Abstract 321: Cardiac Function Improvement Following In vivo Intracoronary Adeno-Associated Virus Type 1 Vector Gene Transfer of SERCA2a in a Pre-Clinical Model of Heart Failure

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Hung Q Ly ◽  
Yoshiaki Kawase ◽  
Fabrice A Prunier ◽  
Djamel Lebeche ◽  
Yafen Shi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Left Ventricular ◽  
Internal Diameter ◽  
Adeno Associated Virus ◽  
Inotropic Effects ◽  
Clinical Model ◽  
Virus Serotype

Background: Reduced activity and expression of sarcoplasmic reticulum Ca 2+ ATPase (SERCA2a) is known to occur in HF. Method: Our 4-month study examined the effects of SERCA2a gene transfer in a swine volume-overload HF (VO-HF) model. Using Yorkshire-Landrace swine, HF was created by severing mitral apparatus chordae to induce mitral regurgitation. Results: At 2 months (M), a compensated state of VO-HF was found: prolongation of the rate of isovolumic relaxation (Tau), increased left ventricular internal diameter diastolic and systolic diameters (LVIDd, LVIDs). At 2M, intracoronary injection of adeno-associated virus serotype 1 vector carrying SERCA2a under a cytomegalovirus promoter (AAV1.SERCA2a) (n = 10) vs. saline (n = 6) was performed. At 4M, gene transfer resulted in (A) positive LV inotropic effects: (dP/dt)/P, 15.5 ± 3.0 sec − 1 SERCA2a-group vs. 21.2 ± 3.2 sec − 1 controls; p < 0.01; (B) a favorable trend in LV lusitropic effects: Tau, 0.037 ± 0.019 vs. 0.051 ± 0.01 msec, p = 0.09; (C) improvement in LV geometry: % change in LVIDs, +15 ± 11% controls vs. −3.0 ± 10% SERCA2a-group, p < 0.01. At 4M, BNP levels remained stable in post- SERCA2a gene transfer, in contrast to the progressive rising levels among controls. Further, cardiac SERCA2a expression was significantly decreased in controls whereas it was restored to normal levels in the SERCA2a group (Figure ). Lastly, there was no histopathological evidence of myocardial inflammatory reaction or necrosis. Conclusion: Overexpression of SERCA2a by in vivo AAV1-mediated intracoronary gene transfer preserved systolic function, potentially prevented diastolic dysfunction and improved ventricular remodeling.

scholarly journals Carotid Occlusion Accentuates Aortic Stenosis and Cardiac Remodeling With Preserved Systolic Function in LDL Receptor-Deficient Mice

2021 ◽  
Vol 11 ◽  
Author(s):  
Yandong Liu ◽  
Jiawei Cai ◽  
Lefeng Qu
Keyword(s):  
Aortic Stenosis ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Ldl Receptor ◽  
Left Ventricular ◽  
Carotid Occlusion ◽  
Plaque Burden ◽  
Control Group ◽  
Internal Diameter ◽  
And Function

Background: Carotid atherosclerotic disease is associated with aortic stenosis and reduced cardiac function. The causality between carotid and cardiac pathologies is unknown. We aim to explore the effects of carotid stenosis or occlusion on cardiac pathology and function.Methods and Results: We produced carotid obstruction or stenosis in 36 atherogenic mice with 150- or 300-μm tandem surgery or sham surgery. The structure and function of the heart were assessed by histology and animal ultrasound. The 150-μm group had larger plaque burden and thicker valve leaflets in the aortic root than did the control group. Also, the two surgery groups had a thicker left ventricular posterior wall and smaller internal diameter compared with controls. Increased myocardial fibrosis was also found in the 150-μm group compared with controls, although the surgery groups had preserved systolic function compared with that of controls.Conclusions: In a mouse model, carotid occlusion accentuated the formation of aortic stenosis and promoted ventricular remodeling without impairing systolic function. Carotid atherosclerotic plaque may be a pathogenic factor for aortic stenosis and ventricular remodeling.

Successful Gene Transfer Using Adeno-Associated Virus Vectors into the Kidney: Comparison among Adeno-Associated Virus Serotype 1–5 Vectors in vitro and in vivo

2004 ◽  
Vol 96 (4) ◽  
pp. e119-e126 ◽  
Author(s):  
Shin-ichi Takeda ◽  
Masafumi Takahashi ◽  
Hiroaki Mizukami ◽  
Eiji Kobayashi ◽  
Koichi Takeuchi ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Virus Vectors ◽  
Virus Serotype ◽  
Serotype 1

scholarly journals Targeted Modifications in Adeno-Associated Virus Serotype 8 Capsid Improves Its Hepatic Gene Transfer Efficiency In Vivo

2013 ◽  
Vol 24 (2) ◽  
pp. 104-116 ◽  
Author(s):  
Dwaipayan Sen ◽  
Rupali A Gadkari ◽  
Govindarajan Sudha ◽  
Nishanth Gabriel ◽  
Yesupatham Sathish Kumar ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Transfer Efficiency ◽  
Adeno Associated Virus ◽  
Gene Transfer Efficiency ◽  
Virus Serotype

The Pattern of Ventricular Remodeling Influences the Level of Oxidative Stress in Heart Failure Patients

2017 ◽  
Vol 68 (7) ◽  
pp. 1506-1511
Author(s):  
Cerasela Mihaela Goidescu ◽  
Anca Daniela Farcas ◽  
Florin Petru Anton ◽  
Luminita Animarie Vida Simiti
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Ventricular Remodeling ◽  
Clinical Laboratory ◽  
Left Ventricular ◽  
Control Group ◽  
Reactive Protein ◽  
Lv Mass ◽  
Few Data

Oxidative stress (OS) is increased in chronic diseases, including cardiovascular (CV), but there are few data on its effects on the heart and vessels. The isoprostanes (IsoP) are bioactive compounds, with 8-iso-PGF25a being the most representative in vivo marker of OS. They correlate with the severity of heart failure (HF), but because data regarding OS levels in different types of HF are scarce, our study was aimed to evaluate it by assessing the urinary levels of 8-iso-PGF2aand its correlations with various biomarkers and parameters. Our prospective study included 53 consecutive patients with HF secondary to ischemic heart disease or dilative cardiomyopathy, divided according to the type of HF (acute, chronic decompensated or chronic compensated HF). The control group included 13 hypertensive patients, effectively treated. They underwent clinical, laboratory - serum NT-proBNP, creatinine, uric acid, lipids, C reactive protein (CRP) and urinary 8-iso-PGF2a and echocardiographic assessment. HF patients, regardless the type of HF, had higher 8-iso-PGF2a than controls (267.32pg/�mol vs. 19.82pg/�mol, p[0.001). The IsoP level was directly correlated with ejection fraction (EF) (r=-0.31, p=0.01) and NT-proBNP level (r=0.29, p=0.019). The relative wall thickness (RWT) was negatively correlated with IsoP (r=-0.55, p[0.001). Also 8-iso-PGF25a was higher by 213.59pg/�mol in the eccentric left ventricular (LV) hypertrophy subgroup comparing with the concentric subgroup (p=0.014), and the subgroups with severe mitral regurgitation (MR) and moderate/severe pulmonary hypertension (PAH) had the highest 8-iso-PGF2a levels. Male sex, severe MR, moderate/severe PAH, high LV mass and low RWT values were predictive for high OS level in HF patients.Eccentric cardiac remodeling, MR severity and PAH severity are independent predictors of OS in HF patients.

Abstract 5553: Hypercholesterolemia Induced Overexpression of Caveolin-1 and LOX-1 Downregulates HO-1/HSP-90 Mediated e-NOS Activation: A Novel Therapeutic Strategy for the Improvement of Left Ventricular Function

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Suresh Varma Penumathsa ◽  
Srikanth Koneru ◽  
Gautam Maulik ◽  
Nilanjana Maulik
Keyword(s):  
Ventricular Remodeling ◽  
Oxidized Ldl ◽  
Immunohistochemical Analysis ◽  
Left Ventricular ◽  
Normal Diet ◽  
High Cholesterol Diet ◽  
Internal Diameter ◽  
Over Expression ◽  
Caveolin 1 ◽  
Hsp 90

Hypercholesterolemia (HC) related decrease in eNOS phosphorylation & endothelial dysfunction may account for impaired angiogenesis and subsequent increased ventricular remodeling. Over expression of Caveolin-1 (Cav-1) and Lectin-like oxidized LDL receptor (LOX-1) has been demonstrated during HC but the mechanism needs to be elucidated. To investigate this we randomized the rats into control (normal diet) and HC (5% high cholesterol diet for 8 weeks). The cholesterol, triglycerides & LDL levels were increased & the HDL levels decreased in HC compared to control. After the experimental diet period the rats were subjected to Left Anterior Descending Artery (LAD) ligation. We evaluated the expression of Cav-1, LOX-1, Heme Oxygenase (HO-1), HSP-90, phospho(p)-Akt & p-eNOS in HC and control. Significant increase in Cav-1, LOX-1 (2, 1.8 fold) & decrease in HO-1, HSP-90, p-Akt, p-eNOS & VEGF (0.5, 0.6, 0.4, 0.5 & 0.6 fold) was observed in HC compared to control. The LV functional reserve was evaluated by measuring the ejection fraction (EF), fractional shortening (FS) & LV internal diameter (LVID) after 30 days of LAD ligation. Significant increase in LVID ( 8.6 vs 7) and decrease in EF (39 vs 53%), FS (20 vs 28%), LVID (2 vs 2.7mm) as well as capillary (1888 vs 2424) & arteriolar density (1.5 vs 2.5) counts/mm2 was observed in HC compared to control. Earlier we have reported that over expression of HO-1 mediates eNOS activation & cardioprotection in MI model. To investigate the mechanism involved in HO-1 mediated cardioprotection we generated cardiac specific HO-1 over expressed transgenic (Tg) mice. Immunohistochemical analysis of HO-1 Tg mice has clearly demonstrated decreased Cav-1-eNOS interaction. Immunoblot analysis has shown to decrease Cav-1 (0.6 fold) & increased HSP-90, p-Akt, p-eNOS & VEGF expression (1.5, 1.6, 1.4 & 1.5 fold) as compared to control. These findings demonstrated that HO-1 over expression regulates HSP-90 & Cav-1 for eNOS activation. In conclusion, we demonstrate a novel mechanism of HO-1/HSP-90 mediated Cav-1-eNOS regulation leading to increased neovascularization & reduced ventricular remodeling during HC for the regression of clinical complications which would be crucial for cardiovascular drug therapy.

Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts

1990 ◽  
Vol 259 (4) ◽  
pp. H1086-H1096 ◽  
Author(s):  
J. M. Capasso ◽  
T. Palackal ◽  
G. Olivetti ◽  
P. Anversa
Keyword(s):  
Ventricular Remodeling ◽  
Volume Fraction ◽  
Diastolic Pressure ◽  
Structural Characteristics ◽  
Myocardial Dysfunction ◽  
Pressure Rise ◽  
Wall Stress ◽  
Left Ventricular ◽  
Cross Sectional

To determine if aging engenders alterations in the functional properties of the myocardium and ventricular remodeling, the hemodynamic performance and structural characteristics of the left ventricle of male Fischer 344 rats at 4, 12, 20, and 29 mo of age were studied by quantitative physiology and morphology. In vivo assessment of cardiac pump function showed no change up to 20 mo, whereas left ventricular end-diastolic pressure was increased at 29 mo. Moreover, peak rates of pressure rise and decay, stroke volume, ejection fraction, and cardiac output were depressed at the later age interval, demonstrating the presence of ventricular failure at this time. The measurements of chamber size and wall thickness showed that ventricular end-diastolic and end-systolic volumes progressively increased with age with the greatest change occurring at 20-29 mo. Aging was also accompanied by a marked augmentation in the volume fraction of fibrotic areas in the ventricular myocardium that was due to an increase in their number and cross-sectional area with time. These architectural rearrangements, in combination with the abnormalities in ventricular function, resulted in an elevation in the volume of wall stress throughout the cardiac cycle. Wall stress increased by 64, 44, and 50% from 4 to 12, 12 to 20, and 20 to 29 mo of age. In conclusion, aging leads to a continuous rise in wall stress that is not normalized by ventricular remodeling. These two independent processes appear to be responsible for the onset of heart failure in the senescent rat.

Inotropic effects of ejection are myocardial properties

1994 ◽  
Vol 266 (3) ◽  
pp. H1202-H1213 ◽  
Author(s):  
P. P. De Tombe ◽  
W. C. Little
Keyword(s):  
Systolic Pressure ◽  
Left Ventricular ◽  
Negative Effects ◽  
Inotropic Effects ◽  
Contraction Duration ◽  
Loading System ◽  
Positive Effect ◽  
Isolated Rat

Recent studies in isolated and in vivo canine hearts have suggested that the left ventricular end-systolic pressure (LVPes) of ejecting beats is the net result of a balance between positive and negative effects of ejection. At present, it is unknown whether these ejection effects are merely a ventricular chamber property or represent a fundamental myocardial property. Accordingly, we examined the effects of ejection in eight isolated rat cardiac trabeculae at the sarcomere level. We approximated in situ sarcomere shortening patterns using an iterative computer loading system. Six isovolumic contractions were compared with four ejecting contractions. The superfusing solution contained either 0.7 mM Ca2+ or 0.65 mM Sr2+ plus 0.15 mM Ca2+. With Ca2+, simulated LVPes ("LVP"es) of ejecting contractions was significantly lower than isovolumic "LVP"es (-5.3 +/- 5.6%), whereas with Sr2+, ejecting "LVP"es was significantly higher than isovolumic "LVP"es (+4.5 +/- 7.5%). Contraction duration and time to end systole were markedly prolonged in ejecting vs. isovolumic contractions with either Ca2+ or Sr2+. As a consequence, comparison of simulated LVP between ejecting and isovolumic beats throughout the contraction, i.e., at the same simulated LVV and time, revealed only a positive effect of ejection with either Ca2+ (+18.8 +/- 5.5%) or Sr2+ (+23.4 +/-9.3%). We conclude that both positive and negative effects of ejection are basic myocardial properties.

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