Diabetes Mellitus in Acute Coronary Syndrome.

The global prevalence of diabetes mellitus (DM) has led to a pandemic, with significant microvascular and macrovascular complications including coronary artery disease (CAD), which worsen clinical outcomes and cardiovascular prognosis. Patients with both acute coronary syndrome (ACS) and DM have worse prognosis and several pathophysiologic mechanisms have been implicated including, insulin resistance, hyperglycemia, endothelial dysfunction, platelet activation and aggregations as well as plaque characteristics and extent of coronary lesions. Therefore, regarding reperfusion strategies in the more complex anatomies coronary artery bypass surgery may be the preferred therapeutic strategy over percutaneous coronary intervention while both hyperglycemia and hypoglycemia should be avoided with closed monitoring of glycemic status during the acute phase of myocardial infraction. However, the best treatment strategy remains undefined. Non-insulin therapies, due to the low risk of hypoglycemia concurrently with the multifactorial CV protective effects, may be proved to be the best treatment option in the future. Nevertheless, evidence for the beneficial effects of glucagon like peptide-1 receptor agonists, dipeptidyl-peptidase 4 inhibitors and sodium glycose cotransporter 2 inhibitors, despite accumulating, is not robust and future randomized control trials may provide more definitive data.

Novel Biomarkers and Their Role in the Diagnosis and Prognosis of Acute Coronary Syndrome.

The burden of cardiovascular diseases and the critical role of acute coronary syndrome (ACS) in their progression underscore the need for effective diagnostic and prognostic tools. Biomarkers have emerged as crucial instruments for ACS diagnosis, risk stratification, and prognosis assessment. Among these, high-sensitivity troponin (hs-cTn) has revolutionized ACS diagnosis due to its superior sensitivity and negative predictive value. However, challenges regarding specificity, standardization, and interpretation persist. Beyond troponins, various biomarkers reflecting myocardial injury, neurohormonal activation, inflammation, thrombosis, and other pathways are being explored to refine ACS management. This review article comprehensively explores the landscape of clinically used biomarkers intricately involved in the pathophysiology, diagnosis, and prognosis of ACS (i.e., troponins, creatine kinase MB (CK-MB), B-type natriuretic peptides (BNP), copeptin, C-reactive protein (CRP), interleukin-6 (IL-6), d-dimers, fibrinogen), especially focusing on the prognostic role of natriuretic peptides and of inflammatory indices. Research data on novel biomarkers (i.e., endocan, galectin, soluble suppression of tumorigenicity (sST2), microRNAs (miRNAs), soluble oxidized low-density lipoprotein receptor-1 (sLOX-1), F2 isoprostanes, and growth differentiation factor 15 (GDF-15)) are further analyzed, aiming to shed light on the multiplicity of pathophysiologic mechanisms implicated in the evolution of ACS. By elucidating the complex interplay of these biomarkers in ACS pathophysiology, diagnosis, and outcomes, this review aims to enhance our understanding of the evolving trajectory and advancements in ACS management. However, further research is necessary to establish the clinical utility and integration of these biomarkers into routine practice to improve patient outcomes.

The Role of Ranolazine in Heart Failure-Current Concepts.

Heart failure is a complex clinical syndrome with a detrimental impact on mortality and morbidity. Energy substrate utilization and myocardial ion channel regulation have gained research interest especially after the introduction of sodium-glucose co-transporter 2 inhibitors in the treatment of heart failure. Ranolazine or N-(2,6-dimethylphenyl)-2-(4-[2-hydroxy-3-(2-methoxyphenoxy) propyl] piperazin-1-yl) acetamide hydrochloride is an active piperazine derivative which inhibits late sodium current thus minimizing calcium overload in the ischemic cardiomyocytes. Ranolazine also prevents fatty acid oxidation and favors glycose utilization ameliorating the "energy starvation" of the failing heart. Heart failure with preserved ejection fraction is characterized by diastolic impairment; according to the literature ranolazine could be beneficial in the management of increased left ventricular end-diastolic pressure, right ventricular systolic dysfunction and wall shear stress which is reflected by the high natriuretic peptides. Fewer data is evident regarding the effects of ranolazine in heart failure with reduced ejection fraction and mainly support the control of the sodium-calcium exchanger and function of sarcoendoplasmic reticulum calcium adenosine triphosphatase. Ranolazine's therapeutic mechanisms in myocardial ion channels and energy utilization are documented in patients with chronic coronary syndromes. Nevertheless, ranolazine might have a broader effect in the therapy of heart failure and further mechanistic research is required.

Lipoprotein-associated phospholipase A2 levels, endothelial dysfunction and arterial stiffness in patients with stable coronary artery disease.

BACKGROUND: Lipoprotein-associated Phospholipase A2 (Lp-PLA2), can exert proinflammatory as well as proatherogenic properties on the vascular wall. The current study sought to evaluate the influence of high Lp-PLA2 levels on indices of arterial wall properties in patients with stable coronary artery disease (CAD). METHODS: Three hundred seventy-four consecutive patients with stable CAD (mean age 61 ± 11 years, 89% males) were enrolled in this single-center cross-sectional study. Flow-mediated dilation (FMD) was used to assess endothelial function and augmentation index (AIx) of the central aortic pressure was used to assess reflected waves. ELISA was used to determine Lp-PLA2 serum levels. RESULTS: After dividing the participants in 3 equal groups based on the tertiles of circulating Lp-PLA2 values, no significant differences were demonstrated between those in the 3rd tertile with Lp-PLA2 values > 138 µg/L, in the 2nd tertile with Lp-PLA2 values between 101 and 138 µg/L and in the 1st tertile (Lp-PLA2 values < 101 µg/L) regarding age, male gender, smoking habits, family history of CAD or history of a previous myocardial infarction, diabetes mellitus, arterial hypertension, hyperlipidemia, duration of CAD and treatment with relevant medication. Importantly, subjects with Lp-PLA2 values in the highest tertile, had significantly reduced FMD values compared to the middle and lower tertile (4.43 ± 2.37% vs. 4.61 ± 1.97% vs. 5.20 ± 2.52% respectively, P = 0.03). Patients in the highest tertile of Lp-PLA2 values had significantly higher AIx values (24.65 ± 8.69% vs. 23.33 ± 9.65%, P = 0.03), in comparison to the lowest tertile, with Lp-PLA2 values < 101 µg/L. A linear regression analysis showed that Lp-PLA2 values > 138 µg/L negatively correlated to FMD [b = - 0.45 (95% CI: - 0.79 - -0.11), P = 0.01] and AIx values [b = 1.81 (95% CI: 0.57-3.05), P < 0.001] independently of cofounders like gender, age, diabetes mellitus, arterial hypertension, dyslipidemia, smoking habits, family history of CAD, history of previous myocardial infarction, serum glucose, circulating lipid levels, duration of CAD, antihypertensive medication, antidiabetic drugs, statin therapy and treatment with ß-blockers. CONCLUSIONS: Elevated Lp-PLA2 levels relate to endothelial dysfunction and arterial stiffness in patients with stable CAD independently from classical risk factors for CAD, statin use, antihypertensive treatment, and duration of the disease.

Meta-Analysis of Population Characteristics and Outcomes of Patients Undergoing Pericardiectomy for Constrictive Pericarditis.

We sought to systematically describe the epidemiology, etiology, clinical and operative characteristics as well as outcomes of patients who underwent pericardiectomy for constrictive pericarditis in the contemporary era. We conducted a systematic search of the MEDLINE, Embase, and Cochrane databases from their inception to April 1, 2020 for studies assessing the outcomes of pericardiectomy in patients with constrictive pericarditis. Studies with patients enrolled before 1985, pediatric patients or studies including >10% tuberculous pericarditis were excluded. The impact of pericarditis etiology on outcomes was evaluated with a meta-analysis. We analyzed 27 eligible studies and 2,114 patients. Etiology was most commonly idiopathic (50.2%), followed by after-cardiac surgery (26.2%) and radiation (6.9%). Patients were mostly men (76%), mean age 58 and with advanced symptoms (NYHA III/IV 70.1%). Total pericardiectomy was preferred (85.8%) and concomitant cardiac surgery was relatively common (23.8%). Operative mortality was 6.9% and 5-year mortality was 32.7%. Radiation and after-cardiac surgery patients had 3 and 2 times higher long-term risk for mortality respectively compared with idiopathic. A sensitivity analysis did not result in changes in the results. Thirty percent of included studies had more than low bias primarily originating from follow up and selection. Pericardiectomy is therefore performed mostly in middle-aged men with advanced symptoms and low co-morbidity burden and still caries significant operative mortality. Radiation and after-cardiac surgery patients have a significantly higher mortality risk compared with idiopathic. Several methodological issues and significant heterogeneity limit the generalization of these data and randomized controlled trials may have to be considered.

Association of Soluble Suppression of Tumorigenesis-2 (ST2) with Endothelial Function in Patients with Ischemic Heart Failure.

Soluble suppression of tumorigenesis-2 (sST2) has been introduced as a marker associated with heart failure (HF) pathophysiology and status. Endothelial dysfunction is a component underlying HF pathophysiology. Therefore, we examined the association of arterial wall properties with sST2 levels in patients with HF of ischemic etiology. We enrolled 143 patients with stable HF of ischemic etiology and reduced left ventricular ejection fraction (LVEF) and 77 control subjects. Flow-mediated dilation (FMD) was used to evaluate endothelial function and pulse wave velocity (PWV) to assess arterial stiffness. Although there was no significant difference in baseline demographic characteristics, levels of sST2 were increased in HF compared to the control (15.8 (11.0, 21.8) ng/mL vs. 12.5 (10.4, 16.3) ng/mL; p < 0.001). In the HF group, there was a positive correlation of sST2 levels with age (rho = 0.22; p = 0.007) while there was no association of LVEF with sST2 (rho = -0.119; p = 0.17) nor with PWV (rho = 0.1; p = 0.23). Interestingly, sST2 was increased in NYHA III [20.0 (12.3, 25.7) ng/mL] compared to patients with NYHA II (15.0 (10.4, 18.2) ng/mL; p = 0.003) and inversely associated with FMD (rho = -0.44; p < 0.001) even after adjustment for possible confounders. In patients with chronic HF of ischemic etiology, sST2 levels are increased and are associated with functional capacity. There is an inverse association between FMD and sST2 levels, highlighting the interplay between the dysfunctional endothelium and HF pathophysiologic mechanisms.

The Predictive Role for ST2 in Patients with Acute Coronary Syndromes and Heart Failure.

Intensive research has shed light on the utilization of novel biomarkers which facilitate the diagnosis and prognosis of patients with different medical problems. One of the most important biomarkers especially in the spectrum of heart failure is soluble ST2 (sST2: soluble Suppression of Tumorigenicity 2), which is involved in inflammation, fibrosis and cardiac stress. In the revised 2017 ACC/AHA/HFSA, "Focused Update Guidelines for the Management of Heart Failure" ST2 was given a class-IIa recommendation for the optimal risk assessment in patients with heart failure. Many studies indicate that not only baseline but also serial measurements of ST2 can accurately predict future cardiovascular events in patients with Acute Coronary Syndromes and heart failure. Therefore, in this review, we are going to discuss the studies about the prognostic significance of ST2 in patients with Acute Coronary Syndromes, acute and chronic heart failure.

Osteoprotegerin and Osteopontin Serum Levels are Associated with Vascular Function and Inflammation in Coronary Artery Disease Patients.

BACKGROUND: Osteoprotegerin and osteopontin have recently emerged as key factors in both vascular remodelling and atherosclerosis progression. Interleukin-6 (IL-6) is an inflammatory cytokine with a key role in atherosclerosis. The relationship of osteoprotegerin, osteopontin, and IL-6 serum levels with endothelial function and arterial stiffness was evaluated in patients with coronary artery disease (CAD). METHODS: We enrolled 219 patients with stable CAD and 112 control subjects. Osteoprotegerin, osteopontin and IL-6 serum levels were measured using an ELISA assay. Endothelial function was evaluated by flow-mediated dilation (FMD) in the brachial artery and carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. RESULTS: There was no significant difference between control subjects and CAD patients according to age and sex. Compared with control subjects, CAD patients had significantly impaired FMD (p<0.001) and increased PWV (p=0.009). CAD patients also had significantly higher levels of osteoprotegerin (p<0.001), osteopontin (p<0.001) and IL-6 (p=0.03), compared with control subjects. Moreover, IL-6 levels were correlated with osteoprotegerin (r=0.17, p=0.01) and osteopontin (r=0.30, p<0.001) levels. FMD was correlated with osteoprotegerin levels independent of possible confounders [b coefficient= - 0.79, 95% CI (-1.54, -0.05), p=0.04]. CONCLUSION: CAD patients have increased osteoprotegerin, osteopontin and IL-6 levels. Moreover, there is a consistent association between osteoprotegerin and osteopontin serum levels, vascular function and inflammation in CAD patients. These findings suggest another possible mechanism linking osteoprotegerin and osteopontin serum levels with CAD progression through arterial wall stiffening and inflammation.

Prognostic role of diastolic dysfunction in patients undergoing transcatheter aortic valve replacement.

OBJECTIVES: Prior studies have shown that left ventricular diastolic dysfunction (DD) is associated with increased mortality after surgical aortic valve replacement but studies on transcatheter aortic valve replacement (TAVR) are limited and have not taken into account mitral annular calcification (MAC), which limits the use of mitral valve annular tissue Doppler imaging. We performed a single-center retrospective analysis to better evaluate the role of baseline DD on outcomes after TAVR. METHODS: After excluding patients with atrial fibrillation, mitral valve prostheses and significant mitral stenosis, 359 consecutive TAVR patients were included in the study. Moderate-to-severe MAC was present in 58% of the patients. We classified patients into severe versus nonsevere DD based on the evaluation of elevated left ventricular filling pressure. The outcome measure was all-cause mortality or heart failure hospitalization. RESULTS: Over a mean follow-up time of 13 months, severe DD was associated with an increased risk for the outcome measure (HR 2.02 [1.23-3.30], p = .005). However, this association was lost in a propensity-matched cohort. In multivariate analysis, STS score was the only independent predictor of all cause mortality of heart failure hospitalization (HR 1.1 [1.05-1.15], p < .001). CONCLUSIONS: We evaluated the role of baseline DD on outcomes after TAVR by taking into account the presence of MAC. Severe DD was associated with increased all-cause mortality or heart failure hospitalization but not independently of other structural parameters and known predictors of the outcome measure.

Transfemoral transcatheter aortic valve replacement in the presence of a mitral prosthesis.

PURPOSE: In the current case series, we present our experience with the self-expanding CoreValve or Evolut R (Medtronic Inc.) in patients with severe symptomatic aortic valve stenosis and concomitant mitral valve prosthesis. METHODS: Twelve patients with previous mitral valve prosthesis underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and/or aortic valve regurgitation. All patients underwent evaluation with an echocardiogram, computed tomography and coronary angiogram. After the index intervention and before discharge all patients underwent transthoracic echocardiography. All outcomes were defined according to the Valve Academic Research Consortium-2 criteria. RESULTS: Eleven patients underwent transcatheter aortic valve replacement for severe symptomatic aortic valve stenosis and one patient for severe aortic valve regurgitation. There was immediate improvement of patients' hemodynamic status; no cases of procedural death, stroke, myocardial infarction, or urgent cardiac surgery occurred. There was no 30-day mortality and all patients improved, with 91.6% in functional New York Heart Association class I-II. CONCLUSION: The current study demonstrates that in patients with severe aortic valve stenosis or regurgitation and mitral valve prosthesis, the implantation of a self-expanding aortic valve via the transfemoral route is safe and feasible, with maintained long-term results.

Associations between Adiponectin Gene Variability, Proinflammatory and Angiogenetic Markers: Implications for Microvascular Disease Development in Type 2 Diabetes Mellitus?

BACKGROUND: Adiponectin gene (ADIPOQ) variability may affect the risk for type 2 diabetes mellitus (T2DM) but it remains unclear whether it is involved in microvascular complications. OBJECTIVE: To explore the impact of ADIPOQ variability on markers of inflammation and angiogenesis in T2DM. METHODS: Overall, 220 consecutive T2DM patients from our outpatient diabetic clinic were genotyped for G276T (rs1501299) and T45G (rs2241766) single nucleotide polymorphisms of ADIPOQ gene. Serum levels of interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1), vascular endothelial growth factor (VEGF) were measured by enzyme-linked immunosorbent assay and high sensitivity Creactive protein (hsCRP) by immunonephelometry. RESULTS: Homozygosity for the G allele on rs2241766 was associated with significantly lower serum VEGF and ICAM-1 levels compared with other genotype groups, but had no effect on IL-6. Genetic variability on rs1501299 was not associated with either VEGF or ICAM-1 levels, but T homozygotes for rs1501299 had significantly lower IL-6 concentrations compared with G carriers. Furthermore, the presence of the G allele on rs2241766 was associated with significantly lower HbA1c, whereas no associations were observed for both body mass index and hsCRP with either rs2241766 or rs1501299. CONCLUSION: Genetic variability on adiponectin gene was associated with serum levels of inflammatory and angiogenetic markers. Further research is required to elucidate the role of adiponectin in the development and/or progression of microvascular disease in T2DM patients.

Biomarkers Associated with Bleeding Risk in the Setting of Atrial Fibrillation.

BACKGROUND: Prevention of thromboembolic disease, mainly stroke, with oral anticoagulants remains a major therapeutic goal in patients with atrial fibrillation. Unfortunately, despite the high efficacy, anticoagulant therapy is associated with a significant risk of, frequently catastrophic, and hemorrhagic complications. Among different clinical and laboratory parameters related to an increased risk of bleeding, several biological markers have been recognized and various risk scores for bleeding have been developed. OBJECTIVES/METHODS: The aim of the present study is to review current evidence regarding the different biomarkers associated with raised bleeding risk in atrial fibrillation. RESULTS: Data originating from large cohorts or the recent large-scale trials of atrial fibrillation have linked numerous individual biomarkers to an increased bleeding risk. Such a relation was revealed for markers of cardiac physiology, such as troponin, BNP and NT-proBNP, markers of renal function, such as GFR and Cystatin or hepatic function, markers involving the system of coagulation, such as D-dimer and Von Willebrand factor, hematologic markers, such as low haemoglobin or low platelets, inflammatory markers, such as interleukin-6, other factors such as GDF-15 and vitamin-E and finally genetic polymorphisms. Many such biomarkers are incorporated in the bleeding risk schemata developed for the prediction of the hemorrhagic risk. CONCLUSIONS: Biomarkers were introduced in clinical practice in order to better estimate the potential risk of haemorrhage in these patients and increase the prognostic impact of clinical risk scores. In the last years this concept is gaining significant importance.

Management of Antithrombotic Therapy in Patients with Coronary Artery Disease or Atrial Fibrillation who Underwent Abdominal Surgical Operations.

BACKGROUND: Patients treated with antithrombotic therapy that require abdominal surgical procedures have progressively increased over time. The management of antithrombotics during both the peri- and postoperative period is of crucial importance. METHODS: The goal of this review is to present current data concerning the management of antiplatelets in patients with coronary artery disease and of anticoagulants in patients with atrial fibrillation who had to undergo abdominal surgical operations. For this purpose, the incidence of major adverse cardiovascular events (MACE) and risk of antithrombotic use during surgical procedures, as well as the recommendations based on recent guidelines were reported. A thorough search of PubMed, Scopus and the Cochrane Databases was conducted to identify randomized controlled trials, observational studies, novel current reviews, as well as ESC and ACC/AHA guidelines on the subject. RESULTS: Antithrombotic use in daily clinical practice leads to two different pathways: reduction of thromboembolic risk, but a simultaneous increase of bleeding risk. This may cause a therapeutic dilemma during the perioperative period. Nevertheless, careless cessation of antithrombotics can increase MACE and thromboembolic events. However, maintenance of antithrombotic therapy may increase bleeding complications. Studies and current guidelines can help clinicians in making decisions for the treatment of patients that undergo abdominal surgical operations while on antithrombotic therapy. Aspirin should not be stopped perioperatively in the majority of surgical operations. Determining whether to discontinue the use of anticoagulants before surgery depends on the surgical procedure. In surgical operations with a low risk for bleeding, oral anticoagulants should not be discontinued. Bridging therapy should only be considered in patients with a high risk of thromboembolism. Finally, in patients with an intermediate risk for thromboembolism, management should be individualized according to patient's thrombotic and bleeding risk. CONCLUSION: Management of antithrombotics therapy during the perioperative period in patients undergoing abdominal surgery should follow a patient-centered approach according to a patient's medical history and thrombotic risk weighted for bleeding risk.

Prognostic significance of arterial stiffness and osteoprotegerin in patients with stable coronary artery disease.

BACKGROUND: Arterial stiffness and vascular calcification significantly contribute to coronary atherosclerosis progression. The prognostic value of increased arterial stiffness and vascular calcification in subjects with stable coronary artery disease (CAD) after percutaneous coronary intervention(PCI) is currently under question. MATERIALS AND METHODS: We randomly enrolled 262 patients with stable CAD 1 month after successful PCI. Carotid-femoral pulse wave velocity (PWV) was measured as a well-established index of central aortic stiffness. Osteoprotegerin (OPG) plasma levels were measured as a biomarker of vascular calcification. Patients were followed up prospectively up to 52 months. The primary endpoint was the composite of death from cardiovascular causes, myocardial infarction, stroke or hospitalization for cardiovascular causes. RESULTS: During the follow-up period, 48 patients presented the primary composite endpoint. Subjects who presented the primary endpoint, compared to subjects free of cardiovascular events, had significantly increased PWV (9.45 ± 2.19 m/s vs 8.73 ± 2.07 m/s, P = .04) and OPG levels (4.21 ± 2.19 pmol/L vs 3.18 ± 1.74 pmol/L, P = .003). Survival analysis indicated that PWV predicted adverse cardiac events MACE (Hazard ratio = 1.29 95%CI: 1.07-1.57, P = .008) independently from confounders such as age, sex, smoking habits, ejection fraction, extent of coronary artery disease, hypertension and diabetes mellitus. Interestingly, for every increase in pulse wave velocity by 1 m/s, there is an anticipated increase in the risk of major adverse cardiovascular event (MACE) by 29%. CONCLUSIONS: These findings extend the current knowledge concerning the role of arterial stiffness as powerful biomarkers in cardiovascular disease. Measurement of PWV might have a role in ascertaining prognosis and managing treatment in patients with stable CAD after PCI.

Colchicine in Post-operative Atrial Fibrillation: A Review.

Post-operative atrial fibrillation (POAF) is a frequent entity increasing hospitalization duration, stroke and mortality. In the recent years, a few studies have sought to investigate the potential effect of colchicine in POAF prevention after cardiac surgery or catheter pulmonary vein isolation for AF. In the present review article, we intend to provide a synopsis of clinical practice guidelines, summarize and critically approach current evidence for or against colchicine as a means of POAF prevention.

Le "canceur des fumeurs" in 19th century: the contribution of the French surgeon Étienne-Frédéric Bouisson (1813-1884).

At the beginning of the 19th century, the alarming rise in tobacco consumption and its consequences in health preoccupied physicians. Several medical authors pointed out the harmful effects of smoking, enumerating related disorders. In 1821, the hygienist Alexandre Parent du Châtelet (1790-1835) and the chemist Félix d'Arcet (1814-1847), studied the effects of tobacco in health and concluded that it was a relatively healthy habit providing also a kind of immunity from contagious diseases. The tobacco controversy opened up and continued for almost 40 years. In 1861, the professor of surgery and politician Étienne-Frédéric Bouisson (1813-1884) in his work entitled: "Tribut à la chirurgie ou mémoires sur divers sujets de cette science" (Tribute to surgery or dissertations on various topics of this science) related for the first time tobacco consumption to oral cancer, applying medical statistics and analyzing meticulously all the available data.

Long-term endothelial dysfunction after trans-radial catheterization: A meta-analytic approach.

BACKGROUND: Following cardiac catheterization using radial artery (RA) access, persistent endothelial dysfunction may limit the use of RA as a conduit during coronary artery bypass graft (CABG) surgery. We reviewed published literature to investigate the effects of transradial coronary catheterization on RA endothelial function. METHODS: We searched PubMed from inception to April 2017 for published studies assessing RA endothelial function late (≥1 month) after coronary catheterization. A total of 12 eligible published studies (n = 490 patients) were included in the final quantitative synthesis. Statistical heterogeneity among studies was assessed by the I2 . A random effects model was used to calculate the pooled estimate for standardized mean difference (SMD). Meta-regression analysis was used to explore predictors of change in RA endothelial function following catheterization. RESULTS: In all studies, a significant reduction in endothelium dependent response was observed post-catheterization (SMD = -0.53, 95% confidence interval [CI]: -0.93 to -0.13, P = 0.01) and a marginal, non-significant, reduction in endothelium independent response (SMD = -0.38, 95%CI: -0.77, 0.01, P < 0.059). In controlled studies, using the contralateral RA as a control, a significant impairment in endothelial function was confirmed (SMD = -6.26, 95%CI: -9.71 to -2.81, P < 0.0001), while the change in endothelium-independent response was not significant (SMD = -4.46, 95%CI: -13.3 to 4.37, P = 0.32). In meta-regression analysis male gender (z = 2.36, P = 0.018) and increasing time following catheterization (z = 2.62, P = 0.009) were associated with less RA endothelial dysfunction. CONCLUSIONS: Transradial catheterization impairs endothelium dependent vasodilatory properties of the cannulated RA, which do not recover even several months post-catheterization. Non-recovery of vasomotor function of cannulated RAs may limit their use as arterial grafts during CABG surgery.

Remote Ischemic Conditioning and Renal Protection.

Over the course of the last 2 decades, the concept of remote ischemic conditioning (RIC) has attracted considerable research interest, because RIC, in most of its embodiments offers an inexpensive way of protecting tissues against ischemic damage inflicted by a number of medical conditions or procedures. Acute kidney injury (AKI) is a common side effect in the context of various medical procedures, and RIC has been suggested as a means of reducing its incidence. Outcomes regarding kidney function have been reported in numerous studies that evaluated the effects of RIC in a variety of settings (eg, cardiac surgery, interventions requiring intravenous administration of contrast media). Although several individual studies have implied a beneficial effect of RIC in preserving kidney function, 3 recently published randomized controlled trials evaluating more than 1000 patients each (Effect of Remote Ischemic Preconditioning in the Cardiac Surgery, Remote Ischaemic Preconditioning for Heart Surgery, and ERICCA) were negative. However, AKI or any other index of renal function was not a stand-alone primary end point in any of these trials. On the other hand, a range of meta-analyses (each including thousands of participants) have reported mixed results, with the most recent among them showing benefit from RIC, pinpointing at the same time a number of shortcomings in published studies, adversely affecting the quality of available data. The present review provides a critical appraisal of the current state of this field of research. It is the opinion of the authors of this review that there is a clear need for a common clinical trial framework for ischemic conditioning studies. If the current babel of definitions, procedures, outcomes, and goals persists, it is most likely that soon ischemic conditioning will be "yesterday's news" with no definitive conclusions having been reached in terms of its real clinical utility.

Genotyping, Platelet Activation, and Cardiovascular Outcome in Patients after Percutaneous Coronary Intervention: Two Pieces of the Puzzle of Clopidogrel Resistance.

OBJECTIVES: Individual platelet responses to antiplatelet therapy depend on genetic, cellular, and clinical factors. CYP2C19 and P2Y12 receptor polymorphisms are implicated in platelet responses to antiplatelet treatment. We aimed to evaluate the impact of CYP2C19 and C34T P2Y12 genotyping on platelet reactivity and cardiovascular outcome in patients after percutaneous coronary intervention (PCI) on clopidogrel treatment. METHODS: We enrolled 408 patients with stable coronary artery disease (CAD) receiving aspirin and clopidogrel (75 mg/day) 1 month after PCI. High on-treatment platelet reactivity was evaluated using the VerifyNow Assay in a subset of patients. CYP2C19*2 and C34T P2Y12 genotyping was performed by real-time polymerase chain reaction. The primary end point was the composite of death or hospitalization for cardiovascular causes, and patients were followed for a median time of 13 months. RESULTS: In the total study population, 37% were carriers of at least 1 CYP2C19*2 loss-of-function allele, and 53% were carriers of at least 1 C34T loss-of-function allele. Interestingly, homozygotes of the CYP2C19*2 loss-of-function allele had significantly increased P2Y12 reaction units (PRU) (p = 0.007). However, PRU did not differ between carriers and noncarriers of the C34T loss-of-function allele (p = 0.41). Moreover, carriers of CYP2C19*2 had an increased hazard ratio (HR) for the occurrence of the primary end point (for carriers HR = 1.96, 95% CI 1.05-3.66, p = 0.03), whereas the C34T polymorphism had no impact on the cardiovascular outcome (p = 0.17). Finally, PRU was associated with cardiovascular outcome even after adjustment for the presence of any reduced function allele polymorphism. CONCLUSIONS: We documented a different effect of CYP2C19 and P2Y12 receptor polymorphisms on platelet reactivity and cardiovascular outcome in CAD patients after PCI on clopidogrel treatment. Importantly, increased platelet reactivity adversely affects the cardiovascular outcome independently of the studied polymorphisms.