William R. Clarke

Coronary heart disease risk factors in school children: The Muscatine study

The frequency of coronary risk factors was documented in 4,829 school children in Muscatine, Iowa, over a 14-month period of time. Serum cholesterol levels were similar for children at all ages; the mean serum cholesterol level was 182 mg/dl (SD lus or minus 29). Twenty four percent had levels larger than or equal to 200 mg/dl, 9% were larger than or equal to 220 mg/dl, 3 % were larger than or equal to 240 mg/dl, and 1% were larger than or equal to 260 mg/dl. Casual levels of serum triglyceride increased with age: the mean level was 71 mg/dl (SD plus or minus 36) at age 6 years and 108 mg/dl (SD plus or minus 45) at age 18 years. Only 15% of the children had serum triglyceride levels of 140 mg/dl or more. Blood pressure increased strikingly with age. No child between 6 and 9 years of age had blood pressures larger than or equal to 140 mm Hg systolic or larger than or equal to 90 mm Hg diastolic. In the age group 14 to 18 years, 8.9% had systolic blood pressures larger than or equal to 140 mm Hg, 12.2% had diastolic blood pressures larger than or equal to 90 mm Hg, and in 4.4% both pressures were at or above these levels. Obesity also increased through the school years. At ages 6 to 9 years, 20% had weights relative to those of the group as a whole of larger than or equal to 110%, and 5% were larger than or equal to 130%; in the 14 to 18 years age group, 25% had relative weights of larger than or equal to 110%, and 8% were larger than or equal to 130%. These data indicate that a considerable number of school-age children have risk factors which in adults are predictive of coronary heart disease.

Level, trend, and variability of blood pressure during childhood: the Muscatine study.

On alternate years from 1970 to 1981 blood pressure has been measured in school children living in Muscatine, Iowa. A total of 4313 children beginning at 5 to 14 years of age have been examined on three to six occasions. To compare blood pressures throughout the period of observation, each value was expressed as a percentile rank. For each subject the average percentile rank (level), the trend in rank, and the variability over time were calculated. Values for height, weight, relative weight, and triceps skinfold thickness were expressed in the same fashion. The relationship between average rank of blood pressure and average rank of body size as well as between trend of blood pressure and trend of body size percentiles were significant (p less than .05). These observations indicate the importance of relative rate of growth in the establishment of the rank order of blood pressure. Using the variables of level, trend, and variability, we identified groups of children who appear to be consistently tracking toward future hypertension: 233 (5.4%) children, whose systolic levels were in the upper quintile with either a flat or rising trend and low variability, and 280 (6.0%) children with systolic levels in the lower four quintiles with high trend and low variability. In addition there were 321 (7.4%) children whose mean systolic levels were in the upper quintile with high variability and who thus resemble adults with labile hypertension. There were similar numbers of children with diastolic pressures showing these features.

Group A streptococcal necrotizing fasciitis complicating primary varicella: a series of fourteen patients.

We retrospectively reviewed the clinical course of group A Streptococcus necrotizing fasciitis complicating primary varicella in children admitted to Childrens Hospital and Medical Center, Seattle, WA, during a 18-month period. The potential benefit of various therapeutic interventions was examined. Fourteen children ages 6 months to 10 years were treated for group A Streptococcus necrotizing fasciitis as a complication of primary varicella. Eight patients experienced a delay in initial diagnosis as a result of nonspecific, early clinical findings of necrotizing fasciitis. Each patient underwent surgical exploration with fasciotomies and debridement. Initial antibiotic therapy was broad spectrum and included clindamycin. Hyperbaric oxygen therapy for as many as 6 treatments was used as adjunctively therapy in 12 patients, with subjective benefit in 6 patients. All 14 patients were discharged home with good function and no long term sequelae. This potentially fatal bacterial infection of the deep fascial layers requires early recognition by primary care physicians and an intensive, multidisciplinary therapeutic approach, including thorough surgical debridement and appropriate antibiotic therapy.

Statistical tools to analyze continuous glucose monitor data.

Continuous glucose monitors (CGMs) generate data streams that are both complex and voluminous. The analyses of these data require an understanding of the physical, biochemical, and mathematical properties involved in this technology. This article describes several methods that are pertinent to the analysis of CGM data, taking into account the specifics of the continuous monitoring data streams. These methods include: (1) evaluating the numerical and clinical accuracy of CGM. We distinguish two types of accuracy metrics-numerical and clinical-each having two subtypes measuring point and trend accuracy. The addition of trend accuracy, e.g., the ability of CGM to reflect the rate and direction of blood glucose (BG) change, is unique to CGM as these new devices are capable of capturing BG not only episodically, but also as a process in time. (2) Statistical approaches for interpreting CGM data. The importance of recognizing that the basic unit for most analyses is the glucose trace of an individual, i.e., a time-stamped series of glycemic data for each person, is stressed. We discuss the use of risk assessment, as well as graphical representation of the data of a person via glucose and risk traces and Poincaré plots, and at a group level via Control Variability-Grid Analysis. In summary, a review of methods specific to the analysis of CGM data series is presented, together with some new techniques. These methods should facilitate the extraction of information from, and the interpretation of, complex and voluminous CGM time series.

Long-Term Follow-Up Evaluation of Blood Glucose Awareness Training

OBJECTIVE Blood glucose awareness training (BGAT) has been found effective in teaching individuals with insulin-requiring diabetes to improve their ability to better recognize blood glucose (BG) fluctuations. This study investigated whether subjects who underwent BGAT a mean of 4.9 years previously were superior to past control subjects in terms of their ability to recognize BG fluctuations, and whether past BGAT subjects had fewer automobile crashes and lost work days and better glycosylated hemoglobin than control subjects. Additionally, the beneficial effects of providing booster training to past BGAT subjects also was evaluated. RESEARCH DESIGN AND METHODS This study followed up 28 past BGAT subjects. Half of these subjects (n = 14) received a simple booster-training program. Twelve previous control subjects also were evaluated. Booster subjects were given a BGAT diary to complete for 2 weeks before evaluation. Evaluation for all subjects included completion of a retrospective questionnaire on work and driving history, blood drawing for a glycosylated hemoglobin analysis, and having subjects estimate and measure their BG levels 50–80 times during a 3- to 4-week period during their daily routine. RESULTS At long-term follow-up, BGAT subjects had significantly fewer automobile crashes than control subjects. BGAT subjects receiving booster training were significantly more accurate at estimating their BG levels and were more aware of hypoglycemia. Post hoc analyses indicated that the ability to accurately estimate BG fluctuations correlated positively with follow-up glycosylated hemoglobin and the number of hypoglycemic and hyperglycemic symptoms participants demonstrated.Both BGAT and control subjects demonstrated significantly improved glycosylated hemoglobin relative to baseline measures. CONCLUSIONS These data suggest that BGAT has long-term benefits, which can be enhanced with booster training. Specifically, BGAT and simple booster training may result in reduction of severe hypoglycemic episodes and automobile crashes in the long term.

Chronic pulmonary hypertension increases fetal lung cGMP phosphodiesterase activity

An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.An experimental ovine fetal model for perinatal pulmonary hypertension of the neonate (PPHN) was characterized by altered pulmonary vasoreactivity and structure. Because past studies had suggested impaired nitric oxide-cGMP cascade in this experimental model, we hypothesized that elevated phosphodiesterase (PDE) activity may contribute to altered vascular reactivity and structure in experimental PPHN. Therefore, we studied the effects of the PDE inhibitors zaprinast and dipyridamole on fetal pulmonary vascular resistance and PDE5 activity, protein, mRNA, and localization in normal and pulmonary hypertensive fetal lambs. Infusion of dipyridamole and zaprinast lowered pulmonary vascular resistance by 55 and 35%, respectively, in hypertensive animals. In comparison with control animals, lung cGMP PDE activity was elevated in hypertensive fetal lambs (150%). Increased PDE5 activity was not associated with either an increased PDE5 protein or mRNA level. Immunocytochemistry demonstrated that PDE5 was localized to vascular smooth muscle. We concluded that PDE5 activity was increased in experimental PPHN, possibly by posttranslational phosphorylation. We speculated that these increases in cGMP PDE activity contributed to altered pulmonary vasoreactivity in experimental perinatal pulmonary hypertension.

Left ventricular hypertrophy in children with blood pressures in the upper quintile of the distribution. The Muscatine Study.

SUMMARY From echocardlographic measurements of left heart dimensions, cardiac output was estimated in 264 school children whose systolic blood pressure persisted in the lowest, middle, or highest quintile of the distribution for their age and sex. Children with blood pressure in the upper quintile were taller, heavier, and more obese. Echocardiographically determined left ventricular wall mass, corrected for body size, was significantly greater in these children than those in the lower quintiles of blood pressure. These children displayed a continuum of cardiac output. Those with the highest cardiac output in the upper blood pressure quintile had the greatest left ventricular wall mass.

Increased coronary mortality in relatives of hypercholesterolemic school children: the Muscatine study.

From 2,874 school children participating in the 1971 and 1973 Muscatine Coronary Risk Factor Survey, we selected three groups of index cases for detailed family study: the HIGH group (n = 56), with cholesterol levels greater than the 95th percentile twice; the MIDDLE group (n = 46), cholesterol levels between the 5th and 95th percentile; and the LOW group (n = 46), cholesterol levels less than the 5th percentile twice. Coronary mortality determined from death certificates was increased in the young relatives (ages 30-59) of the HIGH group index cases, as follows: twofold excess in HIGH male relatives compared with the MIDDLE or LOW group (p less than 0.05); tenfold excess in the HIGH female relatives compared with the MIDDLE and LOW group combined (p less than 0.01). After correction for years at risk, there was an approximately twofold significantly-increased coronary mortality. Stroke mortality was higher, although not significantly, in the older relatives (ages greater than or equal to 60) of the HIGH index cases. Cancer mortality was not significantly different among the relatives of the three groups of index cases. This study indicates that school childrens cholesterol levels cluster with those of their family members and that persistent hypercholesterolemia in children identifies families at risk for coronary artery disease.

Frequency and Severity of Tricuspid Regurgitation Determined by Doppler Echocardiography in Primary Pulmonary Hypertension

W previously described a high prevalence of functional tricuspid regurgitation (TR) in patients with severely symptomatic primary pulmonary hypertension (PPH).1 We report the relations of TR to right ventricular (RV) size and geometry, tricuspid annulus diameter, tricuspid leaflet displacement, hemodynamics, and exercise capacity in these patients. • • • The study group consisted of 78 patients enrolled in a multicenter trial of epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, North Carolina) for the treatment of severe PPH.2 The study consisted of 56 women and 32 men (mean age 40 15 years). Most (74%) had New York Heart Association class III symptoms; their average mean pulmonary arterial pressure was 60 12 mm Hg. All participants met the criteria for PPH as defined by the National Institutes of Health Patient Registry,3 and all had New York Heart Association class III or class IV symptoms. The study was approved by the institutional review committee of each participating center, and informed consent was acquired from each patient before enrollment. Baseline echocardiograms of all participants were obtained using a defined imaging protocol and recorded on videotape. All studies were analyzed using an off-line quantification system by a single observer from the core echocardiographic laboratory. Measurements were obtained on 3 representative beats, and the results averaged. Details of the imaging and quantification protocols, including reproducibility data, have been described previously.1 The severity of TR was determined from 2-dimensional and Doppler color flow images in the apical 4-chamber view. Frame-by-frame analysis of each cardiac cycle was used to identify the maximum area of the Doppler color flow jet. The outline of the regurgitant signal, including aliased signals and contiguous velocities moving in the same direction, was traced and the area determined by computerized planimetry. The area of the right atrium was similarly measured on the same frame. The severity of TR was quantified as the ratio of the Doppler regurgitant jet area to the right atrial (RA) area (the TR/RA ratio). Previous investigators have demonstrated that this ratio is correlated closely with the severity of TR measured by a double thermodilution technique.4 Severe TR was defined as a TR/RA ratio 0.34, a ratio that corresponds to severe TR as judged by thermodilution4 or intraoperative digital palpation.5 TR was considered moderate if the TR/RA ratio was 0.20 and 0.34, and mild if the TR/RA ratio was 0.20. The tricuspid valve was examined in the apical 4-chamber view for thickening or doming, and for abnormal closure. The apical displacement of the tricuspid leaflets, an index of abnormal closure due to chordal tension, was measured as the distance from the coaptation point to the plane of the tricuspid annulus at the time of maximal systolic closure. Loss of coaptation was defined as a visible separation of the septal and anterior leaflets throughout systole. The following echocardiographic measures of RV structure were obtained in the apical 4-chamber view at end-diastole and at end-systole. (1) The tricuspid annulus diameter was measured from the point of attachment of the septal leaflet to the attachment of the anterior leaflet. This diameter was corrected for differences in body size by dividing by height. (2) The RV remodeling index was calculated as the ratio of RV short and long axes; the short axis was defined as the distance between the septal and free wall endocardial surfaces of the right ventricle at the midventricular level. The long axis was measured from the endocardial surface at the tip of the RV apex to the midpoint of the annular plane. (3) RV area was measured by planimetry, tracing the endocardial edge of the right ventricle and the plane of the tricuspid valve, and corrected for height. From the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; University of Washington, Seattle, Washington; Maine Medical Center, Portland, Maine; Washington University, St. Louis, Missouri; Rhode Island Hospitals, Providence, Rhode Island; Louisiana State Medical Center, New Orleans, Louisiana; Cato Research Ltd., Durham, North Carolina; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina; GlaxoSmithKline, Research Triangle Park, North Carolina; and United Therapeutics Inc., Chapel Hill, North Carolina. This study was supported by Burroughs Wellcome Co., Research Triangle Park, North Carolina. Dr. Hinderliter’s address is: Division of Cardiology, University of North Carolina, CB 7075, Chapel Hill, North Carolina, 27599. E-mail: hinderli@med.unc.edu. Manuscript received July 29, 2002; revised manuscript received and accepted December 20, 2002.

The cardiovascular responses to exercise in children across the blood pressure distribution. The Muscatine study.

Children with elevated systolic blood pressure have a wide range of cardiac output. To better understand the mechanisms regulating resting and exercise blood pressure, we investigated the cardiovascular responses to both dynamic and isometric exercise in 264 children who were selected from the low, middle, and upper quintile of the distribution of blood pressure of an entire school population. We sought to identify patterns of response to exercise that correlated with both resting cardiac output and resting blood pressure. During isometric exercise, systolic pressure adjusted for age and body size increased in all groups. The low groups mean pressure remained significantly lower than the high groups pressure throughout the entire exercise period. Body size adjusted group systolic and diastolic blood pressure level differences exist during dynamic exercise. The product of the systolic blood pressure times the heart rate, in the high blood pressure group, was significantly higher throughout dynamic exercise than in the other two groups. Elevated resting resistance is correlated with elevated resistance during isometric exercise and elevated diastolic blood pressure during dynamic exercise. Cardiac index had a significant negative correlation to age (r = -0.58) at all levels of blood pressure. This observation, in children, lends some support to the concept of the evolution from a hyperkinetic circulation in early childhood to a circulation with lower cardiac output and more elevated systemic vascular resistance at an older age.