Demystifying the Contemporary Role of 12-Month Dual Antiplatelet Therapy After Acute Coronary Syndrome.

For almost two decades, 12-month dual antiplatelet therapy (DAPT) in acute coronary syndrome (ACS) has been the only class I recommendation on DAPT in American and European guidelines, which has resulted in 12-month durations of DAPT therapy being the most frequently implemented in ACS patients undergoing percutaneous coronary intervention (PCI) across the globe. Twelve-month DAPT was initially grounded in the results of the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial, which, by design, studied DAPT versus no DAPT rather than the optimal DAPT duration. The average DAPT duration in this study was 9 months, not 12 months. Subsequent ACS studies, which were not designed to assess DAPT duration, rather its composition (aspirin with prasugrel or ticagrelor compared with clopidogrel) were further interpreted as supportive evidence for 12-month DAPT duration. In these studies, the median DAPT duration was 9 or 15 months for ticagrelor and prasugrel, respectively. Several subsequent studies questioned the 12-month regimen and suggested that DAPT duration should either be fewer than 12 months in patients at high bleeding risk or more than 12 months in patients at high ischemic risk who can safely tolerate the treatment. Bleeding, rather than ischemic risk assessment, has emerged as a treatment modifier for maximizing the net clinical benefit of DAPT, due to excessive bleeding and no clear benefit of prolonged treatment regimens in high bleeding risk patients. Multiple DAPT de-escalation treatment strategies, including switching from prasugrel or ticagrelor to clopidogrel, reducing the dose of prasugrel or ticagrelor, and shortening DAPT duration while maintaining monotherapy with ticagrelor, have been consistently shown to reduce bleeding without increasing fatal or nonfatal cardiovascular or cerebral ischemic risks compared with 12-month DAPT. However, 12-month DAPT remains the only class-I DAPT recommendation for patients with ACS despite the lack of prospectively established evidence, leading to unnecessary and potentially harmful overtreatment in many patients. It is time for clinical practice and guideline recommendations to be updated to reflect the totality of the evidence regarding the optimal DAPT duration in ACS.

Impact of Coronary Microvascular Dysfunction in Takotsubo Syndrome: Cause, Consequence or Both?

Takotsubo syndrome (TTS) is an acute cause of heart failure characterized by a reversible left ventricular (LV) impairment usually induced by a physical or emotional trigger. TTS is not always a benign disease since it is associated with a relatively higher risk of life-threatening complications, such as cardiogenic shock, ventricular arrhythmias, respiratory failure, cardiopulmonary resuscitation and death. Despite notable advancements in the management of patients with TTS, physiopathological mechanisms underlying transient LV dysfunction remain largely unknown. Since TTS carries similar prognostic implications than acute myocardial infarction, the identification of mechanisms and predictors of worse prognosis remain key to establish appropriate treatments. The greater prevalence of TTS among post-menopausal women and the activation of the neuro-cardiac axis triggered by physical or emotional stressors paved the way forward to several studies focused on coronary microcirculation and impaired blood flow as the main physiopathological mechanisms of TTS. However, whether microvascular dysfunction is the cause or a consequence of transient LV impairment remains still unsettled. This review provides an up-to-date summary of available evidence supporting the role of microvascular dysfunction in TTS pathogenesis, summarizing contemporary invasive and non-invasive diagnostic techniques for its assessment. We will also discuss novel techniques focused on microvascular dysfunction in TTS which may support clinicians for the implementation of tailored treatments.

Periprocedural Myocardial Infarction following Elective Percutaneous Coronary Interventions.

The prognostic relevance of periprocedural myocardial infarction (PMI) in patients with chronic coronary syndrome undergoing percutaneous coronary intervention (PCI) is still matter of debate, particularly regarding the type (cardiac troponin or creatin kinase-MB) and different thresholds of biomarkers elevation, as the importance of associated ancillary criteria of ischemia or concomitant angiographic complications. There are still uncertainties regarding the value of PMI as event which is prognostically equivalent to spontaneous myocardial infarction or if it simply represents a marker of baseline risk, atherosclerotic burden and procedural complexity. In the present review, we will present the mechanisms and predictors of PMI occurring during PCI and potential treatment strategies to reduce its occurrence. We will also overview all commonly adopted definitions of PMI, which carry different prevalence and prognostic implications in daily practice and clinical trials. Finally, we will discuss the impact of different PMI definitions on the interpretation of trials results, emphasizing the importance of adequate endpoints selection in the planning and interpretation of clinical trials.

Long-term outcomes after transcatheter aortic valve implantation in failed bioprosthetic valves.

AIMS: Due to bioprosthetic valve degeneration, aortic valve-in-valve (ViV) procedures are increasingly performed. There are no data on long-term outcomes after aortic ViV. Our aim was to perform a large-scale assessment of long-term survival and reintervention after aortic ViV. METHODS AND RESULTS: A total of 1006 aortic ViV procedures performed more than 5 years ago [mean age 77.7 ± 9.7 years; 58.8% male; median STS-PROM score 7.3% (4.2-12.0)] were included in the analysis. Patients were treated with Medtronic self-expandable valves (CoreValve/Evolut, Medtronic Inc., Minneapolis, MN, USA) (n = 523, 52.0%), Edwards balloon-expandable valves (EBEV, SAPIEN/SAPIEN XT/SAPIEN 3, Edwards Lifesciences, Irvine, CA, USA) (n = 435, 43.2%), and other devices (n = 48, 4.8%). Survival was lower at 8 years in patients with small-failed bioprostheses [internal diameter (ID) ≤ 20 mm] compared with those with large-failed bioprostheses (ID > 20 mm) (33.2% vs. 40.5%, P = 0.01). Independent correlates for mortality included smaller-failed bioprosthetic valves [hazard ratio (HR) 1.07 (95% confidence interval (CI) 1.02-1.13)], age [HR 1.21 (95% CI 1.01-1.45)], and non-transfemoral access [HR 1.43 (95% CI 1.11-1.84)]. There were 40 reinterventions after ViV. Independent correlates for all-cause reintervention included pre-existing severe prosthesis-patient mismatch [subhazard ratio (SHR) 4.34 (95% CI 1.31-14.39)], device malposition [SHR 3.75 (95% CI 1.36-10.35)], EBEV [SHR 3.34 (95% CI 1.26-8.85)], and age [SHR 0.59 (95% CI 0.44-0.78)]. CONCLUSIONS: The size of the original failed valve may influence long-term mortality, and the type of the transcatheter valve may influence the need for reintervention after aortic ViV.

Late recurrence of a giant left ventricular pseudoaneurysm: the importance of multimodality imaging approach.

Left ventricular pseudoaneurysms (LVP) are rare but may arise after myocardial infarction, trauma or cardiac surgery, tending to expand and rupture over the time. We show the case of a 75-year-old patient with a recurrent giant ventricular pseudoaneurysm, who presented to the emergency department with sustained ventricular tachycardia. Pseudoaneurysmatic lesion was investigated through echocardiography, angiography and Cardiac Computed Tomography, in order to evaluate the size and spatial orientation of the pseudoaneurysm and to set a tailored treatment. At emergency department, sustained ventricular tachycardia may be the first and unique clinical presentation of ventricular pseudoaneurysm late recurrence, whose management requires a multimodality imaging approach to guide surgical correction.

Mutations affecting the BHLHA9 DNA-binding domain cause MSSD, mesoaxial synostotic syndactyly with phalangeal reduction, Malik-Percin type.

Mesoaxial synostotic syndactyly, Malik-Percin type (MSSD) (syndactyly type IX) is a rare autosomal-recessive nonsyndromic digit anomaly with only two affected families reported so far. We previously showed that the trait is genetically distinct from other syndactyly types, and through autozygosity mapping we had identified a locus on chromosome 17p13.3 for this unique limb malformation. Here, we extend the number of independent pedigrees from various geographic regions segregating MSSD to a total of six. We demonstrate that three neighboring missense mutations affecting the highly conserved DNA-binding region of the basic helix-loop-helix A9 transcription factor (BHLHA9) are associated with this phenotype. Recombinant BHLHA9 generated by transient gene expression is shown to be located in the cytoplasm and the cell nucleus. Transcription factors 3, 4, and 12, members of the E protein (class I) family of helix-loop-helix transcription factors, are highlighted in yeast two-hybrid analysis as potential dimerization partners for BHLHA9. In the presence of BHLHA9, the potential of these three proteins to activate expression of an E-box-regulated target gene is reduced considerably. BHLHA9 harboring one of the three substitutions detected in MSSD-affected individuals eliminates entirely the transcription activation by these class I bHLH proteins. We conclude that by dimerizing with other bHLH protein monomers, BHLHA9 could fine tune the expression of regulatory factors governing determination of central limb mesenchyme cells, a function made impossible by altering critical amino acids in the DNA binding domain. These findings identify BHLHA9 as an essential player in the regulatory network governing limb morphogenesis in humans.

ACVR1 p.Q207E causes classic fibrodysplasia ossificans progressiva and is functionally distinct from the engineered constitutively active ACVR1 p.Q207D variant.

Fibrodysplasia ossificans progressiva (FOP) is a disabling genetic disorder of progressive heterotopic ossification (HO). Here, we report a patient with an ultra-rare point mutation [c.619C>G, p.Q207E] located in a codon adjacent to the most common FOP mutation [c.617G>A, p.R206H] of Activin A Receptor, type 1 (ACVR1) and that affects the same intracellular amino acid position in the GS activation domain as the engineered constitutively active (c.a.) variant p.Q207D. It was predicted that both mutations at residue 207 have similar functional effects by introducing a negative charge. Transgenic p.Q207D-c.a. mice have served as a model for FOP HO in several in vivo studies. However, we found that the engineered ACVR1(Q207D-c.a.) is significantly more active than the classic FOP mutation ACVR1(R206H) when overexpressed in chicken limbs and in differentiation assays of chondrogenesis, osteogenesis and myogenesis. Importantly, our studies reveal that the ACVR1(Q207E) resembles the classic FOP receptor in these assays, not the engineered ACVR1(Q207D-c.a.). Notably, reporter gene assays revealed that both naturally occurring FOP receptors (ACVR1(R206H) and ACVR1(Q207E)) were activated by BMP7 and were sensitive to deletion of the ligand binding domain, whereas the engineered ACVR1(Q207D-c.a.) exhibited ligand independent activity. We performed an in silico analysis and propose a structural model for p.Q207D-c.a. that irreversibly relocates the GS domain into an activating position, where it becomes ligand independent. We conclude that the engineered p.Q207D-c.a. mutation has severe limitations as a model for FOP, whereas the naturally occurring mutations p.R206H and p.Q207E facilitate receptor activation, albeit in a reversible manner.

Homeotic arm-to-leg transformation associated with genomic rearrangements at the PITX1 locus.

The study of homeotic-transformation mutants in model organisms such as Drosophila revolutionized the field of developmental biology, but how these mutants relate to human developmental defects remains to be elucidated. Here, we show that Liebenberg syndrome, an autosomal-dominant upper-limb malformation, shows features of a homeotic limb transformation in which the arms have acquired morphological characteristics of a leg. Using high-resolution array comparative genomic hybridization and paired-end whole-genome sequencing, we identified two deletions and a translocation 5' of PITX1. The structural changes are likely to remove active PITX1 forelimb suppressor and/or insulator elements and thereby move active enhancer elements in the vicinity of the PITX1 regulatory landscape. We generated transgenic mice in which PITX1 was misexpressed under the control of a nearby enhancer and were able to recapitulate the Liebenberg phenotype.

Role of Genetic Factors in the Pathogenesis of Radial Deficiencies in Humans.

Radial deficiencies (RDs), defined as under/abnormal development or absence of any of the structures of the forearm, radial carpal bones and thumb, occur with a live birth incidence ranging from 1 out of 30,000 to 1 out 6,000 newborns and represent about one third/one fourth of all the congenital upper limb anomalies. About half of radial disorders have a mendelian cause and pattern of inheritance, whereas the remaining half appears sporadic with no known gene involved. In sporadic forms certain anomalies, such as thumb or radial hypoplasia, may occur either alone or in association with systemic conditions, like vertebral abnormalities or renal defects. All the cases with a mendelian inheritance are syndromic forms, which include cardiac defects (in Holt-Oram syndrome), bone marrow failure (in Fanconi anemia), platelet deficiency (in thrombocytopenia-absent-radius syndrome), ocular motility impairment (in Okihiro syndrome). The genetics of radial deficiencies is complex, characterized by genetic heterogeneity and high inter- and intra-familial clinical variability: this review will analyze the etiopathogenesis and the genotype/phenotype correlations of the main radial deficiency disorders in humans.

VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies) association: disease spectrum in 25 patients ascertained for their upper limb involvement.

OBJECTIVE: To review the clinical characteristics in a series of 25 patients with VACTERL (vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, cardiac defects, renal and limb anomalies) association who were ascertained for upper limb involvement. STUDY DESIGN: The study involved a review of clinical and radiologic data from patients with VACTERL association collected by a hand surgery clinic between 2004 and 2013. RESULTS: Radial axis involvement was found in all 25 patients (100%), with severe thumb function impairment in 79% and complete absence of the radius in roughly 33%. Costovertebral anomalies were the most frequent feature, found in 23 patients (92%). All 3 core features (anal atresia, tracheoesophageal fistula with esophageal atresia, and costovertebral anomalies) were present in only 12% of the patients. Twelve patients (48%) had abnormalities not part of the VACTERL spectrum, showing a specific pattern of non-VACTERL-type malformations, including genitourinary abnormalities (12%), single umbilical artery (8%), and tethered cord (8%). Previously unreported clinical findings were concurrent hypoplasia of both the odontoid process and the coccyx in 2 patients and an isolated sacral dimple in 2 patients. CONCLUSION: Upper limb involvement in VACTERL association is a specific feature of the radial axis that occurs in monolateral form in approximately 75% of cases and, when bilateral, always occurs in a nonsymmetrical fashion. Odontoid and coccygeal hypoplasia and sacral dimple are newly reported malformations of the VACTERL phenotype.

Clopidogrel induced reduction in neutrophil count: An overlooked beneficial effect?

Complement-stimulated neutrophils are able to adhere to the endothelium and damage endothelial cells both in vitro and in vivo. These blood cells participate in the early stages, growth and complications of atherosclerotic plaques. Recent findings, based on mendelian randomization analysis, support the concept that high neutrophil counts are a causal risk factor for ischemic heart disease and myocardial infarction . Clopidogrel decreases leukocyte count and inflammatory markers in patients with acute coronary syndromes; this off-target effect, which is independent of the antiplatelet action, may help explaining secondary prevention data showing a superiority of clopidogrel over aspirin in reducing new cardiovascular events.

Acute Response of the Noninfarcted Myocardium and Surrounding Tissue Assessed by T2 Mapping After STEMI.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is associated with a systemic and local inflammatory response with edema. However, their role at the tissue level is poorly characterized. OBJECTIVES: This study aims to characterize T2 values of the noninfarcted myocardium (NIM) and surrounding tissue and to investigate prognostic relevance of higher NIM T2 values after STEMI. METHODS: A total of 171 consecutive patients with STEMI without prior cardiovascular events who underwent cardiac magnetic resonance after primary percutaneous coronary intervention were analyzed in terms of standard infarct characteristics. Edema of the NIM, liver, spleen, and pectoralis muscle was assessed based on T2 mapping. Follow-up was available for 130 patients. The primary endpoint was major adverse cardiac events (MACE), defined as cardiovascular death, myocardial infarction, unplanned coronary revascularization or rehospitalization for heart failure. The median time from primary percutaneous coronary intervention to cardiac magnetic resonance was 3 days (IQR: 2-5 days). RESULTS: Higher (above the median value of 45 ms) T2 values in the NIM area were associated with larger infarct size, microvascular obstruction, and left ventricular dysfunction and did not correlate with C-reactive protein, white blood cells, or T2 values of the pectoralis muscle, liver, and spleen. At a median follow-up of 17 months, patients with higher (>45 ms) NIM T2 values had increased risk of MACE (P < 0.001) compared with subjects with NIM T2 values ≤45 ms, mainly caused by a higher rate of myocardial reinfarction (26.3% vs 1.4%; P < 0.001). At multivariable analysis, higher NIM T2 values independently predicted MACE (HR: 2.824 [95% CI: 1.254-6.361]; P = 0.012). CONCLUSIONS: Higher NIM T2 values after STEMI are independently associated with worse cardiovascular outcomes, mainly because of higher risk of myocardial infarction.