Natural history and outcomes in paediatric RASopathy-associated hypertrophic cardiomyopathy.

AIMS: This study aimed to describe the natural history and predictors of all-cause mortality and sudden cardiac death (SCD)/equivalent events in children with a RASopathy syndrome and hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: This is a retrospective cohort study from 14 paediatric cardiology centres in the United Kingdom and Ireland. We included children <18 years with HCM and a clinical and/or genetic diagnosis of a RASopathy syndrome [Noonan syndrome (NS), NS with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFCS), and NS with loose anagen hair (NS-LAH)]. One hundred forty-nine patients were recruited [111 (74.5%) NS, 12 (8.05%) NSML, 6 (4.03%) CS, 6 (4.03%) CFCS, 11 (7.4%) Noonan-like syndrome, and 3 (2%) NS-LAH]. NSML patients had higher left ventricular outflow tract (LVOT) gradient values [60 (36-80) mmHg, P = 0.004]. Over a median follow-up of 197.5 [inter-quartile range (IQR) 93.58-370] months, 23 patients (15.43%) died at a median age of 24.1 (IQR 5.6-175.9) months. Survival was 96.45% [95% confidence interval (CI) 91.69-98.51], 90.42% (95% CI 84.04-94.33), and 84.12% (95% CI 75.42-89.94) at 1, 5, and 10 years, respectively, but this varied by RASopathy syndrome. RASopathy syndrome, symptoms at baseline, congestive cardiac failure (CCF), non-sustained ventricular tachycardia (NSVT), and maximal left ventricular wall thickness were identified as predictors of all-cause mortality on univariate analysis, and CCF, NSVT, and LVOT gradient were predictors for SCD or equivalent event. CONCLUSIONS: These findings highlight a distinct category of patients with Noonan-like syndrome with a milder HCM phenotype but significantly worse survival and identify potential predictors of adverse outcome in patients with RASopathy-related HCM.

Prevalence of Inherited Cardiac Conditions in Pediatric First-Degree Relatives of Patients with Idiopathic Ventricular Fibrillation.

Idiopathic ventricular fibrillation (IVF) is diagnosed in out-of-hospital VF survivors after comprehensive investigations have excluded structural heart disease or inherited channelopathies. Current guidelines recommend clinical screening of first-degree relatives of IVF survivors, but this approach has not been validated in children. This study aimed to assess the yield of clinical cardiac screening in child first-degree relatives of IVF victims. A retrospective observational study was conducted of all consecutive pediatric first-degree relatives of IVF patients referred to our center between December 2007 and April 2020. Patients underwent systematic evaluation including medical and family history; 12-lead resting, signal-averaged, and ambulatory electrocardiogram (ECG); echocardiogram; exercise testing; cardiac magnetic resonance imaging; and ajmaline provocation testing. Sixty child first-degree relatives of 32 IVF survivors were included [median follow-up time of 55 months (IQR 27.0-87.0 months); 30 (50%) females]. Eight patients (13.3%) from 6 families (18.8%) received a cardiac diagnosis: long QT syndrome (n = 4); Brugada syndrome (n = 3); and dilated cardiomyopathy (n = 1). There were no deaths during follow-up. This study demonstrates a high yield of clinical screening for inherited cardiac disease in child first-degree relatives of IVF survivors. These findings highlight the variable expression of inherited cardiac conditions and the importance of comprehensive clinical evaluation in pediatric relatives, even when extensive investigations in the proband have not identified a clear etiology. Moreover, our results support the validity of the investigations proposed by current guidelines in family relatives of IVF survivors.

Cardiac myosin binding protein-C variants in paediatric-onset hypertrophic cardiomyopathy: natural history and clinical outcomes.

BACKGROUND: Variants in the cardiac myosin-binding protein C gene (MYBPC3) are a common cause of hypertrophic cardiomyopathy (HCM) in adults and have been associated with late-onset disease, but there are limited data on their role in paediatric-onset HCM. The objective of this study was to describe natural history and clinical outcomes in a large cohort of children with HCM and pathogenic/likely pathogenic (P/LP) MYBPC3 variants. METHODS AND RESULTS: Longitudinal data from 62 consecutive patients diagnosed with HCM under 18 years of age and carrying at least one P/LP MYBPC3 variant were collected from a single specialist referral centre. The primary patient outcome was a major adverse cardiac event (MACE). Median age at diagnosis was 10 (IQR: 2-14) years, with 12 patients (19.4%) diagnosed in infancy. Forty-seven (75%) were boy and 31 (50%) were probands. Median length of follow-up was 3.1 (IQR: 1.6-6.9) years. Nine patients (14.5%) experienced an MACE during follow-up and five (8%) died. Twenty patients (32.3%) had evidence of ventricular arrhythmia, including 6 patients (9.7%) presenting with out-of-hospital cardiac arrest. Five-year freedom from MACE for those with a single or two MYBPC3 variants was 95.2% (95% CI: 78.6% to 98.5%) and 68.4% (95% CI: 40.6% to 88.9%), respectively (HR 4.65, 95% CI: 1.16 to 18.66, p=0.03). CONCLUSIONS: MYBPC3 variants can cause childhood-onset disease, which is frequently associated with life-threatening ventricular arrhythmia. Clinical outcomes in this cohort vary substantially from aetiologically and genetically mixed paediatric HCM cohorts described previously, highlighting the importance of identifying specific genetic subtypes for clinical management of childhood HCM.

Clinical presentation and long-term outcomes of infantile hypertrophic cardiomyopathy: a European multicentre study.

AIMS: Children presenting with hypertrophic cardiomyopathy (HCM) in infancy are reported to have a poor prognosis, but this heterogeneous group has not been systematically characterized. This study aimed to describe the aetiology, phenotype, and outcomes of infantile HCM in a well-characterized multicentre European cohort. METHODS AND RESULTS: Of 301 children diagnosed with infantile HCM between 1987 and 2019 presenting to 17 European centres [male n = 187 (62.1%)], underlying aetiology was non-syndromic (n = 138, 45.6%), RASopathy (n = 101, 33.6%), or inborn error of metabolism (IEM) (n = 49, 16.3%). The most common reasons for presentation were symptoms (n = 77, 29.3%), which were more prevalent in those with syndromic disease (n = 62, 61.4%, P < 0.001), and an isolated murmur (n = 75, 28.5%). One hundred and sixty-one (53.5%) had one or more co-morbidities. Genetic testing was performed in 163 (54.2%) patients, with a disease-causing variant identified in 115 (70.6%). Over median follow-up of 4.1 years, 50 (16.6%) underwent one or more surgical interventions; 15 (5.0%) had an arrhythmic event (6 in the first year of life); and 48 (15.9%) died, with an overall 5 year survival of 85%. Predictors of all-cause mortality were an underlying diagnosis of IEM [hazard ratio (HR) 4.4, P = 0.070], cardiac symptoms (HR 3.2, P = 0.005), and impaired left ventricular systolic function (HR 3.0, P = 0.028). CONCLUSIONS: This large, multicentre study of infantile HCM describes a complex cohort of patients with a diverse phenotypic spectrum and clinical course. Although overall outcomes were poor, this was largely related to underlying aetiology emphasizing the importance of comprehensive aetiological investigations, including genetic testing, in infantile HCM.

Interactions between whole-body heating and citalopram on body temperature, antidepressant-like behaviour, and neurochemistry in adolescent male rats.

Evidence suggests that affective disorders are associated with altered thermoregulation, and it has been hypothesized that therapeutic strategies targeting body-to-brain thermosensory systems may be effective for treating depression. Consistent with this hypothesis, a recent randomized, double blind, placebo-controlled clinical trial has suggested that infrared whole-body hyperthermia has therapeutic potential for the treatment of depression. Preclinical models may help uncover the mechanism(s) underlying the antidepressant-like effects of whole-body heating. We have previously shown that exposure to whole-body heating potentiates antidepressant-like behavioural responses following administration of a behaviourally subthreshold dose of the selective serotonin reuptake inhibitor citalopram, but the neurochemical and behavioural interactions between whole body heating and behaviourally effective doses of citalopram are not known. In these experiments, we examined the effects of whole-body heating, either with or without treatment of a suprathreshold dose of citalopram (20 mg/kg, s.c.), on body temperature, antidepressant-like behavioural responses in the forced swim test, and tissue concentrations of serotonin and its metabolite, 5-hydoxyindoleacetic acid (5-HIAA), in the prefrontal cortex of adolescent male Wistar rats. Although whole-body heating did not potentiate the behavioural effects of suprathreshold citalopram, citalopram was observed to increase body temperature and potentiate the effects of whole-body heating on body temperature. Whole-body heating, by itself, decreased serotonin concentrations in the infralimbic cortex to a level similar to that observed following treatment with citalopram, suggesting that these treatments have convergent effects on a mesolimbocortical system innervating the medial prefrontal cortex, an effect that was correlated with effects of treatment on body temperature.

Whole-body hyperthermia and a subthreshold dose of citalopram act synergistically to induce antidepressant-like behavioral responses in adolescent rats.

BACKGROUND: Open and randomized, double blind, placebo-controlled clinical trials have demonstrated clinical efficacy of infrared whole-body hyperthermia in treatment of major depressive disorder (MDD). Demonstration of antidepressant-like behavioral effects of whole-body hyperthermia in preclinical rodent models would provide further support for the clinical use of infrared whole-body hyperthermia for the treatment of MDD, and would provide additional opportunities to explore underlying mechanisms. METHODS: Adolescent male Wistar rats were habituated daily for 7days to an incubator (23°C, 15min), then exposed, 24h later, to an 85-min period of whole-body hyperthermia (37°C) or control conditions (23°C), with or without pretreatment with a subthreshold dose of the selective serotonin reuptake inhibitor, citalopram (5mg/kg, s.c., 23h, 5h, and 1h before behavioral testing in a 5-min forced swim test). Rectal temperature was monitored daily and immediately before and after the forced swim test to determine the relationship between body temperature and antidepressant-like behavioral responses. RESULTS: Whole-body hyperthermia and citalopram independently increased body temperature and acted synergistically to induce antidepressant-like behavioral responses, as measured by increased swimming and decreased immobility in the absence of any effect on climbing behaviors in the forced swim test, consistent with a serotonergic mechanism of action. CONCLUSIONS: Preclinical data support use of infrared whole-body hyperthermia in the treatment of MDD.

Evidence for in vivo thermosensitivity of serotonergic neurons in the rat dorsal raphe nucleus and raphe pallidus nucleus implicated in thermoregulatory cooling.

The ability to sense and respond appropriately to increases in ambient and body temperatures is critical for the survival of all animals. Although evidence suggests that brain serotonergic systems play a role in thermoregulation, including thermoregulatory cooling, evidence for activation of brainstem serotonergic neurons in vivo, in unanesthetized animals, during heat exposure is lacking. In this experiment we tested the hypothesis that populations of serotonergic neurons in the midbrain and medullary raphe complex are activated following exposure to warm ambient temperature. Rats were exposed to an incubation chamber at either warm ambient temperature (37°C) or room temperature (RT; 23°C) for 105 min. Brains then were removed and processed for immunohistochemical detection of the protein product of the immediate-early gene c-fos (as a marker of neuronal activation) and tryptophan hydroxylase (as a marker of serotonergic neurons). Exposure to warm ambient temperature increased body temperature and c-Fos expression in topographically organized populations of serotonergic neurons in the dorsal raphe nucleus. Activation of the dorsal raphe nucleus serotonergic system was positively correlated with body temperature following exposure to the incubation chamber. In the medulla, exposure to warm ambient temperature, compared with exposure to RT, decreased c-Fos expression in serotonergic neurons in the raphe pallidus nucleus and in non-serotonergic cells in the rostral ventrolateral medulla. Together, these results provide evidence for multiple but anatomically discrete thermosensitive serotonergic systems that may have implications for the regulation of body temperature, as well as, via projections to forebrain targets, cognitive and affective functions.