Ten-Year Clinical Outcomes From a Trial of Three Limus-Eluting Stents With Different Polymer Coatings in Patients With Coronary Artery Disease.

BACKGROUND: New-generation drug-eluting stents offer the potential for enhanced late outcomes in comparison with early generation drug-eluting stents. However, assessment of extended long-term outcomes for these devices is lacking, especially regarding the comparison between new-generation drug-eluting stents with biodegradable or permanent polymers. The aim of this study is to compare the efficacy and safety of biodegradable polymer-based sirolimus-eluting stents (BP-SES; Yukon Choice PC) versus permanent polymer-based everolimus-eluting stents (PP-EES; Xience) versus early generation permanent polymer-based sirolimus-eluting stents (PP-SES; Cypher) at 10-year follow-up. METHODS: Overall, 2603 patients were randomized to treatment with BP-SES (n=1299), PP-EES (n=652), or PP-SES (n=652). The primary end point of this analysis was major adverse cardiac event, the composite of death, myocardial infarction, or target lesion revascularization. The main secondary end point of interest was definite/probable stent thrombosis. Follow-up at 10 years was available in 83% of the study patients. RESULTS: The 10-year incidence of major adverse cardiac event (BP-SES 47.7% versus PP-EES 46.0% versus PP-SES 54.9%, P=0.003) and mortality (BP-SES 31.8% versus PP-EES 30.3% versus PP-SES 37.2%, P=0.02) was different among the groups. Definite/probable stent thrombosis was not significantly different among the groups (BP-SES 1.8% versus PP-EES 2.5% versus PP-SES 3.7%, P=0.09). Definite stent thrombosis was significantly different among the groups (BP-SES 1.1% versus PP-EES 0.8% versus PP-SES 2.4%, P=0.03). There were no significant differences between BP-SES and PP-EES. CONCLUSIONS: In this unique long-term outcome analysis, BP-SES and PP-EES showed comparable clinical outcomes out to 10 years. PP-SES had higher rates of major adverse cardiac events and definite stent thrombosis. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00598676.

Efficacy of drug-coated balloon angioplasty in early versus late occurring drug-eluting stent restenosis: A pooled analysis from the randomized ISAR DESIRE 3 and DESIRE 4 trials.

BACKGROUND: Whether there exist differences concerning clinical outcomes between patients presenting with early versus late DES-ISR undergoing treatment with drug-coated balloons (DCB) remains a scientific knowledge gap. METHODS: This is a pooled analysis including patients with DES-ISR assigned to treatment with DCB in the setting of the ISAR DESIRE 3 and 4 trials. Clinical outcomes were evaluated according to time of occurrence of ISR after DES implantation, in patients presenting with early (≤12 months) versus late DES-ISR (>12 months) undergoing treatment with DCB. The primary endpoint of this analysis was major adverse cardiac event (MACE), defined as the combined incidence of death, myocardial infarction and target lesion revascularization (TLR) at 12 months after DCB treatment. Secondary endpoints included the incidence of death, myocardial infarction, TLR and target lesion thrombosis at 12 months after DCB treatment. RESULTS: This analysis included 352 patients, 199 patients presented with early-ISR, 153 patients with late-ISR. Concerning the primary endpoint, patients with early-DES-ISR as compared those with late-DES-ISR showed significant higher risk (25.9% vs. 17.0%; p = .04). In a multivariate analysis including diabetic status, clinical presentation, previous coronary bypass graft and diameter stenosis after DCB-treatment, the adjusted hazard ratio showed significant higher risk for MACE of early-DES-ISR as compared to late-DES-ISR (HRadj = 1.8, [95% CI = 1.1-3.0], p = .02). CONCLUSION: Clinical outcome at 12 months after treatment of DES-ISR with DCB, showed significant higher clinical event rates in patients presenting with early DES restenosis, as compared with patients presenting with late DES restenosis.

Are we curing one evil with another? A translational approach targeting the role of neoatherosclerosis in late stent failure.

Neoatherosclerosis is defined as foamy macrophage infiltration into the peri-strut or neointimal area after stent implantation, potentially leading to late stent failure through progressive atherosclerotic changes including calcification, fibroatheroma, thin-cap fibroatheroma, and rupture with stent thrombosis (ST) in advanced stages. Human autopsy as well as intravascular imaging studies have led to the understanding of neoatherosclerosis formation as a similar but significantly accelerated pathophysiology as compared to native atherosclerosis. This acceleration is mainly based on disrupted endothelial integrity with insufficient barrier function and augmented transmigration of lipids following vascular injury after coronary intervention and especially after implantation of drug-eluting stents. In this review, we summarize translational insights into disease pathophysiology and discuss therapeutic approaches to tackle this novel disease entity. We introduce a novel animal model of neoatherosclerosis alongside accompanying in vitro experiments, which show impaired endothelial integrity causing increased permeability for low-density lipoprotein cholesterol resulting in foam cell transformation of human monocytes. In addition, we discuss novel intravascular imaging surrogates to improve reliable diagnosis of early stage neoatherosclerosis. Finally, a therapeutic approach to prevent in-stent neoatherosclerosis with magnesium-based bioresorbable scaffolds and systemic statin treatment demonstrated the potential to improve arterial healing and re-endothelialization, leading to significantly mitigated neoatherosclerosis formation in an animal model of neoatherosclerosis.

La neoateroesclerosis se define como infiltración de macrófagos espumosos en la zona periprotésica o de la neoíntima tras una implantación de stent, lo cual posiblemente derive en un fracaso tardío del stent mediante cambios ateroescleróticos progresivos, incluidos la calcificación, fibroateromas, fibroateromas de cápsula fina (FACF) y trombosis del stent (TS). Gracias a los estudios de autopsia humana y de imagen intravascular se ha podido comprender la formación de la neoateroesclerosis de una manera fisiopatológica similar a la ateroesclerosis nativa pero significativamente acelerada. Esta aceleración se basa principalmente en la alteración de la integridad endotelial con una función de barrera insuficiente y una mayor transmigración de lípidos a consecuencia de una lesión vascular tras una intervención coronaria y, especialmente, tras la implantación de stents farmacoactivos. En este artículo ofrecemos un resumen de las perspectivas translacionales sobre la fisiopatología de la enfermedad y analizamos los enfoques terapéuticos para abordar esta nueva enfermedad. Presentamos un modelo animal de neoateroesclerosis innovador junto con experimentos in vitro complementarios, en los cuales se pone de manifiesto que la integridad endotelial dañada causa una mayor permeabilidad para el colesterol de las LDL (LDL), lo que da lugar a que los monocitos se transformen en células espumosas. Asimismo, comentamos los criterios indirectos de valoración de imagen intravascular a fin de mejorar el diagnóstico fiable de la neoateroesclerosis en fase inicial. Por último, en un enfoque terapéutico para prevenir la neoateroesclerosis del stent con andamios de magnesio biorreabsorbibles (BRS) y un tratamiento sistémico con estatinas se demostró la posibilidad de mejorar la cicatrización y la reendotelización arteriales, lo que derivó en la formación de neoateroesclerosis significativamente más lenta en un modelo animal de neoateroesclerosis.

Prospective, randomized trial of bioresorbable scaffolds vs. everolimus-eluting stents in patients undergoing coronary stenting for myocardial infarction: the Intracoronary Scaffold Assessment a Randomized evaluation of Absorb in Myocardial Infarction (ISAR-Absorb MI) trial.

Aims: Bioresorbable scaffolds (BRS) provide short-term coronary artery scaffolding and drug delivery. Although prior trials showed a higher rate of device failure compared with conventional drug-eluting stents (DES), only a single trial investigated patients undergoing percutaneous coronary intervention (PCI) for acute myocardial infarction (MI). We aimed to compare outcomes with BRS vs. DES in patients undergoing PCI for MI. Methods and results: We did a prospective, randomized, multicentre, non-inferiority, clinical trial of everolimus-eluting BRS vs. durable polymer everolimus-eluting stents (EES) in patients with acute MI. Patients were eligible for enrolment if they presented with ST-elevation MI, or non-ST-elevation MI with thrombosis visual at angiography and were randomly allocated to treatment with BRS or EES in 2:1 proportion. Angiographic follow-up was scheduled at 6-8 months and clinical follow-up was done at 12 months. The primary endpoint was percentage diameter stenosis in-segment at follow-up. A total of 262 patients were enrolled and were allocated to BRS (n = 173) or EES (n = 89). Angiographic follow-up was available for 213 (81.3%) patients. Mean diameter stenosis was 24.6 ± 12.2% with BRS vs. 27.3 ± 11.7% with EES (mean difference -2.7%, upper limit of one-sided 97.5% confidence limit 0.7%, pre-specified margin of non-inferiority 5%, Pnon-inferiority <0.001). The rate of the device-oriented composite of cardiac death/target vessel MI/target lesion revascularization [BRS: 12 (7.0%) vs. EES: 6 (6.7%), hazard ratio (HR) 1.04, 95% confidence interval (CI) 0.39-2.78] and definite/probable stent thrombosis [3 (1.7%) vs. 2 (2.3%), HR 0.76, 95% CI 0.13-4.56] were comparable in both groups. Conclusion: In patients undergoing PCI for acute MI BRS were non-inferior to EES for percentage diameter stenosis at angiographic follow-up. Rates of clinical events were comparable between the treatment groups, although the study was not powered to detect differences in clinical outcomes. Clinical trial registration: The trial was registered at www.clinicaltrials.gov (NCT01942070).

Outcome after new generation single-layer polytetrafluoroethylene-covered stent implantation for the treatment of coronary artery perforation.

AIMS: Coronary artery perforation (CAP) is a rare but severe complication during percutaneous coronary intervention (PCI). Implantation of covered stents (CS) represents a potentially life-saving treatment. Concerns exist regarding limited efficacy and high stent thrombosis (ST) rates related to early generation CS. The aim of this study was to evaluate angiographic and clinical outcomes of patients with CAP treated with a new generation single-layer polytetrafluoroethylene (PTFE)-CS. METHODS: Between May 2013 and November 2017, we identified a total of 61 patients who underwent implantation of 71 single layer PTFE-CS after CAP. We analyzed angiographic results at follow up (including binary angiographic restenosis [BAR] and late-lumen-loss [LLL]) and clinical outcomes in hospital and at follow up, including target lesion revascularization (TLR), cardiovascular-, and all-cause mortality, myocardial infarction (MI) and stent thrombosis (ST). RESULTS: Procedural success was achieved in all but two patients (96.7%). Procedure related MI, occurred in 19 cases (31.1%), in hospital death occurred in five cases (8.2%). At follow-up, TLR occurred in 11 cases (18.0%), two patients (3.3%) died from non-cardiovascular cause, there was no case of MI or ST. CONCLUSIONS: In this retrospective analysis, implantation of a new generation PTFE-CS, for the treatment of CAP showed high technical success rates. Although, periprocedural MI-and in-hospital-death rates remain not inconsiderable, new generation PTFE-CS showed favorable angiographic and clinical efficacy and high safety profile, especially with regard to thrombotic events.

Cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: an updated meta-analysis of randomized and observational studies.

AIMS: Radiofrequency (RF) ablation represents a standard of care for pulmonary vein isolation in patients with drug-refractory paroxysmal atrial fibrillation (AF). In this setting, cryoballoon (CB) ablation has emerged as alternative therapy. However, the efficacy and safety of CB vs. RF ablation in patients with paroxysmal AF remain a matter of debate. METHODS AND RESULTS: We searched electronic scientific databases for studies of CB vs. RF ablation in patients with paroxysmal AF. Aggregate data were pooled to perform a meta-analysis. The primary efficacy and safety outcomes were the recurrence of any atrial arrhythmia and procedure-related complications, respectively. A total of 6473 participants from 10 studies (CB, n = 2232 vs. RF, n = 4241) were studied. After a median follow-up of 16 months, the risk of any atrial arrhythmia recurrence (risk ratio, RR 95% confidence interval [95% CI] = 1.01 [0.90-1.14], P = 0.83) and procedure-related complications (RR [95% CI] = 0.92 [0.66-1.28], P = 0.61) were comparable between CB vs. RF ablation. Cryoballoon ablation led to a higher risk of persistent phrenic nerve palsy (RR [95% CI] = 13.60 [3.87-47.81], P < 0.01) and a lower risk of cardiac tamponade (RR [95% CI] = 0.48 [0.25-0.89], P = 0.02) compared with RF ablation. There was a trend of statistically significant interaction between the type of CB and the duration of ablation (P for interaction = 0.09). CONCLUSION: In patients with paroxysmal AF, ablation therapy with CB is associated with efficacy and safety comparable to that of RF. Second-generation CB catheters seem to reduce procedure duration. Further studies are warranted to disclose the impact of second-generation CB catheters compared with RF for ablation of paroxysmal AF.

Association of progression or regression of coronary artery atherosclerosis with long-term prognosis.

BACKGROUND: The association between coronary atherosclerosis progression or regression and long-term prognosis remains poorly defined. We assessed the association of atherosclerosis progression or regression with long-term mortality and factors that promote angiographic progression or regression of coronary atherosclerosis in patients with angiographically proven coronary artery disease. METHODS: The study included 605 patients with coronary artery disease who underwent coronary angiography at baseline and at 2 years later. Pan-coronary artery tree quantitative coronary angiography was performed. Of 6259 coronary segments (10.3 lesions per patient) analyzed, 1790 non-stented segments with ≥25% diameter stenosis at baseline were included. Atherosclerosis progression or regression was defined as a decrease or increase in the mean minimal lumen diameter (MLD) of the non-stented segments of ≥0.2 mm in the 2-year angiography compared to baseline angiography. The primary outcome was all-cause mortality. RESULTS: Based on the change in mean MLD between baseline and 2-year angiography, patients were divided into 3 groups: the group with progression of atherosclerosis (n=53; 8.8%), the group with no progression or regression of atherosclerosis (n=472; 78.0%) and the group with regression of atherosclerosis (n=80; 13.2%). There were 126 deaths over 8-year follow-up: 17 deaths among patients with progression, 103 deaths among patients with no progression/regression and 6 deaths among patients with regression (Kaplan-Meier estimates of mortality, 37.5%, 25.2% and 8.9%, respectively; adjusted hazard ratio=1.16, 95% confidence interval 1.05 to 1.29, P=.004 for 0.1 mm reduction in mean MLD). CONCLUSIONS: Progression or regression of coronary atherosclerosis in non-treated coronary segments was significantly associated with 8-year mortality.

Association of Toll-like receptor 4 polymorphism with age-dependent systolic blood pressure increase in patients with coronary artery disease.

BACKGROUND: Systolic blood pressure (SBP) increases steadily with age and bears an independent continuous relationship with the incidence of cardiovascular events. Low-grade inflammation is a suspected pathomechanism causing vascular aging and promote coronary artery disease (CAD). Recent animal studies give evidence that Toll-like receptor 4 (TLR4) modulate inflammation and contribute to age-dependent SBP increase. However, there are no data about TLR4 and age-dependent blood pressure increase in human. METHODS AND RESULTS: We therefor investigate a human cohort of 2679 patients with CAD aged between 50-80 years. Genotypes were determined for the TLR4 single nucleotide polymorphism rs4986790 (TLR4 896A/G). Patients were stratified according to tertiles of age and the upper tertile was compared to lower tertiles. In this cohort we show that older patients with the TLR4 896 G allele had significantly lower SBP (TLR4 G allele carriers: 148.2 ± 30.4 mmHg versus A/A allele carrier: 154.9 ± 27.2 mmHg; P < 0.05) and lower pulse pressure (TLR4 G allele carriers: 69.1 ± 29.7 mmHg versus A/A allele carrier: 75.5 ± 26.4 mmHg; P < 0.05) as compared to TLR4 896A/A allele carrier. CONCLUSION: We demonstrate an association between the TLR4 SNP rs4986790 genotype and age-dependant blood pressure increase in patients with coronary artery disease.

Prasugrel plus bivalirudin vs. clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction.

AIMS: Whether prasugrel plus bivalirudin is a superior strategy to unfractionated heparin plus clopidogrel in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) has never been assessed in specifically designed randomized trials. METHODS AND RESULTS: The Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 study is an investigator-initiated, randomized, open-label, multicentre trial, designed to test the hypothesis that in STEMI patients with planned primary PCI a strategy based on prasugrel plus bivalirudin is superior to a strategy based on clopidogrel plus heparin in terms of net clinical outcome. Owing to slow recruitment, the trial was stopped prematurely after enrolment of 548 of 1240 planned patients. At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin [relative risk, 1.09; one-sided 97.5% confidence interval (CI) 0-1.79, P = 0.680]. The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, or stroke occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI 0.40-1.96, P = 0.894). Bleeding according to the HORIZONS-AMI definition was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI 0.74-1.88, P = 0.543). Results were consistent across various subgroups of patients. CONCLUSION: In this randomized trial of STEMI patients, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin. Neither the composite of ischaemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with a regimen of clopidogrel plus unfractionated heparin. However, the results must be interpreted in view of the premature termination of the trial. CLINICAL TRIAL REGISTRATION INFORMATION: Unique identifier NCT00976092 (www.clinicaltrials.gov).

Impact of inhospital stent thrombosis and cerebrovascular accidents on long-term prognosis after percutaneous coronary intervention.

BACKGROUND: Inhospital stent thrombosis (ST) and cerebrovascular accidents (CVA) are rare but serious adverse events after percutaneous coronary intervention (PCI). The association of ST or CVA with long-term outcome after PCI remains poorly investigated. METHODS: The study included 18,334 consecutive patients who underwent PCI. Patients were divided into 3 groups: the group with ST, the group with CVA, and the group without these events. The primary outcome was all-cause mortality at 3-year follow-up. RESULTS: Inhospital ST or CVA occurred in 59 patients (0.32%) and in 90 patients (0. 49%), respectively. There were 2,149 deaths (11.7%) during the follow-up: 26 deaths among patients with ST, 32 deaths among patients with CVA, and 2,091 deaths among patients without ST or CVA (Kaplan-Meier estimates of 3-year mortality 45.3%, 38.0%, and 12.9%, odds ratio 6.1, 95% CI 3.6-10.2, P < .001 for ST group vs the group without ST or CVA and odds ratio 4.2 [2.7-6.6], P < .001 for CVA group vs the group without ST or CVA). There was no significant difference in the 3-year mortality between CVA and ST groups (P = .29). The Cox proportional hazards model showed that ST (adjusted hazard ratio 4.97, 95% CI 2.58-9.56, P < .001) and CVA (adjusted hazard ratio 2.25 [1.25-4.04], P = .006) were independently associated with the increased risk of 3-year mortality. CONCLUSION: Inhospital ST and CVA after PCI are associated with the increased risk of 3-year mortality. Both events seem to have a similar impact on long-term survival.

Comparison of vascular closure devices vs manual compression after femoral artery puncture: the ISAR-CLOSURE randomized clinical trial.

IMPORTANCE: The role of vascular closure devices (VCD) for the achievement of hemostasis in patients undergoing transfemoral coronary angiography remains controversial. OBJECTIVE: To compare outcomes with the use of 2 hemostasis strategies after diagnostic coronary angiography performed via transfemoral access-a VCD-based strategy with 2 types of devices, an intravascular device and an extravascular device, vs standard manual compression. The primary hypothesis to be tested was that femoral hemostasis achieved through VCD is noninferior to manual compression in terms of vascular access-site complications. A secondary objective was the comparison of the 2 types of VCD. DESIGN, SETTING, AND PARTICIPANTS: Randomized, large-scale, multicenter, open-label clinical trial. We enrolled 4524 patients undergoing coronary angiography with a 6 French sheath via the common femoral artery from April 2011 through May 2014 in 4 centers in Germany. Last 30-day follow-up was performed in July 2014. INTERVENTIONS: After angiography of the access site, patients were randomized to hemostasis with an intravascular VCD, extravascular VCD, or manual compression in a 1:1:1 ratio. MAIN OUTCOMES AND MEASURES: Primary end point: the composite of access site-related vascular complications at 30 days after randomization with a 2% noninferiority margin. Secondary end points: time to hemostasis, repeat manual compression, and VCD failure. An α-level of .025 was chosen for primary and secondary comparisons. RESULTS: Of the 4524 enrolled patients, 3015 were randomly assigned to a VCD group (1509 received intravascular VCD and 1506 received extravascular VCD) and 1509 patients were randomly assigned to the manual compression group. Before hospital discharge, duplex sonography of the access site was performed in 4231 (94%) patients. The primary end point was observed in 208 patients (6.9%) assigned to receive a VCD and 119 patients (7.9%) assigned to manual compression (difference, -1.0% [1-sided 97.5% CI, 0.7%]; P for noninferiority<.001). Time to hemostasis was significantly shorter in patients with VCD (1 minute [interquartile range {IQR}, 0.5-2.0]), vs manual compression (10 minutes [IQR, 10-15]; P < .001). Time to hemostasis was significantly shorter among patients with intravascular VCD (0.5 minute [IQR, 0.2-1.0]), vs extravascular VCD (2.0 minutes [IQR, 1.0-2.0]; P <.001) and closure device failure was also significantly lower among those with intravascular vs extravascular VCD (80 patients [5.3%], vs 184 patients [12.2%]; P < .001). CONCLUSIONS AND RELEVANCE: In patients undergoing transfemoral coronary angiography, VCDs were noninferior to manual compression in terms of vascular access-site complications and reduced time to hemostasis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01389375.

Bleeding after percutaneous coronary intervention in women and men matched for age, body mass index, and type of antithrombotic therapy.

BACKGROUND: Factors underlying the increased risk of bleeding after percutaneous coronary intervention (PCI) in women compared with men remain incompletely understood. METHODS: The study included 3,351 women and 3,351 men matched for age, body mass index, and type of antithrombotic therapy. Bleeding within the 30 days after PCI was defined using the Bleeding Academic Research Consortium criteria. The main outcome was 1-year mortality. RESULTS: Bleeding occurred in 518 women and 354 men (15.5% vs 10.6%, odds ratio [OR] 1.55, 95% CI 1.34-1.79, P < .001). Severe (Bleeding Academic Research Consortium class ≥2) bleeds (9.4% vs 6.5%, P < .001) and access site bleeds (10.1% vs 5.4%, P < .001) were more common in women. After adjustment, female sex remained an independent correlate of any bleeding (adjusted OR 1.61 [1.35-1.92], P < .001) and access site (adjusted OR 2.00 [1.59-2.50], P < .001) but not of nonaccess site (adjusted OR 1.18 [0.91-1.54], P = .205) bleeding. There were 248 deaths: 32 deaths among men with bleeding versus 107 deaths among men with no bleeding (9.1% vs 3.6%, OR 2.68 [1.78-4.05], P < .001) and 40 deaths among women with bleeding vs 69 deaths among women with no bleeding (7.8% vs 2.5%, OR 3.35 [2.24-5.01], P < .001). No difference in mortality was observed among women and men who bled (P = .487). Bleeding was independently associated 1-year mortality (adjusted hazard ratio 2.18 [1.68-2.84], P < .001) with no bleeding-by-sex interaction (P = .439). CONCLUSIONS: Despite matching for age, body mass index, and type of antithrombotic therapy, bleeding risk after PCI remained significantly higher in women than in men. Bleeding was associated with increased risk of 1-year mortality with no bleeding-by-sex interaction.

Assessment of the 9p21.3 locus in severity of coronary artery disease in the presence and absence of type 2 diabetes.

BACKGROUND: The 9p21.3 locus is strongly associated with the risk of coronary artery disease (CAD) and with type 2 diabetes (T2D). We investigated the association of 9p21.3 variants with severity of CAD (defined by the number of vessel diseased [VD]) in the presence and absence of T2D. METHODS: We tested 11 9p21.3-variants for association in a white Italian study (N = 2,908), and carried out replication in 2 independent white populations, a German study (N = 2,028) and a Canadian Study (N=950). SNP association and permutation analyses were conducted. RESULTS: We identified two 9p21.3-variants, rs4977574 (P < 4×10(-4)) and rs2383207 (P < 1.5×10(-3)) that were associated with severity of CAD in subjects without T2D. Association of rs4977574 with severity of CAD was confirmed in the Canadian Study. Results from subgroup analysis among patients with T2D showed an interaction between rs10738610 and T2D with P = 4.82×10(-2). Further investigation showed that rs10738610 (P < 1.99×10(-2)) was found to be significantly associated with severity of CAD in subjects with T2D. CONCLUSIONS: The 9p21.3 locus is significantly associated with severity of CAD. The number of associations of 9p21.3 variants with severity of CAD is variable to the presence and absence of T2D. In a CAD-susceptible region of 115 kb, there is only one variant associated with the severity of coronary vessel disease in the presence of type 2 diabetes.

The Role of RYR2 in Atrial Fibrillation.

Background. Atrial fibrillation (AF) is a common arrhythmia in elderly patients and is associated with increased risk of mortality. The pathogenesis of AF is complex and based on multiple genetic and environmental factors. Genome-wide association studies identified several loci in AF patients, indicating the complex genetic architecture of this disease. In rare cases, familial forms of AF have been described. Today, pathogenic variants in at least 11 different genes are associated with monogenic AF. Case presentation. The 37-year-old male patient presented to our emergency department with AF. At the age of 35, he had already been diagnosed with paroxysmal AF. Additionally, his 34-year-old brother had also been diagnosed with AF as well as nonobstructive hypertrophic cardiomyopathy. Moreover, the patient's father was diagnosed with AF in his twenties. Transthoracic echocardiography and cardiac MRI revealed a reduced systolic left ventricular ejection without any signs of hypertrophic cardiomyopathy. Genetic testing identified the heterozygous missense variants c.3371C > T, p.(Pro1124Leu) in RYR2 (NM_001035.3) and c.2524C > A, p.(Pro842Thr) in HCN4 (NM_005477.3) in the patient's and his brother's DNA. Discussion. This case of familial AF helps to strengthen the role of RYR2 as a disease gene in the context of AF. Although the variant in RYR2 needs to be classified formally as variant of unknown significance, we regard it as probably disease-causing due to the previously published data. As RYR2 has already been identified as a possible target for prevention and therapy of AF, the knowledge of variants in RYR2 might become even more crucial for individual molecular therapies in the future.

Electroanatomical Conduction Characteristics of Pig Myocardial Tissue Derived from High-Density Mapping.

BACKGROUND: Ultra-high-density mapping systems allow more precise measurement of the heart chambers at corresponding conduction velocities (CVs) and voltage amplitudes (VAs). Our aim for this study was to define and compare a basic value set for unipolar CV and VA in all four heart chambers and their separate walls in healthy, juvenile porcine hearts using ultra-high-density mapping. METHODS: We used the Rhythmia Mapping System to create electroanatomical maps of four pig hearts in sinus rhythm. CVs and VAs were calculated for chambers and wall segments with overlapping circular areas (radius of 5 mm). RESULTS: We analysed 21 maps with a resolution of 1.4 points/mm2. CVs were highest in the left atrium (LA), followed by the left ventricle (LV), right ventricle (RV), and right atrium (RA). As for VA, LV was highest, followed by RV, LA, and RA. The left chambers had a higher overall CV and VA than the right. Within the chambers, CV varied more in the right than in the left chambers, and VA varied in the ventricles but not in the atria. There was a slightly positive correlation between CVs and VAs at velocity values of <1.5 m/s. CONCLUSIONS: In healthy porcine hearts, the left chambers showed higher VAs and CVs than the right. CV differs mainly within the right chambers and VA differs only within the ventricles. A slightly positive linear correlation was found between slow CVs and low VAs.

Machine learning identifies pathophysiologically and prognostically informative phenotypes among patients with mitral regurgitation undergoing transcatheter edge-to-edge repair.

AIMS: Patients with mitral regurgitation (MR) present with considerable heterogeneity in cardiac damage depending on underlying aetiology, disease progression, and comorbidities. This study aims to capture their cardiopulmonary complexity by employing a machine-learning (ML)-based phenotyping approach. METHODS AND RESULTS: Data were obtained from 1426 patients undergoing mitral valve transcatheter edge-to-edge repair (MV TEER) for MR. The ML model was developed using 609 patients (derivation cohort) and validated on 817 patients from two external institutions. Phenotyping was based on echocardiographic data, and ML-derived phenotypes were correlated with 5-year outcomes. Unsupervised agglomerative clustering revealed four phenotypes among the derivation cohort: Cluster 1 showed preserved left ventricular ejection fraction (LVEF; 56.5 ± 7.79%) and regular left ventricular end-systolic diameter (LVESD; 35.2 ± 7.52 mm); 5-year survival in Cluster 1, hereinafter serving as a reference, was 60.9%. Cluster 2 presented with preserved LVEF (55.7 ± 7.82%) but showed the largest mitral valve effective regurgitant orifice area (0.623 ± 0.360 cm2) and highest systolic pulmonary artery pressures (68.4 ± 16.2 mmHg); 5-year survival ranged at 43.7% (P-value: 0.032). Cluster 3 was characterized by impaired LVEF (31.0 ± 10.4%) and enlarged LVESD (53.2 ± 10.9 mm); 5-year survival was reduced to 38.3% (P-value: <0.001). The poorest 5-year survival (23.8%; P-value: <0.001) was observed in Cluster 4 with biatrial dilatation (left atrial volume: 312 ± 113 mL; right atrial area: 46.0 ± 8.83 cm2) although LVEF was only slightly reduced (51.5 ± 11.0%). Importantly, the prognostic significance of ML-derived phenotypes was externally confirmed. CONCLUSION: ML-enabled phenotyping captures the complexity of extra-mitral valve cardiac damage, which does not necessarily occur in a sequential fashion. This novel phenotyping approach can refine risk stratification in patients undergoing MV TEER in the future.

Migratory and anti-fibrotic programmes define the regenerative potential of human cardiac progenitors.

Heart regeneration is an unmet clinical need, hampered by limited renewal of adult cardiomyocytes and fibrotic scarring. Pluripotent stem cell-based strategies are emerging, but unravelling cellular dynamics of host-graft crosstalk remains elusive. Here, by combining lineage tracing and single-cell transcriptomics in injured non-human primate heart biomimics, we uncover the coordinated action modes of human progenitor-mediated muscle repair. Chemoattraction via CXCL12/CXCR4 directs cellular migration to injury sites. Activated fibroblast repulsion targets fibrosis by SLIT2/ROBO1 guidance in organizing cytoskeletal dynamics. Ultimately, differentiation and electromechanical integration lead to functional restoration of damaged heart muscle. In vivo transplantation into acutely and chronically injured porcine hearts illustrated CXCR4-dependent homing, de novo formation of heart muscle, scar-volume reduction and prevention of heart failure progression. Concurrent endothelial differentiation contributed to graft neovascularization. Our study demonstrates that inherent developmental programmes within cardiac progenitors are sequentially activated in disease, enabling the cells to sense and counteract acute and chronic injury.

Impact of sinus rhythm versus atrial fibrillation on left ventricular remodeling after transcatheter aortic valve replacement.

AIMS: Atrial fibrillation (AF) is associated with increased mortality after transcatheter aortic valve replacement (TAVR). Cerebrovascular complications and bleeding events associated with anticoagulation therapy are discussed to be possible causes for this increased mortality. The present study sought to assess whether AF is associated with impaired left ventricular (LV) reverse remodeling representing another possible mechanism for poor outcome. METHODS: All patients who underwent TAVR in our institution and had 1-year echocardiography follow-up were included. LV mass index (LVMI) at baseline and follow-up as well as LVMI change at 1 year were assessed with respect to the presence of AF (either at baseline or during hospitalization after TAVR) and sinus rhythm (SR). RESULTS: A total of 213 patients (n = 95 in AF; n = 118 in SR) were enrolled in the present study. Patients with AF had higher LVMI at 1 year compared to those with SR (173 ± 61 g/m2 vs. 154 ± 55 g/m2; p = 0.02) and they showed lower relative LVMI change at 1 year (- 2 ± 28% vs. - 9 ± 29%; p = 0.04). In linear regression analysis, AF was independently associated with relative LVMI change (regression coefficient ß 0.076 [95% CI 0.001-0.150]; p = 0.04). With respect to clinical outcome depending on AF and LVMI regression, the Kaplan-Meier estimated event-free of death or cardiac rehospitalization at 3 years was lowest among patients with AF and no LVMI regression. CONCLUSIONS: The present study identified a significant association of AF with changes in LVMI after TAVR, which was also shown to be associated with clinical outcome.

Early Bronchoscopy Improves Extubation Rates after Out-of-Hospital Cardiac Arrest: A Retrospective Cohort Analysis.

BACKGROUND: Patients suffering from out-of-hospital cardiac arrest (OHCA) frequently receive a bronchoscopy after being admitted to the ICU. We investigated the optimal timing and the outcome in these patients. METHODS: All patients who suffered from OHCA and were treated in our ICU from January 2013 to December 2018 were retrospectively analyzed. The data were collected from the patients' medical files, and included duration of mechanical ventilation, antibiotics, microbiological test results and neurological outcome. The outcome was the effect of early bronchoscopy (≤48 h after administration) on the rate of intubated patients on day five and day seven. RESULTS: From January 2013 to December 2018, 190 patients were admitted with OHCA. Bronchoscopy was performed in 111 patients out of the 164 patients who survived the first day. Late bronchoscopy >48 h was associated with higher rates of intubation on day five (OR 4.94; 95% CI 1.2-36.72, 86.7% vs. 55.0%, p = 0.036) and day seven (OR 4.96; 95% CI 1.38-24.69; 80.0% vs. 43.3%, p = 0.019). CONCLUSION: This study shows that patients who suffered from OHCA might have a better outcome if they receive a bronchoscopy early after hospital admission. Our data suggests an association of early bronchoscopy with a shorter intubation period.