Intraventricular Septum Thickness Research Articles

Quantitative Analysis of the Chromatin Proteome in Disease Reveals Remodeling Principles and Identifies High Mobility Group Protein B2 as a Regulator of Hypertrophic Growth

A fundamental question in biology is how genome-wide changes in gene expression are enacted in response to a finite stimulus. Recent studies have mapped changes in nucleosome localization, determined the binding preferences for individual transcription factors, and shown that the genome adopts a nonrandom structure in vivo. What remains unclear is how global changes in the proteins bound to DNA alter chromatin structure and gene expression. We have addressed this question in the mouse heart, a system in which global gene expression and massive phenotypic changes occur without cardiac cell division, making the mechanisms of chromatin remodeling centrally important. To determine factors controlling genomic plasticity, we used mass spectrometry to measure chromatin-associated proteins. We have characterized the abundance of 305 chromatin-associated proteins in normal cells and measured changes in 108 proteins that accompany the progression of heart disease. These studies were conducted on a high mass accuracy instrument and confirmed in multiple biological replicates, facilitating statistical analysis and allowing us to interrogate the data bioinformatically for modules of proteins involved in similar processes. Our studies reveal general principles for global shifts in chromatin accessibility: altered linker to core histone ratio; differing abundance of chromatin structural proteins; and reprogrammed histone post-translational modifications. Using small interfering RNA-mediated loss-of-function in isolated cells, we demonstrate that the non-histone chromatin structural protein HMGB2 (but not HMGB1) suppresses pathologic cell growth in vivo and controls a gene expression program responsible for hypertrophic cell growth. Our findings reveal the basis for alterations in chromatin structure necessary for genome-wide changes in gene expression. These studies have fundamental implications for understanding how global chromatin remodeling occurs with specificity and accuracy, demonstrating that isoform-specific alterations in chromatin structural proteins can impart these features.

β1 Integrin Gene Excision in the Adult Murine Cardiac Myocyte Causes Defective Mechanical and Signaling Responses

How mechanical signals are transmitted in the cardiac myocyte is poorly understood. In this study, we produced a tamoxifen-inducible mouse model in which β1 integrin could be reduced specifically in the adult cardiomyocyte, so that the function of this integrin could be assessed in the postnatal and mechanically stressed heart. The expression of β1 integrin was reduced to 35% of control levels, but function remained normal at baseline. With aortic constriction, the knockout mice survived but had a blunted hypertrophic response. Integrin knockout myocytes, in contrast to controls, showed reduced integrin-linked kinase expression both at baseline and after hemodynamic stress; focal adhesion kinase expression was reduced after stress. Alterations in multiple signaling pathways were detected in the integrin knockout group after acute and chronic hemodynamic stress. Most remarkably, when we challenged the knockout mice with short-term loading, the robust responses of several kinases (extracellular signal-regulated kinase 1/2, p38, and Akt) evident in control mice were essentially abolished in the knockout mice. We also found that reduction of myocyte β1 integrin expression modified adrenergic-mediated signaling through extracellular signal-regulated kinase, p38, and Akt. Reduction of β1 integrin expression in the mature cardiac myocyte leads to a varied response compared with when this protein is reduced during either the embryonic or perinatal period. These results show that β1 integrin expression is required for proper mechanotransductive and adrenergic responses of the adult heart.

Abstract A178: Developing chemotherapeutics which selectively disable the actin cytoskeleton of tumor cells.

Abstract Background: The actin cytoskeleton is an important regulator of a variety of cellular functions including cell motility, adhesion, and proliferation, making it an ideal chemotherapeutic target. Despite this promise there are still no anti-actin compounds used in current chemotherapy, primarily due to the inability of existing anti-actin agents to discriminate between the actin cytoskeleton of tumor cells and the actin filaments of the muscle sarcomere. We have previously shown that tropomyosin, an integral component of the actin cytoskeleton, defines functionally distinct populations of actin filaments. We have identified a specific tropomyosin isoform common to all tumor cells tested to date which regulates cell proliferation and have designed a new class of compounds to target this filament population. Summary of Results: Anti-tropomyosin (Tm) compounds were selected based their ability to target the actin cytoskeleton and their efficacy against a panel of neuroblastoma and melanoma cell lines. The lead compound, TR100, was shown to be effective against a panel of tumor cell lines with an average EC50 of 3μM. When tested in 3D melanoma spheroid models, which more accurately mimic the tumor microenvironment, TR100 inhibited melanoma cell growth and motility. This effect translated to a reduction in tumor cell growth in vivo in both neuroblastoma and melanoma xenograft models. In vitro data using isolated rat cardiomyocytes demonstrated that TR100 had minimal impact on contractile function. In vivo data from the drug treated animals also showed no evidence of cardiac damage as measured by blood Troponin I levels and no changes in the intraventricular septum thickness of isolated hearts. These results demonstrate that it is possible to target distinct actin filament populations based on the tropomyosin composition. Next generation anti-Tm compounds with improved efficacy and specificity have now been developed. Preliminary data demonstrate that these compounds exhibit increased selectivity for transformed cells. Conclusions: Taken together, our findings suggest that the anti-Tm compounds show a significant improvement in the therapeutic window compared to existing anti-actin agents. This novel approach and the development of the new class of anti-Tm compounds may be the key for disabling a long sought after target, the actin cytoskeleton, and may lead to a new class of chemotherapeutics active against a broad range of cancer types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A178.

A novel anti-fibrotic agent, baicalein, for the treatment of myocardial fibrosis in spontaneously hypertensive rats

Myocardial interstitial fibrosis causes left ventricular stiffness and diastolic dysfunction. Despite its clinical significance, treatment options are limited. The flavonoid baicalein, extracted from roots of a Chinese medicinal plant, Scutellaria baicalensis Georgi was shown to inhibit liver fibrosis. This study sought to investigate whether chronic treatment with baicalein could attenuate myocardial fibrosis in spontaneously hypertensive rats (SHR). SHR were treated daily with baicalein while the control group received vehicle. At the end of study, SHR control group developed significant myocardial fibrosis that was attenuated by baicalein treatment for 4 and 12 weeks. Rats treated with baicalein were protected against an increase in heart to body weight ratio, plasma level of brain natriuretic peptides, intraventricular septum thickness, myocardial collagen volume of left ventricle (all P < 0.05, respectively). The antifibrotic effects of baicalein were further illustrated by the suppressed expression of left ventricle pro-collagens I and III accompanied by the decreased expression of 12-lipoxygenase, and by reduced expression and activity of matrix metallopeptidase 9 and extracellular signal-regulated kinases. The present results show for the first time that baicalein can inhibit cardiac fibrosis in hypertensive rats.

Diverse patterns of myocardial fibrosis in lifelong, veteran endurance athletes

This study examined the cardiac structure and function of a unique cohort of documented lifelong, competitive endurance veteran athletes (>50 yr). Twelve lifelong veteran male endurance athletes [mean ± SD (range) age: 56 ± 6 yr (50-67)], 20 age-matched veteran controls [60 ± 5 yr; (52-69)], and 17 younger male endurance athletes [31 ± 5 yr (26-40)] without significant comorbidities underwent cardiac magnetic resonance (CMR) imaging to assess cardiac morphology and function, as well as CMR imaging with late gadolinium enhancement (LGE) to assess myocardial fibrosis. Lifelong veteran athletes had smaller left (LV) and right ventricular (RV) end-diastolic and end-systolic volumes (P < 0.05), but maintained LV and RV systolic function compared with young athletes. However, veteran athletes had a significantly larger absolute and indexed LV and RV end-diastolic and systolic volumes, intraventricular septum thickness during diastole, posterior wall thickness during diastole, and LV and RV stroke volumes (P < 0.05), together with significantly reduced LV and RV ejection fractions (P < 0.05), compared with veteran controls. In six (50%) of the veteran athletes, LGE of CMR indicated the presence of myocardial fibrosis (4 veteran athletes with LGE of nonspecific cause, 1 probable previous myocarditis, and 1 probable previous silent myocardial infarction). There was no LGE in the age-matched veteran controls or young athletes. The prevalence of LGE in veteran athletes was not associated with age, height, weight, or body surface area (P > 0.05), but was significantly associated with the number of years spent training (P < 0.001), number of competitive marathons (P < 0.001), and ultraendurance (>50 miles) marathons (P < 0.007) completed. An unexpectedly high prevalence of myocardial fibrosis (50%) was observed in healthy, asymptomatic, lifelong veteran male athletes, compared with zero cases in age-matched veteran controls and young athletes. These data suggest a link between lifelong endurance exercise and myocardial fibrosis that requires further investigation.

Echocardiographic evaluation during weaning from mechanical ventilation

INTRODUCTION:Echocardiographic, electrocardiographic and other cardiorespiratory variables can change during weaning from mechanical ventilation.OBJECTIVES:To analyze changes in cardiac function, using Doppler echocardiogram, in critical patients during weaning from mechanical ventilation, using two different weaning methods: pressure support ventilation and T‐tube; and comparing patient subgroups: success vs. failure in weaning.METHODS:Randomized crossover clinical trial including patients under mechanical ventilation for more than 48 h and considered ready for weaning. Cardiorespiratory variables, oxygenation, electrocardiogram and Doppler echocardiogram findings were analyzed at baseline and after 30 min in pressure support ventilation and T‐tube. Pressure support ventilation vs. T‐tube and weaning success vs. failure were compared using ANOVA and Student's t‐test. The level of significance was p<0.05.RESULTS:Twenty‐four adult patients were evaluated. Seven patients failed at the first weaning attempt. No echocardiographic or electrocardiographic differences were observed between pressure support ventilation and T‐tube. Weaning failure patients presented increases in left atrium, intraventricular septum thickness, posterior wall thickness and diameter of left ventricle and shorter isovolumetric relaxation time. Successfully weaned patients had higher levels of oxygenation.CONCLUSION:No differences were observed between Doppler echocardiographic variables and electrocardiographic and other cardiorespiratory variables during pressure support ventilation and T‐tube. However cardiac structures were smaller, isovolumetric relaxation time was larger, and oxygenation level was greater in successfully weaned patients.

Higher Plasma Cell Burden Predicts for Early Death In Patients with AL Amyloidosis

AbstractAbstract 1893 Background:Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods:We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results:In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion:This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. [Display omitted] Table 1:Variables (median) analyzed in patients who died within 90 days or survived beyond 90 days of diagnosis of AL amyloidosis based on their BM PC%VariableDied within 90 days of diagnosisSurvived beyond 90 days of diagnosisBM PC <10% (n = 38)BM PC 310% (n = 50)p-valueBM PC <10% (n = 79)BM PC 310% (n = 96)p-valueHemoglobin, g/dl13.612.60.0113.413.10.55Serum M-spike, g/dl000.020.51.20.04Beta-2 microglobulin, mcg/ml3.44.60.172.613.160.01Troponin-T, ng/ml0.070.140.010.010.010.30NT-proBNP, pg/ml564493600.09132512610.46EF, %55.5450.0264640.74IVS, mm14150.211213.50.01PCLI, %00.20.1700.10.001BM PC, %520<0.0001516.5<0.0001Involved FLC, mg/dl23.286.9<0.000113.531.10.0004Lambda- restricted patients, %34.137.50.9431.037.40.56 Disclosures:Lacy:Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Relation of Arterial Properties to Left Ventricular Hypertrophy in Hypertensive Adults: Focus on Gender-Related Differences

Although gender-related differences in ventricular remodeling and arterial stiffness have been described, the impact of gender on the association between vascular compliance and left ventricular hypertrophy (LVH) has not been investigated. The current study was designed to determine the gender-related differences in the association between echographically determined LVH measures and arterial stiffness in hypertensive men and women. In the current study, 104 hypertensive participants (61 men and 43 women) were enrolled. Large artery elasticity index (LAEI) and small artery elasticity index (SAEI) were determined using pulse wave contour analysis (HDI CR 2000, Eagan, Minnesota). Left ventricular hypertrophy parameters including intraventricular septum thickness (IVST), posterior wall thickness (PWT), and left ventricular mass index (LVMI) were assessed echographically. Hypertensive male versus female were similar in terms of age, body mass index (BMI), blood pressure, concomitant medications, and cardiovascular risk factors. Left ventricular mass index was significantly, inversely associated with IVST (r = -.32, P = .01), PWT (r = -.32, P = .01), and LVMI (r = -.28, P = .03) in men and significantly, inversely associated with IVST (r = -39, P = .01), PWT (r = -.42, P = .005), LVMI (r = -.54, P < .0001) in women. Small artery elasticity index was significantly, inversely associated with LVMI (r = -0.36, P = .02) in women only. In regression analysis, LAEI explained more variability than SAEI and was an independent predictor of LVH parameters in hypertensive men and women. Compliance of large arteries is potentially an independent predictor of LVH in hypertensive men and women. Therefore, arterial compliance is being considered an important tool in predicting LVH in hypertensive participants.

Copeptin in Heart Transplant Recipients Depends on Kidney Function and Intraventricular Septal Thickness

Copeptin is cosynthesized with vasopressin, also known as antidiuretic hormone, with plasma levels similar to vasopressin. In the past 2 years, copeptin has been studied as a diagnostic and prognostic marker in infections and other diseases. In patients with destabilized heart failure, copeptin is an accurate prognostic marker for mortality. The aim of this study was to assess copeptin in orthotopic heart recipients in relation to New York Heart Association class and kidney function. The studies were performed on 139 prevalent patients after orthotopic heart transplantation-(OHT) including 105 males and 34 females. Glomerular filtration rate (GFR) was estimated using simplified Modification of Diet in Renal Disease (MDRD), Cockcroft-Gault, and new the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. In addition 24-hour creatinine clearances were performed on each patient. Complete blood count, urea, serum lipids, fasting glucose, creatinine, BNP were studied by standard laboratory method in the hospital central laboratory. Plasma copeptin was measured using a commercially available kit. Copeptin correlated with parameters of kidney function: creatinine ( r = .39, P < .001), estimated GFR by MDRD ( r = −.24, P < .01), estimated GFR by CKD-EPI ( r = −.25, P < .01), creatinine clearance by Cockcroft-Gault ( r = −.27, P < .01), 24-hour creatinine clearance ( r = −.21, P < .05), cystatin C ( r = .45, P < .001), and high-density lipoprotein ( r = .18, P < .05), BNP ( r = .25, P < .01), intraventricular septal diameter/thickness (IVS); r = −.30, P < .01), ejection fraction ( r = −.17, P < .05), ferritin ( r = .21, P < .05). Upon multiple regression analysis, predictors of copeptin were cystatin C and IVS, which explained 51% of copeptin variations (F = 3.21, P < .03 and Standard error of estimate was 0.57). Beta value for cystatin C was 0.51 ( P = .024) and for IVS was −0.59 ( P = .018). Copeptin in a heart transplant population was independently associated with kidney function and IVS.

ASSESSMENT OF METABOLIC PARAMETERS AND RENAL FUNCTION AS PROGNOSTIC FACTORS IN CARDIOVASCULAR DISORDERS IN HYPERTENSIVE PATIENTS: PP.35.474

Objective: Usefulness of the assessment of metabolic and renal parameters in cardiovascular risk estimating in patients with hypertension. Design and Method: 58 hospitalized hypertensive patients, aged 29 to 83, were examined (20 women and 38 men). Patients were divided into two groups: A - without coronary artery disease (CAD) (28 patients) and B - with CAD (30 patients). Both groups were not significantly different in the level of systolic (SBP) [(A) 140+/−18 mmHg; (B) 139+/−15 mmHg] and diastolic (DBP) [(A) 88+/−13 mmHg; (B) 82+/−11 mmHg] blood pressure as well as in glomerular filtration rate (GFR) [(A) 78,57+/−24,25 ml/min/1,73m2; (B) 76,76+/−22,11 ml/min/1,73m2]. GFR was estimated according to MDRD formula. Both groups did not differ significantly in hypotensive and lipid lowering therapy. Following measurements were taken: blood pressure (BP), lipid profile and serum creatinine level. Echocardiography was performed in each patient, following parameters were measured in the end-diastolic phase: left ventricle diameter (LVd), right ventricle diameter (RVd), left atrium diameter (LAd), posterior wall thickness (PW) and intraventricular septum thickness (IVS); ejection fraction (EF) was assessed and left ventricle mass index (LVMI) was estimated according to Penn's formula. Results: We revealed statistically significant difference in the levels of total cholesterol [(A) 5,45+/−1,20 mmol/l, (B) 4,55+/−0,94 mmol/l; p = 0,0028] and LDL-cholesterol [(A) 3,47+/−1,03 mmol/l, (B) 2,63+/−0,77 mmol/l; p = 0,0009] between both groups. We also observed significant negative correlation between LVMI and GFR (r = -0,4820; p = 0,0081), LVMI and total cholesterol level (r=-0,3754; p = 0,0448) and LVMI and LDL-cholesterol level (r = -0,3771; p = 0,0438) in the group A. We observed significant positive correlation between GFR and EF (r = 0,4737; p = 0,0109) in the same group. None of these correlations was noticed in group B. Conclusions: 1) In patients with CAD cardiovascular complications are so advanced, that no direct relationship to the metabolic parameters and renal function may be seen. 2) Assessment of metabolic parameters and its influence on LVMI is of greater significance in patients with hypertension and without CAD in prevention of renal failure and CAD.

Heart complications in familial transthyretin amyloidosis: impact of age and gender

Heart arrhythmia is common in Swedish patients with familial amyloidotic polyneuropathy (FAP), as well as cardiomyopathy. We investigated the relationship between Holter ECG and echocardiographic findings in 108 FAP patients, with particular focus on age and gender differences. Female patients were younger than male patients at symptom onset (p < 0.01). Only 4 of 39 patients with septal hypertrophy were females. Regression analysis showed that age of onset, gender and duration of disease were significantly related with intraventricular septum (IVS) thickness. Sixty-five patients (25 females) presented with abnormal 24-h ECG recordings. IVS thickness was not significantly related to conduction disturbances or the presence of ventricular arrhythmia (VA). However, IVS thickness and atrial dimension were both related to increased rate of supraventricular arrhythmia (SVA).Male gender was clearly associated with more pronounced septal thickness of the heart. Conduction disturbances were not related to IVS thickness, indicating that the distribution and extent of infiltration of the heart by amyloid are heterogeneous and related to gender and age of onset. These findings highlight the necessity of 24-h ECGs to detect conduction disturbances, due to their occurrence in the absence of echocardiographic evidence of amyloid deposition in the myocardium.

Left Ventricular Geometric Abnormality Screening in Hypertensive Patients Using a Hand‐Carried Ultrasound Device

The authors assessed the validity of a hand-carried cardiac ultrasound device operated by an internal medicine resident for left ventricular geometric abnormalities (LVGAs) in mild hypertensive patients. LVGAs were diagnosed when at least one of the following was present: left ventricular mass index exceeding 125 g/m(2) and 110 g/m(2) for men and women, respectively; intraventricular septum thickness > or = 10 mm; posterior wall thickness > or = 10 mm; and left ventricular end-diastolic diameter > or = 5.3 mm. For validation, a cardiologist performed standard echocardiography in all patients. A total of 85 patients completed both echocardiographic studies. LVGAs were diagnosed in 19 (22.4%) cases, 18 of which were confirmed by standard echocardiography. Standard echocardiography did not detect any case of LVGA among the hand-carried cardiac ultrasonography LVGA-negative patients. The sensitivity and specificity of the resident's examination were 100% and 98.78%, respectively. Agreement between the two studies was 99% (kappa 0.97, 95% confidence interval). Hand-carried cardiac ultrasonography may be used as a screening tool for LVGA in hypertensive patients.

Plasma adiponectin levels are associated with left ventricular hypertrophy in a random sample of middle-aged subjects

Background. A low adiponectin level is associated with high blood pressure which, in turn, often results in left ventricular hypertrophy. We evaluated the association between plasma adiponectin concentrations and echocardiographic measurements, including left ventricular mass index (LVMI), in 933 middle-aged subjects consisting of 453 hypertensives and 480 controls.Methods. Plasma adiponectin concentrations were measured with an enzyme-linked immunosorbent assay (ELISA) method. One experienced cardiologist performed echocardiographic examinations, and LVMI was calculated according to Devereux’s method.Results. Low plasma adiponectin levels were independently associated with increased intraventricular septum thickness, posterior ventricular wall thickness, and left ventricular mass index (P<0.001) in the whole cohort. In the subgroup analysis, the association between these echocardiographic parameters and adiponectin concentrations was observed only in the hypertensive cohort although fractional shortening revealed an association with adiponectin levels also in the control cohort (P=0.021). Findings remained significant after adjustment for the major risk factors for LVMI, such as age, sex, smoking, and systolic blood pressure.Conclusions. This study in a large population sample detected an association between low plasma adiponectin concentration and LVMI, a marker of left ventricular hypertrophy. This association may be one of the factors that could explain the reported increased cardiovascular risk in subjects with low adiponectin levels.

PICOT, a novel monothiol glutaredoxin, plays a critical role in postembryonic growth and cardiac function in mice under nutritional perturbation

PICOT (Protein Kinase C‐Interacting Cousin of Thioredoxin) is a newly identified monothiol glutaredoxin. In the present study, we demonstrated that MmPICOT had conserved functions in cell proliferation and response to oxidative stresses. Furthermore, disruption of MmPICOT in mice caused embryo lethal. In Picot+/− mice, early postembryonic growth was indistinguishable to wild type littermates, but Picot+/− mice did show significantly less in body weight and lean mass than that of wild type littermates when mice were ageing. Picot+/− mice on chow diet displayed distinct difference in intraventricular septal wall thickness and LV posterior wall thickness at end‐systole in comparison to wild type littermates, but cardiac output in those Picot+/− mice remained similar to wild type littermates. However, under chronic dietary fat intake, Picot+/− mice had significant decrease in ejection fraction and fractional shortening, suggesting impaired cardiac function in those Picot+/− mice. Together, these results suggest that PICOT is essential in embryo development and may also play a critical role in postembryonic growth and heart function, particularly under oxidative stress and nutritional perturbation.

IGF-I replacement therapy in children with congenital IGF-I deficiency (Laron syndrome) maintains heart dimension and function

Objective Untreated patients with congenital growth hormone deficiency (GHD) and IGF-I deficiency are characterized not only by dwarfism but also by acromicria and organomicria, such as the heart. We assessed cardiac dimensions and function in very young patients with Laron syndrome (LS) undergoing IGF-I replacement therapy. Design Two to seven echocardiographic measurements were performed during IGF-I replacement therapy on male ( n = 4) and female ( n = 4) LS -atients, mean ± SD age of 7.1 ± 3.6 years (range 1.6–11.6 years), weight 16.1 ± 9.7 kg, and height 89.9 ± 18.5 cm. As aged- and gender-matched controls served 44 healthy children, age: 8.7 ± 5.5 years, weight: 36.1 ± 22.4 kg, and height: 129.7 ± 33.1 cm. Data of LS patients were normalized to body surface area and compared to the control group as well as nomograms of normal echocardiographic parameters for this age group. Results Left ventricular diastolic and systolic dimensions (LVDD/ LVSD, mm) and LV mass (gr) were significantly smaller in boys and girls with IGF-I treated LS compared with controls while the shortening fraction (%) and intraventricular septum thickness (mm) were similar. When compared with standard values for this age group, all treated LS patients were within 1 standard deviation of the mean. Conclusion IGF-I therapy of young patients with Laron syndrome maintain LV dimensions and function within the normal range of aged-matched controls.

Absence of cardiovascular effects on young adults exposed in utero to ritodrine: A long-term follow-up

Objective To determine, using echocardiographs, if young adults exposed in uterus to Ritodrine have long-term cardiovascular effects. Study design Retrospective follow-up study. Young adults between the ages of 22- and 26-years-old. Young adults ( n = 19) exposed in uterus to Ritodrine and age-matched controls ( n = 27) were studied by means of transthoracic echocardiography. All participants were born following full-term pregnancies. Subgroups of those subjects exposed to the highest dose of Ritodrine and for the longest period of time were established. A multivariate descriptive statistical analysis of the values obtained using transthoracic echocardiography was performed. Echocardiography measurements in M-mode included intraventricular septum and posterior wall thickness, systolic and diastolic diameter of the left ventricle, septum/wall quotient, left ventricle mass and short and ejection fractions. Doppler pressed: E and A peaks in the mitral valve and isovolumetric relaxation time were determined. Results The mass, posterior wall, systolic diameter and the diastolic diameter of the left ventricle were slightly, but not significantly, higher in the Ritodrine group. The E/A peak and the isovolumetric relaxation time were similar in both groups. A negative correlation between the left ventricle mass index and the total Ritodrine dose ( r = −0.67; p = 0.051) was found; this disappeared in the subgroups exposed to higher doses and for longer times. Conclusions The variables studied using echocardiography showed that in uterus exposure to Ritodrine do not have long-term effects on cardiac functionality in young adults.

Evaluation of NT‐Pro BNP and CT‐ANP as Markers of Concentric Hypertrophy in Dogs with a Model of Compensated Aortic Stenosis

Serum C-terminal atrial natriuretic peptide (CT-ANP) and N-terminal pro B-type natriuretic peptide (NT-pro BNP) concentrations have not been measured serially in dogs with chronic pressure overload of the heart. We investigated whether serial evaluation of CT-ANP and NT-pro BNP concentrations is a useful guide to the risk of cardiac remodeling in dogs with a model of aortic stenosis. Six male Beagles. After anesthesia, the aorta was constricted with a polyester band and mean left ventricular systolic pressure (LVPs) was 50 mmHg above baseline. Echocardiographic and intracardiac catheter examinations and blood sampling were performed before surgery and 3 and 6 months after surgery. LVP and left ventricular end-diastolic pressure (LVEDP) were significantly higher at 6 months. Compared with baseline, end-diastolic intraventricular septum thickness (IVSd), left ventricular posterior wall thickness (LVPWd), and relative wall thickness (RWT) were significantly increased 3 and 6 months after aortic constriction. Serum CT-ANP concentrations were increased significantly at 3 months and serum NT-pro BNP concentrations were significantly higher 3 and 6 months after aortic constriction. Serum NT-pro BNP concentration was significantly correlated with LVEDP and IVSd whereas serum CT-ANP concentration was not correlated with any measurement. Stepwise regression analysis showed that LVEDP, IVSd, and RWT could predict serum NT-pro BNP. This study indicated the differential regulation of NT-pro BNP and CT-ANP concentrations during pressure overload. NT-pro BNP assay may be used as an additional screening method to stratify early-stage ventricular remodeling because of aortic constriction.

Selenoproteins regulate contractility during hyperthyroidism‐induced cardiac hypertrophy

We assessed the hypothesis that selenoproteins are important for the heart during hyperthyroidism‐induced myocardial hypertrophy. Mice were injected with 1mg/kg triiodothyronine (T3) or vehicle control for 8 days. Expression levels of several selenoproteins were found to increase in heart tissue with T3‐treatment, with some of the most elevated mRNAs including selenoprotein R (Sel R), thioredoxin reductase−1, and both glutathione peroxidase (GPX)−1 and −3. T3‐treatment induced increases in thioredoxin reductase activity as well as GPX−4 and Sel R, but not GPX−1, proteins. We next utilized a mouse model (trspfl/fl X αMHC‐Cre), which involves reduced expression of Sec‐tRNA in the heart. The mice expressing reduced levels of Sec‐tRNA in the heart (Cre+ mice) developed similar levels of myocardial hypertrophy upon T3 injection compared to negative controls (Cre− mice) as determined by heart mass:body mass. As expected, T3‐treatment of Cre− mice resulted in altered cardiac parameters including increased fractional shortening, decreased systolic left ventricular inner diameter, and increased intraventricular septal thickness. In contrast, these cardiac parameters were not altered in Cre+ mice. These results suggest that restricting the elevation of selenoprotein synthesis by reducing Sec‐tRNA levels may lead to a loss of contractility needed for maintaining cardiac function during hypertrophy.

Respiratory muscle weakness and inefficient ventilation in heart failure due to light-chain amyloidosis

Background. Cardiac involvement in light-chain amyloidosis (AL) frequently results in heart failure with dyspnoea. In heart failure due to ischemic or idiopathic etiology, respiratory muscle dysfunction and ventilatory inefficiency contribute to symptoms and are independent prognostic predictors. However, in patients with AL, respiratory muscle function has not been elucidated.Methods. In 46 consecutive male patients with AL, lung function, maximal inspiratory (Pimax) and expiratory (Pemax) mouth occlusion pressures, cardiopulmonary exercise testing, echocardiography, and cardiac biomarkers were prospectively studied.Results. Pimax and Pemax were reduced, P0.1 did not differ between controls and AL. Pimax and Pemax were reduced in AL with congestive heart failure compared with asymptomatic patients (median (range) 5.4 (2.3–12.4) kPa vs 10.4 (6.5–14.0) kPa; p < 0.05). Respiratory muscle weakness occurred in systolic and diastolic LV dysfunction. Pimax was associated with peak exercise oxygen uptake, respiratory inefficiency, wall thickness, and N-terminal pro-brain natriuretic peptide.Conclusions. Respiratory muscle dysfunction and ventilatory inefficiency correlates well with intraventricular septum thickness and peak oxygen uptake and are present even in patients with diastolic dysfunction. Respiratory muscle dysfunction might contribute to dyspnea and exercise limitation and appears to represent a marker of cardiac impairment even in diastolic heart failure. Further studies of Pimax as a potential non-invasive prognostic marker are needed.

Relationship between Parathyroid Hormone and Cardiac Abnormalities in Chronic Dialysis Patients

It has been shown that parathyroid hormone (PTH) influences cardiac abnormalities in dialysis patients. The purpose of this study was to evaluate the relationship between the plasma PTH level and cardiac abnormalities in these patients without overt cardiac disease. A total of 81 of the 208 patients who received chronic dialysis treatment at our institution were included in this study. Plasma PTH level measurement, other blood examinations and echocardiography were performed in all patients. The subjects were divided into two groups based on plasma PTH level (<300 pg/ml: group A; > or =300 pg/ml: group B). There were no significant differences in echocardiographic parameters between group A and group B. The plasma PTH level was not significantly correlated with any echocardiographic parameter in any patient. In addition, we chose 10 patients with a plasma PTH level of more than 500 pg/ml from group B and 20 patients matched for various characteristics (excluding PTH level) from group A and compared the echocardiographic parameters between them. LVMI and intraventricular septum thickness (IVST) were significantly greater in patients with a plasma PTH level of greater than 500 pg/ml. PTH was not strongly associated with cardiac abnormalities such as LVH or decreased left ventricular function in the overall group of patients. PTH may not play a major role in the pathogenesis of cardiac abnormalities in these patients. However, PTH could influence LVH in patients with remarkably elevated plasma PTH levels.