Flow cytometry for comprehensive assessment of platelet functional activity in response to ADP stimulation.

OBJECTIVES: Flow cytometry with adenosine diphosphate (ADP) allows to characterize molecular changes of platelet function caused by this physiologically important activation, but the methodology has not been thoroughly investigated, standardized and characterized yet. We analyzed the influence of several major variables and chose optimal conditions for platelet function assessment. METHODS: For activation, 2.5 µM CaCl2 , 5 µM ADP and antibodies were added to diluted blood and incubated for 15 min. We analyzed kinetics of antibody binding and effects of their addition sequence, agonist concentration, blood dilution, exogenous calcium addition and platelet fixation. RESULTS: We tested our protocol on 11 healthy children, 22 healthy adult volunteers, 9 patients after a month on dual antiplatelet therapy after percutaneous coronary intervention (PCI), 7 adult patients and 14 children with immune thrombocytopenia (ITP). We found that our protocol is highly sensitive to ADP stimulation with low percentage of aggregates formation. The assay is also sensitive to platelet function inhibition in post-PCI patients. Finally, platelet preactivation with ITP plasma was stronger and caused increase in activation response to ADP stimulation compared to preactivation with low dose of ADP. CONCLUSIONS: Our assay is sensitive to antiplatelet therapy and platelet preactivation in ITP patients under physiological conditions with minimal percentage of aggregates formation.

A Retrospective Observational Real-Word Analysis of the Adherence, Healthcare Resource Consumption and Costs in Patients Treated with Bisoprolol/Perindopril as Single-Pill or Free Combination.

INTRODUCTION: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or free-equivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population. METHODS: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up. RESULTS: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC ≥ 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p < 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p < 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p < 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p < 0.001). CONCLUSION: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs.

Patients with cardiovascular conditions often need to take many pills. This may result in patients not taking their pills as prescribed (i.e., low adherence) and compromise the potential benefits derived from prescription of cardiovascular protective drugs. Simplifying treatment by combining drugs into a single pill can improve adherence and, consequently, patient outcomes. In this analysis using data from real clinical practice, we explored whether using a single pill of perindopril and bisoprolol is associated with higher levels of adherence, lower proportion of patients with hospitalizations and lower economic costs than using the same drugs prescribed as free-equivalent combination in a large sample of the Italian population of approximately 7 million people. We identified two groups of patients taking single pill or free-equivalent combination of perindopril and bisoprolol (4688 patients in each cohort). Over 1-year follow-up, patients taking single pill were more likely to be adherent and were less likely to stop taking their treatment. They also had fewer cardiovascular hospitalizations with shorter hospital admission and had lower healthcare direct costs. In conclusion, simplifying treatment by combining perindopril and bisoprolol in a single pill instead of two may have a positive effect on adherence, outcomes and healthcare costs already after 1 year.

Diabetic Cardiomyopathy: 2023 Update by the International Multidisciplinary Board of Experts.

Diabetes mellitus (DM) is considered by many the pandemic of the 21st century and is associated with multiple organ damages. Among these, cardiovascular complications are responsible for an incredible burden of mortality and morbidity in Western Countries. The study of the pathological mechanisms responsible for the cardiovascular complications in DM patients is key for the development of new therapeutic strategies. The metabolic disorders caused by hyperglycemia, insulin resistance, and dyslipidemia, results in a cascade of pathomorphological changes favoring the atherosclerotic process and leading to myocardial remodeling. Parallel to this, oxidative stress, calcium overload, mitochondrial dysfunction, activation of protein kinase C signaling pathways, myocardial lipomatosis, and low-grade inflammation of the myocardium - are the main pathways responsible for the diabetic cardiomyopathy development. This review aims to appraise and discuss the pathogenetic mechanisms behind the diabetic cardiomyopathy development.

Morbidity and mortality of acute heart failure patients stratified by mitral regurgitation in the Arabian Gulf: Observations from the Gulf acute heart failure registry (Gulf CARE).

This study aimed to evaluate the clinical outcomes of patients with acute heart failure (AHF) stratified by mitral regurgitation (MR) in the Arabian Gulf. Patients from the Gulf CARE registry were identified from 47 hospitals in seven Arabian Gulf countries (Yemen, Oman, Kuwait, Qatar, Bahrain, the United Arab Emirates, and Saudi Arabia) from February to November 2012. The cohort was stratified into two groups based on the presence of MR. Univariable and multivariable statistical analyses were performed. The population cohort included 5005 consecutive patients presenting with AHF, of whom 1491 (29.8 %) had concomitant MR. The mean age of patients with AHF and concomitant MR was 59.2 ± 14.9 years, and 63.1 % (n = 2886) were male. A total of 58.6 % (n = 2683) had heart failure (HF) with reduced ejection fraction (EF) (HFrEF), 21.0 % (n = 961) had HF with mildly reduced EF (HFmrEF), and 20.4 % (n = 932) had HF with preserved EF (HFpEF). Patients with MR had a lower haemoglobin (Hb) level (12.4 vs. 12.7 g/dL; p < 0.001), and a higher prevalence of left atrial enlargement (80.2 % vs. 55.1 %; p < 0.001), cardiogenic shock (9.7 % vs. 7.3 %; p = 0.006) and atrial fibrillation (7.6 % vs. 5.6 %; p = 0.006), and HFrEF (71.0 % vs. 52.6 %; P < 0.001). Multivariable analysis demonstrated that MR was independently associated with increased all-cause mortality at 1-year and 3-month HF rehospitalization [1-year all-cause mortality, adjusted odds ratio (aOR), 1.40; 95 % confidence interval (Cl): 1.13-1.74; p = 0.002; 3-month HF rehospitalization, aOR, 1.26; 95 % Cl: 1.06-1.49; p = 0.009]. In an Arabian Gulf cohort with AHF, concomitant MR was associated with an increased risk of 1-year mortality and 3-months HF rehospitalization.

Development and Validation of R-hf Risk Score in Acute Heart Failure Patients in the Middle East.

Objectives: The Rajan's heart failure (R-hf) score was proposed to aid risk stratification in heart failure patients. The aim of this study was to validate R-hf risk score in patients with acute decompensated heart failure. Methods: R-hf risk score is derived from the product estimated glomerular filtration rate (mL/min), left ventricular ejection fraction (%), and hemoglobin levels (g/dL) divided by N-terminal pro-brain natriuretic peptide (pg/mL). This was a multinational, multicenter, prospective registry of heart failure from seven countries in the Middle East. Univariable and multivariable logistic regression was applied. Results: A total of 776 patients (mean age = 62.0±14.0 years, 62.4% males; mean left ventricular ejection fraction = 33.0±14.0%) were included. Of these, 459 (59.1%) presented with acute decompensated chronic heart failure. The R-hf risk score group (≤ 5) was marginally associated with a higher risk of all-cause cumulative mortality at three months (adjusted odds ratio (aOR) = 4.28; 95% CI: 0.90-20.30; p =0.067) and significantly at 12 months (aOR = 3.84; 95% CI: 1.23-12.00; p =0.021) when compared to those with the highest R score group (≥ 50). Conclusions: Lower R-hf risk scores are associated with increased risk of all-cause cumulative mortality at three and 12 months.

Cardiac device-related infective endocarditis need for lead extraction whatever the device according to the ESC EORP EURO-ENDO registry.

Aims: Cardiac device-related infective endocarditis (CDRIE) is a severe complication of cardiac device (CD) implantation and is usually treated by antibiotic therapy and percutaneous device extraction. Few studies report the management and prognosis of CDRIE in real life. In particular, the rate of device extraction in clinical practice and the management of patients with left heart infective endocarditis (LHIE) and an apparently non-infected CD (LHIE+CDRIE-) are not well described. Methods and results: We sought to study in EURO-ENDO, the characteristics, prognosis, and management of 483 patients with a CD included in the European Society of Cardiology EurObservational Research Programme EURO-ENDO registry. Three populations were compared: 280 isolated CDRIE (66.7 ± 14.3 years), 157 patients with LHIE and an apparently non-infected CD (LHIE+CDRIE-) (71.1 ± 13.6), and 46 patients with both LHIE and CDRIE (LHIE+CDRIE+) (70.2 ± 10.1). Echocardiography was not always transoesophageal echography (TOE); it was transthoracic echography (TTE) for isolated CDRIE in 88.4% (TOE = 67.6%), for LHIE+CDRIE- TTE = 93.0% (TOE = 58.6%), and for CDRIE+LHIE+ TTE = 87.0% (TOE = 63.0%). Nuclear imaging was performed in 135 patients (positive for 75.6%). In-hospital mortality was lower in isolated CDRIE 13.2% vs. 22.3% and 30.4% for LHIE+CDRIE- and LHIE+CDRIE+ (P = 0004). Device extraction was performed in 62.1% patients with isolated CDRIE, 10.2% of LHIE+CDRIE- patients, and 45.7% of CDRIE+LHIE+ patients. Device extraction was associated with a better prognosis [hazard ratio 0.59 (0.40-0.87), P = 0.0068] even in the LHIE+CDRIE- group (P = 0.047). Conclusion: Prognosis of endocarditis in patients with a CD remains poor, particularly in the presence of an associated LHIE. Although recommended by guidelines, device extraction is not always performed. Device removal was associated with better prognosis, even in the LHIE+CDRIE- group.

HIV-Related Atherosclerosis: State-of-the-Art-Review.

The infection caused by the Human Immunodeficiency Virus (HIV) has spread rapidly across the globe, assuming the characteristics of an epidemic in some regions. Thanks to the introduction of antiretroviral therapy into routine clinical practice, there was a considerable breakthrough in the treatment of HIV, that is now HIV is potentially well-controlled even in low-income countries. To date, HIV infection has moved from the group of life-threatening conditions to the group of chronic and well controlled ones and the quality of life and life expectancy of HIV+ people, with an undetectable viral load is closer to that of an HIV- people. However, unsolved issues still persist. For example: people living with HIV are more prone to the age-related diseases, especially atherosclerosis. For this reason, a better understanding of the mechanisms of HIV-associated destabilization of vascular homeostasis seems to be an urgent duty, that may lead to the development of new protocols, bringing the possibilities of pathogenetic therapies to a new level. The purpose of the article was to evaluate the pathological aspects of HIV-induced atherosclerosis.

Effectiveness and Tolerability of Bisoprolol/Perindopril Single-Pill Combination in Patients with Arterial Hypertension and a History of Myocardial Infarction: The PRIDE Observational Study.

INTRODUCTION: This study assessed the real-life effectiveness of a single-pill combination (SPC) of bisoprolol/perindopril for controlling blood pressure (BP) and symptoms of angina in patients with hypertension and a history of myocardial infarction (MI). METHODS: Eligible patients with arterial hypertension and a history of MI were aged 18-79 years and had initiated bisoprolol/perindopril SPC within 3 months of study enrollment as part of routine Russian clinical practice. The primary endpoint was mean change in systolic and diastolic BP (SBP/DBP) at week 12 compared with baseline (data collected retrospectively). Secondary endpoints were assessed at weeks 4 and 12 and included mean change in resting heart rate (HR), proportion of patients reaching target level of resting HR, antianginal effectiveness of the SPC, and proportion of patients reaching target BP levels. RESULTS: A total of 504 patients were enrolled, of whom 481 comprised the full analysis set (mean age 61.4 ± 8.9 years, 68% men). Mean baseline SBP/DBP and HR values were 148.9 ± 16.8/87.7 ± 11.0 mmHg and 77.4 ± 10.5 bpm, respectively. Mean durations of hypertension and CAD were 12.8 ± 8.4 and 6.1 ± 6.3 years, respectively, and time since MI was 3.8 ± 5.3 years. At week 12, SBP/DBP had decreased by 24.9/12.2 mmHg (P < 0.001 vs baseline). Target BP (< 140/90 mmHg) was achieved by 69.8% and 95.9% of patients at weeks 4 and 12, respectively, and target HR (55-60 bpm) by 17.3% and 34.5% at weeks 4 and 12 versus 3.1% at baseline (P < 0.001). Reductions in angina attacks, nitrate consumption, and improvements in HR were statistically significant. Treatment was well tolerated. CONCLUSION: Treatment of symptomatic patients with CAD, hypertension, and a history of MI with a bisoprolol/perindopril SPC was associated with significant decreases in SBP/DBP and a high proportion of patients achieving BP treatment goals. This was accompanied by improvements in angina symptoms and reductions in HR in a broad patient population representative of those seen in everyday clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04656847.

Clinical Outcome and Risk Assessment in Hospitalized COVID-19 Patients with Elevated Transaminases and Acute Kidney Injury: A Single Center Study.

Objectives: Initial reports indicate a high incidence of abnormal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in patients with COVID-19 and possible association with acute kidney injury (AKI). We aimed to investigate clinical features of elevated transaminases on admission, its association with AKI, and outcomes in patients with COVID-19. Methods: A retrospective analysis of the registered data of hospitalized patients with laboratory-confirmed COVID-19 and assessment of the AST and ALT was performed. Multinomial logistic regression was used to determine factors associated with community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI). Results: The subjects comprised 828 patients (mean age = 65.0±16.0 years; 51.4% male). Hypertension was present in 70.3% of patients, diabetes mellitus in 26.0%, and chronic kidney disease in 8.5%. In-hospital mortality was 21.0%. At admission, only 41.5% of patients had hypertransaminasemia. Patients with elevated transaminases at admission were younger, had higher levels of inflammatory markers and D-dimer, and poorer outcomes. The AKI incidence in the study population was 27.1%. Patients with hypertransaminasemia were more likely to develop AKI (33.5% vs. 23.3%, p = 0.003). Patients with predominantly elevated AST (compared to elevated ALT) were more likely to have adverse outcomes. Multinomial logistic regression found that hypertension, chronic kidney disease, elevated AST, and hematuria were associated with CA-AKI. Meanwhile, age > 65 years, hypertension, malignancy, elevated AST, and hematuria were predictors of HA-AKI. Conclusions: Elevated transaminases on admission were associated with AKI and poor outcomes. Patients with elevated AST were more likely to have adverse outcomes. Elevated AST on admission was associated with CA-AKI and was a predictor of HA-AKI.

Validation of R-hf risk score for risk stratification in ischemic heart failure patients: A prospective cohort study.

Background: The aim of this study was to validate R-heart failure (R-hf) risk score in ischemic heart failure patients. Methods: We prospectively recruited a cohort of 179 ischemic and 107 non-ischemic heart failure patients. This study mainly focused on ischemic heart failure patients. Non-ischemic heart failure patients were included for the purpose of validation of the risk score in various heart failure groups. Patients were stratified in high risk, moderate risk and low risk groups according to R-hf risk score. Results: A total of 179 participants with ischemic heart failure were included. Based on R-hf risk score, 82 had high risk, 50 had moderate risk and 47 had low risk heart failure scores. More than half of the patients having R-hf score of <5 had renal failure (n = 91, 50.8%) and anemia (n = 99, 55.3%). Notably, HFrEF was more prevalent in patients with high risk score (74, 90.2%). Patients with high risk score had significantly higher creatinine (2.63 ± 1.96, p < 0.001), Troponin-T HS (59.9 ± 38.0, p < 0.001) and PRO BNP (17842 ± 6684, p < 0.001) when compared to patients with low and moderate risk score. Patients with low risk score had significantly higher Hb (13.2 ± 1.85, p < 0.001), Albumin (3.69 ± 0.42, p < 0.001) and GFR (90.0 ± 8.04, p < 0.001). A R-hf score of <5 was a significant predictor of mortality in ischemic (OR = 50.34; 95% CI [16.94-194.00, p < 0.001) and non-ischemic (OR = 46.34; 95% CI [12.97-225.39], p < 0.001) heart failure patients. Conclusions: Lower R-hf risk score is a significant predictor of mortality in ischemic and non-ischemic heart failure patients. Risk score can be accessed at https://www.hfriskcalc.in.

Hypercoagulation detected by routine and global laboratory hemostasis assays in patients with infective endocarditis.

BACKGROUND: Coagulation system is heavily involved into the process of infective endocarditis (IE) vegetation formation and can facilitate further embolization. In this study we aimed to assess the coagulation and platelet state in IE implementing a wide range of standard and global laboratory assays. We also aim to determine whether prothrombotic genetic polymorphisms play any role in embolization and mortality in IE patients. METHODS: 37 patients with IE were enrolled into the study. Coagulation was assessed using standard coagulation assays (activated partial thromboplastin time (APTT), prothrombin, fibrinogen, D-dimer concentrations) and integral assays (thromboelastography (TEG) and thrombodynamics (TD)). Platelet functional activity was estimated by flow cytometry. Single nuclear polymorphisms of coagulation system genes were studied. RESULTS: Fibrinogen concentration and fibrinogen-dependent parameters of TEG and TD were increased in patients indicating systemic inflammation. In majority of patients clot growth rate in thrombodynamics was significantly shifted towards hypercoagulation in consistency with D-dimers elevation. However, in some patients prothrombin, thromboelastography and thrombodynamics were shifted towards hypocoagulation. Resting platelets were characterized by glycoprotein IIb-IIIa activation and degranulation. In patients with fatal IE, we observed a significant decrease in fibrinogen and thrombodynamics. In patients with embolism, we observed a significant decrease in the TEG R parameter. No association of embolism or mortality with genetic polymorphisms was found in our cohort. CONCLUSIONS: Our findings suggest that coagulation in patients with infective endocarditis is characterized by general hypercoagulability and platelet pre-activation. Some patients, however, have hypocoagulant coagulation profile, which presumably can indicate progressing of hypercoagulation into consumption coagulopathy.

Cancer and Infective Endocarditis: Characteristics and Prognostic Impact.

Background: The interplay between cancer and IE has become of increasing interest. This study sought to assess the prevalence, baseline characteristics, management, and outcomes of IE cancer patients in the ESC EORP EURO-ENDO registry. Methods: Three thousand and eighty-five patients with IE were identified based on the ESC 2015 criteria. Three hundred and fifty-nine (11.6%) IE cancer patients were compared to 2,726 (88.4%) cancer-free IE patients. Results: In cancer patients, IE was mostly community-acquired (74.8%). The most frequently identified microorganisms were S. aureus (25.4%) and Enterococci (23.8%). The most frequent complications were acute renal failure (25.9%), embolic events (21.7%) and congestive heart failure (18.1%). Theoretical indication for cardiac surgery was not significantly different between groups (65.5 vs. 69.8%, P = 0.091), but was effectively less performed when indicated in IE patients with cancer (65.5 vs. 75.0%, P = 0.002). Compared to cancer-free IE patients, in-hospital and 1-year mortality occurred in 23.4 vs. 16.1%, P = 0.006, and 18.0 vs. 10.2%; P < 0.001, respectively. In IE cancer patients, predictors of mortality by multivariate analysis were creatinine > 2 mg/dL, congestive heart failure and unperformed cardiac surgery (when indicated). Conclusions: Cancer in IE patients is common and associated with a worse outcome. This large, observational cohort provides new insights concerning the contemporary profile, management, and clinical outcomes of IE cancer patients across a wide range of countries.

Development and validation of a model for predicting 18-month mortality in type 2 myocardial infarction.

BACKGROUND: Despite the poor prognosis in patients with type 2 myocardial infarction (MI), no prospective data on risk stratification exists. The aim of this study was to develop and validate a model for prediction of 18-month mortality of among patients with type 2 MI (T2MI) and compare its performance with GRACE and TARRACO scores. METHODS: The prospective observational study included 712 consecutive patients diagnosed with MI undergoing coronary angiography <24 h between January 2017 and December 2018. Diagnosis of T2MI was adjusted according to Third universal definition. A prognostic model was developed by using Bayesian approach and logistic regression analysis with identifying predictors for mortality. The model was validated by bootstrap validation. Comparison performance between scores using Delong test. RESULTS: T2MI was identified in 174 (24.4%) patients. The median age of patients was 69 years, 52% were female. The mortality rate was 20.1% at 18 months. Prior MI, presence of ST elevation, hemoglobin level at admission, Charlson comorbidity index and were independently associated with 18-month mortality. The model to predict 18-month mortality showed excellent discrimination (optimism corrected c-statistic = 0.822) and calibration (corrected slope = 0.893). GRACE and TARRACO scores had moderate discrimination [c-statistic = 0.748 (95% CI 0.652-0.843) and 0.741, 95% CI 0.669-0.805), respectively] and inferior compared with model (p = 0.043 and 0.037, respectively). CONCLUSIONS: The risk of mortality among T2MI patients could be accurately predicted by using common clinical characteristics and laboratory tests. Further studies are required with external validation of nomogram prior to clinical implementation.

Concordance and Prognostic Relevance of Angiographic and Clinical Definitions of Myocardial Infarction Type.

BACKGROUND: Atherothrombosis is the principal mechanism of type 1 (T1) myocardial infarction (MI), while type 2 (T2) MI is typically diagnosed in the presence of triggers (anemia, arrhythmia, etc.). We aimed to evaluate the proportions of T1 vs. T2 MI based on angiographic and clinical definitions, their concordance and prognosis. METHODS: Consecutive MI patients [n = 712, 61% male; age 64.6 ± 12.3 years] undergoing coronary angiography were classified according to the presence of atherothrombosis and identifiable triggers. Association of angiographic and clinical MI type criteria with adverse outcomes (Time follow-up was 1.5 years) was evaluated. Predictive ability of GRACE risk score for all-cause mortality was then assessed. RESULTS: Atherothrombosis and clinical triggers were identified in 397 (55.6%) and 324 (45.5%) subjects, respectively. Only 247 (34.7%) patients had "true" T1MI (atherothrombosis+ / triggers-); 174 (24.4%) were diagnosed with "true" T2MI (atherothrombosis- / triggers+), while 291 (40.9%) had discordant clinical and angiographic characteristics. All-cause mortality in T2MI (20.1%) patients was higher than in T1MI (9.3%), P = 0.002. Presence of triggers [odds ratio (OR) 2.4, 95% CI 1.5-3.6, P < 0.0001] but not atherothrombosis [OR 0.8, 95% confidence interval (CI) 0.5-1.3, P = 0.26] was associated with worse prognosis. GRACE score is a better predictor of death in T1MI vs. T2MI: area under curve 0.893 (95% CI 0.830-0.956) vs 0.748 (95% CI 0.652-0.843), P = 0.013. CONCLUSION: Angiographic and clinical definitions of MI type are discordant in a substantial proportion of patients. Clinical triggers are associated with all-cause mortality. Predictive performance of GRACE score is worse in T2MI patients.

PNPLA3 rs738409 associates with alcoholic liver cirrhosis but not with serum levels of IL6, IL10, IL8 or CCL2 in the Russian population.

INTRODUCTION AND AIM: Polymorphic variant rs738409 within the PNPLA3 gene associates with alcoholic liver cirrhosis (ALC) in heavy drinkers of various ancestry but has not yet been established in the Russian population characterized by high incidence of ALC. PNPLA3 rs738409 involvement in the inflammatory process has been proposed as one of the mechanisms of liver dysfunction. Relationship between the PNPLA3 polymorphism and the biochemical markers of inflammation in patients with ALC remains unclear. The current study revealed the association between the rs738409 polymorphism, liver cirrhosis and serum cytokines in heavy drinkers in the Russian population. MATERIALS AND METHODS: The serum levels of IL6, IL10, IL8, and CCL2 along with PNPLA3 rs738409 polymorphism were determined in heavy drinkers (AA, n=71) and heavy drinkers with diagnosed liver cirrhosis (ALC, n=110). All of the recruited individuals were Caucasians and belonged to the Russian population. RESULTS: Heavy drinkers carrying PNPLA3 rs738409 CG or CG+GG genotypes as compared with CC genotype carriers or G allele as compared with C allele carriers had significant risk of ALC. In ALC levels of interleukins and CCL2 increased as compared with AA. PNPLA3 rs738409 CC carriers had lower cirrhosis stage as compared with CG+GG carriers, however there were no differences of IL6, IL10, IL8 or CCL2 levels between G allele carriers and non-carriers in heavy drinkers. CONCLUSION: Thus, in the Russian population heavy drinkers carrying PNPLA3 rs738409 G allele are at higher risk of ALC, however the presence of rs738409 allele does not influence the serum cytokine levels.

Sodium-glucose cotransporter 2 inhibitors at the intersection of cardiovascular, renal and metabolic care: an integrated and multidisciplinary approach to patient-centered care.

PURPOSE OF REVIEW: The management of individuals who live with type 2 diabetes requires an integrated and multifaceted approach. RECENT FINDINGS: Sodium-glucose cotransporter 2 inhibitors effectively prevent and treat cardiorenal complications in the presence of type 2 diabetes. They also reduce death and disease progression in those with established heart failure (with reduced ejection fraction) in the absence of diabetes. SUMMARY: Close collaborations between primary care physicians, cardiovascular specialists, endocrinologists and nephrologists are necessary to optimize cardiovascular, renal and metabolic risk reduction in their shared patients.

Discordance between the Clinical Presentation and Morphology of Myocardial Infarction in a Patient with Acute Post-Hemorrhagic Anemia.

While atherosclerotic plaque disruption remains the hallmark of type 1 myocardial infarction (T1MI), multiple other mechanisms provoking myocardial supply/demand mismatch (eg, anemia and tachyarrhythmias) are recognized as the potential causes of type 2 myocardial infarction (T2MI). In clinical practice, angiography is underutilized in patients with MI that have typical T2MI triggers, although the presence of these triggers and various forms of atherosclerotic coronary artery disease is not mutually exclusive. We describe a 70-year-old man that developed MI during hospitalization for gastrointestinal bleeding. He was treated conservatively without angiography due to posthemorrhagic anemia, which is a recognized T2MI trigger, and subsequently developed refractory cardiogenic shock. Autopsy revealed atherothrombosis, which is characteristic of T1MI.

Phase II Study of Single/Repeated Doses of Acumapimod (BCT197) to Treat Acute Exacerbations of COPD.

Mitogen-activated protein kinase p38 is a key regulator in the inflammation pathway and is activated in the lungs of chronic obstructive pulmonary disease (COPD) patients. Acumapimod is a potent, selective, oral, p38 inhibitor under investigation for treatment of acute exacerbations of COPD (AECOPD). In this Phase II, double-blind, randomized, placebo-controlled dose-exploration study of acumapimod in patients with moderate or severe AECOPD (NCT01332097), patients presenting with AECOPD were randomized to receive single-dose acumapimod (20 mg or 75 mg) on Day 1, repeated single-dose acumapimod (20 mg or 75 mg) on Days 1 and 6, oral prednisone 40 mg (10 days), or placebo. Primary outcome: improvement in forced expiratory volume in 1 s (FEV1) versus placebo at Day 5 (single doses) and Day 10 (repeated doses). N = 183 patients were randomized; 169 (92%) patients completed the study. Although the primary endpoint (FEV1 at Day 10) was not met (p = 0.082), there was a significant improvement in FEV1 with acumapimod repeat-dose 75 mg versus placebo at Day 8 (p = 0.022) which, though not a prespecified endpoint, was part of an overall trend. Differences at lower doses did not achieve significance. Mean change in FEV1 AUC from baseline to Day 14 in the 75 mg repeat-dose group was significantly higher versus placebo (p = 0.02), prednisone (p = 0.01), and 20 mg single-dose groups (p = 0.015) (post-hoc analysis). EXACT-PRO showed numerical differences versus placebo that did not reach significance. Acumapimod was well tolerated. In conclusion, repeated single-dose acumapimod showed a clinically relevant improvement in FEV1 over placebo at Day 8, along with consistent numerical differences in EXACT-PRO. These data can be used to determine dose regimens for a proof-of-clinical-concept trial.