 11), and cardiac rehabilitation (n = 1); general QIs represented about one-quarter (n = 28) of all measures. Fifteen QIs were selected for the final QI set: 7 process, 2 structural, and 6 outcome measures, including 6 general and 9 disease-specific measures. Outcome measures chosen to evaluate general CICU performance included overall CICU mortality, length of stay, and readmission rate. CONCLUSIONS: Numerous QIs relevant to the CICU have been recommended by a variety of organizations. The indicators chosen by the cardiac intensivist-administrators could serve as a basis for future efforts to develop a standardized set of quality measures for the CICU.