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.

Tissue Specificity of Human Angiotensin I-Converting Enzyme.

BACKGROUND: Angiotensin-converting enzyme (ACE), which metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling, as well as in reproductive functions, is expressed as a type-1 membrane glycoprotein on the surface of endothelial and epithelial cells. ACE also presents as a soluble form in biological fluids, among which seminal fluid being the richest in ACE content - 50-fold more than that in blood. METHODS/PRINCIPAL FINDINGS: We performed conformational fingerprinting of lung and seminal fluid ACEs using a set of monoclonal antibodies (mAbs) to 17 epitopes of human ACE and determined the effects of potential ACE-binding partners on mAbs binding to these two different ACEs. Patterns of mAbs binding to ACEs from lung and from seminal fluid dramatically differed, which reflects difference in the local conformations of these ACEs, likely due to different patterns of ACE glycosylation in the lung endothelial cells and epithelial cells of epididymis/prostate (source of seminal fluid ACE), confirmed by mass-spectrometry of ACEs tryptic digests. CONCLUSIONS: Dramatic differences in the local conformations of seminal fluid and lung ACEs, as well as the effects of ACE-binding partners on mAbs binding to these ACEs, suggest different regulation of ACE functions and shedding from epithelial cells in epididymis and prostate and endothelial cells of lung capillaries. The differences in local conformation of ACE could be the base for the generation of mAbs distingushing tissue-specific ACEs.

Independent Predictors of Major Adverse Events following Coronary Stenting over 28 Months of Follow-Up.

BACKGROUND: Despite recent advances in stent design and constantly improving protective pharmacological strategies, complications and adverse events following percutaneous coronary interventions (PCI) are still major factors influencing morbidity and mortality. Therefore, predicting secondary vascular occlusions represents an unmet medical need. OBJECTIVE: The aim of our study was to triage clinical and laboratory predictors of major adverse clinical events (MACE) following coronary stenting. METHODS: This was a prospective, case-controlled, single-center study, which included 94 consecutive patients with documented coronary disease who underwent PCI with drug-eluting stent (DES) implantation. All patients received dual antiplatelet therapy with aspirin and clopidogrel. Numerous clinical characteristics and laboratory biomarkers were assessed before stenting and were correlated with poststenting MACE over the mean follow-up of 28 months. MACE included death, nonfatal myocardial infarction, target vessel revascularisation, stroke, stent thrombosis, angina recurrence and instent restenosis. RESULTS: Twenty-three patients experienced MACE. Independent MACE predictors after PCI with DES implantation were antecedent diabetes mellitus (RR = 0.45; 95% CI 0.20-0.97; p = 0.045), prior thrombolytic therapy (RR = 0.42; 95% CI 0.27-0.83; p = 0.039), baseline plasminogen activator inhibitor -1 (PAI-1; p = 0.008) and plasma von Willebrand factor (vWF) activity (p = 0.007). Other clinical characteristics and laboratory indices showed no correlation with MACE. CONCLUSIONS: Background diabetes mellitus, prior thrombolytic therapy, PAI-1 and vWF prestenting activity may be useful for MACE prediction over 28 months of follow-up.

The Dual Antiplatelet Therapy Trial after the FDA Update: Noncardiovascular Deaths, Cancer and Optimal Treatment Duration.

BACKGROUND: The landmark Dual Antiplatelet Therapy (DAPT) trial revealed an impressive reduction of stent thrombosis and myocardial infarction after prolonged 30-month DAPT compared to the conventional 12-month regimen. However, aside from the expected extra bleeding risks, more cancers and noncardiovascular deaths (NCVD) were observed in the 30-month DAPT arm. OBJECTIVE: We aimed to comprehend the totality of DAPT trial evidence in the light of the FDA medical review. RESULTS: A significant excess of solid cancers that was picked up after prasugrel treatment in the TRITON trial (Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes) and later observed with vorapaxar treatment in the TRACER trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) has now been confirmed by the FDA DAPT review for 30-month therapy with prasugrel [hazard ratio (HR) 1.3] and clopidogrel (HR 1.2). The latest randomized evidence with antiplatelet agents rejected the drug-specific cancer risks, clearly indicating the class effect. The NCVD risks were elevated after treatment with both thienopyridines, but were more prominent after clopidogrel treatment (HR 1.91) than prasugrel treatment (HR 1.17). About half of the NCVD were considered to be caused by cancers occurring after the 24 months of extended antiplatelet therapy. Impression: The DAPT trial confirmed that long-term antiplatelet therapy is associated with cancer that contributes to NCVD. Based on the full disclosure of cancer data by the DAPT study, it can be reflected that the optimal duration of antiplatelet therapy with thienopyridines should be limited to no more than 2 years. This duration allows the preservation of most vascular benefits while avoiding additional cancers and NCVD. © 2015 S. Karger AG, Basel.

Clopidogrel response variability: impact of genetic polymorphism and platelet biomarkers for predicting adverse outcomes poststenting.

The aim of this study was to triage platelet reactivity and adverse vascular outcomes after dual antiplatelet therapy due to percutaneous coronary intervention (PCI) dependent on CYP2C19*2 and CYP2C19*3 genotypes in patients with coronary artery disease. Fifty-five patients with coronary artery disease were studied serially pre-PCI and post-PCI. Platelet reactivity was assessed by conventional light transmission aggregometry, VerifyNow Analyzer, and thromboelastography with platelet mapping. Genetic testing was performed with allele-specific real-time polymerase chain reaction. Adverse events included vascular death, acute myocardial infarction, repeated PCI, definite stent thrombosis, and angina recurrence. The common genotype (GG) was found in 39 patients, heterozygous polymorphism CYP2C19 (GA) G681A allele was detected in 14 patients, and the rare homozygous polymorphism CYP2C19 (AA) G681A allele was exhibited in 2 patients. There were no CYP2C19*3 (Trp212Ter) carriers among index patients. The platelet reactivity was higher in patients with heterozygous and homozygous carriers compared with GG genotype. The largest differences were observed among GG, GA, and AA genotypes, which correlated with the average values of platelet aggregation (P = 0.02). There was a significant link between adverse events and high platelet reactivity assessed by light transmission aggregometry (P = 0.002). We found a trend between different genotype and VerifyNow readings (P = 0.057); moreover, their cumulative impact on adverse events was significant (P = 0.041). Platelet reactivity is higher in patients with heterozygous and homozygous carriers of CYP2C19*2 versus common genotype and may predict an increased risk of clopidogrel response variability and/or experiencing adverse cardiac events.

Switching from generic to brand clopidogrel in male patients after ST-elevated myocardial infarction.

OBJECTIVE: To detect residual platelet aggregation following the switch from generic (GC) to brand clopidogrel (BC) in male patients after ST-elevated myocardial infarction (STEMI). METHODS: The study was designed as an open-label, prospective cohort trial. Thirty-three male STEMI patients were enrolled. All patients received dual antiplatelet therapy with aspirin (100 mg/daily) and one of six GC at a daily dose of 75 mg. After 2 weeks, all patients were switched to BC. Adrenaline- and adenosine diphosphate (ADP)-induced platelet aggregation was assessed twice: on day 14 (before the switch) and on day 21 (after 1 week of BC therapy). RESULTS: Adrenaline-induced platelet aggregation did not differ among clopidogrel formulations. In contrast, residual 5 µM ADP-induced platelet aggregation after BC differs from GC by 14% (28.0 ± 2.5 vs. 23.9 ± 2.1%; p = 0.03). When 20 µM ADP was used as agonist, the difference was smaller (36.2 ± 2.9 vs. 34.6 ± 2.8%) but still significant (p = 0.04) favoring BC. CONCLUSIONS: After 2 weeks of therapy, switching from GC to BC was associated with a mild but significant reduction in ADP-induced platelet aggregation in male post-STEMI patients. The observed differences between GC and BC should be confirmed in a larger randomized study, but may represent a risk in underdeveloped countries, where GC therapy is mandatory for post-MI inpatients.

Cognitive dysfunction after on-pump operations: neuropsychological characteristics and optimal core battery of tests.

Postoperative cognitive dysfunction (POCD) is a mild form of perioperative ischemic brain injury, which emerges as memory decline, decreased attention, and decreased concentration during several months, or even years, after surgery. Here we present results of our three neuropsychological studies, which overall included 145 patients after on-pump operations. We found that the auditory memory span test (digit span) was more effective as a tool for registration of POCD, in comparison with the word-list learning and story-learning tests. Nonverbal memory or visuoconstruction tests were sensitive to POCD in patients after intraoperative opening of cardiac chambers with increased cerebral air embolism. Psychomotor speed tests (digit symbol, or TMT A) registered POCD, which was characteristic for elderly atherosclerotic patients. Finally, we observed that there were significant effects of the order of position of a test on the performance on this test. For example, the postoperative performance on the core tests (digit span and digit symbol) showed minimal impairment when either of these tests was administered at the beginning of testing. Overall, our data shows that the selection of tests, and the order of which these tests are administered, may considerably influence the results of studies of POCD.

Electroencephalography as a tool for assessment of brain ischemic alterations after open heart operations.

Cardiac surgery is commonly associated with brain ischemia. Few studies addressed brain electric activity changes after on-pump operations. Eyes closed EEG was performed in 22 patients (mean age: 45.2 ± 11.2) before and two weeks after valve replacement. Spouses of patients were invited to participate as controls. Generalized increase of beta power most prominent in beta-1 band was an unambiguous pathological sign of postoperative cortex dysfunction, probably, manifesting due to gamma-activity slowing ("beta buzz" symptom). Generalized postoperative increase of delta-1 mean frequency along with increase of slow-wave activity in right posterior region may be hypothesized to be a consequence of intraoperative ischemia as well. At the same time, significant changes of alpha activity were observed in both patient and control groups, and, therefore, may be considered as physiological. Unexpectedly, controls showed prominent increase of electric activity in left temporal region whereas patients were deficient in left hemisphere activity in comparison with controls at postoperative followup. Further research is needed in order to determine the true neurological meaning of the EEG findings after on-pump operations.

Size of left cardiac chambers correlates with cerebral microembolic load in open heart operations.

Background. Microemboli are a widely recognized etiological factor of cerebral complications in cardiac surgery patients. The present study was aimed to determine if size of left cardiac chambers relates to cerebral microembolic load in open heart operations. Methods. Thirty patients participated in the study. Echocardiography was performed in 2-3 days before surgery. A transcranial Doppler system was used for registering intraoperative microemboli. Results. Preoperative left atrium and left ventricular end-systolic and end-diastolic sizes significantly correlated with intraoperative microembolic load (rs = 0.48, 0.57 and 0.53, Ps < .01, resp.). The associations between left ventricular diameters and number of cerebral microemboli remained significant when cardiopulmonary bypass time was included as a covariate into the analysis. Conclusions. The present results demonstrate that increased size of left heart chambers is an influential risk factor for elevated cerebral microembolic load during open heart operations. Mini-invasive surgery and carbon dioxide insufflation into wound cavity may be considered as neuroprotective approaches in patients with high risk of cerebral microembolism.

Alexithymia, depression and heart rate in candidates for cardiac surgery.

Effects of psychological traits on heart rate (HR) and heart rate variability (HRV) were evaluated in patients awaiting cardiac surgery. Alexithymics demonstrated slowed HR, whereas high cognitive performance was associated with elevated HR in 2-3 days before surgery. Depression negatively correlated with HRV low frequency power. These data are consistent with previous findings of diverse moderate stress effects on HR regulation in cardiologic patients and healthy subjects in accordance to differences in psychological characteristics.

Asymmetric cerebral embolic load and postoperative cognitive dysfunction in cardiac surgery.

BACKGROUND: The aim of the study was to determine the effects of asymmetric cerebral embolic load on cognitive functions. METHODS: Thirty-six open heart surgery (OH) and 26 coronary artery bypass grafting (CABG) patients were evaluated by neuropsychological and transcranial Doppler tests. RESULTS: OH was associated with a significantly larger microembolic load in comparison to CABG. In OH patients, the microembolic load at the left middle cerebral artery correlated with a verbal memory decline, whereas the microembolic load at the right middle cerebral artery correlated with a nonverbal memory deficit. CABG patients also showed a postoperative verbal memory decline which correlated with cardiopulmonary bypass length but not with microembolic load. CONCLUSION: Massive microembolic load during OH induces specific cognitive impairment in accordance to the brain region to which they are delivered. In atherosclerotic patients, the left temporal region is especially prone to perioperative ischemia.

Neural correlates of cognitive dysfunction after cardiac surgery.

Patients who underwent cardiac surgery and their relatives often complain on postoperative memory impairment. Most prospective neuropsychological studies also found postoperative cognitive decline early after surgery. Nevertheless, recently several reports questioned the existence of long-term brain alterations in these patient cohorts. The present review was aimed to clear up the true cardiac surgery effects on brain and cognitive functions. The reviewed data evidence that cardiac surgery interventions induce persistent localized brain ischemic lesions along with rapidly reversing global brain swelling and decreased metabolism. A range of studies showed that left temporal region was especially prone to perioperative ischemic injury, and these findings might explain persistent verbal short-term memory decline in a considerable proportion of cardiac surgery patient cohorts. Speed/time of cognitive performance is commonly decreased early after on-pump surgery either. Nevertheless, no association between psychomotor speed slowing and intraoperative embolic load was found. The rapid recovery of the latter cognitive domain might be better explained by surgery related acute global brain metabolism changes rather than ischemic injury effects. Hence, analyses of performance on separate cognitive tests rather than summarized cognitive indexes are strongly recommended for future neuropsychological studies of cardiac surgery outcomes.