Gautam K. Singh

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions A Scientific Statement From the American Heart Association

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Maturational and growth-related changes in left ventricular longitudinal strain and strain rate measured by two-dimensional speckle tracking echocardiography in healthy pediatric population.

OBJECTIVE We aimed to evaluate myocardial strain and strain rate (SR) by novel 2-dimensional speckle tracking echocardiography in a large pediatric cohort (1) to establish their normal values and (2) to discern the influence of maturation and cardiac growth on them. METHODS Echocardiograms of 284 consecutive subjects of a healthy pediatric cohort aged between birth and 18 years were analyzed by vector velocity imaging software to measure longitudinal systolic strain (epsilon) and systolic and diastolic SR in left ventricular septal and lateral segments. Regression analysis was performed to determine the effect of aging and cardiac growth on epsilon and SR. RESULTS Longitudinal epsilon (septal -18.30% +/- 6.67% and lateral -20.68% +/- 8.08%) did not change significantly with maturation and declining heart rate from birth to 18 years. Systolic and early diastolic SR declined until age 5 to 10 years. Longitudinal epsilon significantly (P < .05) correlated with left ventricular growth. CONCLUSION This study establishes reference values for longitudinal epsilon and SR and reveals that epsilon is relatively independent of maturational changes, lending it as a tool for cardiac evaluation across differing ages in pediatric subjects.

Accuracy and Reproducibility of Strain by Speckle Tracking in Pediatric Subjects with Normal Heart and Single Ventricular Physiology: A Two-Dimensional Speckle-Tracking Echocardiography and Magnetic Resonance Imaging Correlative Study

BACKGROUND Myocardial strain is a sensitive measure of ventricular systolic function. Two-dimensional speckle-tracking echocardiography (2DSE) is an angle-independent method for strain measurement but has not been validated in pediatric subjects. The aim of this study was to evaluate the accuracy and reproducibility of 2DSE-measured strain against reference tagged magnetic resonance imaging-measured strain in pediatric subjects with normal hearts and those with single ventricles (SVs) of left ventricular morphology after the Fontan procedure. METHODS Peak systolic circumferential strain and longitudinal strain (LS) in segments (n = 16) of left ventricles in age-matched and body surface area-matched 20 healthy and 12 pediatric subjects with tricuspid atresia after the Fontan procedure were measured by 2DSE and tagged magnetic resonance imaging. Average (global) and regional segmental strains measured by the two methods were compared using Spearmans and Bland-Altman analyses. RESULTS Global strains measured by 2DSE and tagged magnetic resonance imaging demonstrated close agreements, which were better for LS than circumferential strain and in normal left ventricles than in SVs (95% limits of agreement, +0.0% to +3.12%, -2.48% to +1.08%, -4.6% to +1.8%, and -3.6% to +1.8%, respectively). There was variability in agreement between regional strains, with wider limits in apical than in basal regions in normal left ventricles and heterogeneity in SVs. Strain values were significantly (P < .05) higher in normal left ventricles than in SVs except for basal LS, which were similar in both cohorts. The regional strains in normal left ventricles demonstrated an apicobasal magnitude gradient, whereas SVs showed heterogeneity. Reproducibility was the most robust for images obtained with frame rates between 60 and 90 frames/sec, global LS in both cohorts, and basal strains in normal left ventricles. CONCLUSIONS Strains measured by 2DSE agree with strain measured by magnetic resonance imaging globally but vary regionally, particularly in SVs. Global strain may be a more robust tool for cardiac functional evaluation than regional strain in SV physiology. The reliability of 2DSE-measured strain is affected by the frame rate, the nature of strain, and ventricular geometry.

Right ventricular function and exercise performance late after primary repair of tetralogy of fallot with the transannular patch in infancy

To evaluate the late effects of chronic pulmonary regurgitation against the putative benefits from the current surgical trend of primary repair of tetralogy of Fallot with a transannular patch in infancy, 10 patients > 10 years after early primary repair and 7 matched normal controls underwent exercise stress test and cine magnetic resonance imaging assessment of ventricular functions. Right ventricular impaired diastolic function and decreased exercise capacity, both significantly associated with pulmonary regurgitation in patients, indicated that early primary repair of tetralogy may not prevent late ventricular dysfunction and diminished exercise performance if chronic regurgitation results from right ventricular outflow tract reconstruction.

KATP Channels and Cardiovascular Disease Suddenly a Syndrome

ATP-sensitive potassium (KATP) channels were first discovered in the heart 30 years ago. Reconstitution of KATP channel activity by coexpression of members of the pore-forming inward rectifier gene family (Kir6.1, KCNJ8, and Kir6.2 KCNJ11) with sulfonylurea receptors (SUR1, ABCC8, and SUR2, ABCC9) of the ABCC protein subfamily has led to the elucidation of many details of channel gating and pore properties. In addition, the essential roles of Kir6.x and SURx subunits in generating cardiac and vascular KATP(2) and the detrimental consequences of genetic deletions or mutations in mice have been recognized. However, despite this extensive body of knowledge, there has been a paucity of defined roles of KATP subunits in human cardiovascular diseases, although there are reports of association of a single Kir6.1 variant with the J-wave syndrome in the ECG, and 2 isolated studies have reported association of loss of function mutations in SUR2 with atrial fibrillation and heart failure. Two new studies convincingly demonstrate that mutations in the SUR2 gene are associated with Cantu syndrome, a complex multi-organ disorder characterized by hypertrichosis, craniofacial dysmorphology, osteochondrodysplasia, patent ductus arteriosus, cardiomegaly, pericardial effusion, and lymphoedema. This realization of previously unconsidered consequences provides significant insight into the roles of the KATP channel in the cardiovascular system and suggests novel therapeutic possibilities.

Chronic Heart Failure in Congenital Heart Disease: A Scientific Statement from the American Heart Association

### Introduction The past 60 years have brought remarkable advancements in the diagnosis and treatment of congenital heart disease (CHD). Early diagnosis and improvements in cardiac surgery and interventional cardiology have resulted in unprecedented survival of patients with CHD, even those with the most complex lesions. Despite remarkable success in treatments, many interventions are palliative rather than curative, and patients often develop cardiac complications, including heart failure (HF). HF management in the setting of CHD is challenged by the wide range of ages at which HF occurs, the heterogeneity of the underlying anatomy and surgical repairs, the wide spectrum of HF causes, the lack of validated biomarkers for disease progression, the lack of reliable risk predictors or surrogate end points, and the paucity of evidence demonstrating treatment efficacy. The purposes of this statement are to review the literature pertaining to chronic HF in CHD and to elucidate important gaps in our knowledge, emphasizing the need for specific studies of HF mechanisms and improving outcomes for those with HF. In this document, the definition of CHD severity is the definition common in CHD documents, including the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines1 for the management of adults with CHD (Table 11–3). The definition of HF corresponds to that found in the multiple guidelines on diagnosis and management of HF. Although nuances and specific details may be controversial,4 the broad definition from the Heart Failure Society of America guidelines states the following: “In physiologic terms, HF is a syndrome characterized by either or both pulmonary and systemic venous congestion and/or inadequate peripheral oxygen delivery, at rest or during stress, caused by cardiac dysfunction.”5 The definition of chronic HF in this document concurs with that of the European Society of Cardiology guidelines, which emphasize chronic HF …

Normal Ranges of Right Ventricular Systolic and Diastolic Strain Measures in Children: A Systematic Review and Meta-Analysis

BACKGROUND Establishment of the range of normal values and associated variations of two-dimensional (2D) speckle-tracking echocardiography (STE)-derived right ventricular (RV) strain is a prerequisite for its routine clinical application in children. The objectives of this study were to perform a meta-analysis of normal ranges of RV longitudinal strain measurements derived by 2D STE in children and to identify confounders that may contribute to differences in reported measures. METHODS A systematic review was conducted in PubMed, Embase, Scopus, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. Search hedges were created to cover the concepts of pediatrics, STE, and the right heart ventricle. Two investigators independently identified and included studies if they reported the 2D STE-derived RV strain measure RV peak global longitudinal strain, peak global longitudinal systolic strain rate, peak global longitudinal early diastolic strain rate, peak global longitudinal late diastolic strain rate, or segmental longitudinal strain at the apical, middle, and basal ventricular levels in healthy children. Quality and reporting of the studies were assessed. The weighted mean was estimated using random effects with 95% confidence intervals (CIs), heterogeneity was assessed using Cochrans Q statistic and the inconsistency index (I(2)), and publication bias was evaluated using funnel plots and Eggers test. Effects of demographic, clinical, equipment, and software variables were assessed in a metaregression. RESULTS The search identified 226 children from 10 studies. The reported normal mean values of peak global longitudinal strain among the studies varied from -20.80% to -34.10% (mean, -29.03%; 95% CI, -31.52% to -26.54%), peak global longitudinal systolic strain rate varied from -1.30 to -2.40 sec(-1) (mean, -1.88 sec(-1); 95% CI, -2.10 to -1.59 sec(-1)), peak global longitudinal early diastolic strain rate ranged from 1.7 to 2.69 sec(-1) (mean, 2.34 sec(-1); 95% CI, 2.00 to 2.67 sec(-1)), and peak global longitudinal late diastolic strain rate ranged from 1.00 to 1.30 sec(-1) (mean, 1.18 sec(-1); 95% CI, 1.04 to 1.33 sec(-1)). A significant base-to-apex segmental strain gradient (P < .05) was observed in the RV free wall. There was significant between-study heterogeneity and inconsistency (I(2) > 88% and P < .01 for each strain measure), which was not explained by age, gender, body surface area, heart rate, frame rate, tissue-tracking methodology, equipment, or software. The metaregression showed that these effects were not significant determinants of variations among normal ranges of strain values. There was no evidence of publication bias (P = .59). CONCLUSIONS This study is the first to define normal values of 2D STE-derived RV strain in children on the basis of a meta-analysis. The normal mean value in children for RV global strain is -29.03% (95% CI, -31.52% to -26.54%). The normal mean value for RV global systolic strain rate is -1.88 sec(-1) (95% CI, -2.10 to -1.59 sec(-1)). RV segmental strain has a stable base-to-apex gradient that highlights the dominance of deep longitudinal layers of the right ventricle that are aligned base to apex. Variations among different normal ranges did not appear to be dependent on differences in demographic, clinical, or equipment parameters in this meta-analysis. All of the eligible studies used equipment and software from one manufacturer (GE Healthcare).

Alterations in Ventricular Structure and Function in Obese Adolescents with Nonalcoholic Fatty Liver Disease

OBJECTIVE To determine the association among nonalcoholic fatty liver disease (NAFLD), metabolic function, and cardiac function in obese adolescents. STUDY DESIGN Intrahepatic triglyceride (IHTG) content (magnetic resonance spectroscopy), insulin sensitivity and β-cell function (5-hour oral glucose tolerance test with mathematical modeling), and left ventricular function (speckle tracking echocardiography) were determined in 3 groups of age, sex, and Tanner matched adolescents: (1) lean (n=14, body mass index [BMI]=20±2 kg/m2); (2) obese with normal (2.5%) IHTG content (n=15, BMI=35±3 kg/m2); and (3) obese with increased (8.7%) IHTG content (n=15, BMI=37±6 kg/m2). RESULTS The disposition index (β-cell function) and insulin sensitivity index were ∼45% and ∼70% lower, respectively, and whole body insulin resistance, calculated by homeostasis model of assessment-insulin resistance (HOMA-IR), was ∼60% greater, in obese than in lean subjects, and ∼30% and ∼50% lower and ∼150% greater, respectively, in obese subjects with NAFLD than those without NAFLD (P<.05 for all). Left ventricular global longitudinal systolic strain and early diastolic strain rates were significantly decreased in obese than in lean subjects, and in obese subjects with NAFLD than those without NAFLD (P<.05 for all), and were independently associated with HOMA-IR (β=0.634). IHTG content was the only significant independent determinant of insulin sensitivity index (β=-0.770), disposition index (β=-0.651), and HOMA-IR (β=0.738). CONCLUSIONS These findings demonstrate that the presence of NAFLD in otherwise asymptomatic obese adolescents is an early marker of cardiac dysfunction.

Feasibility and Reproducibility of Systolic Right Ventricular Strain Measurement by Speckle Tracking Echocardiography in premature infants

BACKGROUND Right ventricular (RV) systolic function is an important prognostic determinant of cardiopulmonary pathologies in premature infants. Measurements of dominant RV longitudinal deformation are likely to provide a sensitive measure of RV function. An approach for image acquisition and postacquisition processing is needed for reliable and reproducible measurements of myocardial deformation by two-dimensional (2D) speckle-tracking echocardiography. The aims of this study were to determine the feasibility and reproducibility of 2D speckle-tracking echocardiographic measurement of RV peak global longitudinal strain (pGLS) and peak global longitudinal strain rate in premature infants and to establish methods for acquiring and analyzing strain. METHODS The study was designed in two phases: (1) a training phase to develop methods of image acquisition and postprocessing in a cohort of 30 premature infants (born at 28 ± 1 weeks) and (2) a study phase to prospectively test in a separate cohort of 50 premature infants (born at 27 ± 1 weeks) if the methods improved the feasibility and reproducibility of RV pGLS and peak global longitudinal strain rate measurements to a clinically significant level, assessed using Bland-Altman analysis (bias, limits of agreement, coefficient of variation, and intraclass correlation coefficient). RESULTS Strain imaging was feasible from 84% of the acquisitions using the methods developed for optimal speckle brightness and frame rate for RV-focused image acquisition. There was high intraobserver (bias, 3%; 95% limits of agreement, -1.6 to +1.6; coefficient of variation, 2.7%; intraclass correlation coefficient, 0.97; P = .02) and interobserver (bias, 7%; 95% limits of agreement, -4.8 to +4.73; coefficient of variation, 3.9%; intraclass correlation coefficient, 0.93; P < .05) reproducibility, with excellent linear correlation between the two pGLS measurements (r = 0.97 [P < .01] and r = 0.93 [P < .05], respectively). CONCLUSIONS This study demonstrates high clinical feasibility and reproducibility of RV pGLS and RV peak global longitudinal strain rate measurements by 2D speckle-tracking echocardiography in premature infants and offers methods for image acquisition and data analysis for systolic strain imaging that can provide a reliable assessment of global RV function.

Transplantation and Mechanical Circulatory Support in Congenital Heart Disease: A Scientific Statement From the American Heart Association.

Dramatic evolution in the medical and surgical care of children with congenital heart disease (CHD) has led to a growing number of adults with late-onset complications, including heart failure (HF).1 In parallel with an overall increase in hospital admissions for adults with CHD (ACHD) and HF,2 CHD complexity has increased substantially in survivors over the past 2 decades.3 Heart transplant (HTx) specialists face the challenge of determining eligibility for advanced HF treatments among an increasingly complex population of CHD patients in whom guidelines for HTx and mechanical circulatory support (MCS) are scant. The purpose of this review is to provide a state-of-the-art update on HTx and MCS in CHD. HTx remains the surgical procedure of choice for eligible patients with severe advanced HF,4,5 with little change in the number of transplants performed yearly over the past decade. The body of information related to transplantation for CHD is derived almost entirely from registry and single-center–based outcome data; no randomized clinical trial or meta-analysis data are available. CHD presents additional challenges to successful HTx compared with HTx in patients with acquired HF. Many CHD patients require complex vascular reconstruction at the time of transplantation. The presence of antibodies to human leukocyte antigen (HLA) and ABO blood group sensitization are also impediments to timely transplantation. The ability of patients with single-ventricle physiology to survive during the waiting period is also limited by the additional burden of “outgrowing” their pulmonary blood flow and the resultant cyanosis. It is not surprising that CHD remains a risk factor during the waiting period and after transplantation. Therefore, although the management of the CHD patient with end-stage HF must include the option of HTx, its indication and timing are very different from that for acquired HF. Patients with ACHD represent an increasing …