Early and Long-Term Results of Simultaneous and Staged Revascularization of Coronary and Carotid Arteries.

BACKGROUND: Carotid artery disease is prevalent among patients with coronary heart disease. The concomitant severe lesions in the carotid and coronary arteries may necessitate either simultaneous or staged revascularization involving coronary bypass and carotid endarterectomy. However, there is presently a lack of consensus on the optimal choice of surgical treatment tactics for patients with significant stenoses in both carotid and coronary arteries. The aim of the current study was to compare the 30-day and long-term outcomes of coronary and carotid artery revascularization surgery based on the simultaneous or staged surgical tactics. MATERIAL AND METHODS: This single-center retrospective study involved 192 patients with concurrent coronary artery disease and carotid artery stenosis ≥ 70%, of whom 106 patients underwent simultaneous intervention (CABG + CEA) and 86 patients underwent staged CABG/CEA. The mean time between stages ranged from 1 to 4 months (mean 1.88 ± 0.9 months). The endpoints included death from any cause, non-fatal stroke, non-fatal myocardial infarction (MI), and major adverse cardiovascular events (MACEs) (death + non-fatal MI + non-fatal stroke) within 30 days after the last intervention and in the long-term follow-up period (median follow-up-6 years). RESULTS: The 30-day all-cause mortality, incidence of postoperative non-fatal MI, non-fatal stroke, and MACEs did not exhibit differences between the groups after single-stage and staged interventions. However, the overall risk of postoperative complications (adjusted for the risk of any complication per patient) (OR 2.214, 95% CI 1.048-4.674, p = 0.035), as well as the duration of ventilatory support (p = 0.004), was elevated in the group after simultaneous interventions compared with the staged intervention group. This difference did not result in an increased incidence of death and MACEs in the group after simultaneous interventions. In the long-term follow-up period, there were no significant differences observed when comparing simultaneous or staged surgical tactics in terms of overall survival (54.9% and 62.6% in Groups 1 and 2, respectively, P log-rank = 0.068), non-fatal stroke-free survival (45.6% and 33.6% in Groups 1 and 2, respectively, P log-rank = 0.364), non-fatal MI-survival (57.6% and 73.5% in Groups 1 and 2, respectively, P log-rank = 0.169), and MACE-free survival (7.1% and 30.2% in Groups 1 and 2, respectively, P log-rank = 0.060). The risk factors associated with an unfavorable outcome included age, smoking, BMI, LV EF, and atherosclerosis of the lower extremity arteries. CONCLUSIONS: This study revealed no significant difference in the impact of simultaneous CABG + CEA or staged CABG/CEA on the incidence of death, stroke, MI, and MACEs over a 30-day and long-term follow-up period. Although the immediate results indicated an increased risk of a complicated course (attributable to overall complications) and more prolonged ventilation after simultaneous CABG + CEA compared with staged CABG/CEA, this did not lead to an increase in fatal complications. Therefore, the implementation of either tactic is considered eligible and appropriate following a thorough operative risk assessment.

Treatment Strategies for Chronic Coronary Heart Disease with Left Ventricular Systolic Dysfunction or Preserved Ejection Fraction-A Systematic Review and Meta-Analysis.

In this meta-analysis, we examine the advantages of invasive strategies for patients diagnosed with chronic coronary heart disease (CHD) and preserved left ventricular (LV) function, as well as those with significant LV systolic dysfunction (LV ejection fraction (EF) < 45%). MATERIAL AND METHODS: We conducted a systematic search to identify all randomized trials directly comparing invasive strategies with optimal medical therapy (OMT) in patients diagnosed with chronic CHD. Data from these trials were pooled using a random-effects meta-analysis. The primary outcome assessed was the all-cause mortality, while secondary endpoints included cardiovascular (CV) death, stroke, myocardial infarction (MI), and unplanned revascularization. This study was designed to assess the benefits of both invasive strategies and OMT in patients with preserved LV function and in those with LV systolic dysfunction. The statistical analysis of the data was conducted using the Review Manager (RevMan) software, version 5.4.1 (The Cochrane Collaboration, 2020). RESULTS: Twelve randomized studies enrolling 13,912 patients were included in the final analysis. Among the patients with chronic CHD and preserved LV systolic function, revascularization did not demonstrate a reduction in all-cause mortality (8.52% vs. 8.45%, p = 0.45), CV death (3.41% vs. 3.62%, p = 0.08), or the incidence of MI (9.88% vs. 10.49%, p = 0.47). However, the need for unplanned myocardial revascularization was significantly lower in the group following the initial invasive approach compared to patients undergoing OMT (14.75% vs. 25.72%, p < 0.001). In contrast, the invasive strategy emerged as the preferred treatment modality for patients with ischemic LV systolic dysfunction. This approach demonstrated lower rates of all-cause mortality (40.61% vs. 46.52%, p = 0.004), CV death (28.75% vs. 35.82%, p = 0.0004), and MI (8.19% vs. 10.8%, p = 0.03). CONCLUSIONS: In individuals diagnosed with chronic CHD and preserved LV EF, the initial invasive approach did not demonstrate a clinical advantage over OMT. Conversely, in patients with ischemic LV systolic dysfunction, myocardial revascularization was found to reduce the risks of CV events and enhance the overall outcomes. These findings hold significant clinical relevance for optimizing treatment strategies in patients with chronic CHD, contingent upon myocardial contractility status.

The Role of «Novel¼ Biomarkers of Systemic Inflammation in the Development of Early Hospital Events after Aortic Valve Replacement in Patients with Aortic Stenosis.

INTRODUCTION: The pathogenesis of aortic stenosis includes the processes of chronic inflammation, calcification, lipid metabolism disorders, and congenital structural changes. The goal of our study was to determine the predictive value of novel biomarkers of systemic inflammation and some hematological indices based on the numbers of leukocytes and their subtypes in the development of early hospital medical conditions after mechanical aortic valve replacement in patients with aortic stenosis. MATERIALS AND METHODS: This was a cohort study involving 363 patients who underwent surgical intervention for aortic valve pathology between 2014 and 2020. The following markers of systemic inflammation and hematological indices were studied: SIRI (Systemic Inflammation Response Index), SII (Systemic Inflammation Index), AISI (Aggregate Index of Systemic Inflammation), NLR (Neutrophil/Lymphocyte Ratio), PLR (Platelet/Lymphocyte Ratio), and MLR (Monocyte/Lymphocyte Ratio). Associations of the levels of these biomarkers and indices with the development of in-hospital death, acute kidney injury, postoperative atrial fibrillation, stroke/acute cerebrovascular accident, and bleeding were calculated. RESULTS: According to an ROC analysis, an SIRI > 1.5 (p < 0.001), an SII > 718 (p = 0.002), an AISI > 593 (p < 0.001), an NLR > 2.48 (p < 0.001), a PLR > 132 (p = 0.004), and an MLR > 0.332 (p < 0.001) were statistically significantly associated with in-hospital death. Additionally, an SIRI > 1.5 (p < 0.001), an NLR > 2.8 (p < 0.001), and an MLR > 0.392 (p < 0.001) were associated with bleeding in the postoperative period. In a univariate logistic regression, SIRI, SII, AISI, and NLR were statistically significant independent factors associated with in-hospital death. In a multivariate logistic regression model, SIRI was the most powerful marker of systemic inflammation. CONCLUSION: SIRI, SII, AISI, and NLR as novel biomarkers of systemic inflammation were associated with in-hospital mortality. Of all markers and indices of systemic inflammation in our study, SIRI was the strongest predictor of a poor outcome in the multivariate regression model.

Advantages of Multiposition Scanning in Echocardiographic Assessment of the Severity of Discordant Aortic Stenosis.

AIM OF THE STUDY: The aim of this study was to perform a comparative analysis of severity of discordant aortic stenosis (AS) assessment using multiposition scanning and the standard apical window. MATERIALS AND METHODS: All patients (n = 104) underwent preoperative transthoracic echocardiography (TTE) and were ranked according to the degree of AS severity. The reproducibility feasibility of the right parasternal window (RPW) was 75.0% (n = 78). The mean age of the patients was 64 years, and 40 (51.3%) were female. In 25 cases, low gradients were identified from the apical window not corresponding to the visual structural changes in the aortic valve, or disagreement between the velocity and calculated parameters was detected. Patients were divided into two groups: concordant AS (n = 56; 71.8%) and discordant AS (n = 22; 28.2%). Three individuals were excluded from the discordant AS group due to the presence of moderate stenosis. RESULTS: Based on the comparative analysis of transvalvular flow velocities obtained from multiposition scanning, the concordance group showed agreement between the velocity and calculated parameters. We observed an increase in the mean transvalvular pressure gradient (ΔPmean) and peak aortic jet velocity (Vmax), ΔPmean in 95.5% of patients, velocity time integral of transvalvular flow (VTI AV) in 90.9% of patients, and a decrease in aortic valve area (AVA) and indexed AVA in 90.9% of patients after applying RPW in all patients with discordant AS. The use of RPW allowed the reclassification of AS severity from discordant to concordant high-gradient AS in 88% of low-gradient AS cases. CONCLUSION: Underestimation of flow velocity and overestimation of AVA using the apical window may lead to misclassification of AS. The use of RPW helps to match the degree of AS severity with the velocity characteristics and reduce the number of low-gradient AS cases.

Colchicine in Cardiac Surgery: The COCS Randomized Clinical Trial.

BACKGROUND: In patients who underwent cardiac surgery, first-time postoperative atrial fibrillation (POAF) is associated with increased incidence of hospital-acquired complications and mortality. Systemic inflammation is one of confirmed triggers of its development. The anti-inflammatory properties of colchicine can be effective for the POAF prevention. However, the results of several studies were questionable and required further investigation. Hence, we aimed to evaluate the effectiveness of low-dose short-term colchicine administration for POAF prevention in patients after the open-heart surgery. This double-blind randomized placebo-controlled trial included 267 patients, but 27 of them dropped out in the course of the study. Study subjects received the test drug on the day before the surgery and on postoperative days 2, 3, 4 and 5. The rhythm control was conducted immediately after the operation and until the discharge from the hospital. The final analysis included 240 study subjects: 113 in the colchicine group and 127 in the placebo group. POAF was observed in 21 (18.6%) patients of the colchicine group vs. 39 (30.7%) control patients (OR 0.515; 95% Cl 0.281-0.943; p = 0.029). We observed no statistically significant differences between the patient groups in the secondary endpoints of the study (hospital mortality, respiratory failure, stroke, bleeding, etc.). For other parameters characterizing the severity of inflammation (pericardial effusion, pleural effusion, WBC count, neutrophil count), there were statistically significant differences between the groups in the early postoperative period (days 3 and 5). Also, statistically significant differences between the groups in the frequency of adverse events were revealed: the incidence of diarrhea in the colchicine group was 25.7% vs. 11.8% in the placebo group (OR 2.578; 95% Cl 1.300-5.111; p = 0.005); for abdominal pain, incidence values were 7% vs. 1.6%, correspondingly (OR 4.762; 95% Cl 1.010-22.91; p = 0.028). Thus, there were statistically significant differences between groups in the primary endpoint, thereby confirming the effectiveness of short-term colchicine use for the POAF prevention after coronary artery bypass grafting and/or aortic valve replacement. Also, we detected statistically significant differences between groups in the frequency of side effects to colchicine: diarrhea and abdominal pain were more common in the colchicine group. This clinical trial is registered with ClinicalTrials database under a unique identifier: NCT04224545.

Mid-regional pro-adrenomedullin as a predictor of in-hospital mortality in adult patients with COVID-19: a single-centre prospective study.

BACKGROUND: To determine the predictive value of mid-regional pro-adrenomedullin (MR-proADM) compared to routine clinical and laboratory parameters in patients with COVID-19. METHODS: A total of 135 adult patients hospitalized with COVID-19 were included in a prospective single-centre study. In addition to routine parameters, the levels of MR-proADM in blood plasma were measured on the day of hospitalization. The patients were divided into 2 groups: those who survived and were discharged (n = 115, 85%) and those who did not survive (n = 20, 15%). Data are presented as median and interquartile range. RESULTS: The non-survivors had a statistically significantly greater age (73.4 [63.5-84.8] vs. 62.2 [50.3-71.4] years, P = 0.001), a lower level of haemoglobin oxygen saturation (91 [87-92] vs. 92 [92-93]%, P < 0.001), lower lymphocyte level (13 [7-30] vs. 21 [15-27]%, P = 0.03), higher lactate dehydrogenase (338 [273-480] vs. 280 [233-383] EU L-1, P = 0.04) and aspartate aminotransferase levels (49 [28-72] vs. 33 [23-47] EU L-1, P = 0.03), a higher National Early Warning (NEWS) score (7 [7- 8] vs. 6 [5-7] points, P < 0.001), and higher procalcitonin (0.16 [0.11-0.32] vs. 0.1 [0.07-0.18] ng mL-1, P = 0.006) and MR-proADM levels (1.288 [0.886-1.847] vs. 0.769 [0.6-0.955] nmol L-1, P < 0.001). MR-proADM had the highest predictive value for death during hospital stay (cut-off: 0.895 nmol L-1, AUC ROC 0.78 [95% CI: 0.66-0.90], sensitivity 75%, specificity 69%, OR 6.58 [95% CI: 2.22-19.51]). CONCLUSIONS: Compared with other indicators, MR-proADM has the highest predictive value for in-hospital mortality in patients with COVID-19.

Transthoracic Echocardiography-Based Prediction Model of Adverse Event Risk in Patients with COVID-19.

Cardiopulmonary disorders cause a significant increase in the risk of adverse events in patients with COVID-19. Therefore, the development of new diagnostic and treatment methods for comorbid disorders in COVID-19 patients is one of the main public health challenges. The aim of the study was to analyze patient survival and to develop a predictive model of survival in adults with COVID-19 infection based on transthoracic echocardiography (TTE) parameters. We conducted a prospective, single-center, temporary hospital-based study of 110 patients with moderate to severe COVID-19. All patients underwent TTE evaluation. The predictors of mortality we identified in univariate and multivariable models and the predictive performance of the model were assessed using receiver operating characteristic (ROC) analysis and area under the curve (AUC). The predictive model included three factors: right ventricle (RV)/left ventricle (LV) area (odds ratio (OR) = 1.048 per 1/100 increase, p = 0.03), systolic pulmonary artery pressure (sPAP) (OR = 1.209 per 1 mm Hg increase, p < 0.001), and right ventricle free wall longitudinal strain (RV FW LS) (OR = 0.873 per 1% increase, p = 0.036). The AUC-ROC of the obtained model was 0.925 ± 0.031 (95% confidence interval (95% CI): 0.863−0.986). The sensitivity (Se) and specificity (Sp) measures of the models at the cut-off point of 0.129 were 93.8% and 81.9%, respectively. A binary logistic regression method resulted in the development of a prognostic model of mortality in patients with moderate and severe COVID-19 based on TTE data. It may also have additional implications for early risk stratification and clinical decision making in patients with COVID-19.

Human Angiotensin I-Converting Enzyme Produced by Different Cells: Classification of the SERS Spectra with Linear Discriminant Analysis.

Angiotensin I-converting enzyme (ACE) is a peptidase widely presented in human tissues and biological fluids. ACE is a glycoprotein containing 17 potential N-glycosylation sites which can be glycosylated in different ways due to post-translational modification of the protein in different cells. For the first time, surface-enhanced Raman scattering (SERS) spectra of human ACE from lungs, mainly produced by endothelial cells, ACE from heart, produced by endothelial heart cells and miofibroblasts, and ACE from seminal fluid, produced by epithelial cells, have been compared with full assignment. The ability to separate ACEs' SERS spectra was demonstrated using the linear discriminant analysis (LDA) method with high accuracy. The intervals in the spectra with maximum contributions of the spectral features were determined and their contribution to the spectrum of each separate ACE was evaluated. Near 25 spectral features forming three intervals were enough for successful separation of the spectra of different ACEs. However, more spectral information could be obtained from analysis of 50 spectral features. Band assignment showed that several features did not correlate with band assignments to amino acids or peptides, which indicated the carbohydrate contribution to the final spectra. Analysis of SERS spectra could be beneficial for the detection of tissue-specific ACEs.

Prognostic Value of Characterizing Myocardial Tissue by Cardiac MRI with T1 Mapping in HFpEF Patients: A Systematic Review and Meta-Analysis.

Objectives: Our study aimed at conducting a systematic review and meta-analysis, with the objective of evaluating the prognostic value of T1 mapping techniques via cardiac magnetic resonance (CMR) in heart failure with preserved ejection fraction (HFpEF) patients. Materials and methods: The protocol was prospectively registered in the international prospective register of systematic reviews PROSPERO (registration number CRD42022300991). We searched PubMed, Google Scholar, and EMBASE for studies examining the prognostic value of characterizing myocardial tissue via CMR imaging with T1 mapping in HFpEF. Hazard ratios (HRs) for uniformly defined predictors were pooled for meta-analysis. Results: In total, 7 studies were retrieved from 351 publications for this systematic review and meta-analysis. A total of 1930 patients (mean age of 69.4 years, mean follow-up duration of 25.6 months) was included in the analysis. The meta-analysis demonstrated that higher extracellular volume (ECV) was associated with an increased risk of death and/or hospitalization with heart failure (HF) (HR:1.12; 95% CI: 1.06−1.18; p < 0.0001). After adjusting for baseline characteristics, the higher extent of ECV remained strongly associated with the risk of death and/or hospitalization with HF (HRadjusted: 1.08; 95% CI: 1.04−1.13; p = 0.0001). However, no significant association of native T1 value with risk of death or adverse cardiovascular events was found (HR:1.01; 95% CI: 1.00−1.02; p = 0.21). Conclusion: Assessment of ECV via CMR has an important prognostic value for outcomes of death and/or hospitalization with HF, and can therefore be used as an effective tool for risk stratification of patients with HFpEF.

Should We Monitor Glucose and Biomarkers in Diabetics over Heart Surgery?

Hyperglycemia is associated with adverse outcomes after coronary artery bypass grafting (CABG). While there is a consensus that blood glucose control may benefit patients undergoing CABG, the role of biomarkers, optimal method, and duration of such monitoring are still unclear. The aim of this study is to define the efficacy of a continuous glucose monitoring system (CGMS) and link it to pro-inflammatory biomarkers while on insulin pump therapy in diabetic patients undergoing CABG. We prospectively assessed CGMS for 72 h in 105 patients including 52 diabetics undergoing isolated CABG. In diabetics, CGMS was connected to an insulin pump for precise glucose control. On top of conventional biomarkers (HbA1C, lipid profile), high sensitive C-reactive protein (hs-CRP), Regulated upon Activation Normal T cell Expressed and presumably Secreted (RANTES), and leptin levels were collected before surgery, 1 h, 12 h, 7 days, and at 1 year after CABG. Overall, CGMS revealed high glucose independently from underlying diabetes during first 48 h following CABG but was higher (p < 0.05) in diabetics. The insulin pump improved glycemic control over early follow-up (72 h) post-CABG. There were no hypoglycemic episodes in patients on insulin pump therapy and those receiving bolus insulin therapy. We revealed a lower rate of postpericardiotomy syndrome (PCTS) in patients on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (p = 0.03). Hs-CRP and RANTES levels were lower in patients with T2DM on insulin pump therapy compared to patients prescribed bolus insulin therapy in the early postoperative period (p < 0.05). It is most likely due to the fact that insulin pump therapy decreases systemic inflammatory response. Further controlled trials should assess whether CGMS improves outcomes after cardiac surgery.

Conformational fingerprint of blood and tissue ACEs: Personalized approach.

BACKGROUND: The pattern of binding of monoclonal antibodies (mAbs) to 18 epitopes on human angiotensin I-converting enzyme (ACE)-"conformational fingerprint of ACE"-is a sensitive marker of subtle conformational changes of ACE due to mutations, different glycosylation in various cells, the presence of ACE inhibitors and specific effectors, etc. METHODOLOGY/PRINCIPAL FINDINGS: We described in detail the methodology of the conformational fingerprinting of human blood and tissue ACEs that allows detecting differences in surface topography of ACE from different tissues, as well detecting inter-individual differences. Besides, we compared the sensitivity of the detection of ACE inhibitors in the patient's plasma using conformational fingerprinting of ACE (with only 2 mAbs to ACE, 1G12 and 9B9) and already accepted kinetic assay and demonstrated that the mAbs-based assay is an order of magnitude more sensitive. This approach is also very effective in detection of known (like bilirubin and lysozyme) and still unknown ACE effectors/inhibitors which nature and set could vary in different tissues or different patients. CONCLUSIONS/SIGNIFICANCE: Phenotyping of ACE (and conformational fingerprinting of ACE as a part of this novel approach for characterization of ACE) in individuals really became informative and clinically relevant. Appreciation (and counting on) of inter-individual differences in ACE conformation and accompanying effectors make the application of this approach for future personalized medicine with ACE inhibitors more accurate. This (or similar) methodology can be applied to any enzyme/protein for which there is a number of mAbs to its different epitopes.

Body Mass Index and Plasma P-Selectin before Coronary Stenting Predict High Residual Platelet Reactivity at 6 Months on Dual Antiplatelet Therapy.

BACKGROUND: High residual platelet reactivity (HRPR) during dual antiplatelet therapy (DAPT) may impact clinical outcomes following percutaneous coronary interventions (PCI). However, whether any biomarkers assessed before PCI at DAPT loading may predict delayed maintenance HRPR is not clear. OBJECTIVE: The aim of this study was to determine whether conventional clinical or laboratory indices at loading before stenting may predict HRPR at 6 months of maintenance DAPT. METHODS: The study was designed on a single-center prospective cohort, and included 94 pre-PCI patients. All patients underwent elective PCI with drug-eluting stent implantation, and received DAPT with aspirin and clopidogrel. Platelet reactivity was assessed with 5 µmol/L of adenosine diphosphate-induced light transmission aggregometry before PCI, but after 24 h of DAPT loading, and repeated at 6 months. Baseline clinical characteristics, CYP2C19 polymorphism, C-reactive protein, soluble P-selectin, CD40L, interleukin-6, PAI-1 levels, and von Willebrand factor activity were analyzed. RESULTS: The incidence (light transmission aggregometry <50%) of prestent HRPR was 16%. By univariate regression, body mass index (BMI; p = 0.02), total cholesterol (p = 0.01), low-density lipoproteins (p = 0.004), CYP2C19*2 allele carriage (p = 0.006), soluble P-selectin (p = 0.009), and von Willebrand factor (p = 0.04) were linked to future HRPR. However, multivariate regression analysis suggested that only BMI and P-selectin were independent predictors of HRPR. CONCLUSIONS: Platelet reactivity before elective stenting is associated with numerous biomarkers; however, only BMI and soluble P-selectin were independent predictors of future HRPR during maintenance-phase DAPT. This may be important for future tailored antiplatelet strategies in patients with metabolic syndrome and diabetics.

ACE phenotyping in human heart.

AIMS: Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, is expressed as a type-1 membrane glycoprotein on the surface of different cells, including endothelial cells of the heart. We hypothesized that the local conformation and, therefore, the properties of heart ACE could differ from lung ACE due to different microenvironment in these organs. METHODS AND RESULTS: We performed ACE phenotyping (ACE levels, conformation and kinetic characteristics) in the human heart and compared it with that in the lung. ACE activity in heart tissues was 10-15 lower than that in lung. Various ACE effectors, LMW endogenous ACE inhibitors and HMW ACE-binding partners, were shown to be present in both heart and lung tissues. "Conformational fingerprint" of heart ACE (i.e., the pattern of 17 mAbs binding to different epitopes on the ACE surface) significantly differed from that of lung ACE, which reflects differences in the local conformations of these ACEs, likely controlled by different ACE glycosylation in these organs. Substrate specificity and pH-optima of the heart and lung ACEs also differed. Moreover, even within heart the apparent ACE activities, the local ACE conformations, and the content of ACE inhibitors differ in atria and ventricles. CONCLUSIONS: Significant differences in the local conformations and kinetic properties of heart and lung ACEs demonstrate tissue specificity of ACE and provide a structural base for the development of mAbs able to distinguish heart and lung ACEs as a potential blood test for predicting atrial fibrillation risk.

Lysozyme and bilirubin bind to ACE and regulate its conformation and shedding.

Angiotensin I-converting enzyme (ACE) hydrolyzes numerous peptides and is a critical participant in blood pressure regulation and vascular remodeling. Elevated tissue ACE levels are associated with increased risk for cardiovascular and respiratory disorders. Blood ACE concentrations are determined by proteolytic cleavage of ACE from the endothelial cell surface, a process that remains incompletely understood. In this study, we identified a novel ACE gene mutation (Arg532Trp substitution in the N domain of somatic ACE) that increases blood ACE activity 7-fold and interrogated the mechanism by which this mutation significantly increases blood ACE levels. We hypothesized that this ACE mutation disrupts the binding site for blood components which may stabilize ACE conformation and diminish ACE shedding. We identified the ACE-binding protein in the blood as lysozyme and also a Low Molecular Weight (LMW) ACE effector, bilirubin, which act in concert to regulate ACE conformation and thereby influence ACE shedding. These results provide mechanistic insight into the elevated blood level of ACE observed in patients on ACE inhibitor therapy and elevated blood lysozyme and ACE levels in sarcoidosis patients.

Noninvasive Predictors of Malignant Arrhythmias.

BACKGROUND: Prediction and potential prevention of sudden cardiac death (SCD) due to malignant ventricular arrhythmia (MVA) represent an obvious unmet medical need. We estimated the prognostic relevance of numerous biomarkers associated with future MVA development in patients with coronary artery disease (CAD) over 2 years of follow-up. METHODS: Patients with stable documented CAD (n = 97) with a mean age of 61 ± 10 years were prospectively enrolled in a single-center observational cohort study. Heart failure was diagnosed in 68% of the patients (NYHA class II-III). The mean left ventricular ejection fraction (LVEF) was 50 ± 13%, while 20% of patients had LVEF ≤35%. Sixty-two patients underwent myocardial revascularization during the follow-up (mean 25 ± 11 months). Clinical characteristics (age, gender, diabetes, history of coronary disease and arrhythmias, prior interventions and antecedent medications), noninvasive electrophysiological markers [microvolt T-wave alterations, signal-averaged electrocardiography, QT interval duration and alteration, and heart rate turbulence (HRT) and HR variability], laboratory indices [serum creatinine and creatinine clearance, brain natriuretic peptide (BNP), NT-proBNP, and C-reactive protein and troponin T levels] were assessed with regard to the MVA prognosis. RESULTS: MVA was diagnosed in 11 patients during the prospective follow-up. Prior percutaneous coronary intervention (p < 0.05), MVA or syncope (p < 0.05), on-pump coronary artery bypass grafting during follow-up (p < 0.01), LVEF ≤47% (p < 0.01), a left atrium size ≥4.7 cm (p < 0.05), left atrium index (p = 0.01), filtered QRS duration (p < 0.05), abnormal HRT (x03C7;2 = 6.2, p = 0.01) or turbulence slope (x03C7;2 = 9.5, p < 0.01), BNP ≥158 pg/ml (p < 0.01) and NT-proBNP ≥787 pg/ml (x03C7;2 = 4.4, p < 0.05) were significantly associated with MVA risk by univariate analysis. However, only prior MVA or syncope [odds ratio (OR) 11.1; 95% confidence interval (CI) 2.8-44.4; p < 0.01], abnormal HRT (x041E;R 13.6; 95% CI 2.8-66.1; p < 0.01) and plasma BNP (x041E;R 14.3; 95% CI 3.2-65.0; p < 0.01) remained independent predictors of MVA occurrence by multivariate Cox regression analysis. CONCLUSION: Prior syncope or MVA, HRT and elevated plasma BNP were independent MVA predictors, advocating for the prospective screening of high-risk CAD patients for potential SCD awareness.

Continued vorapaxar versus withdrawed clopidogrel both on top of low dose aspirin in patients undergoing heart surgery: A call for randomized trial.

Despite advanced techniques and improved clinical outcomes, the optimal antiplatelet strategy following coronary artery bypass grafting (CABG) is an unsolved mystery. Vorapaxar, a novel platelet thrombin receptor (PAR-1/4) blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We here summarize the outcomes in patients after CABG for justification of a future vorapaxar trial. We comprehended the CABG outcomes after vorapaxar yielded from TRACER, TRA2P trials, and affiliated FDA reviews. The verified evidence suggests that composite of death, myocardial infarction and stroke occurred in 2.2% of vorapaxar vs. 8.1% placebo in TRA2P. These data were similar to the endpoint differences (5.9% after vorapaxar vs. 8.3% for placebo) in TRACER. The mortality reduction also consistently suggests vorapaxar advantage (1.7% vs. 2.5% in TRA2P, and 1.7% vs. 3.9% in TRACER). Notably, the post-CABG bleeding risks after vorapaxar were only slightly, but not significantly higher. Moreover, the bleeding disadvantage in the experimental arm was most likely related to overtreatment since majority of patients in both TRACER and TRA2P received triple antiplatelet therapy with aspirin, clopidogrel on top of vorapaxar. Overall, the FDA-confirmed evidence advocate for the future vorapaxar post-CABG outcome-driven trial. The head-to-head trial testing dual therapy with continued over CABG vorapaxar versus withdrawed clopidogrel, both on top of low dose aspirin is warranted. We conclude that the primary outcomes including mortality were consistently better for heart surgery patients after vorapaxar, while the excess of bleeding was mild. Continuing vorapaxar during CABG may be superior to currently recommended withdrawal antiplatelet strategies, and should be tested in an adequately powered randomized outcome-driven trial.