Aortic valve replacement versus conservative treatment in asymptomatic severe aortic stenosis: long-term follow-up of the AVATAR trial.

BACKGROUND AND AIMS: The question of when and how to treat truly asymptomatic patients with severe aortic stenosis (AS) and normal left ventricular (LV) systolic function is still subject to debate and ongoing research. Here, the results of extended follow-up of the AVATAR trial are reported (NCT02436655, clinical trials.gov). METHODS: The AVATAR trial randomly assigned patients with severe, asymptomatic AS and LV ejection fraction ≥50% to undergo either early surgical aortic valve replacement (AVR) or conservative treatment with watchful waiting strategy. All patients had negative exercise stress testing. The primary hypothesis was that early AVR will reduce a primary composite endpoint comprising all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure (HF), as compared to conservative treatment strategy. RESULTS: A total of 157 low-risk patients (mean age 67 years, 57% men, mean Society of Thoracic Surgeons score 1.7%) were randomly allocated to either early AVR group (n=78) or conservative treatment group (n=79). In an intention-to-treat analysis, after a median follow-up of 63 months, the primary composite endpoint outcome event occurred in 18/78 patients (23.1%) in the early surgery group and in 37/79 patients (46.8%) in the conservative treatment group (hazard ratio [HR] early surgery vs. conservative treatment 0.42; 95% confidence interval [CI] 0.24-0.73, p=0.002). The Kaplan-Meier estimates for individual endpoints of all-cause death and HF hospitalization were significantly lower in the early surgery compared with the conservative group (HR 0.44; 95% CI 0.23-0.85, p=0.012 for all-cause death, and HR 0.21; 95% CI 0.06-0.73, p=0.007 for HF hospitalizations). CONCLUSIONS: The extended follow-up of the AVATAR trial demonstrates better clinical outcomes with early surgical AVR in truly asymptomatic patients with severe AS and normal LV ejection fraction compared with patients treated with conservative management on watchful waiting. TRIAL REGISTRATION NUMBER: NCT02436655 (ClinicalTrials.gov).

Successful clinical approach to the metastatic uterine leiomyosarcoma to the epicardium-a case report.

BACKGROUND: Uterine leiomyosarcoma is a rare and aggressive tumour with a poor prognosis. Its metastases to the heart are even rarer, especially to the epicardium. The majority of reported cardiac metastases of uterine leiomyosarcoma were in the cardiac chambers or intramyocardial. Surgical resection of the uterine leiomyosarcoma in the early stages is the only definitive treatment for this disease. However, in the cases of cardiac metastasis, surgery is recommended only in emergencies and patients with expected beneficial outcomes. CASE PRESENTATION: Our patient was a 49-year-old female referred to the Department of Cardiac Surgery for scheduled surgery of pericardial neoplasia. The patient underwent a hysterectomy and adnexectomy three years prior owing to the uterine leiomyosarcoma. A regular follow-up magnetic resonance imaging of the abdomen and pelvis discovered neoplasia in the diaphragmic portion of the pericardium. No other signs of primary disease relapse or metastases were found. The patient was asymptomatic. The multidisciplinary team concluded that the patient is a candidate for surgery. Surgery included diastolic cardiac arrest achievement and resection of the tumour. Macroscopically, a parietal layer of the pericardium was completely free from the tumour that invaded only the apical myocardium of the left ventricle. Completed histopathology confirmed the diagnosis of leiomyosarcoma of the uterine origin. Three months after surgery, the patient received adjuvant chemotherapy with doxorubicin and dacarbazine. One year after surgery, there are no signs of new metastases. CONCLUSIONS: Strict surveillance of patients with uterine leiomyosarcoma after successful treatment of the early stage of the disease is of utmost importance to reveal metastatic disease to the heart in a timely manner and to treat it with beneficial outcomes. Surgery with adjuvant chemotherapy might be a good approach in patients with a beneficial prognosis. From a surgical point of view, it is challenging to assess the appropriate width of the resection edges to be radical enough and, at the same time, sufficiently conservative to ensure the satisfactory postoperative function of the remaining myocardium and avoid repetitive tumour growth. Therefore, intraoperative histopathology should always be performed.

Cardiotoxicity of Iron and Zinc and Their Association with the Mitochondrial Unfolded Protein Response in Humans.

This study was designed to examine the association between myocardial concentrations of the trace elements Cu, Fe, Mn, Mo, and Zn and the expression of mitochondrial unfolded protein response (UPRmt) elements and the age of patients who received heart transplantation or a left-ventricular assist device (ageHTx/LVAD). Inductively coupled plasma mass spectrometry was used to determine the concentration of Cu, Fe, Mn, Mo, and Zn in the myocardium of control subjects and patients undergoing heart transplantation or left-ventricular assist device (LVAD) implantation. We used ELISA to quantify the expression of UPRmt proteins and 4-Hydroxynonenal (4-HNE), which served as a marker of oxidative-stress-induced lipid peroxidation. Concentrations of Cu, Mn, Mo, and Zn were similar in the control and heart failure (HF) myocardium, while Fe showed a significant decrease in the HF group compared to the control. A higher cumulative concentration of Fe and Zn in the myocardium was associated with reduced ageHTx/LVAD, which was not observed for other combinations of trace elements or their individual effects. The trace elements Cu, Mn, and Zn showed positive correlations with several UPRmt proteins, while Fe had a negative correlation with UPRmt effector protease YME1L. None of the trace elements correlated with 4-HNE in the myocardium. The concentrations of the trace elements Mn and Zn were significantly higher in the myocardium of patients with dilated cardiomyopathy than in patients with ischemic cardiomyopathy. A higher cumulative concentration of Fe and Zn in the myocardium was associated with a younger age at which patients received heart transplantation or LVAD, potentially suggesting an acceleration of HF. A positive correlation between myocardial Cu, Mn, and Zn and the expression of UPRmt proteins and a negative correlation between myocardial Fe and YME1L expression suggest that these trace elements exerted their actions on the human heart by interacting with the UPRmt. An altered generation of oxidative stress was not an underlying mechanism of the observed changes.

Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial.

BACKGROUND: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. METHODS: The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm2 with aortic jet velocity >4 m/s or a mean transaortic gradient ≥40 mm Hg), and with normal left ventricular function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite end point of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. RESULTS: Between June 2015 and September 2020, 157 patients (mean age, 67 years; 57% men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment group. In the early surgery group, 72 patients (92.3%) underwent SAVR with operative mortality of 1.4%. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite end point than those in the conservative arm (hazard ratio, 0.46 [95% CI, 0.23-0.90]; P=0.02). There was no statistical difference in secondary end points, including all-cause mortality, first heart failure hospitalizations, major bleeding, or thromboembolic complications, but trends were consistent with the primary outcome. CONCLUSIONS: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02436655.

A Novel Three-Dimensional Approach Towards Evaluating Endomyocardial Biopsies for Follow-Up After Heart Transplantation: X-Ray Phase Contrast Imaging and Its Agreement With Classical Histopathology.

Endomyocardial biopsies are the gold standard for surveillance of graft rejection following heart transplantation, and are assessed by classical histopathology using a limited number of previously stained slices from several biopsies. Synchrotron propagation-based X-ray phase contrast imaging is a non-destructive method to image biological samples without tissue preparation, enabling virtual 2D and 3D histopathology. We aimed to show the feasibility of this method to assess acute cellular rejection and its agreement to classical histopathology. Right ventricular biopsies were sampled from 23 heart transplantation recipients (20 males, mean age 54±14 years) as part of standard follow-up. The clinical diagnosis of potential rejection was made using classical histopathology. One additional study sample was harvested and imaged by X-ray phase contrast imaging, producing 3D datasets with 0.65 µm pixel size, and up to 4,320 images per sample. An experienced pathologist graded both histopathological and X-ray phase contrast images in a blinded fashion. The agreement between methods was assessed by weighted kappa, showing substantial agreement (kappa up to 0.80, p < 0.01) between X-ray phase contrast imaging and classical histopathology. X-ray phase contrast imaging does not require tissue processing, allows thorough analysis of a full myocardial sample and allows identification of acute cellular rejection.

The Association between Glycosylated Hemoglobin Level and Platelets Reactivity in Patients with Diabetes Mellitus Undergoing Elective Coronary Artery Bypass Grafting.

BACKGROUND: Diabetic patients tend to have increased platelet reactivity after coronary artery bypass grafting (CABG). The aim of this study was to determine the association between hemoglobin A1c (HbA1c) values and platelet reactivity and to evaluate the consequent impact on clinical outcomes in patients undergoing CABG. METHODS: This prospective observational trial consecutively enrolled 225 diabetic patients undergoing CABG, between February 2014 and October 2018. HbA1c levels and platelet function (multiple electrode aggregometry [MEA]) were analyzed the day before surgery and on postoperative day 4 (POD 4). Patients were divided into two groups according to the HbA1c value: HBA1c < 7% and HbA1c ≥ 7%. RESULTS: Significantly higher postoperative ASPI (platelet function test based on arachidonic acid) and ADP (platelet function test based on adenosine diphosphate) test values were observed at POD 4 compared with preoperative values (ASPI test: p < 0.001; ADP test: p < 0.001). The prevalence of preoperative aspirin resistance (AR) was 46.4% relative to 57.2% after surgery showing consistent increase in postoperative AR by approximately 10%. In addition, the prevalence of AR in the HbA1c < 7% group was higher by 10% compared with the HbA1c ≥ 7% group, both before and after surgery. We did not demonstrate differences in clinical outcomes between the HbA1c groups. CONCLUSION: Perioperative assessment of platelet reactivity in diabetic patients detects those with AR who may be at increased risk of adverse ischemic events. A personalized approach guided by MEA and administration of early and more potent antiaggregation therapy after CABG can be beneficial in this group of patients.

Recurrent HeartMate 3 Right Ventricular Assist Device Stoppages in a Biventricular Assist Device Carrier.

A 44-year-old female patient with chemotherapy-induced cardiomyopathy presented with acute cardiogenic shock requiring ECMO support. Multiple failed weaning trials from temporary mechanical circulatory assistance prompted a transition to staged durable biventricular support. Her course was complicated with recurrent RVAD stoppages. The initial event was treated with pump exchange, while for the subsequent RVAD standstill, we employed a device wash-out and reimplantation strategy. A brief period of circulatory arrest was employed to explore the right-sided cardiac chambers using a single-use bronchoscope.

Right ventricular dissection after arterial switch operation.

Herein we present the right ventricular dissection and describe its successful management after arterial switch operation in a full-term male neonate. There are no evidence-based recommendations for the management of this rare complication. Our management included veno-arterial extracorporeal membrane oxygenation placement and delayed surgical evacuation of the dissecting haematoma with beneficial outcomes.

Impact of progressive aortic regurgitation on outcomes after left ventricular assist device implantation.

Aortic regurgitation (AR) following continuous flow left ventricular assist device implantation (cf-LVAD) may adversely impact outcomes. We aimed to assess the incidence and impact of progressive AR after cf-LVAD on prognosis, biomarkers, functional capacity and echocardiographic findings. In an analysis of the PCHF-VAD database encompassing 12 European heart failure centers, patients were dichotomized according to the progression of AR following LVAD implantation. Patients with de-novo AR or AR progression (AR_1) were compared to patients without worsening AR (AR_0). Among 396 patients (mean age 53 ± 12 years, 82% male), 153 (39%) experienced progression of AR over a median of 1.4 years on LVAD support. Before LVAD implantation, AR_1 patients were less frequently diabetic, had lower body mass indices and higher baseline NT-proBNP values. Progressive AR did not adversely impact mortality (26% in both groups, HR 0.91 [95% CI 0.61-1.36]; P = 0.65). No intergroup variability was observed in NT-proBNP values and 6-minute walk test results at index hospitalization discharge and at 6-month follow-up. However, AR_1 patients were more likely to remain in NYHA class III and had worse right ventricular function at 6-month follow-up. Lack of aortic valve opening was related to de-novo or worsening AR (P < 0.001), irrespective of systolic blood pressure (P = 0.67). Patients commonly experience de-novo or worsening AR when exposed to continuous flow of contemporary LVADs. While reducing effective forward flow, worsening AR did not influence survival. However, less complete functional recovery and worse RV performance among AR_1 patients were observed. Lack of aortic valve opening was associated with progressive AR.

Ventricular Assist Device Driveline Infections: A Systematic Review.

Infection is the most common complication in patients undergoing ventricular assist device (VAD) implantation. Driveline exit site (DLES) infection is the most frequent VAD infection and is a significant cause of adverse events in VAD patients, contributing to morbidity, even mortality, and repetitive hospital readmissions. There are many risk factors for driveline infection (DLI) including younger age, smaller constitution of patients, obesity, exposed velour at the DLES, longer duration of device support, lower cardiac index, higher heart failure score, DLES trauma, and comorbidities such as diabetes mellitus, chronic kidney disease, and depression. The incidence of DLI depends also on the device type. Numerous measures to prevent DLI currently exist. Some of them are proven, whereas the others remain controversial. Current recommendations on DLES care and DLI management are predominantly based on expert consensus and clinical experience of the certain centers. However, careful and uniform DLES care including obligatory driveline immobilization, previously prepared sterile dressing change kits, and continuous patient education are probably crucial for prevention of DLI. Diagnosis and treatment of DLI are often challenging because of certain immunological alterations in VAD patients and microbial biofilm formation on the driveline surface areas. Although there are many conservative and surgical methods described in the DLI treatment, the only possible permanent solution for DLI resolution in VAD patients is heart transplantation. This systematic review brings a comprehensive synthesis of recent data on the prevention, diagnostic workup, and conservative and surgical management of DLI in VAD patients.

Propensity-score matched comparison between minimally invasive and conventional aortic valve replacement.

AIM: To evaluate the impact of minimally invasive aortic valve replacement (mini-AVR) on clinical outcomes in comparison with the gold standard. METHODS: We retrospectively reviewed the records of all patients who underwent isolated AVR at the University Hospital Center Zagreb from 2010 to 2020. Patients undergoing mini-AVR were compared with patients undergoing conventional AVR (fs-AVR). The primary outcome measure was blood product consumption. Propensity score matching was used to create a balanced covariate distribution across treatment groups. Additionally, we compared the contemporary outcomes with a historical control. RESULTS: The final sample consisted of 1088 patients. In the unmatched cohorts, mini-AVR patients were younger (65±12 vs 68±10 years, P<0.001) and had lower risk profiles (EuroSCORE2 2.8±2.0 vs 3.5±3.1, P=0.003). After matching, mini-AVR patients required less blood transfusion than fs-AVR patients (270 [0-790] vs 510 [0-970] mL, P=0.029). The incidences of stroke, dialysis, new AV block, and mortality were comparable. Cross-clamp times were longer in the mini-AVR group (71 [60-87] vs 66 [53-83] minutes, P=0.013). Outcomes were improved in the contemporary mini-AVR era compared with our early mini-AVR experience across multiple metrics. Blood product consumption was reduced in the latter tercile of experience (0 [0-520] vs 500 [0-1018] mL, P<0.001), and the operation was performed more expeditiously (cross-clamp times: 63 [54,80] vs 74 [62,88] minutes, P<0.001) in comparison with earlier periods. CONCLUSIONS: We showed that mini-AVR was associated with less blood product requirement than conventional surgery. Our data supports wider adoption of minimally invasive techniques in dedicated centers of excellence.

Association among Clopidogrel Cessation, Platelet Function, and Bleeding in Coronary Bypass Surgery: An Observational Trial.

OBJECTIVES: This study sought to determine (1) the association between the length of preoperative clopidogrel discontinuation, blood loss, and transfusion requirements and (2) whether preoperative platelet function testing predicts excessive postoperative bleeding in patients undergoing coronary artery bypass grafting (CABG) surgery. METHODS: In this retrospective analysis, patients undergoing CABG were divided into three groups with regard to the period between preoperative clopidogrel cessation and surgery: group 1 (n = 94, ≤3 days), group 2 (n = 100, 4-5 days), and group 3 (n = 83, 6-7 days), respectively. Impedance aggregometry (Multiplate) with arachidonic acid (ASPI) test assay (used for platelets stimulation) and adenosine diphosphate (ADP) test (used for platelets stimulation) was performed before the surgery. Primary outcome was 24 hours chest tube output (CTO) and transfusion requirements (red blood cell concentrate [RBCC], platelet concentrate [PC], fibrinogen concentrate [FC], and fresh-frozen plasma [FFP]) were considered as secondary outcomes. RESULTS: CTO during 24 hours was significantly higher in group 1 as compared with groups 2 and 3, respectively (p = 0.003). Considering secondary outcomes, RBCC (p = 0.043), PC (p = 0.001), FC (p = 0.003), and FFP (p = 0.010) were more frequently transfused in group 1 as compared with groups 2 and 3, respectively. Multiple electrode aggregometry ASPI and ADP tests were significantly correlated with the 24-hour CTO (ASPI test-rho = -0.258, p < 0.001; ADP test-rho = -0.164, p = 0.007). A significant correlation was observed between clopidogrel-free interval and 24-hour CTO (rho = -0.200, p < 0.001). Receiver-operating characteristics (ROC) curve analysis revealed cutoff values to delineate bleeding tendency (ASPI test ≤ 25 area under the aggregation curve [AUC], ADP test ≤63 AUC, and clopidogrel-free interval ≤3 days). CONCLUSION: Excessive postoperative bleeding occurred less frequently if the period between clopidogrel discontinuation and surgery was longer than 3 days, as compared with shorter waiting time. Inadequate recovery of the platelets function following clopidogrel cessation in preoperative period was associated with increased bleeding risk. Platelet function testing was found to be a useful tool for postoperative bleeding management in our hands.

Cost Analysis of Transfusion Therapy in Coronary Artery Surgery.

BACKGROUND: In patients undergoing coronary artery bypass grafting (CABG), wide variability in transfusion rate (7.8% to 92.8%) raises the question of the amount of unnecessary transfusions. The aim of the study was (1) to identify CABG patients at low risk of bleeding to whom transfusion treatment should be avoided and (2) to calculate the amount of possible cost savings that would be achieved by avoiding transfusion in low bleeding risk patients. METHODS: This retrospective observational study enrolled patients undergoing isolated elective CABG from January 2010 to January 2018. Patients were divided with respect to the presence of excessive bleeding and transfusion costs were compared between the two groups. Predictors for postoperative excessive bleeding were defined and multivariable logistic regression analysis and risk modeling were performed. The use of a model to predict patients at low risk of bleeding allowed for the estimation of transfusion cost savings assuming the patients who were found to be at low risk of bleeding should not be transfused. RESULTS: A total of 1,426 patients were enrolled in the analysis. Of those, 28.3% had excessive postoperative bleeding. The multivariate logistic regression analysis model was developed to identify/predict patients without excessive bleeding (receiver operating characteristic curve analysis, area under the curve 72.3%, p < 0.001). When applied to the existing database, the use of the developed model identifying patients at low risk of bleeding may result in a 39.1% reduction of transfusions. Specifically, cost savings would be 48.2% for packed red blood cells, 38.9% for fresh frozen plasma, 10.9% for platelets concentrate, and 17.9% for fibrinogen concentrate. CONCLUSION: The clinical and economic burdens associated with unnecessary transfusions are significant. Avoiding transfusion in CABG patients found to be at low risk of bleeding may result in significant reduction of transfusion rate and transfusion-associated costs.

Correction to: Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes.

The authors regret that Nish Chaturvedi's name was spelt incorrectly in the author list. The details given in this correction are correct.

Staged management of a giant cardiac hydatid cyst: a case report.

BACKGROUND: We report on a 21-year-old patient with a giant symptomatic hydatid cyst of the interventricular septum, to whom a staged management approach was employed. Induction medical therapy led to a reduction in the size of the cyst, which was then completely removed via surgical excision. CASE PRESENTATION: A 21-year-old male Caucasian, with main complaints of fatigue and palpitations, was referred to our Centre due to a cystic formation in his left ventricle. The workup consisted of transthoracic echocardiography and cardiac magnetic resonance, which revealed a huge hydatid cyst in an active stage of disease, occupying the basal and mid part of the interventricular septum. Due to the size of the lesion and lack of viable myocardium in the affected area, the patient was declared inoperable and medical therapy was initiated. Serial echocardiography revealed a significant reduction in the size of the lesion and degradation to transitional and inactive stage, after which successful surgical excision of the cyst was performed. In the course of the medical treatment, the patient experienced sustained ventricular tachycardia causing loss of consciousness, which did not reoccur after surgical excision. CONCLUSION: Medical therapy can result in the degradation of a giant heart hydatid cyst, enabling surgical excision. Heart hydatid cyst can lead to potentially lethal arrhythmia irrespective of its size and stage, which does not reoccur after successful surgical excision.

Preponderance of microbial isolates among heart transplantation recipients requiring renal replacement therapy: a propensity score-adjusted analysis.

AIM: To assess the association between renal replacement therapy (RRT) and post-transplant infection incidence. METHODS: This single-center retrospective cohort study included 158 patients who underwent heart transplantation (HTx) in our center from 2008 to 2016, survived beyond the first post-procedural day, and had available microbial data. The patients were dichotomized according to the need for periprocedural RRT. Twenty-seven patients in RRT group had lower preoperative creatinine clearance, greater body mass index, and higher likelihood of having diabetes. Propensity score adjustment was used to account for multiple covariates. The primary outcome measure was the presence of bacteremia in patients with and without the need for RRT. The secondary outcome measures were the presence of microbial isolates from any culture and clinical outcome data. RESULTS: Unadjusted analysis showed that the RRT group had higher incidence of any positive microbial isolate (93% vs 73%; odds ratio [OR] 4.77, 95% confidence interval [CI] 1.01-30.53; P=0.026) and an increased susceptibility to bacteremia (50% vs 22%; OR 3.50, 95% CI 1.28-9.67; P=0.012). Propensity score-adjusted analysis corroborated the between-group difference in positive blood cultures (OR 3.97, 95% CI 1.28-12.32; P=0.017). There was no difference in the incidence of total microbial isolates between the groups (OR 4.55, 95% CI 0.90-23.05; P=0.067). CONCLUSIONS: Patients requiring RRT after HTx had an increased susceptibility to infections via various portals of entry, predominantly due to an increase in blood-borne infections. Understanding the underlying conditions leading to infection-related morbidity is important for infection control and prevention.

Increased plasma N-glycome complexity is associated with higher risk of type 2 diabetes.

AIMS/HYPOTHESIS: Better understanding of type 2 diabetes and its prevention is a pressing need. Changes in human plasma N-glycome are associated with many diseases and represent promising diagnostic and prognostic biomarkers. Variations in glucose metabolism directly affect glycosylation through the hexosamine pathway but studies of plasma glycome in type 2 diabetes are scarce. The aim of this study was to determine whether plasma protein N-glycome is changed in individuals who are at greater risk of developing type 2 diabetes. METHODS: Using a chromatographic approach, we analysed N-linked glycans from plasma proteins in two populations comprising individuals with registered hyperglycaemia during critical illness (increased risk for development of type 2 diabetes) and individuals who stayed normoglycaemic during the same condition: AcuteInflammation (59 cases vs 49 controls) and AcuteInflammation Replication (52 cases vs 14 controls) populations. N-glycome was also studied in individuals from FinRisk (37 incident cases of type 2 diabetes collected at baseline vs 37 controls), Orkney Complex Disease Study (ORCADES; 94 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 658 controls) and Southall and Brent Revisited (SABRE) cohort studies (307 individuals with HbA1c > 6.5% [47.5 mmol/mol] vs 307 controls). RESULTS: Individuals with increased risk for diabetes type 2 development (AcuteInflammation and AcuteInflammation Replication populations), incident cases of type 2 diabetes collected at baseline (FinRisk population) and individuals with elevated HbA1c (ORCADES and SABRE populations) all presented with increased branching, galactosylation and sialylation of plasma protein N-glycans and these changes were of similar magnitude. CONCLUSIONS/INTERPRETATION: Increased complexity of plasma N-glycan structures is associated with higher risk of developing type 2 diabetes and poorer regulation of blood glucose levels. Although further research is needed, this finding could offer a potential new approach for improvement in prevention of diabetes and its complications.

Rationale and design of the Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR trial): A randomized multicenter controlled event-driven trial.

Aortic valve replacement (AVR) therapy is an obvious choice for symptomatic severe aortic stenosis (AS) patients as it improves symptoms, left ventricular function, and survival. The treatment decisions and indication for AVR in asymptomatic patients with severe AS and normal left ventricular ejection fraction are less well established and the subject of ongoing debate. Many efforts have been made to define the best treatment option in asymptomatic AS patients with normal left ventricular ejection fraction. Retrospective and observational data imply that elective AVR for asymptomatic severe AS may lead to improvement in outcomes in comparison to surgery performed after onset of symptoms. The AVATAR trial will aim to assess outcomes among asymptomatic AS patients randomized to either elective early AVR or medical management with vigilant follow-up. In the latter group, AVR would be delayed until either the onset of symptoms or changes in predefined echocardiographic parameters. To the best of the authors' knowledge, it will be the first large prospective, randomized, controlled, multicenter clinical trial that will evaluate the safety and efficacy of elective AVR in this specific group of patients.