Phenotypic expression, genotypic profiling and clinical outcomes of infantile hypertrophic cardiomyopathy: a retrospective study.

BACKGROUND: Infantile hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder. Apart from registries in high-income nations, there is a shortage of data on the aetiological basis of infantile HCM in low- and middle-income nations. This study attempts to characterise the phenotypic expression, genetic architecture and short-term clinical outcomes of infantile HCM from a South Asian tertiary referral centre. METHODS: This study includes all infants from the Amrita HCM cohort between January 2011 and July 2021. Clinical history, ECG, echocardiographic data, and genetic analyses were evaluated. RESULTS: 34 patients with infantile HCM were diagnosed at a median age of 3.7 months (IQR 1-6 months). Underlying aetiologies were RASopathy (n=13; 38%), non-syndromic (n=12; 35%) and inborn errors of metabolism (n=9; 27%). Genetic analysis was done in 20 patients (59%) with a yield of 90%. Clinical presentation included failure to thrive (n=29; 85%), dyspnoea on exertion (n=23; 68%) and clinical heart failure (n=24; 71%). Echo showed concentric left ventricular hypertrophy in 22 patients (65%), obstructive HCM in 11 patients (32%) and left ventricular systolic dysfunction in 6 patients (18%). The mortality rate was 10.0 deaths per 100 patient years over a median follow-up period of 3.1 years. The main risk markers for mortality were the age at diagnosis, gender and concentric Left ventricular hypertrophy. CONCLUSIONS: This cohort demonstrates the morphological, functional and genetical heterogeneity of infantile HCM, enunciating the need for integration of cardiology, metabolic and genetic services to achieve optimum outcomes in these patients.

BMPR2 mutation and clinical response to imatinib in a case of heritable pulmonary arterial hypertension.

Bone morphogenetic protein receptor 2 (BMPR2) mutation is the most common gene mutation implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We describe, for the first time, an excellent clinical response to tyrosine kinase inhibitor imatinib in a patient with heritable PAH from BMPR2 mutation.

Comparison of intravenous sildenafil with inhaled nitric oxide for acute vasodilator testing in pulmonary arterial hypertension.

Acute vasodilator testing (AVT) identifies acute responders for initiation of calcium channel blockers in pulmonary arterial hypertension (PAH) and operability in congenital heart disease (CHD). We sought to determine the feasibility of intravenous sildenafil (ivS) as an alternative to inhaled nitric oxide (iNO) in AVT. All patients with PAH undergoing cardiac catheterization for AVT (November 2015 to December 2020) were prospectively enrolled. Hemodynamic data were obtained at baseline, with iNO 20 ppm and ivS (0.25 mg/kg for children and 10 mg for adults). We studied 44 patients with a mean age of 20.5 ± 14.4 years (27 [61%] females and 20 [45%] children). There were 17 (38.6%) patients in the CHD group for operability assessment and 27 patients in non-CHD group (idiopathic pulmonary arterial hypertension-16 [36.3%], residual PAH after shunt closure-7 [15.9%], and 2 cases [4.5%] each of familial PAH and portopulmonary hypertension). There was an excellent intraclass correlation for mean pulmonary artery pressures (0.903, 95% confidence interval, CI: 0.809-0.949, p < 0.001), mean aortic pressures (0.745, 95% CI: 0.552-0.858, p < 0.001), pulmonary vascular resistance index (0.920, 95% CI: 0.858-0.956, p < 0.001), systemic vascular resistance (SVR) index (0.828, 95% CI: 0.706-0.902, p < 0.001), and the ratio of pulmonary and SVR indices (0.857, 95% CI: 0.752-0.919, p < 0.001) between the two agents. There were two responders, both in non-CHD group, and were identified by iNO and ivS. The hemodynamic effects of ivS show excellent correlation with iNO and could be a potential alternative agent for identifying acute responders during AVT.

Pregnancy and pulmonary arterial hypertension-improving surveillance and outcomes with multidisciplinary care and N terminal pro-brain natriuretic peptide trends.

OBJECTIVE: To describe maternal and fetal outcomes and N Terminal pro-brain natriuretic peptide (NT-proBNP) trends in pregnancy with pulmonary arterial hypertension (PAH). METHODS: The medical records of all pregnant women with PAH referred to Pulmonary Hypertension Clinic were retrospectively reviewed and analyzed. RESULTS: We identified 35 pregnancies in 22 women (mean age 27.9 ± 4.7 years, mean weight 50.6 ± 8.1 kg). The diagnoses were Eisenmenger syndrome (16, 72.7%), postoperative residual PAH (3, 13.6%), idiopathic PAH (2, 9.1%), and one (4.5%) had systemic lupus erythematosus. About 23 babies (65.7%) were born alive, gestational age of 35.1 ± 2.9 weeks, 47.8% at term, with a birth weight of 2.1 ± 0.8 kg. There was an elevation of NT-proBNP in the initial 72 h postdelivery (median 138 pg/ml, IQR 112-561). Those with a persistent rise beyond 72 h (median 686 pg/ml, IQR 370-3691) had prolonged recovery postpartum (median postdelivery hospital stay 18 days, IQR 12-22) reflecting continued right ventricular stress and maladaptation. There was single maternal mortality (4.5%). CONCLUSIONS: Maternal and fetal outcomes of pregnancy associated with PAH are better with strict surveillance and multidisciplinary team effort. Postpartum period remains the most vulnerable time. NT-proBNP trends during this period may be a promising objective monitoring tool in identifying at-risk subsets thus improving outcomes.

Should not we be using aspirin in patients with a ventriculoatrial shunt? Borrowing a leaf from other specialities: a case for surrogate evidence.

INTRODUCTION: Ventriculoatrial (VA) shunts are life-saving in circumstances where ventriculoperitoneal shunts (VP) have failed. They are at risk for different complications, and more specific of them are cardiopulmonary complications. Currently, there are no standard recommendations concerning screening for risk factors, prophylaxis, or anticoagulation treatment in patients after VA shunt placement. Our study aims to prospectively study the possible role and efficacy of the use of aspirin to increase the survival of shunts in children with VA shunt and avoid secondary morbidity. In this article, the authors describe the interim results of an ongoing prospective study which supports the use of aspirin for VA shunt. MATERIALS AND METHODS: The study design is prospective. The duration of the study is 2011 onwards and is ongoing. Hospital ethics board clearance and consent from the family were taken before inclusion in the study. All patients who had VA shunt were given a once-a-day low-antiplatelet dose of aspirin 5 mg/kg, from the first postoperative day onwards. Primary endpoints of the study are as follows: (1) major distal end malfunction documented on echocardiography or (2) any cardiac complications associated with the VA shunt catheter. RESULTS: We have 6 patient since march 2011, who are being followed up. None of the shunts had malfunctioned until the reporting. None of the patients had any cardiac issues reported. The patients are to be followed continually. The present follow-up ranges from 2.5 to 10 years. The patient follow-up is being continued. CONCLUSIONS: Aspirin is a drug with well-accepted safety profile, and its use and our preliminary observation and outcome of the use of aspirin in VA shunt are promising.

Active right atrial emptying fraction predicts reduced survival and increased adverse events in childhood pulmonary arterial hypertension.

BACKGROUND: Right atrial (RA) function has been studied rarely in childhood pulmonary arterial hypertension (PAH). We sought to determine if RA and right ventricular (RV) area changes measured by echocardiography predicted outcomes. METHODS: We reviewed data from children with PAH undergoing cardiac catheterization and echocardiography. RA and RV areas were obtained from the apical 4-chamber view. Clinical worsening indicated initiation of parenteral prostanoid therapy, heart and/or lung transplantation, Potts shunt surgery or death. RESULTS: We studied 57 children (27 females), median age 3 years (range 0.30-17 years), body surface area 0.56 m2 (0.2-1.8), follow up 3 years (0.21-8.35), time to clinical worsening was 1.14 years (0.03-6.14) and mortality was 1.55 years (range 0.88-4.95). We determined from receiver operator curves that RA active emptying fraction (RA EaF) ≥60% predicted clinical worsening (sensitivity 78%, specificity 69%, AUC 0.7) and mortality (sensitivity 100%, specificity 65%, AUC 0.82). RV fractional area change (RVFAC) <25% predicted clinical worsening (sensitivity 72%, specificity 79%, AUC 0.85) and death (sensitivity 67%, specificity 69%, AUC 0.77). The combination of RA EaF ≥60% and RVFAC <33% were best predictors of clinical worsening (sensitivity 72%, specificity 82%, partial AUC 0.65) and mortality (sensitivity 100%, specificity 77%, partial AUC 0.75). CONCLUSION: In childhood PAH, RA EaF ≥ 60% and RVFAC <25% were associated with poor outcomes. RA EaF ≥60% and RVFAC <33% were best predictors of clinical worsening and may be useful markers in children with PAH who require closer observation and more intensive therapy.

Hyperoxia Reduces Oxygen Consumption in Children with Pulmonary Hypertension.

High inspired oxygen concentration (FiO2 > 0.85) is administered to test pulmonary vascular reactivity in children with pulmonary hypertension (PH). It is difficult to measure oxygen consumption (VO2) if the subject is breathing a hyperoxic gas mixture so the assumption is made that baseline VO2 does not change. We hypothesized that hyperoxia changes VO2. We sought to compare the VO2 measured by a thermodilution catheter in room air and hyperoxia. A retrospective review of the hemodynamic data obtained in children with PH who underwent cardiac catheterization was conducted between 2009 and 2014. Cardiac index (CI) was measured by a thermodilution catheter in room air and hyperoxia. VO2 was calculated using the equation CI = VO2/arterial-venous oxygen content difference. Data were available in 24 subjects (males = 10), with median age 8.3 years (0.8-17.6 years), weight 23.3 kg (7.5-95 kg), and body surface area 0.9 m2 (0.4-2.0 m2). In hyperoxia compared with room air, we measured decreased VO2 (154 ± 38 to 136 ± 34 ml/min/m2, p = 0.007), heart rate (91 [Formula: see text] 20 to 83 [Formula: see text] 21 beats/minute, p=0.005), mean pulmonary artery pressure (41 [Formula: see text] 16 to 35 [Formula: see text] 14 mmHg, p=0.024), CI (3.6 [Formula: see text] 0.8 to 3.3 [Formula: see text] 0.9 L/min/m2, p = 0.03), pulmonary vascular resistance (9 [Formula: see text] 6 to 7 [Formula: see text] 3 WU m2, p = 0.029), increased mean aortic (61 [Formula: see text] 11 to 67 [Formula: see text] 11 mmHg, p = 0.005), pulmonary artery wedge pressures (11 [Formula: see text] 8 to 13 [Formula: see text] 9 mmHg, p = 0.006), and systemic vascular resistance (12 [Formula: see text] 6 to 20 [Formula: see text] 7 WU m2, p=0.001). Hyperoxia decreased VO2 and CI and caused pulmonary vasodilation and systemic vasoconstriction in children with PH. The assumption that VO2 remains unchanged in hyperoxia may be incorrect and, if the Fick equation is used, may lead to an overestimation of pulmonary blood flow and underestimation of PVRI.

Acoustic diagnosis of pulmonary hypertension: automated speech- recognition-inspired classification algorithm outperforms physicians.

We hypothesized that an automated speech- recognition-inspired classification algorithm could differentiate between the heart sounds in subjects with and without pulmonary hypertension (PH) and outperform physicians. Heart sounds, electrocardiograms, and mean pulmonary artery pressures (mPAp) were recorded simultaneously. Heart sound recordings were digitized to train and test speech-recognition-inspired classification algorithms. We used mel-frequency cepstral coefficients to extract features from the heart sounds. Gaussian-mixture models classified the features as PH (mPAp ≥ 25 mmHg) or normal (mPAp < 25 mmHg). Physicians blinded to patient data listened to the same heart sound recordings and attempted a diagnosis. We studied 164 subjects: 86 with mPAp ≥ 25 mmHg (mPAp 41 ± 12 mmHg) and 78 with mPAp < 25 mmHg (mPAp 17 ± 5 mmHg) (p < 0.005). The correct diagnostic rate of the automated speech-recognition-inspired algorithm was 74% compared to 56% by physicians (p = 0.005). The false positive rate for the algorithm was 34% versus 50% (p = 0.04) for clinicians. The false negative rate for the algorithm was 23% and 68% (p = 0.0002) for physicians. We developed an automated speech-recognition-inspired classification algorithm for the acoustic diagnosis of PH that outperforms physicians that could be used to screen for PH and encourage earlier specialist referral.

Measurement of Oxygen Consumption in Critically Ill Children: Breath-by-Breath Method vs Mass Spectrometry.

BACKGROUND: Measurement of oxygen consumption (Vȯ2) is difficult in children but is essential to calculate cardiac index and systemic vascular resistance. OBJECTIVE: To compare measurements of Vȯ2 using respiratory mass spec trometry and the breath-by-breath method. METHODS: Vȯ2 was measured simultaneously and continuously for 10 minutes by using respiratory mass spectrometry and the breath-by-breath method in children receiving mechanical ventilation via cuffed endotracheal tubes. RESULTS: Sixteen children (7 boys; median [range]: age, 1.5 [0.2-6] years; weight, 11.5 [2.8-23.5] kg; body surface area, 0.55 [0.18-0.98] m(2)) were studied. The correlation between measurements of Vȯ2 by the 2 methods was good (R = 0.924). Mean Vȯ2 measured by mass spectrometry was 63 (95% CI, 47-78) mL/min vs 65 (95% CI, 47-83) mL/min measured by the breath-by-breath method. The mean Vȯ2 difference between the 2 methods was 3 (95% CI, -9 to 5) mL/min and statistically insignificant. Bland-Altman analysis showed that the 95% limits of agreement were between -28 and +23. Cardiac index did not differ significantly when calculated using Vȯ2 measured with one method or the other (mean difference, 0.1; 95% CI, -0.2 to 0.3). CONCLUSIONS: Measurements of Vȯ2 did not differ between mass spectrometry and the breath-by-breath method. Use of the breath-by-breath method may facilitate calculation of cardiac index and systemic vascular resistance in critically ill children.

The unique heart sound signature of children with pulmonary artery hypertension.

We hypothesized that vibrations created by the pulmonary circulation would create sound like the vocal cords during speech and that subjects with pulmonary artery hypertension (PAH) might have a unique sound signature. We recorded heart sounds at the cardiac apex and the second left intercostal space (2LICS), using a digital stethoscope, from 27 subjects (12 males) with a median age of 7 years (range: 3 months-19 years) undergoing simultaneous cardiac catheterization. Thirteen subjects had mean pulmonary artery pressure (mPAp) < 25 mmHg (range: 8-24 mmHg). Fourteen subjects had mPAp ≥ 25 mmHg (range: 25-97 mmHg). We extracted the relative power of the frequency band, the entropy, and the energy of the sinusoid formants from the heart sounds. We applied linear discriminant analysis with leave-one-out cross validation to differentiate children with and without PAH. The significance of the results was determined with a t test and a rank-sum test. The entropy of the first sinusoid formant contained within an optimized window length of 2 seconds of the heart sounds recorded at the 2LICS was significantly lower in subjects with mPAp ≥ 25 mmHg relative to subjects with mPAp < 25 mmHg, with a sensitivity of 93% and specificity of 92%. The reduced entropy of the first sinusoid formant of the heart sounds in children with PAH suggests the existence of an organized pattern. The analysis of this pattern revealed a unique sound signature, which could be applied to a noninvasive method to diagnose PAH.

Detection of Heart Sounds in Children with and without Pulmonary Arterial Hypertension--Daubechies Wavelets Approach.

BACKGROUND: Automatic detection of the 1st (S1) and 2nd (S2) heart sounds is difficult, and existing algorithms are imprecise. We sought to develop a wavelet-based algorithm for the detection of S1 and S2 in children with and without pulmonary arterial hypertension (PAH). METHOD: Heart sounds were recorded at the second left intercostal space and the cardiac apex with a digital stethoscope simultaneously with pulmonary arterial pressure (PAP). We developed a Daubechies wavelet algorithm for the automatic detection of S1 and S2 using the wavelet coefficient 'D6' based on power spectral analysis. We compared our algorithm with four other Daubechies wavelet-based algorithms published by Liang, Kumar, Wang, and Zhong. We annotated S1 and S2 from an audiovisual examination of the phonocardiographic tracing by two trained cardiologists and the observation that in all subjects systole was shorter than diastole. RESULTS: We studied 22 subjects (9 males and 13 females, median age 6 years, range 0.25-19). Eleven subjects had a mean PAP < 25 mmHg. Eleven subjects had PAH with a mean PAP ≥ 25 mmHg. All subjects had a pulmonary artery wedge pressure ≤ 15 mmHg. The sensitivity (SE) and positive predictivity (+P) of our algorithm were 70% and 68%, respectively. In comparison, the SE and +P of Liang were 59% and 42%, Kumar 19% and 12%, Wang 50% and 45%, and Zhong 43% and 53%, respectively. Our algorithm demonstrated robustness and outperformed the other methods up to a signal-to-noise ratio (SNR) of 10 dB. For all algorithms, detection errors arose from low-amplitude peaks, fast heart rates, low signal-to-noise ratio, and fixed thresholds. CONCLUSION: Our algorithm for the detection of S1 and S2 improves the performance of existing Daubechies-based algorithms and justifies the use of the wavelet coefficient 'D6' through power spectral analysis. Also, the robustness despite ambient noise may improve real world clinical performance.

Palliative stenting of patent ductus arteriosus in older children and young adults with congenital cyanotic heart disease.

OBJECTIVE: To describe the indications, technique and results (early and short-term follow-up) of palliative patent ductus arteriosus (PDA) stenting in selected patients (2 years and older) with congenital cyanotic heart disease with reduced pulmonary blood flow who were not candidates for definitive surgery in the immediate future. BACKGROUND: Stenting of PDA as a palliation has been advocated as safe and effective procedure in neonates, but this modality is underutilized for children and adults. METHODS: Hospital records of patients (≥2 years) undergoing PDA stenting between January 2007 and September 2009 were reviewed. The access and approach was dictated by the anatomy of the PDA. A coronary guiding catheter or a long sheath was used to access the PDA. Coronary or peripheral stents were used for stenting. RESULTS: Fifteen patients with median age 14 years (range: 2-18 years); median weight 17.5 kg (range: 7-57 Kg) were included. Indication for intervention was hypoxia (mean saturation 69% ± 8.9%, hemoglobin 19.8 ± 2.69 g/dl), unsuitable anatomy or economic considerations. Successful stenting was accomplished in all (mean fluoroscopy time of 24.6 ± 16.7 min) with no complications and the saturations improved to mean of 88% ± 2.3 %. The most recent oxygen saturations on follow-up (median: 13 months; range: 1-21 months) were 82% ± 2.8%. One patient underwent corrective repair. CONCLUSION: PDA stenting can provide effective palliation in selected older patients with cyanotic congenital heart disease.

Conotruncal anomalies in the fetus: Referral patterns and pregnancy outcomes in a dedicated fetal cardiology unit in South India.

OBJECTIVE: To describe the referral patterns and pregnancy outcomes of fetuses with conotruncal anomalies (CTA) from a fetal cardiology unit in South India. METHODS: Records of 68 women identified to have diagnosis of CTA on fetal echocardiography (mean gestational age 26.8 ± 5.9 weeks; range 17-38 weeks) during the period 2008-2011 were reviewed. RESULTS: The most common indication for referral was suspected congenital heart disease during routine antenatal scan (89.7%). The various CTA diagnosed included Tetralogy of Fallot (TOF, 44.1%), Double outlet right ventricle (DORV, 27.9%), Transposition of great vessels (TGA, 8.8%), TOF with pulmonary atresia (TOF-PA, 8.8%), TOF absent pulmonary valve (TOF-APV, 7.4%) and truncus arteriosus (TA, 2.9%). Extra cardiac anomalies were reported in 4 fetuses (7.1%). Pregnancy outcomes included pregnancies not culminating in live-birth (54.4%), delivery at term (41.2%) with 3 patients (4.4%) being lost to follow-up. Proportion of pregnancies not culminating in live-birth lesion wise include: TOF (53.3%), DORV (52.6%), TGA (50%), TOF -APV (80%), TOF-PA (50%), and TA (50%). Twenty-four babies (35.3%) received post-natal cardiac care with 5 (7.4%) undergoing neonatal surgical procedures. Seven babies (10.3%) died in neonatal period, including 2 who underwent surgery. The accuracy of fetal echo was 96.4% for primary lesion and 67.9% for complete segmental diagnosis. CONCLUSIONS: Pre-natal diagnosis of CTA, despite a high diagnostic accuracy, prompted utilization of post-natal tertiary cardiac care in a limited proportion of patients, including those with reparable lesions. Focus in developing countries should shift towards earlier referral, improving awareness about treatment options and a comprehensive evaluation for associated anomalies.

Elevated red cell distribution width is associated with delayed postoperative recovery after correction of Tetralogy of Fallot.

OBJECTIVE: To study the impact of red cell distribution width (RDW) on postoperative recovery after correction of Tetralogy of Fallot (TOF). BACKGROUND: Increased RDW indicates dysregulated erythropoiesis and predicts survival in critical illnesses that include idiopathic pulmonary artery hypertension and chronic heart failure. Myocardial injury and oxidative stress induced by cardiopulmonary bypass potentially contribute to prolonged recovery in post TOF repair patients. MATERIALS AND METHODS: Retrospective analysis of data on 94 consecutive children with TOF undergoing corrective repair (January 2010-March 2011) was done. RDW was higher for the study population when compared to acyanotic patients with ventricular septal defect (17.7 ± 3.7 vs. 16.2 ± 4.2; P < 0.001). The mean RDW obtained from 100 separate age-, sex-, and weight-matched TOF patients (17.8) was chosen as a cut-off. Of 93 survivors (median age: 12 (4-204) months, weight: 8.6 (3.2-70) kg), 29 patients with higher RDW (> 17.8) had a longer ICU stay (155.6 ± 71.3 vs. 122.4 ± 61.3 hours, P = 0.02), hospital stay (18.6 ± 10.5 days vs. 13.4 ± 6.5 days, P = 0.01), ventilation time (57.9 ± 41.6 vs. 38.3 ± 30.8 hours, P = 0.01), and more surgical site infection (24.1% vs. 6.2%, P = 0.01). On multivariate analysis only elevated RDW (other variables included age, weight, hemoglobin, hematocrit, and surgical support times) showed a significant association with hospital stay. CONCLUSIONS: Elevated RDW appears to be associated with prolonged recovery after TOF repair, the precise underlying mechanisms are worth investigating.