Variants of the promoter of MYH6 gene in congenital isolated and sporadic patent ductus arteriosus: case-control study and cellular functional analyses.

Patent ductus arteriosus (PDA) is a common form of congenital heart disease. The MYH6 gene has important effects on cardiovascular growth and development, but the effect of variants in the MYH6 gene promoter on ductus arteriosus is unknown. DNA was extracted from blood samples of 721 subjects (428 patients with isolated and sporadic PDA and 293 healthy controls) and analyzed by sequencing for MYH6 gene promoter region variants. Cellular function experiments with three cell lines (HEK-293, HL-1, and H9C2 cells) and bioinformatics analyses were performed to verify their effects on gene expression. In the MYH6 gene promoter, 11 variants were identified. Four variants were found only in patients with PDA and 2 of them (g.3434G>C and g.4524C>T) were novel. Electrophoretic mobility shift assay showed that the transcription factors bound by the promoter variants were significantly altered in comparison to the wild-type in all three cell lines. Dual luciferase reporter showed that all the 4 variants reduced the transcriptional activity of the MYH6 gene promoter (P < 0.05). Prediction of transcription factors bound by the variants indicated that these variants alter the transcription factor binding sites. These pathological alterations most likely affect the contraction of the smooth muscle of ductus arteriosus, leading to PDA. This study is the first to focus on variants at the promoter region of the MYH6 gene in PDA patients with cellular function tests. Therefore, this study provides new insights to understand the genetic basis and facilitates further studies on the mechanism of PDA formation.

Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC.

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

Recent advances in the development of Rho kinase inhibitors (2015-2021).

Rho-associated coiled-coil kinases (ROCKs) are key downstream effectors of small GTPases. ROCK plays a central role in diverse cellular events with accumulating evidence supporting the concept that ROCK is important in tumor development and progression. Numerous ROCK inhibitors have been investigated for their therapeutic potential in the treatment of cancers. In this article, we review recent research progress on ROCK inhibitors, especially those with potential for the treatment of cancers, reported in the literature from 2015 to 2021. Most ROCK inhibitors show potent in vitro and in vivo antitumor activities and have potential in the treatment of cancers.

Patent Foramen Ovale Management for Secondary Stroke Prevention: State-of-the-Art Appraisal of Current Evidence.

Patent foramen ovale (PFO) is frequently identified in young patients with ischemic stroke. Randomized controlled trials provide robust evidence supporting PFO closure in selected patients with cryptogenic ischemic stroke; however, several questions remain unanswered. This report summarizes current knowledge on the epidemiology of PFO-associated stroke, the role of PFO as a cause of stroke, and anatomic high-risk features. We also comment on breakthrough developments in patient selection algorithms for PFO closure in relation to the PFO-associated stroke causal likelihood risk stratification system. We further highlight areas for future research in PFO-associated stroke including the efficacy and safety of PFO closure in the elderly population, incidence, and long-term consequences of atrial fibrillation post-PFO closure, generalizability of the results of clinical trials in the real world, and the need for assessing the effect of neurocardiology teams on adherence to international recommendations. Other important knowledge gaps such as sex, race/ethnicity, and regional disparities in access to diagnostic technologies, PFO closure devices, and clinical outcomes in the real world are also discussed as priority research topics.

Secular Trends in Patent Ductus Arteriosus Management in Infants Born Preterm in the National Institute of Child Health and Human Development Neonatal Research Network.

We evaluated changes in patent ductus arteriosus (PDA) diagnosis and treatment from 2012 through 2021 in a network of US academic hospitals. PDA treatment decreased among infants born at 26-28 weeks but not among infants born at 22-25 weeks. Rates of indomethacin use and PDA ligation decreased while acetaminophen use and transcatheter PDA closure increased.

Cardiorespiratory Instability after Percutaneous Patent Ductus Arteriosus Closure: A Multicenter Cohort Study.

OBJECTIVE: To evaluate postprocedural clinical characteristics of preterm infants undergoing transcatheter patent ductus arteriosus (PDA) closure, including oxygenation/ventilation failure and cardiovascular compromise. STUDY DESIGN: Multicenter retrospective cohort study of preterm infants who were ≤2 kg at the time of percutaneous PDA closure between August 2018 and July 2021. Indices of cardiorespiratory stability were collected pre-closure, immediately post-closure, and subsequently averaged every 4 hours for the first 24 hours post-procedure. The primary outcome was incidence of post-transcatheter cardiorespiratory syndrome: composite of hemodynamic instability (defined by systemic hypotension, systemic hypertension, or use of new inotropes/vasopressors in the first 24 hours after catheterization) and at least one of the following: (i) ventilation failure or (ii) oxygenation failure. RESULTS: A total of 197 patients were included with a median [IQR] age and weight at catheterization of 34 [25, 43] days and 1090 [900, 1367] grams, respectively. The primary composite outcome of post-transcatheter cardiorespiratory syndrome was reported in 46 (23.3%). CONCLUSION: Post-transcatheter cardiorespiratory syndrome is characterized primarily by systemic hypertension and oxygenation failure, with a very low incidence of hypotension and need for inotropes.

Recent Development of Biodegradable Occlusion Devices for Intra-Atrial Shunts.

Atrial septal defect (ASD) is the third most common type of structural congenital heart defect. Patent foramen ovale (PFO) is an anatomical anomaly in up to 25% of the general population. With the innovation of occlusion devices and improvement of transcatheter techniques, percutaneous closure has become a first-line therapeutic alternative for treatment of ASD and PFO. During the past few decades, the development of biodegradable occlusion devices has become a promising direction for transcatheter closure of ASD/PFO due to their biodegradability and improved biocompatibility. The purpose of this review is to comprehensively summarize biodegradable ASD/PFO occlusion devices, regarding device design, materials, biodegradability, and evaluation of animal or clinical experiments (if available). The current challenges and the research direction for the development of biodegradable occluders for congenital heart defects are also discussed.

Antithrombotic Therapy Following Structural Heart Disease Interventions: Current Status and Future Directions.

Interventions in structural heart disease cover many catheter-based procedures for congenital and acquired conditions including valvular diseases, septal defects, arterial or venous obstructions, and fistulas. Among the available procedures, the most common are aortic valve implantation, mitral or tricuspid valve repair/implantation, left atrial appendage occlusion, and patent foramen ovale closure. Antithrombotic therapy for transcatheter structural heart disease interventions aims to prevent thromboembolic events and reduce the risk of short-term and long-term complications. The specific approach to antithrombotic therapy depends on the type of intervention and individual patient factors. In this review, we synopsize contemporary evidence on antithrombotic therapies for structural heart disease interventions and highlight the importance of a personalized approach. These recommendations may evolve over time as new evidence emerges and clinical guidelines are updated. Therefore, it's crucial for healthcare professionals to stay updated on the most recent guidelines and individualize therapy based on patient-specific factors and procedural considerations.

The 2022 FASEB Virtual Catalyst Conference on the Cardiac Interatrial Septum and Stroke Risk, December 7, 2022.

There is emerging evidence that the cardiac interatrial septum has an important role as a thromboembolic source for ischemic strokes. There is little consensus on treatment of patients with different cardiac interatrial morphologies or pathologies who have had stroke. In this paper, we summarize the important background, diagnostic, and treatment considerations for this patient population as presented during the Federation of American Societies for Experimental Biology (FASEB) Virtual Catalytic Conference on the Cardiac Interatrial Septum and Stroke Risk, held on December 7, 2022. During this conference, many aspects of the cardiac interatrial septum were discussed. Among these were the embryogenesis of the interatrial septum and development of anatomic variants such as patent foramen ovale and left atrial septal pouch. Also addressed were various mechanisms of injury such as shunting physiologies and the consequences that can result from anatomic variants, as well as imaging considerations in echocardiography, computed tomography, and magnetic resonance imaging. Treatment options including anticoagulation and closure were addressed, as well as an in-depth discussion on whether the left atrial septal pouch is a stroke risk factor. These issues were discussed and debated by multiple experts from neurology, cardiology, and radiology.

Mobile bedside ductus arteriosus closure in severely premature neonates using only echocardiographic guidance.

BACKGROUND: Transcatheter closure of the patent ductus arteriosus (PDA) in premature infants is currently dependent on fluoroscopic guidance and transportation to the catheterization laboratory. AIM: We describe a new echocardiographically guided technique to allow our team to move to the bedside at the neonatal intensive care unit (NICU) of the referring center for percutaneous treatment of PDA in premature infants. METHODS: This is a single-center, retrospective, primarily descriptive analysis. Clinical details about the procedure, its outcomes, and complications were collected. RESULTS: Fifty-eight neonates with a median weight of 1110 g (range 730-2800) and postnatal age of 28 days (range 9-95) underwent percutaneous PDA closure. Five of them were treated in our center with ultrasound guidance only and the other 53 in 18 different neonatology units in 12 towns. The median duration of the procedure was 40 min (range 20-195 min). There were no procedural deaths. There was one residual shunt for 3 weeks, in all other patients the duct closed completely in the first few hours after the intervention. In one patient the procedure had to be interrupted because of a pericardial effusion which had to be drained, the PDA was closed successfully interventionally 5 days later. One device-related aortic coarctation had to be stented. One embolization and one late migration occurred and required treatment. CONCLUSIONS: Echocardiographically guided transcatheter closure of the PDA in prematures was repeatedly possible and allowed that the procedure is performed at the bedside at the NICU with an acceptable rate of complications.

Left atrial appendage occlusion and patent foramen ovale closure using a steerable sheath and intracardiac echocardiography.

A patient presenting with acute ischemic stroke associated with patent foramen ovale (PFO) had concurrent deep vein thrombosis, pulmonary embolism, and new-onset atrial fibrillation. Upon initiation of anticoagulation therapy, the patient developed hemorrhagic transformation of the stroke. The patient's multiple potential sources of embolic stroke were treated with concomitant left atrial appendage occlusion and PFO closure through the PFO, made possible by using the Steerable Amulet Sheath under 3D-intracardiac echocardiography guidance.

Using a customized telescoped stent complex in the percutaneous treatment of a residual superior sinus venosus defect.

The management of superior sinus venosus defects (SVD) via transcatheter covered stent (CS) placement is becoming an acceptable alternative to open heart surgery. Though the medium-term success of this procedure has been described, residual shunting from damage to the covering of the implanted stents, use of stents which are too short and unanticipated shortening of stents may result in immediate or short-term procedural failure. In such cases, placement of a second CS may be required to address a residual defect. Preprocedural prediction of the length of stent required for residual leak treatment may not be as accurate as predicting the required stent length in a native defect, meaning that compassionate use applications to facilitate acquiring non-standard stent and balloon combinations may not be practical. We present a successful case of residual SVD closure using a novel sutured telescoping stent technique. Further collaboration with industry should encourage regulatory approval of longer CS, to mitigate the need for potentially unpredictable modifications such as this.

Headache patterns in patent foramen ovale patients: beyond migraine with aura.

Patent foramen ovale (PFO) is a common cardiac anomaly linked with cryptogenic strokes and migraine, particularly migraine with aura. This study aims to explore the spectrum of headache disorders in PFO patients, focusing on identifying patterns beyond the well-established migraine-PFO connection. A retrospective observational study was conducted on patients diagnosed with PFO. Headache types were classified using the International Classification of Headache Disorders, 3rd edition. The study analyzed headache prevalence and patterns in PFO patients, comparing those with and without a history of stroke. Of 177 participants, 63 (35.59%) reported headaches. Tension-type headache was the most common (15.25%), followed by migraine without aura (11.30%) and migraine with aura (8.47%). Notably, migraine without aura was more prevalent than migraine with aura, contrasting previous assumptions. No significant differences were found in headache types based on stroke history. The study reveals a diverse spectrum of headache types in PFO patients, with migraine without aura being more common than migraine with aura. These findings suggest a need for broader diagnostic perspective and individualized treatment approaches in PFO patients with headaches.

Advances in Recurrent Stroke Prevention: Focus on Antithrombotic Therapies.

The past decade has seen significant advances in stroke prevention. These advances include new antithrombotic agents, new options for dyslipidemia treatment, and novel techniques for surgical stroke prevention. In addition, there is greater recognition of the benefits of multifaceted interventions, including the role of physical activity and dietary modification. Despite these advances, the aging of the population and the high prevalence of key vascular risk factors pose challenges to reducing the burden of stroke. Using a cause-based framework, current approaches to prevention of cardioembolic, cryptogenic, atherosclerotic, and small vessel disease stroke are outlined in this paper. Special emphasis is given to recent trials of antithrombotic agents, including studies that have tested combination treatments and responses according to genetic factors.

The reporting checklist for Chinese patent medicine guidelines: RIGHT for CPM.

Existing reporting checklists lack the necessary level of detail and comprehensiveness to be used in guidelines on Chinese patent medicines (CPM). This study aims to develop a reporting guidance for CPM guidelines based on the Reporting Items of Practice Guidelines in Healthcare (RIGHT) statement. We extracted information from CPM guidelines, existing reporting standards for traditional Chinese medicine (TCM), and the RIGHT statement and its extensions to form the initial pool of reporting items for CPM guidelines. Seventeen experts from diverse disciplines participated in two rounds of Delphi process to refine and clarify the items. Finally, 18 authoritative consultants in the field of TCM and reporting guidelines reviewed and approved the RIGHT for CPM checklist. We added 16 new items and modified two items of the original RIGHT statement to form the RIGHT for CPM checklist, which contains 51 items grouped into seven sections and 23 topics. The new and revised items are distributed across four sections (Basic information, Background, Evidence, and Recommendations) and seven topics: title/subtitle (one new and one revised item), Registration information (one new item), Brief description of the health problem (four new items), Guideline development groups (one revised item), Health care questions (two new items), Recommendations (two new items), and Rationale/explanation for recommendations (six new items). The RIGHT for CPM checklist is committed to providing users with guidance for detailed, comprehensive and transparent reporting, and help practitioners better understand and implement CPM guidelines.

Age-Related Variations in Patterns of Patent Foramen Ovale-Stroke versus Other Cryptogenic Stroke.

INTRODUCTION: Patent foramen ovale (PFO)-stroke, a form of cryptogenic stroke, has certain identifying clinical and imaging features. However, data describing this stroke type remain inconsistent. This study examined the potential variations in PFO-stroke features, depending on age. METHODS: From a hospital registry, cryptogenic stroke patients were retrospectively selected, and PFO-strokes were identified by the presence of >10 microembolic signals on transcranial Doppler saline agitation test. Cryptogenic strokes were grouped according to age (<70 as young, ≥70 as elderly). Clinical and imaging variables of PFO-strokes and non-PFO-strokes were compared, with and without age considered. RESULTS: Of the 462 cryptogenic patients, 30.5% (141/462) were PFO-strokes, while majority (321/462) had no PFO. When cryptogenic strokes were analyzed by age, the significant difference was noted in the lesion number, pattern, and side. A single (72.8 vs. 57.9%, p = 0.020) and a small single lesion (51.1 vs. 35.5%, p = 0.039) were frequently seen in the younger PFO-strokes than the non-PFO counterpart, while mixed territory lesions identified the elderly PFO-strokes (30.6 vs. 8.9%, p = 0.001). A multivariate logistic regression analysis of PFO-strokes further showed that age was independently associated with lesion side (OR 1.12 [1.05-1.20], p < 0.001) and lesion number (OR 1.06 [1.02-1.10], p = 0.005). CONCLUSIONS: Incorporating age-specific imaging criteria in the identification of PFO-strokes may be of additional value. Further, PFO may remain contributory to the stroke risk in the elderly, in association with vascular risk factors.

World Stroke Organization Brain & hEart globAl iniTiative Program.

INTRODUCTION: The World Stroke Organization (WSO) Brain & Heart Task Force developed the Brain & hEart globAl iniTiative (BEAT), a pilot feasibility implementation program to establish clinical collaborations between cardiologists and stroke physicians who work at large healthcare facilities. METHODS: The WSO BEAT pilot project focused on atrial fibrillation (AF) and patent foramen ovale (PFO) detection and management, and poststroke cardiovascular complications known as the stroke-heart syndrome. The program included 10 sites from 8 countries: Brazil, China, Egypt, Germany, Japan, Mexico, Romania, and the USA The primary composite feasibility outcome was the achievement of the following 3 implementation metrics (1) developing site-specific clinical pathways for the diagnosis and management of AF, PFO, and the stroke-heart syndrome; (2) establishing regular Neurocardiology rounds (e.g., monthly); and (3) incorporating a cardiologist to the stroke team. The secondary objectives were (1) to identify implementation challenges to guide a larger program and (2) to describe qualitative improvements. RESULTS: The WSO BEAT pilot feasibility program achieved the prespecified primary composite outcome in 9 of 10 (90%) sites. The most common challenges were the limited access to specific medications (e.g., direct oral anticoagulants) and diagnostic (e.g., prolonged cardiac monitoring) or therapeutic (e.g., PFO closure devices) technologies. The most relevant qualitative improvement was the achievement of a more homogeneous diagnostic and therapeutic approach. CONCLUSION: The WSO BEAT pilot program suggests that developing neurocardiology collaborations is feasible. The long-term sustainability of the WSO BEAT program and its impact on quality of stroke care and clinical outcomes needs to be tested in a larger and longer duration program.

Challenges of Incorporating Life Cycle Drug Pricing in Cost-Effectiveness Models: A Review of Methods and Modeling Suggestions.

OBJECTIVES: This study aimed to conduct a review of existing methods used to incorporate life cycle drug pricing (LCDP) in cost-effectiveness analyses (CEAs), identify common methodological challenges, and suggest modeling approaches for prospectively implementing LCDP in CEA. METHODS: Two complementary searches were conducted in PubMed, combined with hand searching and reference mining, to identify English language full-text articles that explored (1) how drug prices change over time and (2) methods used to apply dynamic pricing in cost-effectiveness models (CEMs). Relevant articles were reviewed, and authors discussed the common methodological practices used in the literature and their associated challenges on prospectively implementing LCDP in CEMs. For each key challenge identified, we provide modeling suggestions to address the issue. RESULTS: We screened 1200 studies based on title and abstract; 117 were reviewed for eligibility, and 47 individual studies were included across both searches. Variations in prices over a product's life cycle are complex and multifactorial, and models applying LCDP in CEA varied in their methodology. We identified 4 key challenges to modeling LCDP in CEA, including how to model price trends before and after loss of exclusivity, how to capture the effect of price changes on future patient cohorts, and how to report results. CONCLUSION: Accurately quantifying the impact of LCDP requires careful consideration of multiple aspects pertaining to both the evolution of drug prices and how to reflect these in CEA. Although uncertainties remain, our findings can aid implementation and evaluation of LCDP in economic evaluations.

Oral DHA supplementation and retinopathy of prematurity: the Joinville DHA Clinical Trial.

Retinopathy of prematurity (ROP) is a leading cause of blindness in premature infants. The condition is associated with DHA deficiency. This study aimed to investigate the effect of DHA supplementation on the occurrence of ROP in infants receiving oral oil drops. It is part of the Joinville DHA study, a non-parallel-group cohort study conducted from March 2020 to January 2023 at a public maternity hospital in Brazil. Infants born before 33 weeks of gestational age or with a birth weight ≤ 1500 g were recruited. Among 155 infants, 81 did not receive and 74 received DHA supplementation until complete vascularisation of the peripheral retina. There was a higher incidence of infants with ROP in the unsupplemented group (58·6 %) compared with the DHA group (41·4 %), but this difference was NS (P = 0·22). Unadjusted logistic regression analysis showed that patent ductus arteriosus and neonatal corticosteroids were significantly (P < 0·05) associated with ROP in both groups. In the DHA group, surfactant use was also associated with ROP (P = 0·003). After adjusting for important covariates, patent ductus arteriosus and neonatal corticosteroids continued to be significant for infants in the unsupplemented group (OR = 3·99; P = 0·022 and OR = 5·64; P = 0·019, respectively). In the DHA group, only surfactant use continued to be associated with ROP (OR = 4·84; P = 0·015). In summary, DHA supplementation was not associated with ROP. Further studies are necessary to better understand the relationship between DHA supplementation, ROP and associated comorbidities.

Whole-exome sequencing analysis of patent ductus arteriosus in a Japanese macaque (Macaca fuscata).

We performed whole-exome sequencing using a human exome capture kit to analyze the potential genetic factors related to patent ductus arteriosus in Japanese macaques. Compared with the reference sequences of other primates, we identified potential missense variants in five genes: ADAM15, AZGP1, CSPG4, TNFRSF13B, and EPOR.