Fibroblast Growth Factor 2 Mediates Isoproterenol-induced Cardiac Hypertrophy through Activation of the Extracellular Regulated Kinase.

Fibroblast growth factor 2 (basic FGF or FGF2) has been shown to affect growth and differentiation in some tissues and to be required for cardiac hypertrophy in vivo. FGF2 has been shown in vitro to signal through the mitogen-activated protein kinase (MAPK) to affect cell survival and growth. To ascertain the role of FGF2 in cardiac hypertrophy, wildtype, Fgf2 knockout, non-transgenic, and FGF2 transgenic mice were treated with isoproterenol or saline via subcutaneous mini-osmotic pump implants to induce a hypertrophic response to ß-adrenergic stimulation. Fgf2 knockout hearts are protected from isoproterenol-induced cardiac hypertrophy; whereas, FGF2 transgenic hearts show exacerbated cardiac hypertrophy as assessed by heart weight-to-body weight ratios and myocyte cross-sectional area. Echocardiography reveals significantly decreased fractional shortening in isoproterenol-treated FGF2 transgenic mice but not in Fgf2 knockout mice suggesting that FGF2 mediates the maladaptive cardiac dysfunction seen in cardiac hypertrophy induced by isoproterenol. Western blot analysis also reveals alterations in MAPK signaling in Fgf2 knockout and FGF2 transgenic hearts subjected to isoproterenol treatment, suggesting that this cascade mediates FGF2's pro-hypertrophic effect. Pharmacologic inhibition of extracellular signal-regulated kinase (ERK) signaling results in an attenuated hypertrophic response in isoproterenol-treated FGF2 transgenic mice, but this response is not seen with p38 mitogen-activated protein kinase (p38) pathway inhibition, suggesting that FGF2 activation of ERK but not p38 is necessary for FGF2's role in the mediation of cardiac hypertrophy.

Subclinical systolic dysfunction in pediatric patients with chronic kidney disease.

OBJECTIVES: Midwall shortening (mwSF) is thought to be a more accurate measure of myocardial performance in the presence of left ventricular hypertrophy (LVH). We examined mwSF in pediatric patients with varying degrees of chronic kidney disease (CKD). STUDY DESIGN: Fifty-seven children with CKD stages 2 to 4, 25 who were undergoing hemodialysis and 49 who were transplant recipients, were compared with 35 healthy control subjects. Left ventricular (LV) geometry and indices of LV function were assessed echocardiographically. RESULTS: There were no significant differences in LV contractility or endocardial shortening fraction between patients and control subjects. Yet, patients undergoing hemodialysis had significantly lower mwSF compared with control subjects (P < .01) and patients with stage 2 to 4 CKD (P < .01). Renal transplant patients had lower mwSF compared with control subjects (P < .01). The prevalence of abnormal mwSF (ie, <16) was significantly higher in patients undergoing hemodialysis (40%) compared with patients who were renal transplant recipeints (12%) and patients with CKD stages 2 to 4 (9%; P = .03). With stepwise regression, mwSF was demonstrated to be predicted by using relative wall thickness (P < .0001), dialysis group (P = .005), and endocardial shortening fraction (P = .001; model R(2) = 0.86). CONCLUSIONS: Children undergoing maintenance hemodialysis and children with concentric LVH have subclinical systolic dysfunction, which might be an indicator for the development of more severe cardiac disease.

Flow-mediated vasodilatation of the brachial artery in children with chronic kidney disease.

We sought to determine flow-mediated vasodilatation (FMD) of the brachial artery and to assess the relationship of FMD with multiple demographic, clinical and biochemical parameters and cardiac and vascular structure and function in children with chronic kidney disease (CKD) stages 2-4. Forty-three patients, aged 6-20 years, with CKD [mean glomerular filtration rate (GFR) 47 +/- 21 ml/min per 1.73 m2 body surface area, range 16-89 ml/min per 1.73 m2] and 34 healthy age-matched controls were included and studied cross-sectionally between 2001 and 2005. The peak FMD was similar in the CKD and control subjects (mean 6.3% vs 6.7%, P = 0.85). However, abnormally low FMD (< 1.1%) was found in ten (23%) children with CKD. Among children with CKD, those with low FMD were younger, shorter, lighter, and had lower body mass index (BMI) than children with normal FMD, but the difference reached statistical significance only for weight and BMI. Serum triglyceride levels were significantly lower in those with low FMD; otherwise, the two groups were similar with respect to multiple clinical and biochemical parameters. Cardiac and vascular structure was similar in children with normal and low FMD. In conclusion, children with CKD stage 2-4 appear to have increased prevalence of decreased FMD of the brachial artery. However, our study identified few significant factors associated with low FMD in children with CKD.

Reversibility of cardiac abnormalities in morbidly obese adolescents.

OBJECTIVES: The purpose of this study was to evaluate changes in cardiac geometry, systolic and diastolic function before and after weight loss in morbidly obese adolescents. BACKGROUND: Cardiac abnormalities are present in morbidly obese adolescents; however, it is unclear if they are reversible with weight loss. METHODS: Data from 38 adolescents (13 to 19 years; 29 females, 9 males, 33 Caucasians, 5 African Americans) were evaluated before and after bariatric surgery. Left ventricular mass (LVM), left ventricular (LV) geometry, systolic and diastolic function were assessed by echocardiography. Mean follow up was 10 +/- 3 months. RESULTS: Weight and body mass index decreased post-operatively (mean weight loss 59 +/- 15 kg, pre-operative body mass index 60 +/- 9 kg/m(2) vs. follow-up 40 +/- 8 kg/m(2), p < 0.0001). Change in LVM index (54 +/- 13 g/m(2.7) to 42 +/- 10 g/m(2.7), p < 0.0001) correlated with weight loss (r = 0.41, p = 0.01). Prevalence of concentric left ventricular hypertrophy (LVH) improved from 28% at pre-operative to only 3% at follow up (p = 0.007), and normal LV geometry improved from 36% to 79% at follow up (p = 0.009). Diastolic function also improved (mitral E/Ea lateral 7.7 +/- 2.3 at pre-operative vs. 6.3 +/- 1.6 at post-operative, p = 0.003). In addition, rate-pressure product improved suggesting decreased cardiac workload (p < 0.001). CONCLUSIONS: Elevated LVM index, concentric LVH, altered diastolic function, and cardiac workload significantly improve following surgically induced weight loss in morbidly obese adolescents. Large weight loss due to bariatric surgery improves predictors of future cardiovascular morbidity in these young people.

Mouse heart valve structure and function: echocardiographic and morphometric analyses from the fetus through the aged adult.

The purpose of this study is to provide standard echocardiographic and morphometric data for normal mouse valve structure and function from late fetal to aged adult stages. Cross-sectional, two-dimensional and Doppler transthoracic echocardiography was performed in C57BL6 mice anesthetized with 1% to 2% isoflurane at embryonic day 18.5 (late fetal), 10 days (neonate), 1 mo (juvenile), 2 mo (young adult), 9 mo (old adult), and 16 mo (aged adult). Normal annulus dimensions indexed to age or weight, and selected flow velocities, were established by echocardiography. After echocardiographic imaging, hearts were harvested and histological and morphometric analyses were performed. Morphometric analysis demonstrated a progressive valve thinning and elongation during the fetal and juvenile stages that plateaued during adult stages (ANOVA, P < 0.01); however, there was increased thickening of the hinge of the aortic valve with advanced age, reminiscent of human aortic valve sclerosis. There was no age-related calcification. The results of this study provide comprehensive echocardiographic and morphometric data for normal mouse valve structure and function from late fetal to aged adult stages and should prove useful as a reference standard for future studies using mouse models of progressive valve disease.

Decreased maximal aerobic capacity in pediatric chronic kidney disease.

Adult and pediatric patients with ESRD have impaired maximum oxygen consumption (VO(2) max), a reflection of the cardiopulmonary system's ability to meet increased metabolic demands. We sought to determine factors associated with decreased VO(2) max in pediatric patients with different stages of CKD. VO(2) max was measured using a standardized exercise testing protocol in patients with stage 2 to 4 chronic kidney disease (CKD) (n = 46), in renal transplant recipients (n = 22), in patients treated with maintenance hemodialysis (n = 12), and in age-matched healthy controls (n = 33). VO(2) max was similar between children with stage 2 CKD and controls, whereas lower VO(2) max was observed among children with stage 3 to 4 CKD, those treated with hemodialysis, and transplant recipients. In univariate analysis, VO(2) max was significantly associated with body mass index, resting heart rate, C-reactive protein, serum triglycerides, serum creatinine, and measures of diastolic function; no significant associations with left ventricular structure or systolic function were identified. In multivariate regression analysis, patient category versus control and the presence of diastolic dysfunction were independent predictors of lower VO(2) max. These results suggest that aerobic capacity is decreased in the early stages of CKD in children and that lower VO(2) max can be predicted by the presence of diastolic dysfunction, even if systolic function is normal.

Diastolic filling abnormalities in children with essential hypertension.

OBJECTIVE: To evaluate whether essential hypertension impacts diastolic function in children. STUDY DESIGN: In this cross-sectional study, patients with essential hypertension (n = 50) were compared with a normotensive group (n = 53). Echocardiographic assessment of diastolic function included measures derived from transmitral, color M-mode, and tissue Doppler interrogation. Cardiac dimensions, wall thickness, geometry, and systolic function were also assessed. Multiple linear regression analysis was performed to identify predictors of altered diastolic function. RESULTS: Diastolic filling abnormalities were found in 36% of the children with blood pressure elevation. Those subjects with concentric hypertrophy were more significantly affected. Abnormalities in indices reflective of left ventricular (LV) relaxation occurred more commonly (39%) than those of LV compliance (33%). Elevated indexed LV mass was found to be the most significant independent predictor of diastolic filling abnormalities. CONCLUSIONS: LV diastolic filling abnormalities were found in one-third of the pediatric subjects with essential hypertension. Whether these changes represent an adaptive or maladaptive response requires further study.

Progression of left ventricular hypertrophy in children with early chronic kidney disease: 2-year follow-up study.

OBJECTIVE: To determine the prevalence and incidence of left ventricular hypertrophy (LVH) and LV geometry and identify variables associated with LV mass (LVM) growth and development of LVH in children and adolescents with chronic kidney disease (CKD). STUDY DESIGN: A 2-year longitudinal study of children with CKD (glomerular filtration rate [GFR] 15-89 mL/minute/1.73 m2). Thirty-one subjects had baseline and repeated echocardiography. RESULTS: Six (19%) of 31 children had LVH at baseline; the prevalence of LVH increased to 39% at 2-year follow-up. Eccentric LVH was the most common geometric pattern throughout the study. Among 25 children with initially normal LVM index, 8 (32%) developed new LVH. Children with incident LVH had significantly higher mean parathyroid hormone (iPTH), lower hemoglobin and calcium levels at baseline, and significantly larger increase in iPTH during a follow-up than children with normal LVM index. Stepwise regression analysis showed that lower initial LVM index and hemoglobin level and interval increase in iPTH and nighttime systolic blood pressure (SBP) load during a follow-up independently predicted interval increase in LVM index. CONCLUSIONS: LVH progresses in children during early stages of CKD. More aggressive control of anemia, BP, and hyperparathyroidism might be important in preventing the development of LVH in these patients.

Cardiac and vascular adaptation in pediatric patients with chronic kidney disease: role of calcium-phosphorus metabolism.

In children, cardiac abnormalities such as increased left ventricular mass (LVM) and diastolic dysfunction develop at the time of mild to moderate chronic renal insufficiency (CRI) and progress as renal function deteriorates. It was hypothesized that in this age group, vascular abnormalities develop early in the course of chronic kidney disease (CKD) in parallel with cardiac abnormalities and become more severe as end-stage disease is reached. Echocardiography and ultrasound of the carotid artery were performed on 44 patients with CKD stages 2 to 4 (CRI group), 16 patients who were on maintenance dialysis, and 35 healthy individuals. Carotid artery intima-media thickness (cIMT) was measured and distensibility and stiffness were calculated to assess carotid artery structure and function. Both the CRI and dialysis groups had greater cIMT, higher LVM index, and poorer diastolic function than the control subjects (P < 0.0001). Children who were on dialysis had greater cIMT and higher LVM index than those with CRI (P < 0.001) and greater arterial stiffness than both CRI patients and control subjects (P < 0.001). Arterial compliance was similar in CRI and control subjects. In all patients with CKD (CRI and dialysis), increased calcium-phosphorus product predicted increased cIMT. Increased serum phosphorus and intact parathyroid hormone predicted increased arterial stiffness. Elevated intact parathyroid hormone was a predictor of increased LVM index and poor diastolic function. In dialysis patients, the cumulative dose of phosphate binders and calcitriol predicted abnormal vascular structure and function. It is concluded that vascular abnormalities are already present in children and adolescents during early stages of CKD; they are more severe in children who are on maintenance dialysis and are related to abnormal calcium-phosphorus metabolism.

Structural cardiac changes as a predictor of respiratory complications after adenotonsillectomy for obstructive breathing during sleep in children.

BACKGROUND AND PURPOSE: To determine the association between structural cardiac changes and postoperative respiratory complications after adenotonsillectomy for obstructive breathing during sleep. PATIENTS AND METHODS: Forty-eight children, ages 2-18 years, undergoing adenotonsillectomy for obstructive breathing during sleep were recruited for this case control study. The case group consisted of 24 children with postoperative respiratory complications after adenotonsillectomy who also had an echocardiogram. An equal number of children without postoperative respiratory complications after adenotonsillectomy were recruited as controls. Left ventricular mass (LVM) was calculated from 2D guided M mode echocardiographic measurements of the left ventricle. Left ventricular mass index (LVMI) was calculated as left ventricular mass/height(2.7). Left ventricular hypertrophy (LVH) was defined as LVMI index greater than the 95th percentile for age. The two groups were compared for demographic variables and cardiac structure. RESULTS: The two groups did not significantly differ by age, height, gender or racial distribution. LVH and right ventricular (RV) dimension greater than the 95th percentile for age remained significantly associated with the occurrence of postoperative respiratory complications after controlling for body mass index (BMI) Z score, age, gender, race, systolic and diastolic blood pressure. CONCLUSIONS: The increased prevalence of structural cardiac changes in the group with complications (P<0.01) suggests an underlying cardiac origin for postoperative respiratory complications in this group of children.

Left ventricular function in children with sleep-disordered breathing.

Severe obstructive sleep apnea in children leads to congestive heart failure. We studied the early changes in left ventricular function across a range of severity of the disorder. A dose-dependent decrease in diastolic function with increased severity of obstructive apnea was demonstrated.

Abnormal carotid artery structure and function in children and adolescents with successful renal transplantation.

BACKGROUND: Abnormal carotid artery compliance and increased intima-media thickness (IMT), markers of early atherosclerosis, are prevalent in adults with chronic kidney failure. However, little is known about the extent of these abnormalities in children after transplantation. METHODS AND RESULTS: Thirty-one children (age, 14.5+/-4.1 years) with renal transplant (estimated glomerular filtration rate, 78.1+/-24.5 mL/min per 1.73 m2; range, 44 to 128 mL/min per 1.73 m2) and 33 age- and sex-matched control subjects had ultrasound of the carotid artery, echocardiography, and ambulatory blood pressure monitoring (transplant patients only). IMT was measured, and distensibility and stiffness parameter (beta) were calculated to assess carotid artery structure and function. The results were correlated with demographic, clinical, and biochemical variables. Compared with control subjects, children with transplant had higher IMT (P=0.03) and beta (P<0.0001) and lower distensibility (P<0.001). In multiple regression analysis, increased IMT in children who had received transplants was associated with higher mean office systolic blood pressure taken within 1 year before the study (R2=0.19, P=0.024) and receipt of >1 transplant (R2=0.16, P=0.02). Worse distensibility and beta were significantly associated with higher daytime systolic blood pressure load calculated from ambulatory blood pressure and receipt of cadaveric kidney. When number of antihypertensives was added to the models, only higher number of blood pressure medications independently predicted abnormal distensibility (R2=0.38, P=0.002) and beta (R2=0.25, P=0.016). CONCLUSIONS: Carotid arteriopathy is present in children with successful renal transplant and is associated with hypertension. The results suggest that these children might be at risk for accelerated atherosclerosis and premature cardiovascular disease.

Impaired left ventricular diastolic function in children with chronic renal failure.

BACKGROUND: Diastolic dysfunction is frequent in adults with renal failure. However, in children with mild-to-moderate chronic renal insufficiency (CRI), it has not been evaluated. We compared diastolic function and assessed risk factors associated with diastolic dysfunction in children with CRI with those on dialysis. METHODS: Thirty-three children with CRI, 17 on chronic dialysis, and 33 control patients, had echocardiography performed. Early diastole was assessed using indices of left ventricular (LV) relaxation derived from transmitral and tissue Doppler, and reported as the peak E/A wave ratio, and septal mitral annular velocities (Em). Late diastole was determined using an index of LV compliance (E/Em ratio). Left atrial (LA) dimension was also determined. RESULTS: Children with CRI had worse diastolic function (lower Em, and higher E/Em ratio than control patients, P < 0.001). Dialysis patients had worse diastolic function (lower E/A ratio and Em, and higher E/Em ratio, P < 0.001) than CRI children. LA dimension was higher in renal patients when compared with control patients (P < 0.001). In children on dialysis, LV relaxation (Em) was significantly related to left ventricular mass (LVM) index (r=-0.58, P= 0.04), and LV compliance (E/Em) was significantly associated with LA index (r= 0.67, P= 0.01), LVM index (r= 0.75, P < 0.01), hemoglobin level (r=-0.65, P= 0.02), serum phosphorus (r= 0.56, P= 0.05), and calcium-phosphorus ion product (r= 0.59, P= 0.04). CONCLUSION: Our results indicate that diastolic dysfunction is already present in children with mild-to-moderate CRI. Worse diastolic function in dialysis patients might be related to LV hypertrophy. The results suggest that children with advanced renal failure and diastolic dysfunction may be at risk for ultimate worsening of cardiac function over time.

Abnormal cardiac function in children after renal transplantation.

BACKGROUND: Cardiac hypertrophy frequently is found in children with a renal transplant. In adults with a transplant, left ventricular (LV) mass (LVM) is associated with cardiac dysfunction. However, in children with a transplant, the relationship between LVM and LV function has not been evaluated. METHODS: Twenty-nine children who underwent transplantation and 33 controls had echocardiographic evaluations during rest and peak exercise. LV contractility was determined based on the relation between heart rate-corrected velocity of circumferential fiber shortening and end-systolic wall stress. Contractile reserve was assessed by the difference between contractility at rest and peak exercise. Early diastole was assessed using indices of LV relaxation derived from transmitral and tissue Doppler and reported as maximal early (E wave) and late (A wave) wave ratio (E-A ratio) and septal mitral annular velocities (Em). Late diastole was determined using an index of LV compliance (E-Em ratio). RESULTS: Compared with controls, children with a transplant had a significantly greater LVM index (P < 0.001) and high prevalence of LV hypertrophy (LVH; 55%). Transplant recipients had increased LV contractility (P < 0.001). Contractile reserve was similar to that of controls. Patients with a transplant had a lower E-A ratio and Em (P < 0.01 for both variables) and higher E-Em ratio (P < 0.001) than controls. In children with a transplant, LVM index was a significant independent predictor for both abnormal LV relaxation (Em; P = 0.03) and abnormal LV compliance (E-Em ratio; P = 0.02). CONCLUSION: Results show impaired cardiac structure and diastolic function in pediatric renal allograft recipients. This suggests that LVH may be a risk factor for diastolic dysfunction in these children.

Right ventricular strain rate and strain analysis in patients with repaired tetralogy of Fallot: possible interventricular septal compensation.

BACKGROUND: Indices such as strain rate (SR) and strain (epsilon) are free of geometric assumptions and, thus, may provide new insights into right ventricular (RV) function and compensatory mechanisms in repaired tetralogy of Fallot (TOF). METHODS: All those with postoperative (>1 year) TOF had echocardiography evaluation of SR and epsilon indices along the RV lateral free wall (RVFW) and the interventricular septum (IVS) in the apical 4-chamber view. Pulmonary regurgitation, pulmonary stenosis, QRS duration, RV ejection fraction, and RV dimension were also measured and compared with control subjects. RESULTS: There were 15 patients with TOF (7 +/- 4 years old) 6 +/- 3 years remote from surgical repair and 25 control subjects (10 +/- 5 years old). In the patients with TOF, systolic and diastolic SR and epsilon in the RVFW were significantly reduced but were normal in the IVS. In the RVFW, reduced systolic SR and epsilon correlated with reduced RV ejection fraction (r = -0.7 [P <.01] and -0.6 [P <.03], respectively), and poorer early diastolic SR correlated with poorer RV ejection fraction (r = 0.7, P <.01). CONCLUSIONS: In patients with postoperative TOF, systolic and diastolic RV SR and epsilon were impaired in the RVFW but preserved in the IVS. We speculate that IVS myocardial function is preserved as a compensatory mechanism for impaired RVFW function.

Calcineurin Abeta gene targeting predisposes the myocardium to acute ischemia-induced apoptosis and dysfunction.

Cardiovascular disease is the leading cause of mortality and morbidity within the industrialized nations of the world, with coronary heart disease (CHD) accounting for as much as 66% of these deaths. Acute myocardial infarction is a typical sequelae associated with long-standing coronary heart disease resulting in large scale loss of ventricular myocardium through both apoptotic and necrotic cell death. In this study, we investigated the role that the calcium calmodulin-activated protein phosphatase calcineurin (PP2B) plays in modulating cardiac apoptosis after acute ischemia-reperfusion injury to the heart. Calcineurin Abeta gene-targeted mice showed a greater loss of viable myocardium, enhanced DNA laddering and TUNEL, and a greater loss in functional performance compared with strain-matched wild-type control mice after ischemia-reperfusion injury. RNA expression profiling was performed to uncover potential mechanisms associated with this loss of cardioprotection. Interestingly, calcineurin Abeta-/- hearts were characterized by a generalized downregulation in gene expression representing approximately 6% of all genes surveyed. Consistent with this observation, nuclear factor of activated T cells (NFAT)-luciferase reporter transgenic mice showed reduced expression in calcineurin Abeta-/- hearts at baseline and after ischemia-reperfusion injury. Finally, expression of an activated NFAT mutant protected cardiac myocytes from apoptotic stimuli, whereas directed inhibition of NFAT augmented cell death. These results represent the first genetic loss-of-function data showing a prosurvival role for calcineurin-NFAT signaling in the heart.

Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity.

We recently developed a mouse model with a single functional allele of Serca2 (Serca2+/-) that shows impaired cardiac contractility and relaxation without overt heart disease. The goal of this study was to test the hypothesis that chronic reduction in sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)2 levels in combination with an increased hemodynamic load will result in an accelerated pathway to heart failure. Age-matched wild-type and Serca2+/- mice were subjected to 10 wk of pressure overload via transverse aortic coarctation surgery. Cardiac hypertrophy and heart failure were assessed by echocardiography, gravimetry/histology, hemodynamics, and Western blotting analyses. Our results showed that approximately 64% of coarcted Serca2+/- mice were in heart failure compared with 0% of coarcted wild-type mice (P < 0.05). Overall, morbidity and mortality were greatly increased in Serca2+/- mice under pressure overload. Echocardiography assessment revealed a significant increase in left ventricular (LV) mass, and LV hypertrophy in coarcted Serca2+/- mice converted from a concentric to an eccentric pattern, similar to that seen in human heart failure. Coarcted Serca2+/- mice had decreased contractile/systolic and relaxation/diastolic performance and/or function compared with coarcted wild-type mice (P < 0.05), despite a similar duration and degree of pressure overload. SERCA2a protein levels were significantly reduced (>50%) in coarcted Serca2+/- mice compared with noncoarcted and coarcted wild-type mice. Our findings suggest that reduction in SERCA2 levels in combination with an increased hemodynamic load results in an accelerated pathway to heart failure.

Normal values of left ventricular systolic and diastolic function derived from signal-averaged acoustic quantification waveforms: a multicenter study.

Automated border-detection techniques such as acoustic quantification have proven accurate and useful for quantifying left ventricular (LV) function. We acquired LV acoustic quantification waveforms from the parasternal short-axis window in 140 healthy patients in the age range of 16 to 78 years. Signal-averaged waveforms were analyzed for parameters of systolic and diastolic performance. The average fractional area change was 54 +/- 12%, and there were no significant changes in LV systolic function in the age range studied. There were significant changes in diastolic parameters with aging. The percentage of contribution to total LV filling occurring during atrial filling nearly tripled during the 6 decades studied, from 13% in the youngest cohort to 36% in the eighth decade of life. This study provides normal reference values for systolic and diastolic parameters of LV function determined from signal-averaged acoustic quantification waveforms acquired from the parasternal short-axis view in adult and adolescent patients over a wide age range.

Color M-mode and Doppler tissue evaluation of diastolic function in children: simultaneous correlation with invasive indices.

OBJECTIVE: The purpose of this study was to explore the validity of diastolic indices derived from color M-mode Doppler and Doppler tissue imaging in a heterogeneous group of pediatric patients by comparing them with simultaneously obtained invasive indices of diastolic function. METHODS: A total of 20 children undergoing left heart catheterization had echocardiographic images recorded simultaneously with high-fidelity left ventricular (LV) pressure tracings. Transmitral Doppler, pulmonary vein Doppler, Doppler tissue imaging, and color M-mode Doppler flow propagation velocity were recorded. LV peak negative dP/dt, the time constant of isovolumic relaxation, and LV end-diastolic pressure were compared with the echocardiographic indices. RESULTS: The ratio of peak E-wave mitral velocity/propagation velocity correlated significantly with LV end-diastolic pressure (r = 0.71; P <.001). Propagation velocity correlated with the time constant of isovolumic relaxation (r = -0.56; P =.01) and peak negative dP/dt (r = 0.50; P <.03). Septal mitral annular myocardial velocity correlated significantly with the time constant of isovolumic relaxation (r = -0.58, P =.01). CONCLUSION: The newer diastolic indices derived from color M-mode Doppler and Doppler tissue imaging appear to be a helpful adjunct in the noninvasive assessment of diastolic function in children.

Targeted inhibition of p38 MAPK promotes hypertrophic cardiomyopathy through upregulation of calcineurin-NFAT signaling.

The MAPKs are important transducers of growth and stress stimuli in virtually all eukaryotic cell types. In the mammalian heart, MAPK signaling pathways have been hypothesized to regulate myocyte growth in response to developmental signals or physiologic and pathologic stimuli. Here we generated cardiac-specific transgenic mice expressing dominant-negative mutants of p38alpha, MKK3, or MKK6. Remarkably, attenuation of cardiac p38 activity produced a progressive growth response and myopathy in the heart that correlated with the degree of enzymatic inhibition. Moreover, dominant-negative p38alpha, MKK3, and MKK6 transgenic mice each showed enhanced cardiac hypertrophy following aortic banding, Ang II infusion, isoproterenol infusion, or phenylephrine infusion for 14 days. A mechanism underlying this enhanced-growth profile was suggested by the observation that dominant-negative p38alpha directly augmented nuclear factor of activated T cells (NFAT) transcriptional activity and its nuclear translocation. In vivo, NFAT-dependent luciferase reporter transgenic mice showed enhanced activation in the presence of the dominant-negative p38alpha transgene before and after the onset of cardiac hypertrophy. More significantly, genetic disruption of the calcineurin Abeta gene rescued hypertrophic cardiomyopathy and depressed functional capacity observed in p38-inhibited mice. Collectively, these observations indicate that reduced p38 signaling in the heart promotes myocyte growth through a mechanism involving enhanced calcineurin-NFAT signaling.