ObjectiveTo establish which risk factors are predictive for sudden death in hypertrophic cardiomyopathy (HCM) diagnosed in childhood.MethodsA Swedish national cohort of patients with HCM diagnosed <19 years of age was collected between 1972 and 2014, consisting of 155 patients with available ECGs, with average follow-up of 10.9±(SD 9.0) years, out of whom 32 had suffered sudden death or cardiac arrest (SD/CA group). Previously proposed risk factors and clinical features, ECG and ultrasound measures were compared between SD/CA group and patients surviving >2 years (n=100), and features significantly more common in SD/CA group were further analysed with univariate and multivariate Cox hazard regression in the total cohort.ResultsRanked according to relative risk (RR) the ECG risk score >5 points had an RR of 46.5 (95% CI 6.6 to 331), sensitivity of 97% (83% to 100%) and specificity of 80% (71% to 88%) (p<0.0001), and was the best ECG predictor, predicting a 5-year risk of SD/CA of 30.6%. The following are other features with importantly raised RR: Detroit wall thickness Z-score >4.5: 9.9 (3.1 to 31.2); septal thickness ≥190% of upper limit of normal for age (septum in % of 95th centile for age (SEPPER) ≥190%): 7.9 (3.2 to 19.4); ventricular tachycardia: 9.1 (3.6 to 22.8); ventricular ectopics on exercise testing: 7.4 (2.7 to 20.2); and left ventricular outflow gradient (left ventricular outflow tract obstruction (LVOTO)) >50 mm Hg: 6.6 (4.0 to 11.0). Family history was non-significant. Multivariate Cox hazard analysis gives the following as early predictors: limb-lead QRS amplitude sum (p=0.020), SEPPER ≥190% (p<0.001) and LVOTO at rest (p=0.054); and for late predictors: last ECG risk score (p=0.002) and last Detroit Z-score (p=0.001). Both early (p=0.028) and late (p=0.037) beta-blocker doses reduced risk in the models.ConclusionsECG phenotype as assessed by ECG risk score is important for risk of sudden death and should be considered for inclusion in risk stratification of paediatric patients with HCM.

Development of heart block in children of SSA/SSB-autoantibody-positive women is associated with maternal age and displays a season-of-birth pattern, 2012, Annals of the Rheumatic Diseases, (71) Methods. The influence of fetal gender, maternal age, parity and time of birth on heart block development was analyzed in 145 families including Ro/La-positive (n= 190) and Ro/Lanegative (n=165) pregnancies.Results. We observed a recurrence rate of 12.1% in Ro/La-positive women, and no recurrence in Ro/La-negative women. Fetal gender and parity did not influence the development of heart block in either group. Maternal age in Ro/La-positive pregnancies with a child affected by heart block was however significantly higher than in pregnancies resulting in babies without heart block (p<0.01). Further, seasonal timing of pregnancy influenced the outcome. Gestational susceptibility-weeks 18-24 occurring during January-March correlated with a higher proportion of heart block pregnancies and lower vitamin D levels, and a corresponding higher proportion of children with heart block born in the summer (p<0.02). Maternal age or seasonal timing of pregnancy did not affect the outcome in Ro/La-negative pregnancies.Conclusion. This study identifies maternal age and seasonal timing of pregnancy as novel risk factors for congenital heart block development in Ro/La positive pregnancy. These observations indicate that the risk can be modified, and will be important for counseling when a pregnancy is considered. 4Congenital complete heart block without cardiac malformation is a rare disease, affecting 1 in 15,000 to 20,000 births in the general population. An association with the presence of maternal autoantibodies to Ro/SSA and/or La/SSB is however well established [1,2], and the risk of complete congenital heart block is 1-2% in Ro/SSA-positive pregnancies [3][4][5][6]. Furthermore, the reported risk of giving birth to a second child with complete heart block for anti-Ro/SSA positive mothers ranges from 12 to 20% [7][8][9], despite the persistence of the maternal autoantibodies [10].This indicates that additional factors are critical for establishing the heart block. Fetal genetic susceptibility has been suggested as a potential risk factor [11,12], and polymorphisms in the gene encoding TGFβ have been implicated in the development of heart block [13,14]. Variations in the intrauterine environment between pregnancies have also been suggested to contribute to the penetrance of the disease. Maternal disease severity has been investigated as such a potential risk factor, but was not found to contribute to the development of congenital heart block [15].Given the rarity of congenital heart block occurrence in the general population, it is difficult to investigate potential risk factors associated with the disease. In particular, very little information is available on the influence of maternal age and parity on pregnancy outcome in anti-Ro/La positive mothers. In an effort to address these questions in a reasonable cohort we identified heart ...

The objective of the study was to investigate the antigen specificity and occurrence of individual autoantibodies in mothers of children diagnosed with atrioventricular (AV) block in a nation-wide setting. Patients with AV block detected before 15 years of age were identified using national quality registries as well as a network of pediatric and adult cardiologists and rheumatologists at the six university hospitals in Sweden. Patients with gross heart malformations, surgically or infectiously induced blocks were excluded. Blood samples were obtained from the mothers and maternal autoantibody profile, including the occurrence of antibodies against Ro52, Ro60, La, SmB, SmD, RNP-70k, RNP-A, RNP-C, CENP-C, Scl-70, Jo-1, ribosomal RNP and histones was investigated in 193 mothers of children with AV block by immunoblotting and ELISA. Autoantibody reactivity was detected in 48% (93/193) of the mothers of children with AV block. In autoantibody-positive mothers, the vast majority, 95% (88/93), had antibodies against Ro52, while 63% (59/93) had autoantibodies to Ro60 and 58% (54/93) had autoantibodies to La. In addition, 13% (12/93) of the autoantibody-positive mothers had antibodies to other investigated antigens besides Ro52, Ro60 and La, and of these anti-histone antibodies were most commonly represented, detected in 8% (7/93) of the mothers. In conclusion, this Swedish population-based study confirms that maternal autoantibodies may associate with heart block in the child. Further, our data demonstrate a dominant role of Ro52 antibodies in association with AV block.Funding Agencies|KIRCNET (Karolinska Institutet Circulation and Respiratory Research Network)||Magn Bergvalls Foundation||Jerringfoundation||Stiftelsen Samariten||Karolinska Institute||Royal Swedish Academy of Sciences||Swedish Research Council||Goran Gustafsson Foundation||Torsten and Ragnar Soderberg Foundation||King Gustaf the V:th 80-year foundation||Swedish Foundation for Strategic Research||Heart-Lung Foundation||Swedish Rheumatism Association|

Recurrent copy number variants (CNVs) are found in a significant proportion of patients with congenital heart disease (CHD) and some of these CNVs are associated with other developmental defects. In some syndromic patients, CHD may be the first presenting symptom, thus screening of patients with CHD for CNVs in specific genomic regions may lead to early diagnosis and awareness of extracardiac symptoms. We designed a multiplex ligation-dependent probe amplification (MLPA) assay specifically for screening of CHD patients. The MLPA assay allows for simultaneous analysis of CNVs in 25 genomic regions previously associated with CHD. We screened blood samples from 402 CHD patients and identified 14 rare CNVs in 13 (3.2%) patients. Five CNVs were de novo and six where inherited from a healthy parent. The MLPA screen led to early syndrome diagnosis in two of these patients. We conclude that the MLPA assay detects clinically relevant CNVs and suggest that it could be used within pediatric cardiology as a first tier screen to detect clinically relevant CNVs and identify syndromic patients at an early stage.

Aim To compare risk algorithms (HCMRisk‐Kids, ECG Risk‐score) in hypertrophic cardiomyopathy (HCM) without syndrome association (ns‐HCM) and with Noonan‐like syndromes (RAS‐HCM). Methods A national paediatric HCM cohort (n = 151), presenting <19 years of age, mean follow‐up 13.3 years, from all Swedish centres of Paediatric Cardiology (presenting 1972–2015), with 41 RAS‐HCM patients (61% males), and 110 ns‐HCM patients (68% familial; 65% males). The end‐point was a composite of sudden cardiac death and resuscitated cardiac arrest (SCD/CA). Risk‐factors were studied with Cox‐hazard regression, and receiver operating characteristic curve analysis (C‐statistic). Results There were 33 SCD/CA, 27/110 in ns‐HCM and 6/41 in RAS‐HCM (p = 0.27). In ns‐HCM HCMRisk‐Kids ≥6% at diagnosis had C‐statistic of 0.69 for predicting SCD/CA during first 5 years of follow‐up and positive predictive value (PPV) of 22%. After 7 years of age (HCMRisk‐Kids7plus), C‐statistic was 0.76. ECG Risk‐score ≥6 at diagnosis had C‐statistic 0.87 and PPV of 31%. Independent risk factors for SCD/CA were HCMRisk‐Kids7plus score (p = 0.005) and ECG risk‐score (p < 0.001), whereas early beta‐blocker dose (p = 0.001) and myectomy (p = 0.004) reduced risk. The sum of HCMRisk‐Kids7yplus and ECG Risk‐score7yplus ≥14 best predicted SCD/CA within 5 years in ns‐HCM with C‐statistic of 0.90 [0.83–0.96], sensitivity 100% and PPV 38%. Conclusion Combining the ECG Risk‐score with HCMRisk‐Kids improves risk stratification in ns‐HCM and shows promise in RAS‐HCM.

Hypertrophic cardiomyopathy (HCM) remains the leading cause of sudden cardiac death in the young. Early markers for HCM are important to identify individuals at risk. The aim of this study was to investigate novel serum biomarkers reflecting myocardial remodeling, microfibrosis, and vascular endotheliopathy in the early stages of familial HCM in young patients. Twenty-three HCM patients, 16 HCM-risk individuals, and 66 controls (median 15 years) underwent echocardiography and serum analysis for cathepsin S, endostatin, myostatin, type I collagen degradation marker (ICTP), matrix metalloproteinase (MMP)-9, vascular endothelial growth factor receptor (VEGFR)-1, and vascular and intercellular adhesion molecules (VCAM, ICAM). In a subset of the population, global myocardial perfusion was performed by magnetic resonance imaging. Cathepsin S (p = 0.0009), endostatin (p < 0.0001), MMP-9 (p = 0.008), and VCAM (p = 0.04) were increased in the HCM group and correlated to left ventricular mass index and mitral E/e′ (p < 0.01). In the HCM-risk group, myostatin was decreased (p = 0.004), whereas ICAM was increased (p = 0.002). Global perfusion was decreased in the HCM group (p < 0.05) versus controls. Endostatin and mitral E/e′ correlated inversely to myocardial perfusion (p ≤ 0.05). This is the first study demonstrating adverse changes in biomarkers reflecting myocardial matrix remodeling, microfibrosis, and vascular endotheliopathy in early stage of hypertrophic cardiomyopathy in the young.

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The relationship between hypertrophy, perfusion abnormalities and fibrosis is unknown in young patients with hypertrophic cardiomyopathy (HCM). Since mounting evidence suggests causal relationship between myocardial ischemia and major adverse cardiac events, we sought to investigate whether (1) regional myocardial perfusion is decreased in young HCM patients and in individuals at risk of HCM, and (2) hypoperfused areas are larger than areas with fibrosis. HCM patients (n = 12), HCM-risk subjects (n = 15) and controls (n = 9) were imaged on a 1.5 T MRI scanner. Myocardial hypertrophy was assessed on cine images. Perfusion images were acquired during adenosine hyperemia and at rest. Maximum upslope ratios of perfusion (stress/rest) were used for semiquantitative analysis. Fibrosis was assessed by late gadolinium enhancement (LGE). Results are presented as median and range. Perfusion in HCM-risk subjects and in non-hypertrophied segments in HCM patients showed no difference compared to controls (P = ns). Hypertrophic segments in HCM patients without LGE showed decreased perfusion compared to segments without hypertrophy [1.5 (1.1–2.3) vs. 2.0 (1.8–2.6), P < 0.001], and hypertrophic segments with LGE showed even lower perfusion using a segmental analysis [0.9 (0.6–1.8), P < 0.05]. The extent of hypoperfused myocardium in HCM patients during adenosine exceeded the extent of fibrosis on LGE [20 (0–48) vs. 4 (0–7) % slice area, P < 0.05] and hypoperfused areas at rest (P < 0.001). Regional perfusion is decreased in hypertrophied compared to non-hypertrophied myocardium and is lowest in fibrotic myocardium in young HCM patients but does not discriminate HCM-risk subjects from controls. The stress-induced hypoperfused regions exceed regions with LGE, indicating that hypoperfusion precedes fibrosis and may be a more sensitive marker of diseased myocardium in HCM.