Heart rate in newborns is associated with age, sex and maternal levothyroxine therapy.

AIM: To evaluate the definition and causes of neonatal bradycardias. METHODS: This retrospective study included 135 term-born newborns referred for 24-hour Holter monitoring due to bradycardia. Bradycardia was defined as either a heart rate below 80 beats per minute (standard definition) or a heart rate below our recently published age-specific reference values for neonatal heart rate. RESULTS: The mean (SD) age was 6.1 (1.3) days. With standard definition, 107 newborns (79%) had bradycardia, whereas only 20 (15%) had a minimum heart rate lower than the age-specific reference. Younger newborns had lower heart rates. Each day increased the minimum, mean and maximum heart rate by 1.8 (95% CI: 1.0, 2.6), 4.2 (95% CI: 3.0, 5.3) and 2.1 beats per minute (95% CI: 0.3, 3.8), respectively. Male sex and maternal levothyroxine medication were negatively associated with the mean and maximum heart rate. None of the newborns had a cardiac cause for low heart rate. CONCLUSION: Among term newborns with bradycardias, younger age, male sex and maternal levothyroxine medication were associated with a lower heart rate on Holter monitoring. Given the age-related increase in heart rate, the 80 beats per minute limit as a universal threshold for abnormal heart rate in newborns appears inappropriate.

Recessive TMOD1 mutation causes childhood cardiomyopathy.

Familial cardiomyopathy in pediatric stages is a poorly understood presentation of heart disease in children that is attributed to pathogenic mutations. Through exome sequencing, we report a homozygous variant in tropomodulin 1 (TMOD1; c.565C>T, p.R189W) in three individuals from two unrelated families with childhood-onset dilated and restrictive cardiomyopathy. To decipher the mechanism of pathogenicity of the R189W mutation in TMOD1, we utilized a wide array of methods, including protein analyses, biochemistry and cultured cardiomyocytes. Structural modeling revealed potential defects in the local folding of TMOD1R189W and its affinity for actin. Cardiomyocytes expressing GFP-TMOD1R189W demonstrated longer thin filaments than GFP-TMOD1wt-expressing cells, resulting in compromised filament length regulation. Furthermore, TMOD1R189W showed weakened activity in capping actin filament pointed ends, providing direct evidence for the variant's effect on actin filament length regulation. Our data indicate that the p.R189W variant in TMOD1 has altered biochemical properties and reveals a unique mechanism for childhood-onset cardiomyopathy.

Younger postnatal age is associated with a lower heart rate on Holter monitoring during the first week of life.

To evaluate heart rate (HR), the presence of extrasystoles and other Holter findings among healthy newborns, and to collect data for new normal limits for Holter parameters in newborns. For this cross-sectional study, 70 healthy term newborns were recruited to undergo 24-h Holter monitoring. Linear regression analysis was used in HR analyses. The age-specific limits for HRs were calculated using linear regression analysis coefficients and residuals. The mean (SD) age of the infants was 6.4 (1.7) days during the recording. Each consecutive day of age raised the minimum and mean HR by 3.8 beats per minute (bpm) (95% CI: 2.4, 5.2; P < .001) and 4.0 bpm (95% CI: 2.8, 5.2; P < .001), respectively. Age did not correlate with maximum HR. The lowest calculated limit for minimum HR ranged from 56 bpm (aged 3 days) to 78 bpm (aged 9 days). A small number of atrial extrasystoles and ventricular extrasystoles were observed in 54 (77%) and 28 (40%) recordings, respectively. Short supraventricular or ventricular tachycardias were found in 6 newborns (9%). CONCLUSION:  The present study shows an increase of 20 bpm in both the minimum and mean HRs of healthy term newborns between the 3rd and 9th days of life. Daily reference values for HR could be adopted in the interpretation of HR monitoring results in newborns. A small number of extrasystoles are common in healthy newborns, and isolated short tachycardias may be normal in this age group. WHAT IS KNOWN: • The current definition of bradycardia in newborns is 80 beats per minute. • This definition does not fit into the modern clinical setting of continuously monitored newborns, where benign bradycardias are commonly observed. WHAT IS NEW: • A linear and clinically significant increase in heart rate was observed in infants between the ages of 3 and 9 days. • It appears as though lower normal limits for heart rate could be applied to the youngest newborns.

Extrasystoles or short bradycardias of the newborn seldom require subsequent 24-hour electrocardiographic monitoring.

AIM: To retrospectively assess the indications for and findings on 24-hour electrocardiographic (Holter) monitoring in newborns, focussing on bradycardias and extrasystoles. METHODS: Data included 337 term-born infants. Holter indications were categorised into bradycardias below 80 beats per minute, extrasystoles, any tachycardia and other. Heart rate below 60 beats per minute, pathological atrioventricular conduction, supraventricular or ventricular tachycardia, or either atrial premature contractions over 10% or ventricular premature contractions over 5% of total beats were defined as significant arrhythmia on Holter. RESULTS: The median age was 6 days (range: 2-62 days). Bradycardia (42%) or extrasystoles (32%) were the most common Holter indications. Fifty-three infants (16%) had significant arrhythmia on Holter. Heart disease or 12-lead electrocardiogram expressing extrasystoles or conduction abnormalities were associated with significant arrhythmias (p = 0.046 and p < 0.001, respectively). Twenty-seven of 109 infants (25%) with extrasystoles as a Holter indication had abnormal Holter results, but only seven (6.4%) had significant arrhythmia on Holter if the 12-lead electrocardiogram was normal. No pathology was found behind bradycardias below 80 beats per minute in the absence of heart disease. CONCLUSION: Among term newborns with extrasystoles or bradycardias, Holter monitoring could be targeted to infants with heart disease or abnormal electrocardiograms.

Cardiac Function After Cardiotoxic Treatments for Childhood Cancer-Left Ventricular Longitudinal Strain in Screening.

Background: The majority of childhood cancer survivors (CCSs) have been exposed to cardiotoxic treatments and often present with modifiable cardiovascular risk factors. Our aim was to evaluate the value of left ventricular (LV) longitudinal strain for increasing the sensitivity of cardiac dysfunction detection among CCSs. Methods: We combined two national cohorts: neuroblastoma and other childhood cancer survivors treated with anthracyclines. The final data consisted of 90 long-term CCSs exposed to anthracyclines and/or high-dose chemotherapy with autologous stem cell rescue and followed up for > 5 years and their controls (n = 86). LV longitudinal strain was assessed with speckle tracking (Qlab) and LV ejection fraction (EF) by three-dimensional echocardiography (3DE). Results: Of the CCSs, 11% (10/90) had abnormal LV longitudinal strain (i.e., < -17.5%); of those, 70% (7/10) had normal 3DE LV EF. Multivariable linear model analysis demonstrated that follow-up time (p = 0.027), sex (p = 0.020), and BMI (p = 0.002) were significantly associated with LV longitudinal strain. Conversely, cardiac risk group, hypertension, age, cumulative anthracycline dose or exposure to chest radiation were not. Conclusion: LV longitudinal strain is a more sensitive method than LV EF for the detection of cardiac dysfunction among CCSs. Therefore, LV longitudinal strain should be added to the screening panel, especially for those with modifiable cardiovascular risk factors.

Levosimendan Versus Milrinone for Inotropic Support in Pediatric Cardiac Surgery: Results From a Randomized Trial.

OBJECTIVE: The present study aimed to determine the differential effects of intraoperative administration of milrinone versus levosimendan on myocardial function after pediatric cardiac surgery. Transthoracic echocardiography was used for myocardial function evaluation using biventricular longitudinal strain with 2-dimensional speckle tracking echocardiography in addition to conventional echocardiographic variables. DESIGN: A secondary analysis of a randomized, prospective, double-blinded clinical drug trial. SETTING: Two pediatric tertiary university hospitals. PARTICIPANTS: Infants between 1 and 12 months old diagnosed with ventricular septal defect, complete atrioventricular septal defect, or tetralogy of Fallot who were scheduled for corrective surgery with cardiopulmonary bypass. INTERVENTIONS: The patients were randomly assigned to receive an infusion of milrinone or levosimendan at the start of cardiopulmonary bypass and for 26 consecutive hours. MEASUREMENTS AND MAIN RESULTS: Biventricular longitudinal strain and conventional echocardiographic variables were measured preoperatively, on the first postoperative morning, and before hospital discharge. The association between perioperative parameters and postoperative myocardial function also was investigated. Images were analyzed for left ventricular (n = 67) and right ventricular (n = 44) function. The day after surgery, left ventricular longitudinal strain deteriorated in both the milrinone and levosimendan groups (33% and 39%, respectively). The difference was not significant. The corresponding deterioration in right ventricular longitudinal strain was 42% and 50% (nonsignificant difference). For both groups, biventricular longitudinal strain approached preoperative values at hospital discharge. Preoperative N-terminal pro-brain natriuretic peptide could predict the left ventricular strain on postoperative day 1 (p = 0.014). CONCLUSIONS: Levosimendan was comparable with milrinone for left and right ventricular inotropic support in pediatric cardiac surgery.

Biomarkers to diagnose ventricular dysfunction in childhood cancer survivors: a systematic review.

OBJECTIVE: To systematically review the literature and assess the diagnostic value of biomarkers in detection of late-onset left ventricular (LV) dysfunction in childhood cancer survivors (CCS) treated with anthracyclines. METHODS: We systematically searched the literature for studies that evaluated the use of biomarkers for detection of LV dysfunction in CCS treated with anthracyclines more than 1 year since childhood cancer diagnosis. LV dysfunction definitions were accepted as an ejection fraction <50% or <55% and/or a fractional shortening <28%, <29% or <30%. Contingency tables were created to assess diagnostic accuracies of biomarkers for diagnosing LV dysfunction. RESULTS: Of 1362 original studies screened, eight heterogeneous studies evaluating four different biomarkers in mostly asymptomatic CCS were included. In four studies, an abnormal N-terminal pro-B-type natriuretic peptide (NT-proBNP, cut-off range 63-125 ng/L) had low sensitivity (maximally 22%) and a specificity of up to 97% for detection of LV dysfunction. For troponin levels, in five studies one patient had an abnormal troponin value as well as LV dysfunction, while in total 127 patients had LV dysfunction without troponin elevations above cut-off values (lowest 0.01 ng/mL). Two studies that evaluated brain natriuretic peptide and nitric oxide were underpowered to draw conclusions. CONCLUSIONS: In individual studies, the diagnostic value of NT-proBNP for detection of LV dysfunction in CCS is limited. Troponins have no role in detecting late-onset LV dysfunction with cut-off values as low as 0.01 ng/mL. Further study on optimal NT-proBNP cut-off values for rule out or rule in of LV dysfunction is warranted.

Speckle tracking echocardiography detects decreased cardiac longitudinal function in anthracycline-exposed survivors of childhood cancer.

UNLABELLED: Longitudinal motion significantly contributes to the contraction of the ventricles. We studied the left (LV) and right ventricular (RV) longitudinal functions in 75 anthracycline-exposed, long-term childhood cancer survivors and 75 healthy controls with conventional echocardiography, tissue Doppler imaging (TDI), speckle tracking echocardiography (STE) of the mitral and tricuspid annular motion, and real-time three-dimensional echocardiography (RT-3DE). Cardiac magnetic resonance (CMR) imaging was performed on 61 of the survivors. The survivors had lower systolic myocardial velocities in the LV and lower diastolic velocities in both ventricles by TDI than did their healthy peers. The STE-based tissue motion annular displacement (TMAD) values describing the LV and RV systolic longitudinal function (MAD and TAD mid%, respectively) were also lower among the survivors (15.4 ± 2.4 vs. 16.1 ± 2.2 %, p = 0.049 and 22.5 ± 3.0 vs. 23.5 ± 3.0 %, p = 0.035). MAD and TAD mid in millimeters correlated with the respective ventricular volumes measured with RT-3DE or CMR. CONCLUSION: Childhood cancer survivors exposed to low to moderate anthracycline doses had decreased longitudinal systolic and diastolic functions (TDI or STE) compared with healthy controls. The STE-based TMAD is a fast and reproducible method to assess cardiac longitudinal function. What is Known? • High anthracycline doses cause LV dysfunction as evidenced by a decreased ejection fraction. What is new? • Low to moderate anthracycline doses also have a negative impact on the LV and RV longitudinal systolic and diastolic function. • TMAD is a new and fast method to assess the cardiac longitudinal function after anthracycline exposure.

Cardiac biomarkers indicate a need for sensitive cardiac imaging among long-term childhood cancer survivors exposed to anthracyclines.

AIM: The role that plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) and cardiac troponins T (cTnT) and I (cTnI) play in supplementing imaging to screen for cardiac late effects remains controversial and the impact of high-sensitivity cTnT and troponin-specific autoantibodies (cTnAAbs) remains unexplored. We studied the role of cardiac biomarkers as indicators of the late effects of anthracyclines among childhood cancer survivors. METHODS: We measured NT-proBNP, cTnT, high-sensitivity cTnT, cTnI and cTnAAbs in 76 childhood cancer survivors at a median of 9 years after primary diagnosis. The survivors underwent conventional and real-time three-dimensional echocardiography and 62 underwent cardiac magnetic resonance imaging (MRI). RESULTS: Of the survivors, four (5.3%) without risk factors for cardiotoxicity were cTnAAb-positive with an impaired cardiac function in MRI. Another four (5.3%) had an abnormal NT-proBNP level associated with an abnormal cardiac function and risk factors for cardiotoxicity. None showed measurable cardiac troponins, determined by the three different methods, with even the high-sensitivity cTnT-levels remaining normal. CONCLUSION: Elevated plasma NT-proBNP or cTnAAbs indicated that childhood cancer survivors benefitted from being evaluated with modern imaging, despite normal function in conventional echocardiography. However, troponins did not seem to provide additional information on the late cardiotoxicity of anthracyclines.

Three-dimensional echocardiography and cardiac magnetic resonance imaging in the screening of long-term survivors of childhood cancer after cardiotoxic therapy.

The left ventricular (LV) volumes, ejection fraction (EF), and dyssynchrony indexes for the 16 and 12 cardiac segments (Tmsv16-SD and Tmsv12-SD, respectively) were analyzed among nonadult, anthracycline-exposed long-term survivors of childhood cancer and compared with those of healthy controls using conventional and real-time 3-dimensional echocardiography (RT-3DE) with cardiac magnetic resonance (CMR) imaging in a prospective, cross-sectional, single tertiary center setting. Seventy-one survivors and gender-, body surface area-, and age-matched healthy controls were studied by conventional echocardiography and RT-3DE. Fifty-eight of the 71 survivors underwent also CMR. The survivors were evaluated in 2 groups. Group I consisted of 63 exposed to anthracyclines and group II consisted of 8 also exposed to cardiac irradiation. By RT-3DE, the group I survivors had a lower LVEF (57% vs 60%, respectively, p = 0.003) and larger body surface area-indexed LV end-systolic volume (31 vs 28 ml/m(2), respectively, p = 0.001) than controls. The Tmsv16-SD was higher in group II than in I (1.93% vs 1.39%, respectively, p = 0.003). None of the survivors had an abnormal fractional shortening (<28%), but 10% had an LVEF <50% by RT-3DE. An LVEF <55% was detected in 45 of 58 (78%) of those imaged with CMR. In conclusion, RT-3DE seems to detect more abnormalities in cardiac function than conventional echocardiography following childhood cancer therapy. The LV dyssynchrony indexes derived from RT-3DE appear potentially useful in assessing the early signs of cardiotoxicity between anthracycline and cardiac irradiation exposed long-term survivors of childhood cancer.

Cardiac magnetic resonance imaging in the evaluation of the late effects of anthracyclines among long-term survivors of childhood cancer.

OBJECTIVES: This study sought to examine the left ventricular (LV) and right ventricular (RV) function and signs of focal fibrosis among long-term survivors of childhood cancer with the use of cardiac magnetic resonance (CMR) imaging. BACKGROUND: Increased myocardial fibrosis has been detected in the endomyocardial biopsies of survivors. CMR has established its role in the assessment of both cardiac function and structure, and focal fibrosis of the myocardium is detectable with late gadolinium enhancement (LGE). METHODS: Sixty-two anthracycline-exposed long-term survivors of childhood cancer were studied at a mean age of 14.6 years. The LV and RV ejection fractions (EFs) and volumes were measured, and LGE was assessed using CMR. RESULTS: An abnormal LV function (EF <45%) was detected in 18% (11 of 62) of the survivors, and an abnormal RV function was detected in 27% (17 of 62) of the survivors. Subnormal (45% ≤ EF <55%) LV function were demonstrated in 61% (38 of 62) and subnormal RV function in 53% (33 of 62) of the survivors, respectively. Both the LV and RV end-systolic and LV end-diastolic volumes were increased compared with reference values. None of the study patients showed LGE. CONCLUSIONS: A considerable proportion of the long-term survivors of childhood cancer with anthracycline exposure demonstrate signs of cardiac dysfunction detectable by CMR, with the RV also being involved. Yet, myocardial fibrosis does not seem to be detectable at a median of 7.8 years after anthracycline therapy.

Bilateral absence of the superior vena cava.

Bilateral absence of the superior vena cava (SVC) is a very rarely detected, mainly asymptomatic congenital vascular anomaly. Though usually innocent, this anomaly may complicate cardiothoracic surgery and certain procedures like central venous catheter insertion. This SVC anomaly is poorly known, and we assume that its incidence in the general population may be higher than detected. In this paper, we summarize current knowledge on this anomaly and its clinical implications. In addition, we present a neonatal case with bilateral absence of the SVC associated with a fetal cystic hygroma. Conclusion. Totally absent SVC can cause unexpected problems during cardiothoracic surgery. Suspicion of SVC absence should arise in basic echocardiography. Our paper suggests that, like other congenital anomalies, bilateral absent SVC may be associated with a fetal cyctic hygroma.

Catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder that causes syncopal episodes related with stress or emotion and even sudden cardiac deaths. Signs and symptoms usually begin in childhood. A suspicion of CPVT should be kept in mind when a child or an adolescent suddenly loses consciousness, particularly if this happens upon physical exercise or sudden mental stress. During the past decade, the knowledge of CPVT genetics and physiology has increased. Exercise testing is essential when suspecting arrhythmogenic origin of syncope, and in the case of CPVT, it may be even more sensitive than Holter monitoring. Beta-antiadrenergic medication can substantially decrease the mortality associated with CPVT. Asymptomatic patients with known CPVT gene defects should also be treated because sudden cardiac death may be the first manifestation of the disease. An implantable cardioverter-defibrillator may also be required in the most severe CPVT cases. In this review, we summarise the current knowledge on the clinical characteristics, diagnostic, genetic and prognostic features of CPVT in children. In all, 133 publications covering 60 years were checked, and those written in English and containing ten or more, mainly paediatric CPVT cases, were included. In addition, a CPVT family with three members and delayed diagnoses until late childhood and adulthood is presented.