A systems approach using Diversity Outbred mice distinguishes the cardiovascular effects and genetics of circulating GDF11 from those of its homolog, myostatin

Abstract Growth differentiation factor 11 (GDF11) is a member of the TGF-β protein family that has been implicated in the development of cardiac hypertrophy. While some studies have suggested that systemic GDF11 protects against cardiomyocyte enlargement and left ventricular wall thickening, there remains uncertainty about the true impact of GDF11 and whether its purported effects are actually attributable to its homolog myostatin. The present study was conducted to resolve the statistical and genetic relationships among GDF11, myostatin, and cardiac hypertrophy in a mouse model of human genetics, the Diversity Outbred (DO) stock. In the DO population, serum GDF11 concentrations positively correlated with cardiomyocyte cross sectional area, while circulating myostatin levels were negatively correlated with body weight, heart weight, and left ventricular wall thickness and mass. Genetic analyses revealed that serum GDF11 concentrations are modestly heritable (0.23) and identified a suggestive peak on murine chromosome 3 in close proximity to the gene Hey1, a transcriptional repressor. Bioinformatic analyses located putative binding sites for the HEY1 protein upstream of the Gdf11 gene in the mouse and human genomes. In contrast, serum myostatin concentrations were more heritable (0.57) than GDF11 concentrations, and mapping identified a significant locus near the gene FoxO1, which has binding motifs within the promoter regions of human and mouse myostatin genes. Together, these findings more precisely define the independent cardiovascular effects of GDF11 and myostatin, as well as their distinct regulatory pathways. Hey1 is a compelling candidate for the regulation of GDF11 and will be further evaluated in future studies.

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Abstract 15687: Loss of Tribbles 3 (TRIB3) Attenuates Pressure-Overload Induced Myocardial Hypertrophy

Circulation ◽

10.1161/circ.130.suppl_2.15687 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Eltyeb Abdelwahid ◽

Rongxue Wu ◽

Amy K Rines ◽

Hossein Ardehali

Keyword(s):

Cardiac Hypertrophy ◽

Wall Thickness ◽

Pressure Overload ◽

Cellular Metabolism ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Heart Weight ◽

Sham Operation ◽

Ventricular Wall ◽

Exact Function

Introduction: Tribbles 3 (TRIB3) is a pseudokinase that regulates several biological functions such as cell proliferation and differentiation through its role in cellular metabolism. TRIB3 expression is modulated by various signals such as endoplasmic reticulum (ER) stress, nutrient availability, and insulin. The exact function of TRIB3 in the heart is largely unknown. We hypothesized that loss of TRIB3 protects against cardiac hypertrophy through its role in the regulation of cellular metabolism. Results: To elucidate the role of TRIB3 loss in the heart, we generated TRIB3 knock-out (KO) mice. The animals were then subjected to transverse aortic constriction (TAC) and sham-surgery control. In the sham operation groups, there was no hypertrophy in both TRIB3-/- and Wild type (WT) age matched control mice. WT mice subjected to TAC (WT-TAC) showed cardiac hypertrophy evidenced by increased heart weight/body weight, increased left ventricular wall thickness and increased cardiomyocyte cross-sectional area. These hypertrophic findings were significantly reduced in TRIB3 KO-TAC hearts (P<0.05). Echocardiographic analysis revealed increased diastolic interventricular septum wall (IVSd), increased left ventricular wall posterior wall thickness (LVPWd) and decreased fractional shortening (FS) in WT-TAC mice, however these changes were significantly blocked in TRIB3 KO-TAC group suggesting that TAC-induced left ventricular hypertrophy and dysfunction was attenuated in TRIB3 KO mice (P<0.05). The blunted response to hypertrophy seen in TRIB3 KO-TAC group was further demonstrated by the significant decrease in mRNA expression of myocardial hypertrophic markers (ANP, BNP and MHC) in TRIB3 KO-TAC hypertrophied left ventricles compared to WT-TAC control subjects (P<0.05). Furthermore, our data indicated increased TRIB3 expression in the WT-TAC hypertrophied left ventricles compared to WT-Sham group (P<0.05). Conclusions: The present study demonstrated that TRIB3 expression is promoted in hypertrophied hearts. TRIB3 deletion suppresses cardiac pressure overload-induced hypertrophy. Thus, TRIB3 is a novel target that plays a role in cardiac hypertrophy and maladaptation following pressure overload.

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Regional left ventricular wall thickening by magnetic resonance imaging: Evaluation in normal persons and patients with global and regional dysfunction

The American Journal of Cardiology ◽

10.1016/s0002-9149(87)80088-7 ◽

1987 ◽

Vol 59 (1) ◽

pp. 145-151 ◽

Cited By ~ 114

Author(s):

Udo Sechtem ◽

Barbara A. Sommerhoff ◽

Walter Markiewicz ◽

Richard D. White ◽

Melvin D. Cheitlin ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Wall Thickening ◽

Ventricular Wall ◽

Resonance Imaging ◽

Imaging Evaluation ◽

Magnetic Resonance Imaging Evaluation ◽

Regional Dysfunction

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Heterogeneity of segmental left ventricular wall thickening and excursion in two-dimensional echocardiograms of normal humans

The American Journal of Cardiology ◽

10.1016/0002-9149(81)90884-5 ◽

1981 ◽

Vol 47 ◽

pp. 452 ◽

Cited By ~ 7

Author(s):

Natesa Pandian ◽

David Skorton ◽

Steve Collins ◽

Ed Burke ◽

Herman Falsetti ◽

...

Keyword(s):

Left Ventricular ◽

Left Ventricular Wall ◽

Wall Thickening ◽

Ventricular Wall ◽

Two Dimensional ◽

Normal Humans

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Abstract 16165: Inorganic Arsenic Induces Sex-Dependent Pathological Cardiac Hypertrophy

Circulation ◽

10.1161/circ.142.suppl_3.16165 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Raihan Kabir ◽

Prithvi Sinha ◽

Sumita Mishra ◽

Obialunanma V Ebenebe ◽

Nicole Taube ◽

...

Keyword(s):

Blood Pressure ◽

Cardiac Hypertrophy ◽

Inorganic Arsenic ◽

Left Ventricular ◽

Luciferase Assay ◽

Heart Weight ◽

Left Ventricular Geometry ◽

Wall Thickening ◽

Pathological Cardiac Hypertrophy ◽

Relevant Dose

Exposure to inorganic arsenic (iAS) through drinking water is well-associated with adverse cardiovascular outcomes, yet the mechanisms through which it induces these effects are not fully understood. Recent epidemiological findings highlight an association between iAS exposure and altered left ventricular geometry in both the presence and absence of hypertension. We therefore tested the hypothesis that iAS exposure has a bimodal impact on cardiac-intrinsic and hemodynamic mechanisms that together induce pathological remodeling of the myocardium. Adult male and female mice were exposed to an environmentally relevant dose of 615 μg/L NaAsO 2 for eight weeks. Males (n=9-10 mice/group) exhibited increased systolic blood pressure (115.1±3.0 vs. 106.0±2.3 mmHg, p=0.0350) via tail cuff photoplethysmography, left ventricular wall thickening (0.98±0.01 vs. 0.88±0.01 mm, p<0.0001) via transthoracic echocardiography, increased heart weight to tibia length (8.56±0.21 vs. 7.15±0.24 mg/mm; n=24 mice/group), and increased plasma atrial natriuretic peptide (47.85±12.0 vs. 15.14±3.73 pg/mL, p=0.0379) via enzyme immunoassay. Myocardial mRNA transcript levels (n=10 hearts/group) of Acta1 (1.36±0.18 vs. 0.73±0.11, p=0.0037), Myh7 (1.53±0.15 vs. 1.04±0.10, p=0.0138), and Nppa (2.40±0.29 vs. 1.02±0.07, p=0.0001) were increased, and Myh6 (0.92±0.17 vs. 1.14±0.23, p=0.0001) was decreased, evidencing pathological hypertrophy in the male heart. Female hearts, however, were largely protected at this eight-week timepoint as similar changes were not detected. Further investigation found that Rcan1 was upregulated (1.47±0.19 vs. 0.97±0.04, p=0.0161; n=10 hearts/group) in male hearts, suggesting that calcineurin-NFAT was activated. Interestingly, iAS was sufficient to activate NFAT (0.82±0.11 vs. 0.46±0.05, p=0.0214; n=8 wells/group) independent of blood pressure via luciferase assay. In conclusion, these results demonstrate for the first time that iAS may cause pathological cardiac hypertrophy not only by increasing hemodynamic load, but also by activating calcineurin-NFAT and inducing fetal gene expression in the male heart, thus providing novel mechanistic insight into the threat of iAS exposure to the cardiovascular system.

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Dobutamine stress echo for suspected paradoxical low-flow low-gradient severe aortic stenosis: Value of left ventricular wall thickening assessment

International Journal of Cardiology ◽

10.1016/j.ijcard.2015.06.176 ◽

2015 ◽

Vol 198 ◽

pp. 182-184 ◽

Cited By ~ 1

Author(s):

A. Vamvakidou ◽

I. Ramzy ◽

R. Senior

Keyword(s):

Aortic Stenosis ◽

Severe Aortic Stenosis ◽

Dobutamine Stress ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Low Flow ◽

Wall Thickening ◽

Ventricular Wall ◽

Stress Echo

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Influence of hereditary haemochromatosis on left ventricular wall thickness: does iron overload exacerbate cardiac hypertrophy?

Folia Morphologica ◽

10.5603/fm.a2019.0025 ◽

2019 ◽

Vol 78 (4) ◽

pp. 746-753

Author(s):

K. Rozwadowska ◽

G. Raczak ◽

K. Sikorska ◽

M. Fijałkowski ◽

D. Kozłowski ◽

...

Keyword(s):

Cardiac Hypertrophy ◽

Iron Overload ◽

Wall Thickness ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Ventricular Wall ◽

Left Ventricular Wall Thickness ◽

Hereditary Haemochromatosis ◽

Ventricular Wall Thickness

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Contribution of laminar myofiber architecture to load-dependent changes in mechanics of LV myocardium

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00261.2001 ◽

2002 ◽

Vol 282 (4) ◽

pp. H1510-H1520 ◽

Cited By ~ 64

Author(s):

Yasuo Takayama ◽

Kevin D. Costa ◽

James W. Covell

Keyword(s):

Radial Direction ◽

Diastolic Pressure ◽

Ventricular Myocardium ◽

Left Ventricular ◽

Left Ventricular Wall ◽

Wall Thickening ◽

Ventricular Wall ◽

Predominant Factor ◽

Essential Contribution ◽

Systolic And Diastolic Function

The ventricular myocardium consists of a syncytium of myocytes organized into branching, transmurally oriented laminar sheets approximately four cells thick. When systolic deformation is expressed in an axis system determined by the anatomy of the laminar architecture, laminar sheets of myocytes shear and laterally extend in an approximately radial direction. These deformations account for ∼90% of normal systolic wall thickening in the left ventricular free wall. In the present study, we investigated whether the changes in systolic and diastolic function of the sheets were sensitive to alterations in systolic and diastolic load. Our results indicate that there is substantial reorientation of the laminar architecture during systole and diastole. Moreover, this reorientation is both site and load dependent. Thus as end-diastolic pressure is increased and the left ventricular wall thins, sheets shorten and rotate away from the radial direction due to transverse shearing, opposite of what occurs in systole. Both mechanisms of thickening contribute substantially to normal left ventricular wall function. Whereas the relative contributions of shear and extension are comparable at the base, sheet shear is the predominant factor at the apex. The magnitude of shortening/extension and shear increases with preload and decreases with afterload. These findings underscore the essential contribution of the laminar myocardial architecture for normal ventricular function throughout the cardiac cycle.

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