One-Year Outcomes in Anticoagulated Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention: Insights From the Greek Antiplatelet Atrial Fibrillation Registry.

ABSTRACT: GReek-AntiPlatElet Atrial Fibrillation registry is a multicenter, observational, noninterventional study of atrial fibrillation patients undergoing percutaneous coronary intervention. Primary endpoint included clinically significant bleeding rate at 12 months between different antithrombotic regimens prescribed at discharge; secondary endpoints included major adverse cardiovascular events and net adverse clinical events. A total of 647 patients were analyzed. Most (92.9%) were discharged on novel oral anticoagulants with only 7.1% receiving the vitamin K antagonist. A little over half of patients (50.4%) received triple antithrombotic therapy (TAT)-mostly (62.9%) for ≤1 month-whereas the rest (49.6%) received dual antithrombotic therapy (DAT). Clinically significant bleeding risk was similar between TAT and DAT [Hazard ratio (HR) = 1.08; 95% confidence interval (CI), 0.66-1.78], although among TAT-receiving patients, the risk was lower in those receiving TAT for ≤1 month (HR = 0.50; 95% CI, 0.25-0.99). Anticoagulant choice (novel oral anticoagulant vs. vitamin K antagonist) did not significantly affect bleeding rates ( P = 0.258). Age, heart failure, leukemia/myelodysplasia, and acute coronary syndrome were associated with increased bleeding rates. Risk of major adverse cardiovascular events and net adverse clinical events was similar between ΤAT and DAT (HR = 1.73; 95% CI, 0.95-3.18, P = 0.075 and HR = 1.39; 95% CI, 0.93-2.08, P = 0.106, respectively). In conclusion, clinically significant bleeding and ischemic rates were similar between DAT and TAT, although TAT >1 month was associated with higher bleeding risk.

Stem cell genes in atheromatosis: The role of Klotho, HIF1α, OCT4, and BMP4.

During fetal development, shear stress regulates several aspects of vascular development. Alterations in signaling pathways due to disturbed flow in atheroprone regions closely mirror phenomena seen during embryogenesis. This flow-dependent dysregulation of developmental genes appears to promote atherogenesis by mediating inflammatory phenomena, cell cycle progression, apoptosis, cell migration, and oxidative stress. Indeed, several stem cell genes have been implicated in vascular health and atheromatosis. Klotho is key in maintaining endothelial integrity, reducing oxidative stress, and sustaining endothelial nitric oxide production. In atherosclerotic lesions, OCT4 mediates the conversion of vascular smooth muscle cells from contractile to a de-dedifferentiated proliferative phenotype with phagocytic ability. HIF1α drives atherosclerotic plaque progression by promoting intraplaque angiogenesis. BMP4 promotes osteochondrogenic development and arterial calcification. Strategic extracellular matrix changes are also seen during the various phases of atherosclerosis. The aforementioned conceptual framework explains how proatherogenic inflammation develops in response to low shear stress. In the present review, we explored the effect of cardinal atheroprotective (Klotho, OCT4) and proatherogenic (HIF1α, BMP4) genes in mediating proatherogenic inflammation.

Angiotensin receptor-neprilysin inhibition in patients with acute decompensated heart failure: an expert consensus position paper.

The short-term mortality and rehospitalization rates after admission for acute heart failure (AHF) remain high, despite the high level of adherence to contemporary practice guidelines. Observational data from non-randomized studies in AHF strongly support the in-hospital administration of oral evidence-based modifying chronic heart failure (HF) medications (i.e., b-blockers, ACE inhibitors, mineralocorticoid receptor antagonists) to reduce morbidity and mortality. Interestingly, a well-designed prospective randomized multicenter study (PIONEER-HF) showed an improved clinical outcome and stress/injury biomarker profile after in-hospital administration of sacubitril/valsartan (sac/val) as compared to enalapril, in hemodynamically stable patients with AHF. However, sac/val implementation during hospitalization remains suboptimal due to the lack of an integrated individualized plan or well-defined appropriateness criteria for transition to oral therapies, an absence of specific guidelines regarding dose selection and the up-titration process, and uncertainty regarding patient eligibility.In the present expert consensus position paper, clinical practical recommendations are proposed, together with an action plan algorithm, to encourage and facilitate sac/val administration during hospitalization after an AHF episode with the aim of improving efficiencies of care and resource utilization.

Lysed Erythrocyte Membranes Promote Vascular Calcification.

BACKGROUND: Intraplaque hemorrhage promotes atherosclerosis progression, and erythrocytes may contribute to this process. In this study we examined the effects of red blood cells on smooth muscle cell mineralization and vascular calcification and the possible mechanisms involved. METHODS: Erythrocytes were isolated from human and murine whole blood. Intact and lysed erythrocytes and their membrane fraction or specific erythrocyte components were examined in vitro using diverse calcification assays, ex vivo by using the murine aortic ring calcification model, and in vivo after murine erythrocyte membrane injection into neointimal lesions of hypercholesterolemic apolipoprotein E-deficient mice. Vascular tissues (aortic valves, atherosclerotic carotid artery specimens, abdominal aortic aneurysms) were obtained from patients undergoing surgery. RESULTS: The membrane fraction of lysed, but not intact human erythrocytes promoted mineralization of human arterial smooth muscle cells in culture, as shown by Alizarin red and van Kossa stain and increased alkaline phosphatase activity, and by increased expression of osteoblast-specific transcription factors (eg, runt-related transcription factor 2, osterix) and differentiation markers (eg, osteopontin, osteocalcin, and osterix). Erythrocyte membranes dose-dependently enhanced calcification in murine aortic rings, and extravasated CD235a-positive erythrocytes or Perl iron-positive signals colocalized with calcified areas or osteoblast-like cells in human vascular lesions. Mechanistically, the osteoinductive activity of lysed erythrocytes was localized to their membrane fraction, did not involve membrane lipids, heme, or iron, and was enhanced after removal of the nitric oxide (NO) scavenger hemoglobin. Lysed erythrocyte membranes enhanced calcification to a similar extent as the NO donor diethylenetriamine-NO, and their osteoinductive effects could be further augmented by arginase-1 inhibition (indirectly increasing NO bioavailability). However, the osteoinductive effects of erythrocyte membranes were reduced in human arterial smooth muscle cells treated with the NO scavenger 2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide or following inhibition of NO synthase or the NO receptor soluble guanylate cyclase. Erythrocytes isolated from endothelial NO synthase-deficient mice exhibited a reduced potency to promote calcification in the aortic ring assay and after injection into murine vascular lesions. CONCLUSIONS: Our findings in cells, genetically modified mice, and human vascular specimens suggest that intraplaque hemorrhage with erythrocyte extravasation and lysis promotes osteoblastic differentiation of smooth muscle cells and vascular lesion calcification, and also support a role for erythrocyte-derived NO.

Angiotensin Receptor Neprilysin Inhibitors-2019 Update.

An abundance of new data regarding the use of the novel drug compound sacubitril/valsartan in chronic heart failure (CHF) patients is published every year since the initial publication of the PARADIGM-HF study in 2014. This review summarises the most recent evidence (2019 and onwards) of sacubitril/valsartan in CHF patients as well as provides a critical appraisal of these data. New data are grouped in categories such as real-world data, randomised controlled trials, surrogate end-points, cost-effectiveness, use of sacubitril/valsartan as an anti-hypertensive treatment, effect on diuretic dosing and implementation of this novel compound in other populations. This review of recent literature identified important messages such as early initiation during index hospitalisation or immediately post-discharge, barriers against implementation of this novel treatment modality, analytical issues regarding measuring natriuretic peptides in patients under treatment and extrapolated use of sacubitril/valsartan in other than PARADIGM-HF populations. This update may serve as a very helpful evidence-based resource for practising clinicians, future research planning and health-related policy makers.

Age-Dependent and -Independent Effects of Perivascular Adipose Tissue and Its Paracrine Activities during Neointima Formation.

Cardiovascular risk factors may act by modulating the composition and function of the adventitia. Here we examine how age affects perivascular adipose tissue (PVAT) and its paracrine activities during neointima formation. Aortic tissue and PVAT or primary aortic smooth muscle cells from male C57BL/6JRj mice aged 52 weeks ("middle-aged") were compared to tissue or cells from mice aged 16 weeks ("adult"). Vascular injury was induced at the carotid artery using 10% ferric chloride. Carotid arteries from the middle-aged mice exhibited smooth muscle de-differentiation and elevated senescence marker expression, and vascular injury further aggravated media and adventitia thickening. Perivascular transplantation of PVAT had no effect on these parameters, but age-independently reduced neointima formation and lumen stenosis. Quantitative PCR analysis revealed a blunted increase in senescence-associated proinflammatory changes in perivascular tissue compared to visceral adipose tissue and higher expression of mediators attenuating neointima formation. Elevated levels of protein inhibitor of activated STAT1 (PIAS1) and lower expression of STAT1- or NFκB-regulated genes involved in adipocyte differentiation, inflammation, and apoptosis/senescence were present in mouse PVAT, whereas PIAS1 was reduced in the PVAT of patients with atherosclerotic vessel disease. Our findings suggest that age affects adipose tissue and its paracrine vascular activities in a depot-specific manner. PIAS1 may mediate the age-independent vasculoprotective effects of perivascular fat.

The Incidence and the Prognostic Impact of Acute Kidney Injury in Acute Myocardial Infarction Patients: Current Preventive Strategies.

Acute kidney injury (AKI) is one of the most common complications during hospitalization in various clinical settings. The goal of this review was to assess the incidence of AKI in acute myocardial infarction patients (AMI), how this incidence is affected by the diverse definitions, and if there is variability in the reported rates over recent years. Additionally, we sought to appraise the impact of AKI on short- and long-term prognosis of these patients. Finally, we report on the current preventive measures as they are suggested in the current guidelines of various societies, we comment on the evidence that support them, and we review the literature for other proposed therapeutic strategies, which either failed to prove their efficacy or they are not adequately confirmed yet. Due to the heterogeneity in AKI definition and in the population studied of the published data, the incidence of AKI ranged from 5.2 to 59%. A recent meta-analysis reported a median value of 15.8%. All studies assessing AKI-related prognosis in AMI patients suggested that presence of AKI has detrimental effect on patients prognosis, raising mortality two- to threefold not only during the 30 first days but also during the first year after the acute event. Various treatment modalities have been proposed for prevention of AKI in AMI patients; however, the majority of them failed to prove their efficacy in the clinical trial arena. Hydration, use of iso- or low-osmolar agents at the lowest possible dose during coronary interventions, and use of statins have been proposed among others. Nonetheless, the prevalence of AKI after an AMI still remains high today and therefore it is crucial for the practicing physician to be aware of its presence and for the scientific community to identify novel measures for a more efficacious prevention.

C-terminal fragment of agrin (CAF) levels predict acute kidney injury after acute myocardial infarction.

BACKGROUND: Patients with acute myocardial infarction are at high risk for acute kidney injury. Novel biomarkers that can predict acute kidney injury in AMI may allow timely interventions. C-terminal fragment of agrin (CAF), a proteoglycan of the glomerular and tubular basement membrane, have been recently associated with rapid renal function deterioration and proximal tubular dysfunction. It is unknown whether elevated CAF levels may serve as a novel AKI biomarker in patients presenting with AMI. METHODS: In 436 persons enrolled in a multicenter prospective observational cohort study of patients with acute myocardial infarction, we measured plasma and urine levels of several kidney injury biomarkers including CAF, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and cystatin-C.The relationship between biomarker levels at baseline and the development of AKI and long-term mortality were analyzed after adjustment for demographic and clinical variables. RESULTS: AKI incidence was up to 15% during hospitalization. The predictive accuracy for AKI of urinary CAF was similar to NGAL and superior to other tested kidney injury biomarkers. In a multivariate model that included all possible confounding variables only urinary CAF continued to be an independent marker for AKI (OR 1.35 95%CI 1.05 -1.74). During the 2 years follow-up, only plasma CAF levels remained a significant independent predictor of mortality (OR 2.5 95%CI 1.02-6.2; P = 0.04). CONCLUSIONS: Elevated CAF levels are associated with AKI in patients with acute myocardial infarction. Our study provides preliminary evidence that CAF levels may predict AKI and mortality after AMI in low risk patients with relative preserved kidney function at baseline.

Novel echocardiographic prognostic markers for cardiac tamponade in patients with large malignant pericardial effusions: A paradigm shift from flow to tissue imaging.

BACKGROUND: With this study, we sought to investigate the prognostic value of echocardiographic tissue imaging markers in predicting tamponade among patients with large malignant pericardial effusion compared to routinely used echocardiographic signs. METHODS: A total of 96 consecutive patients with large malignant pericardial effusion, not in clinical cardiac tamponade, underwent an echocardiographic examination and were prospectively assessed for 1 month. Clinically evident cardiac tamponade was considered as the study endpoint. The prognostic performance of tricuspid valve annular plane systolic excursion (TAPSE) and peak systolic annular velocity at the lateral margin of the tricuspid valve annulus (STV ) was assessed and compared to routinely used imaging signs. RESULTS: During follow-up, 37 patients (39%) developed clinically evident cardiac tamponade. TAPSE (area under the curve [AUC] 0.958) and STV (AUC 0.948) had excellent predictive accuracy for tamponade. Multivariate analysis showed that TAPSE (Hazard ratio [HR] 3.03; 95% CI 1.60-5.73, P=.001) and STV (HR 1.17; 95% CI 1.05-1.29, P=.005) remained independent significant predictors of cardiac tamponade. Reclassification analysis and decision curve analysis showed additive prognostic value and adjunct clinical benefit of these markers when added to a recently published triage pericardiocentesis score. CONCLUSION: Echocardiographic tissue imaging markers such as TAPSE and STV are characterized by an excellent prognostic ability for development of cardiac tamponade and better prognostic value compared to routine echocardiographic signs in patients with large malignant pericardial effusion. Incorporating these markers to a recent triage pericardiocentesis score resulted in additional prognostic value and increased clinical benefit.

A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon.

BACKGROUND: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy. METHODS: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks. RESULTS: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events. CONCLUSIONS: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy. (Funded by the European Commission Seventh Framework Programme and others; EU-PACT ClinicalTrials.gov numbers, NCT01119261 and NCT01119274.).

Contrast-Induced Acute Kidney Injury: An Update.

Contrast-induced acute kidney injury (CI-AKI) is defined as an abrupt deterioration in renal function associated with the administration of iodinated contrast media. This type of acute kidney injury is frequently encountered as a complication of percutaneous coronary intervention (PCI) and is associated with adverse short- and long-term outcomes including mainly mortality, cardiovascular morbidity and prolongation of hospitalization. The incidence of CI-AKI after PCI ranges from 2 to 20 % according to baseline kidney function. It may also range according to the clinical setting, being higher after emergency PCI. The primary manifestation is a small decline in kidney function, occurring 1 to 3 days after the procedure. Kidney function usually returns to preexisting levels within 7 days. Incidence of acute renal failure requiring dialysis following PCI is rare (<1 %). The present article aims to review up-to-date published data concerning diagnosis, definition, epidemiology and prognosis of this novel in-hospital epidemic.

Prevention of Contrast-Induced Acute Kidney Injury: an Update.

Contrast-induced acute kidney injury (CI-AKI) is a common complication of intravascular administration of contrast media used in coronary angiography, percutaneous coronary intervention and other diagnostic and interventional procedures. This review article aims at summarizing the published literature regarding the prevention of CI-AKI, by focusing on available high-quality meta-analyses addressing this matter. Apart from adequate hydration, a number of pharmacologic agents have been proposed as potential candidates to be included in the routine preparation, prior to the patient's arrival in the cardiac catheterization laboratory. Among them, statins and N-acetylcysteine appear to be the most extensively studied ones. Throughout this article we present the available data on CI-AKI prevention and provide a critical clinical appraisal, as well as a summary of currently available guidelines.

Images of an ectopic balloon expandable valve deployed at the aortic arch level following valve embolization.

An 83-year-old man with severe aortic stenosis underwent implantation of a 29-mm SAPIEN-3 (Edwards Lifesciences) transcatheter aortic valve (TAV) appropriately sized for an aortic annulus area of 543.6 mm2.

An Armored Heart: A Diagnosis Hidden in Plain Sight.

We report a case of an overtly symptomatic patient with delayed diagnosis of massive (>25-mm thickness), circular, constrictive pericarditis. Our patient underwent a successful surgical pericardiectomy-a high-risk procedure-revealing an armored heart, with an impressive clinical improvement. Diagnosis of constrictive pericarditis is challenging and requires high clinical suspicion.

Circulating microRNAs and DNA Methylation as Regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation and Key Elements for the Identification of the Mechanism of Action (miR-CRAFT): Study Design and Patient Enrolment.

Direct oral anticoagulants (DOACs) are the standard treatment for thromboembolic protection in atrial fibrillation (AF) patients. Epigenetic modifications, such as DNA methylation and microRNAs, have emerged as potential biomarkers of AF. The epigenetics of DOACs is still an understudied field. It is largely unknown whether epigenetic modifications interfere with DOAC response or whether DOAC treatment induces epigenetic modifications. To fill this gap, we started the miR-CRAFT (Circulating microRNAs and DNA methylation as regulators of Direct Oral Anticoagulant Response in Atrial Fibrillation) research study. In miR-CRAFT, we follow, over time, changes in DNA methylation and microRNAs expression in naïve AF patients starting DOAC treatment. The ultimate goal of miR-CRAFT is to identify the molecular pathways epigenetically affected by DOACs, beyond the coagulation cascade, that are potentially mediating DOAC pleiotropic actions and to propose specific microRNAs as novel circulating biomarkers for DOAC therapy monitoring. We herein describe the study design and briefly present the progress in participant enrolment.

EXPLORATORY ANALYSIS OF URINE PO2 PERI-PROCEDURAL KINETICS AND CI-AKI PROGNOSTIC ABILITIES IN PATIENTS UNDERGOING PCI.

Novel contrast-induced acute kidney injury (CI-AKI) biomarkers are needed to detect earlier and with greater precision the pathophysiological changes in renal medulla associated with kidney damage. We prospectively assessed the kinetics of urine oxygen tension (PO2) in control healthy individuals, and its prognostic ability for CI-AKI in patients undergoing percutaneous coronary intervention (PCI). We enrolled 202 consecutive patients (78% men, mean age 66±10 years) treated with elective or urgent PCI. PO2 was measured using a point-of-care (POC) standard blood gas analyzer at 3 time points (baseline, post -within 3 hours- PCI and at 24 hours post PCI) in urine samples. CI-AKI was defined as an increase of ≥25% or ≥0.5 mg/dl in pre-PCI serum creatinine at 48 hours post PCI. Between baseline and post-PCI measurements, patients without CI-AKI showed a decrease of -37 (36) mmHg in PO2 urine levels whereas patients with CI-AKI showed a decrease of only -23 (38) mmHg. (P=0.014). Using ROC analysis, percentage change in urine PO2 immediately after PCI relative to baseline levels, significantly predicted CI-AKI (AUC 0.804 95%CI 0.717-0.892). A significant drop in urine oxygen tension appears as a normal response of the kidney medulla to an acute insult (contrast media) immediately post PCI with a recovery to baseline levels 24 hours later. Absence or attenuation of this drop in urine oxygen tension could predict CI-AKI earlier and more precisely.

Newly detected diabetes mellitus patients with acute coronary syndrome have an adverse cardiometabolic profile similar to patients with prior diabetes and a more extensive ischemic myocardial insult.

AIMS: The impact of newly detected diabetes mellitus (NDDM) on metabolic parameters and extent of myocardial necrosis in patients with acute coronary syndrome (ACS) is not fully explored. We examined the impact of NDDM on cardiometabolic characteristics and myocardial necrosis in ACS patients. METHODS: CALLINICUS-Hellas Registry is an ongoing prospective multicenter observational study evaluating the adherence to lipid-lowering therapy (LLT) among ACS patients in Greece. Three groups were created: a) patients with NDDM (abnormal fasting glucose, HbA1c ≥ 6.5 % and no previous history of DM), b) patients without known DM and HbA1c < 6.5 % (non-DM) and c) patients with prior DM. RESULTS: The prevalence of NDDM among 1084 patients was 6.9 %. NDDM patients had lower HDL-C [38 (32-45) vs 42 (36-50) mg/dL] and higher triglycerides levels [144 (104-231) vs 115 (87-152) mg/dL] compared to non-DM patients (p < 0.05). NDDM patients featured both higher body mass index [29.5 (26.4-34.3) vs 27.1 (24.9-29.9) kg/m2] and waist circumference [107 (100-114) vs 98 (91-106) cm] compared to non-DM patients (p < 0.05). In addition, NDDM patients had more extensive myocardial necrosis than patients with prior DM. CONCLUSIONS: ACS patients with NDDM have an adverse cardiometabolic profile similar to patients with prior DM and have more extensive myocardial insult.

Differential effect of baseline adiponectin on all-cause mortality in hemodialysis patients depending on initial body mass index. Long-term follow-up data of 4.5 years.

OBJECTIVES: We sought to investigate the interaction of adiponectin levels and body mass index (BMI) for predicting all-cause mortality in a cohort of hemodialysis (HD) patients. DESIGN: Longitudinal, observational cohort study. SETTING: HD unit. SUBJECTS: Sixty patients (mean age: 64 ± 13 years, 39 men) with end-stage renal disease on maintenance HD followed up for 4.5 years represented the prospective study cohort. INTERVENTION: Associations between baseline plasma adiponectin levels and initial BMI with all-cause mortality were assessed taking into account the assumption of nonlinear correlations. The association between adiponectin, BMI, and serum levels of interleukin-10 (IL-10) and interleukin-6 (IL-6) with survival was determined cross-sectionally. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Nonlinear survival modeling showed that there was a U-shaped association of BMI with all-cause mortality, whereas there was an inverse U-shaped association for plasma adiponectin levels. Using a BMI of 24 kg/m(2) as a cutoff, an interaction effect of BMI on the association between adiponectin and mortality was observed (P = .045). In participants with BMI ≥ 24 kg/m(2), each 15 µg/mL increase in plasma adiponectin levels was associated with a decreased hazard of death (hazard ratio: 0.57, 95% CI: 0.32 to 0.99) in unadjusted analysis. In HD patients with BMI < 24 kg/m(2), no significant association was observed between adiponectin and mortality (P = .989). Cross-sectional analysis showed that in the subgroup of patients in whom the protective effect of adiponectin was observed (BMI ≥ 24 kg/m(2)), a positive linear association existed between adiponectin and IL-10 levels (r = 0.345, P = .027) as well as a negative association with IL-6 levels (r = -0.322, P = .040). No association was observed in patients with BMI < 24 kg/m(2), neither with IL-10 nor with IL-6. CONCLUSIONS: Obesity possibly modifies the effect of adiponectin on all-cause mortality in HD patients, thus explaining the published conflicting results in recent literature regarding the association of plasma adiponectin levels and mortality in chronic kidney disease patients.