Delayed CCL23 response is associated with poor outcomes after cardiac arrest.

Chemokines, a family of chemotactic cytokines, mediate leukocyte migration to and entrance into inflamed tissue, contributing to the intensity of local inflammation. We performed an analysis of chemokine and immune cell responses to cardiac arrest (CA). Forty-two patients resuscitated from cardiac arrest were analyzed, and twenty-two patients who underwent coronary artery bypass grafting (CABG) surgery were enrolled. Quantitative antibody array, chemokines, and endotoxin quantification were performed using the patients blood. Analysis of CCL23 production in neutrophils obtained from CA patients and injected into immunodeficient mice after CA and cardiopulmonary resuscitation (CPR) were done using flow cytometry. The levels of CCL2, CCL4, and CCL23 are increased in CA patients. Temporal dynamics were different for each chemokine, with early increases in CCL2 and CCL4, followed by a delayed elevation in CCL23 at forty-eight hours after CA. A high level of CCL23 was associated with an increased number of neutrophils, neuron-specific enolase (NSE), worse cerebral performance category (CPC) score, and higher mortality. To investigate the role of neutrophil activation locally in injured brain tissue, we used a mouse model of CA/CPR. CCL23 production was increased in human neutrophils that infiltrated mouse brains compared to those in the peripheral circulation. It is known that an early intense inflammatory response (within hours) is associated with poor outcomes after CA. Our data indicate that late activation of neutrophils in brain tissue may also promote ongoing injury via the production of CCL23 and impair recovery after cardiac arrest.

Multicenter experience with valve-in-valve transcatheter aortic valve replacement compared with primary, native valve transcatheter aortic valve replacement.

BACKGROUND: Valve-in-valve (ViV) transcatheter aortic valve replacement (TAVR) offers an alternative to reoperative surgical aortic valve replacement. The short- and intermediate-term outcomes after ViV TAVR in the real world are not entirely clear. PATIENTS AND METHODS: A multicenter, retrospective analysis of a consecutive series of 121 ViV TAVR patients and 2200 patients undergoing primary native valve TAVR from 2012 to 2017 at six medical centers. The main outcome measures were in-hospital mortality, 30-day mortality, stroke, myocardial infarction, acute kidney injury, and pacemaker implantation. RESULTS: ViV patients were more likely male, younger, prior coronary artery bypass graft, "hostile chest," and urgent. 30% of the patients had Society of Thoracic Surgeons risk score <4%, 36.3% were 4%-8% and 33.8% were >8%. In both groups many patients had concomitant coronary artery disease. Median time to prosthetic failure was 9.6 years (interquartile range: 5.5-13.5 years). 82% of failed surgical valves were size 21, 23, or 25 mm. Access was 91% femoral. After ViV, 87% had none or trivial aortic regurgitation. Mean gradients were <20 mmHg in 54.6%, 20-29 mmHg in 30.6%, 30-39 mmHg in 8.3% and ≥40 mmHg in 5.87%. Median length of stay was 4 days. In-hospital mortality was 0%. 30-day mortality was 0% in ViV and 3.7% in native TAVR. There was no difference in in-hospital mortality, postprocedure myocardial infarction, stroke, or acute kidney injury. CONCLUSION: Compared to native TAVR, ViV TAVR has similar peri-procedural morbidity with relatively high postprocedure mean gradients. A multidisciplinary approach will help ensure patients receive the ideal therapy in the setting of structural bioprosthetic valve degeneration.

Decreased expression of ErbB2 on left ventricular epicardial cells in patients with diabetes mellitus.

We investigated the cell surface expression of ErbB receptors on left ventricular (LV) epicardial endothelial cells and CD105+ cells obtained from cardiac biopsies of patients undergoing coronary artery bypass grafting surgery (CABG). Endothelial cells and CD105+ non-endothelial cells were freshly isolated from LV epicardial biopsies obtained from 15 subjects with diabetes mellitus (DM) and 8 controls. The expression of ErbB receptors was examined using flow cytometry. We found that diabetes mellitus (DM) and high levels of hemoglobin A1C are associated with reduced expression of ErbB2. To determine if the expression of ErbB2 receptors is regulated by glucose levels, we examined the effect of high Glucose in human microvascular endothelial cells (HMEC-1) and CD105+ non-endothelial cells, using a novel flow cytometric approach to simultaneously determine the total level, cell surface expression, and phosphorylation of ErbB2. Incubation of cells in the presence of 25 mM d-glucose resulted in decreased cell surface but not total levels of ErbB2. The level of ErbB2 at the cell surface is controlled by disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) that is expressed on LV epicardial cells. Inhibition of ADAM10 prevented the high glucose-dependent decrease in the cell surface expression of ErbB2. We suggest that high Glucose depresses ErbB receptor signaling in endothelial cells and cardiac progenitor cells via the promotion of ADAM10-dependent cleavage of ErbB2 at the cell surface, thus contributing to vascular dysfunction and adverse remodeling seen in diabetic patients.

Intraoperative changes and prognostic implications of pulmonary hypertension in patients with hypertrophic obstructive cardiomyopathy undergoing surgical septal myectomy.

OBJECTIVES: Patients with hypertrophic cardiomyopathy often have concomitant pulmonary hypertension, which has a negative prognostic effect in patients undergoing myectomy. Our objective was to investigate the effect of myectomy on pulmonary artery pressure obtained via Swan-Ganz catheter and characterize how changes in pulmonary artery systolic pressure may indicate outcomes in these patients. METHODS: We performed a single-center retrospective analysis of 271 patients with recordings of intraoperative pulmonary artery pressures during surgical myectomy. We analyzed primary composite outcomes as 30-day or in-hospital major cardiopulmonary adverse events. RESULTS: There was a 5.17% adverse event rate. Patients with adverse events were older, were more likely to be female, had chronic obstructive pulmonary disease, and had longer cardiopulmonary bypass times. Some 35.7% of those with adverse events had moderate to severe pulmonary hypertension (pulmonary artery systolic pressure ≥50 mm Hg) on postbypass stress test, compared with 4.3% of those without adverse events (P < .001). Further, 21.4% of patients with adverse events had pulmonary artery systolic pressure 50 mm Hg or greater at the end of surgery, compared with 1.9% of patients without adverse events (P < .001). The pulmonary artery systolic pressure decrease after surgery in those without adverse events was on average 5 mm Hg more than in those with adverse events. CONCLUSIONS: Postoperative pulmonary hypertension was associated with a higher rate of adverse cardiopulmonary events. This may influence the decision to use Swan-Ganz catheters in patients undergoing septal myectomy in monitoring pulmonary artery pressures to better risk stratify and manage these patients postoperatively.

Comparative effectiveness of revascularization strategies for early coronary artery disease: A multicenter analysis.

OBJECTIVES: The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years. METHODS: We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups. RESULTS: After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001). CONCLUSIONS: Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.

Protective role of ErbB3 signaling in myeloid cells during adaptation to cardiac pressure overload.

BACKGROUND: Myeloid cells play an important role in a wide variety of cardiovascular disorders, including both ischemic and non-ischemic cardiomyopathies. Neuregulin-1 (NRG-1)/ErbB signaling has recently emerged as an important factor contributing to the control of inflammatory activation of myeloid cells after an ischemic injury. However, the role of ErbB signaling in myeloid cells in non-ischemic cardiomyopathy is not fully understood. This study investigated the role of ErbB3 receptors in the regulation of early adaptive response using a mouse model of transverse aortic constriction (TAC) for non-ischemic cardiomyopathy. METHODS AND RESULTS: TAC surgery was performed in groups of age- and sex-matched myeloid cell-specific ErbB3-deficient mice (ErbB3MyeKO) and control animals (ErbB3MyeWT). The number of cardiac CD45 immune cells, CD11b myeloid cells, Ly6G neutrophils, and Ly6C monocytes was determined using flow cytometric analysis. Five days after TAC, survival was dramatically reduced in male but not female ErbB3MyeKO mice or control animals. The examination of lung weight to body weight ratio suggested that acute pulmonary edema was present in ErbB3MyeKO male mice after TAC. To determine the cellular and molecular mechanisms involved in the increased mortality in ErbB3MyeKO male mice, cardiac cell populations were examined at day 3 post-TAC using flow cytometry. Myeloid cells accumulated in control but not in ErbB3MyeKO male mouse hearts. This was accompanied by increased proliferation of Sca-1 positive non-immune cells (endothelial cells and fibroblasts) in control but not ErbB3MyeKO male mice. No significant differences in intramyocardial accumulation of myeloid cells or proliferation of Sca-1 cells were found between the groups of ErbB3MyeKO and ErbB3MyeWT female mice. An antibody-based protein array analysis revealed that IGF-1 expression was significantly downregulated only in ErbB3MyeKO mice hearts compared to control animals after TAC. CONCLUSION: Our data demonstrate the crucial role of myeloid cell-specific ErbB3 signaling in the cardiac accumulation of myeloid cells, which contributes to the activation of cardiac endothelial cells and fibroblasts and development of an early adaptive response to cardiac pressure overload in male mice.

High ErbB3 activating activity in human blood is not due to circulating neuregulin-1 beta.

Neuregulin-1ß (NRG-1) is a membrane-bound or secreted growth and differentiation factor that mediates its action by binding to ErbB receptors. Circulating levels of NRG-1 are characterized by large inter-individual variability with the range of absolute values covering two orders of magnitude, from hundreds to tens of thousands of picograms per milliliter of blood. NRG-1 signaling via ErbB receptors contributes to the cell survival and downregulation of the inflammatory response. A higher level of circulating NRG-1 may indicate increased shedding of membrane-bound NRG-1, which in turn can contribute to better protection against cardiovascular stress or injury. However, it is unknown whether circulating NRG-1 can induce activation of ErbB receptors. In the current study, we performed an analysis of circulating NRG-1 functional activity using a cell-based ELISA measuring phosphorylation of ErbB3 induced by blood plasma obtained from healthy donors. We found high levels of ErbB3 activating activity in human plasma. No correlations were found between the levels of circulating NRG-1 and plasma ErbB3 activating activity. To determine the direct effect of circulating NRG-1, we incubated plasma with neutralizing antibody, which prevented the stimulatory effect of recombinant NRG-1 on activation of ErbB3. No effect of the neutralizing antibody was found on plasma-induced phosphorylation of ErbB3. We also found that a significant portion of circulating NRG-1 is comprised of full-length NRG-1 associated with large extracellular vesicles. Our results demonstrate that circulating NRG-1 does not contribute to plasma-induced ErbB3 activating activity and emphasizes the importance of functional testing of NRG-1 proteins in biological samples.

Comparison of intraoperative tranexamic acid and epsilon-aminocaproic acid in cardiopulmonary bypass patients.

Objective: To compare tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) in patients undergoing cardiac surgery with cardiopulmonary bypass. Methods: Over a consecutive 2-year period, 824 adult cardiac surgery patients who received TXA during an EACA shortage were compared with 778 patients who received EACA postshortage. Patient characteristics and process and outcome variables were collected through chart review and database queries. This retrospective analysis used inverse probability of treatment weighting to control for confounding by indication, and propensity scores were calculated using a logistic regression model. Results: In adjusted models, overall transfusion rates for the TXA cohort (odds ratio [OR], 0.94; 95% confidence interval [95% CI], 0.81-1.10) and administration of platelets (OR, 1.04; 95% CI, 0.85-1.27), red blood cells (OR, 0.93; 95% CI, 0.80-1.09), fresh frozen plasma (OR, 1.00; 95% CI, 0.79-1.25), and cryoprecipitate (OR, 1.08; 95% CI, 0.71-1.64) were equivalent to the EACA cohort. In addition, there was no statistical difference with respect to stroke, seizure, mortality, reoperation for bleeding, chest tube drainage, and acute kidney injury. Patients who received TXA had shorter ventilator times (difference in medians -1.33 hours [95% CI, -1.86 to -0.80]) and lower postsurgical charges (difference of medians -$2913 [95% CI, -5147 to -679]). Conclusions: Substituting TXA for EACA during cardiac surgery with cardiopulmonary bypass did not change transfusion rate or amount, nor was there a significant difference in chest tube drainage. Patients who received TXA had a statistically significant but not clinically significant lower postoperative ventilator times and charges without an increase in mortality, stroke, reoperation for bleeding, acute kidney injury, or seizures.

Repair of Spontaneous Left Atrial Dissection Resulting in Severe Paravalvular Native Mitral Valve Regurgitation.

A 54-year-old male with history of end-stage renal disease secondary to hypertension on hemodialysis with moderate aortic valve insufficiency presented with progressive exertional dyspnea and lower extremity edema over several weeks. Relevant history included hospitalization for Staphylococcus epidermidis bacteremia secondary to dialysis catheter line infection 6 months prior. (Level of Difficulty: Advanced.).

Tissue versus mechanical aortic valve replacement in younger patients: A multicenter analysis.

OBJECTIVE: The goal of this study was to examine the long-term survival of patients between the ages of 50 and 65 years who underwent tissue versus mechanical aortic valve replacement (AVR) in a multicenter cohort. METHODS: A multicenter, retrospective analysis of all AVR patients (n = 9388) from 1991 to 2015 among 7 medical centers reporting to a prospectively maintained clinical registry was conducted. Inclusion criteria were: patients aged 50 to 65 years who underwent isolated AVR. Baseline comorbidities were balanced using inverse probability weighting for a study cohort of 1449 AVRs: 840 tissue and 609 mechanical. The primary end point of the analysis was all-cause mortality. Secondary end points included in-hospital morbidity, 30-day mortality, length of stay, and risk of reoperation. RESULTS: During the study period, there was a significant shift from mechanical to tissue valves (P < .001). There was no significant difference in major in-hospital morbidity, mortality, or length of hospitalization. Also, there was no significant difference in adjusted 15-year survival between mechanical versus tissue valves (hazard ratio, 0.87; 95% confidence interval [CI], 0.67-1.13; P = .29), although tissue valves were associated with a higher risk of reoperation with a cumulative incidence of 19.1% (95% CI, 14.4%-24.3%) versus 3.0% (95% CI, 1.7%-4.9%) for mechanical valves. The reoperative 30-day mortality rate was 2.4% (n = 2) for the series. CONCLUSIONS: Among patients 50 to 65 years old who underwent AVR, there was no difference in adjusted long-term survival according to prosthesis type, but tissue valves were associated with a higher risk of reoperation.

Surgical Atrial Fibrillation Ablation Improves Long-Term Survival: A Multicenter Analysis.

BACKGROUND: The Society of Thoracic Surgeons guidelines recommend surgical ablation (SA) at the time of concomitant mitral operations, aortic valve replacement, coronary artery bypass grafting (CABG), and aortic valve replacement plus CABG for patients in atrial fibrillation (AF). The goal of this analysis was to assess the influence of SA on long-term survival. METHODS: A retrospective analysis of 20,407 consecutive CABG or valve procedures from 2008 to 2015 among seven centers reporting to a prospectively maintained clinical registry was conducted. Patients undergoing operation with documented preoperative AF were included (n = 2,740). Patients receiving SA were compared with patients receiving no SA. The primary end point was all-cause mortality. Secondary end points included in-hospital morbidity and mortality. RESULTS: The frequency of SA was 23.1% (n = 634), and an increase was seen in the rate of SA over the study period (p < 0.001). Concomitant SA was performed in 16.2% of CABG, 30.6% of valve, and 24.3% of valve plus CABG procedures. A substantial improvement was found in unadjusted survival among patients undergoing SA (hazard ratio 0.54, 95% confidence interval: 0.42 to 0.70). Moreover, no differences were found in postoperative complications. SA did have longer bypass times (p < 0.001) but a shorter overall length of stay (p < 0.001). After risk adjustment, SA patients had an improved 5-year survival (hazard ratio 0.69, 95% confidence interval: 0.51 to 0.92), and the effect was observed across all operations. CONCLUSIONS: In a multicenter cohort of patients with AF, concomitant SA resulted in substantially improved long-term survival across patients who underwent CABG, valve, and valve plus CABG. These findings support current guidelines from The Society of Thoracic Surgeons that recommend broader application of concomitant SA.

Intensity of Glycemic Control Affects Long-Term Survival After Coronary Artery Bypass Graft Surgery.

BACKGROUND: A patient's hemoglobin (Hb) A1c level, regardless of diabetic status, is a measure of glycemic control. Studies have found it is an independent predictor of short-term death in patients undergoing coronary artery bypass grafting (CABG). In this study, we used preoperative HbA1c to assess whether levels are associated with short-term and long-term survival after CABG. METHODS: From a regional registry of consecutive cases, we identified 6,415 patients undergoing on-pump isolated CABG from 2008 to 2015 with documented preoperative HbA1c level. We defined four HbA1c groups: less than 5.7% (n = 1,713), 5.7% to 6.4% (n = 2,505), 6.5% to 8.0% (n = 1,377), and more than 8% (n = 820). Relationship to in-hospital outcomes and long-term survival was assessed. Outcome rates and hazard ratios were adjusted for patient and disease risk factors using multivariable logistic regression and Cox models. RESULTS: The study included 3,740 patients (58%) not diagnosed as having diabetes and 2,674 with diabetes. Prediabetes (HbA1c 5.7% to 6.4%) was documented in 52% (n = 1,933) of nondiabetic patients. Higher HbA1c values were associated with younger age, female sex, greater body mass index, more comorbid diseases, lower ejection fraction, more 3-vessel coronary disease, and recent myocardial infarction (p < 0.05 trend for all). After adjustment for patient risk, greater HbA1c values were not associated with higher rates of in-hospital death or morbidity. Long-term survival was significantly worse as HbA1c increased. Risk of death increased by 13% for every unit increase in HbA1c (adjusted hazard ratio, 1.13; 95% confidence interval, 1.07 to 1.19; p < 0.001). CONCLUSIONS: Preadmission glycemic control, as assessed by HbA1c, is predictive of long-term survival, with higher levels associated with poorer prognosis. Whether this risk can be modified by better glycemic control postoperatively remains to be determined.

Comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention in a real-world Surgical Treatment for Ischemic Heart Failure trial population.

OBJECTIVE: There are no prospective randomized trial data to guide decisions on optimal revascularization strategies for patients with multivessel coronary artery disease and reduced ejection fraction. In this analysis, we describe the comparative effectiveness of coronary artery bypass grafting (CABG) versus percutaneous coronary intervention (PCI) in this patient population. METHODS: A multicenter, retrospective analysis of all CABG (n = 18,292) and PCIs (n = 55,438) performed from 2004 to 2014 among 7 medical centers reporting to the Northern New England Cardiovascular Disease Study Group. After applying inclusion and exclusion criteria from the Surgical Treatment for Ischemic Heart Failure trial, there were 955 CABG and 718 PCI patients with an ejection fraction ≤ 35% and 2- or 3-vessel disease. Inverse probability weighting was used for risk adjustment. The primary end point was all-cause mortality. Secondary end points included rates of 30-day mortality, stroke, acute kidney injury, and incidence of repeat revascularization. RESULTS: The median duration of follow-up was 4.3 years (range, 1.59-6.71 years). CABG was associated with improved long-term survival compared with PCI after risk adjustment (hazard ratio, 0.59; 95% confidence interval, 0.50-0.71; P < .01). Although CABG and PCI had similar 30-day mortality rates (P = .14), CABG was associated with a higher frequency of stroke (P < .001) and acute kidney injury (P < .001), whereas PCI was associated with a higher incidence of repeat revascularization (P < .001). CONCLUSIONS: Among patients with reduced ejection fraction and multivessel disease, CABG was associated with improved long-term survival compared with PCI. CABG should be strongly considered in patients with ischemic cardiomyopathy and multivessel coronary disease.

ErbB2 promotes endothelial phenotype of human left ventricular epicardial highly proliferative cells (eHiPC).

The adult human heart contains a subpopulation of highly proliferative cells. The role of ErbB receptors in these cells has not been studied. From human left ventricular (LV) epicardial biopsies, we isolated highly proliferative cells (eHiPC) to characterize the cell surface expression and function of ErbB receptors in the regulation of cell proliferation and phenotype. We found that human LV eHiPC express all four ErbB receptor subtypes. However, the expression of ErbB receptors varied widely among eHiPC isolated from different subjects. eHiPC with higher cell surface expression of ErbB2 reproduced the phenotype of endothelial cells and were characterized by endothelial cell-like functional properties. We also found that EGF/ErbB1 induces VEGFR2 expression, while ligands for both ErbB1 and ErbB3/4 induce expression of Tie2. The number of CD31posCD45neg endothelial cells is higher in LV biopsies from subjects with high ErbB2 (ErbB2high) eHiPC compared to low ErbB2 (ErbB2low) eHiPC. These findings have important implications for potential strategies to increase the efficacy of cell-based revascularization of the injured heart, through promotion of an endothelial phenotype in cardiac highly proliferative cells.