Animal Models of Repaired Tetralogy of Fallot: Current Applications and Future Perspectives

Tetralogy of Fallot is the most common cyanotic congenital heart disease. Despite ongoing improvements in the initial surgical repair, there are lingering concerns regarding the long-term outcomes that may be complicated by right ventricular dysfunction, right ventricular dyssynchrony, and sudden cardiac death. The mechanisms leading to these late complications remain incompletely understood. Experimental animal models have been developed as preclinical steps to gain better insight into the pathophysiology of diseases and to develop new therapeutic strategies. This article summarizes the various types of experimental animal models of repaired tetralogy of Fallot published to date in the literature, with the aim of achieving a greater understanding of the deleterious mechanisms that may lead to these known late and sometimes lethal complications. In addition to analysing the type of animals that can be used according to a given study’s objectives, needs, and constraints, the present review also evaluates the type of dysfunction that can be reproduced in our model according to the research objectives, as well as the different types of studies in which these models can be used. In view of all that, we propose a decision algorithm to create an animal model of repaired tetralogy of Fallot. This synthesis should furthermore help in the development of future studies and in the design of new experimental models, thus allowing greater insight into this disease, while not forgetting the ultimate goal of broadening future therapeutic measures to reduce the morbidity and mortality of this prevalent congenital heart disease.     

Mechanisms of Arrhythmia and Sudden Cardiac Death in Patients With HIV Infection

Long-term survival of HIV-infected patients has significantly improved with the use of antiretroviral therapy (ART). As a consequence, cardiovascular diseases are now emerging as an important clinical problem in this population. Sudden cardiac death is the third leading cause of mortality in HIV patients. Twenty percent of patients with HIV who died of sudden cardiac death had previous cardiac arrhythmias including ventricular tachycardia, atrial fibrillation, and other unspecified rhythm disorders. This review presents a summary of HIV-related arrhythmias, associated risk factors specific to the HIV population, and underlying mechanisms. Compared with the general population, patients with HIV have several cardiac conditions and electrophysiological abnormalities. As a result, they have an increased risk of developing severe arrhythmias, that can lead to sudden cardiac death. Possible explanations may be related to non-ART polypharmacy, electrolyte imbalances, and use of substances observed in HIV-infected patients; many of these conditions are associated with alterations in cardiac electrical activity, increasing the risk of arrhythmia and sudden cardiac death. However, clinical and experimental evidence has also revealed that cardiac arrhythmias occur in HIV-infected patients, even in the absence of drugs. This indicates that HIV itself can change the electrophysiological properties of the heart profoundly and cause cardiac arrhythmias and related sudden cardiac death. The current knowledge of the underlying mechanisms, as well as the emerging role of inflammation in these arrhythmias, are discussed here.     

Sex-Specific Considerations in Guidelines Generation and Application

New knowledge about male–female differences in pathophysiology, diagnosis, and treatment is shifting the practice of medicine from a one-size-fits all approach to a more individualized process that considers sex-specific interventions at the point of care. In this article, we review how clinical practice guideline committees can incorporate a structured framework to determine whether sex-specific assessments of the quality of the evidence or the particular recommendations should be made. The process can be operationalized by societies who author clinical practice guidelines by developing formal policies to approach biological sex in a systematic way, and by ensuring that writing committees include an individual who will champion the formal appraisal of the literature for associations between sex and the outcomes of interest. Ongoing challenges are discussed, and solutions are provided for how to disaggregate the evidence, how to assess bias, how to improve search strategies, and what to do when the data are insufficient to make sex-specific recommendations. Application of sex-specific recommendations will involve routinely asking whether the presentation, diagnostic workup, or management might change for each patient if they were the opposite sex.     

Mechanisms and Clinical Significance of Arrhythmia-Induced Cardiomyopathy

Arrhythmia-induced cardiomyopathy (AIC) is characterized by left ventricular systolic dysfunction for which the primary cause is arrhythmia. The hallmark of AIC is its reversibility once the arrhythmia is properly controlled. Any tachyarrhythmia can potentially cause AIC (often called “tachycardiomyopathy”), with atrial fibrillation (AF) being by far the most common in clinical practice. The pathophysiological mechanisms underlying AIC need further clarification, but the available evidence, principally from animal models, implicates metabolic dysfunction due to increased oxygen requirements, neurohormonal adaptive mechanisms, and cellular Ca²⁺ mishandling as important contributors. Tachycardia is a common denominator of most cases of AIC, but other components specific to the patient and the arrhythmia have been implicated. The diagnosis of AIC requires the exclusion of a primary causative role of other conditions such as hypertension, primary cardiomyopathies, and valve disease, which may require specific pharmacological and invasive therapies. Catheter ablation is emerging as a safe and effective alternative to antiarrhythmic medication and has an established role in the management of AIC. Recent studies showing improved cardiac function and mortality rates in patients with heart failure and concomitant AF dramatically illustrate the often-unrecognized scope of AIC and the potential benefits of interventional therapy. Major AF trials do not otherwise focus specifically on AIC, and careful analysis of the literature is necessary to appreciate the clinical characteristics and therapeutic implications. This contemporary review summarizes the current understanding of pathophysiological mechanisms underlying AIC, discusses the clinical implications, and offers a general approach to management, with a particular focus on AF-induced cardiomyopathy.     

Functional Dosage of Muscarinic Cholinergic Receptor 3 Signalling,Not the Gene Dose,Determines Its Hypertension Pathogenesis

Background

Multiple quantitative trait loci for blood pressure (BP) have been localized throughout human and rodent genomes. Few of them have been functionally identified especially in humans, and little is known about their pathogenic directionality when identified. We focused on Chrm3 encoding the muscarinic cholinergic receptor 3 (M3R) as the causal gene for C17QTL1 in the Dahl salt-sensitive rat model.

Improving Quality of Congenital Heart Disease Research in Canada: Standardizing Nomenclature Across Canada

In an effort to improve the quality of interinstitutional and nation-wide research into congenital heart disease (CHD) in Canada, the authors propose the national implementation of a single nomenclature list for CHD as a first step towards achieving a common disease classification system in all Canadian institutions that deal with congenital heart malformations. The authors offer a brief overview of the history and state of nomenclature for CHD in Canada and recommend the national use of the CHD diagnostic list that was recently finalized by the International Society for Nomenclature of Paediatric and Congenital Heart Disease. This list was submitted to the World Health Organization for incorporation into the 11th iteration of the International Classification of Diseases and was recently translated into French by members of the International Society for Nomenclature of Paediatric and Congenital Heart Disease. The bilingual list of the 11th iteration of the International Classification of Diseases CHD terms is published online in this issue of the Canadian Journal of Cardiology. The national standardization of the nomenclature pertaining to CHD using the bilingual list of terms published herein will optimize national efforts to establish longitudinal CHD cohorts, capitalizing on Canada’s health care infrastructure and solidifying Canadian leadership in CHD research.     

Second Time’s a Charm: Percutaneous Edge-to-Edge Repair With the MitraClip Device as Rescue Therapy After a Failed Surgical Edge-to-Edge Alfieri Stitch

Surgical mitral valve repair for mitral regurgitation is associated with an increased risk of recurrent mitral regurgitation compared to surgical mitral valve replacement. We describe the case of an 80-year-old man with recurrent severe symptomatic mitral regurgitation after a failed surgical Alfieri technique attempt, who then underwent successful MitraClip (Abbott Vascular, Santa Clara, CA) implantation.     

Age as a Critical Determinant of Atrial Fibrillation: A Two-sided Relationship

The incidence of atrial fibrillation (AF), the most common sustained arrhythmia and a major public health burden, increases exponentially with age. However, mechanisms underlying this long-recognized association remain incompletely understood. Experimental and human studies have demonstrated the involvement of aging in several arrhythmogenic processes, including atrial electrical and structural remodelling, disturbed calcium homeostasis, and enhanced atrial ectopic activity/increased vulnerability to re-entry induction. Given this wide range of putative mechanisms, the task of delineating the specific effects of aging responsible for AF promotion is not simple, as aging is itself associated with increasing prevalence of a host of AF-predisposing conditions, including heart failure, coronary artery disease, and hypertension. Although we usually think of old age promoting AF, there is also evidence that young age may actually have a protective effect against AF occurrence. For example, the low AF incidence among populations of young patients with significant structural congenital heart disease and substantial atrial enlargement/remodelling suggests that younger age might protect against fibrillation in the diseased atrium; efforts at understating how younger age may prevent AF might be helpful in elucidating missing mechanistic links between AF and age. The goal of this paper is to review the epidemiologic and pathophysiologic evidence regarding mechanisms underlying age-related AF. Although the therapeutic options for AF have recently improved, major gaps still remain and a better understanding of the special relationship between age and AF may be important for the identification of new targets for therapeutic innovation.     

The 2017 American College of Cardiology/American Heart Association vs Hypertension Canada High Blood Pressure Guidelines and Potential Implications

In this report we examine the differences between the 2017 Hypertension Canada and 2017 American College of Cardiology and American Heart Association (ACC/AHA) blood pressure (BP) guidelines regarding the proportions of individuals with a diagnosis of hypertension, BP above thresholds for treatment initiation, and BP below targets using the CARTaGENE cohort. Compared with the 2017 Canadian guidelines, the 2017 ACC/AHA guidelines would result in increases of 8.7% in hypertension diagnosis and 3.4% of individuals needing treatment, with 17.2% having a different BP target. In conclusion, implementing the 2017 ACC/AHA hypertension guidelines in Canada could result in major effects for millions of Canadians.     

Transcatheter Tricuspid Valve Replacement for Treating Severe Tricuspid Regurgitation: Initial Experience With the NaviGate Bioprosthesis

Despite the growing evidence with emerging transcatheter tricuspid valve repair therapies, the experience with transcatheter tricuspid valve replacement remains sparse. We describe a case of severe tricuspid regurgitation in a 79-year-old patient deemed unsuitable for isolated tricuspid valve surgery, successfully treated with a 40-mm self-expandable NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA) valved stent via a transatrial approach, with excellent result and hemodynamic performance at 4 months.     

Myocardial Partition Coefficient of Gadolinium: A Pilot Study in Patients With Acute Myocarditis,Chronic Myocardial Infarction,and in Healthy Volunteers

Background

The tissue-blood partition coefficient (PC) of gadolinium, derived from T1 measurements, reflects myocardial connective tissue fraction and tissue injury, increasing in proportion with edema or fibrosis. We determined the myocardial PC of gadolinium in patients with acute myocarditis, chronic myocardial infarction (MI), and healthy volunteers. We hypothesized that the characteristics of the injured myocardium in patients with MI and myocarditis may differ and that the PC will be higher in chronically injured myocardium (MI) compared with acutely injured myocardium (myocarditis).

Technological Advances in Arrhythmia Management Applied to Adults With Congenital Heart Disease

Arrhythmias are a leading cause of morbidity in adults with congenital heart disease. Numerous challenges to managing arrhythmias include vascular access issues, intracardiac shunts, unconventional locations of the conduction system, and anatomical complexities. Technological advances are improving our ability to diagnose and treat arrhythmias. Implantable loop recorders and various technologies developed for consumers to record electrocardiographic tracings using smartphone applications, watches, and dedicated portable devices are expanding our armamentarium of diagnostic tools. Remote magnetic-guided catheter ablation is enhancing access to otherwise difficult to reach arrhythmia substrates. Cryoablation allows perinodal arrhythmias to be safely treated in patients with displaced or difficult to predict locations of the atrioventricular conduction system. Interventions that minimize radiation exposure to near 0 levels are gaining interest and pulmonary vein isolation procedures to treat atrial fibrillation are increasingly performed. Cardiac implantable electronic devices compatible with magnetic resonance imaging have become the norm. Subcutaneous defibrillators and leadless pacemakers are providing effective solutions to patients in whom transvenous leads are contraindicated or not desired. His-bundle pacing is emerging as a viable option to provide more physiological pacing. Progressive advances in multicomponent communicating leadless devices carry the promise of providing leadless dual chamber pacing and cardiac resynchronization therapy in the near future. The safety of transvenous lead extraction procedures is likely to improve with advances such as the low-pressure balloon to manage superior vena cava lacerations. Awareness of these developments and referral to sites with dedicated expertise could contribute to further improving outcomes in adults with congenital heart disease.     

Transcatheter Aortic Valve Replacement for Severe Aortic Stenosis in Women: Clinical Characteristics and Outcomes

Aortic stenosis (AS), 1 of the most common valve diseases in developed countries, carries a poor prognosis if left untreated. Transcatheter aortic valve replacement (TAVR) has become the standard of care for high-risk and inoperable patients with severe aortic stenosis (AS). Women represent a significant proportion of patients with severe AS and demonstrate specific clinical, anatomic, and pathophysiological features that are evident both before and after valve replacement. In this review, we discuss these features as well as the outcomes of women undergoing TAVR for AS.     

Peridevice Leak After Left Atrial Appendage Closure: Incidence,Risk Factors,and Clinical Impact

Background

Limited studies reported the rate and clinical impact of peridevice leaks (PDL) after percutaneous left atrial appendage closure (LAAC).

A Practical Approach to Pericardiocentesis With Periprocedural Use of Ultrasound Training Initiative

Tamponade is a life-threatening condition characterized by fluid accumulation in the pericardium, which compresses the cardiac chambers, impairs diastolic filling, and can lead to clinical shock. The diagnosis is a clinical one that is supported by echocardiographic findings. Pericardiocentesis is the definitive treatment for tamponade; however, it remains a challenge for trainees because of the infrequent exposure compared with other invasive procedures. Moreover, this technique, unlike others, can lead to serious complications including cardiac perforation and arrhythmia. There has been increased attention to periprocedural use of ultrasound in various techniques, particularly pericardiocentesis, given its ability to assess the pericardial effusion as well as the safety and feasibility of the procedure from various trajectories to minimize major and minor complications. As such, periprocedural use of ultrasound for pericardiocentesis has emerged as the preferred initial technique for pericardiocentesis. We outline a simple stepwise approach to prepare and perform pericardiocentesis, facilitated by periprocedural ultrasound, including practical tips from our centre's experiences. These include the proper assessment of the target area defined as the most pericardial fluid with the least interfering structures and troubleshooting the introduction of the needle into the pericardium. Absolute contraindications are few and often require surgery, but knowledge of them is mandatory when assessing patients for pericardiocentesis.