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Cardiac Remodeling (cardiac + remodeling)
Selected AbstractsReduction in the Sodium Currents in Isolated Ventricular Myocytes of Guinea Pigs Treated by Chronic L-Thyroxin MedicationJOURNAL OF CARDIAC SURGERY, Issue 6 2002Yu-Ping Ma Objective: Cardiac remodeling induced by chronic medication of L-thyroxin is manifested by a much more severe cardiac arrhythmias on the occlusion/reperfusion of the coronary artery in rats. A pattern of changes in ion currents in a diseased heart (L-thyroxin induced cardiac remodeling) is possibly provided as a basis of promoting malignant cardiac arrhythmias. An enhanced delayed outward rectifier potassium currents the rapid (IKr) and slow (IKS) component was found in the remodeled heart by L-thyroxin chronic medication. It is interested to investigate the changes in the sodium currents in the L-thyroxin remodeled guinea pig ventricle. Method: The remodeling model in guinea pig was developed by L-thyroxin 4 mg po for 10 days. On d 11, the heart was removed and perfused to isolate ventricular myocytes with medium of Ca2+ free medium containing collagen. The whole cell holding technique was applied. Results: The INa density in the L-thyroxin caused hypertrophied myocytes was reduced significantly at holding potential ,30 mV, ,53.20 +/,10.78pA/pF against ,73.78+/,14.66pA/pF in the normal. (n = 45, p < 0.001). No difference in the steady-state inactivation and recovery kinetics between the remodeled and the normal was found. The recovery constant 37.54+/,3.63 ms in the remodeled vs 36.57+/,2.81 ms in the normal (n = 18, p > 0.05). The accelerated deactivation time constant 3.67+/,0.14 of the remodeled (n = 39) against the normal 4.14+/,0.15 ms (n = 43) (p < 0.05). Conclusion: There is a reduced INa in the L-thyroxin remodeled ventricular myocytes and the deactivation of the current is accelerated. A changed depolarization of the affected myocardium is likely involved in the mechanism of arrhythmogenesis of the remodeled ventricle. [source] BNP-induced activation of cGMP in human cardiac fibroblasts: Interactions with fibronectin and natriuretic peptide receptorsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 3 2006Brenda K. Huntley Cardiac remodeling involves the accumulation of extracellular matrix (ECM) proteins including fibronectin (FN). FN contains RGD motifs that bind integrins at DDX sequences allowing signaling from the ECM to the nucleus. We noted that the natriuretic peptide receptor A (NPR-A) sequence contains both RGD and DDX sequences. The goal of the current investigation was to determine potential interactions between FN and NPR-A on BNP induction of cGMP in cultured human cardiac fibroblasts (CFs). Further, we sought to determine whether a Mayo designed NPR-A specific RGD peptide could modify this interaction. Here we reconfirm the presence of all three natriuretic peptide receptors (NPR) in CFs. CFs plated on FN demonstrated a pronounced increase in cGMP production to BNP compared to non-coated plates. This production was also enhanced by the NPR-A specific RGD peptide, which further augmented FN associated cGMP production. Addition of HS-142-1, a NPR-A/B antagonist, abrogated the responses of BNP to both FN and the NPR-A specific RGD peptide. Finally, we defined a possible role for the NPR-C through non-cGMP mechanisms in mediating the anti-proliferative actions of BNP in CFs where the NPR-C antagonist cANF 4-28 but not HS-142-1 blocked BNP-mediated inhibition of proliferation of CFs. We conclude that NPR-A interacts with components of the ECM such as FN to enhance BNP activation of cGMP and that a small NPR-A specific RGD peptide augments this action of BNP with possible therapeutic implications. Lastly, the NPR-C may also have a role in mediating anti-proliferative actions of BNP in CFs. J. Cell. Physiol. 209: 943,949, 2006. © 2006 Wiley-Liss, Inc. [source] The effects of ACE inhibitor therapy on left ventricular myocardial mass and diastolic filling in previously untreated hypertensive patients: A Cine MRI studyJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2001U. Hoffmann MD Abstract Cardiac remodeling in case of hypertension induces hypertrophy of myocytes and elevated collagen content and, subsequently, impaired diastolic filling of the left ventricle. The purpose of this prospective study was to evaluate changes of left ventricular (LV) myocardial mass, as well as diastolic filling properties, in hypertensive patients treated with the ACE inhibitor fosinopril. Sixteen hypertensive patients with echocardiographically documented LV hypertrophy and diastolic dysfunction received fosinopril (10,20 mg daily). Measurements of LV myocardial mass and properties of diastolic filling (peak filling fraction (PFF); peak filling rate (PFR)) were performed prior to medication, as well as after 3 and 6 months of therapy using cine magnetic resonance imaging (MRI). Ten healthy subjects served as a control group. LV myocardial mass (g/m2) decreased continuously within 3,6 months of follow-up by 32% (148 ± 40 vs. 120 ± 26 vs. 101 ± 22 g/m2; P < 0.0001/0.005). The extent of regression correlated to the severity of LV hypertrophy at baseline (r = 0.77; P < 0.004). Early diastolic filling increased significantly within 6 months of therapy (PFF (%): 36 ± 6 vs. 61 ± 7, P < 0.0001; PFR (mL/second): 211 ± 48 vs. 282 ± 48, P < 0.001). Cine MRI can be used to assess the time course of pharmacological effects on cardiac remodeling in the course of hypertension. ACE inhibitor therapy results in a significant reduction of LV mass within 3 months and is accompanied by a normalization of diastolic filling that is completed after 6 months. J. Magn. Reson. Imaging 2001;14:16,22. © 2001 Wiley-Liss, Inc. [source] Pharmacological and Clinical Studies with Temocapril, an Angiotensin Converting Enzyme Inhibitor that is Excreted in the BileCARDIOVASCULAR THERAPEUTICS, Issue 3 2004Kenichi Yasunari ABSTRACT Temocapril is an angiotensin converting enzyme inhibitor (ACEI), a prodrug with a thiazepine ring. Its active form, temocaprilat, is slightly more potent than enalaprilat in inhibiting ACE isolated from rabbit lung. The inhibitory potency of temocaprilat on isolated rat aorta is 3 times that of enalaprilat. Temocapril is excreted in the bile and urine and can be used in patients with renal insufficiency. It reduces blood pressure without causing any significant change in heart rate or cardiac output. Temocapril has been reported to improve endothelial dysfunction in vitro by suppressing increased oxidative stress. In vivo it improves reactive hyperemia in patients with essential hypertension. It has been reported to prevent coronary vascular remodeling in vivo by suppressing local ACE and increased oxidative stress. In humans temocapril has been found to improve insulin resistance partly by increasing adiponectin levels. Cardiac remodeling was improved by temocapril not only in experiment animals but also in humans. It improves renal function and decreases urinary albumin excretion in diabetics as well as in hypertensive patients. Temocapril is currently marketed only in Japan. Considering its beneficial effects and unique pharmaco-kinetics, temocapril, is likely to be introduced in other countries as well. [source] Reduction in the Sodium Currents in Isolated Ventricular Myocytes of Guinea Pigs Treated by Chronic L-Thyroxin MedicationJOURNAL OF CARDIAC SURGERY, Issue 6 2002Yu-Ping Ma Objective: Cardiac remodeling induced by chronic medication of L-thyroxin is manifested by a much more severe cardiac arrhythmias on the occlusion/reperfusion of the coronary artery in rats. A pattern of changes in ion currents in a diseased heart (L-thyroxin induced cardiac remodeling) is possibly provided as a basis of promoting malignant cardiac arrhythmias. An enhanced delayed outward rectifier potassium currents the rapid (IKr) and slow (IKS) component was found in the remodeled heart by L-thyroxin chronic medication. It is interested to investigate the changes in the sodium currents in the L-thyroxin remodeled guinea pig ventricle. Method: The remodeling model in guinea pig was developed by L-thyroxin 4 mg po for 10 days. On d 11, the heart was removed and perfused to isolate ventricular myocytes with medium of Ca2+ free medium containing collagen. The whole cell holding technique was applied. Results: The INa density in the L-thyroxin caused hypertrophied myocytes was reduced significantly at holding potential ,30 mV, ,53.20 +/,10.78pA/pF against ,73.78+/,14.66pA/pF in the normal. (n = 45, p < 0.001). No difference in the steady-state inactivation and recovery kinetics between the remodeled and the normal was found. The recovery constant 37.54+/,3.63 ms in the remodeled vs 36.57+/,2.81 ms in the normal (n = 18, p > 0.05). The accelerated deactivation time constant 3.67+/,0.14 of the remodeled (n = 39) against the normal 4.14+/,0.15 ms (n = 43) (p < 0.05). Conclusion: There is a reduced INa in the L-thyroxin remodeled ventricular myocytes and the deactivation of the current is accelerated. A changed depolarization of the affected myocardium is likely involved in the mechanism of arrhythmogenesis of the remodeled ventricle. [source] Beneficial effect of enalapril in spontaneously hypertensive rats cardiac remodeling with nitric oxide synthesis blockadeJOURNAL OF CELLULAR AND MOLECULAR MEDICINE, Issue 4 2002R. L. de Andrade Zorzi Abstract Aims. To study the efficiency of an angiotensin converting enzyme inhibitor on the blood pressure (BP) and the myocardium remodeling when spontaneously hypertensive rats (SHRs) are submitted to nitric oxide synthesis (NOs) blockade (with L-NAME) and simultaneously treated. Methods. Young adult male SHRs were separated in four groups (n = 5) and treated for 20 days: Control, L-NAME, L-NAME+Enalapril, and Enalapril. The alterations of the BP, heart mass/body mass ratio and stereological parameters for myocytes, connective tissue and intramyocardial vessels were studied among the groups. Results. The SHRs with NOs blockade showed a great modification of the myocardium with extensive areas of reparative and interstitial fibrosis and accentuated hypertrophy of the cardiac myocytes (cross sectional area 60% higher in animals taking L-NAME than in Control SHRs). Comparing the SHRs with NO deficiency (L-NAME group), the Control SHRs and the Enalapril treated SHRs significant differences were found in the BP and in all stereological parameters. The NO deficiency caused an important BP increment in SHRs that was partially attenuated by Enalapril. This Enalapril effect was more pronounced in Control SHRs. A significant increment of the intramyocardial vessels was observed in NO deficient SHRs and Control SHRs treated with Enalapril demonstrated by the stereology (greater microvascular densities in treated SHRs). Conclusion. Enalapril administration showed a beneficial effect on vascular remodeling and myocardial hypertrophy in SHRs. In SHRs with NO blockade, however, the beneficial effect of Enalapril occurred only in vascular remodeling. [source] Mitochondrial mechanism of oxidative stress and systemic hypertension in hyperhomocysteinemiaJOURNAL OF CELLULAR BIOCHEMISTRY, Issue 4 2005Neetu Tyagi Abstract Formation of homocysteine (Hcy) is the constitutive process of gene methylation. Hcy is primarily synthesized by de-methylation of methionine, in which s-adenosyl-methionine (SAM) is converted to s-adenosyl-homocysteine (SAH) by methyltransferase (MT). SAH is then hydrolyzed to Hcy and adenosine by SAH-hydrolase (SAHH). The accumulation of Hcy leads to increased cellular oxidative stress in which mitochondrial thioredoxin, and peroxiredoxin are decreased and NADH oxidase activity is increased. In this process, Ca2+ -dependent mitochondrial nitric oxide synthase (mtNOS) and calpain are induced which lead to cytoskeletal de-arrangement and cellular remodeling. This process generates peroxinitrite and nitrotyrosine in contractile proteins which causes vascular dysfunction. Chronic exposure to Hcy instigates endothelial and vascular dysfunction and increases vascular resistance causing systemic hypertension. To compensate, the heart increases its load which creates adverse cardiac remodeling in which the elastin/collagen ratio is reduced, causing cardiac stiffness and diastolic heart failure in hyperhomocysteinemia. J. Cell. Biochem. © 2005 Wiley-Liss, Inc. [source] Pathophysiologic role of myocardial apoptosis in post-infarction left ventricular remodelingJOURNAL OF CELLULAR PHYSIOLOGY, Issue 2 2002Antonio Abbate Left ventricular (LV) remodeling and heart failure (HF) complicate acute myocardial infarction (AMI) even weeks to months after the initial insult. Apoptosis may represent an important pathophysiologic mechanism causing progressive myocardiocyte loss and LV dilatation even late after AMI. This review will discuss the role of apoptosis according to findings in animal experimental data and observational studies in humans in order to assess clinical relevance, determinants, and mechanisms of myocardial apoptosis and potential therapeutic implications. More complete definition of the impact of myocardiocyte loss on prognosis and of the mechanisms involved may lead to improved understanding of cardiac remodeling and possibly improved patients' care. Mitochondrial damage and bcl-2 to bax balance play a central role in ischemia-dependent apoptosis while angiotensin II and ,1 -adrenergic-stimulation may be major causes of receptor-mediated apoptosis. Benefits due to treatment with ACE-inhibitors and ,-blockers appear to be in part due to reduced myocardial apoptosis. Moreover, infarct-related artery patency late after AMI may be a major determinant of myocardial apoptosis and clinical benefits deriving from an open artery late post AMI (the "open artery hypothesis") may be, at least in part, due to reduced myocardiocyte loss. © 2002 Wiley-Liss, Inc. [source] The effects of ACE inhibitor therapy on left ventricular myocardial mass and diastolic filling in previously untreated hypertensive patients: A Cine MRI studyJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2001U. Hoffmann MD Abstract Cardiac remodeling in case of hypertension induces hypertrophy of myocytes and elevated collagen content and, subsequently, impaired diastolic filling of the left ventricle. The purpose of this prospective study was to evaluate changes of left ventricular (LV) myocardial mass, as well as diastolic filling properties, in hypertensive patients treated with the ACE inhibitor fosinopril. Sixteen hypertensive patients with echocardiographically documented LV hypertrophy and diastolic dysfunction received fosinopril (10,20 mg daily). Measurements of LV myocardial mass and properties of diastolic filling (peak filling fraction (PFF); peak filling rate (PFR)) were performed prior to medication, as well as after 3 and 6 months of therapy using cine magnetic resonance imaging (MRI). Ten healthy subjects served as a control group. LV myocardial mass (g/m2) decreased continuously within 3,6 months of follow-up by 32% (148 ± 40 vs. 120 ± 26 vs. 101 ± 22 g/m2; P < 0.0001/0.005). The extent of regression correlated to the severity of LV hypertrophy at baseline (r = 0.77; P < 0.004). Early diastolic filling increased significantly within 6 months of therapy (PFF (%): 36 ± 6 vs. 61 ± 7, P < 0.0001; PFR (mL/second): 211 ± 48 vs. 282 ± 48, P < 0.001). Cine MRI can be used to assess the time course of pharmacological effects on cardiac remodeling in the course of hypertension. ACE inhibitor therapy results in a significant reduction of LV mass within 3 months and is accompanied by a normalization of diastolic filling that is completed after 6 months. J. Magn. Reson. Imaging 2001;14:16,22. © 2001 Wiley-Liss, Inc. [source] Effect of Chronic Ethanol Ingestion and Gender on Heart Left Ventricular p53 Gene ExpressionALCOHOLISM, Issue 8 2005Heidi Jänkälä Background: Although the beneficial effects of mild to moderate ethanol consumption have been implied with respect to heart, alcohol abuse has proven to be a major cause of nonischemic cardiomyopathy in Western society. However, the biochemical and molecular mechanisms, which mediate the pathologic cardiac effects of ethanol, remain largely unknown. The aim of the present study was to explore the effects of chronic ethanol exposure on cardiac apoptosis and expression of some of the genes associated with cardiac remodeling in vivo. Methods: Alcohol-avoiding Alko Non Alcohol rats of both sexes were used. The ethanol-exposed rats (females, n= 6; males, n= 8) were given 12% (v/v) ethanol as the only available fluid from age of three to 24 months of age. The control rats (females, n= 7; males, n= 5) had only water available. At the end of the experiment, free walls of left ventricles of hearts were immediately frozen. Cytosolic DNA fragmentation, reflecting apoptosis, was measured using a commercial quantitative sandwich enzyme-linked immunosorbent assay kit, and mRNA levels were analyzed using a quantitative reverse transcriptase,polymerase chain reaction method. Results: Ethanol treatment for two years increased cardiac left ventricular p53 mRNA levels significantly (p= 0.014) compared with control rats. The gene expression was also dependent on the gender (p= 0.001), so that male rats had higher left ventricular p53 mRNA levels than female rats. However, no significant differences in levels of DNA fragmentation were detected. Conclusions: Chronic ethanol exposure in vivo induces rat cardiac left ventricular p53 gene expression. Expression of p53 is also gender-dependent, males having higher p53 mRNA levels than females. This preliminary finding suggests a role for the p53 gene in ethanol-induced cardiac remodeling. The results might also have some relevance for the known gender-dependent differences in propensity to cardiovascular disease. [source] Cardiac Troponin I Is Associated with Severity of Myxomatous Mitral Valve Disease, Age, and C-Reactive Protein in DogsJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2010I. Ljungvall Background: Concentrations of cardiac troponin I (cTnI) and C-reactive protein (CRP) might be associated with cardiac remodeling in dogs with myxomatous mitral valve disease (MMVD). Age- and sex-dependent variations in cTnI concentration have been described. Objective: To investigate whether plasma concentrations of cTnI and CRP are associated with severity of MMVD, and investigate potential associations of dog characteristics on cTnI and CRP concentrations. Animals: Eighty-one client-owned dogs with MMVD of varying severity. Methods: Dogs were prospectively recruited for the study. Dogs were classified according to severity of MMVD. Plasma cTnI was analyzed by a high sensitivity cTnI assay with a lower limit of detection of 0.001 ng/mL, and plasma CRP was analyzed by a canine-specific CRP ELISA. Results: Higher cTnI concentrations were detected in dogs with moderate (0.014 [interquartile range 0.008,0.029] ng/mL, P= .0011) and severe (0.043 [0.031,0.087] ng/mL, P < .0001) MMVD, compared with healthy dogs (0.001 [0.001,0.004] ng/mL). Dogs with severe MMVD also had higher cTnI concentrations than dogs with mild (0.003 [0.001,0.024] ng/mL, P < .0001) and moderate (P= .0019) MMVD. There were significant associations of age, CRP, heart rate, and left ventricular end-diastolic diameter, on cTnI concentration C-reactive protein did not differ among severity groups, but was significantly associated with cTnI, breed, and systolic blood pressure on CRP concentration. Conclusions and Clinical Importance: Analysis of cTnI concentration has potential to increase knowledge of overall cardiac remodeling in dogs with MMVD. However, effect of age on cTnI needs consideration when assessing cTnI. [source] Cardiac Resynchronization Therapy in Non-Left Bundle Branch Block MorphologiesPACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 5 2010JOHN RICKARD M.D. Introduction: In select patients with systolic heart failure, cardiac resynchronization therapy (CRT) has been shown to improve quality of life, exercise capacity, ejection fraction (EF), and survival. Little is known about the response to CRT in patients with right bundle branch block (RBBB) or non-specific intraventricular conduction delay (IVCD) compared with traditionally studied patients with left bundle branch block (LBBB). Methods: We assessed 542 consecutive patients presenting for the new implantation of a CRT device. Patients were placed into one of three groups based on the preimplantation electrocardiogram morphology: LBBB, RBBB, or IVCD. Patients with a narrow QRS or paced ventricular rhythm were excluded. The primary endpoint was long-term survival. Secondary endpoints were changes in EF, left ventricular end-diastolic and systolic diameter, mitral regurgitation, and New York Heart Association (NYHA) functional class. Results: Three hundred and thirty-five patients met inclusion criteria of which 204 had LBBB, 38 RBBB, and 93 IVCD. There were 32 deaths in the LBBB group, 10 in the RBBB, and 27 in the IVCD group over a mean follow up of 3.4 ± 1.2 years. In multivariate analysis, no mortality difference amongst the three groups was noted. Patients with LBBB had greater improvements in most echocardiographic endpoints and NYHA functional class than those with IVCD and RBBB. Conclusion: There is no difference in 3-year survival in patients undergoing CRT based on baseline native QRS morphology. Patients with RBBB and IVCD derive less reverse cardiac remodeling and symptomatic benefit from CRT compared with those with a native LBBB. (PACE 2010; 590,595) [source] Clinical and Experimental Aspects of Olmesartan Medoxomil, a New Angiotensin II Receptor AntagonistCARDIOVASCULAR THERAPEUTICS, Issue 4 2004Kazunori Yoshida ABSTRACT Olmesartan medoxomil is a new orally active angiotensin II (Ang II) type 1 receptor antagonist. It is a prodrug and is rapidly de-esterified during absorption to form olmesartan, the active metabolite. Olmesartan is a potent, competitive and selective Ang II type 1 receptor antagonist. Olmesartan is not metabolized by the cytochrome P-450 and has a dual route of elimination, by kidneys and liver. In patients with essential hypertension olmesartan medoxomil administered once daily at doses of 10,80 mg dose-dependently reduced diastolic blood pressure (DBP). Troughto-peak ratios for both DBP and systolic blood pressure (SBP) were above 50%. At the recommended once-daily starting doses, olmesartan medoxomil (20 mg) was more effective than losartan (50 mg), valsartan (80 mg) or irbesartan (150 mg) in reducing cuff DBP in patients with essential hypertension. The results of cuff SBP and mean 24-h DBP and SBP were similar to those of cuff DBP measurement. In mild-to-moderate hypertensive patients the recommended starting dose of olmesartan medoxomil was as effective as that of amlodipine besylate (5 mg/day) in reducing both cuff and 24-h blood pressure. In lowering DBP olmesartan medoxomil, at 10,20 mg/day, was as effective as atenolol at 50,100 mg/day. In mild-to-moderate hypertensive patients, olmesartan medoxomil, at 5,20 mg once daily, was more effective than captopril at 12.5,50 mg twice daily. At 20,40 mg once daily olmesartan medoxomil was as effective as felodipine, at 5,10 mg once daily. Olmesartan medoxomil has minimal adverse effects with no clinically important drug interactions. Animal studies have shown that olmesartan medoxomil provides a wide range of organ protection. Olmesartan medoxomil ameliorated atherosclerosis in hyperlipidemic animals and ameliorated cardiac remodeling and improved survival in rats with myocardial infarction. Olmesartan medoxomil has renoprotective effects in a remnant kidney model and type 2 diabetes models. Future investigation should reveal whether these beneficial effects of olmesartan medoxomil are applicable to human diseases. [source] The Presence of B-type Natriuretic Peptide in Burns and the Responsiveness of Fibroblasts to BNP: Proof of PrincipleACADEMIC EMERGENCY MEDICINE, Issue 6 2007Adam J. Singer MD Background:B-type natriuretic peptide (BNP) released from cardiac myocytes plays an important role in cardiac homeostasis through cyclic guanosine monophosphate (cGMP) activation. BNP also reduces cardiac remodeling and fibrosis. The antifibrotic effects of BNP are mediated in part by blocking the effects of transforming growth factor ,, a profibrotic cytokine that plays a significant role in cutaneous wound healing. It is unclear if BNP plays any role in cutaneous wound healing.ObjectivesTo investigate if BNP levels would be elevated in thermally injured human skin and if human-derived fibroblasts would respond to BNP exposure by increasing levels of cGMP.MethodsThis was an in vitro analysis of human skin. Skin samples and cells were collected from patients with and without thermal injury. The authors stained three skin samples from normal skin (taken at the time of elective cosmetic surgery) with antibodies to BNP and compared these with three tissue samples obtained from burned human skin taken during tangential excision of deep burns. Normal human-derived fibroblasts and keratinocytes were exposed in triplicate to BNP in vitro, and cGMP accumulation was evaluated. Levels of cGMP were quantified and compared with analysis of variance.ResultsBNP was present in all specimens of thermally injured skin (especially around collagen, epithelial cells, and endothelial cells) but not in any uninjured skin samples (p = 0.05, single-tailed Fisher's exact test). In vitro grown fibroblasts showed significant increases of cGMP levels with increasing levels of BNP exposure (mean [±SD]: 0.6 [±0.3], 1.2 [±0.2], 4.6 [±0.1], and 5.0 [±0.9] pmol/mL with BNP concentrations of 0, 10, 500, and 1,000 nmol/L, respectively; p < 0.001). The effect of BNP on keratinocytes was minimal and below the level of quantification.Conclusions:These findings demonstrate proof of principle that human fibroblasts are responsive to the effects of BNP in vitro and that BNP is present in injured skin, suggesting that BNP may play a role in cutaneous wound healing. [source] Sex-Specific Impact of Aldosterone Receptor Antagonism on Ventricular Remodeling and Gene Expression after Myocardial InfarctionCLINICAL AND TRANSLATIONAL SCIENCE, Issue 2 2009Ph.D., Rosemeire M. Kanashiro-Takeuchi D.V.M. Abstract Aldosterone receptor antagonism reduces mortality and improves post-myocardial infarction (Ml) remodeling. Because aldosterone and estrogen signaling pathways interact, we hypothesized that aldosterone blockade is sex-specific. Therefore, we investigated the mpact of eplerenone on left ventricular (LV) remodeling and gene expression of male infarcted rats versus female infarcted rats. Ml and Sham animals were randomized to receive eplerenone (100 mg/kg/day) or placebo 3 days post-surgery for 4 weeks and assessed by echocardiography. In the Ml placebo group, left ventricular end-diastolic dimension (LVEDD) increased from 7.3 ± 0.4 mm to 10.2 ± 1.0 mm (p < 0.05) and ejection fraction (EF) decreased from 82.3 + 4% to 45.5 + 11% (p < 0.05) in both sexes (p= NS between groups). Eplerenone attenuated LVEDD enlargement more effectively in females (8.8 ± 0.2 mm, p < 0.05 vs. placebo) than in males (9.7 ± 0.2 mm, p= NS vs. placebo) and improved EF in females (56.7 ± 3%, p < 0.05 vs. placebo) but not in males (50.6 + 3%, p= NS vs. placebo). Transcriptomic analysis using Rat_230,2.0 microarrays (Affymetrix) revealed that in females 19% of downregu-lated genes and 44% of upregulated genes post-MI were restored to normal by eplerenone. In contrast, eplerenone only restored 4% of overexpressed genes in males. Together, these data suggest that aldosterone blockade reduces Ml-induced cardiac remodeling and phenotypic alterations of gene expression preferentially in females than in males. The use of transcriptomic signatures to detect greater benefit of eplerenone in females has potential implications for personalized medicine. [source] Overview of the relationship between ischemia and congestive heart failureCLINICAL CARDIOLOGY, Issue S4 2000PH.D., Willem J. Remme M.D. Abstract Ischemic heart disease is the principal etiology of heart failure in the Western world. Myocardial ischemia is important in cardiac remodeling, a process that leads to a progressive change in the shape and size of the heart and significantly worsens the prognosis of patients with heart failure. Preventing ischemic events, therefore, is an important goal in the management of patients with coronary artery disease. Statins have been shown to reduce the number of ischemic events in these patients, whereas the benefit of beta-blocker and aldosterone antagonist therapy on ischemic causes of heart failure remains unclear. Several large trials involving patients with asymptomatic left ventricular dysfunction after myocardial infarction or heart failure have shown that angiotensin-converting enzyme (ACE) inhibitors reduce the incidence of progressive heart failure, death, and ischemic events, thus establishing ACE inhibitors as first-line therapy for these patients. Other lines of evidence have suggested that ACE inhibitor therapy may also benefit patients with preserved left ventricular function, a hypothesis that is being evaluated in three large, controlled, randomized trials. One of these trials, the Heart Outcomes Prevention Evaluation (HOPE) study, was terminated prematurely because it demonstrated the significant positive effects of the ACE inhibitor ramipril on cardiovascular outcomes in patients with coronary artery disease and preserved left ventricular function. A growing body of data confirms the relationship between ischemia and heart failure and the benefits of ACE inhibitor treatment in a broad range of high-risk patients. [source] | |||||||||||||