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Background:The best management of stable coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) is still unclear due to the marked inconsistency of the available evidence. Methods:The REVASC-TAVI registry (Management of Myocardial Revascularization in Patients Undergoing Transcatheter Aortic Valve Implantation With Coronary Artery Disease) collected data from 30 centers worldwide on patients undergoing TAVI who had significant, stable CAD at preprocedural work-up. For the purposes of this analysis, patients with either complete or incomplete myocardial revascularization were compared in a propensity score matched analysis, to take into account of baseline confounders. The primary and co-primary outcomes were all-cause death and the composite of all-cause death, stroke, myocardial infarction, and rehospitalization for heart failure, respectively, at 2 years. Results:Among 2407 patients enrolled, 675 pairs of patients achieving complete or incomplete myocardial revascularization were matched. The primary (21.6% versus 18.2%, hazard ratio, 0.88 [95% CI, 0.66-1.18]; P=0.38) and co-primary composite (29.0% versus 27.1%, hazard ratio, 0.97 [95% CI, 0.76-1.24]; P=0.83) outcome did not differ between patients achieving complete or incomplete myocardial revascularization, respectively. These results were consistent across different prespecified subgroups of patients (< or >75 years of age, Society of Thoracic Surgeons score > or <4%, angina at baseline, diabetes, left ventricular ejection fraction > or <40%, New York Heart Association class I/II or III/IV, renal failure, proximal CAD, multivessel CAD, and left main/proximal anterior descending artery CAD; all P values for interaction >0.10). Conclusions:The present analysis of the REVASC-TAVI registry showed that, among TAVI patients with significant stable CAD found during the TAVI work-up, completeness of myocardial revascularization achieved either staged or concomitantly with

Background: Recurrent mitral regurgitation (MR) following MitraClip has not been thoroughly investigated. We aimed to examine the predictive factors, morphology, and long-term outcome of recurrent MR after MitraClip. Methods: We assessed data from the Heart Failure Network Rhineland registry from August 2010 to October 2018. Competing risk analyses were performed using the Fine and Gray model to assess the risk of recurrent MR. Results: Among 685 MitraClip patients with a reduction in MR to <= 2+, 61 patients developed recurrent MR within the first 12 months. Flail leaflet (hazard ratio, 3.68; P=0.002) and residual MR (MR grade 2+ versus <= 1+: hazard ratio, 2.56; P=0.03) were the predictors of recurrent MR in primary MR patients, while left atrial volume (per 10 mL increase: hazard ratio, 1.11; P<0.001) and residual MR (hazard ratio, 2.45; P=0.01) were independently associated with recurrent MR in secondary MR patients. In primary MR patients, loss of leaflet insertion or leaflet tear were the predominant morphologies with recurrent MR. In secondary MR patients, more than half of the patients with recurrent MR did not show any disorder of the clip or leaflets. Patients with recurrent MR were more likely to experience unplanned heart failure hospitalization or heart failure symptom with New York Heart Association scale III/IV (54.1% versus 37.8%; P=0.018) and undergo a repeat mitral valve intervention (9.8% versus 2.2%; P=0.005) during the follow-up. In the landmark survival analysis, patients with recurrent MR tended to have lower long-term survival (58.7% versus 83.9%; P=0.08) than patients without recurrent MR. Conclusions: Flail leaflet and residual MR were the predictors of recurrent MR in primary MR patients, while a larger left atrial volume and residual MR were associated with recurrent MR in secondary MR patients, which may be associated with long-term clinical outcomes of patients after MitraClip.

Background: Treatment options for secondary tricuspid regurgitation (TR) remain limited. Early real-world data of a new percutaneous direct annuloplasty system for tricuspid repair were examined. Methods: The first 60 patients treated with the Cardioband tricuspid valve repair system at 4 centers were included in this retrospective study. The primary efficacy end point was technical success with reduction of TR >= 2 grades at discharge. Combined primary safety end point was major adverse events (death, myocardial infarction, cardiothoracic surgery, and stroke) at 30 days. Results: Median patient age was 76 years (73-82), median EuroScore II was 3.9% (2.2-8.1), heart failure with preserved ejection fraction was present in 78%, and 81.7% were in the New York Heart Association class III/IV. Massive or torrential TR was found in 51.7%, and severe TR in 48.3%. The primary efficacy end point was achieved in 45%, while 60.3% of patients had less-than-severe TR at discharge. Vena contracta was reduced by 47% from 12.9 +/- 4.8 to 7.0 +/- 3.4 mm (P<0.001). Overall, the majority of patients (81.7%) improved at least by 1 New York Heart Association class. At follow-up 81.3% of patients presented in the New York Heart Association class I or II. The primary safety end point occurred in 4 patients with 2 in-hospital deaths, both not device related. Right coronary artery complications (vessel perforation or stent implantation) occurred in 9 patients (15%). Procedural time decreased from 298 to 185 minutes (P<0.001) with efficacy remaining stable (P=0.817) when comparing procedure numbers 11 or more to the earliest 5 procedures per center. Conclusions: This first real-world experience suggests that transcatheter treatment of advanced secondary TR using direct annuloplasty is feasible and reasonably safe early in the learning curve, with significant symptomatic benefit. Further studies are warranted to provide data on long-term outcome and patient prognosis.

Background: Given their advanced age and high comorbidity, individual risk assessment is crucial in patients undergoing transcatheter mitral and tricuspid valve repair. Therefore, we evaluated the use of a comprehensive geriatric assessment score, the multidimensional prognostic index (MPI), for risk stratification in these patients. Methods: We conducted a prospective, observational single-center study, including 226 patients undergoing percutaneous repair for mitral or tricuspid regurgitation. The MPI was calculated preprocedural and covers 8 domains (activities of daily living, instrumental activities of daily living, mental status, nutrition, risk of pressure ulcers, comorbidity, medication, and marital/cohabitation status). We sought to identify an association of MPI score with procedural outcomes and 6-month mortality. Results: A total of 53.1% of patients were stratified as low risk according to MPI (MPI-1 group), 44.2% as medium risk (MPI-2 group), and 2.7% as high risk (MPI-3 group). Procedural efficacy and safety were similar between groups. The estimated survival rate at 6 months was 97 +/- 2% in MPI-1 group, 79 +/- 4% in MPI-2 group (hazard ratio, 6.90 [95% CI, 2.36-12.2]; P <= 0.001) and 50 +/- 20% in MPI-3 group (hazard ratio, 20.3 [95% CI, 4.51-91.3]; P<0.001). An increase in 1 SD of the MPI score (0.14 points, possible range of MPI score 0-1) was associated with a hazard ratio of 2.13 (95% CI, 1.58-2.73; P <= 0.001) for death after 6 months. The risk association of the MPI with mortality remained significant in multivariate analysis including risk factors, such as peripheral artery disease and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Conclusions: A comprehensive geriatric assessment with the MPI score provides additional information on mortality risk beyond established cardiovascular risk factors.

Purpose of review Pulmonary hypertension is a common phenomenon in heart failure patients that is highly relevant for morbidity and outcome. Although postcapillary in nature, the pathophysiology of pulmonary hypertension in patients with heart failure with reduced or preserved ejection fraction is complex, and decisions about management strategies remain challenging. Recent findings Recently, the hemodynamic definitions and subclassification of postcapillary pulmonary hypertension have been revisited. The distinction between isolated postcapillary pulmonary hypertension (IpcPH) and combined post and precapillary pulmonary hypertension (CpcPH) and their definition are essential. Novel data on the prognostic impact of hemodynamic variables and right ventricular function highlight the importance of cardiopulmonary interaction in patients with left-sided heart failure (LHF). Furthermore, the impact of management strategies including medical therapy, remote hemodynamic monitoring, and interventional approaches on hemodynamics and outcome has recently been investigated. Here, we critically review recent developments and future considerations in this field, and highlight distinct treatment strategies targeting the underlying left heart condition, the pulmonary circulation, and/or impaired right ventricular function. Detailed hemodynamic characterization and proper phenotyping are essential for prognostication and the management of patients with pulmonary hypertension associated with LHF, both in clinical practice and when addressing research questions.

Background: Atrial arrhythmias are common in patients with implantable cardioverter-defibrillator (ICD). External shocks and internal cardioversion through commanded ICD shock for electrical cardioversion are used for rhythm-control. However, there is a paucity of data on efficacy of external versus internal cardioversion and on the risk of lead and device malfunction. We hypothesized that external cardioversion is noninferior to internal cardioversion for safety, and superior for successful restoration of sinus rhythm. Methods: Consecutive patients with ICD undergoing elective cardioversion for atrial arrhythmias at 13 centers were randomized in 1:1 fashion to either internal or external cardioversion. The primary safety end point was a composite of surrogate events of lead or device malfunction. Conversion of atrial arrhythmia to sinus rhythm was the primary efficacy end point. Myocardial damage was studied by measuring troponin release in both groups. Results: N=230 patients were randomized. Shock efficacy was 93% in the external cardioversion group and 65% in the internal cardioversion group (P<0.001). Clinically relevant adverse events caused by external or internal cardioversion were not observed. Three cases of pre-existing silent lead malfunction were unmasked by internal shock, resulting in lead failure. Troponin release did not differ between groups. Conclusions: This is the first randomized trial on external vs internal cardioversion in patients with ICDs. External cardioversion was superior for the restoration of sinus rhythm. The unmasking of silent lead malfunction in the internal cardioversion group suggests that an internal shock attempt may be reasonable in selected ICD patients presenting for electrical cardioversion.

Objective Recruitment of immunologic competent cells to the vessel wall is a crucial step in formation of abdominal aortic aneurysms (AAA). Innate immunity effectors (eg, macrophages), as well as mediators of adaptive immunity (eg, T cells), orchestrate a local vascular inflammatory response. IL-10 (interleukin-10) is an immune-regulatory cytokine with a crucial role in suppression of inflammatory processes. We hypothesized that an increase in systemic IL-10-levels would mitigate AAA progression. Approach and Results Using a single intravenous injection protocol, we transfected an IL-10 transcribing nonimmunogenic minicircle vector into the Ang II (angiotensin II)-ApoE(-/-) infusion mouse model of AAA. IL-10 minicircle transfection significantly reduced average aortic diameter measured via ultrasound at day 28 from 166.110.8% (control) to 131.0 +/- 5.8% (IL-10 transfected). Rates of dissecting AAA were reduced by IL-10 treatment, with an increase in freedom from dissecting AAA from 21.5% to 62.3%. Using flow cytometry of aortic tissue from minicircle IL-10-treated animals, we found a significantly higher percentage of CD4(+)/CD25(+)/Foxp3 (forkhead box P3)(+) regulatory T cells, with fewer CD8(+)/GZMB(+) (granzyme B) cytotoxic T cells. Furthermore, isolated aortic macrophages produced less TNF- (tumor necrosis factor-), more IL-10, and were more likely to be MRC1 (mannose receptor, C type 1)-positive alternatively activated macrophages. These results concurred with gene expression analysis of lipopolysaccharide-stimulated and Ang II-primed human peripheral blood mononuclear cells. Conclusions Taken together, we provide an effective gene therapy approach to AAA in mice by enhancing antiinflammatory and dampening proinflammatory pathways through minicircle-induced augmentation of systemic IL-10 expression.

Objective The leukocyte heme-enzyme MPO (myeloperoxidase) exerts proinflammatory effects on the vascular system primarily linked to its catalytic properties. Recent studies have shown that MPO, depending on its cationic charge, mediates neutrophil recruitment and activation. Here, we further investigated MPO's extracatalytic properties and its effect on endothelial glycocalyx (EG) integrity. Approach and Results In vivo staining of murine cremaster muscle vessels with Alcian Blue 8GX provided evidence of an MPO-dependent decrease in anionic charge of the EG. MPO binding to the glycocalyx was further characterized using Chinese hamster ovary cells and its glycosaminoglycan mutantspgsA-745 (mutant Chinese hamster ovary cells lacking heparan sulfate and chondroitin sulfate glycosaminoglycan) and pgsD-677 (mutant Chinese hamster ovary cells lacking heparan sulfate glycosaminoglycan), which revealed heparan sulfate as the main mediator of MPO binding. Further, EG integrity was assessed in terms of thickness using intravital microscopy of murine cremaster muscle. A significant reduction in EG thickness was observed on infusion of catalytically active MPO, as well as mutant inactive MPO and cationic polymer polylysine. Similar effects were also observed in wild-type mice after a local inflammatory stimulus but not in MPO-knockout mice. The reduction in EG thickness was reversed after removal of vessel-bound MPO, suggesting a possible physical collapse of the EG. Last, experiments with in vivo neutrophil depletion revealed that MPO also induced neutrophil-mediated shedding of the EG core protein, Sdc1 (syndecan-1). Conclusions These findings provide evidence that MPO, via ionic interaction with heparan sulfate side chains, can cause neutrophil-dependent Sdc1 shedding and collapse of the EG structure.

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b(-/-)) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo(-/-)) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wildtype mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo(-/-) mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2 incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo(-/-) mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias

Background-Surgical aortic valve replacement in patients with small annular dimensions is challenging because they are at increased risk for prosthesis-patient mismatch and impaired outcomes. Transcatheter aortic valve replacement might be a good alternative; however, comparative data on different transcatheter heart valves are missing. Methods and Results-This multicenter, propensity score-matched study compared hemodynamics and early clinical outcomes in 246 patients with an aortic annulus area <400 mm(2) undergoing transcatheter aortic valve replacement with either a self-expanding transcatheter heart valve (Symetis ACURATE neo, n=129) or a balloon-expandable transcatheter heart valve (Edwards SAPIEN 3, n=117). The 1: 1 propensity score matching resulted in 92 matched pairs. For ACURATE neo versus SAPIEN 3-treated patients, 30-day mortality (0.0% versus 1.0%), 1-year mortality (8.3% versus 13.3%), incidence of stroke (3.3% versus 2.2%), life-threatening bleeding (1.1% versus 1.1%), and major vascular complications (2.2% versus 6.5%), as well as pacemaker implantation rate (12.0% versus 15.2%), were similar. Paravalvular regurgitation >= moderate was rare in both groups (4.5% versus 3.6%). The ACURATE neo presented lower mean transvalvular gradients (9.3 versus 14.5 mm Hg; P<0.001), larger indexed effective orifice areas (0.96 versus 0.80 cm(2)/m(2); P=0.003), and lower rates of severe prosthesis-patient mismatch (3% versus 22%; P=0.004). Hemodynamics were sustained at 1-year follow-up. Conclusions-Albeit a similar safety profile with low clinical event rates, transcatheter aortic valve replacement with the ACURATE neo valve resulted in lower transvalvular gradients and consequently less prosthesis-patient mismatch compared with the SAPIEN 3 in patients with small annulus. These results emphasize the need of careful prosthesis selection in each individual patient.

Objective-Neointima formation after vascular injury remains a significant problem in clinical cardiology, and current preventive strategies are suboptimal. Phosphatidylinositol 3'-kinase is a central downstream mediator of growth factor signaling, but the role of phosphatidylinositol 3'-kinase isoforms in vascular remodeling remains elusive. We sought to systematically characterize the precise role of catalytic class IA phosphatidylinositol 3'-kinase isoforms (p110 alpha, p110 beta, p110 delta), which signal downstream of receptor tyrosine kinases, for vascular remodeling in vivo. Approach and Results-Western blot analyses revealed that all 3 isoforms are abundantly expressed in smooth muscle cells. To analyze their significance for receptor tyrosine kinases-dependent cellular responses, we used targeted gene knockdown and isoform-specific small molecule inhibitors of p110 alpha (PIK-75), p110 beta (TGX-221), and p110 delta (IC-87114), respectively. We identified p110 alpha to be crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of rat, murine, and human smooth muscle cells, whereas p110 beta and p110 delta activities were dispensable. Surprisingly, p110 delta exerted noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration. Based on these results, we generated a mouse model of smooth muscle cell-specific p110 alpha deficiency (sm-p110 alpha(-/-)). Targeted deletion of p110 alpha in sm-p110 alpha(-/-) mice blunted growth factor-induced cellular responses and abolished neointima formation after balloon injury of the carotid artery in mice. In contrast, p110 delta deficiency did not affect vascular remodeling in vivo. Conclusions-Receptor tyrosine kinases-induced phosphatidylinositol 3'-kinase signaling via the p110 alpha isoform plays a central role for vascular remodeling in vivo. Thus, p110 alpha represents a selective target for the prevention of neointima formation after vascul

Vascular dysfunction importantly contributes to mortality and morbidity in various cardiac and metabolic diseases. Among endogenous molecules regulating vascular tone is adenosine, with the adenosine A(3) receptor (A(3)AR) exerting cardioprotective properties in ischemia and reperfusion. However, overexpression of A(3)AR is suggested to result in vascular dysfunction and inflammation. The leukocyte enzyme myeloperoxidase (MPO) is an important modulator of vascular function with nitric oxide-consuming and proinflammatory properties. Increased MPO plasma levels are observed in patients with cardiovascular disorders like heart failure, acute coronary syndromes, and arrhythmias. Given that vascular dysfunction and inflammation are also hallmarks of diabetes, the role of MPO in adenosine-dependent vasomotor function was investigated in a murine model of diabetes mellitus. Wild-type (WT) and MPO-deficient (Mpo(-/-)) mice were treated with Streptozotocin (STZ), which induced an increase of MPO plasma levels in WT mice and led to enhanced aortic superoxide generation as assessed by dihydroethidium staining in STZ-treated WT mice as compared with controls. The vasoconstriction of aortic segments in response to the A(3)AR agonist Cl-IB-MECA (2-Chloro-N6-(3-iodobenzyl)-N-methyl-5-carbamoyladenosine) as determined by isometric force measurements was augmented in diabetic WT as compared with diabetic Mpo(-/-) mice. Moreover, A(3)AR protein expression was enhanced in STZ-treated mice but was attenuated by MPO deficiency. The current data reveal an MPO-mediated increase of vascular A(3)AR expression under diabetic conditions, which leads to enhanced vasoconstriction in response to A(3)AR agonists and discloses an additional mechanism of MPO-mediated vascular dysfunction.

Background Endogenous arginine homologues, including homoarginine, have been identified as novel biomarkers for cardiovascular disease and outcomes. Our studies of human cohorts and a confirmatory murine model associated the arginine homologue homoarginine and its metabolism with stroke pathology and outcome. Methods and Results Increasing homoarginine levels were independently associated with a reduction in all-cause mortality in patients with ischemic stroke (7.4 years of follow-up; hazard ratio for 1-SD homoarginine, 0.79 [95% confidence interval, 0.64-0.96]; P=0.019; n=389). Homoarginine was also independently associated with the National Institutes of Health Stroke Scale+age score and 30-day mortality after ischemic stroke (P<0.05; n=137). A genome-wide association study revealed that plasma homoarginine was strongly associated with single nucleotide polymorphisms in the l-arginine:glycine amidinotransferase (AGAT) gene (P<2.1x10(-8); n=2806), and increased AGAT expression in a cell model was associated with increased homoarginine. Next, we used 2 genetic murine models to investigate the link between plasma homoarginine and outcome after experimental ischemic stroke: (1) an AGAT deletion (AGAT(-/-)) and (2) a guanidinoacetate N-methyltransferase deletion (GAMT(-/-)) causing AGAT upregulation. As suggested by the genome-wide association study, homoarginine was absent in AGAT(-/-) mice and increased in GAMT(-/-) mice. Cerebral damage and neurological deficits in experimental stroke were increased in AGAT(-/-) mice and attenuated by homoarginine supplementation, whereas infarct size in GAMT(-/-) mice was decreased compared with controls. Conclusions Low homoarginine appears to be related to poor outcome after ischemic stroke. Further validation in future trials may lead to therapeutic adjustments of homoarginine metabolism that alleviate stroke and other vascular disorders.