Biallelic PKP2 loss of function variants are associated with a lethal perinatal-onset biventricular dilated cardiomyopathy with excessive trabeculations and ventricular septal defects.

Homozygous plakophilin-2 (PKP2) variants have been identified as a cause of a lethal form of dilated cardiomyopathy with excessive trabeculations (DCM-ET) in three cases. We report three more cases from two families with homozygous pathogenic PKP2 variants and perinatal-onset, lethal DCM-ET. Identification of the genetic abnormalities played a key role in decision-making and family counselling in these cases. This case series supports the published evidence that biallelic loss of function PKP2 variants cause a lethal, perinatal-onset cardiomyopathy.

Clinical presentation of calmodulin mutations: the International Calmodulinopathy Registry.

AIMS: Calmodulinopathy due to mutations in any of the three CALM genes (CALM1-3) causes life-threatening arrhythmia syndromes, especially in young individuals. The International Calmodulinopathy Registry (ICalmR) aims to define and link the increasing complexity of the clinical presentation to the underlying molecular mechanisms. METHODS AND RESULTS: The ICalmR is an international, collaborative, observational study, assembling and analysing clinical and genetic data on CALM-positive patients. The ICalmR has enrolled 140 subjects (median age 10.8 years [interquartile range 5-19]), 97 index cases and 43 family members. CALM-LQTS and CALM-CPVT are the prevalent phenotypes. Primary neurological manifestations, unrelated to post-anoxic sequelae, manifested in 20 patients. Calmodulinopathy remains associated with a high arrhythmic event rate (symptomatic patients, n = 103, 74%). However, compared with the original 2019 cohort, there was a reduced frequency and severity of all cardiac events (61% vs. 85%; P = .001) and sudden death (9% vs. 27%; P = .008). Data on therapy do not allow definitive recommendations. Cardiac structural abnormalities, either cardiomyopathy or congenital heart defects, are present in 30% of patients, mainly CALM-LQTS, and lethal cases of heart failure have occurred. The number of familial cases and of families with strikingly different phenotypes is increasing. CONCLUSION: Calmodulinopathy has pleiotropic presentations, from channelopathy to syndromic forms. Clinical severity ranges from the early onset of life-threatening arrhythmias to the absence of symptoms, and the percentage of milder and familial forms is increasing. There are no hard data to guide therapy, and current management includes pharmacological and surgical antiadrenergic interventions with sodium channel blockers often accompanied by an implantable cardioverter-defibrillator.

Long-term outcomes of pacemaker implantation in children with univentricular versus complex biventricular surgical repair.

Objective: Pacing in a univentricular circulation has been associated with worsened outcomes. We investigated the long-term outcomes of pacing in children with a univentricular circulation compared to a complex biventricular circulation. We also identified predictors of adverse outcomes. Methods: A retrospective study of all children with major congenital heart disease who underwent pacemaker implantation under the age of 18 years between November 1994 and October 2017. Results: Eighty-nine patients were included; 19 with a univentricular and 70 with a complex biventricular circulation. A total of 96% of pacemaker systems were epicardial. Median follow up was 8.3 years. The incidence of adverse outcome was similar between the two groups. Five (5.6%) patients died and two (2.2%) underwent heart transplantation. Most adverse events occurred within the first 8 years after pacemaker implantation. Univariate analysis identified five predictors of adverse outcomes in the patients in the biventricular but none in the univentricular group. The predictors of adverse outcome in the biventricular circulation were a right morphologic ventricle as the systemic ventricle, age at first congenital heart disease (CHD) operation, number of CHD operations, and female gender. The nonapical lead position was associated with a much higher risk of an adverse outcome. Conclusions: Children with a pacemaker and a complex biventricular circulation have similar survival to the ones with a pacemaker and a univentricular circulation. The only modifiable predictor was the epicardial lead position on the paced ventricle, emphasizing the importance of apical placement of the ventricular lead.

Co-occurrence of Proteus syndrome and ventricular tachycardia cardiac arrest in a teenager.

Proteus syndrome is an extremely rare overgrowth condition caused by a somatic variant of the AKT1 gene. It can involve multiple organ systems though rarely is there symptomatic cardiac involvement. Fatty infiltration of the myocardium has been described but has not been reported to cause functional or conduction abnormalities. We present an individual with Proteus syndrome who suffered a sudden cardiac arrest.

PPA2-associated sudden cardiac death: extending the clinical and allelic spectrum in 20 new families.

PURPOSE: Biallelic hypomorphic variants in PPA2, encoding the mitochondrial inorganic pyrophosphatase 2 protein, have been recently identified in individuals presenting with sudden cardiac death, occasionally triggered by alcohol intake or a viral infection. Here we report 20 new families harboring PPA2 variants. METHODS: Synthesis of clinical and molecular data concerning 34 individuals harboring five previously reported PPA2 variants and 12 novel variants, 11 of which were functionally characterized. RESULTS: Among the 34 individuals, only 6 remain alive. Twenty-three died before the age of 2 years while five died between 14 and 16 years. Within these 28 cases, 15 died of sudden cardiac arrest and 13 of acute heart failure. One case was diagnosed prenatally with cardiomyopathy. Four teenagers drank alcohol before sudden cardiac arrest. Progressive neurological signs were observed in 2/6 surviving individuals. For 11 variants, recombinant PPA2 enzyme activities were significantly decreased and sensitive to temperature, compared to wild-type PPA2 enzyme activity. CONCLUSION: We expand the clinical and mutational spectrum associated with PPA2 dysfunction. Heart failure and sudden cardiac arrest occur at various ages with inter- and intrafamilial phenotypic variability, and presentation can include progressive neurological disease. Alcohol intake can trigger cardiac arrest and should be strictly avoided.

Clinical outcomes and programming strategies of implantable cardioverter-defibrillator devices in paediatric hypertrophic cardiomyopathy: a UK National Cohort Study.

AIMS: Sudden cardiac death (SCD) is the most common mode of death in paediatric hypertrophic cardiomyopathy (HCM). This study describes the implant and programming strategies with clinical outcomes following implantable cardioverter-defibrillator (ICD) insertion in a well-characterized national paediatric HCM cohort. METHODS AND RESULTS: Data from 90 patients undergoing ICD insertion at a median age 13 (±3.5) for primary (n = 67, 74%) or secondary prevention (n = 23, 26%) were collected from a retrospective, longitudinal multi-centre cohort of children (<16 years) with HCM from the UK. Seventy-six (84%) had an endovascular system [14 (18%) dual coil], 3 (3%) epicardial, and 11 (12%) subcutaneous system. Defibrillation threshold (DFT) testing was performed at implant in 68 (76%). Inadequate DFT in four led to implant adjustment in three patients. Over a median follow-up of 54 months (interquartile range 28-111), 25 (28%) patients had 53 appropriate therapies [ICD shock n = 45, anti-tachycardia pacing (ATP) n = 8], incidence rate 4.7 per 100 patient years (95% CI 2.9-7.6). Eight inappropriate therapies occurred in 7 (8%) patients (ICD shock n = 4, ATP n = 4), incidence rate 1.1/100 patient years (95% CI 0.4-2.5). Three patients (3%) died following arrhythmic events, despite a functioning device. Other device complications were seen in 28 patients (31%), including lead-related complications (n = 15) and infection (n = 10). No clinical, device, or programming characteristics predicted time to inappropriate therapy or lead complication. CONCLUSION: In a large national cohort of paediatric HCM patients with an ICD, device and programming strategies varied widely. No particular strategy was associated with inappropriate therapies, missed/delayed therapies, or lead complications.

Novel PRKAG2 Variant Manifesting with a Cardiac Arrest in a Child.

We describe the case of a novel PRKAG2 mutation that manifested with a ventricular fibrillation cardiac arrest in a child. The previously healthy 13-year old boy, was subsequently diagnosed with Wolff-White-Parkinson syndrome, mild left ventricular hypertrophy and atrial fibrillation. His father had also been diagnosed in the past with Wolff-White-Parkinson syndrome and developed left ventricular hypertrophy. A novel heterozygous likely pathogenic variant, c.911C>G, p.Ala304Gly was identified in the father and his son, which is absent from population databases. PRKAG2 gene variants have previously been shown to cause a familial syndrome of ventricular hypertrophy, ventricular pre-excitation, supraventricular tachycardia, and conduction abnormalities. However, to the best of our knowledge, this is the first description of this rare syndrome manifesting with a more severe phenotype in a second generation relative within the same family.

Growth and the subcutaneous implantable cardioverter defibrillator in a small child.

The effect of growth on the subcutaneous cardioverter defibrillators when implanted in small children is unknown. These two chest X-rays demonstrate that these devices can cope well with growth.

Virtual clinics for follow-up of pacemakers and implantable cardioverter defibrillators in children.

There is growing interest in the use of digital medicine to reduce the need for traditional outpatient follow-up. Remote interrogation of pacemakers and implantable cardioverter defibrillators is now possible with most devices. The aim of our study was to evaluate the safety and efficacy of virtual pacing clinics in following up children with pacemakers and implantable cardioverter defibrillators, including epicardial systems. METHODS: The study was retrospective over 8 years (2010-2017), with review of patient records and analysis of downloads from the implantable cardiac devices to the virtual clinics. RESULTS: A total of 75 patients were set up for virtual clinic follow-up during the study period, 94.5% with a pacemaker and 5.5% an implantable cardioverter defibrillator. The majority (76.8%) had an epicardial system. Data on lead impedance, battery longevity, programmed parameters, detected arrhythmias, percentage pacing and delivered defibrillator therapies were obtainable by download. Lead threshold measurements were obtainable via download in 83.7% of the devices, including epicardial systems. No concerning device issue was missed. In 15% of patients a major issue was detected remotely, including three patients with lead fractures. The virtual clinics resulted in fewer hospital attendances while enhancing monitoring and enabling more frequent device checks. The vast majority (91.4%) of families who responded to a questionnaire were satisfied with the virtual clinic follow-up. CONCLUSIONS: Virtual clinics allow safe and effective follow-up of children with pacemakers and implantable cardioverter defibrillators, including those with epicardial systems and are associated with high levels of parent satisfaction.

Thyroid function and postpartum mood disturbances in Greek women.

BACKGROUND: Postpartum mood disturbances are very common with postpartum blues being as high as 44.5% among Greek women. This study aimed to investigate whether thyroid function within the normal range affects the incidence of postpartum mood disturbances. METHODS: In a cross-sectional study in the maternity ward of Aretaieion Hospital, 57 Greek women were evaluated for postpartum mood swings by the Maternity Blues Questionnaire and the Edinburgh Postnatal Depression Scale on the first and sixth week postpartum. Serum Free T4, Free T3 and TSH concentrations as well as thyroglobulin and thyroid peroxidase antibodies were measured on admission for delivery and daily until the fourth postpartum day. We examined the association between hormone and antibody levels, and scores in the two scales evaluating postpartum mood disturbances. RESULTS: Prepartum serum FT3 and FT4 correlated negatively with blues scores in the first week postpartum (blues on day 4: with FT3, rho=-0.44, p < or = 0.01; with FT4 rho=-0.36, p < or = 0.01). Women with lower FT3 and FT4 levels belonged to the high scoring group (high scoring group: FT3=1.22 pg/ml, FT4=0.66 ng/dl; low scoring group: FT3=1.64 pg/ml, FT4=0.73 ng/dl). Serum FT3 showed a negative independent correlation with postpartum blues scores in the first postpartum days. No association was found between thyroid antibody levels and mood scores. CONCLUSION: Our findings indicate an association between the occurrence of postpartum mood disorders and antenatal thyroid function. Within normal limits, lower levels of serum FT3 and FT4 are associated with increased incidence of mood disturbances in the first postpartum week.