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Find video protocols related to scientific articles indexed in Pubmed.
Endogenous Drp1 Mediates Mitochondrial Autophagy and Protects the Heart Against Energy Stress.
Circ. Res.
PUBLISHED: 10-22-2014
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Rationale: Both fusion and fission contribute to mitochondrial quality control. How unopposed fusion affects survival of cardiomyocytes (CMs) and left ventricular (LV) function in the heart is poorly understood. Objective: We investigated the role of Dynamin-related protein 1 (Drp1), a GTPase that mediates mitochondrial fission, in mediating mitochondrial autophagy, ventricular function, and stress resistance in the heart. Methods and Results: Drp1 downregulation induced mitochondrial elongation, accumulation of damaged mitochondria, and increased apoptosis in CMs at baseline. Drp1 downregulation also suppressed autophagosome formation and autophagic flux at baseline and in response to glucose deprivation in CMs. The lack of lysosomal translocation of mitochondrially-targeted Keima indicates that Drp1 downregulation suppressed mitochondrial autophagy. Mitochondrial elongation and accumulation of damaged mitochondria were also observed in tamoxifen-inducible cardiac-specific Drp1 knockout (Drp1-CKO) mice. Following Drp1 downregulation, Drp1-CKO mice developed LV dysfunction, preceded by mitochondrial dysfunction, and died within 13 weeks. Autophagic flux is significantly suppressed in Drp1-CKO mice. Although LV function in cardiac-specific Drp1 heterozygous KO (Drp1-hetCKO) mice was normal at 12 weeks of age, LV function decreased more severely after 48 hours of fasting and the infarct size/area at risk after ischemia/reperfusion (I/R) was significantly greater in Drp1-hetCKO than in control mice. Conclusions: Disruption of Drp1 induces mitochondrial elongation, inhibits mitochondrial autophagy, and causes mitochondrial dysfunction, thereby promoting cardiac dysfunction and increased susceptibility to I/R.
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T2238C ANP gene variant and risk of recurrent acute coronary syndromes in an Italian cohort of ischemic heart disease patients.
J Cardiovasc Med (Hagerstown)
PUBLISHED: 09-25-2014
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The role of C2238/atrial natriuretic peptide (ANP) minor allele, at the T2238C ANP gene variant, as a predisposing risk factor for acute cardiovascular events, has been previously reported. We aimed at evaluating, by a retrospective approach, the long-term impact of C2238/ANP-minor allele carrier status toward the risk of recurrent acute coronary syndromes (re-ACS) in an Italian cohort of ischemic heart disease patients.
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An easy and reproducible parameter for the assessment of the pressure gradient in patients with aortic stenosis disease: A magnetic resonance study.
J Cardiol
PUBLISHED: 08-22-2014
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Cardiovascular magnetic resonance (CMR) has been increasingly used as an alternative method to evaluate the severity of aortic stenosis. The aim of our study was to evaluate whether the indirect measurement of the aortic gradient (Calc-PG), derived from Gorlin's formula, is a reproducible parameter for gradient assessment. Then, we evaluated if this parameter is correlated with left ventricular hypertrophy, considered as a marker of severity of aortic stenosis, better than phase-contrast sequences-derived pressure gradient (PC-PG) and aortic valve area.
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New insights into the role of mitochondrial dynamics and autophagy during oxidative stress and aging in the heart.
Oxid Med Cell Longev
PUBLISHED: 07-15-2014
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The heart is highly sensitive to the aging process. In the elderly, the heart tends to become hypertrophic and fibrotic. Stiffness increases with ensuing systolic and diastolic dysfunction. Aging also affects the cardiac response to stress. At the molecular level, the aging process is associated with accumulation of damaged proteins and organelles, partially due to defects in protein quality control systems. The accumulation of dysfunctional and abnormal mitochondria is an important pathophysiological feature of the aging process, which is associated with excessive production of reactive oxygen species. Mitochondrial fusion and fission and mitochondrial autophagy are crucial mechanisms for maintaining mitochondrial function and preserving energy production. In particular, mitochondrial fission allows for selective segregation of damaged mitochondria, which are afterward eliminated by autophagy. Unfortunately, recent evidence indicates that mitochondrial dynamics and autophagy are progressively impaired over time, contributing to the aging process. This suggests that restoration of these mechanisms could delay organ senescence and prevent age-associated cardiac diseases. Here, we discuss the current understanding of the close relationship between mitochondrial dynamics, mitophagy, oxidative stress, and aging, with a particular focus on the heart.
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Folliculin (Flcn) inactivation leads to murine cardiac hypertrophy through mTORC1 deregulation.
Hum. Mol. Genet.
PUBLISHED: 06-06-2014
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Cardiac hypertrophy, an adaptive process that responds to increased wall stress, is characterized by the enlargement of cardiomyocytes and structural remodeling. It is stimulated by various growth signals, of which the mTORC1 pathway is a well-recognized source. Here, we show that loss of Flcn, a novel AMPK-mTOR interacting molecule, causes severe cardiac hypertrophy with deregulated energy homeostasis leading to dilated cardiomyopathy in mice. We found that mTORC1 activity was upregulated in Flcn-deficient hearts, and that rapamycin treatment significantly reduced heart mass and ameliorated cardiac dysfunction. Phospho-AMP-activated protein kinase (AMPK)-alpha (T172) was reduced in Flcn-deficient hearts and nonresponsive to various stimulations including metformin and AICAR (5-amino-1-?-D-ribofuranosyl-imidazole-4-carboxamide). ATP levels were elevated and mitochondrial function was increased in Flcn-deficient hearts, suggesting that excess energy resulting from up-regulated mitochondrial metabolism under Flcn deficiency might attenuate AMPK activation. Expression of Ppargc1a, a central molecule for mitochondrial metabolism, was increased in Flcn-deficient hearts and indeed, inactivation of Ppargc1a in Flcn-deficient hearts significantly reduced heart mass and prolonged survival. Ppargc1a inactivation restored phospho-AMPK-alpha levels and suppressed mTORC1 activity in Flcn-deficient hearts, suggesting that up-regulated Ppargc1a confers increased mitochondrial metabolism and excess energy, leading to inactivation of AMPK and activation of mTORC1. Rapamycin treatment did not affect the heart size of Flcn/Ppargc1a doubly inactivated hearts, further supporting the idea that Ppargc1a is the critical element leading to deregulation of the AMPK-mTOR-axis and resulting in cardiac hypertrophy under Flcn deficiency. These data support an important role for Flcn in cardiac homeostasis in the murine model.
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Atrial natriuretic peptide gene variants and circulating levels: implications in cardiovascular diseases.
Clin. Sci.
PUBLISHED: 03-12-2014
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ANP (atrial natriuretic peptide), discovered 30 years ago in rat cardiac atria, has been extensively investigated with regard to physiology, pathophysiology, cardiovascular disease therapeutics and molecular genetic aspects. Besides its diuretic, natriuretic and vasorelaxant effects, novel properties of this hormone have been described. Thus anti-hypertrophic, anti-fibrotic, anti-proliferative and anti-inflammatory actions suggest that ANP contributes not only to haemodynamic homoeostasis and adjustments, but has also a role in cardiovascular remodelling. Circulating ANP levels represent a valuable biomarker in cardiovascular diseases. ANP structure is highly conserved among species, indicating a key role in cardiovascular health. Thus an abnormal ANP structure may contribute to an increased risk of disease due to altered functions at either the vascular or cardiac level. Among others, the 2238T>C exon 3 variant has been associated with endothelial cell damage and dysfunction and with an increased risk of acute cardiovascular events, a frameshift mutation within exon 3 has been related to increased risk of atrial fibrillation, and ANP gene variants have been linked to increased risk of hypertension in different ethnic groups. On the other hand, the rs5068 variant, falling within the 3' UTR and associated with higher circulating ANP levels, has been shown to have a beneficial cardioprotective and metabolic effect. Dissecting out the disease mechanisms dependent on specific ANP molecular variants may reveal information useful in the clinical setting for diagnostic, prognostic and therapeutic purposes. Furthermore, insights from molecular genetic analysis of ANP may well integrate advancing knowledge on the role of ANP as a significant biomarker in patients affected by cardiovascular diseases.
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A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation.
Cell Metab.
PUBLISHED: 02-11-2014
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5'-AMP-activated protein kinase (AMPK) is a key regulator of metabolism and survival during energy stress. Dysregulation of AMPK is strongly associated with oxidative-stress-related disease. However, whether and how AMPK is regulated by intracellular redox status remains unknown. Here we show that the activity of AMPK is negatively regulated by oxidation of Cys130 and Cys174 in its ? subunit, which interferes with the interaction between AMPK and AMPK kinases (AMPKK). Reduction of Cys130/Cys174 is essential for activation of AMPK during energy starvation. Thioredoxin1 (Trx1), an important reducing enzyme that cleaves disulfides in proteins, prevents AMPK oxidation, serving as an essential cofactor for AMPK activation. High-fat diet consumption downregulates Trx1 and induces AMPK oxidation, which enhances cardiomyocyte death during myocardial ischemia. Thus, Trx1 modulates activation of the cardioprotective AMPK pathway during ischemia, functionally linking oxidative stress and metabolism in the heart.
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Hypertension in premenopausal women: is there any difference?
High Blood Press Cardiovasc Prev
PUBLISHED: 02-03-2014
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Hypertension is one of the most important cardiovascular (CV) risk factor, and that lowering blood pressure levels reduces the incidence of CV morbidity and mortality. The higher incidence of hypertension in post-menopausal than in pre-menopausal women raises the attention on the pathophysiological mechanisms potentially involved in post-menopausal ones and outweigh those involved in pre-menopausal women. However, CV disease is one of the leading causes of death in reproductive-age women. Thus, improved awareness, early identification and prompt clinical management of hypertension should be key elements in order to prevent hypertension-related CV morbidity and mortality in pre-menopausal women. However, available data in this specific age group of women are relatively poor and inconsistent, so that the clinical management of young hypertensive women is still debated. The aim of this review is to assess whether there are clear evidences on differences between men and women in epidemiological data, pathophysiological mechanisms, diagnostic options and therapeutic interventions of hypertension and its prognosis, in order to establish the correct approach to this group of hypertensive patients.
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Mammalian target of rapamycin signaling in cardiac physiology and disease.
Circ. Res.
PUBLISHED: 02-01-2014
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The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under intense investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.
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NOX4 regulates autophagy during energy deprivation.
Autophagy
PUBLISHED: 01-31-2014
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NADPH oxidase is a cellular enzyme devoted to the production of reactive oxygen species (ROS). NOX4 and NOX2 are the main isoforms of NADPH oxidase in the cardiovascular system. In our recent study, we demonstrated that NOX4, but not NOX2, is a critical mediator of the cardiomyocyte adaptive response to energy stress. NOX4 activity and protein levels are increased in the endoplasmic reticulum (ER) but not in mitochondria of cardiomyocytes during the early phase of energy deprivation. NOX4-derived production of ROS in the ER is a critical event that activates autophagy through stimulation of the EIF2AK3/PERK-EIF2S1/eIF-2?-ATF4 pathway. NOX4-dependent autophagy is an important mechanism to preserve cellular energy and limit cell death in energy-deprived cardiomyocytes. Aside from elucidating a crucial physiological function of NOX4 during cellular energy stress, our study dissects a novel signaling mechanism that regulates autophagy under this condition.
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A functional interaction between Hippo-YAP signalling and FoxO1 mediates the oxidative stress response.
Nat Commun
PUBLISHED: 01-24-2014
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The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Here we report that Yes-associated protein (YAP), the terminal effector of the Hippo pathway, interacts with FoxO1 in the nucleus of cardiomyocytes, thereby promoting survival. YAP and FoxO1 form a functional complex on the promoters of the catalase and manganese superoxide dismutase (MnSOD) antioxidant genes and stimulate their transcription. Inactivation of YAP, induced by Hippo activation, suppresses FoxO1 activity and decreases antioxidant gene expression, suggesting that Hippo signalling modulates the FoxO1-mediated antioxidant response. In the setting of ischaemia/reperfusion (I/R) in the heart, activation of Hippo antagonizes YAP-FoxO1, leading to enhanced oxidative stress-induced cell death through downregulation of catalase and MnSOD. Conversely, restoration of YAP activity protects against I/R injury. These results suggest that YAP is a nuclear co-factor of FoxO1 and that the Hippo pathway negatively affects cardiomyocyte survival by inhibiting the function of YAP-FoxO1.
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Rag GTPases are cardioprotective by regulating lysosomal function.
Nat Commun
PUBLISHED: 01-02-2014
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The Rag family proteins are Ras-like small GTPases that have a critical role in amino-acid-stimulated mTORC1 activation by recruiting mTORC1 to lysosome. Despite progress in the mechanistic understanding of Rag GTPases in mTORC1 activation, little is known about the physiological function of Rag GTPases in vivo. Here we show that loss of RagA and RagB (RagA/B) in cardiomyocytes results in hypertrophic cardiomyopathy and phenocopies lysosomal storage diseases, although mTORC1 activity is not substantially impaired in vivo. We demonstrate that despite upregulation of lysosomal protein expression by constitutive activation of the transcription factor EB (TFEB) in RagA/B knockout mouse embryonic fibroblasts, lysosomal acidification is compromised owing to decreased v-ATPase level in the lysosome fraction. Our study uncovers RagA/B GTPases as key regulators of lysosomal function and cardiac protection.
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The C2238/?ANP Variant Is a Negative Modulator of Both Viability and Function of Coronary Artery Smooth Muscle Cells.
PLoS ONE
PUBLISHED: 01-01-2014
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Abnormalities of vascular smooth muscle cells (VSMCs) contribute to development of vascular disease. Atrial natriuretic peptide (ANP) exerts important effects on VSMCs. A common ANP molecular variant (T2238C/?ANP) has recently emerged as a novel vascular risk factor.
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Activation of NADPH oxidase 4 in the endoplasmic reticulum promotes cardiomyocyte autophagy and survival during energy stress through the protein kinase RNA-activated-like endoplasmic reticulum kinase/eukaryotic initiation factor 2?/activating transcripti
Circ. Res.
PUBLISHED: 09-30-2013
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Autophagy is an essential survival mechanism during energy stress in the heart. Oxidative stress is activated by energy stress, but its role in mediating autophagy is poorly understood. NADPH oxidase (Nox) 4 is an enzyme that generates reactive oxygen species (ROS) at intracellular membranes. Whether Nox4 acts as a sensor of energy stress to mediate activation of autophagy is unknown.
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Relation between right and left ventricular function in patients undergoing chronic dialysis.
J Cardiovasc Med (Hagerstown)
PUBLISHED: 08-29-2013
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Occurrence of heart failure during dialysis treatment is associated with high mortality. However, mechanisms underlying left ventricular dysfunction (LVD) in these patients are still elusive. In patients undergoing haemodialysis, arteriovenous fistula (AVF) is associated with right ventricular dysfunction (RVD) and a further impairment is observed when AVF is brachial rather than radial. However, it is not known whether AVF-induced RVD is associated with an impaired left ventricular function. We studied the relation between right and left ventricular function in 120 patients undergoing either haemodialysis or peritoneal dialysis and 100 healthy age-matched controls.
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The Importance of Autophagy in Cardioprotection.
High Blood Press Cardiovasc Prev
PUBLISHED: 08-19-2013
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Autophagy is an intracellular lysosomal-mediated catabolic process in which senescent or damaged proteins and organelles are sequestered by double membrane-limited vesicles called autophagosomes, and then degraded by lysosomes. While the role of autophagy in different pathological states is context-dependent, it has been shown that during cardiac ischemia, autophagy is upregulated as a cardioprotective adaptation. We recently demonstrated that Rheb, a small GTP-binding protein that directly activates the complex 1 of the mechanistic target of rapamycin, is a critical regulator of autophagy during cardiac ischemia. We found that cardiac Rheb/mTORC1 signaling is activated in a deregulated manner during ischemia in obesity and metabolic syndrome. This uncontrolled activation of the Rheb/mTORC1 pathway leads to autophagy inhibition and to a reduction of myocardial tolerance to ischemia. This data further supports the relevance of autophagy as a fundamental protective mechanism during myocardial ischemia and suggests that reactivation of autophagy, in particular through the inhibition of Rheb/mTORC1 signaling may represent a promising therapeutic option to treat subjects with an acute myocardial infarction, particularly those affected by metabolic derangements. This review will deal with the biological significance of autophagy in cardioprotection.
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Mst1 inhibits autophagy by promoting the interaction between Beclin1 and Bcl-2.
Nat. Med.
PUBLISHED: 04-12-2013
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Here we show that Mst1, a proapoptotic kinase, impairs protein quality control mechanisms in the heart through inhibition of autophagy. Stress-induced activation of Mst1 in cardiomyocytes promoted accumulation of p62 and aggresome formation, accompanied by the disappearance of autophagosomes. Mst1 phosphorylated the Thr108 residue in the BH3 domain of Beclin1, which enhanced the interaction between Beclin1 and Bcl-2 and/or Bcl-xL, stabilized the Beclin1 homodimer, inhibited the phosphatidylinositide 3-kinase activity of the Atg14L-Beclin1-Vps34 complex and suppressed autophagy. Furthermore, Mst1-induced sequestration of Bcl-2 and Bcl-xL by Beclin1 allows Bax to become active, thereby stimulating apoptosis. Mst1 promoted cardiac dysfunction in mice subjected to myocardial infarction by inhibiting autophagy, associated with increased levels of Thr108-phosphorylated Beclin1. Moreover, dilated cardiomyopathy in humans was associated with increased levels of Thr108-phosphorylated Beclin1 and signs of autophagic suppression. These results suggest that Mst1 coordinately regulates autophagy and apoptosis by phosphorylating Beclin1 and consequently modulating a three-way interaction among Bcl-2 proteins, Beclin1 and Bax.
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Differential roles of GSK-3? during myocardial ischemia and ischemia/reperfusion.
Circ. Res.
PUBLISHED: 07-07-2011
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Inhibition of glycogen synthase kinase-3 (GSK-3) protects the heart during ischemia/reperfusion (I/R), yet the underlying mechanisms of cardioprotection afforded by beta isoform-specific inhibition GSK-3 remain to be elucidated.
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[The progression from hypertension to congestive heart failure].
Recenti Prog Med
PUBLISHED: 04-15-2011
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Arterial hypertension still represents one of the major modifiable risk factors for cardiovascular and renal disease. Solid evidences are available demonstrating the large and significant benefits deriving from blood pressure lowering therapies in terms of reduced incidence of major cardiovascular events, including myocardial infarction, ischemic stroke and cardiovascular death. It should be also noted, however, that hypertensive patients are at increased risk of developing congestive heart failure, being this risk substantially independent by the concomitant presence of left ventricular hypertrophy or dysfunction. Indeed, it has been demonstrated that blood pressure reduction and control significantly reduce the risk of developing congestive heart failure. In particular, several recent meta-analyses have demonstrated that the use of diuretics and renin-angiotensin system blockers is superior to calcium-antagonists and beta-blockers in terms of prevention of new-onset heart failure. The present paper overviews the main pathophysiological aspects of the progression from arterial hypertension to congestive heart failure and the potential therapeutic interventions able to reduce or prevent this progression.
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Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers and diabetes: a meta-analysis of placebo-controlled clinical trials.
Am. J. Hypertens.
PUBLISHED: 02-17-2011
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To determine whether the administration of angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) on top of standard cardiovascular (CV) therapies may reduce the incidence of new onset diabetes (NOD) in placebo-controlled clinical trials. The effects of these drugs on CV and non-CV mortality were also tested.
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A case for assessment of oscillatory breathing during cardiopulmonary exercise test in risk stratification of elderly patients with chronic heart failure.
Int. J. Cardiol.
PUBLISHED: 01-10-2011
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The prognostic value of exercise oscillatory breathing (EOB) during cardiopulmonary test (CPX) has been described in young chronic heart failure (HF) patients. We assessed the prognostic role of EOB vs other clinical and ventilatory parameters in elderly HF patients performing a maximal CPX.
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Is autophagy in response to ischemia and reperfusion protective or detrimental for the heart?
Pediatr Cardiol
PUBLISHED: 11-20-2010
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Autophagy is a catabolic process that degrades long-lived proteins and damaged organelles by sequestering them into double membrane structures termed "autophagosomes" and fusing them with lysosomes. Autophagy is active in the heart at baseline and further stimulated under stress conditions including starvation, ischemia/reperfusion, and heart failure. It plays an adaptive role in the heart at baseline, thereby maintaining cardiac structure and function and inhibiting age-related cardiac abnormalities. Autophagy is activated by ischemia and nutrient starvation in the heart through Sirt1-FoxO- and adenosine monophosphate (AMP)-activated protein kinase (AMPK)-dependent mechanisms, respectively. Activation of autophagy during ischemia is essential for cell survival and maintenance of cardiac function. Autophagy is strongly activated in the heart during reperfusion after ischemia. Activation of autophagy during reperfusion could be either protective or detrimental, depending on the experimental model. However, strong induction of autophagy accompanied by robust upregulation of Beclin1 could cause autophagic cell death, thereby proving to be detrimental. This review provides an overview regarding both protective and detrimental functions of autophagy in the heart and discusses possible applications of current knowledge to the treatment of heart disease.
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Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk.
Arch. Intern. Med.
PUBLISHED: 11-08-2010
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It is still debated whether there are differences among the various antihypertensive strategies in heart failure prevention. We performed a network meta-analysis of recent trials in hypertension aimed at investigating this issue.
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Right ventricular dysfunction in patients with end-stage renal disease.
Am. J. Nephrol.
PUBLISHED: 08-10-2010
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While chronic dialysis treatment has been suggested to increase pulmonary pressure values, right ventricular dysfunction (RVD) is a major cause of death in patients with end-stage renal disease. We investigated the impact of different dialysis treatments on right ventricular function.
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Determinants of N-terminal proatrial natriuretic peptide plasma levels in a survey of adult male population from Southern Italy.
J. Hypertens.
PUBLISHED: 05-11-2010
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Natriuretic peptides control cardiovascular functions through diuretic, natriuretic, and vasodilatory properties. Several anthropometric, cardiac and renal variables were found to be independently correlated to their levels. Few studies, however, systematically investigated the independent determinants of natriuretic peptide levels in large populations.
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NPR-C: a component of the natriuretic peptide family with implications in human diseases.
J. Mol. Med.
PUBLISHED: 05-03-2010
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The natriuretic peptide (NP) family includes atrial natriuretic peptide (ANP), B-type natriuretic peptide, C-type natriuretic peptide and their receptors NPR-A, NPR-B and NPR-C. The effects exerted by this hormonal system in the control of cardiovascular, renal and endocrine functions have been extensively investigated. Moreover, the involvement of NP in the pathogenesis of cardiovascular diseases has been demonstrated. Among the NP components, NPR-C has been described, at the time of its discovery, as the clearance receptor of NP devoid of any physiological functions. Emerging roles of NPR-C, however, have been highlighted over the last few years in relation to its effects on the cardiovascular system and other organs. These effects appear to be directly mediated through distinct cAMP-dependent intracellular mechanisms. Moreover, evidence has been accumulated on a potential pathophysiological role of NPR-C in human diseases. Ongoing studies from our group are revealing its involvement in the mediation of antiproliferative effects exerted on vascular cells by a molecular variant of human ANP. Thus, a new appraisal of NPR-C is overcoming the traditional view of a mere clearance receptor. This review focuses on the most important evidence supporting an involvement of NPR-C in mediating some of the actions of NP and its direct implication in cardiovascular diseases. The current state of knowledge highlights the need of further studies to better clarify the specific roles of NPR-C in pathophysiological processes.
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Reactive oxygen species-mediated effects on vascular remodeling induced by human atrial natriuretic peptide T2238C molecular variant in endothelial cells in vitro.
J. Hypertens.
PUBLISHED: 08-25-2009
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T2238C ANP (atrial natriuretic peptide) gene variant has been associated with increased cardiovascular risk in humans and with a significant pharmacogenomic effect on cardiovascular disease outcome in hypertensive patients. We investigated the impact of T2238C ANP gene variant on oxidative stress production, cell proliferation and migration, angiogenesis and vascular remodeling in human umbilical vein endothelial cells in vitro.
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Angiotensin II receptor blockers and myocardial infarction: an updated analysis of randomized clinical trials.
J. Hypertens.
PUBLISHED: 04-22-2009
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To evaluate the effects of treatments based on angiotensin II receptor blockers (ARBs) on the risk of myocardial infarction (MI), cardiovascular and all-cause death, as compared with conventional treatment or placebo.
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Independent association of ECG abnormalities with microalbuminuria and renal damage in hypertensive patients without overt cardiovascular disease: data from Italy-Developing Education and awareness on MicroAlbuminuria in patients with hypertensive Disease
J. Hypertens.
PUBLISHED: 02-21-2009
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Renal abnormalities are strongly associated with cardiac damage in essential hypertension. Detection of preclinical cardiac and renal abnormalities is a key clinical step in hypertension management. This study investigated the relationship between ECG abnormalities and microalbuminuria (MAU) in hypertensive patients without overt cardiovascular disease. This relationship, in fact, has never been extensively studied.
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Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction.
Clin. Sci.
PUBLISHED: 02-10-2009
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Left ventricular diastolic dysfunction represents a frequent clinical condition and is associated with increased cardiovascular morbidity and mortality. Diastolic dysfunction is the most common cause of HF-PSF (heart failure with preserved ejection fraction). Therefore it becomes important to understand the pathophysiological mechanisms underlying diastolic dysfunction, as well as the effective therapeutic strategies able to antagonize its development and progression. Among the complex pathophysiological factors that may contribute to the development of diastolic dysfunction, the RAAS (renin-angiotensin-aldosterone system) has been shown to play a significant role. Paracrine and autocrine signals of the RAAS promote structural and functional changes in the heart largely linked to increased myocardial fibrosis. Enhanced and dysregulated activity of the RAAS also contributes to the development of volume overload and vasoconstriction with subsequent increases in left ventricular diastolic filling pressures and a higher susceptibility of developing CHF (congestive heart failure). More recently, it has also been suggested that the RAAS may play a role in triggering myocardial and vascular inflammation through the activation of different cell types and the secretion of cytokines and chemokines. RAAS-induced myocardial inflammation leads to perivascular myocardial fibrosis and to the development or progression of diastolic dysfunction. For these reasons pharmacological blockade of the RAAS has been proposed as a rational approach for the treatment of diastolic dysfunction. In fact, ACEIs (angiotensin-converting enzyme inhibitors), ARBs (angiotensin II receptor blockers) and AAs (aldosterone antagonists) have been demonstrated to delay the development and progression from pre-clinical diastolic dysfunction towards CHF, as well as to reduce the morbidity and mortality associated with this condition.
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Evaluation of systolic properties in hypertensive patients with different degrees of diastolic dysfunction and normal ejection fraction.
Am. J. Hypertens.
PUBLISHED: 01-29-2009
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Left ventricular (LV) diastolic dysfunction (DD) associated with a preserved ejection fraction (EF) is a frequent alteration in hypertensive patients, usually considered an impairment of the diastolic phase alone. However, because systole and diastole are strictly correlated to one another, it is possible that hypertensive patients with isolated DD may also present with initial abnormalities of LV systolic properties, particularly those presenting with a more severe degree of DD. We performed a multiparametric echocardiographic assessment of LV systolic properties in patients without cardiovascular diseases, with preserved EF and different degrees of DD.
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Do diabetes, metabolic syndrome or their association equally affect biventricular function? A tissue Doppler study.
Hypertens. Res.
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Metabolic syndrome (MetS) and type 2 diabetes (T2DM) have been associated with an impairment of left (LV) and right ventricular (RV) function as well as an increased risk of heart failure (HF). However, it remains unclear whether these clinical entities or their associations promote a similar derangement of biventricular function. Overall, 345 patients without overt cardiovascular disease consecutively underwent routine blood chemistry including high-sensitivity C reactive protein (hs-CRP) and echocardiographical examination with conventional and tissue Doppler imaging (TDI) of both ventricles. According to the ATP III criteria and fasting glucose levels, the study population was stratified into four groups: (1) healthy controls (n=120); (2) MetS without T2DM (n=84); (3) T2DM without MetS (n=49); and (4) MetS+T2DM (n=92). The Myocardial performance index (MPI) of the RV and LV was obtained with a multi-segmental approach using TDI. Patients with MetS and T2DM exhibited a similar impairment of biventricular function compared with healthy controls, whereas a further decline was observed in patients having both MetS and T2DM. In addition to MetS markers, hs-CRP exhibited the strongest association with the MPI of both ventricles. Regression analyses indicated that individual MetS markers were inferior to MetS in identifying subtle cardiac dysfunction. Independent associations of MetS and T2DM with biventricular dysfunction were comparable, and the coexistence of MetS and T2DM exhibited the highest risk for biventricular dysfunction. Our findings emphasize the importance of MetS as an equivalent of T2DM and support a synergic effect of these clinical conditions on cardiac organ damage requiring more aggressive therapeutic strategies to prevent HF.
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Cardiac magnetic resonance evaluation of the impact of interventricular and intraventricular dyssynchrony on cardiac ventricular systolic and diastolic function in patients with isolated left bundle branch block.
Am. J. Cardiol.
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Ventricular dyssynchrony significantly impairs cardiac performance. However, the independent role of interventricular dyssynchrony (interVD) and intraventricular dyssynchrony (intraVD) in the development of abnormalities of systolic and diastolic performance is unclear. Cardiac magnetic resonance imaging was performed in 39 patients with left bundle branch block and 13 healthy patients. Structural and functional parameters of the left ventricle and degrees of interVD and intraVD were measured. We found that interVD was inversely correlated with left ventricular (LV) ejection fraction (r = -0.8, p <0.0001) and positively correlated with LV end-diastolic volume (r = 0.4, p <0.01), LV end-systolic volume (r = 0.6, p <0.0001), and LV mass (r = 0.4, p <0.01), thus indicating that interVD significantly affects systolic function and favors ventricular remodeling. Multivariate analysis further confirmed that interVD was an independent predictor of systolic dysfunction. Interestingly, we found that interVD was not associated with abnormalities of diastolic performance. Conversely, we found that intraVD significantly impaired diastolic function, whereas it had no effect on systolic function. IntraVD was inversely correlated with peak filling rate (r = -0.7, p <0.0001) and 1/2 filling fraction (r = 0.4, p = 0.04) and positively correlated with time to peak filling rate (r = 0.6, p <0.0001), validated parameters of diastolic function. Multivariate analysis confirmed that intraVD was an independent predictor of diastolic dysfunction. In conclusion, our study suggests that the 2 components of ventricular dyssynchrony differently affect cardiac performance. If confirmed in prospective studies, our results may help to predict the prognosis of patients with left bundle branch block and different degrees of interVD and intraVD, particularly those subjects undergoing cardiac resynchronization therapy.
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Pharmacological modulation of autophagy during cardiac stress.
J. Cardiovasc. Pharmacol.
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Autophagy is an evolutionarily conserved intracellular mechanism for degradation of long-lived proteins and organelles. Accumulating lines of evidence indicate that autophagy is deeply involved in the development of cardiac disease. Autophagy is upregulated in almost all cardiac pathological states, exerting both protective and detrimental functions. Whether autophagy activation is an adaptive or maladaptive mechanism during cardiac stress seems to depend upon the pathological context in which it is upregulated, the extent of its activation, and the signaling mechanisms promoting its enhancement. Pharmacological modulation of autophagy may therefore represent a potential therapeutic strategy to limit myocardial damage during cardiac stress. Several pharmacological agents that are able to modulate autophagy have been identified, such as mammalian target of rapamycin inhibitors, adenosine monophosphate-dependent kinase modulators, sirtuin activators, myo-inositol-1,4,5-triphosphate and calcium-lowering agents, and lysosome inhibitors. Although few of these modulators of autophagy have been directly tested during cardiac stress, many of them seem to have high potential to be efficient in the treatment of cardiac disease. We will discuss the potential usefulness of different pharmacological activators and inhibitors of autophagy in the treatment of cardiac diseases.
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Is reactivation of autophagy a possible therapeutic solution for obesity and metabolic syndrome?
Autophagy
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The molecular mechanism regulating the cardiomyocyte response to energy stress has been a hot topic in cardiac research in recent years, since this mechanism could be targeted for treatment of patients with ischemic heart disease. We have shown recently that the activity of RAS homolog enriched in brain (RHEB), a small GTP binding protein, is inhibited in response to glucose deprivation (GD) in cardiomyocytes and ischemia in the mouse heart. This is a physiological adaptation, since it inhibits complex 1 of the mechanistic target of rapamycin (MTORC1) and activates autophagy, thereby promoting cell survival during GD and prolonged ischemia. Importantly, the physiological inhibition of RHEB-MTORC1 signaling during myocardial ischemia is impaired in the presence of obesity and metabolic syndrome caused by high-fat diet (HFD) feeding, leading to a dramatic increase in ischemic injury. Although MTORC1 and autophagy can be regulated through RHEB-independent mechanisms, such as the AMPK-dependent phosphorylation of RPTOR and ULK1, RHEB appears to be critical in the regulation of MTORC1 and autophagy during ischemia in cardiomyocytes, and its dysregulation is relevant to human disease. Here we discuss the biological relevance of the dysregulation of RHEB-MTORC1 signaling and the suppression of autophagy in obesity and metabolic syndrome.
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Influence of rs5065 atrial natriuretic peptide gene variant on coronary artery disease.
J. Am. Coll. Cardiol.
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The aim of this study was to investigate the impact of rs5065 atrial natriuretic peptide (ANP) gene variant on coronary artery disease (CAD) and its outcomes and to gain potential mechanistic insights on the association with CAD.
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Rheb is a critical regulator of autophagy during myocardial ischemia: pathophysiological implications in obesity and metabolic syndrome.
Circulation
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Rheb is a GTP-binding protein that promotes cell survival and mediates the cellular response to energy deprivation (ED). The role of Rheb in the regulation of cell survival during ED has not been investigated in the heart.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.