Advancements in the use of gene therapy for cardiac arrhythmia.
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ABSTRACT:
SUBMITTER: Murphy NP
PROVIDER: S-EPMC5942548 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Arrhythmia is an extremely common finding in patients receiving cardiac resynchronisation therapy (CRT). Despite this, in the majority of randomised trials testing CRT efficacy, patients with a recent history of arrhythmia were excluded. Most of our knowledge into the management of arrhythmia in CRT is therefore based on arrhythmia trials in the heart failure (HF) population, rather than from trials dedicated to the CRT population. However, unique to CRT patients is the aim to reach as close to 100% biventricular pacing (BVP) as possible, with HF outcomes greatly influenced by relatively small changes in pacing percentage. Thus, in comparison to the average HF patient, there is an even greater incentive for controlling arrhythmia, to achieve minimal interference with the effective delivery of BVP. In this review, we examine both atrial and ventricular arrhythmias, addressing their impact on CRT, and discuss the available evidence regarding optimal arrhythmia management in this patient group. We review pharmacological and procedural-based approaches, and lastly explore novel ways of harnessing device data to guide treatment of arrhythmia in CRT.
| S-EPMC10440957 | biostudies-literature
Project description:The human fetal heart develops arrhythmias and conduction disturbances in response to ischemia, inflammation, electrolyte disturbances, altered load states, structural defects, inherited genetic conditions, and many other causes. Yet sinus rhythm is present without altered rate or rhythm in some of the most serious electrophysiological diseases, which makes detection of diseases of the fetal conduction system challenging in the absence of magnetocardiographic or electrocardiographic recording techniques. Life-threatening changes in QRS or QT intervals can be completely unrecognized if heart rate is the only feature to be altered. For many fetal arrhythmias, echocardiography alone can assess important clinical parameters for diagnosis. Appropriate treatment of the fetus requires awareness of arrhythmia characteristics, mechanisms, and potential associations. Criteria to define fetal bradycardia specific to gestational age are now available and may allow detection of ion channelopathies, which are associated with fetal and neonatal bradycardia. Ectopic beats, once thought to be entirely benign, are now recognized to have important pathologic associations. Fetal tachyarrhythmias can now be defined precisely for mechanism-specific therapy and for subsequent monitoring of response. This article reviews the current and future diagnostic techniques and pharmacologic treatments for fetal arrhythmia.
| S-EPMC2995324 | biostudies-literature
Project description:Cardiac tachyarrhythmias are a major cause of morbidity and mortality. Treatments for these tachyarrhythmias include antiarrhythmic drugs, catheter ablation, surgical ablation, cardiac implantable electronic devices, and cardiac transplantation. Each of these treatment approaches is effective in some patients but there is considerable room for improvement, particularly with respect to the most common of the tachydysrhythmias, atrial fibrillation, and the most dangerous of the tachydysrhythmias, ventricular tachycardia (VT) or ventricular fibrillation. Noninvasive stereotactic ablative radiation therapy is emerging as an effective treatment for refractory tachyarrhythmias. Animal models have shown successful ablation of arrhythmogenic myocardial substrates with minimal short-term complications. Studies of stereotactic radioablation involving patients with refractory VT have shown a reduction in VT recurrence and promising early safety data. In this review, we provide the background for the application of stereotactic arrhythmia radioablation therapy along with promising results from early applications of the technology.
| S-EPMC7984992 | biostudies-literature
Project description:BackgroundNo data exist on comparative risk of cardiac arrhythmias among 3 Medication-Assisted Therapy (MAT) medications in patients with opioid use disorder. Understanding MAT medications with the least risk of arrhythmia can guide clinical decision-making.MethodA multicenter retrospective cohort study was performed of patients 18 years or older diagnosed with opioid use disorder by the International Classification of Diseases, 10th revision, Clinical Modification without baseline arrhythmia in 2018-2019, using Clinformatics Data Mart Database (Optum, Eden Prairie, Minn). Everyone required 1 year of continuous enrollment prior to and after the diagnosis. Patients with MAT were propensity score-matched to those without MAT. Primary outcome was rate of arrhythmia across MAT (methadone, naltrexone, and buprenorphine). A multivariable logistic regression model was built to examine the outcome difference across 3 medications adjusted for patient's demographic and comorbidity.ResultOnly 14.1% of the 66,083 patients with opioid use disorder received MAT prescriptions in the 12 months after diagnosis. New-onset arrhythmia diagnoses occur more frequently among MAT vs non-MAT users (4.86% vs 3.92%), with 29% risk of incident arrhythmias among MAT users, even after adjusting relevant confounders (adjusted odds ratio [aOR] 1.29; 95% confidence interval [CI], 1.11-1.52). Incidence of arrhythmia varied by drugs: naltrexone (9.57%), methadone (5.71%), and buprenorphine (3.81%). Difference among the MAT drugs in incidence of arrhythmia remained significant even after adjusting covariates (aOR 2.44; 95% CI, 1.63-3.64 and buprenorphine aOR 0.77; 95% CI, 0.59-1.00, with methadone as reference).ConclusionMAT users had higher risk of cardiac arrhythmia than non-users. Naltrexone is associated with the highest risk of arrhythmia, suggesting caution with naltrexone use, especially in opioid use disorder patients with pre-existing heart conditions.
| S-EPMC9232850 | biostudies-literature
Project description:Pompe disease (glycogen storage disease type II) is caused by mutations in acid α-glucosidase (GAA) resulting in lysosomal pathology and impairment of the muscular and cardio-pulmonary systems. Enzyme replacement therapy (ERT), the only approved therapy for Pompe disease, improves muscle function by reducing glycogen accumulation but this approach entails several limitations including a short drug half-life and an antibody response that results in reduced efficacy. To address these limitations, new treatments such as gene therapy are under development to increase the intrinsic ability of the affected cells to produce GAA. Key components to gene therapy strategies include the choice of vector, promoter, and the route of administration. The efficacy of gene therapy depends on the ability of the vector to drive gene expression in the target tissue and also on the recipient's immune tolerance to the transgene protein. In this review, we discuss the preclinical and clinical studies that are paving the way for the development of a gene therapy strategy for patients with early and late onset Pompe disease as well as some of the challenges for advancing gene therapy.
| S-EPMC7029369 | biostudies-literature
Project description:Hereditary retinal dystrophies (HRDs) are degenerative diseases of the retina which have marked clinical and genetic heterogeneity. Common presentations among these disorders include night or colour blindness, tunnel vision, and subsequent progression to complete blindness. The known causative disease genes have a variety of developmental and functional roles, with mutations in more than 120 genes shown to be responsible for the phenotypes. In addition, mutations within the same gene have been shown to cause different disease phenotypes, even amongst affected individuals within the same family, highlighting further levels of complexity. The known disease genes encode proteins involved in retinal cellular structures, phototransduction, the visual cycle, and photoreceptor structure or gene regulation. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been proposed as potentially efficacious therapies. Because of its favorable anatomical and immunological characteristics, the eye has been at the forefront of translational gene therapy. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Dozens of promising proofs of concept have been obtained in animal models of HRDs and some of them have been relayed to the clinic. The results from the first clinical trials for a congenital form of blindness have generated great interest and have demonstrated the safety and efficacy of intraocular administrations of viral vectors in humans. This review summarizes the clinical development of retinal gene therapy.
| S-EPMC5758769 | biostudies-literature
Project description:Conduction disorders and arrhythmias remain difficult to treat and are increasingly prevalent owing to the increasing age and body mass of the general population, because both are risk factors for arrhythmia. Many of the underlying conditions that give rise to arrhythmia - including atrial fibrillation and ventricular arrhythmia, which frequently occur in patients with acute myocardial ischaemia or heart failure - can have an inflammatory component. In the past, inflammation was viewed mostly as an epiphenomenon associated with arrhythmia; however, the recently discovered inflammatory and non-canonical functions of cardiac immune cells indicate that leukocytes can be arrhythmogenic either by altering tissue composition or by interacting with cardiomyocytes; for example, by changing their phenotype or perhaps even by directly interfering with conduction. In this Review, we discuss the electrophysiological properties of leukocytes and how these cells relate to conduction in the heart. Given the thematic parallels, we also summarize the interactions between immune cells and neural systems that influence information transfer, extrapolating findings from the field of neuroscience to the heart and defining common themes. We aim to bridge the knowledge gap between electrophysiology and immunology, to promote conceptual connections between these two fields and to explore promising opportunities for future research.
| S-EPMC9703448 | biostudies-literature
Project description:BackgroundReduced biventricular pacing (BiVP) is a common phenomenon in cardiac resynchronization therapy (CRT) with impact on CRT-response and patients' prognosis. Data on treatment strategies for patients with ventricular arrhythmia and BiVP reduction is sparse. We sought to assess the effects of ventricular arrhythmia treatment on BiVP.MethodsIn this retrospective analysis, the data of CRT patients with a reduced BiVP ≤ 97% due to ventricular arrhythmia were analyzed. Catheter ablation or intensified medical therapy was performed to optimize BiVP.ResultsWe included 64 consecutive patients (73 ± 10 years, 89% male, LVEF 30 ± 7%). Of those, 22/64 patients (34%) underwent ablation of premature ventricular contractions (PVC) and 15/64 patients (23%) underwent ventricular tachycardia (VT) ablation while 27/64 patients (42%) received intensified medical treatment. Baseline BiVP was 88.1% ± 10.9%. An overall increase in BiVP percentage points of 8.8% (range - 5 to + 47.6%) at 6-month follow-up was achieved. No changes in left ventricular function were observed but improvement in BiVP led to an improvement in NYHA class in 24/64 patients (38%). PVC ablation led to a significantly better improvement in BiVP [9.9% (range 4 to 22%) vs. 3.2% (range - 5 to + 10.7%); p = < 0.001] and NYHA class (12/22 patients vs. 4/27 patients; p = 0.003) than intensified medical therapy. All patients with VT and reduced BiVP underwent VT ablation with an increase of BiVP of 16.3 ± 13.4%.ConclusionIn this evaluation of ventricular arrhythmia treatment aiming for CRT optimization, both medical therapy and catheter ablation were shown to be effective. Compared to medical therapy, a higher increase in BiVP was observed after PVC ablation, and more patients improved in NYHA class.Clinical trial registrationThe study was registered at clinical trials.org in August 2019: NCT04065893.
| S-EPMC9977698 | biostudies-literature
Project description:About 92.1 million Americans suffer from at least one type of cardiovascular disease. Worldwide, cardiovascular diseases are the number one cause of death (about 31% of all global deaths). Recent technological advancements in cardiac ultrasound imaging are expected to aid in the clinical diagnosis of many cardiovascular diseases. This article provides an overview of such recent technological advancements, specifically focusing on tissue Doppler imaging, strain imaging, contrast echocardiography, 3D echocardiography, point-of-care echocardiography, 3D volumetric flow assessments, and elastography. With these advancements ultrasound imaging is rapidly changing the domain of cardiac imaging. The advantages offered by ultrasound imaging include real-time imaging, imaging at patient bed-side, cost-effectiveness and ionizing-radiation-free imaging. Along with these advantages, the steps taken towards standardization of ultrasound based quantitative markers, reviewed here, will play a major role in addressing the healthcare burden associated with cardiovascular diseases.
| S-EPMC5808891 | biostudies-literature
Project description:The rhythmical nature of the cardiovascular system constantly generates dynamic mechanical forces. At the centre of this system is the heart, which must detect these changes and adjust its performance accordingly. Mechanoelectric feedback provides a rapid mechanism for detecting even subtle changes in the mechanical environment and transducing these signals into electrical responses, which can adjust a variety of cardiac parameters such as heart rate and contractility. However, pathological conditions can disrupt this intricate mechanosensory system and manifest as potentially life-threatening cardiac arrhythmias. Mechanosensitive ion channels are thought to be the main proponents of mechanoelectric feedback as they provide a rapid response to mechanical stimulation and can directly affect cardiac electrical activity. Here, we demonstrate that the mechanosensitive ion channel PIEZO1 is expressed in zebrafish cardiomyocytes. Furthermore, chemically prolonging PIEZO1 activation in zebrafish results in cardiac arrhythmias. indicating that this ion channel plays an important role in mechanoelectric feedback. This also raises the possibility that PIEZO1 gain of function mutations could be linked to heritable cardiac arrhythmias in humans.
| S-EPMC10094979 | biostudies-literature