The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction.

BACKGROUND: Brugada syndrome is associated with loss-of-function SCN5A variants, yet these account for only ≈20% of cases. A recent genome-wide association study identified a novel locus within MAPRE2, which encodes EB2 (microtubule end-binding protein 2), implicating microtubule involvement in Brugada syndrome. METHODS: A mapre2 knockout zebrafish model was generated using CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/clustered regularly interspaced short palindromic repeat-associated protein 9) and validated by Western blot. Larval hearts at 5 days post-fertilization were isolated for voltage mapping and immunocytochemistry. Adult fish hearts were used for ECG, patch clamping, and immunocytochemistry. Morpholinos were injected into embryos at 1-cell stage for knockdown experiments. A transgenic zebrafish line with cdh2 tandem fluorescent timer was used to study adherens junctions. Microtubule plus-end tracking and patch clamping were performed in human induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) with MAPRE2 knockdown and knockout, respectively. RESULTS: Voltage mapping of mapre2 knockout hearts showed a decrease in ventricular maximum upstroke velocity of the action potential and conduction velocity, suggesting loss of cardiac voltage-gated sodium channel function. ECG showed QRS prolongation in adult knockout fish, and patch clamping showed decreased sodium current density in knockout ventricular myocytes and arrhythmias in knockout iPSC-CMs. Confocal imaging showed disorganized adherens junctions and mislocalization of mature Ncad (N-cadherin) with mapre2 loss of function, associated with a decrease of detyrosinated tubulin. MAPRE2 knockdown in iPSC-CMs led to an increase in microtubule growth velocity and distance, indicating changes in microtubule dynamics. Finally, knockdown of ttl encoding tubulin tyrosine ligase in mapre2 knockout larvae rescued tubulin detyrosination and ventricular maximum upstroke velocity of the action potential. CONCLUSIONS: Genetic ablation of mapre2 led to a decrease in voltage-gated sodium channel function, a hallmark of Brugada syndrome, associated with disruption of adherens junctions, decrease of detyrosinated tubulin as a marker of microtubule stability, and changes in microtubule dynamics. Restoration of the detyrosinated tubulin fraction with ttl knockdown led to rescue of voltage-gated sodium channel-related functional parameters in mapre2 knockout hearts. Taken together, our study implicates microtubule dynamics in the modulation of ventricular conduction.

Ischemic Stroke Temporally Associated With New-Onset Atrial Fibrillation: A Population-Based Registry-Linkage Study.

BACKGROUND: Limited data exist on the temporal relationship between new-onset atrial fibrillation (AF) and ischemic stroke and its impact on patients' clinical characteristics and mortality. METHODS: A population-based registry-linkage database includes all patients with new-onset AF in Finland from 2007 to 2018. Ischemic stroke temporally associated with AF (ISTAF) was defined as an ischemic stroke occurring within ±30 days from the first AF diagnosis. Clinical factors associated with ISTAF were studied with logistic regression and 90-day survival with Cox proportional hazards analysis. RESULTS: Among 229 565 patients with new-onset AF (mean age, 72.7 years; 50% female), 204 774 (89.2%) experienced no ischemic stroke, 12 209 (5.3%) had past ischemic stroke >30 days before AF, and 12 582 (5.8%) had ISTAF. The annual proportion of ISTAF among patients with AF decreased from 6.0% to 4.8% from 2007 to 2018. Factors associated positively with ISTAF were higher age, lower education level, and alcohol use disorder, whereas vascular disease, heart failure, chronic kidney disease cancer, and psychiatric disorders were less probable with ISTAF. Compared with patients without ischemic stroke and those with past ischemic stroke, ISTAF was associated with ≈3-fold and 1.5-fold risks of death (adjusted hazard ratios, 2.90 [95% CI, 2.76-3.04] and 1.47 [95% CI, 1.39-1.57], respectively). The 90-day survival probability of patients with ISTAF increased from 0.79 (95% CI, 0.76-0.81) in 2007 to 0.89 (95% CI, 0.87-0.91) in 2018. CONCLUSIONS: ISTAF depicts the prominent temporal clustering of ischemic strokes surrounding AF diagnosis. Despite having fewer comorbidities, patients with ISTAF had worse, albeit improving, survival than patients with a history of or no ischemic stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04645537. URL: https://www.encepp.eu; Unique identifier: EUPAS29845.

Prolonged Systemic Inflammatory Response Syndrome After Cardiac Surgery.

OBJECTIVES: Cardiac surgery induces systemic inflammatory response syndrome (SIRS), leading to higher morbidity and mortality. There are no individualized predictors for worse outcomes or biomarkers for the multifactorial, excessive inflammatory response. The interest of this study was to evaluate whether a systematic use of the SIRS criteria could be used to predict postoperative outcomes beyond infection and sepsis, and if the development of an exaggerated inflammation response could be observed preoperatively. DESIGN: The study was observational, with prospectively enrolled patients. SETTING: This was a single institution study in a hospital setting combined with laboratory findings. PARTICIPANTS: The study included a cohort of 261 volunteer patients. INTERVENTIONS: Patients underwent cardiac surgery with cardiopulmonary bypass, and were followed up to 90 days. Biomarker profiling was run preoperatively. MEASUREMENTS AND MAIN RESULTS: Altogether, 17 of 261 (6.4%) patients had prolonged SIRS, defined as fulfilling at least 2 criteria on 4 consecutive postoperative days. During hospitalization, postoperative atrial fibrillation (POAF) was found in 42.2% of patients, and stroke and transient ischemic attack in 3.8% of patients. Prolonged SIRS was a significant predictor of POAF (odds ratio [OR] 4.5, 95% CI 1.2-17.3), 90-day stroke (OR 4.5, 95% CI 1.1-18.0), and mortality (OR 10.7, 95% CI 1.7-68.8). Biomarker assays showed that preoperative nerve growth factor and interleukin 5 levels were associated with prolonged SIRS (OR 5.6, 95%, CI 1.4-23.2 and OR 0.7, 95%, CI 0.4-1.0, respectively). CONCLUSIONS: Nerve growth factor and interleukin 5 can be used to predict prolonged systemic inflammatory response, which is associated with POAF, stroke, and mortality.

Mechanocardiography in the Detection of Acute ST Elevation Myocardial Infarction: The MECHANO-STEMI Study.

Novel means to minimize treatment delays in patients with ST elevation myocardial infarction (STEMI) are needed. Using an accelerometer and gyroscope on the chest yield mechanocardiographic (MCG) data. We investigated whether STEMI causes changes in MCG signals which could help to detect STEMI. The study group consisted of 41 STEMI patients and 49 control patients referred for elective coronary angiography and having normal left ventricular function and no valvular heart disease or arrhythmia. MCG signals were recorded on the upper sternum in supine position upon arrival to the catheterization laboratory. In this study, we used a dedicated wearable sensor equipped with 3-axis accelerometer, 3-axis gyroscope and 1-lead ECG in order to facilitate the detection of STEMI in a clinically meaningful way. A supervised machine learning approach was used. Stability of beat morphology, signal strength, maximum amplitude and its timing were calculated in six axes from each window with varying band-pass filters in 2-90 Hz range. In total, 613 features were investigated. Using logistic regression classifier and leave-one-person-out cross validation we obtained a sensitivity of 73.9%, specificity of 85.7% and AUC of 0.857 (SD = 0.005) using 150 best features. As a result, mechanical signals recorded on the upper chest wall with the accelerometers and gyroscopes differ significantly between STEMI patients and stable patients with normal left ventricular function. Future research will show whether MCG can be used for the early screening of STEMI.

Mechanocardiography-Based Measurement System Indicating Changes in Heart Failure Patients during Hospital Admission and Discharge.

Heart failure (HF) is a disease related to impaired performance of the heart and is a significant cause of mortality and treatment costs in the world. During its progression, HF causes worsening (decompensation) periods which generally require hospital care. In order to reduce the suffering of the patients and the treatment cost, avoiding unnecessary hospital visits is essential, as hospitalization can be prevented by medication. We have developed a data-collection device that includes a high-quality 3-axis accelerometer and 3-axis gyroscope and a single-lead ECG. This allows gathering ECG synchronized data utilizing seismo- and gyrocardiography (SCG, GCG, jointly mechanocardiography, MCG) and comparing the signals of HF patients in acute decompensation state (hospital admission) and compensated condition (hospital discharge). In the MECHANO-HF study, we gathered data from 20 patients, who each had admission and discharge measurements. In order to avoid overfitting, we used only features developed beforehand and selected features that were not outliers. As a result, we found three important signs indicating the worsening of the disease: an increase in signal RMS (root-mean-square) strength (across SCG and GCG), an increase in the strength of the third heart sound (S3), and a decrease in signal stability around the first heart sound (S1). The best individual feature (S3) alone was able to separate the recordings, giving 85.0% accuracy and 90.9% accuracy regarding all signals and signals with sinus rhythm only, respectively. These observations pave the way to implement solutions for patient self-screening of the HF using serial measurements.

Metastable Atrial State Underlies the Primary Genetic Substrate for MYL4 Mutation-Associated Atrial Fibrillation.

BACKGROUND: Atrial fibrillation (AF) is the most common clinical arrhythmia and is associated with heart failure, stroke, and increased mortality. The myocardial substrate for AF is poorly understood because of limited access to primary human tissue and mechanistic questions around existing in vitro or in vivo models. METHODS: Using an MYH6:mCherry knock-in reporter line, we developed a protocol to generate and highly purify human pluripotent stem cell-derived cardiomyocytes displaying physiological and molecular characteristics of atrial cells. We modeled human MYL4 mutants, one of the few definitive genetic causes of AF. To explore non-cell-autonomous components of AF substrate, we also created a zebrafish Myl4 knockout model, which exhibited molecular, cellular, and physiologic abnormalities that parallel those in humans bearing the cognate mutations. RESULTS: There was evidence of increased retinoic acid signaling in both human embryonic stem cells and zebrafish mutant models, as well as abnormal expression and localization of cytoskeletal proteins, and loss of intracellular nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide + hydrogen. To identify potentially druggable proximate mechanisms, we performed a chemical suppressor screen integrating multiple human cellular and zebrafish in vivo endpoints. This screen identified Cx43 (connexin 43) hemichannel blockade as a robust suppressor of the abnormal phenotypes in both models of MYL4 (myosin light chain 4)-related atrial cardiomyopathy. Immunofluorescence and coimmunoprecipitation studies revealed an interaction between MYL4 and Cx43 with altered localization of Cx43 hemichannels to the lateral membrane in MYL4 mutants, as well as in atrial biopsies from unselected forms of human AF. The membrane fraction from MYL4-/- human embryonic stem cell derived atrial cells demonstrated increased phospho-Cx43, which was further accentuated by retinoic acid treatment and by the presence of risk alleles at the Pitx2 locus. PKC (protein kinase C) was induced by retinoic acid, and PKC inhibition also rescued the abnormal phenotypes in the atrial cardiomyopathy models. CONCLUSIONS: These data establish a mechanistic link between the transcriptional, metabolic and electrical pathways previously implicated in AF substrate and suggest novel avenues for the prevention or therapy of this common arrhythmia.

A randomized prospective multicenter trial for stroke prevention by prophylactic surgical closure of the left atrial appendage in patients undergoing bioprosthetic aortic valve surgery--LAA-CLOSURE trial protocol.

Patients undergoing surgical aortic valve replacement (SAVR) are at high risk for atrial fibrillation (AF) and stroke after surgery. There is an unmet clinical need to improve stroke prevention in this patient population. The LAA-CLOSURE trial aims to assess the efficacy and safety of prophylactic surgical closure of the left atrial appendage for stroke and cardiovascular death prevention in patients undergoing bioprosthetic SAVR. This randomized, open-label, prospective multicenter trial will enroll 1,040 patients at 13 European sites. The primary endpoint is a composite of cardiovascular mortality, stroke and systemic embolism at 5 years. Secondary endpoints include cardiovascular mortality, stroke, systemic embolism, bleed fulfilling academic research consortium (BARC) criteria, hospitalization for decompensated heart failure and health economic evaluation. Sample size is based on 30% risk reduction in time to event analysis of primary endpoint. Prespecified reports include 30-day safety analysis focusing on AF occurrence and short-term outcomes and interim analyses at 1 and 3 years for primary and secondary outcomes. Additionally, substudies will be performed on the completeness of the closure using transesophageal echocardiography/cardiac computed tomography and long-term ECG recording at one year after the operation.

Minor troponin T elevation and mortality in patients with atrial fibrillation presenting to the emergency department.

BACKGROUND: There are limited data on the association of minor troponin elevation in unselected patients with atrial fibrillation (AF) presenting to the emergency department (ED) with adverse events. In this study, we sought to assess the early and mid-term mortality of these patients. METHODS: In this observational study, 2911 patients with AF were admitted to the ED. They were divided into 3 groups based on peak high-sensitivity troponin (TnT) levels: normal (<15 ng/L), 15-50 ng/L and 51-100 ng/L. The primary outcomes of this study were all-cause mortality at 30 days and 1 year. RESULTS: All-cause mortality was 6.7% (n = 196) at 30 days and 22.2% (n = 646) at 1 year. Mortality rate increased along with increasing levels of TnT irrespective of baseline covariates, primary discharge diagnosis and type of AF. A significant association between TnT levels and all-cause mortality was observed. The adjusted hazard ratio (HR) at 30 days was 6.02 (95% CI 2.62-13.83) for TnT 15-50 ng/L and 11.28 (95% CI 4.87-26.12) for TnT 51-100 ng/L (P<.001 for both) compared to TnT <15 ng/L. At 1 year, the adjusted HRs were 3.08 (95% CI 2.15-4.40) and 5.07 (95% CI 3.49-7.35), respectively (P < .001). When patients with TnT <15 ng/L were divided into two groups at the median value, TnT elevation of 10 to 14 ng/L was also associated with increased 1-year mortality (HR 2.51; 95% CI 1.09-5.74; P = .03). CONCLUSIONS: Among patients with AF admitted to the ED, increased TnT levels were associated with increased early and mid-term all-cause mortality irrespective of baseline covariates and type of AF.

Assessment of myocardial viability with [15O]water PET: A validation study in experimental myocardial infarction.

BACKGROUND: Assessment of myocardial viability is often needed in patients with chest pain and reduced ejection fraction. We evaluated the performance of reduced resting MBF, perfusable tissue fraction (PTF), and perfusable tissue index (PTI) in the assessment of myocardial viability in a pig model of myocardial infarction (MI). METHODS AND RESULTS: Pigs underwent resting [15O]water PET perfusion study 12 weeks after surgical (n = 16) or 2 weeks after catheter-based (n = 4) occlusion of the proximal left anterior descending coronary artery. MBF, PTF, and PTI were compared with volume fraction of MI in matched segments as assessed by triphenyl tetrazolium chloride staining of LV slices. MBF and PTF were lower in infarcted than non-infarcted segments. Segmental analysis of MBF showed similar area under the curve (AUC) of 0.85, 0.86, and 0.90 with relative MBF, PTF, and PTI for the detection of viable myocardium defined as infarct volume fraction of < 75%. Cut-off values of relative MBF of ≥ 67% and PTF of ≥ 66% resulted in accuracies of 90% and 81%, respectively. CONCLUSIONS: Our results indicate that resting MBF, PTF, and PTI based on [15O]water PET perfusion imaging are useful for the assessment of myocardial viability.

Interatrial block, P terminal force or fragmented QRS do not predict new-onset atrial fibrillation in patients with severe chronic kidney disease.

BACKGROUND: The prevalence of left atrial enlargement (LAE) and fragmented QRS (fQRS) diagnosed using ECG criteria in patients with severe chronic kidney disease (CKD) is unknown. Furthermore, there is limited data on predicting new-onset atrial fibrillation (AF) with LAE or fQRS in this patient group. METHODS: We enrolled 165 consecutive non-dialysis patients with CKD stage 4-5 without prior AF diagnosis between 2013 and 2017 in a prospective follow-up cohort study. LAE was defined as total P-wave duration ≥120 ms in lead II ± > 1 biphasic P-waves in leads II, III or aVF; or duration of terminal negative portion of P-wave > 40 ms or depth of terminal negative portion of P-wave > 1 mm in lead V1 from a baseline ECG, respectively. fQRS was defined as the presence of a notched R or S wave or the presence of ≥1 additional R waves (R') or; in the presence of a wide QRS complex (> 120 ms), > 2 notches in R or S waves in two contiguous leads corresponding to a myocardial region, respectively. RESULTS: Mean age of the patients was 59 (SD 14) years, 56/165 (33.9%) were female and the mean estimated glomerular filtration rate was 12.8 ml/min/1.73m2. Altogether 29/165 (17.6%) patients were observed with new-onset AF within median follow-up of 3 [IQR 3, range 2-6] years. At baseline, 137/165 (83.0%) and 144/165 (87.3%) patients were observed with LAE and fQRS, respectively. Furthermore, LAE and fQRS co-existed in 121/165 (73.3%) patients. Neither findings were associated with the risk of new-onset AF within follow-up. CONCLUSION: The prevalence of LAE and fQRS at baseline in this study on CKD stage 4-5 patients not on dialysis was very high. However, LAE or fQRS failed to predict occurrence of new-onset AF in these patients.

Population trends in aortic valve surgery in Finland between 2001 and 2016.

Objectives. To investigate nationwide changes in procedure rates, patient selection, and prognosis after all surgical aortic valve replacements. Design. Patients undergoing primary surgical aortic valve replacement between 2001 and 2016 were identified from three nationwide registers with compulsory reporting to examine trends in aortic valve surgery over four four-year time periods. Results. A total of 12,139 surgical aortic valve replacement procedures (mean age 61.9 ± 11.8 years, 39.1% women) were performed. The total number of biological valves increased from 1001 (42.9%) to 2526 (75.5%) from 2001-2004 to 2013-2016 (p < .001). During the first and last time periods the comorbidity burden increased; share of patients with hypertension increased from 37.5% to 46.9% (p < .001), diabetes from 14% to 16.5% (p = .01) and previous stroke from 5.2% to 7.2% (p = .01). The proportion of women undergoing surgery decreased from 40% to 36.1% from 2001-2004 to 2013-2016, respectively (p = .01). Overall 28-day mortality was 3.5%. In patients with biologic valve the multivariable-adjusted risk of short-term mortality decreased steadily in every four-year period from 2001-2004 to 2005-2008 (HR, 0.66; 95% CI 0.47-9.92), 2009-2012 (HR, 0.54; 95% CI, 0.39-0.75) and 2013-2016 (HR, 0.41; 95% CI, 0.29-0.58), whereas short-term mortality remained similar in patients with mechanical valve. The risk of four-year postoperative mortality after all surgical aortic valve replacements stayed constant. Conclusions. The use of biologic aortic valve prosthesis has increased from 2001 to 2016. The proportion of women has declined markedly. The short-term mortality has decreased and the long-term mortality has stayed constant despite increasing comorbidity burden.

Impact of preoperative thrombocytopenia on the outcome after coronary artery bypass grafting.

The impact of thrombocytopenia on postoperative bleeding and other major adverse events after cardiac surgery is unclear. This issue was investigated in a series of patients who underwent isolated coronary artery bypass grafting (CABG) from the prospective, multicenter E-CABG registry. Preoperative thrombocytopenia was defined as preoperative platelet count <150 × 109/L and it was considered moderate-severe when preoperative platelet count was <100 × 109/L. Multilevel mixed-effects regression analysis was performed to adjust the effect of thrombocytopenia on outcomes for baseline and operative covariates as well as for interinstitutional differences in patient-blood management. Among 7189 patients included in this analysis, 599 (8.3%) had preoperative thrombocytopenia. Patient with preoperative thrombocytopenia had an increased chest drainage output at 12 h (mean, 519 vs. 456 mL, adjusted coeff. 39, 95%CI 18-60) and rates of severe-massive bleeding (Universal Definition of Perioperative Bleeding (UDPB) severity grades 3-4: 12.7% vs. 8.1%, adjusted OR 1.47, 95%CI 1.11-1.93; E-CABG bleeding severity grades 2-3: 10.4% vs. 6.1%, adjusted OR 1.78, 95%CI 1.30-2.43). Thrombocytopenia was associated with an increased risk of hospital/30-day death (3.2% vs. 1.9%, adjusted OR 2.02, 95%CI 1.20-3.42), 1-year death (5.7% vs. 3.4%, adjusted HR 1.68, 95%CI 1.16-2.44), deep sternal wound infection (3.5% vs. 2.4%, adjusted OR 1.65, 95%CI 1.02-2.66), acute kidney injury (28.1% vs. 22.2%, OR 1.45, 1.18-1.78), and prolonged stay in the intensive care unit (mean, 3.6 vs 2.8 days, adjusted coeff. 0.74, 95%CI 0.40-1.09). Similar results were observed in a subset of patients with moderate-severe thrombocytopenia (51 patients, 0.7%). In particular, these patients had a markedly higher rate of acute kidney injury (40%, adjusted OR, 1.94, 95%CI 1.05-3.57), resternotomy for bleeding (7.8%, adjusted OR 3.49, 95%CI 1.20-10.21), and severe-massive bleeding (UDPB severity grades 3-4: 23.5%, adjusted OR 3.08, 95%CI 1.52-6.22; E-CABG bleeding severity grades 2-3: 23.5%, adjusted OR 4.43, 95%CI 2.15-9.15) compared to patients with normal preoperative platelet count. Mild preoperative thrombocytopenia is associated with increased risk of severe-massive bleeding, mortality, and other major adverse events after CABG. Such risks are markedly increased in patients with moderate-severe preoperative thrombocytopenia.

Population trends in mitral valve surgery in Finland between 1997 and 2014: the finnish CVD register.

OBJECTIVES: Contemporary, nationwide data on trends in mitral valve surgery are scarce. Our aim was to investigate changes in procedure rates, patient selection, and post-procedural prognosis of open-heart mitral valve surgery in Finland. DESIGN: We combined data from three nationwide administrative registers with compulsory reporting. We identified patients who had undergone first-ever open-heart mitral valve surgery between 1997 and 2014 and followed them for adverse events. We examined trends in mitral valve surgery over three six-year time periods (1997-2002, 2003-2008, and 2009-2014). RESULTS: 3684 mitral valve procedures (mean age: 67.0 ± 10.9 years, 42.6% women) were performed in 1997-2014 in Finland. During this period, mitral valve repair operations became more common than replacements and we observed an increasing trend in the use of bioprosthetic valves. Between 1997-2002 and 2009-2014, the mean age of patients undergoing mitral valve surgery and the proportion of urgent surgeries increased (p < .001 for both). The proportion of women undergoing surgery decreased while the share of patients with hypertension (p = .023) or diabetes (p = .026) increased. The multivariable-adjusted risk of 28-day (hazard ratio, 0.55; 95% confidence interval, 0.37-0.83) and 6-year (hazard ratio, 0.80; 95% confidence interval, 0.67-0.97) post-operative mortality was lower in the last six-year period than in 1994-1998. CONCLUSIONS: Short- and long-term mortality of mitral valve surgery patients in Finland has decreased from 1997 to 2014 despite the patients being older and having more comorbidities. Understanding the changing characteristics and prognosis of these patients is important for the interpretation of previous and future cohort studies and trials.

Meta-analysis of the Sources of Bleeding after Adult Cardiac Surgery.

OBJECTIVE: The aim of this study was to pool data on the proportion and prognostic impact of sources of bleeding in patients requiring re-exploration after adult cardiac surgery. DESIGN: Systematic review of the literature and meta-analysis. SETTING: Multistitutional study. MEASUREMENTS AND MAIN RESULTS: A literature review was performed to identify studies published since 1990 evaluating the outcome after reoperation for bleeding or tamponade after adult cardiac surgery. Eighteen studies including 5,1497 patients fulfilled the selection criteria. Reoperation for bleeding/tamponade was performed in 2,455 patients (4.6%; 95% confidence interval [CI] 3.9%-5.2%, I2 92%). These had a significantly higher risk of in-hospital/30-day mortality compared with patients not reoperated for bleeding (pooled rates: 9.3% v 2.3%; risk ratio 3.30; 95% CI 2.52-4.32; I2 47%; 8 studies; 25,463 patients). Surgical sites of bleeding were identified in 65.7% of cases (95% CI 58.3%-73.2%; I2 94%), cardiac site bleeding in 40.9% of cases (95% CI 29.7%-52.0%; I2 94%), and mediastinal/sternum site bleeding in 27.0% of cases (95% CI 16.8%-37.3%; I2 94%). The main sites of bleeding were the body of the graft (20.2%), the sternum (17.0%), vascular sutures (12.5%), the internal mammary artery harvest site (13.0%), and anastomoses (9.9%). In metaregression, surgical site bleeding was associated with a lower risk of in-hospital/30-day mortality compared with diffuse bleeding (p = 0.003). CONCLUSIONS: Surgical site bleeding is identified in two-thirds of patients undergoing re-exploration after adult cardiac surgery. Meticulous surgical technique and systematic intraoperative checking of potential surgical sites of bleeding at the time of the original cardiac surgery may reduce the risk of such a severe complication.

Time in therapeutic range and major adverse outcomes in atrial fibrillation patients undergoing percutaneous coronary intervention: The Atrial Fibrillation Undergoing Coronary Artery Stenting (AFCAS) registry.

BACKGROUND: Combination of oral anticoagulation (OAC) and antiplatelets is used in atrial fibrillation (AF) patients undergoing percutaneous coronary intervention and stent (PCI-S) procedure but is associated with increased bleeding when triple antithrombotic therapy (TAT) is used. Our aim was to analyze the impact of time in therapeutic range (TTR) on outcomes, in patients prescribed with TAT. METHODS: Ancillary analysis from the AFCAS registry in patients assigned to TAT. TTR was calculated with Rosendaal method. Outcomes were analyzed according to TTR tertiles (T1 [≤56.8%] vs. T2 [56.9-93.8%] vs. T3 [≥93.9%]). Major bleeding was the primary outcome. RESULTS: Of 963 patients enrolled, 470(48.8%) were prescribed with TAT at discharge and qualified for this analysis. Median [IQR] TTR was 80.0% [45.3-100%]. After 359 [341-370] days, major bleeding rates were progressively lower with increasing TTR tertiles (T1 vs. T2 vs. T3: 10.3% vs. 4.7% vs. 2.3%, P=.006). Kaplan-Meier analysis demonstrated a progressively lower risk for major bleeding across tertiles (P=.006). Patients in the highest TTR tertile had a non-significant lower risk for major adverse coronary and cerebrovascular events (MACCE) (log-rank: 4.905, P=.086). Cox regression analysis showed that T2 and T3 were inversely associated with major bleeding (hazard ratio [HR]:0.39, P=.050 and HR: 0.21, P=.005). Continuous TTR was inversely associated with major bleeding (HR: 0.98, P<.001). For MACCE, adjusted Cox analysis found a non-significant lower risk for T3 (HR: 0.64, P=.128). CONCLUSIONS: In AF patients undergoing PCI-S prescribed TAT, good quality anticoagulation control (as reflected by TTR) was closely related to bleeding outcomes during follow-up. Despite some suggestive trends for an inverse relationship between TTR and MACCE, no definitive conclusions can be drawn, and further large studies are needed.

Imaging of αvß3 integrin expression in experimental myocardial ischemia with [68Ga]NODAGA-RGD positron emission tomography.

BACKGROUND: Radiolabeled RGD peptides detect αvß3 integrin expression associated with angiogenesis and extracellular matrix remodeling after myocardial infarction. We studied whether cardiac positron emission tomography (PET) with [68Ga]NODAGA-RGD detects increased αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs, and whether αvß3 integrin is expressed in viable ischemic or injured myocardium. METHODS: We studied 8 Finnish landrace pigs 13 ± 4 days after percutaneous implantation of a bottleneck stent in the proximal left anterior descending coronary artery. Antithrombotic therapy was used to prevent stent occlusion. Myocardial uptake of [68Ga]NODAGA-RGD (290 ± 31 MBq) was evaluated by a 62 min dynamic PET scan. The ischemic area was defined as the regional perfusion abnormality during adenosine-induced stress by [15O]water PET. Guided by triphenyltetrazolium chloride staining, tissue samples from viable and injured myocardial areas were obtained for autoradiography and histology. RESULTS: Stent implantation resulted in a partly reversible myocardial perfusion abnormality. Compared with remote myocardium, [68Ga]NODAGA-RGD PET showed increased tracer uptake in the ischemic area (ischemic-to-remote ratio 1.3 ± 0.20, p = 0.0034). Tissue samples from the injured areas, but not from the viable ischemic areas, showed higher [68Ga]NODAGA-RGD uptake than the remote non-ischemic myocardium. Uptake of [68Ga]NODAGA-RGD correlated with immunohistochemical detection of αvß3 integrin that was expressed in the injured myocardial areas. CONCLUSIONS: Cardiac [68Ga]NODAGA-RGD PET demonstrates increased myocardial αvß3 integrin expression after induction of flow-limiting coronary stenosis in pigs. Localization of [68Ga]NODAGA-RGD uptake indicates that it reflects αvß3 integrin expression associated with repair of recent myocardial injury.

Aberrant circulating levels of purinergic signaling markers are associated with several key aspects of peripheral atherosclerosis and thrombosis.

RATIONALE: Purinergic signaling plays an important role in inflammation and vascular integrity, but little is known about purinergic mechanisms during the pathogenesis of atherosclerosis in humans. OBJECTIVE: The objective of this study is to study markers of purinergic signaling in a cohort of patients with peripheral artery disease. METHODS AND RESULTS: Plasma ATP and ADP levels and serum nucleoside triphosphate diphosphohydrolase-1 (NTPDase1/CD39) and ecto-5'-nucleotidase/CD73 activities were measured in 226 patients with stable peripheral artery disease admitted for nonurgent invasive imaging and treatment. The major findings were that ATP, ADP, and CD73 values were higher in atherosclerotic patients than in controls without clinically evident peripheral artery disease (P<0.0001). Low CD39 activity was associated with disease progression (P=0.01). In multivariable linear regression models, high CD73 activity was associated with chronic hypoxia (P=0.001). Statin use was associated with lower ADP (P=0.041) and tended to associate with higher CD73 (P=0.054), while lower ATP was associated with the use of angiotensin receptor blockers (P=0.015). CONCLUSIONS: Purinergic signaling plays an important role in peripheral artery disease progression. Elevated levels of circulating ATP and ADP are especially associated with atherosclerotic diseases of younger age and smoking. The antithrombotic and anti-inflammatory effects of statins may partly be explained by their ability to lower ADP. We suggest that the prothrombotic nature of smoking could be a cause of elevated ADP, and this may explain why cardiovascular patients who smoke benefit from platelet P2Y12 receptor antagonists more than their nonsmoking peers.

Prediction of ineffective elective cardioversion of atrial fibrillation: a retrospective multi-center patient cohort study.

BACKGROUND: Elective cardioversion (ECV) of atrial fibrillation (AF) is a standard procedure to restore sinus rhythm. However, predictors for ineffective ECV (failure of ECV or recurrence of AF within 30 days) are unknown. METHODS: We investigated 1998 ECVs performed for AF lasting >48 h in 1,342 patients in a retrospective multi-center study. Follow-up data were collected from 30 days after ECV. RESULTS: Median number of cardioversions was one per patient with a range of 1-10. Altogether 303/1998 (15.2%) ECVs failed. Long (>5 years) AF history and over 30 days duration of the index AF episode were independent predictors for ECV failure and low (<60/min) ventricular rate of AF predicted success of ECV. In patients with successful ECVs an early recurrence of AF was detected in 549 (32.4%) cases. Female gender, high (>60/min) ventricular rate, renal failure and antiarrhythmic agents at discharge were the independent predictors for recurrence. In total ECV was ineffective in 852 (42.6%) cases. Female gender (OR 1.44, CI95% 1.15-1.80, p < 0.01), young (<65 years) age (OR 1.31, CI95% 1.07-1.62, p = 0.01), ventricular rate >60/min (OR 1.92, CI95% 1.08-3.41, p = 0.03), antiarrhythmic medication at discharge (OR 1.48, CI95% 1.14-1.93, p < 0.01) and low (<60/ml/min) estimated glomerular filtration rate (OR 1.59, CI95% 1.08-2.33, p = 0.02) were predictors of ineffective ECV. CONCLUSIONS: Female gender, use of antiarrhythmic drug therapy and renal failure predicted both recurrence of AF and the composite end point. For the first time in a large real-life study several clinical predictors for clinically ineffective ECV were identified.

Early neointimal coverage and vasodilator response following biodegradable polymer sirolimus-eluting vs. durable polymer zotarolimus-eluting stents in patients with acute coronary syndrome ­HATTRICK-OCT trial.

BACKGROUND: Patients at high bleeding risk would benefit from a shorter dual antiplatelet therapy after PCI. Compared to first-generation devices, the design of newer generation drug-eluting stents may facilitate more rapid anatomical and functional healing of stented vessel based on thinner stent platforms, biodegradable/biocompatible polymers and rapid drug elution. METHODS AND RESULTS: Forty-four non-diabetic patients with acute coronary syndrome (ACS) and culprit lesion in the LAD were randomized to receive either biodegradable polymer sirolimus-eluting stent (BP-SES) or durable polymer zotarolimus-eluting stent (DP-ZES). Neointimal strut coverage was examined using optical coherence tomography, and vasodilator response on invasive thermodilution-derived coronary flow reserve (CFR) at 3-month follow-up. The primary endpoints were percent uncovered struts and CFR. A total of 425 cross-sections (4,897 struts) were analyzed in the BP-SES group, and 425 cross-sections (5,467 struts) in the DP-ZES group. The percent uncovered struts was lower in the BP-SES group compared with the DP-ZES group, both at strut level (3.9% vs. 8.9%, respectively, P<0.001), and stent level (3.9 ± 3.2% vs. 8.9 ± 6.9%, respectively, P=0.019). No significant difference was found between the 2 groups regarding CFR (3.0 ± 1.3 vs. 3.2 ± 1.0, respectively, P>0.05). CONCLUSIONS: In non-diabetic patients with ACS, BP-SES provided slightly better stent strut coverage at 3 months compared with DP-ZES, but neither stent was fully covered. No difference in vasodilator response was seen.