The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

AIMS/HYPOTHESIS: We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. METHODS: Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. RESULTS: Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). CONCLUSIONS/INTERPRETATION: Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

Dobutamine stress echocardiography in the evaluation of young patients with Kawasaki disease.

There has been no consistent approach to the follow-up of Kawasaki disease patients for remote coronary perfusion abnormalities. Dobutamine stress echocardiography (DSE) has become a standard method for evaluation of perfusion abnormalities in adults with coronary artery disease. In addition, DSE has been used with success in some pediatric patients. The purposes of this study were to evaluate safety and accuracy of DSE in the follow-up of patients with Kawasaki disease, to evaluate whether DSE adds any additional value to the resting echocardiogram, and to determine the association of DSE results with American Heart Association (AHA) risk level categories. DSE was performed 1 month to 13 years after acute Kawasaki disease in 47 patients (range, 3.8-22.6 years; 33 males and 16 females). Patients were stratified according to AHA risk level categories (I-V). Ischemia was defined as a new or worsening regional wall motion abnormality or >1 mm ST segment depression on the electrocardiogram during DSE. In 45/47 patients, DSE was completed successfully (i.e., achievement of target heart rate or development of ischemia). No patients in risk levels lower than V (i.e., patients without coronary artery stenoses) had positive DSE, whereas 2/4 (50%) in the risk level V category had positive DSE, both of whom had coronary occlusion >50% confirmed by angiography. Of the 2 AHA risk level V patients with negative DSE, 1 had extensive collateralization and the other had coronary obstruction <50%. DSE is a safe and feasible method for the evaluation of children with Kawasaki disease. DSE provides a confirmatory benefit and may be a useful screening alternative to cardiac catheterization during follow-up. Patients in AHA risk levels I-IV are unlikely to have dobutamine-induced coronary perfusion abnormalities. Patients in the risk level V category may or may not have positive DSE depending on the degree of both coronary obstruction and collateralization.

Noncircumferential myofiber function: impact on early diastolic filling in children.

Circumferential and noncircumferential myofiber contraction may have varying impact on systolic and diastolic function. The purpose of this study was to determine the relation of circumferential, longitudinal, and oblique fiber shortening to early diastolic filling in children. Twenty-five patients (8.1 +/- 5.6 years of age; 12 boys and 13 girls) with normal echocardiograms and no heart disease had prospective echocardiographic evaluation of circumferential (shortening fraction, fractional area change), longitudinal (left ventricular axial shortening), combined circumferential and longitudinal (left ventricular ejection fraction), oblique (left ventricular systolic twist [LVST]) shortening, and early diastolic filling. Mean LVST was 16 +/- 8 degrees. There was no relation between early diastolic filling indexes and indexes of circumferential or longitudinal shortening. However, there was a significant inverse relation between heart rate-corrected E-wave acceleration time and LVST (r = 0.63, P <.001). Oblique fiber shortening affects early diastolic filling in children. Describing the functional role of noncircumferential left ventricular myofibers may improve our understanding of global left ventricular function.

Relation of heart rate to left ventricular dimensions in normotensive, normal-weight children, adolescents and adults.

BACKGROUND: The quantitative relation between body growth and changes in heart rate, and the relationship of heart rate to left ventricular (LV) dimensions, independent of the influence of body size, have been only marginally investigated. Accordingly, we designed this study to investigate the relation between heart rate, body size and LV dimensions in children, adolescents and adults over a broad age span. METHODS: Eight hundred and nineteen normotensive, multi-racial, normal-weight individuals (444 males, 375 females, aged 1-85 years) with normal LV systolic function were studied at echocardiography in three centers, using previously reported methods. The resting heart rate was measured on the M-mode echo-tracing or right after the echocardiogram with the subject still in the supine position. RESULTS: In children and adolescents (up to 17 years), the heart rate decreased with increasing body height (r = -0.51, p < 0.0001) and body weight (r = -0.42, p < 0.0001), in a similar manner in girls and boys. In adults, the heart rate was higher in women than in men, but it was not independently related to body size. The LV diastolic diameter was higher in males and decreased with increasing heart rate in children and adolescents (r = -0.45) as well as in adults (r = -0.25, both p < 0.0001). This relation was also independent of the effect of body size, sex and race. Similarly, the LV mass increased with decreasing heart rate in children and adolescents (r = -0.45), but the association was not confirmed after controlling for body size, sex and race. In adults, heart rate was inversely related to LV mass (r = -0.21, p < 0.0001), and this relation was also independent of body size, sex, race, age and blood pressure (p < 0.001). In women, the relation of heart rate to LV mass/height2.7 was less close than in men, due to the greater increase in LV mass with age. CONCLUSIONS: The heart rate has an inverse association with the LV chamber diameter and with the LV mass in children-adolescents and in adults. This relation is largely, but not uniquely, mediated by body proportions, especially during body growth.

Design and baseline characteristics for the ACE Inhibitor After Anthracycline (AAA) study of cardiac dysfunction in long-term pediatric cancer survivors.

PURPOSE: The ACE Inhibitor After Anthracycline (AAA) study is a randomized, double-blind, controlled clinical trial comparing enalapril with placebo to determine whether treatment can slow the progression of cardiac decline in patients who screen positive for anthracycline cardiotoxicity. METHODS: The primary outcome measure is the rate of decline, over time, in maximal cardiac index (in liters per minute per meters squared) at peak exercise; the secondary outcome measure is the rate of increase in left ventricular end systolic wall stress (in grams per centimeters squared). Patients >2 years off therapy and <4 years from diagnosis, aged 8 years and older, were eligible if they had received anthracyclines and had at least one cardiac abnormality identified at any time after anthracycline exposure. RESULTS: A total of 135 patients were randomized to enalapril or placebo. Baseline characteristics were similar across treatment groups. CONCLUSIONS: The AAA study will provide important information concerning the efficacy of using angiotensin-converting enzyme inhibitors to offset the effects of late anthracycline cardiotoxicity.

Temporally regulated and tissue-specific gene manipulations in the adult and embryonic heart using a tamoxifen-inducible Cre protein.

The advent of conditional and tissue-specific recombination systems in gene-targeted or transgenic mice has permitted an assessment of single gene function in a temporally regulated and cell-specific manner. Here we generated transgenic mice expressing a tamoxifen-inducible Cre recombinase protein fused to two mutant estrogen-receptor ligand-binding domains (MerCreMer) under the control of the alpha-myosin heavy chain promoter. These transgenic mice were crossed with the ROSA26 lacZ-flox-targeted mice to examine Cre recombinase activity and the fidelity of the system. The data demonstrate essentially no Cre-mediated recombination in the embryonic, neonatal, or adult heart in the absence of inducing agent but >80% recombination after only four tamoxifen injections. Expression of the MerCreMer fusion protein within the adult heart did not affect cardiac performance, cellular architecture, or expression of hypertrophic marker genes, demonstrating that the transgene-encoded protein is relatively innocuous. In summary, MerCreMer transgenic mice represent a tool for temporally regulated inactivation of any loxP-targeted gene within the developing and adult heart or for specifically directing recombination and expression of a loxP-inactivated cardiac transgene in the heart.

Changes in left ventricular mass index in children and adolescents after renal transplantation.

Recent reports indicate a high prevalence of left ventricular hypertrophy (LVH) in children on dialysis and after renal transplantation (Tx), as identified by cross-sectional analysis. However, the evolution of LVH in pediatric patients with end-stage renal disease after renal Tx is not well established. To assess changes of left ventricular mass (LVM), we prospectively performed echocardiography in 23 children and adolescents between November 1998 and July 2000. Each patient had an echocardiographic evaluation while on dialysis (for at least 6 weeks) and a follow-up evaluation at least 6 months after successful renal Tx (i.e. with a measured glomerular filtration rate [GFR] of at least 40 mL/min/1.73 m2). The LVM index was estimated by indexing LVM to height(2.7). Sixteen patients had a cadaveric transplant and seven had a live donor transplant; the mean duration between the two studies was 1.9 +/- 1.6 yr; and the mean GFR was 55.0 +/- 21.4 mL/min/1.73 m2. There was no significant difference in the mean values of the LVM index while on dialysis and after renal Tx (43.9 +/- 17.8 g/m2.7 and 39.3 +/- 12.0 g/m2.7, respectively, p = 0.19), or in the prevalence of LVH (52% and 56%, respectively). Interval changes in the LVM index in individual subjects between the two studies were significantly associated with interval changes in indexed systolic (r = 0.42, p = 0.04) and diastolic (r = 0.42, p = 0.05) blood pressures. Interval changes in hemoglobin, blood urea nitrogen (BUN), creatinine, and duration after Tx did not correlate with changes in the LVM index. There was no significant difference in LVM index change according to the type of dialysis, donor source, and the cause of renal failure. In multivariate analysis, the baseline LVM index and changes in indexed SBP were independent predictors for LVM index change after renal Tx. We conclude that LVH persists in children and adolescents after renal Tx. Control of blood pressure might be an important factor in regression or prevention of progression of LVH in these patients.

The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo.

The zinc finger-containing transcription factors GATA4 and GATA6 are important regulators of basal and inducible gene expression in cardiac and smooth muscle cell types. Here we demonstrate a direct functional role for GATA4 and GATA6 as regulators of cardiomyocyte hypertrophic growth and gene expression. To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor was overexpressed in cardiomyocytes using recombinant adenovirus. Overexpression of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypertrophy characterized by enhanced sarcomeric organization, a greater than 2-fold increase in cell surface area, and a significant increase in total protein accumulation. In vivo, transgenic mice with 2.5-fold overexpression of GATA4 within the adult heart demonstrated a slowly progressing increase in heart to body weight ratio, histological features of cardiomyopathy, and activation of hypertrophy-associated genes, suggesting that GATA factors are sufficient regulators of cardiomyocyte hypertrophy in vitro and in vivo. To evaluate the requirement of GATA factors as downstream transcriptional mediators of hypertrophy, a dominant negative GATA4-engrailed repressor fusion-encoding adenovirus was generated. Expression of GATA4-engrailed blocked GATA4- and GATA6-directed transcriptional responses and agonist-induced cardiomyocyte hypertrophy, demonstrating that cardiac-expressed GATA factors are necessary mediators of this process.

Guidelines for cardiac sonographer education: recommendations of the American Society of Echocardiography Sonographer Training and Education Committee.

In 1992, the American Society of Echocardiography published a report of the Sonographer Education and Training Committee's recommendations for education of sonographers who perform echocardiographic procedures. Since the publication of the original document, there has been continual progress in technology with the development of more sophisticated diagnostic applications that allow more information to be obtained from echocardiographic procedures. These recent changes in the clinical application of echocardiography should be included in all cardiac sonographer education programs. The American Society of Echocardiography, a professional society that currently represents approximately 2500 cardiac sonographers, provides these updated guidelines.

Unique echocardiographic features associated with deployment of the Amplatzer atrial septal defect device.

The purpose of this study was to describe the unique echocardiographic findings associated with deployment of the Amplatzer atrial septal defect (ASD) device. Thirty-five patients (2 to 40 years old; 23 female and 12 male patients) underwent echocardiography during attempted ASD closure with the Amplatzer device. Transesophageal and transthoracic echocardiograms were performed during the placement and follow-up of the device, respectively. In 5 patients, the device was not deployed because of transesophageal echocardiography (TEE) findings (an exceedingly large defect in 3 patients, partial obstruction of the upper right pulmonary vein by the device in 1, and complex atrial septal anatomy in 1). In the remaining 30 patients, after deployment but before release, the device distorted the atrial septum from the normal vertical orientation to an oblique transverse orientation. Excessive septal distortion (i.e., > or =90 degrees in 1 patient) was associated with device embolization upon release. In other patients, TEE also identified mild splaying of the device on the aortic wall, mild abutment of the device upon the mitral valve, and temporary partial obstruction of pulmonary vein flow. Color Doppler revealed residual shunts in 21 of 29 patients immediately after release, but in none of 15 patients at 1-year follow-up. Transesophageal echocardiography is essential to ensure proper Amplatzer device placement. Distortion of the atrial septum and Amplatzer device orientation occur before release but resolve on release from the delivery cable. Small residual shunts are common early, but they resolve in 6 to 12 months.

Effects of aging on left atrial reservoir, conduit, and booster pump function: a multi-institution acoustic quantification study.

OBJECTIVE: To assess the feasibility of measuring left atrial (LA) function with acoustic quantification (AQ) and then assess the effects of age and sex on LA reservoir, conduit, and booster pump function. PATIENTS AND SETTING: 165 subjects without cardiovascular disease, 3-79 years old, were enrolled by six tertiary hospital centres. INTERVENTIONS: Continuous LA AQ area data were acquired and signal averaged to form composite waveforms which were analysed off-line. MAIN OUTCOME MEASURES: Parameters of LA performance according to age and sex. RESULTS: Signal averaged LA waveforms were sufficiently stable and detailed to allow automated analysis in all cases. An age related increase in LA area was noted. LA reservoir function did not vary with age or sex. All parameters of LA passive and active emptying revealed a significant age dependency. Overall, the passive emptying phase accounted for 66% of total LA emptying ranging from 76% in the youngest to 44% in the oldest decade. LA contraction accounted for 34% of atrial emptying in all subjects combined with the older subjects being more dependent on atrial booster pump function. When adjusted for atrial size, there were no sex related differences in LA function. CONCLUSIONS: LA reservoir, conduit, and booster pump function can be assessed with automated analysis of signal averaged LA area waveforms. As LA performance varies with age, establishment of normal values should enhance the evaluation of pathologic states in which LA function is important.

The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo.

Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.

One-year follow-up of the amplatzer device to close atrial septal defects.

The early and 1-year follow-up of a single United States center using the Amplatzer atrial septal defect closure device is reported. Complete closure was documented in all patients by 1 year after device implantation.

The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice.

Members of the mitogen-activated protein kinase (MAPK) cascade such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 are implicated as important regulators of cardiomyocyte hypertrophic growth in culture. However, the role that individual MAPK pathways play in vivo has not been extensively evaluated. Here we generated nine transgenic mouse lines with cardiac-restricted expression of an activated MEK1 cDNA in the heart. MEK1 transgenic mice demonstrated concentric hypertrophy without signs of cardiomyopathy or lethality up to 12 months of age. MEK1 transgenic mice showed a dramatic increase in cardiac function, as measured by echocardiography and isolated working heart preparation, without signs of decompensation over time. MEK1 transgenic mice and MEK1 adenovirus-infected neonatal cardiomyocytes each demonstrated ERK1/2, but not p38 or JNK, activation. MEK1 transgenic mice and MEK1 adenovirus-infected cultured cardiomyocytes were also partially resistant to apoptotic stimuli. The results of the present study indicate that the MEK1-ERK1/2 signaling pathway stimulates a physiologic hypertrophy response associated with augmented cardiac function and partial resistance to apoptotsis.

Exposure to ionizing radiation in children undergoing Amplatzer device placement to close atrial septal defects.

To evaluate exposure to ionizing radiation during Amplatzer device occlusion, a prospective study was performed to measure surface entrance radiation dose by thermoluminescent dosimetry (TLD). Between June 1998 and April 1999, dosimetry was carried out on 12 patients with Amplatzer device occlusion of atrial septal defects (n = 10) or Fontan fenestration (n =) and 12 age-matched patients who underwent diagnostic catherization. TLD chips were placed at the posterior (PA) and right lateral (LA) chest wall as well as the thyroid (TH) and gonadal (GN) regions. The Amplatzer group had a median age of 6.4 yr (2.4-12.4 yr) and a median weight of 23.7 kg (15.6-28.9 kg), which were similar (p = NS) to those of the control group, who had a median age of 7.9 yr (3.3-16.2 yr) and a median weight of 29.9 kg (10.6-58.0 kg). Device placement was successful in 11 of 12 patients; one device was removed owing to partial obstruction of the right-upper pulmonary vein. Fluoroscopy times were also similar in the Amplatzer group (23.5 +/- 2.1 min) and the control group (16.4 +/- 3.1 min; P = NS). The measured surface entrance doses of the Amplatzer group was similar (p = NS) to those of the control group in all four regions: PA (4.96 +/- 1.88 vs. 6.07 +/- 2.16 cGy), LA (5.22 +/- 1.68 vs. 3.13 +/- 1.25 cGy), TH (0.92 +/- 0.14 vs. 0.69 +/- 0.09 cGy), and GN (0.20 +/- 0.00 vs. 0.22 +/- 0.01cGy). Fluoroscopy times and measured surface entrance doses of ionizing radiation in patients undergoing Amplatzer device occlusion are similar to those in patients undergoing routine diagnostic catheterization.

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.

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.

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.

Calcineurin expression, activation, and function in cardiac pressure-overload hypertrophy.

BACKGROUND: Vascular hypertension resulting in increased cardiac load is associated with left ventricular hypertrophy and is a leading predicator for progressive heart disease. The molecular signaling pathways that respond to increases in cardiac load are poorly understood. One potential regulator of the hypertrophic response is the calcium-sensitive phosphatase calcineurin. METHODS AND RESULTS: We showed that calcineurin enzymatic activity is increased 3. 2-fold in the heart in response to pressure-overload hypertrophy induced by abdominal aortic banding in the rat. Western blot analysis further demonstrates that calcineurin A (catalytic subunit) protein content and association with calmodulin are increased in response to pressure-overload hypertrophy. This increase in calcineurin protein content was prevented by administration of the calcineurin inhibitor cyclosporine A (CsA). CsA administration attenuated load-induced cardiac hypertrophy in a dose-dependent manner over a 14-day treatment protocol. CsA administration also partially reversed pressure-overload hypertrophy in aortic-banded rats after 14 days. CsA also attenuated the histological and molecular indexes of pressure-overload hypertrophy. CONCLUSIONS: These data suggest that calcineurin is an important upstream regulator of load-induced hypertrophy.