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      Congestive Heart Failure: Experimental Model


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          Introduction: Surgically induced, combined volume and pressure overload has been used in rabbits to create a simplified and reproducible model of acute left ventricular (LV) failure.

          Materials and Methods: New Zealand white male rabbits ( n = 24, mean weight 3.1 ± 0.2 kg) were randomly assigned to either the Control group ( n = 10) or to the Heart Failure group (HF, n = 14). Animals in the Control group underwent “sham” procedures. Animals in the HF group underwent procedures to induce LV volume overload by inducing severe aortic valve regurgitation with aortic cusp disruption and pressure overload using an occlusive silver clip positioned around the pre-renal abdominal aorta.

          Results: Following Procedure-1 (volume overload) echocardiography confirmed severe aortic regurgitation in all animals in the HF group, with increased mean pulse pressure difference from 18 ± 3 to 38 ± 3 mmHg ( P < 0.0001). After Procedure-2 (pressure overload) all animals in the HF group showed clinical and echocardiographic signs of constriction of the abdominal aorta and echocardiography confirmed progressively declining LV function. At the end of the protocol there was a significant increase of the heart/body weight ratio in the HF group vs. Control group (4.6 ± 0.2 vs. 2.9 ± 0.1 g/kg, P < 0.05), and echocardiography showed in HF group significant increase of the LV end-diastolic diameter (2.15 ± 0.09 vs. 1.49 ± 0.03 cm, P < 0.001) and reduction of the LV shortening fraction (26.3 ± 3.8 vs. 41.3 ± 1.6%, P < 0.001).

          Conclusion: This experimental model: (a) consistently produces LV hypertrophy/dilatation and subsequent congestive heart failure, (b) provides new data on the time course of LV dilatation, hypertrophy and failure, (c) allows study of the progress and evolution of LV systolic and diastolic dysfunction in the presence of induced LV failure, (d) is suitable to study intervention or pharmacological administration to reduce the negative effects of acute LV failure.

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          Most cited references 40

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          Two-kidney, one clip and one-kidney, one clip hypertension in mice.

          The mouse remains the animal of choice in transgenic experiments, creating a need for methods of evaluating the physiology of genetically modified animals. We have established and characterized two murine models of renovascular hypertension known as the two-kidney, one clip and one-kidney, one clip models. The appropriate size of the clip lumen needed to induce high blood pressure was determined to be 0.12 mm. Clips with a lumen of 0.11 mm induced a high percentage of renal infarction, and clips with a 0.13-mm opening did not produce hypertension. Four weeks after clipping, two-kidney, one clip hypertensive mice exhibited blood pressure approximately 20 mm Hg higher than their sham-operated controls. After a similar period, this increase reached almost 35 mm Hg in the one-kidney, one clip model. Depending on the model, mice develop either renin-dependent or renin-independent hypertension. Both models are characterized by the development of cardiovascular hypertrophy.
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            Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure.

            In patients with heart disease, the transition from compensatory hypertrophy to heart failure (HF) is associated with altered calcium handling. Up-regulated Na(+)/H(+)-exchanger (NHE-1) activity underlies increased [Na(+)](i) and disturbance of cellular calcium handling in HF. We hypothesize that chronic inhibition of NHE-1 activity prevents the hypertrophic response, cellular remodeling, and development of HF. Rabbits received a control or cariporide (inhibitor of NHE-1) diet for 3 months, starting after induction of combined volume and pressure overload. Age-matched animals served as control. Development of HF was examined echocardiographically and electrocardiographically after 3 months. [Na(+)](i), [Ca(2+)](i), pH(i), and action potentials were measured in left ventricular midmural myocytes with SBFI, indo-1, SNARF, and di-4-anepps. Sarcoplasmic reticulum calcium content was calculated from the response of [Ca(2+)](i) to rapid cooling. Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin. Chronic treatment of rabbits with the specific Na(+)/H(+)-exchanger activity inhibitor cariporide greatly attenuated development of hypertrophy and entirely abolished development of HF; the heart/body weight ratio increased only little, no change in lung weight occurred, left ventricular dimensions and fractional shortening changed mildly, ascites was not present, QT duration did not increase, and sudden death did not occur. Chronic cariporide treatment also prevented cellular electrical and ionic remodeling. Myocyte dimensions were unaltered, action potentials were not prolonged, cytoplasmic sodium and NHE-1 activity did not increase, cytoplasmic and SR calcium handling remained undisturbed, and no increase of the incidence of calcium after-transient dependent delayed after depolarizations (DADs) occurred. We conclude that enhanced activity of NHE-1 underlies cardiac cellular electrical and ionic remodeling in experimental heart failure, and that chronic dietary treatment with cariporide attenuates hypertrophy, development of HF, and cellular remodeling.
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              Early intravenous heart failure therapy and outcomes among older patients hospitalized for acute decompensated heart failure: findings from the Acute Decompensated Heart Failure Registry Emergency Module (ADHERE-EM).

              Timing of initial treatment for acute decompensated heart failure (ADHF) varies across hospitals and its impact on outcomes remains poorly defined. We examined the association between time to first intravenous (IV) heart failure (HF) therapy and patient outcomes. Using the ADHERE-EM linked to Medicare claims data, we identified patients ≥65 years old who were hospitalized for ADHF and received IV HF therapy during index admission. Cox proportional hazard model was used to assess the association of time to treatment with a composite of 30-day all-cause mortality or re-admission. Generalized linear mixed models were used to examine the association of time to treatment with in-hospital all-cause mortality, index hospitalization length of stay, and total days alive and out-of-hospital at 30 days. Of 6,971 patients, the median time to first IV HF therapy was 2.3-hours (interquartile range 1.1, 4.4). The cumulative incidence of 30-day all-cause mortality or readmission was 27.4%. After adjusting for covariates, time to treatment was not associated with increased risk of composite 30-day all-cause mortality or re-admission (HR 1.00; 95% CI 1.00-1.00; P = .221). However, every hour delay in treatment was associated with a modest increased risk of in-hospital mortality (adjusted OR 1.01; 95% CI 1.00-1.02; P = .001) and an approximately 1.4-hour increase in index admission length of stay (P < .001). Among older patients presenting with ADHF, delay in initiating IV HF therapy was associated with modestly higher risk for in-hospital mortality and longer length of stay, but was not associated with 30-day outcomes. Copyright © 2013 Mosby, Inc. All rights reserved.

                Author and article information

                URI : http://frontiersin.org/people/u/67709
                URI : http://frontiersin.org/people/u/118525
                URI : http://frontiersin.org/people/u/68209
                Front Pediatr
                Front Pediatr
                Front. Pediatr.
                Frontiers in Pediatrics
                Frontiers Media S.A.
                28 October 2013
                : 1
                [1] 1School of Medical Sciences, Health Campus, University Sains Malaysia , Kubang Kerian, Kelantan, Malaysia
                [2] 2Core Technology Facility, University of Manchester , Manchester, UK
                [3] 3Alder Hey Children NHS Foundation Trust , Liverpool, UK
                [4] 4John Moores University , Liverpool, UK
                Author notes

                Edited by: Oswin Grollmuss, Centre Chirurgical Marie Lannelongue, France

                Reviewed by: Gianni Pedrizzetti, University of Trieste, Italy; Umberto Morbiducci, Politecnico di Torino, Italy; Jan Brazdil, FN Motol, Czech Republic

                *Correspondence: Antonio Francesco Corno, School of Medical Sciences, Health Campus, University Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia e-mail: tonycorno@ 123456hotmail.com

                This article was submitted to Pediatric Cardiology, a section of the journal Frontiers in Pediatrics.

                Copyright © 2013 Corno, Cai, Jones, Mondani, Boyett, Jarvis and Hart.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 7, Tables: 1, Equations: 0, References: 43, Pages: 6, Words: 4455
                Original Research


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