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T R Kimball

Publications and source records attributed to T R Kimball.

At least 37 records · Page 2Linked to original sources
PubMed2000

Apolipoprotein J/clusterin limits the severity of murine autoimmune myocarditis.

Apolipoprotein J/clusterin (apoJ/clusterin), an intriguing protein with unknown function, is induced in myocarditis and numerous other inflammatory injuries. To test its ability to modify myosin-induced autoimmune myocarditis, we generated apoJ-deficient mice. ApoJ-deficient and wild-type mice exhibited similar initial onset of myocarditis, as evidenced by the induction of two early markers of the T cell-mediated immune response, MHC-II and TNF receptor p55. Furthermore, autoantibodies against the primary antigen cardiac myosin were induced to the same extent. Although the same proportion of challenged animals exhibited some degree of inflammatory infiltrate, inflammation was more severe in apoJ-deficient animals. Inflammatory lesions were more diffuse and extensive in apoJ-deficient mice, particularly in females. In marked contrast to wild-type animals, the development of a strong generalized secondary response against cardiac antigens in apoJ-deficient mice was predictive of severe myocarditis. Wild-type mice with a strong Ab response to secondary antigens appeared to be protected from severe inflammation. After resolution of inflammation, apoJ-deficient, but not wild-type, mice exhibited cardiac function impairment and severe myocardial scarring. These results suggest that apoJ limits progression of autoimmune myocarditis and protects the heart from postinflammatory tissue destruction.

Animals↗
PubMed2000

Early onset heart failure in transgenic mice with dilated cardiomyopathy.

In children, dilated cardiomyopathy is due to a variety of etiologies and usually carries a grave prognosis. The purpose of the present study was to carefully follow the progression of events leading to cardiac dilatation and congestive heart failure in a dilated cardiomyopathy model in neonatal and juvenile mice. These initial steps are often not well characterized. Furthermore, the loss of gap junctions and reduced electrical coupling of cardiomyocytes frequently found in human cardiomyopathies are also observed in these early stages. By 2 wk of age, molecular markers associated with hypertrophy were already altered. Cardiomyocyte hypertrophy, reduced connexin43 expression, and decreased conduction velocity were apparent by 4 wk, before overt cardiac dysfunction (decreased shortening fraction and chamber remodeling) that was not present until 12 wk of age. Our results show that in this model cardiomyopathic changes are present by 2 wk after birth and progress rapidly during the subsequent 2 postnatal weeks. Combined with the observations of other models of heart disease, we suggest that the first 2 wk of postnatal life are absolutely critical for normal cardiac development, and events that perturb homeostasis during this period determine whether the heart will continue to develop normally. These animals exhibit early symptoms of disease including reduced connexin43 and conduction defects before impaired cardiac function and demonstrate for the first time a temporal association between decreased connexin43 levels and the initiation of a contractility deficit that ends in heart failure.

Aging↗
PubMed2000

Relation of left ventricular chamber and midwall function to age in normal children, adolescents and adults.

BACKGROUND: The goal of this study was to identify the effect of body growth and aging, and normal limits of the relation of left ventricular endocardial and midwall shortening to wall stress. METHODS: Endocardial and midwall shortening and circumferential end-systolic stress were assessed in 388 normotensive, normal-weight adults (226 men, 162 women, age 18 to 85 years) and 332 children and adolescents (180 males, 152 females, age 4 to 17 years) by two-dimensional targeted M-mode echocardiography and cuff blood pressure measurements. RESULTS: End-systolic stress decreased with age in children and adolescents (p < 0.001), but not during adulthood and maturity. The negative relation of endocardial shortening to end-systolic stress was stronger in adults than in children and adolescents (slope difference p < 0.005). The negative relation of midwall shortening to end-systolic stress was negligible in children and adolescents (r = -0.07, p = 0.18), whereas it was more evident, although weak, in adults (r = -0.14, p < 0.007). For a given level of end-systolic stress, endocardial shortening decreased by 0.32%/year in children and adolescents (multiple r = 0.51, p < 0.0001) and by 0.05%/year in adults, whereas midwall shortening decreased by 0.26%/year during body growth and by 0.02%/year in adults. CONCLUSIONS: In the presence of normal blood pressure and normal weight, the relations between left ventricular wall stress and both chamber and myocardial function are weakly but significantly influenced by age. Left ventricular chamber function is markedly influenced by wall stress, while this influence is reduced for left ventricular wall mechanics.

Adolescent↗
PubMed1999

Abnormal cardiac structure and function in mice expressing nonphosphorylatable cardiac regulatory myosin light chain 2.

A role for myosin phosphorylation in modulating normal cardiac function has long been suspected, and we hypothesized that changing the phosphorylation status of a cardiac myosin light chain might alter cardiac function in the whole animal. To test this directly, transgenic mice were created in which three potentially phosphorylatable serines in the ventricular isoform of the regulatory myosin light chain were mutated to alanines. Lines were obtained in which replacement of the endogenous species in the ventricle with the nonphosphorylatable, transgenically encoded protein was essentially complete. The mice show a spectrum of cardiovascular changes. As previously observed in skeletal muscle, Ca(2+) sensitivity of force development was dependent upon the phosphorylation status of the regulatory light chain. Structural abnormalities were detected by both gross histology and transmission electron microscopic analyses. Mature animals showed both atrial hypertrophy and dilatation. Echocardiographic analysis revealed that as a result of chamber enlargement, severe tricuspid valve insufficiency resulted in a detectable regurgitation jet. We conclude that regulated phosphorylation of the regulatory myosin light chains appears to play an important role in maintaining normal cardiac function over the lifetime of the animal.

Amino Acid Sequence↗
PubMed1999

Association of body fat distribution and cardiovascular risk factors in children and adolescents.

BACKGROUND: Obesity is associated with increased risk of cardiovascular disease in adults and less favorable cardiovascular risk factor status in children and adolescents. In adults, fat distribution has been shown to be related to lipid and lipoprotein concentrations, blood pressure levels, and left ventricular mass. These relationships have not been extensively studied in young subjects. METHODS AND RESULTS: This was a cross-sectional study of 127 children and adolescents 9 to 17 years of age. Dual-energy x-ray absorptiometry was used to measure total and regional fat mass. The dependent variables were fasting lipid and lipoprotein concentrations, systolic and diastolic blood pressures, and left ventricular mass. There were significant (P<0.05) univariate correlations between fat distribution and log triglycerides (r=0.27), log HDL cholesterol (r=-0.23), systolic blood pressure (r=0.26), and left ventricular mass (r=0.37). Multiple regression analysis showed that the significant independent correlates for triglycerides and HDL cholesterol were age and fat distribution; for systolic blood pressure, height and fat distribution; and for left ventricular mass, height, race, sex, and fat distribution. CONCLUSIONS: These results demonstrate that fat distribution is a more important independent correlate of cardiovascular risk factors than percent body fat in children and adolescents. Greater deposition of central fat (an android fat pattern) is associated with less favorable plasma lipid and lipoprotein concentrations, blood pressure, and left ventricular mass.

Adipose Tissue↗
PubMed1999

Purulent pericarditis presenting as acute abdomen in children: abdominal imaging findings.

Purulent pericarditis is rapidly fatal if untreated [1,2]. With increased development of bacterial resistance to antibiotics, severe bacterial infections in children are becoming more frequent [3,4]. We report two children with purulent pericarditis who presented in a 1-month period for evaluation of acute abdominal distention and signs of sepsis. In both, one evaluated with computed tomography (CT) and one with ultrasound, abdominal findings included periportal edema, gallbladder wall thickening, and ascites secondary to right heart failure from cardiac tamponade. Radiologists should be aware that children with purulent pericarditis may have a normal heart size on radiographs, present with acute abdominal symptoms, and demonstrate findings of right sided heart failure on abdominal imaging.

Abdomen, Acute↗
PubMed1999

Fibroblast growth factor-2 mediates pressure-induced hypertrophic response.

In vitro, fibroblast growth factor-2 (FGF2) has been implicated in cardiomyocyte growth and reexpression of fetal contractile genes, both markers of hypertrophy. However, its in vivo role in cardiac hypertrophy during pressure overload is not well characterized. Mice with or without FGF2 (Fgf2(+/+) and Fgf2(-/-), respectively) were subjected to transverse aortic coarctation (AC). Left ventricular (LV) mass and wall thickness were assessed by echocardiography preoperatively and once a week postoperatively for 10 weeks. In vivo LV function during dobutamine stimulation, cardiomyocyte cross-sectional area, and recapitulation of fetal cardiac genes were also measured. AC Fgf2(-/-) mice develop significantly less hypertrophy (4-24% increase) compared with AC Fgf2(+/+) mice (41-52% increase). Cardiomyocyte cross-sectional area is significantly reduced in AC Fgf2(-/-) mice. Noncoarcted (NC) and AC Fgf2(-/-) mice have similar beta-adrenergic responses, but those of AC Fgf2(+/+) mice are blunted. A lack of mitotic growth in both AC Fgf2(+/+) and Fgf2(-/-) hearts indicates a hypertrophic response of cardiomyocytes. Consequently, FGF2 plays a major role in cardiac hypertrophy. Comparison of alpha- and beta-cardiac myosin heavy chain mRNA and protein levels in NC and AC Fgf2(+/+) and Fgf2(-/-) mice indicates that myosin heavy chain composition depends on hemodynamic stress rather than on FGF2 or hypertrophy, and that isoform switching is transcriptionally, not posttranscriptionally, regulated.

Animals↗
PubMed1998

Left ventricular geometry and severe left ventricular hypertrophy in children and adolescents with essential hypertension.

BACKGROUND: Left ventricular (LV) hypertrophy has been established as an independent risk factor for cardiovascular disease in adults. Recent research has refined this relationship by determining a cutpoint of 51 g/m(2.7) for LV mass index indicative of increased risk and defining LV geometric patterns that are associated with increased risk. The purpose of this study was to evaluate severe LV hypertrophy and LV geometry in children and adolescents with essential hypertension. METHODS AND RESULTS: A cross-sectional study of young patients (n=130) with persistent blood pressure elevation above the 90th percentile was conducted. Nineteen patients (14%) had LV mass greater than the 99th percentile; 11 of these were also above the adult cutpoint of 51 g/m(2.7). Males, subjects with greater body mass index, and those who had lower heart rate at maximum exercise were at significantly (P<.05) higher risk of severe LV hypertrophy. In addition, 22 patients (17%) had concentric LV hypertrophy, a geometric pattern that is associated with increased risk of cardiovascular disease in adults. Seven patients had LV mass index above the cutpoint and concentric hypertrophy. No consistent significant determinants of LV geometry were identified in these children and adolescents with hypertension. CONCLUSIONS: Severe LV hypertrophy and abnormal LV geometry are relatively prevalent in young patients with essential hypertension. These findings suggest that these patients may be at risk for future cardiovascular disease and underscore the importance of recognition and treatment of blood pressure elevation in children and adolescents. Weight loss is an important component of therapy in young patients with essential hypertension who are overweight.

Adolescent↗
PubMed1998

Myofibril degeneration caused by tropomodulin overexpression leads to dilated cardiomyopathy in juvenile mice.

Loss of myofibril organization is a common feature of chronic dilated and progressive cardiomyopathy. To study how the heart compensates for myofibril degeneration, transgenic mice were created that undergo progressive loss of myofibrils after birth. Myofibril degeneration was induced by overexpression of tropomodulin, a component of the thin filament complex which determines and maintains sarcomeric actin filament length. The tropomodulin cDNA was placed under control of the alpha-myosin heavy chain gene promoter to overexpress tropomodulin specifically in the myocardium. Offspring with the most severe phenotype showed cardiomyopathic changes between 2 and 4 wk after birth. Hearts from these mice present characteristics consistent with dilated cardiomyopathy and a failed hypertrophic response. Histological analysis showed widespread loss of myofibril organization. Confocal microscopy of isolated cardiomyocytes revealed intense tropomodulin immunoreactivity in transgenic mice together with abnormal coincidence of tropomodulin and alpha-actinin reactivity at Z discs. Contractile function was compromised severely as determined by echocardiographic analyses and isolated Langendorff heart preparations. This novel experimentally induced cardiomyopathy will be useful for understanding dilated cardiomyopathy and the effect of thin filament-based myofibril degeneration upon cardiac structure and function.

Animals↗
PubMed1998

Coarctation of the aorta following coil occlusion of a patent ductus arteriosus.

A case is described in which coarctation of the aorta develops following coil occlusion of a patent ductus arteriosus with a single Gianturco coil. This finding has yet to be reported in children undergoing this procedure and demonstrates the possibility of its occurrence and brings into question the need for and the duration of antibiotic prophylaxis following coil deployment.

Aortic Coarctation↗
PubMed1998

Nocturnal blood pressure in young patients with insulin-dependent diabetes mellitus: correlation with cardiac function.

Lack of a decline in nocturnal blood pressure is associated with an adverse effect on end organs in adults with insulin-dependent diabetes mellitus (IDDM). The role of the decline in nocturnal blood pressure in young patients with IDDM is not known. We studied 25 white subjects with IDDM (age = 20.8 +/- 3.7 years, mean +/- SD), 8 of whom were female. The duration of IDDM in these subjects was 12.9 +/- 5.4 years (mean +/- SD). We determined the values for glycosylated hemoglobin (HgbA1), 24-hour ambulatory blood pressure, diastolic cardiac function (the ratio of peak E wave to peak A wave velocity (E/A) and indexed peak filling rate ¿PFR/SV¿ by Doppler echocardiography), and albumin excretion rate. The HgbA1 level was 10.9% +/- 1.9% (mean +/- SD; normal range = 4.5%-8.5%). The HgbA1 concentration was inversely correlated (p < 0.005) with the decline in systolic (r = 0.57) and diastolic (r = -0.55) nocturnal blood pressure. Diastolic cardiac dysfunction ¿E/A ratio [r = 0.42, p < 0.03) and PFR/SV (r = 0.52, p < 0.01)¿ correlated with a smaller decrease in nocturnal diastolic blood pressure. An inverse correlation between decline in nocturnal systolic blood pressure and log albumin excretion rate (r = -0.37, p = 0.07) approached statistical significance. We conclude that poor glycemic control adversely affects nocturnal blood pressure and that the latter may play an important role in cardiac and possibly renal dysfunction in early IDDM.

Adolescent↗
PubMed1998

Effect of veno-venous ultrafiltration on myocardial performance immediately after cardiac surgery in children. A prospective randomized study.

OBJECTIVES: This study sought to evaluate the effects of veno-venous ultrafiltration on myocardial contractility in children undergoing cardiopulmonary bypass (CPB) for repair of congenital heart defects. BACKGROUND: Ultrafiltration (UF) is currently used to diminish postoperative fluid accumulation following CPB in children. Previous reports indicate improvement in hemodynamics immediately after UF, but the mechanism of its action is unknown. METHODS: Twenty-three patients (ages 2 months to 9.1 years; 13 males, 10 females) underwent UF for 10 min after CPB. Twelve patients underwent UF immediately after CPB (Group A). They were studied: (1) before and (2) after CPB, (3) after UF, and (4) 10 min after UF. Eleven patients underwent UF 10 min after CPB (Group B). They were studied: (1) before and (2) after CPB, (3) after a 10-min delay before UF, and (4) after UF. Contractility was determined by the difference in the observed and predicted velocity of circumferential fiber shortening for the measured wall stress, using transesophageal echocardiography. Left ventricular wall thickness was also measured. RESULTS: There was significant improvement in contractility after UF in both groups (mean+/-SD, Group A: -0.28+/-0.13 to -0.01+/-0.21 circ/s, p < 0.05; Group B: -0.26+/-0.16 to -0.11+/-0.17 circ/s, p < 0.05). Myocardial thickness to cavity dimension decreased in both groups following UF (Group A: 0.19+/-0.04 to 0.14+/-0.03, p < 0.05; Group B: 0.18+/-0.04 to 0.14+/-0.03, p < 0.05). CONCLUSIONS: UF improves hemodynamics by improving contractility and possibly by reducing myocardial edema in children following cardiac surgery. Enhanced patient outcome after ultrafiltration may in part be due to these changes.

Cardiopulmonary Bypass↗
PubMed1998

Diastolic dysfunction in young patients with insulin-dependent diabetes mellitus as determined by automated border detection.

Diastolic dysfunction is an early harbinger for systolic dysfunction in insulin-dependent diabetes mellitus (IDDM). To determine the role of automated border detection (ABD) in detecting diastolic abnormalities and whether IDDM control correlates with abnormalities, 21 young IDDM patients (22 +/- 4 years old) and 19 control subjects underwent echocardiography. ABD indices included the percent contribution to total left ventricular filling of the three phases of diastole (rapid filling, diastasis, and atrial contraction) and peak filling rate. Doppler indices included E/A ratio and peak filling rate. Rapid filling phase was lower in the IDDM patients compared with control subjects (73% +/- 5% versus 80% +/- 5%, p = 0.0006), and atrial contraction filling was higher (19% +/- 4% versus 14% +/- 3%, p = 0.0003). Doppler indexes showed similar changes. Glycosylated hemoglobin, insulin dosage, and duration of IDDM since puberty were associated with filling abnormalities. Young patients with IDDM have increased atrial contraction and reduced rapid filling phases detected by automatic border detection, and these diastolic abnormalities are related to the diabetic disease process.

Adult↗
PubMed1998

End-systolic stress-velocity and pressure-dimension relationships by transthoracic echocardiography in mice.

The purposes of this study were to assess load-independent, end-systolic relationships in mice and compare these relationships to ejection phase indexes in assessing contractility. In 13 mice, ejection phase indexes (shortening fraction and velocity of fiber shortening) and end-systolic relationships [pressure-dimension relationship (ESPDR) and stress-velocity relationship (ESSVR)] were determined using M-mode echocardiography and simultaneous left ventricular pressure. Load was altered with phenylephrine and nitroprusside. Contractility was increased with dobutamine and decreased by induction of hypothyroidism. Ejection phase indexes increased with dobutamine infusion but were not significantly decreased with hypothyroidism. However, end-systolic relationships changed significantly with both dobutamine (gamma-intercepts: ESPDR from 22 to 48 mmHg, ESSVR from 3.7 to 6.6 circ/s, P < 0.05) and hypothyroidism (gamma-intercepts: ESPDR from 22 to 11 mmHg, ESSVR from 3.7 to 3.2 circ/s, P < 0.05). We conclude that end-systolic indexes can be accurately measured in the intact mouse by echocardiography with simultaneous left ventricular pressure recording and appear to be more sensitive to inotropic state than ejection phase indexes.

Animals↗
PubMed1998

Interaction between body size and cardiac workload: influence on left ventricular mass during body growth and adulthood.

The development of the left ventricle parallels body growth. During infancy, the relation between body size and left ventricular (LV) mass is very close. With advancing age, variability of LV mass in relation to body size markedly increases. To test the hypothesis that the age-related increase in variability of LV mass is due to the progressive impact of hemodynamic stimuli on LV growth, quantitative M-mode echocardiograms were obtained in 766 normal-weight, normotensive individuals over a range of ages from 1 day to 85 years (330 female subjects, 373 subjects younger than 18 years). LV mass was linearly related to height2.7 (r2=.69). Prediction of values of LV mass by body size was more accurate at birth and progressively less precise with increasing age. Stroke work (stroke volume times systolic pressure) was closely related to LV mass (r2=.74). The explained variance of LV mass increased from 69% in the univariate regression with height2.7 to 82% in a multivariate model including height2.7, stroke work, and gender. In children and adolescents (younger than 18 years), height2.7 was the main determinant of LV mass, whereas during adulthood stroke work and gender were more important predictors of LV mass than height2.7. Thus (1) the influence of body growth on development of LV mass decreases after early infancy because of both the variability of hemodynamic load and the increasing effect of gender; (2) after adolescence, during adulthood, in normotensive, normal-weight individuals, the impact of hemodynamic load and male gender on LV mass is greater than the one of body size; and (3) an appreciable proportion of variability of LV mass remains unexplained with the studied models. This might be due to genotypic variations and/or measurement error.

Adult↗
PubMed1997

Cardiac compartment-specific overexpression of a modified retinoic acid receptor produces dilated cardiomyopathy and congestive heart failure in transgenic mice.

Retinoids play a critical role in cardiac morphogenesis. To examine the effects of excessive retinoid signaling on myocardial development, transgenic mice that overexpress a constitutively active retinoic acid receptor (RAR) controlled by either the alpha- or beta-myosin heavy chain (MyHC) promoter were generated. Animals carrying the alpha-MyHC-RAR transgene expressed RARs in embryonic atria and in adult atria and ventricles, but developed no signs of either malformations or disease. In contrast, beta-MyHC-RAR animals, where expression was activated in fetal ventricles, developed a dilated cardiomyopathy that varied in severity with transgene copy number. Characteristic postmortem lesions included biventricular chamber dilation and left atrial thrombosis; the incidence and severity of these lesions increased with increasing copy number. Transcript analyses showed that molecular markers of hypertrophy, alpha-skeletal actin, atrial natriuretic factor and beta-MyHC, were upregulated. Cardiac performance of transgenic hearts was evaluated using the isolated perfused working heart model as well as in vivo, by transthoracic M-mode echocardiography. Both analyses showed moderate to severe impairment of left ventricular function and reduced cardiac contractility. Thus, expression of a constitutively active RAR in developing atria and/ or in postnatal ventricles is relatively benign, while ventricular expression during gestation can lead to significant cardiac dysfunction.

Animals↗
PubMed1997

Stroke volume and cardiac output in normotensive children and adults. Assessment of relations with body size and impact of overweight.

BACKGROUND: Relations between organs and body size are not linear but rather follow allometric (growth) relations characterized by their powers (exponents). METHODS AND RESULTS: Stroke volume (SV) by M-mode echocardiography was related to height, weight, body surface area (BSA), and ideal BSA (derived from ideal body weight for given height) in 970 normotensive individuals (1 day to 85 years old; 426 < 18 years old; 204 overweight to obese; 426 female). In normal-weight children, adults, and the entire population, SV was related by allometric relations to BSA (power = 0.82 to 1.19), body weight (power = 0.57 to 0.71), and height (power = 1.45 to 2.04) (all P < .0001). Relations of cardiac output to measures of body size had lower allometric powers than those for SV in the entire population (0.41 for body weight, 0.62 for BSA, and 1.16 for height). In overweight adults, observed SVs were 17% greater than predicted for ideal BSA, a difference that was approximated by normalization of SV for height to age-specific allometric powers. Similarly, observed cardiac output was 19% greater than predicted for ideal BSA, a difference that was accurately detected by use of cardiac output/height to age-specific allometric powers but not of BSA to the first power. CONCLUSIONS: Indices of SV and cardiac output for BSA are pertinent when the effect of obesity needs to be removed, because these indices obscure the impact of obesity. To detect the effect of obesity on LV pump function, normalization of SV and cardiac output for ideal BSA or for height to its age-specific allometric power should be practiced.

Adolescent↗