Journal articles on the topic 'Heart Hypertrophy Molecular aspects'
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1
Elsherif, Laila, Raymond V. Ortines, Jack T. Saari, and Y. James Kang. "Congestive Heart Failure in Copper-Deficient Mice." Experimental Biology and Medicine 228, no. 7 (July 2003): 811–17. http://dx.doi.org/10.1177/15353702-0322807-06.
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Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (−dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the β-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.
2
Pedram, Ali, Mahnaz Razandi, Ramesh Narayanan, James T. Dalton, Timothy A. McKinsey, and Ellis R. Levin. "Estrogen regulates histone deacetylases to prevent cardiac hypertrophy." Molecular Biology of the Cell 24, no. 24 (December 15, 2013): 3805–18. http://dx.doi.org/10.1091/mbc.e13-08-0444.
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The development and progression of cardiac hypertrophy often leads to heart failure and death, and important modulators of hypertrophy include the histone deacetylase proteins (HDACs). Estrogen inhibits cardiac hypertrophy and progression in animal models and humans. We therefore investigated the influence of 17-β-estradiol on the production, localization, and functions of prohypertrophic (class I) and antihypertrophic (class II) HDACs in cultured neonatal rat cardiomyocytes. 17-β-Estradiol or estrogen receptor β agonists dipropylnitrile and β-LGND2 comparably suppressed angiotensin II–induced HDAC2 (class I) production, HDAC-activating phosphorylation, and the resulting prohypertrophic mRNA expression. In contrast, estrogenic compounds derepressed the opposite effects of angiotensin II on the same parameters for HDAC4 and 5 (class II), resulting in retention of these deacetylases in the nucleus to inhibit hypertrophic gene expression. Key aspects were confirmed in vivo from the hearts of wild-type but not estrogen receptor β (ERβ) gene–deleted mice administered angiotensin II and estrogenic compounds. Our results identify a novel dual regulation of cardiomyocyte HDACs, shown here for the antihypertrophic sex steroid acting at ERβ. This mechanism potentially supports using ERβ agonists as HDAC modulators to treat cardiac disease.
3
Kang, Y. James. "Cardiac Hypertrophy: A Risk Factor for QT-Prolongation and Cardiac Sudden Death." Toxicologic Pathology 34, no. 1 (January 2006): 58–66. http://dx.doi.org/10.1080/01926230500419421.
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Cardiac hypertrophy was viewed as a compensatory response to hemodynamic stress. However, cumulative evidence obtained from studies using more advanced technologies in human patients and animal models suggests that cardiac hypertrophy is a maladaptive process of the heart in response to intrinsic and extrinsic stimuli. Although hypertrophy can normalize wall tension, it is a risk factor for QT-prolongation and cardiac sudden death. Studies using molecular biology techniques such as transgenic and knockout mice have revealed many important molecules that are involved in the development of heart hypertrophy and have demonstrated signaling pathways leading to the pathogenesis. With the same approach, the consequence of heart hypertrophy has been examined. The significance of hypertrophy in the development of overt heart failure has been demonstrated and several critical molecular pathways involved in the process were revealed. A comprehensive understanding of the threats of heart hypertrophy to patients has helped to develop novel treatment strategies. The recognition of hypertrophy as a major risk factor for QT-prolongation and cardiac sudden death is an important advance in cardiac medicine. Cellular and molecular mechanisms of this risk aspect are currently under extensively exploring. These studies would lead to more comprehensive approaches to prevention of potential life threatening arrhythmia and cardiac sudden death. The adaptation of new approaches such as functional genomics and proteomics will further advance our knowledge of heart hypertrophy.
4
Zhou, Yiqiu. "Excitation Contraction Coupling in Hypertrophy and Failing Heart Cells." E3S Web of Conferences 271 (2021): 03008. http://dx.doi.org/10.1051/e3sconf/202127103008.
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The contraction of the heart is dependent on a process named the excitation-contraction coupling (E-C coupling). In hypertrophy and failing heart models, the expression, phosphorylation and function of key calcium handling proteins involved in E-C coupling are altered. It’s important to figure out the relationship changes between calcium channel activity and calcium release from sarcoplasmic reticulum (SR). This review will therefore focus on novel components of E-C coupling dysfunction in hypertrophy and failing heart, such as L-type Ca2+ channel (LCC), ryanodine receptor type-2 channel (RyR2) and SR Ca ATPase (SERCA), and how these molecular modifications altered excitation-contraction coupling. A lot of literature was well read and sorted. Recent findings in E-C coupling during hypertrophy and heart failure were focused on. Most importantly, the electrophysiological and signal pathway data was carefully analyzed. This review summarizes key principles and highlights novel aspects of E-C coupling changes during hypertrophy and heart failure models. Although LCC activity changed little, the loss of notch in action potential, reduced Ca2+ transient amplitude and desynchronized Ca2+ sparks resulted in a decreased contraction strength in hypertrophy and heart failure models. What’s more, L-type Ca2+ current becomes ineffective in triggering RyR2 Ca2+ release from SR and the SR uptake is reduced in some models. It has great meanings in understanding the E-C coupling changes during different heart diseases. Theses novel changes suggest potential therapeutic approaches for certain types of hypertrophy and heart failure.
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Popa-Fotea, Nicoleta Monica, Miruna Mihaela Micheu, Vlad Bataila, Alexandru Scafa-Udriste, Lucian Dorobantu, Alina Ioana Scarlatescu, Diana Zamfir, Monica Stoian, Sebastian Onciul, and Maria Dorobantu. "Exploring the Continuum of Hypertrophic Cardiomyopathy—From DNA to Clinical Expression." Medicina 55, no. 6 (June 23, 2019): 299. http://dx.doi.org/10.3390/medicina55060299.
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The concepts underlying hypertrophic cardiomyopathy (HCM) pathogenesis have evolved greatly over the last 60 years since the pioneering work of the British pathologist Donald Teare, presenting the autopsy findings of “asymmetric hypertrophy of the heart in young adults”. Advances in human genome analysis and cardiac imaging techniques have enriched our understanding of the complex architecture of the malady and shaped the way we perceive the illness continuum. Presently, HCM is acknowledged as “a disease of the sarcomere”, where the relationship between genotype and phenotype is not straightforward but subject to various genetic and nongenetic influences. The focus of this review is to discuss key aspects related to molecular mechanisms and imaging aspects that have prompted genotype–phenotype correlations, which will hopefully empower patient-tailored health interventions.
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Bacharova, Ljuba. "Missing Link Between Molecular Aspects of Ventricular Arrhythmias and QRS Complex Morphology in Left Ventricular Hypertrophy." International Journal of Molecular Sciences 21, no. 1 (December 19, 2019): 48. http://dx.doi.org/10.3390/ijms21010048.
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The aim of this opinion paper is to point out the knowledge gap between evidence on the molecular level and clinical diagnostic possibilities in left ventricular hypertrophy (LVH) regarding the prediction of ventricular arrhythmias and monitoring the effect of therapy. LVH is defined as an increase in left ventricular size and is associated with increased occurrence of ventricular arrhythmia. Hypertrophic rebuilding of myocardium comprises interrelated processes on molecular, subcellular, cellular, tissue, and organ levels affecting electrogenesis, creating a substrate for triggering and maintaining arrhythmias. The knowledge of these processes serves as a basis for developing targeted therapy to prevent and treat arrhythmias. In the clinical practice, the method for recording electrical phenomena of the heart is electrocardiography. The recognized clinical electrocardiogram (ECG) predictors of ventricular arrhythmias are related to alterations in electrical impulse propagation, such as QRS complex duration, QT interval, early repolarization, late potentials, and fragmented QRS, and they are not specific for LVH. However, the simulation studies have shown that the QRS complex patterns documented in patients with LVH are also conditioned remarkably by the alterations in impulse propagation. These QRS complex patterns in LVH could be potentially recognized for predicting ventricular arrhythmia and for monitoring the effect of therapy.
7
Petriz, Bernardo A., and Octavio L. Franco. "Effects of Hypertension and Exercise on Cardiac Proteome Remodelling." BioMed Research International 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/634132.
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Left ventricle hypertrophy is a common outcome of pressure overload stimulus closely associated with hypertension. This process is triggered by adverse molecular signalling, gene expression, and proteome alteration. Proteomic research has revealed that several molecular targets are associated with pathologic cardiac hypertrophy, including angiotensin II, endothelin-1 and isoproterenol. Several metabolic, contractile, and stress-related proteins are shown to be altered in cardiac hypertrophy derived by hypertension. On the other hand, exercise is a nonpharmacologic agent used for hypertension treatment, where cardiac hypertrophy induced by exercise training is characterized by improvement in cardiac function and resistance against ischemic insult. Despite the scarcity of proteomic research performed with exercise, healthy and pathologic heart proteomes are shown to be modulated in a completely different way. Hence, the altered proteome induced by exercise is mostly associated with cardioprotective aspects such as contractile and metabolic improvement and physiologic cardiac hypertrophy. The present review, therefore, describes relevant studies involving the molecular characteristics and alterations from hypertensive-induced and exercise-induced hypertrophy, as well as the main proteomic research performed in this field. Furthermore, proteomic research into the effect of hypertension on other target-demerged organs is examined.
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Turner and Blythe. "Cardiac Fibroblast p38 MAPK: A Critical Regulator of Myocardial Remodeling." Journal of Cardiovascular Development and Disease 6, no. 3 (August 7, 2019): 27. http://dx.doi.org/10.3390/jcdd6030027.
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The cardiac fibroblast is a remarkably versatile cell type that coordinates inflammatory, fibrotic and hypertrophic responses in the heart through a complex array of intracellular and intercellular signaling mechanisms. One important signaling node that has been identified involves p38 MAPK; a family of kinases activated in response to stress and inflammatory stimuli that modulates multiple aspects of cardiac fibroblast function, including inflammatory responses, myofibroblast differentiation, extracellular matrix turnover and the paracrine induction of cardiomyocyte hypertrophy. This review explores the emerging importance of the p38 MAPK pathway in cardiac fibroblasts, describes the molecular mechanisms by which it regulates the expression of key genes, and highlights its potential as a therapeutic target for reducing adverse myocardial remodeling.
9
Papait, Roberto, Simone Serio, and Gianluigi Condorelli. "Role of the Epigenome in Heart Failure." Physiological Reviews 100, no. 4 (October 1, 2020): 1753–77. http://dx.doi.org/10.1152/physrev.00037.2019.
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Gene expression is needed for the maintenance of heart function under normal conditions and in response to stress. Each cell type of the heart has a specific program controlling transcription. Different types of stress induce modifications of these programs and, if prolonged, can lead to altered cardiac phenotype and, eventually, to heart failure. The transcriptional status of a gene is regulated by the epigenome, a complex network of DNA and histone modifications. Until a few years ago, our understanding of the role of the epigenome in heart disease was limited to that played by histone deacetylation. But over the last decade, the consequences for the maintenance of homeostasis in the heart and for the development of cardiac hypertrophy of a number of other modifications, including DNA methylation and hydroxymethylation, histone methylation and acetylation, and changes in chromatin architecture, have become better understood. Indeed, it is now clear that many levels of regulation contribute to defining the epigenetic landscape required for correct cardiomyocyte function, and that their perturbation is responsible for cardiac hypertrophy and fibrosis. Here, we review these aspects and draw a picture of what epigenetic modification may imply at the therapeutic level for heart failure.
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Sartoretto, Juliano L., Benjamin Y. Jin, Michael Bauer, Frank B. Gertler, Ronglih Liao, and Thomas Michel. "Regulation of VASP phosphorylation in cardiac myocytes: differential regulation by cyclic nucleotides and modulation of protein expression in diabetic and hypertrophic heart." American Journal of Physiology-Heart and Circulatory Physiology 297, no. 5 (November 2009): H1697—H1710. http://dx.doi.org/10.1152/ajpheart.00595.2009.
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Vasodilator-stimulated phosphoprotein (VASP) is a major substrate for cyclic nucleotide-dependent kinases that has been implicated in cardiac pathology, yet many aspects of VASP's molecular regulation in cardiomyocytes are incompletely understood. In these studies, we explored the role of VASP, both in signaling pathways in isolated murine myocytes, as well as in a model of cardiac hypertrophy in VASPnull mice. We found that the β-adrenergic agonist isoproterenol promotes the rapid and reversible phosphorylation of VASP at Ser157 and Ser239. Forskolin and the cAMP analog 8-(4-chlorophenylthio)-cAMP promote a similar pattern of VASP phosphorylation at both sites. The effects of isoproterenol are blocked by atenolol and by compound H-89, an inhibitor of the cAMP-dependent protein kinase. By contrast, phosphorylation of VASP only at Ser239 is seen following activation of particulate guanylate cyclase by atrial natriuretic peptide, or following activation of soluble guanylate cyclase by sodium nitroprusside, or following treatment of myocytes with cGMP analog. We found that basal and isoproterenol-induced VASP phosphorylation is entirely unchanged in cardiomyocytes isolated from either endothelial or neuronal nitric oxide synthase knockout mice. In cardiomyocytes isolated from diabetic mice, only basal VASP phosphorylation is increased, whereas, in cells isolated from mice subjected to ascending aortic constriction (AAC), we found a significant increase in basal VASP expression, along with an increase in VASP phosphorylation, compared with cardiac myocytes isolated from sham-operated mice. Moreover, there is further increase in VASP phosphorylation in cells isolated from hypertrophic hearts following isoproterenol treatment. Finally, we found that VASPnull mice subjected to transverse aortic constriction develop cardiac hypertrophy with a pattern similar to VASP+/+ mice. Our findings establish differential receptor-modulated regulation of VASP phosphorylation in cardiomyocytes by cyclic nucleotides. Furthermore, these studies demonstrate for the first time that VASP expression is upregulated in hypertrophied heart.
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Shakaryants, G. A., M. V. Kozhevnikova, V. Yu Kaplunova, E. V. Privalova, A. S. Lishuta, E. O. Korobkova, and Yu N. Belenkov. "Focus on the Myocardial Hypertrophy from the Perspective of Transcriptomics and Metabolomics." Kardiologiia 60, no. 4 (May 4, 2020): 120–29. http://dx.doi.org/10.18087/cardio.2020.4.n1063.
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This review presents major directions in studies of myocardial hypertrophy from the aspect of transcriptomics and metabolomics. Understanding of trigger mechanisms of myocardial hypertrophy will permit transition from basic studies to individualized clinical application of innovative technologies in the treatment of heart diseases, such as targeted therapy. At the present time, methods have been developed for diagnostics and prediction of cardiovascular diseases based on the metabolomic profiling and the evaluation of microRNA expression. Progress in studying molecular and genetic processes underlying the development of cardiovascular diseases may provide invaluable information for clinical cardiology.
12
Simmonds, Steven J., Ilona Cuijpers, Stephane Heymans, and Elizabeth A. V. Jones. "Cellular and Molecular Differences between HFpEF and HFrEF: A Step Ahead in an Improved Pathological Understanding." Cells 9, no. 1 (January 18, 2020): 242. http://dx.doi.org/10.3390/cells9010242.
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Heart failure (HF) is the most rapidly growing cardiovascular health burden worldwide. HF can be classified into three groups based on the percentage of the ejection fraction (EF): heart failure with reduced EF (HFrEF), heart failure with mid-range—also called mildly reduced EF— (HFmrEF), and heart failure with preserved ejection fraction (HFpEF). HFmrEF can progress into either HFrEF or HFpEF, but its phenotype is dominated by coronary artery disease, as in HFrEF. HFrEF and HFpEF present with differences in both the development and progression of the disease secondary to changes at the cellular and molecular level. While recent medical advances have resulted in efficient and specific treatments for HFrEF, these treatments lack efficacy for HFpEF management. These differential response rates, coupled to increasing rates of HF, highlight the significant need to understand the unique pathogenesis of HFrEF and HFpEF. In this review, we summarize the differences in pathological development of HFrEF and HFpEF, focussing on disease-specific aspects of inflammation and endothelial function, cardiomyocyte hypertrophy and death, alterations in the giant spring titin, and fibrosis. We highlight the areas of difference between the two diseases with the aim of guiding research efforts for novel therapeutics in HFrEF and HFpEF.
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Tingare, Asmita, Bernard Thienpont, and H. Llewelyn Roderick. "Epigenetics in the heart: the role of histone modifications in cardiac remodelling." Biochemical Society Transactions 41, no. 3 (May 23, 2013): 789–96. http://dx.doi.org/10.1042/bst20130012.
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Understanding the molecular mechanisms underlying cardiac development and growth has been a longstanding goal for developing therapies for cardiovascular disorders. The heart adapts to a rise in its required output by an increase in muscle mass and alteration in the expression of a large number of genes. However, persistent stress diminishes the plasticity of the heart, consequently resulting in its maladaptive growth, termed pathological hypertrophy. Recent developments suggest that the concomitant genome-wide remodelling of the gene expression programme is largely driven through epigenetic mechanisms such as post-translational histone modifications and DNA methylation. In the last few years, the distinct functions of histone modifications and of the enzymes catalysing their formation have begun to be elucidated in processes important for cardiac development, disease and cardiomyocyte proliferation. The present review explores how repressive histone modifications, in particular methylation of H3K9 (histone H3 Lys9), govern aspects of cardiac biology.
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Mattiazzi, Alicia, Rosana A. Bassani, Ariel L. Escobar, Julieta Palomeque, Carlos A. Valverde, Martín Vila Petroff, and Donald M. Bers. "Chasing cardiac physiology and pathology down the CaMKII cascade." American Journal of Physiology-Heart and Circulatory Physiology 308, no. 10 (May 15, 2015): H1177—H1191. http://dx.doi.org/10.1152/ajpheart.00007.2015.
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Calcium dynamics is central in cardiac physiology, as the key event leading to the excitation-contraction coupling (ECC) and relaxation processes. The primary function of Ca2+ in the heart is the control of mechanical activity developed by the myofibril contractile apparatus. This key role of Ca2+ signaling explains the subtle and critical control of important events of ECC and relaxation, such as Ca2+ influx and SR Ca2+ release and uptake. The multifunctional Ca2+-calmodulin-dependent protein kinase II (CaMKII) is a signaling molecule that regulates a diverse array of proteins involved not only in ECC and relaxation but also in cell death, transcriptional activation of hypertrophy, inflammation, and arrhythmias. CaMKII activity is triggered by an increase in intracellular Ca2+ levels. This activity can be sustained, creating molecular memory after the decline in Ca2+ concentration, by autophosphorylation of the enzyme, as well as by oxidation, glycosylation, and nitrosylation at different sites of the regulatory domain of the kinase. CaMKII activity is enhanced in several cardiac diseases, altering the signaling pathways by which CaMKII regulates the different fundamental proteins involved in functional and transcriptional cardiac processes. Dysregulation of these pathways constitutes a central mechanism of various cardiac disease phenomena, like apoptosis and necrosis during ischemia/reperfusion injury, digitalis exposure, post-acidosis and heart failure arrhythmias, or cardiac hypertrophy. Here we summarize significant aspects of the molecular physiology of CaMKII and provide a conceptual framework for understanding the role of the CaMKII cascade on Ca2+ regulation and dysregulation in cardiac health and disease.
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Thakker, Geeta D., Nikolaos G. Frangogiannis, Marcin Bujak, Paul Zymek, John W. Gaubatz, Anilkumar K. Reddy, George Taffet, Lloyd H. Michael, Mark L. Entman, and Christie M. Ballantyne. "Effects of diet-induced obesity on inflammation and remodeling after myocardial infarction." American Journal of Physiology-Heart and Circulatory Physiology 291, no. 5 (November 2006): H2504—H2514. http://dx.doi.org/10.1152/ajpheart.00322.2006.
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Epidemiological studies indicate that obesity, insulin resistance, and diabetes are important comorbidities of patients with ischemic heart disease and increase mortality and development of congestive heart failure after myocardial infarction. Although ob/ob and db/db mice are commonly used to study obesity with insulin resistance or diabetes, mutations in the leptin gene or its receptor are rarely the cause of obesity in humans, which is, instead, primarily a consequence of dietary and lifestyle factors. Therefore, we used a murine model of diet-induced obesity to examine the physiological effects of obesity and the inflammatory and healing response of diet-induced obese (DIO) mice after myocardial ischemia-reperfusion injury. DIO mice developed hyperinsulinemia and insulin resistance and hepatic steatosis, with significant ectopic lipid deposition in the heart and cardiac hypertrophy in the absence of significant changes in blood pressure. The mRNA levels of chemokines at 24 h and cytokines at 24 and 72 h of reperfusion were higher in DIO than in lean mice. In granulation tissue at 72 h of reperfusion, macrophage density was significantly increased, whereas neutrophil density was reduced, in DIO mice compared with lean mice. At 7 days of reperfusion, collagen deposition in the scar was significantly reduced and left ventricular (LV) dilation and cardiac hypertrophy were increased, indicative of adverse LV remodeling, in infarcted DIO mice. Characterization of a murine diet-induced model of obesity and insulin resistance that satisfies many aspects commonly observed in human obesity allows detailed examination of the adverse cardiovascular effects of diet-induced obesity at the molecular level.
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Chung, Eunhee, Kaylan M. Haizlip, and Leslie A. Leinwand. "Pregnancy late in rodent life has detrimental effects on the heart." American Journal of Physiology-Heart and Circulatory Physiology 315, no. 3 (September 1, 2018): H482—H491. http://dx.doi.org/10.1152/ajpheart.00020.2018.
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During pregnancy, the heart undergoes significant and numerous changes, including hypertrophy, that are usually described as physiological and reversible. Two aspects of the cardiac response to pregnancy are relatively understudied: advanced maternal age and multiple pregnancies (multiparity). Repeated breeder (RB) mice that have undergone five to seven consecutive pregnancies were euthanized 21 days after the weaning of their last pups and compared with age-matched primiparous, one-time pregnant (O1P) mice. The ages of the older mouse groups were similar (12 ± 1 mo). Pregnancy at a later age resulted in reduced fertility (40%); resorption was 29%, maternal mortality was 10%, and mortality of the pups was 17%. Contractile function as indicated by percent fractional shortening was significantly decreased in O1P and RB groups compared with the old nonpregnant control (ONP) group. There was no pathological induction of the fetal program of gene expression, with the exception of β-myosin heavy chain mRNA, which was induced in O1P compared with ONP mice ( P < 0.05) but not in RB mice. MicroRNA-208a was significantly increased in O1P compared with ONP mice ( P < 0.05) but significantly decreased in RB compared with ONP mice ( P < 0.05). mRNA of genes regulating angiogenesis (i.e., vascular endothelial growth factor-A) were significantly downregulated, whereas proinflammatory genes [i.e., interleukin-6, chemokine (C-C motif) ligand 2, and Cd36] were significantly upregulated in O1P ( P < 0.05) but not in RB mice. Overall, our results suggest that rather than multiparity, pregnancy in advanced age is a much more stressful event in both pregnant dams and fetuses, as evidenced by increased mortality, lower fertility, downregulation of angiogenesis, upregulation of inflammation, and cardiac dysfunction. NEW & NOTEWORTHY Pregnancy in older mice significantly decreases cardiac function, although repeated breeder mice demonstrated increased wall hypertrophy and dilated chamber size compared with one-time pregnant mice. Interestingly, many of the molecular changes were altered in one-time pregnant mice but not in repeated breeder mice, which may contribute to adverse pregnancy outcomes in a first pregnancy at a later age.
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Severino, Paolo, Andrea D’Amato, Silvia Prosperi, Francesca Fanisio, Lucia Ilaria Birtolo, Bettina Costi, Lucrezia Netti, et al. "Myocardial Tissue Characterization in Heart Failure with Preserved Ejection Fraction: From Histopathology and Cardiac Magnetic Resonance Findings to Therapeutic Targets." International Journal of Molecular Sciences 22, no. 14 (July 17, 2021): 7650. http://dx.doi.org/10.3390/ijms22147650.
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Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome responsible for high mortality and morbidity rates. It has an ever growing social and economic impact and a deeper knowledge of molecular and pathophysiological basis is essential for the ideal management of HFpEF patients. The association between HFpEF and traditional cardiovascular risk factors is known. However, myocardial alterations, as well as pathophysiological mechanisms involved are not completely defined. Under the definition of HFpEF there is a wide spectrum of different myocardial structural alterations. Myocardial hypertrophy and fibrosis, coronary microvascular dysfunction, oxidative stress and inflammation are only some of the main pathological detectable processes. Furthermore, there is a lack of effective pharmacological targets to improve HFpEF patients’ outcomes and risk factors control is the primary and unique approach to treat those patients. Myocardial tissue characterization, through invasive and non-invasive techniques, such as endomyocardial biopsy and cardiac magnetic resonance respectively, may represent the starting point to understand the genetic, molecular and pathophysiological mechanisms underlying this complex syndrome. The correlation between histopathological findings and imaging aspects may be the future challenge for the earlier and large-scale HFpEF diagnosis, in order to plan a specific and effective treatment able to modify the disease’s natural course.
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Prylutskaya, V. A., A. V. Sukalo, and T. A. Derkach. "Adaptation of the cardiovascular system of infants born by mothers with diabetes mellitus." Proceedings of the National Academy of Sciences of Belarus, Medical series 18, no. 1 (February 23, 2021): 94–108. http://dx.doi.org/10.29235/1814-6023-2021-18-1-94-108.
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It is known, that diabetes mellitus has a significant impact on the growth and development of the fetus. Hyperglycemia during pregnancy increases significantly the incidence of congenital malformations, perinatal morbidity and neonatal mortality. Over the past decades has been a steady increase in the prevalence of diabetes mellitus both in the general population and among pregnant women. In this regard, the study of the influence of diabetes mellitus in the mother on the condition of the fetus and newborn is today a relevant problem of obstetric-gynecological, neonatological and pediatric services. Hyperglycemia during pregnancy has the greatest effect on the fetal cardiovascular system. Diabetes mellitus of the mother causes an increase in the frequency of congenital heart defects in the newborn, myocardial hypertrophy, as well as various functional disorders of the cardiovascular system.This review mainly discusses the pathogenetic aspects and molecular mechanisms of the effect of hyperglycemia on the development of the fetal heart, provides an assessment of clinical, echocardiographic and some laboratory changes in the functioning of the cardiovascular system in newborns from mothers with diabetes mellitus, and also systematizes data on the relationship between maternal diabetes and the risks of cardiovascular disease in their children in the long term.
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Kolkhof, Peter, Robert Lawatscheck, Gerasimos Filippatos, and George L. Bakris. "Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems." International Journal of Molecular Sciences 23, no. 16 (August 17, 2022): 9243. http://dx.doi.org/10.3390/ijms23169243.
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Perception of the role of the aldosterone/mineralocorticoid receptor (MR) ensemble has been extended from a previously renal epithelial-centered focus on sodium and volume homeostasis to an understanding of their role as systemic modulators of reactive oxygen species, inflammation, and fibrosis. Steroidal MR antagonists (MRAs) are included in treatment paradigms for resistant hypertension and heart failure with reduced ejection fraction, while more recently, the nonsteroidal MRA finerenone was shown to reduce renal and cardiovascular outcomes in two large phase III trials (FIDELIO-DKD and FIGARO-DKD) in patients with chronic kidney disease and type 2 diabetes, respectively. Here, we provide an overview of the pathophysiologic role of MR overactivation and preclinical evidence with the nonsteroidal MRA finerenone in a range of different disease models with respect to major components of the aggregate mode of action, including interfering with reactive oxygen species generation, inflammation, fibrosis, and hypertrophy. We describe a time-dependent effect of these mechanistic components and the potential modification of major clinical parameters, as well as the impact on clinical renal and cardiovascular outcomes as observed in FIDELIO-DKD and FIGARO-DKD. Finally, we provide an outlook on potential future clinical indications and ongoing clinical studies with finerenone, including a combination study with a sodium–glucose cotransporter-2 inhibitor.
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Pandey, Kailash N. "Molecular and genetic aspects of guanylyl cyclase natriuretic peptide receptor-A in regulation of blood pressure and renal function." Physiological Genomics 50, no. 11 (November 1, 2018): 913–28. http://dx.doi.org/10.1152/physiolgenomics.00083.2018.
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Natriuretic peptides (NPs) exert diverse effects on several biological and physiological systems, such as kidney function, neural and endocrine signaling, energy metabolism, and cardiovascular function, playing pivotal roles in the regulation of blood pressure (BP) and cardiac and vascular homeostasis. NPs are collectively known as anti-hypertensive hormones and their main functions are directed toward eliciting natriuretic/diuretic, vasorelaxant, anti-proliferative, anti-inflammatory, and anti-hypertrophic effects, thereby, regulating the fluid volume, BP, and renal and cardiovascular conditions. Interactions of NPs with their cognate receptors display a central role in all aspects of cellular, biochemical, and molecular mechanisms that govern physiology and pathophysiology of BP and cardiovascular events. Among the NPs atrial and brain natriuretic peptides (ANP and BNP) activate guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA) and initiate intracellular signaling. The genetic disruption of Npr1 (encoding GC-A/NPRA) in mice exhibits high BP and hypertensive heart disease that is seen in untreated hypertensive subjects, including high BP and heart failure. There has been a surge of interest in the NPs and their receptors and a wealth of information have emerged in the last four decades, including molecular structure, signaling mechanisms, altered phenotypic characterization of transgenic and gene-targeted animal models, and genetic analyses in humans. The major goal of the present review is to emphasize and summarize the critical findings and recent discoveries regarding the molecular and genetic regulation of NPs, physiological metabolic functions, and the signaling of receptor GC-A/NPRA with emphasis on the BP regulation and renal and cardiovascular disorders.
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Chrysanthus, Chukwuma Sr. "The complex interplay in the regulation of cardiac pathophysiologic functionalities by protein kinases and phosphatases." Journal of Cardiology and Cardiovascular Medicine 6, no. 3 (August 26, 2021): 048–54. http://dx.doi.org/10.29328/journal.jccm.1001118.
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Protein phosphorylation regulates several dimensions of cell fate and is substantially dysregulated in pathophysiological instances as evident spatiotemporally via intracellular localizations or compartmentalizations with discrete control by specific kinases and phosphatases. Cardiovascular disease manifests as an intricately complex entity presenting as a derangement of the cardiovascular system. Cardiac or heart failure connotes the pathophysiological state in which deficient cardiac output compromises the body burden and requirements. Protein kinases regulate several pathophysiological processes and are emerging targets for drug lead or discovery. The protein kinases are family members of the serine/threonine phosphatases. Protein kinases covalently modify proteins by attaching phosphate groups from ATP to residues of serine, threonine and/or tyrosine. Protein kinases and phosphatases are pivotal in the regulatory mechanisms in the reversible phosphorylation of diverse effectors whereby discrete signaling molecules regulate cardiac excitation and contraction. Protein phosphorylation is critical for the sustenance of cardiac functionalities. The two major contributory ingredients to progressive myocardium derangement are dysregulation of Ca2+ processes and contemporaneous elevated concentrations of reactive oxygen species, ROS. Certain cardiac abnormalities include cardiac myopathy or hypertrophy due to response in untoward haemodynamic demand with concomitant progressive heart failure. The homeostasis or equilibrium between protein kinases and phosphatases influence cardiac morphology and excitability during pathological and physiological processes of the cardiovascular system. Inasmuch as protein kinases regulate numerous dimensions of normal cellular functions, the pathophysiological dysfunctionality of protein kinase signaling pathways undergirds the molecular aspects of several cardiovascular diseases or disorders as related in this study. These have presented protein kinases as essential and potential targets for drug discovery and heart disease therapy.
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Saryeva, Olga P., Ludmila V. Kulida, Elena V. Protsenko, and Maria V. Malysheva. "Cardiomyopathy in children – clinical, genetic and morphological aspects." I.P. Pavlov Russian Medical Biological Herald 28, no. 1 (April 9, 2020): 99–110. http://dx.doi.org/10.23888/pavlovj202028199-110.
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Cardiomyopathy is one of serious and complex problems of pediatric cardiology. Many of them are the cause of sudden death and are familial in character. Disappointing statistics increases the relevance of the problem of cardiomyopathy and dictates the need for in-depth study of the etiology and pathogenesis, structural bases and experience in clinical and morphological diagnosis of this pathology in children. Of particular importance from a practical point of view is the development of prognostic factors in primary and secondary cardiomyopathies. This literature review provides information on the etiology, pathogenesis, clinical manifestations, pathomorphological changes and outcomes of such cardiomyopathies as hypertrophic, dilated cardiomyopathies, non-compact left ventricular myocardium and histiocytoid cardiomyopathy. Peculiarities of restructure of the myocardium in the analyzed cardiomyopathies and their relationship with systolic and diastolic myocardial dysfunction are shown. Molecular genetic aspects of diagnosis of etiology and pathogenesis of this pathology in children are given in detail. The necessity of systematic pathomorphological study of the heart with full analysis of contractile, conducting microcirculatory and neuroautonomic structures in considered variants of cardiovascular pathology is emphasized. These data will help outline future research priorities for this group of diseases to provide earlier diagnosis, improve clinical outcomes and the quality of life of these children and their families.
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Baban, Anwar, Valentina Lodato, Giovanni Parlapiano, Corrado di Mambro, Rachele Adorisio, Enrico Silvio Bertini, Carlo Dionisi-Vici, Fabrizio Drago, and Diego Martinelli. "Myocardial and Arrhythmic Spectrum of Neuromuscular Disorders in Children." Biomolecules 11, no. 11 (October 25, 2021): 1578. http://dx.doi.org/10.3390/biom11111578.
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Neuromuscular disorders (NMDs) are highly heterogenous from both an etiological and clinical point of view. Their signs and symptoms are often multisystemic, with frequent cardiac involvement. In fact, childhood onset forms can predispose a person to various progressive cardiac abnormalities including cardiomyopathies (CMPs), valvulopathies, atrioventricular conduction defects (AVCD), supraventricular tachycardia (SVT) and ventricular arrhythmias (VA). In this review, we selected and described five specific NMDs: Friedreich’s Ataxia (FRDA), congenital and childhood forms of Myotonic Dystrophy type 1 (DM1), Kearns Sayre Syndrome (KSS), Ryanodine receptor type 1-related myopathies (RYR1-RM) and Laminopathies. These changes are widely investigated in adults but less researched in children. We focused on these specific topics due their relative frequency and their potential unexpected cardiac manifestations in children. Moreover these conditions present different inheritance patterns and mechanisms of action. We decided not to discuss Duchenne and Becker muscular dystrophies due to extensive work regarding the cardiac aspects in children. For each described NMD, we focused on the possible cardiac manifestations such as different types of CMPs (dilated-DCM, hypertrophic-HCM, restrictive-RCM or left ventricular non compaction-LVNC), structural heart abnormalities (including valvulopathies), and progressive heart rhythm changes (AVCD, SVT, VA). We describe the current management strategies for these conditions. We underline the importance, especially for children, of a serial multidisciplinary personalized approach and the need for periodic surveillance by a dedicated heart team. This is largely due to the fact that in children, the diagnosis of certain NMDs might be overlooked and the cardiac aspect can provide signs of their presence even prior to overt neurological diagnosis.
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Barilli, Maria, Maria Cristina Tavera, Serafina Valente, and Alberto Palazzuoli. "Structural and Hemodynamic Changes of the Right Ventricle in PH-HFpEF." International Journal of Molecular Sciences 23, no. 9 (April 20, 2022): 4554. http://dx.doi.org/10.3390/ijms23094554.
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One of the most important diagnostic challenges in clinical practice is the distinction between pulmonary hypertension (PH) due to primitive pulmonary arterial hypertension (PAH) and PH due to left heart diseases. Both conditions share some common characteristics and pathophysiological pathways, making the two processes similar in several aspects. Their diagnostic differentiation is based on hemodynamic data on right heart catheterization, cardiac structural modifications, and therapeutic response. More specifically, PH secondary to heart failure with preserved ejection fraction (HFpEF) shares features with type 1 PH (PAH), especially when the combined pre- and post-capillary form (CpcPH) takes place in advanced stages of the disease. Right ventricular (RV) dysfunction is a common consequence related to worse prognosis and lower survival. This condition has recently been identified with a new classification based on clinical signs and progression markers. The role and prevalence of PH and RV dysfunction in HFpEF remain poorly identified, with wide variability in the literature reported from the largest clinical trials. Different parenchymal and vascular alterations affect the two diseases. Capillaries and arteriole vasoconstriction, vascular obliteration, and pulmonary blood fluid redistribution from the basal to the apical district are typical manifestations of type 1 PH. Conversely, PH related to HFpEF is primarily due to an increase of venules/capillaries parietal fibrosis, extracellular matrix deposition, and myocyte hypertrophy with a secondary “arteriolarization” of the vessels. Since the development of structural changes and the therapeutic target substantially differ, a better understanding of pathobiological processes underneath PH-HFpEF, and the identification of potential maladaptive RV mechanisms with an appropriate diagnostic tool, become mandatory in order to distinguish and manage these two similar forms of pulmonary hypertension.
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Da'as, Sahar I., Khalid Fakhro, Angelos Thanassoulas, Navaneethakrishnan Krishnamoorthy, Alaaeldin Saleh, Brian L. Calver, Bared Safieh-Garabedian, et al. "Hypertrophic cardiomyopathy-linked variants of cardiac myosin-binding protein C3 display altered molecular properties and actin interaction." Biochemical Journal 475, no. 24 (December 14, 2018): 3933–48. http://dx.doi.org/10.1042/bcj20180685.
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The most common inherited cardiac disorder, hypertrophic cardiomyopathy (HCM), is characterized by thickening of heart muscle, for which genetic mutations in cardiac myosin-binding protein C3 (c-MYBPC3) gene, is the leading cause. Notably, patients with HCM display a heterogeneous clinical presentation, onset and prognosis. Thus, delineating the molecular mechanisms that explain how disparate c-MYBPC3 variants lead to HCM is essential for correlating the impact of specific genotypes on clinical severity. Herein, five c-MYBPC3 missense variants clinically associated with HCM were investigated; namely V1 (R177H), V2 (A216T), V3 (E258K), V4 (E441K) and double mutation V5 (V3 + V4), all located within the C1 and C2 domains of MyBP-C, a region known to interact with sarcomeric protein, actin. Injection of the variant complementary RNAs in zebrafish embryos was observed to recapitulate phenotypic aspects of HCM in patients. Interestingly, V3- and V5-cRNA injection produced the most severe zebrafish cardiac phenotype, exhibiting increased diastolic/systolic myocardial thickness and significantly reduced heart rate compared with control zebrafish. Molecular analysis of recombinant C0–C2 protein fragments revealed that c-MYBPC3 variants alter the C0–C2 domain secondary structure, thermodynamic stability and importantly, result in a reduced binding affinity to cardiac actin. V5 (double mutant), displayed the greatest protein instability with concomitant loss of actin-binding function. Our study provides specific mechanistic insight into how c-MYBPC3 pathogenic variants alter both functional and structural characteristics of C0–C2 domains leading to impaired actin interaction and reduced contractility, which may provide a basis for elucidating the disease mechanism in HCM patients with c-MYBPC3 mutations.
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Alami, Tara, and Jun-Li Liu. "Metabolic Effects of CCN5/WISP2 Gene Deficiency and Transgenic Overexpression in Mice." International Journal of Molecular Sciences 22, no. 24 (December 14, 2021): 13418. http://dx.doi.org/10.3390/ijms222413418.
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CCN5/WISP2 is a matricellular protein, the expression of which is under the regulation of Wnt signaling and IGF-1. Our initial characterization supports the notion that CCN5 might promote the proliferation and survival of pancreatic β-cells and thus improve the metabolic profile of the animals. More recently, the roles of endogenous expression of CCN5 and its ectopic, transgenic overexpression on metabolic regulation have been revealed through two reports. Here, we attempt to compare the experimental findings from those studies, side-by-side, in order to further establish its roles in metabolic regulation. Prominent among the discoveries was that a systemic deficiency of CCN5 gene expression caused adipocyte hypertrophy, increased adipogenesis, and lipid accumulation, resulting in insulin resistance and glucose intolerance, which were further exacerbated upon high-fat diet feeding. On the other hand, the adipocyte-specific and systemic overexpression of CCN5 caused an increase in lean body mass, improved insulin sensitivity, hyperplasia of cardiomyocytes, and increased heart mass, but decreased fasting glucose levels. CCN5 is clearly a regulator of adipocyte proliferation and maturation, affecting lean/fat mass ratio and insulin sensitivity. Not all results from these models are consistent; moreover, several important aspects of CCN5 physiology are yet to be explored.
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Petramala, Luigi, Antonio Concistrè, Federica Olmati, Vincenza Saracino, Cristina Chimenti, Andrea Frustaci, Matteo A. Russo, and Claudio Letizia. "Cardiomyopathies and Adrenal Diseases." International Journal of Molecular Sciences 21, no. 14 (July 17, 2020): 5047. http://dx.doi.org/10.3390/ijms21145047.
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Cardiomyopathies are myocardial disorders in which heart muscle is structurally and/or functionally abnormal. Previously, structural cardiomyocyte disorders due to adrenal diseases, such as hyperaldosteronism, hypercortisolism, and hypercatecholaminism, were misunderstood, and endomyocardial biopsy (EMB) was not performed because was considered dangerous and too invasive. Recent data confirm that, if performed in experienced centers, EMB is a safe technique and gives precious information about physiopathological processes implied in clinical abnormalities in patients with different systemic disturbances. In this review, we illustrate the most important features in patients affected by primary aldosteronism (PA), Cushing’s syndrome (CS), and pheochromocytoma (PHEO). Then, we critically describe microscopic and ultrastructural aspects that have emerged from the newest EMB studies. In PA, the autonomous hypersecretion of aldosterone induces the alteration of ion and water homeostasis, intracellular vacuolization, and swelling; interstitial oedema could be a peculiar feature of myocardial toxicity. In CS, cardiomyocyte hypertrophy and myofibrillolysis could be related to higher expression of atrogin-1. Finally, in PHEO, the hypercontraction of myofilaments with the formation of contraction bands and occasional cellular necrosis has been observed. We expect to clear the role of EMB in patients with cardiomyopathies and adrenal disease, and we believe EMB is a valid tool to implement new management and therapies.
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Padula, Stephanie L., Nivedhitha Velayutham, and Katherine E. Yutzey. "Transcriptional Regulation of Postnatal Cardiomyocyte Maturation and Regeneration." International Journal of Molecular Sciences 22, no. 6 (March 23, 2021): 3288. http://dx.doi.org/10.3390/ijms22063288.
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During the postnatal period, mammalian cardiomyocytes undergo numerous maturational changes associated with increased cardiac function and output, including hypertrophic growth, cell cycle exit, sarcomeric protein isoform switching, and mitochondrial maturation. These changes come at the expense of loss of regenerative capacity of the heart, contributing to heart failure after cardiac injury in adults. While most studies focus on the transcriptional regulation of embryonic or adult cardiomyocytes, the transcriptional changes that occur during the postnatal period are relatively unknown. In this review, we focus on the transcriptional regulators responsible for these aspects of cardiomyocyte maturation during the postnatal period in mammals. By specifically highlighting this transitional period, we draw attention to critical processes in cardiomyocyte maturation with potential therapeutic implications in cardiovascular disease.
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Schotten, Ulrich, Sander Verheule, Paulus Kirchhof, and Andreas Goette. "Pathophysiological Mechanisms of Atrial Fibrillation: A Translational Appraisal." Physiological Reviews 91, no. 1 (January 2011): 265–325. http://dx.doi.org/10.1152/physrev.00031.2009.
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Atrial fibrillation (AF) is an arrhythmia that can occur as the result of numerous different pathophysiological processes in the atria. Some aspects of the morphological and electrophysiological alterations promoting AF have been studied extensively in animal models. Atrial tachycardia or AF itself shortens atrial refractoriness and causes loss of atrial contractility. Aging, neurohumoral activation, and chronic atrial stretch due to structural heart disease activate a variety of signaling pathways leading to histological changes in the atria including myocyte hypertrophy, fibroblast proliferation, and complex alterations of the extracellular matrix including tissue fibrosis. These changes in electrical, contractile, and structural properties of the atria have been called “atrial remodeling.” The resulting electrophysiological substrate is characterized by shortening of atrial refractoriness and reentrant wavelength or by local conduction heterogeneities caused by disruption of electrical interconnections between muscle bundles. Under these conditions, ectopic activity originating from the pulmonary veins or other sites is more likely to occur and to trigger longer episodes of AF. Many of these alterations also occur in patients with or at risk for AF, although the direct demonstration of these mechanisms is sometimes challenging. The diversity of etiological factors and electrophysiological mechanisms promoting AF in humans hampers the development of more effective therapy of AF. This review aims to give a translational overview on the biological basis of atrial remodeling and the proarrhythmic mechanisms involved in the fibrillation process. We pay attention to translation of pathophysiological insights gained from in vitro experiments and animal models to patients. Also, suggestions for future research objectives and therapeutical implications are discussed.
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Leinonen, Jussi V., Päivi Leinikka, Miikka Tarkia, Milla Lampinen, Avishag K. Emanuelov, Ronen Beeri, Esko Kankuri, and Eero Mervaala. "Structural and Functional Support by Left Atrial Appendage Transplant to the Left Ventricle after a Myocardial Infarction." International Journal of Molecular Sciences 23, no. 9 (April 22, 2022): 4661. http://dx.doi.org/10.3390/ijms23094661.
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The left atrial appendage (LAA) of the adult heart has been shown to contain cardiac and myeloid progenitor cells. The resident myeloid progenitor population expresses an array of pro-regenerative paracrine factors. Cardiac constructs have been shown to inhibit deleterious remodeling of the heart using physical support. Due to these aspects, LAA holds promise as a regenerative transplant. LAAs from adult mT/mG mice were transplanted to the recipient 129X1-SvJ mice simultaneously as myocardial infarction (MI) was performed. A decellularized LAA patch was implanted in the control group. Two weeks after MI, the LAA patch had integrated to the ventricular wall, and migrated cells were seen in the MI area. The cells had two main phenotypes: small F4/80+ cells and large troponin C+ cells. After follow-up at 8 weeks, the LAA patch remained viable, and the functional status of the heart improved. Cardiac echo demonstrated that, after 6 weeks, the mice in the LAA-patch-treated group showed an increasing and statistically significant improvement in cardiac performance when compared to the MI and MI + decellularized patch controls. Physical patch-support (LAA and decellularized LAA patch) had an equal effect on the inhibition of deleterious remodeling, but only the LAA patch inhibited the hypertrophic response. Our study demonstrates that the LAA transplantation has the potential for use as a treatment for myocardial infarction. This method can putatively combine cell therapy (regenerative effect) and physical support (inhibition of deleterious remodeling).
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Gough, N. R. "Limiting Heart Hypertrophy." Science Signaling 4, no. 165 (March 22, 2011): ec88-ec88. http://dx.doi.org/10.1126/scisignal.4165ec88.
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Trivedi, Chinmay M., and Jonathan A. Epstein. "Heart-Healthy Hypertrophy." Cell Metabolism 13, no. 1 (January 2011): 3–4. http://dx.doi.org/10.1016/j.cmet.2010.12.012.
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Yamazaki, Tsutomu, Issei Komuro, and Yoshio Yazaki. "Molecular aspects of mechanical stress-induced cardiac hypertrophy." Molecular and Cellular Biochemistry 163-164, no. 1 (1996): 197–201. http://dx.doi.org/10.1007/bf00408658.
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Balberova, Olga V., Evgeny V. Bykov, Natalia A. Shnayder, Marina M. Petrova, Oksana A. Gavrilyuk, Daria S. Kaskaeva, Irina A. Soloveva, et al. "The “Angiogenic Switch” and Functional Resources in Cyclic Sports Athletes." International Journal of Molecular Sciences 22, no. 12 (June 17, 2021): 6496. http://dx.doi.org/10.3390/ijms22126496.
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Regular physical activity in cyclic sports can influence the so-called “angiogenic switch”, which is considered as an imbalance between proangiogenic and anti-angiogenic molecules. Disruption of the synthesis of angiogenic molecules can be caused by local changes in tissues under the influence of excessive physical exertion and its consequences, such as chronic oxidative stress and associated hypoxia, metabolic acidosis, sports injuries, etc. A review of publications on signaling pathways that activate and inhibit angiogenesis in skeletal muscles, myocardium, lung, and nervous tissue under the influence of intense physical activity in cyclic sports. Materials: We searched PubMed, SCOPUS, Web of Science, Google Scholar, Clinical keys, and e-LIBRARY databases for full-text articles published from 2000 to 2020, using keywords and their combinations. Results: An important aspect of adaptation to training loads in cyclic sports is an increase in the number of capillaries in muscle fibers, which improves the metabolism of skeletal muscles and myocardium, as well as nervous and lung tissue. Recent studies have shown that myocardial endothelial cells not only respond to hemodynamic forces and paracrine signals from neighboring cells, but also take an active part in heart remodeling processes, stimulating the growth and contractility of cardiomyocytes or the production of extracellular matrix proteins in myofibroblasts. As myocardial vascularization plays a central role in the transition from adaptive heart hypertrophy to heart failure, further study of the signaling mechanisms involved in the regulation of angiogenesis in the myocardium is important in sports practice. The study of the “angiogenic switch” problem in the cerebrovascular and cardiovascular systems allows us to claim that the formation of new vessels is mediated by a complex interaction of all growth factors. Although the lungs are one of the limiting systems of the body in cyclic sports, their response to high-intensity loads and other environmental stresses is often overlooked. Airway epithelial cells are the predominant source of several growth factors throughout lung organogenesis and appear to be critical for normal alveolarization, rapid alveolar proliferation, and normal vascular development. There are many controversial questions about the role of growth factors in the physiology and pathology of the lungs. The presented review has demonstrated that when doing sports, it is necessary to give a careful consideration to the possible positive and negative effects of growth factors on muscles, myocardium, lung tissue, and brain. Primarily, the “angiogenic switch” is important in aerobic sports (long distance running). Conclusions: Angiogenesis is a physiological process of the formation of new blood capillaries, which play an important role in the functioning of skeletal muscles, myocardium, lung, and nervous tissue in athletes. Violation of the “angiogenic switch” as a balance between proangiogenic and anti-angiogenic molecules can lead to a decrease in the functional resources of the nervous, musculoskeletal, cardiovascular, and respiratory systems in athletes and, as a consequence, to a decrease in sports performance.
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Luft, Friedrich C. "Harbingers of hypertrophy and heart failure." Journal of Molecular Medicine 82, no. 10 (September 14, 2004): 635–37. http://dx.doi.org/10.1007/s00109-004-0577-5.
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Артифексова, A. Artifeksova, Зубеева, G. Zubeeva, Харламова, O. Kharlamova, Суслова, et al. "Structural and morphological aspects of heart failure in chronic renal failure." Journal of New Medical Technologies. eJournal 8, no. 1 (November 5, 2014): 0. http://dx.doi.org/10.12737/7377.
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The purpose of the study was to identify the structural and morphological characteristics of myocardium in patients with chronic renal insufficiency with clinical signs of heart failure and coronary heart disease. Surveyed 141 patients with chronic renal insufficiency 0, I, II, III stages. An eсhocardioscopiс study were held on the Vivid S6, General Electric, United States, which was of course-diastolic left ventricular cavity transverse dimension, thickness of the ventricular septal and posterior wall of the left ventricle, the length of the left ventricle in diastolic phase. Calculation is made of left ventricular myocardial mass index, index of the sphericity of the eccentricity. Determined the content of creatinine, CK-MB, troponin I and myoglobin. Morphological study on myocardial autopsic material 46 deaths of patients with chronic renal failure of varying degrees of severity. The Results. Initial displays remodeling appear in patients in the early stages of the disease. The loading phase of the disease is growing concentric hypertrophy of the left ventricle, there has been a progression of remodeling in increasing the frequency of occurrence of spherisation the cavity of the left ventricle. Dialysis reduces the severity of concentric hypertrophy of the left ventricle. As a result of the microscopic study of the heart was installed correlative dependence of structural changes in the myocardium of symptoms of chronic kidney failure.
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Iemitsu, Motoyuki, Takashi Miyauchi, Seiji Maeda, Satoshi Sakai, Tsutomu Kobayashi, Nobuharu Fujii, Hitoshi Miyazaki, Mitsuo Matsuda, and Iwao Yamaguchi. "Physiological and pathological cardiac hypertrophy induce different molecular phenotypes in the rat." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 281, no. 6 (December 1, 2001): R2029—R2036. http://dx.doi.org/10.1152/ajpregu.2001.281.6.r2029.
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Pressure overload, such as hypertension, to the heart causes pathological cardiac hypertrophy, whereas chronic exercise causes physiological cardiac hypertrophy, which is defined as athletic heart. There are differences in cardiac properties between these two types of hypertrophy. We investigated whether mRNA expression of various cardiovascular regulating factors differs in rat hearts that are physiologically and pathologically hypertrophied, because we hypothesized that these two types of cardiac hypertrophy induce different molecular phenotypes. We used the spontaneously hypertensive rat (SHR group; 19 wk old) as a model of pathological hypertrophy and swim-trained rats (trained group; 19 wk old, swim training for 15 wk) as a model of physiological hypertrophy. We also used sedentary Wistar-Kyoto rats as the control group (19 wk old). Left ventricular mass index for body weight was significantly higher in SHR and trained groups than in the control group. Expression of brain natriuretic peptide, angiotensin-converting enzyme, and endothelin-1 mRNA in the heart was significantly higher in the SHR group than in control and trained groups. Expression of adrenomedullin mRNA in the heart was significantly lower in the trained group than in control and SHR groups. Expression of β1-adrenergic receptor mRNA in the heart was significantly higher in SHR and trained groups than in the control group. Expression of β1-adrenergic receptor kinase mRNA, which inhibits β1-adrenergic receptor activity, in the heart was markedly higher in the SHR group than in control and trained groups. We demonstrated for the first time that the manner of mRNA expression of various cardiovascular regulating factors in the heart differs between physiological and pathological cardiac hypertrophy.
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Mandache, Eugen. "Endothelial cell mitosis in experimental heart hypertrophy." Journal of Cellular and Molecular Medicine 4, no. 3 (July 2000): 226–27. http://dx.doi.org/10.1111/j.1582-4934.2000.tb00121.x.
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JOHNSTON, C., M. HIWATARI, and L. ARNOLDA. "Hormonal aspects of cardiac hypertrophy and failure." Journal of Molecular and Cellular Cardiology 18 (1986): 20. http://dx.doi.org/10.1016/s0022-2828(86)80545-4.
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Ritter, Oliver, and Ludwig Neyses. "The molecular basis of myocardial hypertrophy and heart failure." Trends in Molecular Medicine 9, no. 7 (July 2003): 313–21. http://dx.doi.org/10.1016/s1471-4914(03)00114-x.
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Eghbali, Mansoureh, Rupal Deva, Abderrahmane Alioua, Tamara Y. Minosyan, Hongmei Ruan, Yibin Wang, Ligia Toro, and Enrico Stefani. "Molecular and Functional Signature of Heart Hypertrophy During Pregnancy." Circulation Research 96, no. 11 (June 10, 2005): 1208–16. http://dx.doi.org/10.1161/01.res.0000170652.71414.16.
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Sarkar, Sagartirtha, Douglas W. Leaman, Sudhiranjan Gupta, Parames Sil, David Young, Annitta Morehead, Debabrata Mukherjee, et al. "Cardiac Overexpression of Myotrophin Triggers Myocardial Hypertrophy and Heart Failure in Transgenic Mice." Journal of Biological Chemistry 279, no. 19 (February 16, 2004): 20422–34. http://dx.doi.org/10.1074/jbc.m308488200.
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Cardiac hypertrophy and heart failure remain leading causes of death in the United States. Many studies have suggested that, under stress, myocardium releases factors triggering protein synthesis and stimulating myocyte growth. We identified and cloned myotrophin, a 12-kDa protein from hypertrophied human and rat hearts. Myotrophin (whose gene is localized on human chromosome 7q33) stimulates myocyte growth and participates in cellular interaction that initiates cardiac hypertrophyin vitro. In this report, we present data on the pathophysiological significance of myotrophinin vivo, showing the effects of overexpression of cardio-specific myotrophin in transgenic mice in which cardiac hypertrophy occurred by 4 weeks of age and progressed to heart failure by 9-12 months. This hypertrophy was associated with increased expression of proto-oncogenes, hypertrophy marker genes, growth factors, and cytokines, with symptoms that mimicked those of human cardiomyopathy, functionally and morphologically. This model provided a unique opportunity to analyze gene clusters that are differentially up-regulated during initiation of hypertrophyversustransition of hypertrophy to heart failure. Importantly, changes in gene expression observed during initiation of hypertrophy were significantly different from those seen during its transition to heart failure. Our data show that overexpression of myotrophin results in initiation of cardiac hypertrophy that progresses to heart failure, similar to changes in human heart failure. Knowledge of the changes that take place as a result of overexpression of myotrophin at both the cellular and molecular levels will suggest novel strategies for treatment to prevent hypertrophy and its progression to heart failure.
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Barreto-Chaves, M. L. M., N. Senger, M. R. Fevereiro, A. C. Parletta, and A. P. C. Takano. "Impact of hyperthyroidism on cardiac hypertrophy." Endocrine Connections 9, no. 3 (March 2020): R59—R69. http://dx.doi.org/10.1530/ec-19-0543.
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The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.
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Arantes, Victor Hugo F., Dailson Paulucio da Silva, Renato Luiz de Alvarenga, Augusto Terra, Alexander Koch, Marco Machado, and Fernando Augusto Monteiro Saboia Pompeu. "Skeletal muscle hypertrophy: molecular and applied aspects of exercise physiology." German Journal of Exercise and Sport Research 50, no. 2 (April 8, 2020): 195–207. http://dx.doi.org/10.1007/s12662-020-00652-z.
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Carre, F., P. Maison-Blanche, L. Ollivier, P. Mansier, B. Chevalier, R. Vicuna, Y. Lessard, P. Coumel, and B. Swynghedauw. "Heart rate variability in two models of cardiac hypertrophy in rats in relation to the new molecular phenotype." American Journal of Physiology-Heart and Circulatory Physiology 266, no. 5 (May 1, 1994): H1872—H1878. http://dx.doi.org/10.1152/ajpheart.1994.266.5.h1872.
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The analysis of heart rate variability (HRV) provides information on neural control of the heart. We investigated HRV in normal rats and in models of experimental cardiac hypertrophy using the Holter monitoring and peak/trough method. In normal rats, two heart rate oscillations with different wavelengths, high frequency (HF) and low frequency (LF) oscillations, were detected. The HF oscillations were insensitive to propranolol and suppressed by atropine. The LF oscillations were sensitive to both antagonists. Thyrotoxicosis resulted in cardiac hypertrophy (+20%) and tachycardia. The HF oscillations were unchanged, whereas LF oscillations were hampered at low heart rate in this group. Aortic stenosis resulted in cardiac hypertrophy (+53%), but heart rate oscillations were unchanged. The (number x amplitude) product for both types of oscillations correlated with heart rate in controls but not in the thyrotoxicosis or aortic stenosis models. Alterations of HRV in cardiac hypertrophy occur in rats as in humans. They may reflect the changes in the molecular components of the adrenergic/muscarinic system, which defines the new myocardial phenotype.
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Diwan, Abhinav, and Gerald W. Dorn. "Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic Targets." Physiology 22, no. 1 (February 2007): 56–64. http://dx.doi.org/10.1152/physiol.00033.2006.
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Cardiac hypertrophy leads to heart failure, and both conditions can ultimately prove lethal. Here, traditional and novel mechanisms relating hypertrophy and heart failure are described at the physiological, cellular, and molecular levels. The rational application of these mechanistic considerations to therapeutics targeting hypertrophy and heart failure is discussed.
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Peter, Angela K., Maureen A. Bjerke, and Leslie A. Leinwand. "Biology of the cardiac myocyte in heart disease." Molecular Biology of the Cell 27, no. 14 (July 15, 2016): 2149–60. http://dx.doi.org/10.1091/mbc.e16-01-0038.
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Cardiac hypertrophy is a major risk factor for heart failure, and it has been shown that this increase in size occurs at the level of the cardiac myocyte. Cardiac myocyte model systems have been developed to study this process. Here we focus on cell culture tools, including primary cells, immortalized cell lines, human stem cells, and their morphological and molecular responses to pathological stimuli. For each cell type, we discuss commonly used methods for inducing hypertrophy, markers of pathological hypertrophy, advantages for each model, and disadvantages to using a particular cell type over other in vitro model systems. Where applicable, we discuss how each system is used to model human disease and how these models may be applicable to current drug therapeutic strategies. Finally, we discuss the increasing use of biomaterials to mimic healthy and diseased hearts and how these matrices can contribute to in vitro model systems of cardiac cell biology.
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Clerk, Angela, Daniel N. Meijles, Michelle A. Hardyman, Stephen J. Fuller, Sonia P. Chothani, Joshua J. Cull, Susanna T. E. Cooper, et al. "Cardiomyocyte BRAF and type 1 RAF inhibitors promote cardiomyocyte and cardiac hypertrophy in mice in vivo." Biochemical Journal 479, no. 3 (February 11, 2022): 401–24. http://dx.doi.org/10.1042/bcj20210615.
Full textAbstract:
The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the ‘RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a ‘RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the ‘RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.
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Kang, Peter M., Patrick Yue, Zhilin Liu, Oleg Tarnavski, Natalya Bodyak, and Seigo Izumo. "Alterations in apoptosis regulatory factors during hypertrophy and heart failure." American Journal of Physiology-Heart and Circulatory Physiology 287, no. 1 (July 2004): H72—H80. http://dx.doi.org/10.1152/ajpheart.00556.2003.
Full textAbstract:
Cardiac hypertrophy from pathological stimuli often proceeds to heart failure, whereas cardiac hypertrophy from physiological stimuli does not. In this study, physiological hypertrophy was created by a daily exercise regimen and pathological hypertrophy was created from a high-salt diet in Dahl salt-sensitive rats. The rats continued on a high-salt diet progressed to heart failure associated with an increased rate of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cardiomyocytes. We analyzed primary cultures of these hearts and found that only cardiomyocytes made hypertrophic by a pathological stimulus show increased sensitivity to apoptosis. Examination of the molecular changes associated with these distinct types of hypertrophy revealed changes in Bcl-2 family members and caspases favoring survival during physiological hypertrophy. However, in pathological hypertrophy, there were more diffuse proapoptotic changes, including changes in Fas, the Bcl-2 protein family, and caspases. Therefore, we speculate that this increased sensitivity to apoptotic stimulation along with proapoptotic changes in the apoptosis program may contribute to the development of heart failure seen in pathological cardiac hypertrophy.
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Sarkar, Sagartirtha, Mamta Chawla-Sarkar, David Young, Kazutoshi Nishiyama, Mary E. Rayborn, Joe G. Hollyfield, and Subha Sen. "Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure." Journal of Biological Chemistry 279, no. 50 (September 21, 2004): 52630–42. http://dx.doi.org/10.1074/jbc.m402037200.
Full textAbstract:
Cardiac hypertrophy and ensuing heart failure are among the most common causes of mortality worldwide, yet the triggering mechanisms for progression of hypertrophy to failure are not fully understood. Tissue homeostasis depends on proper relationships between cell proliferation, differentiation, and death and any imbalance between them results in compromised cardiac function. Recently, we developed a transgenic (Tg) mouse model that overexpress myotrophin (a 12-kDa protein that stimulates myocyte growth) in heart resulting in hypertrophy that progresses to heart failure. This provided us an appropriate model to study the disease process at any point from initiation of hypertrophy end-stage heart failure. We studied detailed apoptotic signaling and regenerative pathways and found that the Tg mouse heart undergoes myocyte loss and regeneration, but only at a late stage (during transition to heart failure). Several apoptotic genes were up-regulated in 9-month-old Tg hearts compared with age-matched wild type or 4-week-old Tg hearts. Cardiac cell death during heart failure involved activation of Fas, tumor necrosis factor-α, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised functionshowedsignificantup-regulationofcyclins,cyclin-dependent kinases (Cdks), and cell regeneration markers in myocytes. Furthermore, in human failing and nonfailing hearts, similar observations were documented including induction of active caspase 3 and Ki-67 proteins in dilated cardiomyopathic myocytes. Taken together, our data suggest that the stress of extensive myocardial damage from longstanding hypertrophy may cause myocytes to reenter the cell cycle. We demonstrate, for the first time in an animal model, that cell death and regeneration occur simultaneously in myocytes during end-stage heart failure, a phenomenon not observed at the onset of the disease process.