Very Late Stent Thrombosis 42 Months after Implantation of Sirolimus-Eluting Stent and Discontinuation of Antiplatelet Therapy

Although safety profiles of sirolimus-eluting stents do not seem to differ in short-to-medium term from those of bare-metal stents, late stent thrombosis after deployment of drug-eluting stents has emerged as a potential safety concern in the era of high-pressure stent implantation. Here, we describe the case of a patient with acute myocardial infarction due to stent thrombosis of a sirolimus-eluting stent 42 months after stent deployment and 5 weeks after discontinuation of aspirin treatment. To the best of our knowledge, this is one of the most delayed cases of sirolimus-eluting stent thrombosis described so far. The case emphasizes the potential risk that late stent thrombosis can unpredictably occur at any time point after drug-eluting stent deployment

MicroRNAs in a Cardiac Loop: Progenitor or Myocyte?

Like transcription factors, microRNAs are emerging as regulators of cell fate decisions. In this issue, Wang et al. (2010) identify a critical microRNA pathway under the control of Bmp signaling that promotes outflow tract myocardial differentiation from cardiac progenitors in vivo

Domain zipping and unzipping modulates TRPM4's properties in human cardiac conduction disease

The transient receptor potential melastatin 4 (TRPM4) is a Ca2+‐activated nonselective cation channel linked to human cardiac diseases. The human mutation K914R within TRPM4’s S4‐S5 linker was identified in patients with atrioventricular block. During UV‐flash‐mediated Ca2+ transients, TRPM4K914R generated a threefold augmented membrane current concomitant with 2 to 3‐fold slowed down activation and deactivation kinetics resulting in excessive membrane currents during human cardiac action potentials. Mutagenesis of K914 paired with molecular modeling suggested the importance of the nanoscopic interface between the S4‐S5 linker, the MHR4‐, and TRP‐domain as a major determinant for TRPM4’s behavior. Rational mutagenesis of an interacting amino acid (R1062Q) in the TRP domain was able to offset K914R`s gain‐of‐function by zipping and unzipping of this nanoscopic interface. In conclusion, repulsion and attraction between the amino acids at positions 914 and 1062 alters the flexibility of the nanoscopic interface suggesting a zipping and unzipping mechanism that modulates TRPM4’s functions. Pharmacological modulation of this intramolecular mechanism might represent a novel therapeutic strategy for the management of TRPM4‐mediated cardiac diseases

Impact of Coronary Anatomy and Stenting Technique on Long-Term Outcome After Drug-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease

ObjectivesThis study sought to evaluate the impact of anatomic and procedural variables on the outcome of the unprotected left main coronary artery (uLMCA) itself after drug-eluting stent (DES) implantation.BackgroundThere is a controversial debate regarding when and how to perform percutaneous coronary intervention (PCI) for an uLMCA stenosis.MethodsThis analysis is based on a randomized study of 607 patients undergoing PCI for uLMCA, randomized 1:1 to receive paclitaxel- or sirolimus-eluting stents. We evaluated the impact of the SYNTAX score, uLMCA anatomy, and stenting technique on in-stent restenosis (ISR), target lesion revascularization (TLR), and the 3-year outcomes.ResultsThe 3-year cardiac mortality rate was 5.8%; 235 (39%) patients had a true bifurcation lesion (TBL), and the median SYNTAX score was 27. TBL was associated with a higher need for multiple stents (72% vs. 37%, p < 0.001). TBL was a significant predictor of ISR (23% vs. 14%, p = 0.008) and for TLR (18% vs. 9%, p < 0.001). The need for multiple stents was a predictor of ISR (22% vs. 13%, p = 0.005) and for TLR (16% vs. 9%, p = 0.005). Culotte stenting showed better results compared with T-stenting for ISR (21% vs. 56%, p = 0.02) and for TLR (15% vs. 56%, p < 0.001). We observed a significant association between uLMCA-TLR and SYNTAX scores (9.2% for scores ≤22, 14.9% for scores 23 to 32, and 13.0% for scores ≥33, p = 0.008).ConclusionsPCI of uLMCA lesions with DES is safe and effective out to 3 years. TBL and multiple stents were independent predictors for ISR. In the multivariate analysis, independent predictors for TLR were TBL, age, and EuroSCORE (European System for Cardiac Operative Risk Evaluation). (Drug-Eluting-Stents for Unprotected Left Main Stem Disease [ISAR-LEFT-MAIN]; NCT00133237

Antisense-mediated exon skipping: a therapeutic strategy for titin-based dilated cardiomyopathy

Frameshift mutations in the TTN gene encoding titin are a major cause for inherited forms of dilated cardiomyopathy (DCM), a heart disease characterized by ventricular dilatation, systolic dysfunction, and progressive heart failure. To date, there are no specific treatment options for DCM patients but heart transplantation. Here, we show the beneficial potential of reframing titin transcripts by antisense oligonucleotide (AON)-mediated exon skipping in human and murine models of DCM carrying a previously identified autosomal-dominant frameshift mutation in titin exon 326. Correction of TTN reading frame in patient-specific cardiomyocytes derived from induced pluripotent stem cells rescued defective myofibril assembly and stability and normalized the sarcomeric protein expression. AON treatment in Ttn knock-in mice improved sarcomere formation and contractile performance in homozygous embryos and prevented the development of the DCM phenotype in heterozygous animals. These results demonstrate that disruption of the titin reading frame due to a truncating DCM mutation canbe restored by exon skipping in both patient cardiomyocytes invitro and mouse heart invivo, indicating RNA-based strategies as a potential treatment option for DCM

Long-Term Efficacy and Safety of Paclitaxel-Eluting Balloon for the Treatment of Drug-Eluting Stent Restenosis 3-Year Results of a Randomized Controlled Trial

AbstractObjectivesThis study sought to investigate the long-term comparative efficacy and safety of paclitaxel-eluting balloon (PEB), paclitaxel-eluting stent (PES), or balloon angioplasty (BA) for the treatment of drug-eluting stent restenosis.BackgroundThe optimal treatment of drug-eluting stent restenosis remains unknown. Although PEB has shown encouraging results, the long-term clinical efficacy and safety of PEB remains poorly defined.MethodsA total of 402 patients with clinically significant restenosis in limus-eluting stents were randomly assigned to receive PEB (n = 137), PES (n = 131), or BA (n = 134). For this analysis, PEB versus PES and PEB versus BA were compared. The primary efficacy and safety endpoints were target lesion revascularization and the composite of death or myocardial infarction.ResultsAt a median follow-up of 3 years, the risk of target lesion revascularization was comparable with PEB versus PES (hazard ratio [HR]: 1.46, 95% confidence interval [CI]: 0.91 to 2.33; p = 0.11) and lower with PEB versus BA (HR: 0.51, 95% CI: 0.34 to 0.74; p < 0.001). The risk of death/myocardial infarction tended to be lower with PEB versus PES (HR: 0.55, 95% CI: 0.28 to 1.07; p = 0.08), due to a lower risk of death (HR: 0.38, 95% CI: 0.17 to 0.87; p = 0.02). The risk of death/myocardial infarction was similar with PEB versus BA (HR: 0.96, 95% CI: 0.46 to 2.0; p = 0.91).ConclusionsAt 3 years, the use of PEB as compared with PES to treat patients with limus-eluting stent restenosis has similar efficacy and safety. PEB remains superior to BA. The sustained efficacy without trade-off in safety supports the role of PEB as treatment option for patients with drug-eluting stent restenosis. (Intracoronary Stenting and Angiographic Results: Drug Eluting Stent In-Stent Restenosis: 3 Treatment Approaches [ISAR-DESIRE 3]; NCT00987324

Biodegradable Polymer Versus Permanent Polymer Drug-Eluting Stents and Everolimus- Versus Sirolimus-Eluting Stents in Patients With Coronary Artery Disease 3-Year Outcomes From a Randomized Clinical Trial

ObjectivesThe aim of this study was to compare the 3-year efficacy and safety of biodegradable polymer with permanent polymer stents and of everolimus-eluting stents (EES) with sirolimus-eluting stents (SES).BackgroundBiodegradable polymer drug-eluting stents (DES) offer potential for enhanced late outcomes in comparison with permanent polymer stents. In addition, there is increasing interest in the comparison of EES (Xience, Abbott Vascular, Abbott Park, Illinois) versus SES (Cypher, Cordis Corporation, Miami Lakes, Florida).MethodsThe ISAR-TEST 4 (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting Stents-4) was a randomized clinical trial with broad inclusion criteria, enrolling 2,603 patients at 2 clinics in Munich, Germany. Patients were randomized to either biodegradable polymer (n = 1,299) or permanent polymer stents (n = 1,304); patients treated with permanent polymer stents were randomly allocated to EES (n = 652) or SES (n = 652). The primary endpoint was the composite of cardiac death, target vessel-related myocardial infarction, or target lesion revascularization.ResultsClinical events continued to accrue at a low rate out to 3 years in all groups. Overall, there was no significant difference between biodegradable polymer and permanent polymer DES with regard to the primary endpoint (20.1% vs. 20.9%, hazard ratio [HR]: 0.95, 95% confidence interval [CI]: 0.80 to 1.13; p = 0.59). Rates of definite/probable stent thrombosis were also similar in both groups (1.2% vs. 1.7%, respectively; HR: 0.71, 95% CI: 0.37 to 1.39; p = 0.32). In patients treated with permanent polymer stents, EES were comparable to SES with regard to the primary endpoint (19.6% vs. 22.2%, respectively; HR: 0.87, 95% CI: 0.68 to 1.11; p = 0.26) as well as definite/probable stent thrombosis (1.4% vs. 1.9%, HR: 0.75, 95% CI: 0.32 to 1.78; p = 0.51).ConclusionsBiodegradable polymer and permanent polymer DES are associated with similar clinical outcomes at 3 years. In addition, EES are comparable to SES in terms of overall clinical efficacy and safety. (Intracoronary Stenting and Angiographic Results: Test Efficacy of 3 Limus-Eluting STents [ISAR-TEST 4]: Prospective, Randomized Trial of 3-limus Agent-eluting Stents With Different Polymer Coatings; NCT00598676

Thymosin beta 4 Improves Differentiation and Vascularization of EHTs

Induced pluripotent stem cells (iPSC) constitute a powerful tool to study cardiac physiology and represents a promising treatment strategy to tackle cardiac disease. However, iPSCs remain relatively immature after differentiation. Additionally, engineered heart tissue (EHT) has been investigated as a therapy option in preclinical disease models with promising results, although their vascularization and functionality leave room for improvement. Thymosin beta 4 (T beta 4) has been shown to promote the differentiation of progenitor cell lines to cardiomyocytes while it also induces angiogenic sprouting and vascular maturation. We examined the potential impact of T beta 4 to enhance maturation of cardiomyocytes from iPSCs. Assessing the expression of transcription factors associated with cardiac differentiation, we were able to demonstrate the increased generation of cells displaying cardiomyocyte characteristics in vitro. Furthermore, we demonstrated, in a zebrafish model of embryonic vascular development, that T beta 4 is crucial for the proper execution of lymphatic and angiogenic vessel sprouting. Finally, utilizing T beta 4-transduced EHTs generated from mice genetically engineered to label endothelial cells in vitro, we show that treatment with T beta 4 promotes vascularization and contractility in EHTs, highlighting T beta 4 as a growth factor improving the formation of cardiomyocytes from iPSC and enhancing the performance of EHTs generated from neonatal cardiomyocytes

Functional Comparison of Induced Pluripotent Stem Cell- and Blood-Derived GPIIbIIIa Deficient Platelets

Human induced pluripotent stem cells (hiPSCs) represent a versatile tool to model genetic diseases and are a potential source for cell transfusion therapies. However, it remains elusive to which extent patient-specific hiPSC-derived cells functionally resemble their native counterparts. Here, we generated a hiPSC model of the primary platelet disease Glanzmann thrombasthenia (GT), characterized by dysfunction of the integrin receptor GPIIbIIIa, and compared side-by-side healthy and diseased hiPSC-derived platelets with peripheral blood platelets. Both GT-hiPSC-derived platelets and their peripheral blood equivalents showed absence of membrane expression of GPIIbIIIa, a reduction of PAC-1 binding, surface spreading and adherence to fibrinogen. We demonstrated that GT-hiPSC-derived platelets recapitulate molecular and functional aspects of the disease and show comparable behavior to their native counterparts encouraging the further use of hiPSC-based disease models as well as the transition towards a clinical application

Multipotent Embryonic Isl1+ Progenitor Cells Lead to Cardiac, Smooth Muscle, and Endothelial Cell Diversification

SummaryCardiogenesis requires the generation of endothelial, cardiac, and smooth muscle cells, thought to arise from distinct embryonic precursors. We use genetic fate-mapping studies to document that isl1+ precursors from the second heart field can generate each of these diverse cardiovascular cell types in vivo. Utilizing embryonic stem (ES) cells, we clonally amplified a cellular hierarchy of isl1+ cardiovascular progenitors, which resemble the developmental precursors in the embryonic heart. The transcriptional signature of isl1+/Nkx2.5+/flk1+ defines a multipotent cardiovascular progenitor, which can give rise to cells of all three lineages. These studies document a developmental paradigm for cardiogenesis, where muscle and endothelial lineage diversification arises from a single cell-level decision of a multipotent isl1+ cardiovascular progenitor cell (MICP). The discovery of ES cell-derived MICPs suggests a strategy for cardiovascular tissue regeneration via their isolation, renewal, and directed differentiation into specific mature cardiac, pacemaker, smooth muscle, and endothelial cell types