The presence of a systemic right ventricle (sRV) with biventricular physiology (biV) is associated with increased patient morbidity and mortality. To date, no pharmacologic therapy for heart failure ...has been proven effective for patients with systolic dysfunction of the sRV-biV. We designed a randomized, double-blind, placebo-controlled crossover trial to compare sacubitril/valsartan treatment to placebo in adults (aged ≥ 18 years) with moderate-to-severe sRV-biV dysfunction and New York Heart Association functional class II to III symptoms. Two primary efficacy endpoints are assessed in the trial: exercise capacity (submaximal exercise duration) and neurohormonal activation (N-terminal prohormone brain natriuretic peptide). Secondary objectives include assessing a change in the Kansas City Cardiomyopathy Questionnaire score and evaluating the safety and tolerance of sacubitril/valsartan. A 6-week open run-in phase identifies the maximum tolerated dose of sacubitril/valsartan, up to 97 mg/103 mg twice daily. After a 2-week washout period, patients are randomized 1:1 to sacubitril/valsartan treatment vs placebo for a 24-week phase, followed by another 2-week washout period and subsequent crossover to the alternative treatment arm for an additional 24-week phase. Data to assess primary and secondary endpoints are collected at baseline and at the end of each phase. A total of 48 patients is required to provide > 80% power to detect a 30% difference in distance walked and in N-terminal prohormone brain natriuretic peptide levels with sacubitril/valsartan treatment vs placebo, each with a 2-sided P-value of 0.025. In summary, the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor vs Placebo in Patients With Congenital Systemic Right Ventricular Heart Failure Trial (PARACYS-RV) should determine the role of sacubitril/valsartan in treating heart failure in patients with sRV-biV and carries the potential to alter management of this patient population.
La présence d’un ventricule droit systémique (VDs) avec physiologie biventriculaire (PbiV) est associée à une morbidité et une mortalité accrues chez les patients. À ce jour, aucune pharmacothérapie de l’insuffisance cardiaque ne s’est révélée efficace chez les patients atteints d’une dysfonction systolique du VDs-PbiV. Nous avons conçu un essai croisé, à répartition aléatoire et à double insu, contrôlé par placebo pour comparer la bithérapie sacubitril-valsartan au placebo chez les adultes (≥ 18 ans) ayant une dysfonction modérée ou sévère du VDs-PbiV et des symptômes de la classe fonctionnelle II à III de la New York Heart Association. Deux paramètres d’évaluation principaux de l’efficacité sont définis pour l’essai : tolérance à l’effort (durée d’effort sous-maximal) et activation neurohormonale (propeptide natriurétique de type B N-Terminal NT-proBNP). La mesure d’une variation du score au questionnaire sur la cardiomyopathie de Kansas City de même que l’évaluation de l’innocuité et de la tolérance de la bithérapie sacubitril-valsartan sont des objectifs secondaires. Une phase préparatoire de six semaines en mode ouvert permet d’établir la dose maximale tolérée de sacubitril-valsartan, jusqu’à concurrence de 97 mg/103 mg deux fois par jour. Après une période de repos thérapeutique de deux semaines, les patients sont affectés au hasard, dans un rapport 1:1, à la bithérapie sacubitril-valsartan ou au placebo pendant une phase de traitement de 24 semaines, suivie d’une autre période de repos thérapeutique de deux semaines et d’un passage subséquent à l’autre groupe de traitement pendant une phase additionnelle de 24 semaines. Les données sur les paramètres d’évaluation principaux et secondaires sont recueillies au début de l’essai et à la fin de chaque phase. Il faut un total de 48 patients afin d’obtenir une puissance supérieure à 80 % pour détecter une différence de 30 % entre la bithérapie sacubitril-valsartan et le placebo quant à la distance parcourue à la marche et aux taux de NT-proBNP, la valeur p bilatérale étant de 0,025 pour les deux valeurs. En résumé, l’essai PARACYS-RV (Prospective Comparison ofAngiotensinReceptor-Neprilysin Inhibitor vs Placebo in Patients WithCongenital SystemicRightVentricular Heart Failure) doit déterminer le rôle de la bithérapie sacubitril-valsartan dans le traitement de l’insuffisance cardiaque chez les patients ayant un VDs-PbiV et pourrait modifier la prise en charge de cette population de patients.
Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk ...situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes.
Using a variant in Kir2.1 (Gly52Val) revealed by whole-exome sequencing in a patient presenting with symptoms of long-QT syndrome as a proof of principle, we demonstrated that commercially available human induced pluripotent stem cell-derived cardiomyocytes are a powerful model for screening variants involved in genetic cardiac diseases. Immunohistochemistry experiments and whole-cell current recordings in human embryonic kidney cells expressing the wild-type or the mutant Kir2.1 demonstrated that Kir2.1-52V alters channel cellular trafficking and fails to form a functional channel. Using human induced pluripotent stem cell-derived cardiomyocytes, we not only confirmed these results but also further demonstrated that Kir2.1-52V is associated with a dramatic prolongation of action potential duration with evidence of arrhythmic activity, parameters which could not have been studied using human embryonic kidney cells.
Our study confirms the pathogenicity of Kir2.1-52V in 1 patient with long-QT syndrome and also supports the use of isogenic human induced pluripotent stem cell-derived cardiomyocytes as a physiologically relevant model for the screening of variants of unknown function.
Up to one-half of adults with congenital heart disease (CHD) experience psychological distress, including anxiety.
This paper sought to: 1) assess the contribution of illness perception in explaining ...anxiety symptoms beyond sociodemographic and medical variables in adults with CHD; and 2) investigate the potential mediating effect of coping style.
CHD adult patients were recruited at Montreal Heart Institute between June 2019 and April 2021 for this cross-sectional study. Participants responded to self-reported questionnaires (Hospital Anxiety and Depression Scale, Brief Illness Perception Questionnaire, and Brief COPE). Medical characteristics (CHD complexity, NYHA functional class, and cardiac devices) were collected from medical records. We conducted hierarchical multiple linear regression and mediation analyses.
Of the 223 participants (mean age 46 ± 14 years, 59% women), 15% had clinically significant anxiety symptoms. Medical and sociodemographic variables explained 15% of the variation in anxiety symptoms. Adding illness perception explained an additional 18% of the variation in anxiety. This R2 change was significant (F1,188 = 49.06, P < 0.0001). Illness perception explained more variance (18%) than medical and sociodemographic variables combined. A more threatening perception of illness was associated with greater anxiety symptoms (β = 0.45, P < 0.0001). Furthermore, illness perception was associated with coping, which was linked to reduced anxiety symptoms. Coping response style accounted for 20% of the total effect of illness perception on anxiety.
Illness perception and coping are associated with anxiety in adults with CHD. Future initiatives should assess whether targeting these potentially modifiable factors effectively prevents or mitigates anxious symptoms in adults with CHD.
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Primary pulmonary artery sarcoma is an exceedingly rare and aggressive malignancy that carries poor prognosis. Clinical manifestations are nonspecific and include chest pain, dyspnea, syncope, ...palpitations, and asthenia, among others. Delay to diagnosis is common and compromises the prognosis. Here, we report an interesting case of primary pulmonary artery sarcoma presenting with frequent monomorphic premature ventricular contractions arising from the right/left ventricle outflow tract. Cardiac imaging is key in the evaluation of patients with frequent premature ventricular contractions to rule out rare pathologies such as tumour compression.
Le sarcome primaire de l’artère pulmonaire est une tumeur maligne extrêmement rare et agressive de mauvais pronostic. Les manifestations cliniques sont non spécifiques et peuvent inclure de la douleur thoracique, de la dyspnée, des syncopes, des palpitations et de l'asthénie. Le retard diagnostic est fréquent et compromet le pronostic. Nous rapportons ici un cas intéressant de sarcome primaire de l’artère pulmonaire pour lequel le patient présentait des extrasystoles ventriculaires prématurées monomorphes qui provenaient des chambres de chasse des ventricules gauche et droit. L'imagerie est essentielle à l'évaluation des patients présentant de fréquentes extrasystoles ventriculaires afin d'écarter des pathologies rares comme la compression tumorale d'une chambre cardiaque.
Sudden death of presumed arrhythmic etiology is a leading cause of mortality in adults with congenital heart disease. Anticipated benefits of the implantable cardioverter-defibrillator (ICD) must be ...weighed against high complication rates. Without robust evidence from randomized trials, caregivers face difficult decisions in selecting appropriate candidates. Although secondary prevention indications are often clear-cut, risk stratification for primary prevention ICDs is more challenging. Factors associated with sudden death in patients with tetralogy of Fallot are reasonably consistent across studies. In contrast, identification of high-risk patients with systemic right ventricles or univentricular hearts remains controversial.
Sudden death is the leading cause of mortality in patients with transposition of the great arteries (TGA) and atrial switch surgery. Understanding underlying mechanisms could contribute to ...identifying high-risk patients and preventing such catastrophic deaths.
A total of 144 adults (≥18 years) with TGA and atrial switch surgery were followed at our adult congenital center since 1989. Four patients were excluded: two with double-outlet right ventricles and two with subsequent arterial switch surgery in childhood.
Of the remaining 140 patients, age 37.6 ± 7.8 years, 37.1% female, 8 (6%) had a cardiac arrest of presumed arrhythmic etiology of whom 3 were resuscitated. The arrests occurred in 3 women and 5 men at age 30.5 ± 8.6 (range 22 to 50) years. None had established coronary artery disease, sustained ventricular arrhythmias, or syncope. Four (50%) had atrial arrhythmias and 6 (75%) had at least moderate systemic right ventricular dysfunction. For 5 patients in whom circumstances surrounding the arrests were documented, 3 occurred on exertion, 1 after consuming recreational methamphetamine, and 1 in the context of an atrial tachyarrhythmia. Autopsies were performed in 2 of 5 patients. Both revealed acute massive myocardial infarction of the hypertrophied systemic right ventricle with normal coronary arteries and chronic subendocardial ischemic lesions.
This is the first report to provide histopathological evidence in support of a myocardial ischemia hypothesis as a cause of sudden death in this patient population, despite the absence of coronary atherosclerosis.
•Attempts to reliably identify patients with TGA and atrial switch surgery at high risk for sudden death have been disappointing.•Among 140 adults with TGA and atrial switch surgery, 8 (6%) had a cardiac arrest of presumed arrhythmic etiology of whom 3 were resuscitated.•Documented circumstances surrounding the arrests included physical exertion, recreational methamphetamine use, and atrial tachyarrhythmias.•Autopsies revealed acute massive myocardial infarction of the systemic right ventricle and chronic subendocardial ischemia in the absence of coronary atherosclerosis.•These findings inform the identification of high-risk patients and have important implications regarding counselling and management.
Abstract
Sudden cardiac death (SCD) accounts for up to 25% of deaths in patients with congenital heart disease (CHD). To date, research has largely been driven by observational studies and real-world ...experience. Drawbacks include varying definitions, incomplete taxonomy that considers SCD as a unitary diagnosis as opposed to a terminal event with diverse causes, inconsistent outcome ascertainment, and limited data granularity. Notwithstanding these constraints, identified higher-risk substrates include tetralogy of Fallot, transposition of the great arteries, cyanotic heart disease, Ebstein anomaly, and Fontan circulation. Without autopsies, it is often impossible to distinguish SCD from non-cardiac sudden deaths. Asystole and pulseless electrical activity account for a high proportion of SCDs, particularly in patients with heart failure. High-quality cardiopulmonary resuscitation is essential to improve outcomes. Pulmonary hypertension and CHD complexity are associated with lower likelihood of successful resuscitation. Risk stratification for primary prevention implantable cardioverter-defibrillators (ICDs) should consider the probability of SCD due to a shockable rhythm, competing causes of mortality, complications of ICD therapy, and associated costs. Risk scores to better estimate probabilities of SCD and CHD-specific guidelines and consensus-based recommendations have been proposed. The subcutaneous ICD has emerged as an attractive alternative to transvenous systems in those with vascular access limitations, prior device infections, intra-cardiac shunts, or a Fontan circulation. Further improving SCD-related outcomes will require a multidimensional approach to research that addresses disease processes and triggers, taxonomy to better reflect underlying pathophysiology, high-risk features, early warning signs, access to high-quality cardiopulmonary resuscitation and specialized care, and preventive therapies tailored to underlying mechanisms.
Graphical Abstract
Graphical Abstract
Multidimensional aspects of SCD in CHD. Maximizing outcomes related to SCD in patients with CHD requires comprehensively addressing the many facets involved (blue ellipses). Three key aspects for each dimension are indicated in adjoining boxes. SCD, sudden cardiac death; CHD, congenital heart disease; CPR, cardiopulmonary resuscitation; ICD, implantable cardioverter-defibrillator; S-ICD, subcutaneous implantable cardioverter-defibrillator.
Patients with congenital heart disease (CHD) and their parents face challenges throughout their lives that can lead to anxiety lasting into adulthood. We aim to assess the association between ...perceived parenting practices and anxiety beyond paediatric medical-surgical histories in adults with CHD.
A cross-sectional study of adults with CHD was conducted at the Montreal Heart Institute (MHI). Perception of parental practices during childhood was retrospectively assessed with the use of validated self-report questionnaires, and anxiety in adulthood was assessed with the use of the Hospital Anxiety and Depression Scale. Sociodemographic and medical information were collected from a questionnaire and medical records. Hierarchic multiple linear regression was conducted.
Of the 223 participants, the mean age was 46 ± 14 years and 59% were female. Perceived parenting practices explained more variance (11%) in the anxiety score than paediatric medical-surgical history (2%). In our final model, anxiety was significantly associated with age, parental history of anxiety, and positive parenting practices, but not with overprotection.
Parenting practices are associated with anxiety in adults with CHD beyond paediatric medical-surgical history and sociodemographic. Positive parenting practices may be protective against anxiety in adulthood. Longitudinal studies are needed to determine causality.
Les patients atteints de cardiopathies congénitales et leurs parents sont confrontés à des défis tout au long de leur vie. Ces difficultés peuvent donner lieu à une anxiété qui persiste à l’âge adulte. Nous avons voulu évaluer le lien entre les pratiques parentales perçues et l’anxiété, au-delà des antécédents médico-chirurgicaux pédiatriques, chez des adultes atteints de cardiopathies congénitales.
Nous avons réalisé une étude transversale chez des adultes atteints de cardiopathie congénitale à l’Institut de cardiologie de Montréal (ICM). La perception des pratiques parentales durant l’enfance a été évaluée de manière rétrospective à l’aide de questionnaires d’auto-évaluation validés; l’anxiété à l’âge adulte a été évaluée à l’aide de l’échelle HADS (Hospital Anxiety and Depression Scale – échelle d’évaluation de l’anxiété et de la dépression en milieu hospitalier). Les données sociodémographiques et médicales ont été recueillies à l’aide d’un questionnaire et des dossiers médicaux. Une analyse de régression linéaire multiple hiérarchique a été réalisée.
L’âge moyen des 223 participants était de 46 ± 14 ans et 59 % étaient de sexe féminin à la naissance. Les pratiques parentales perçues ont expliqué une plus grande partie de la variance (11 %) du score d’anxiété que les antécédents médico-chirurgicaux pédiatriques (2 %). Dans notre modèle final, une association significative a été établie entre l’anxiété et l’âge, les antécédents parentaux d’anxiété et les pratiques parentales positives, mais pas entre l’anxiété et la surprotection.
Les pratiques parentales sont associées à l’anxiété chez les adultes atteints de cardiopathies congénitales, indépendamment des antécédents médico-chirurgicaux pédiatriques et des caractéristiques sociodémographiques. Les pratiques parentales positives peuvent avoir un effet protecteur contre l’anxiété à l’âge adulte. Des études longitudinales sont nécessaires pour établir le lien de causalité.
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