Right ventricular remodeling in response to volume overload in fetal sheep

The fetal myocardium is known to be sensitive to hemodynamic load, responding to systolic overload with cellular hypertrophy, proliferation, and accelerated maturation. However, the fetal cardiac growth response to primary volume overload is unknown. We hypothesized that increased venous return would stimulate fetal cardiomyocyte proliferation and terminal differentiation, particularly in the right ventricle (RV). Vascular catheters and pulmonary artery flow probes were implanted in 16 late-gestation fetal sheep: a right carotid artery-jugular vein (AV) fistula was surgically created in nine fetuses, and sham operations were performed on seven fetuses. Instrumented fetuses were studied for 1 wk before hearts were dissected for component analysis or cardiomyocyte dispersion for cellular measurements. Within 1 day of AV fistula creation, RV output was 20% higher in experimental than sham fetuses ( P < 0.0001). Circulating atrial natriuretic peptide levels were elevated fivefold in fetuses with an AV fistula ( P < 0.002). On the terminal day, RV-to-body weight ratios were 35% higher in the AV fistula group ( P < 0.05). Both left ventricular and RV cardiomyocytes grew longer in fetuses with an AV fistula ( P < 0.02). Cell cycle activity was depressed by >50% [significant in left ventricle ( P < 0.02), but not RV ( P < 0.054)]. Rates of terminal differentiation were unchanged. Based on these studies, we speculate that atrial natriuretic peptide suppressed fetal cardiomyocyte cell cycle activity. Unlike systolic overload, fetal diastolic load appears to drive myocyte enlargement, but not cardiomyocyte proliferation or maturation. These changes could predispose to RV dysfunction later in life. NEW & NOTEWORTHY Adaptation of the fetal heart to changes in cardiac load allows the fetus to maintain adequate blood flow to its systemic and placental circulations, which is necessary for the well-being of the fetus. Addition of arterial-venous fistula flow to existing venous return increased right ventricular stroke volume and output. The fetal heart compensated by cardiomyocyte elongation without accelerated cellular maturation, while cardiomyocyte proliferation decreased. Even transient volume overload in utero alters myocardial structure and cardiomyocyte endowment.

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Sequential growth of fetal sheep cardiac myocytes in response to simultaneous arterial and venous hypertension

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00484.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. R913-R919 ◽

Cited By ~ 41

Author(s):

Sonnet S. Jonker ◽

J. Job Faber ◽

Debra F. Anderson ◽

Kent L. Thornburg ◽

Samantha Louey ◽

...

Keyword(s):

Cell Cycle ◽

Cross Sections ◽

Terminal Differentiation ◽

Perinatal Period ◽

Venous Hypertension ◽

Cardiomyocyte Proliferation ◽

Growth Data ◽

Ki 67 ◽

Fetal Sheep ◽

Two Phases

While the fetal heart grows by myocyte enlargement and proliferation, myocytes lose their capacity for proliferation in the perinatal period after terminal differentiation. The relationship between myocyte enlargement, proliferation, and terminal differentiation has not been studied under conditions of combined arterial and venous hypertension, as occurs in some clinical conditions. We hypothesize that fetal arterial and venous hypertension initially leads to cardiomyocyte proliferation, followed by myocyte enlargement. Two groups of fetal sheep received intravascular plasma infusions for 4 or 8 days (from 130 days gestation) to increase vascular pressures. Fetal hearts were arrested in diastole and dissociated. Myocyte size, terminal differentiation (%binucleation), and cell cycle activity (Ki-67[+] cells as a % of mononucleated myocytes) were measured. We found that chronic plasma infusion greatly increased venous and arterial pressures. Heart (but not body) weights were ∼30% greater in hypertensive fetuses than controls. The incidence of cell cycle activity doubled in hypertensive fetuses compared with controls. After 4 days of hypertension, myocytes were (∼11%) longer, but only after 8 days were they wider (∼12%). After 8 days, %binucleation was ∼50% greater in hypertensive fetuses. We observed two phases of cardiomyocyte growth and maturation in response to fetal arterial and venous hypertension. In the early phase, the incidence of cell cycle activity increased and myocytes elongated. In the later phase, the incidence of cell cycle activity remained elevated, %binucleation increased, and cross sections were greater. This study highlights unique fetal adaptations of the myocardium and the importance of experimental duration when interpreting fetal cardiac growth data.

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Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart

Journal of Applied Physiology ◽

10.1152/japplphysiol.00937.2006 ◽

2007 ◽

Vol 102 (3) ◽

pp. 1130-1142 ◽

Cited By ~ 101

Author(s):

Sonnet S. Jonker ◽

Lubo Zhang ◽

Samantha Louey ◽

George D. Giraud ◽

Kent L. Thornburg ◽

...

Keyword(s):

Cell Cycle ◽

Cardiac Myocytes ◽

Cardiac Myocyte ◽

Terminal Differentiation ◽

Normal Growth ◽

Mass Gain ◽

Perinatal Period ◽

Cross Sectional ◽

Fetal Sheep ◽

Cardiac Growth

The generation of new myocytes is an essential process of in utero heart growth. Most, or all, cardiac myocytes lose their capacity for proliferation during the perinatal period through the process of terminal differentiation. An increasing number of studies focus on how experimental interventions affect cardiac myocyte growth in the fetal sheep. Nevertheless, fundamental questions about normal growth of the fetal heart remain unanswered. In this study, we determined that during the last third of gestation the hearts of fetal sheep grew primarily by four processes. 1) Myocyte proliferation contributed substantially to daily cardiac mass gain, and the number of cardiac myocytes continued to increase to term. 2) The (hitherto unrecognized) contribution to cardiac growth by the increase in myocyte size associated with the transition from mononucleation to binucleation (terminal differentiation) became considerable from ∼115 days of gestational age (dGA) until term (145dGA). Because binucleation became the more frequent outcome of myocyte cell cycle activity after ∼115dGA, the number of binucleated myocytes increased at the expense of the number of mononucleated myocytes. Both the interval between nuclear divisions and the duration of cell cycle activity in myocytes decreased substantially during this same period. Finally, cardiac growth was in part due to enlargement of 3) mononucleated and 4) binucleated myocytes, which grew in cross-sectional diameter but not length during the last third of gestation. These data on normal cardiac growth may enable a more detailed understanding of the consequences of experimental and pathological interventions in prenatal life.

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323: Increased serum atrial natriuretic peptide levels are associated with improved right ventricular relaxation in chronically anemic fetal sheep

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2010.10.341 ◽

2011 ◽

Vol 204 (1) ◽

pp. S133

Author(s):

A. Roger Hohimer ◽

Leah Bernard ◽

Jason Hashima ◽

David Sahn ◽

Muhammad Ashraf ◽

...

Keyword(s):

Atrial Natriuretic Peptide ◽

Right Ventricular ◽

Natriuretic Peptide ◽

Fetal Sheep ◽

Ventricular Relaxation ◽

Atrial Natriuretic

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Postnatal Right Ventricular Developmental Track Changed by Volume Overload

Journal of the American Heart Association ◽

10.1161/jaha.121.020854 ◽

2021 ◽

Author(s):

Sijuan Sun ◽

Yuqing Hu ◽

Yingying Xiao ◽

Shoubao Wang ◽

Chuan Jiang ◽

...

Keyword(s):

Cell Cycle ◽

Gene Ontology ◽

Right Ventricular ◽

Cardiac Muscle ◽

Signaling Pathways ◽

Signaling Pathway ◽

Rna Sequencing ◽

Volume Overload ◽

Neonatal Mouse ◽

Cellular Respiration

Background Current right ventricular (RV) volume overload (VO) is established in adult mice. There are no neonatal mouse VO models and how VO affects postnatal RV development is largely unknown. Methods and Results Neonatal VO was induced by the fistula between abdominal aorta and inferior vena cava on postnatal day 7 and confirmed by abdominal ultrasound, echocardiography, and hematoxylin and eosin staining. The RNA‐sequencing results showed that the top 5 most enriched gene ontology terms in normal RV development were energy derivation by oxidation of organic compounds, generation of precursor metabolites and energy, cellular respiration, striated muscle tissue development, and muscle organ development. Under the influence of VO, the top 5 most enriched gene ontology terms were angiogenesis, regulation of cytoskeleton organization, regulation of vasculature development, regulation of mitotic cell cycle, and regulation of the actin filament‐based process. The top 3 enriched signaling pathways for the normal RV development were PPAR signaling pathway, citrate cycle (Tricarboxylic acid cycle), and fatty acid degradation. VO changed the signaling pathways to focal adhesion, the PI3K‐Akt signaling pathway, and pathways in cancer. The RNA sequencing results were confirmed by the examination of the markers of metabolic and cardiac muscle maturation and the markers of cell cycle and angiogenesis. Conclusions A neonatal mouse VO model was successfully established, and the main processes of postnatal RV development were metabolic and cardiac muscle maturation, and VO changed that to angiogenesis and cell cycle regulation.

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Suppression of miRNA let-7i-5p promotes cardiomyocyte proliferation and repairs heart function post injury by targetting CCND2 and E2F2

Clinical Science ◽

10.1042/cs20181002 ◽

2019 ◽

Vol 133 (3) ◽

pp. 425-441 ◽

Cited By ~ 10

Author(s):

Yinlan Hu ◽

Guoqing Jin ◽

Bing Li ◽

Yanmei Chen ◽

Lintao Zhong ◽

...

Keyword(s):

Cell Cycle ◽

Therapeutic Strategy ◽

Heart Function ◽

Terminal Differentiation ◽

Transcriptional Level ◽

Cardiomyocyte Proliferation ◽

Post Injury

Abstract MiRNAs regulate the cardiomyocyte (CM) cell cycle at the post-transcriptional level, affect cell proliferation, and intervene in harmed CM repair post-injury. The present study was undertaken to characterize the role of let-7i-5p in the processes of CM cell cycle and proliferation and to reveal the mechanisms thereof. In the present study, we used real-time qPCR (RT-qPCR) to determine the up-regulated let-7i-5p in CMs during the postnatal switch from proliferation to terminal differentiation and further validated the role of let-7i-5p by loss- and gain-of-function of let-7i-5p in CMs in vitro and in vivo. We found that the overexpression of let-7i-5p inhibited CM proliferation, whereas the suppression of let-7i-5p significantly facilitated CM proliferation. E2F2 and CCND2 were identified as the targets of let-7i-5p, mediating its effect in regulating the cell cycle of CMs. Supperession of let-7i-5p promoted the recovery of heart function post-myocardial infarction by enhancing E2F2 and CCND2. Collectively, our results revealed that let-7i-5p is involved in the regulation of the CM cell cycle and further impacts proliferation, which may offer a new potential therapeutic strategy for cardiac repair after ischemic injury.

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Reduced systolic pressure load decreases cell-cycle activity in the fetal sheep heart

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00754.2009 ◽

2010 ◽

Vol 299 (2) ◽

pp. R573-R578 ◽

Cited By ~ 21

Author(s):

P. F. O'Tierney ◽

D. F. Anderson ◽

J. J. Faber ◽

S. Louey ◽

K. L. Thornburg ◽

...

Keyword(s):

Cell Cycle ◽

Fetal Heart ◽

Ventricular Myocytes ◽

Enzyme Inhibitor ◽

Mechanical Load ◽

Systolic Pressure ◽

The Body ◽

Heart Weight ◽

Fetal Sheep ◽

Pressure Load

The fetal heart is highly sensitive to changes in mechanical load. We have previously demonstrated that increased cardiac load can stimulate cell cycle activity and maturation of immature cardiomyocytes, but the effects of reduced load are not known. Sixteen fetal sheep were given either continuous intravenous infusion of lactated Ringer solution (LR) or enalaprilat, an angiotensin-converting enzyme inhibitor beginning at 127 days gestational age. After 8 days, fetal arterial pressure in the enalaprilat-infused fetuses (23.8 ± 2.8 mmHg) was lower than that of control fetuses (47.5 ± 4.7 mmHg) ( P < 0.0001). Although the body weights of the two groups of fetuses were similar, the heart weight-to-body weight ratios of the enalaprilat-infused fetuses were less than those of the LR-infused fetuses (5.6 ± 0.5 g/kg vs. 7.0 ± 0.6 g/kg, P < 0.0001). Dimensions of ventricular myocytes were not different between control and enalaprilat-infused fetuses. However, there was a significant decrease in cell cycle activity in both the right ventricle ( P < 0.005) and the left ventricle ( P < 0.002) of the enalaprilat-infused fetuses. Thus, we conclude a sustained reduction in systolic pressure load decreases hyperplastic growth in the fetal heart.

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Faculty Opinions recommendation of A double-assurance mechanism controls cell cycle exit upon terminal differentiation in Drosophila.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1084779.537695 ◽

2007 ◽

Author(s):

Duojia Pan

Keyword(s):

Cell Cycle ◽

Terminal Differentiation ◽

Cell Cycle Exit

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Regional shape, global function and mechanics in right ventricular volume and pressure overload conditions: a three-dimensional echocardiography study

The International Journal of Cardiovascular Imaging ◽

10.1007/s10554-020-02117-8 ◽

2021 ◽

Author(s):

Jurate Bidviene ◽

Denisa Muraru ◽

Francesco Maffessanti ◽

Egle Ereminiene ◽

Attila Kovács ◽

...

Keyword(s):

Right Ventricular ◽

Interventricular Septum ◽

Three Dimensional ◽

Pressure Overload ◽

Volume Overload ◽

Ventricular Volume ◽

Longitudinal Contraction ◽

Convex Shape ◽

Dimensional Echocardiography ◽

Three Dimensional Echocardiography

AbstractOur aim was to assess the regional right ventricular (RV) shape changes in pressure and volume overload conditions and their relations with RV function and mechanics. The end-diastolic and end-systolic RV endocardial surfaces were analyzed with three-dimensional echocardiography (3DE) in 33 patients with RV volume overload (rToF), 31 patients with RV pressure overload (PH), and 60 controls. The mean curvature of the RV inflow (RVIT) and outflow (RVOT) tracts, RV apex and body (both divided into free wall (FW) and septum) were measured. Zero curvature defined a flat surface, whereas positive or negative curvature indicated convexity or concavity, respectively. The longitudinal and radial RV wall motions were also obtained. rToF and PH patients had flatter FW (body and apex) and RVIT, more convex interventricular septum (body and apex) and RVOT than controls. rToF demonstrated a less bulging interventricular septum at end-systole than PH patients, resulting in a more convex shape of the RVFW (r = − 0.701, p < 0.0001), and worse RV longitudinal contraction (r = − 0.397, p = 0.02). PH patients showed flatter RVFW apex at end-systole compared to rToF (p < 0.01). In both groups, a flatter RVFW apex was associated with worse radial RV contraction (r = 0.362 in rToF, r = 0.482 in PH at end-diastole, and r = 0.555 in rToF, r = 0.379 in PH at end-systole, respectively). In PH group, the impairment of radial contraction was also related to flatter RVIT (r = 0.407) and more convex RVOT (r = − 0.525) at end-systole (p < 0.05). In conclusion, different loading conditions are associated to specific RV curvature changes, that are related to longitudinal and radial RV dysfunction.

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