Justin P. Zachariah

Update: Ambulatory Blood Pressure Monitoring in Children and Adolescents: A Scientific Statement From the American Heart Association

Ambulatory blood pressure monitoring (ABPM) has established roles in the evaluation and management of hypertension in adults but has only been applied to children and adolescents more recently.1 In 2008, the American Heart Association (AHA) issued the first set of consensus recommendations for performance and interpretation of ABPM in pediatrics. Since then, ABPM has found increasing use in children and adolescents, as recently summarized.2 The present document updates the 2008 AHA statement on the use of ABPM in the pediatric population3 with additional data published since the release of that report and also presents a revised interpretation schema. Because no outcome studies are yet available relating ABPM levels in children to outcomes such as myocardial infarction or stroke, these guidelines are largely driven by expert opinion, although they are also informed by available pediatric data on ABPM and surrogate markers of cardiovascular disease. ### Epidemiology of Hypertension High blood pressure (BP) is the leading risk factor–related cause of death throughout the world, accounting for 12.8% of all deaths, including 51% of stroke deaths and 45% of coronary heart disease deaths.4 In the United States, 33.0% of adults >20 years of age have hypertension.5 As our population continues to age, this will only increase, because 90% of people with normal BP at age 55 years will go on to develop hypertension in their lifetimes.6 The prevalence of hypertension in youths is also on the rise. US National Health and Nutrition Examination Survey (NHANES) data from 1963 to 2002 showed a 2.3% increase in prehypertension and a 1% increase in hypertension from 1988 to 1999, with higher rates in non-Hispanic blacks and Mexican Americans.7 In fact, the entire distribution of childhood BP has shifted upward in the United States by 1.4 mm Hg for systolic BP (SBP) and 3.3 …

Association of Circulating Cholesteryl Ester Transfer Protein Activity With Incidence of Cardiovascular Disease in the Community

Background— Plasma high-density lipoprotein cholesterol concentration is related inversely to the risk of cardiovascular disease (CVD). Inhibiting cholesteryl ester transfer protein (CETP) activity raises high-density lipoprotein cholesterol and may be cardioprotective, but an initial clinical trial with a CETP inhibitor was stopped prematurely because of increased CVD in treated patients, raising concerns about this approach. Data relating circulating CETP concentrations to CVD incidence in the community are conflicting. Methods and Results— Plasma CETP activity was measured in 1978 Framingham Heart Study participants (mean age, 51 years; 54% women) who attended a routine examination in 1987–1990 and were free of CVD. On follow-up (mean, 15.1 years), 320 participants experienced a first CVD event (fatal or nonfatal coronary heart disease, cerebrovascular disease, peripheral vascular disease, or heart failure). In multivariable analyses adjusted for standard risk factors including high-density lipoprotein cholesterol, plasma CETP activity was related inversely to the incidence of CVD events (hazard ratio for activity, at or above the median of 0.72; 95% confidence interval, 0.57 to 0.90; P=0.004 [compared with below median]; hazard ratio per SD increment, 0.86; 95% confidence interval, 0.76 to 0.97; P=0.01). The inverse association of CETP activity with CVD incidence remained robust in time-dependent models updating standard risk factors every 4 years and was maintained in analyses of incident “hard” CVD events (myocardial infarction, stroke, or heart failure). Conclusions— In our prospective investigation of a community-based sample, lower plasma CETP activity was associated with greater CVD risk. These observations, if confirmed, challenge the concept that CETP inhibition may lower CVD risk.

Myocardial infarction and remodeling in mice: effect of reperfusion

Anatomic and functional changes after either a permanent left anterior descending coronary artery occlusion (PO) or 2 h of occlusion followed by reperfusion (OR) in C57BL/6 mice were examined and compared with those in sham-operated mice. Both interventions generated infarcts comprising 30% of the left ventricle (LV) measured at 24 h and equivalent suppression of LV ejection velocity and filling velocity measured by Doppler ultrasound at 1 wk. Serial follow-up revealed that the ventricular ejection velocity and filling velocity returned to the levels of the sham-operated controls in the OR group at 2 wk and remained there; in contrast, PO animals continued to display suppression of both systolic and diastolic function. In contrast, ejection fractions of PO and OR animals were depressed equivalently (50% from sham-operated controls). Anatomic reconstruction of serial cross sections revealed that the percentage of the LV endocardial area overlying the ventricular scar (expansion ratio) was significantly larger in the PO group vs. the OR group (18 ± 1.7% vs. 12 ± 0.9%, P < 0.05). The septum that was never involved in the infarction had a significantly ( P < 0.002) increased mass in PO animals (22.5 ± 1.08 mg) vs. OR (17.8 ± 1.10 mg) or sham control (14.8 ± 0.99 mg) animals. Regression analysis demonstrated that the extent of septal hypertrophy correlated with LV expansion ratio. Thus late reperfusion appears to reduce the degree of infarct expansion even under circumstances in which it no longer can alter infarct size. We suggest that reperfusion promoted more effective ventricular repair, less infarct expansion, and significant recovery or preservation of ventricular function.Anatomic and functional changes after either a permanent left anterior descending coronary artery occlusion (PO) or 2 h of occlusion followed by reperfusion (OR) in C57BL/6 mice were examined and compared with those in sham-operated mice. Both interventions generated infarcts comprising 30% of the left ventricle (LV) measured at 24 h and equivalent suppression of LV ejection velocity and filling velocity measured by Doppler ultrasound at 1 wk. Serial follow-up revealed that the ventricular ejection velocity and filling velocity returned to the levels of the sham-operated controls in the OR group at 2 wk and remained there; in contrast, PO animals continued to display suppression of both systolic and diastolic function. In contrast, ejection fractions of PO and OR animals were depressed equivalently (50% from sham-operated controls). Anatomic reconstruction of serial cross sections revealed that the percentage of the LV endocardial area overlying the ventricular scar (expansion ratio) was significantly larger in the PO group vs. the OR group (18 +/- 1.7% vs. 12 +/- 0.9%, P < 0.05). The septum that was never involved in the infarction had a significantly (P < 0.002) increased mass in PO animals (22.5 +/- 1.08 mg) vs. OR (17.8 +/- 1.10 mg) or sham control (14.8 +/- 0.99 mg) animals. Regression analysis demonstrated that the extent of septal hypertrophy correlated with LV expansion ratio. Thus late reperfusion appears to reduce the degree of infarct expansion even under circumstances in which it no longer can alter infarct size. We suggest that reperfusion promoted more effective ventricular repair, less infarct expansion, and significant recovery or preservation of ventricular function.

Longitudinal Tracking of Left Atrial Diameter over the Adult Life Course: Clinical Correlates in the Community

Background— Increased left atrial diameter (LAD) is associated with elevated risk of atrial fibrillation (AF) and cardiovascular disease. Information is limited regarding the short- or long-term correlates of LAD. Methods and Results— We evaluated clinical correlates of LAD for a 16-year period in 4403 Framingham Study participants (mean age, 45 years; 52% women; median observations/participant=3) using multilevel modeling. We related age, sex, body mass index (BMI), systolic and diastolic blood pressure (BP), diabetes, and antihypertensive treatment to LAD. Sex-specific growth curves for LAD were estimated for individuals with low, intermediate, and high risk factor burden. We also related risk factors to changes in LAD during a 4-year period in 3365 participants. Age, male sex (3.83 mm compared to women), greater BMI, higher systolic BP (0.24 mm per 10 mm Hg increment), and antihypertensive treatment (0.54 mm) were associated positively with LAD (P<0.001). Men had a greater increase in LAD with BMI than women (2.02 versus 1.77 mm in women, per 5-unit increment), and individuals receiving antihypertensive treatment experienced a greater increase in LAD with age (0.95 versus 0.63 mm per 10-year age increment) when compared with those not receiving antihypertensive treatment. Overall, greater risk factor burden was positively associated with LAD. These risk factors were also associated positively with 4-year change in LAD (P<0.001). Conclusions— Our longitudinal study of a large community-based sample identified higher BP and greater BMI as key modifiable correlates of LAD, suggesting that maintaining optimal levels of these risk factors through the life course may prevent atrial remodeling and AF.

Insulin Resistance and the Relationship of a Dyslipidemia to Coronary Heart Disease The Framingham Heart Study

Objective—The goal of this study was to examine the effect of insulin resistance (IR) in subjects without diabetes on the relationship of a dyslipidemia with high triglycerides and low high-density lipoprotein cholesterol (HDL-C) to the development of coronary heart disease (CHD). Methods and Results—Lower and higher fasting plasma HDL-C and triglyceride concentrations (defined at the study population median) and presence or absence of IR (defined by upper quartile Homeostatic Model Assessment values) were related to the development of myocardial infarction or CHD death in Framingham Heart Study participants without diabetes or a history of CHD (n=2910) attending the 1991 to 1995 examination. During follow-up (mean, 14 years), 128 participants experienced an incident CHD event. With Kaplan-Meier plots, the incidence of CHD was significantly greater with than without IR at either the lowest HDL-C or the highest triglycerides (P<0.001). In multivariable Cox models adjusted for major CHD risk factors, including waist circumference, only subgroups with IR had a significantly higher incidence of CHD. Compared with a reference group without IR and with higher-than-median HDL-C or lower-than-median triglycerides, the hazard ratio (HR) for incident events was significant with only IR and a lower HDL-C (HR 2.83, P<0.001) or higher triglycerides (HR 2.50, P<0.001). These findings were similar in men and women. Conclusion—In this community-based sample exclusive of diabetes, incident CHD risk associated with plasma HDL-C or triglycerides was significantly increased only in the presence of IR.

Clinical and Genetic Correlates of Circulating Angiopoietin-2 and Soluble Tie-2 in the Community

Background—Experimental studies suggest that endothelial growth factors play an important role in angiogenesis and vascular remodeling. The clinical and genetic correlates of circulating angiopoietin-2 (Ang-2) and its soluble receptor/regulator Tie-2 (sTie-2) have not been determined in a community-based sample. Methods and Results—Serum Ang-2 and sTie-2 were assayed in 3778 third-generation cohort participants of the Framingham Heart Study (mean age, 40±9 years; 53% women). Clinical correlates and heritability of both biomarkers were assessed using generalized estimating equations and variance-component analyses. Ang-2 levels were higher and sTie-2 levels were lower in women than in men. Ang-2 was positively related to age, smoking, systolic blood pressure, hypertension treatment, and diabetes (P<0.05 for all) but was inversely associated with total cholesterol and diastolic blood pressure (P<0.0001 for both), and sTie-2 was positively associated with body mass index, diabetes, and triglycerides but was inversely related to age, alcohol consumption, and glomerular filtration rate (P<0.05 for all). Both Ang-2 and sTie-2 were higher in participants with metabolic syndrome (P<0.005), with stronger associations of Ang-2 with blood pressure traits and of sTie-2 with obesity-dyslipidemia components. Heritability estimates for Ang-2 and sTie-2 were 27% and 56%, respectively (P<0.0001). A region on chromosome 9 was significantly linked to circulating sTie-2 levels (logarithm of the odds score, 8.31). Conclusion—Circulating levels of Ang-2 and sTie-2 are heritable traits associated with cardiovascular disease risk factors, including the metabolic syndrome. These observations are consistent with the notion that angiogenesis and vascular remodeling are determined in part by genetic influences and associated with metabolic risk factors.

Cardiovascular Health Promotion in Children: Challenges and Opportunities for 2020 and Beyond: A Scientific Statement from the American Heart Association

This document provides a pediatric-focused companion to “Defining and Setting National Goals for Cardiovascular Health Promotion and Disease Reduction: The American Heart Association’s Strategic Impact Goal Through 2020 and Beyond,” focused on cardiovascular health promotion and disease reduction in adults and children. The principles detailed in the document reflect the American Heart Association’s new dynamic and proactive goal to promote cardiovascular health throughout the life course. The primary focus is on adult cardiovascular health and disease prevention, but critical to achievement of this goal is maintenance of ideal cardiovascular health from birth through childhood to young adulthood and beyond. Emphasis is placed on the fundamental principles and metrics that define cardiovascular health in children for the clinical or research setting, and a balanced and critical appraisal of the strengths and weaknesses of the cardiovascular health construct in children and adolescents is provided. Specifically, this document discusses 2 important factors: the promotion of ideal cardiovascular health in all children and the improvement of cardiovascular health metric scores in children currently classified as having poor or intermediate cardiovascular health. Other topics include the current status of cardiovascular health in US children, opportunities for the refinement of health metrics, improvement of health metric scores, and possibilities for promoting ideal cardiovascular health. Importantly, concerns about the suitability of using single thresholds to identify elevated cardiovascular risk throughout the childhood years and the limits of our current knowledge are noted, and suggestions for future directions and research are provided.

Multiple accessory pathways in the young: the impact of structural heart disease.

BACKGROUND The presence of multiple accessory pathways (MultAP) is described in structural heart disease (SHD) such as Ebsteins anomaly and cardiomyopathies. Structural defects can impact the tolerability of tachyarrhythmia and can complicate both medical management and ablation. In a large cohort of pediatric patients with and without SHD undergoing invasive electrophysiology study, we examined the prevalence of MultAP and the effect of both MultAP and SHD on ablation outcomes. METHODS Accessory pathway number and location, presence of SHD, ablation success, and recurrence were analyzed in consecutive patients from our center over a 16-year period. RESULTS In 1088 patients, 1228 pathways (36% retrograde only) were mapped to the right side (TV) in 18%, septum (S) in 39%, and left side (MV) in 43%. MultAP were present in 111 pts (10%), involving 250 distinct pathways. SHD tripled the risk of MultAP (26% SHD vs 8% no SHD, P < .001). Multivariable adjusted risk factors for MultAP included Ebsteins (OR 8.7[4.4-17.5], P < .001) and cardiomyopathy (OR 13.3[5.1-34.5], P < .001). Of 1306 ablation attempts, 94% were acutely successful with an 8% recurrence rate. Ablation success was affected by SHD (85% vs 95% for no SHD, P < .01) but not by MultAP (91% vs 94% for single, P = .24). Recurrence rate was higher for SHD (17% SHD vs 8% no SHD, P < .05) and MultAP (19% MultAP vs 8% single, P < .001). CONCLUSIONS MultAP are found in 10% of pediatric patients, and are more common in SHD compared to those with normal hearts. Both the presence of MultAP and SHD negatively influence ablation outcomes.

Circulating Vascular Growth Factors and Central Hemodynamic Load in the Community

Mean and pulsatile components of hemodynamic load are related to cardiovascular disease. Vascular growth factors play a fundamental role in vascular remodeling. The links between growth factors and hemodynamic load components are not well described. In 3496 participants from the Framingham Heart Study third generation cohort (mean age: 40±9 years; 52% women), we related 4 tonometry-derived measures of central arterial load (carotid femoral pulse wave velocity and forward pressure wave, mean arterial pressure, and the global reflection coefficient) to circulating concentrations of angiopoietin 2, its soluble receptor; vascular endothelial growth factor, its soluble receptor; hepatocyte growth factor; insulin-like growth factor 1; and its binding protein 3. Using multivariable linear regression models, adjusted for standard cardiovascular risk factors, serum insulin-like growth factor 1 concentrations were negatively associated with carotid femoral pulse wave velocity, mean arterial pressure, and reflection coefficient (P⩽0.01 for all), whereas serum vascular endothelial growth factor levels were positively associated with carotid femoral pulse wave velocity and mean arterial pressure (P<0.04). Serum insulin-like growth factor binding protein 3 and soluble angiopoietin 2 receptor levels were positively related to mean arterial pressure and to forward pressure wave, respectively (P<0.05). In our cross-sectional study of a large community-based sample, circulating vascular growth factor levels were related to measures of mean and pulsatile hemodynamic load in a pattern consistent with the known physiological effects of insulin-like growth factor 1 and vascular endothelial growth factor.

Cardiovascular Consequences of Childhood Secondhand Tobacco Smoke Exposure: Prevailing Evidence, Burden, and Racial and Socioeconomic Disparities: A Scientific Statement From the American Heart Association

Background: Although public health programs have led to a substantial decrease in the prevalence of tobacco smoking, the adverse health effects of tobacco smoke exposure are by no means a thing of the past. In the United States, 4 of 10 school-aged children and 1 of 3 adolescents are involuntarily exposed to secondhand tobacco smoke (SHS), with children of minority ethnic backgrounds and those living in low-socioeconomic-status households being disproportionately affected (68% and 43%, respectively). Children are particularly vulnerable, with little control over home and social environment, and lack the understanding, agency, and ability to avoid SHS exposure on their own volition; they also have physiological or behavioral characteristics that render them especially susceptible to effects of SHS. Side-stream smoke (the smoke emanating from the burning end of the cigarette), a major component of SHS, contains a higher concentration of some toxins than mainstream smoke (inhaled by the smoker directly), making SHS potentially as dangerous as or even more dangerous than direct smoking. Compelling animal and human evidence shows that SHS exposure during childhood is detrimental to arterial function and structure, resulting in premature atherosclerosis and its cardiovascular consequences. Childhood SHS exposure is also related to impaired cardiac autonomic function and changes in heart rate variability. In addition, childhood SHS exposure is associated with clustering of cardiometabolic risk factors such as obesity, dyslipidemia, and insulin resistance. Individualized interventions to reduce childhood exposure to SHS are shown to be at least modestly effective, as are broader-based policy initiatives such as community smoking bans and increased taxation. Purpose: The purpose of this statement is to summarize the available evidence on the cardiovascular health consequences of childhood SHS exposure; this will support ongoing efforts to further reduce and eliminate SHS exposure in this vulnerable population. This statement reviews relevant data from epidemiological studies, laboratory-based experiments, and controlled behavioral trials concerning SHS and cardiovascular disease risk in children. Information on the effects of SHS exposure on the cardiovascular system in animal and pediatric studies, including vascular disruption and platelet activation, oxidation and inflammation, endothelial dysfunction, increased vascular stiffness, changes in vascular structure, and autonomic dysfunction, is examined. Conclusions: The epidemiological, observational, and experimental evidence accumulated to date demonstrates the detrimental cardiovascular consequences of SHS exposure in children. Implications: Increased awareness of the adverse, lifetime cardiovascular consequences of childhood SHS may facilitate the development of innovative individual, family-centered, and community health interventions to reduce and ideally eliminate SHS exposure in the vulnerable pediatric population. This evidence calls for a robust public health policy that embraces zero tolerance of childhood SHS exposure.