Transcatheter tricuspid valve-in-valve replacement: Making it simpler.

Transcatheter tricuspid valve-in-valve replacement (TTVR) represents an attractive therapeutic option in very high surgical risk patients with degenerated tricuspid bioprostheses. However, the procedural management of these patients might be challenging due to their comorbidities, long lasting heart valve disease and the presence of left-sided mechanical prostheses. Thus, a more "minimally disruptive" procedure would have several potential benefits in such a frail population. We present the cases of four patients admitted for congestive heart failure due to severe degeneration of their tricuspid bioprostheses who were treated with a minimalist TTVR. The protocol combined continuation of the oral anticoagulant treatment with no bridging therapy, the use of a single venous access with local anesthesia, rapid pacing via the stiff right ventricular wire, and transthoracic echocardiographic guidance and assessment, with no need for contrast injection. Our protocol aims at simplifying the TTVR procedure and might be a useful tool to avoid procedural complications and reduce hospital stay.

Spontaneous coronary artery dissection: how often do we miss this diagnosis? The role of cardiac computed tomography angiography.

Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome particularly among young women. Although coronary angiogram (CAG) is the gold standard exam for the diagnosis, SCAD may be missed by CAG alone. Our case series illustrates the adjunctive role of cardiac computed tomography angiography (cCTA) to CAG in ascertaining the diagnosis of SCAD. Three young women were admitted with ST-segment elevation myocardial infarction. CAG showed no significant coronary artery stenosis. In two patients, cCTA performed after CAG revealed an intramural hematoma compressing the coronary lumen. In one patient, SCAD was initially misdiagnosed as Takotsubo cardiomyopathy and cCTA performed 1 month later allowed to make the correct diagnosis of SCAD assessing the spontaneous healing of the dissected vessel.

Oral Anticoagulant Type and Outcomes After Transcatheter Aortic Valve Replacement.

OBJECTIVES: The purpose of the study was to investigate the impact of oral anticoagulation (OAC) type on clinical outcomes 1 year after transcatheter aortic valve replacement (TAVR). BACKGROUND: Non-vitamin K oral anticoagulants (NOACs) are superior to vitamin K antagonists (VKAs) in nonvalvular atrial fibrillation (AF), while their comparative performance among patients in need of OAC undergoing TAVR is underinvestigated. METHODS: The study enrolled 962 consecutive patients who underwent TAVR in 4 tertiary European centers and were discharged on either NOACs (n = 326) or VKAs (n = 636). By using propensity scores for inverse probability of treatment weighting (IPTW), the comparison of treatment groups was adjusted to correct for potential confounding. RESULTS: Mean age and Society of Thoracic Surgeons score of the population were 81.3 ± 6.3 years and 4.5% (interquartile range: 3.0% to 7.3%); 52.5% were women and a balloon-expandable valve was used in 62.7% of cases. The primary outcome of interest, combined incidence of all-cause mortality, myocardial infarction, and any cerebrovascular event at 1-year after TAVR, was 21.2% with NOACs versus 15.0% with VKAs (hazard ratio [HR]: 1.44; 95% confidence interval [CI]: 1.00 to 2.07; p = 0.050, IPTW-adjusted). The 1-year incidence of any Bleeding Academic Research Consortium bleeds and all-cause mortality were comparable between the NOAC and VKA groups, 33.9% versus 34.1% (HR: 0.97; 95% CI: 0.74 to 1.26; p = 0.838, IPTW-adjusted) and 16.5% versus 12.2% (HR: 1.36; 95% CI: 0.90 to 2.06; p = 0.136, IPTW-adjusted), respectively. CONCLUSIONS: Chronic use of both NOACs and VKAs among patients in need of OAC after TAVR are comparable regarding 1-year bleeding risk. The higher ischemic event rate observed with NOACs needs to be evaluated in large randomized trials.

Interplay among H3K9-editing enzymes SUV39H1, JMJD2C and SRC-1 drives p66Shc transcription and vascular oxidative stress in obesity.

Aims: Accumulation of reactive oxygen species (ROS) promotes vascular disease in obesity, but the underlying molecular mechanisms remain poorly understood. The adaptor p66Shc is emerging as a key molecule responsible for ROS generation and vascular damage. This study investigates whether epigenetic regulation of p66Shc contributes to obesity-related vascular disease. Methods and results: ROS-driven endothelial dysfunction was observed in visceral fat arteries (VFAs) isolated from obese subjects when compared with normal weight controls. Gene profiling of chromatin-modifying enzymes in VFA revealed a significant dysregulation of methyltransferase SUV39H1 (fold change, -6.9, P < 0.01), demethylase JMJD2C (fold change, 3.2, P < 0.01), and acetyltransferase SRC-1 (fold change, 5.8, P < 0.01) in obese vs. control VFA. These changes were associated with reduced di-(H3K9me2) and trimethylation (H3K9me3) as well as acetylation (H3K9ac) of histone 3 lysine 9 (H3K9) on p66Shc promoter. Reprogramming SUV39H1, JMJD2C, and SRC-1 in isolated endothelial cells as well as in aortas from obese mice (LepOb/Ob) suppressed p66Shc-derived ROS, restored nitric oxide levels, and rescued endothelial dysfunction. Consistently, in vivo editing of chromatin remodellers blunted obesity-related vascular p66Shc expression. We show that SUV39H1 is the upstream effector orchestrating JMJD2C/SRC-1 recruitment to p66Shc promoter. Indeed, SUV39H1 overexpression in obese mice erased H3K9-related changes on p66Shc promoter, while SUV39H1 genetic deletion in lean mice recapitulated obesity-induced H3K9 remodelling and p66Shc transcription. Conclusion: These results uncover a novel epigenetic mechanism underlying endothelial dysfunction in obesity. Targeting SUV39H1 may attenuate oxidative transcriptional programmes and thus prevent vascular disease in obese individuals.

Percutaneous coronary and structural interventions in women: a position statement from the EAPCI Women Committee.

Several expert documents on sex-based differences in interventional outcomes are now available, however this is the first position paper from the EAPCI Women Committee discussing the potential influence of sex in the percutaneous treatment of coronary and structural heart disease. Despite the misconception that coronary artery disease is a 'man's disease', contemporary data shows a growing incidence in women. However, women are under-represented in randomised coronary clinical trials (~25%). The generalisation of such studies is therefore problematic in decision-making for females undergoing coronary intervention. Differences in pathophysiology between sexes exist, highlighting the need for greater awareness amongst healthcare professionals to enable best evidence-based therapies for women as well as for men. Reassuringly, women represent half of the population included in transcatheter aortic valve implantation clinical trials and may actually benefit more. Growing evidence is also emerging for other interventional atrial procedures which may well be advantageous to women. Awareness of sex disparities is increasing, and we must all work collaboratively within our profession to ensure we provide effective care for all patients with heart disease. The EAPCI Women Committee aim to highlight such issues through this position paper and through visibility within the interventional community.

Rotational atherectomy in the subadventitial space to allow safe and successful chronic total occlusion recanalization: Pushing the limit further.

Dissection and re-entry (DR) techniques have played a key role in the increase of success rates of chronic total occlusion (CTO) recanalization. DR usually allows wiring complex occlusions, even in case of important calcification. In extreme cases, such as in balloon failure-to-cross, rotational atherectomy (RA) might be decisive. However, according to experts' recommendations, RA should not be performed in dissection planes because of the high risk of perforation and further extending the dissection, so that its use after DR might be limited. Here, we describe a case of successful right coronary artery CTO recanalization in which, after failure of several antegrade and retrograde techniques, RA was safely performed antegradely in the subadventitial space, thus eventually enabling reverse controlled antegrade and retrograde subintimal tracking (CART). Although the feasibility of RA in CTO percutaneous coronary intervention had already been suggested, this case reports on the novel use of RA to allow further manipulation of the subadventitial space (reverse CART) prior to successful recanalization. © 2017 Wiley Periodicals, Inc.

Impact of Glycemic Variability on Chromatin Remodeling, Oxidative Stress, and Endothelial Dysfunction in Patients With Type 2 Diabetes and With Target HbA1c Levels.

Intensive glycemic control (IGC) targeting HbA1c fails to show an unequivocal reduction of macrovascular complications in type 2 diabetes (T2D); however, the underlying mechanisms remain elusive. Epigenetic changes are emerging as important mediators of cardiovascular damage and may play a role in this setting. This study investigated whether epigenetic regulation of the adaptor protein p66Shc, a key driver of mitochondrial oxidative stress, contributes to persistent vascular dysfunction in patients with T2D despite IGC. Thirty-nine patients with uncontrolled T2D (HbA1c >7.5%) and 24 age- and sex-matched healthy control subjects were consecutively enrolled. IGC was implemented for 6 months in patients with T2D to achieve a target HbA1c of ≤7.0%. Brachial artery flow-mediated dilation (FMD), urinary 8-isoprostaglandin F2α (8-isoPGF2α), and epigenetic regulation of p66Shc were assessed at baseline and follow-up. Continuous glucose monitoring was performed to determine the mean amplitude of glycemic excursion (MAGE) and postprandial incremental area under the curve (AUCpp). At baseline, patients with T2D showed impaired FMD, increased urinary 8-isoPGF2α, and p66Shc upregulation in circulating monocytes compared with control subjects. FMD, 8-isoPGF2α, and p66Shc expression were not affected by IGC. DNA hypomethylation and histone 3 acetylation were found on the p66Shc promoter of patients with T2D, and IGC did not change such adverse epigenetic remodeling. Persistent downregulation of methyltransferase DNMT3b and deacetylase SIRT1 may explain the observed p66Shc-related epigenetic changes. MAGE and AUCpp but not HbA1c were independently associated with the altered epigenetic profile on the p66Shc promoter. Hence, glucose fluctuations contribute to chromatin remodeling and may explain persistent vascular dysfunction in patients with T2D with target HbA1c levels.

Suprasternal brachiocephalic approach as an alternative route for transcatheter aortic valve implantation: a single-centre experience.

AIMS: The aim of this study was to evaluate the feasibility, safety and outcomes of TAVI performed via the suprasternal brachiocephalic approach in selected patients at high or prohibitive surgical risk who are not eligible for transfemoral or subclavian TAVI. METHODS AND RESULTS: From March 2014 to March 2016, 26 high-risk patients without transfemoral or subclavian access options were considered for TAVI via a suprasternal brachiocephalic approach. The feasibility of the suprasternal brachiocephalic approach was determined according to computed tomography findings. In 23 (88.4%) patients the procedure was performed as intended, whereas in three (11.5%) patients the approach was converted to a right carotid access. Both self-expanding (n=20, 76.9%) and balloon-expandable prostheses (n=6, 23.1%) were used. At 30 days, no patient had died; there was one major stroke (3.8%) and there were three major vascular access site-related complications (11.5%). After a median follow-up of 317 days (57-705), two patients had died, both from cardiovascular causes, and 19 out of 24 survivors (79.2%) were in New York Heart Association functional Class I or II. CONCLUSIONS: This single-centre case series suggests that TAVI using the suprasternal brachiocephalic approach is feasible in selected patients and may represent an additional alternative route in patients who are not eligible for other approaches.

Targeting prolyl-isomerase Pin1 prevents mitochondrial oxidative stress and vascular dysfunction: insights in patients with diabetes.

AIM: Diabetes is a major driver of cardiovascular disease, but the underlying mechanisms remain elusive. Prolyl-isomerase Pin1 recognizes specific peptide bonds and modulates function of proteins altering cellular homoeostasis. The present study investigates Pin1 role in diabetes-induced vascular disease. METHODS AND RESULTS: In human aortic endothelial cells (HAECs) exposed to high glucose, up-regulation of Pin1-induced mitochondrial translocation of pro-oxidant adaptor p66(Shc) and subsequent organelle disruption. In this setting, Pin1 recognizes Ser-116 inhibitory phosphorylation of endothelial nitric oxide synthase (eNOS) leading to eNOS-caveolin-1 interaction and reduced NO availability. Pin1 also mediates hyperglycaemia-induced nuclear translocation of NF-κB p65, triggering VCAM-1, ICAM-1, and MCP-1 expression. Indeed, gene silencing of Pin1 in HAECs suppressed p66(Shc)-dependent ROS production, restored NO release and blunted NF-kB p65 nuclear translocation. Consistently, diabetic Pin1(-/-) mice were protected against mitochondrial oxidative stress, endothelial dysfunction, and vascular inflammation. Increased expression and activity of Pin1 were also found in peripheral blood monocytes isolated from diabetic patients when compared with age-matched healthy controls. Interestingly, enough, Pin1 up-regulation was associated with impaired flow-mediated dilation, increased urinary 8-iso-prostaglandin F2α and plasma levels of adhesion molecules. CONCLUSIONS: Pin1 drives diabetic vascular disease by causing mitochondrial oxidative stress, eNOS dysregulation as well as NF-kB-induced inflammation. These findings provide molecular insights for novel mechanism-based therapeutic strategies in patients with diabetes.

Adverse epigenetic signatures by histone methyltransferase Set7 contribute to vascular dysfunction in patients with type 2 diabetes mellitus.

BACKGROUND: Cellular studies showed that histone methyltransferase Set7 mediates high glucose-induced inflammation via epigenetic regulation of the transcription factor NF-kB. However, the link between Set7 and vascular dysfunction in patients with diabetes mellitus remains unknown. This study was designed to investigate whether Set7 contributes to vascular dysfunction in patients with type 2 diabetes mellitus (T2DM). METHODS AND RESULTS: Set7-driven epigenetic changes on NF-kB p65 promoter and expression of NF-kB-dependent genes, cyclooxygenase 2 and inducible endothelial nitric oxide synthase, were assessed in peripheral blood mononuclear cells isolated from 68 subjects (44 patients with T2DM and 24 age-matched controls). Brachial artery flow-mediated dilation, 24-hour urinary levels of 8-isoprostaglandin F2α, and plasma adhesion molecules, intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1, were also determined. Experiments in human aortic endothelial cells exposed to high glucose were performed to elucidate the mechanisms of Set7-driven inflammation and oxidative stress. Set7 expression increased in peripheral blood mononuclear cells from patients with T2DM when compared with controls. Patients with T2DM showed Set7-dependent monomethylation of lysine 4 of histone 3 on NF-kB p65 promoter. This epigenetic signature was associated with upregulation of NF-kB, subsequent transcription of oxidant/inflammatory genes, and increased plasma levels of intercellular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Interestingly, we found that Set7 expression significantly correlated with oxidative marker 8-isoprostaglandin F2α (r=0.38; P=0.01) and flow-mediated dilation (r=-0.34; P=0.04). In human aortic endothelial cells, silencing of Set7 prevented monomethylation of lysine 4 of histone 3 and abolished NF-kB-dependent oxidant and inflammatory signaling. CONCLUSIONS: Set7-induced epigenetic changes contribute to vascular dysfunction in patients with T2DM. Targeting this chromatin-modifying enzyme may represent a novel therapeutic approach to prevent atherosclerotic vascular disease in this setting.

[Novel concepts in beta-adrenergic receptor signaling: therapeutic options for heart failure]. / Nuovi concetti nella segnalazione beta-adrenergica: prospettive terapeutiche per lo scompenso cardiaco.

Heart failure is a common and complex clinical syndrome characterized by progressive ventricular dilatation, depressed contractile function and premature death. Abnormalities in the beta-adrenergic receptor (betaAR) signaling such as betaAR down-regulation and desensitization are hallmarks of heart failure. Results from previous studies suggest that chronic betaAR dysfunction in the failing heart is maladaptive and contributes to the deterioration in cardiac function. In this review we will discuss a number of recent studies on betaAR signaling and addressing the role of phosphoinositide-3 kinase (PI3K) in the development of betaAR dysfunction and the progression of heart failure. Novel possible strategies to ameliorate cardiac dysfunction in heart failure through the competitive inhibition of PI3K are also described.

Induction of mitogen-activated protein kinases is proportional to the amount of pressure overload.

Pressure overload has been shown to induce mitogen activated protein kinases (MAPKs) and reactivate the atrial natriuretic factor in the heart. To test the sensitivity of these signals to pressure overload, we assayed the activity of MAPKs extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 in protein lysates from the left ventricle (LV) or white blood cells (WBC) isolated from aortic banded mice with varying levels of pressure overload. In separated mice we measured atrial natriuretic factor mRNA levels by Northern blotting. As expected, a significant induction of atrial natriuretic factor mRNA levels was observed after aortic banding, and it significantly correlated with the trans-stenotic systolic pressure gradient but not with the LV weight:body weight ratio. In contrast, a significant correlation with systolic pressure gradient or LV weight:body weight ratio was observed for all of the MAPK activity detected in LV samples or WBCs. Importantly, LV activation of MAPKs significantly correlated with their activation in WBCs from the same animal. To test whether MAPK activation in WBCs might reflect uncontrolled blood pressure levels in humans, we assayed extracellular signal-regulated kinase, c-Jun N-terminal kinase 1, and p38 activation in WBCs isolated from normotensive volunteers, hypertensive patients with controlled blood pressure values, or hypertensive patients with uncontrolled blood pressure values. Interestingly, in hypertensive patients with controlled blood pressure values, LV mass and extracellular signal-regulated kinase phosphorylation were significantly reduced compared with those in hypertensive patients with uncontrolled blood pressure values. These results suggest that MAPKs are sensors of pressure overload and that extracellular signal-regulated kinase activation in WBCs might be used as a novel surrogate biomarker of uncontrolled human hypertension.

Endovascular repair for isolated iliac artery aneurysms: case report and review of the current literature.

For a long time, open surgical repair has been considered the preferred management option for the exclusion of isolated iliac artery aneurysms.The development of transluminally placed endovascular stent grafts, which have been studied extensively for aneurysm exclusion in the abdominal and thoracic aorta, provided a less invasive approach for exclusion of iliac artery aneurysms as compared with surgical reconstruction or open surgical graft placement.Here we report a case of concomitant bilateral common and internal iliac artery aneurysms excluded successfully with multiple stent-grafting deployment with extension to the external iliac arteries and without coil embolization requirements.

Coronary angioplasty with stenting for acute coronary syndrome in patients with isolated single coronary artery: a report of two cases.

In the largest reported series of patients, the overall angiographical incidence of congenital coronary anomalies was 1.3%. Among these anomalies, an isolated single coronary artery is a rare, congenital coronary anomaly with an incidence of 0.044-0.23%. In this kind of anomaly, the coronary arteries arise by a single coronary ostium in the right or left sinus of Valsalva. Percutaneous coronary revascularization plays an important role in the management of acute coronary syndrome, and coronary anomalies may determine a lower success rate of this intervention. We report two cases of isolated single coronary arteries who underwent successful coronary angioplasty and stenting for acute coronary syndrome.

[Tako-tsubo cardiomyopathy complicated by left apical thrombus]. / Cardiomiopatia simil-tako-tsubo complicata da formazione di trombo apicale.

Tako-tsubo cardiomyopathy is a rare syndrome usually described in postmenopausal women, with a presentation mimicking an acute myocardial infarction. We report an unusual case of tako-tsubo cardiomyopathy complicated by left ventricular apical thrombus.