Cardiomyopathic Syrian Hamster Research Articles

Modulation of Vascular ACE by Oxidative Stress in Young Syrian Cardiomyopathic Hamsters: Therapeutic Implications.

Increased vascular angiotensin-converting enzyme (ACE) activity and oxidative stress are present in young Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of heart failure (HF). The developmental time-course of these alterations and their potential interactions, however, are still unknown. We evaluated mRNA and protein levels of ACE, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) in the vasculature of SCH from one to four months of age. Total RNA and proteins were quantified with real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The role of nitric oxide (NO) on vascular ACE activity was also assessed. ACE mRNA and protein levels were up-regulated in SCH at two months of age compared with controls (CT) (p < 0.05). At this two-month stage, eNOS protein levels were lower in SCH (87%) than in CT (100%) (p < 0.05), although iNOS protein levels increased significantly (482%) compared to CT (100%; p < 0.05). In addition, ACE mRNA expression and activity were modulated by NO at two months of age. Thus, the combination of low eNOS and high iNOS protein levels may underlie vascular renin-angiotensin system (RAS) over-activation. Altogether, these factors may contribute to the development of endothelial dysfunction and vascular hyper-reactivity in the early stages of heart failure, and eventually trigger cardiac deterioration in this animal model of HF.

Complete mitochondrial genome sequence of the heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus)

In this study we sequenced the complete mitochondrial genome sequencing of a heart failure model of cardiomyopathic Syrian hamster (Mesocricetus auratus) for the first time. The total length of the mitogenome was 16,267 bp. It harbored 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and 1 non-coding control region.

ACE and iNOS overexpression correlates with vascular reactivity in young Syrian cardiomyopathic hamsters (1075.7)

Vascular alterations are present in 2‐month‐old Syrian cardiomyopathic hamsters (SCH) before the clinical manifestation of HF. Aortic ACE, eNOS, and iNOS mRNA and protein levels were assessed in SCH from 1 to 4 months of age to elucidate the timeframe and the mechanisms underlying these alterations. Total RNA and proteins were extracted from aortas, and quantified with Real‐Time RT‐PCR and Western blot. ACE mRNA and protein were upregulated in 2‐month‐old SCH by 41% and 43%, respectively, when compared to control (CT; P&lt;0.05). Protein levels of iNOS were higher in SCH (482%) than in CT (100%) at 2 months of age. In addition, eNOS mRNA increased by 77% in SCH, whereas eNOS protein levels were 15% lower in SCH than in CT (P&lt;0.05). These findings suggest that the vascular reactivity present in 2‐month‐old SCH is secondary to overactivation of RAS resulting from increased levels of ACE mRNA and protein. A combination of lower eNOS and higher iNOS protein levels may underlie endothelial dysfunction present in SCH at this stage. Altogether, these factors will likely promote vascular hyper‐reactivity in the early stages of heart failure in SCH and eventually trigger cardiac deterioration.Grant Funding Source: Supported by MBRS‐RISE R25‐GM061838

Genetic variation at the delta‐sarcoglycan (SGCD) locus elevates heritable sympathetic nerve activity in human twin pairs

The Syrian Cardiomyopathic Hamster (BIO-14.6/53.58 strains) model of cardiac failure, resulting from naturally occurring deletion at the SGCD (delta-sarcoglycan) locus, displays widespread disturbances in catecholamine metabolism. Rare Mendelian myopathy disorders of human SGCD occur, although common naturally occurring SGCD genetic variation has not been evaluated for effects on human norepinephrine (NE) secretion. This study investigated the effect of SGCD genetic variation on control of NE secretion in healthy twin pairs. Genetic associations profiled SNPs across the SGCD locus. Trait heritability (h(2)) and genetic covariance (pleiotropy; shared h(2)) were evaluated. Sympathochromaffin exocytosis in vivo was probed in plasma by both catecholamines and Chromogranin B (CHGB). Plasma NE is substantially heritable (p = 3.19E-16, at 65.2 ± 5.0% of trait variance), sharing significant (p < 0.05) genetic determination with circulating and urinary catecholamines, CHGB, eGFR, and several cardio-metabolic traits. Participants with higher pNE showed significant (p < 0.05) differences in several traits, including increased BP and hypertension risk factors. Peak SGCD variant rs1835919 predicted elevated systemic vascular compliance, without changes in specifically myocardial traits. We used a chimeric-regulated secretory pathway photoprotein (CHGA-EAP) to evaluate the effect of SGCD on the exocytotic pathway in transfected PC12 cells; in transfected cells, expression of SGCD augmented CHGA trafficking into the exocytotic regulated secretory pathway. Thus, our investigation determined human NE secretion to be a highly heritable trait, influenced by common genetic variation within the SGCD locus. Circulating NE aggregates with BP and hypertension risk factors. In addition, coordinate NE and CHGB elevation by rs1835919 implicates exocytosis as the mechanism of release.

Increased ACE Expression and iNOS Protein Levels in the Aorta of 2‐month‐old Syrian Cardiomyopathic Hamsters

Endothelial dysfunction, increased ACE activity, and oxidative stress are present in 2‐month‐old Syrian cardiomyopathic hamsters (SCH) before the clinical manifestations of heart failure. To evaluate the mechanisms underlying vascular alterations at this early stage, we assessed RNA expression and protein levels of ACE, eNOS and iNOS in aortic tissue of SCH and age matched controls (CT). RNA expression was quantified with Real‐Time RT‐PCR and protein levels with Western blot. ACE RNA expression and protein levels were higher in SCH than in CT (141 % and 1.54 AU vs. 100% and 0.030 AU respectively, P&lt;0.05). eNOS RNA was four‐fold higher in SCH than in CT (P&lt;0.05), although no changes in protein levels were found. In contrast, iNOS RNA expression was significantly lower in SCH (38%) than in CT (100%), whereas protein levels were higher in SCH (0.416 AU) than in CT (0.155 AU)(N=6, P&lt;0.05). Our results suggest that overactivation of vascular ACE combined with increased iNOS protein content are crucial in the etiology of the vascular abnormalities that precede cardiac dysfunction in young SCH. Supported by MBRS‐RISE R25‐GM061838.

Effect of RAS inhibition on ACE activity in Plasma, Kidney and the Heart of Syrian Cardiomyopathic Hamster.

Previous studies of RAS inhibition in Syrian cardiomyopathic hamsters (SCH) using the renin inhibitor aliskiren (10 mg/kg/day) suggested that the kidney at variance with the heart, is resistant to renin inhibition. RAS inhibition induces compensatory increases in ACE activity in target tissues. Thus, we hypothesized that ACE in kidney homogenates, is relatively insensitive to treatment with aliskiren in contrast to those from heart and plasma. To test this hypothesis, ACE activity was determined in plasma, heart and kidney homogenates, from 6‐month‐old SCH treated over 5 months with aliskiren, valsartan (AT1receptor blocker), and these drugs in combination. Age‐matched golden hamsters were used as controls (CT). ACE activity was determined, using a fluorimetric assay. Compared to CT, basal ACE activity in SCH is higher in the kidney, heart and plasma by 12% (P&lt;0.05), 93% (P&lt;0.05) and 12% (P&lt;0.05), respectively. Neither aliskiren nor valsartan changed ACE activity in the heart, kidney or plasma of SCH. The combination of these drugs however, increase ACE activity only in SCH hearts (30%, P&lt;0.05). These results suggest that the differential ACE activity that occurs in the heart, kidney, and plasma of SCH after RAS suppression may explain the observed differences in organ protection in this animal model. The reason for these differential effects of aliskiren is unknown. Supported by MBRS‐RISE R25‐GM061838.

Aliskiren Improves Left Ventricular Dysfunction and Reduces Cardiac Dilation in Syrian Cardiomyopathic Hamsters

Chronic activation of the renin-angiotensin-aldosterone system is a major contributing factor to the pathogenesis and progression of cardiovascular and renal diseases. To evaluate the role of renin-angiotensin-aldosterone system blockade with aliskiren, a direct renin inhibitor, in the development and progression of dilated cardiomyopathy in the Syrian cardiomyopathic hamster (SCH) model, we treated 1-month-old SCH with aliskiren (10 mg·kg·d) over a 4-month period. For comparative purposes, we also evaluated the effects of the angiotensin receptor blocker valsartan (10 mg·kg·d) and the combination of both drugs. Age-matched golden hamsters were used as controls. Left ventricular end-diastolic volume and end-systolic volume, ejection fraction, and diastolic function were determined by echocardiography. Systolic blood pressure (SBP) was also measured in the left femoral artery by sphygmomanometry. Results indicate that at 2 months of age, SBP is higher in SCH than in controls, and administration for 1 month of aliskiren, valsartan, or the combination of these drugs normalized SBP in SCH to a similar extent. In 5-month-old SCH, aliskiren improved ejection fraction (from 48.6% ± 5.8% to 69.4% ± 3.2%, n = 5, P < 0.05), left ventricular end-systolic volume (from 0.28 ± 0.06 to 0.10 ± 0.01 mL/100 g body weight), left ventricular end-diastolic volume (from 0.61 ± 0.05 to 0.34 ± 0.02 mL/100 g body weight), and normalized diastolic function (E:A ratio increases from 0.93 ± 0.13 to 1.70 ± 0.03, n = 5, P < 0.05). Similar results were observed with valsartan or the combination of aliskiren and valsartan. Our results indicate that in this animal model, aliskiren is as effective as valsartan, or the combination of both drugs, in improving diastolic function and in preventing the development of dilated cardiomyopathy. These findings suggest that aliskiren may be used as a monotherapy in heart failure management. Clinical studies, however, are needed to assess the effectiveness of this drug in patients with heart failure.

Developmental Time‐course of Vascular RNA Expression and Protein Levels for ACE, eNOS and iNOS in Young Syrian Cardiomyopathic Hamsters

Endothelial dysfunction, increased oxidative stress, and alterations in the renin‐angiotensin system (RAS) are present in 2‐month‐old Syrian cardiomyopathic hamsters (SCH). To evaluate the developmental time‐course of these alterations, we assessed the protein levels and RNA expression of ACE, eNOS and iNOS in the vasculature of SCH from 1 to 4 months of age. Age‐matched golden hamsters were used as controls (CT). Total RNA and protein were extracted from aortic tissue. RNA expression was quantified with Real‐Time RT‐PCR, and protein levels were determined with Western blot. We found that ACE RNA was upregulated in 2‐month‐old SCH (from 38.85% to 141.18 %, P&lt;0.05), when compared with 1‐month‐old SCH, and reached a plateau at 4 months. ACE protein levels were higher at 2‐months (1.54 arbritrary units; AU) than at 1 month (0.98 AU) and 4 months (.79 AU). In addition, eNOS RNA increased significantly in SCH from 1 to 4 months (from 49 % to 273%; P&lt;0.05), but eNOS protein levels decreased after 1 month (1.06 AU), reaching its minimum at 2 months (0.34 AU, P&lt;0.05). Vascular iNOS RNA and protein levels, by contrast, remained unchanged in SCH from 1 to 4 months. These results suggest that the increased ACE RNA and protein levels, together with the decreased eNOS protein content observed at 2 months, may be involved in the etiology of endothelial dysfunction that is present in 2‐month‐old SCH. Supported by MBRS‐RISE R25‐GM061838.

Elevated O‐GlcNAcylation of ATP synthase β subunits in cardiomyopathic hearts in Syrian hamsters

In recent years, the posttranslational modification of serine and threonine residues of heart proteins by O‐linked attachment of the monosaccharide β‐N‐acetylglucosamine (O‐GlcNAc) has received a lot of attention as a key regulator in the cardiovascular function. To study the possible involvement of the O‐GlcNAcylation in the cardiomyopathy, we examined the O‐GlcNAcylation status of ventricular proteins from both normal (J2N‐n strain) and cardiomyopathic (J2N‐k strain) Syrian hamsters. Soluble fractions of heart proteins were extracted from left ventricles of both strains using a ReadyPrep sequential extraction kit (Bio‐Rad). Western blot analysis of the soluble fractions with a mouse monoclonal antibody against O‐GlcNAc (clone CTD110.6) indicated one J2N‐k specific band (~52 kDa). After isolation by monoclonal antibody columns and SDS‐PAGE, the band was suggested to be an ATP synthase β subunit (ATP5B) by mass spectrometry. These results suggest that the energy production machinery is modulated by O‐GlcNAcylation in the cardiomyopathy. This work was supported by a grant from the Ministry of Health, Labor, and Welfare of Japan.

Vascular eNOS and iNOS Expression is Altered in Young Syrian Cardiomyopathic Hamsters

Vascular eNOS and iNOS Expression is Altered in Young Syrian Cardiomyopathic Hamsters

Chronic Treatment With N-acetylcysteine Improves Cardiac Function but Does Not Prevent Progression of Cardiomyopathy in Syrian Cardiomyopathic Hamsters

Oxidative stress has been postulated to contribute to the onset and development of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N-acetylcysteine (NAC, 1 g/kg per day) on cardiovascular function in 2- and 6-month-old Bio-TO2 Syrian cardiomyopathic hamsters (SCH) after treatment for 1 month and 5 months with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. Age-matched F1-B golden hamsters were used as controls. One month of NAC administration significantly decreased SBP in 2-month-old SCH (n = 5, P < 0.001) without modifying echocardiographic values. Five-month treatment of cardiomyopathic animals with the antioxidant improved the acetylcholine-induced relaxation in aortic rings by 24% (E( Max) value from 45.8% ± 4% to 55.3% ± 2% n = 7, P < .05) but did not modify EC(50) values for the acetylcholine concentration-response curve. In addition, 5-month administration of NAC to SCH increased ejection fraction from 39% ± 4% to 57% ± 4% (n = 11, P < .001) and decreased left ventricular end-diastolic and end-systolic volumes (from 0.38 ± 0.04 mL/100 g body weight (BW) and 0.22 ± 0.03 mL/100 g BW, before, to 0.24 ± 0.04 mL/100 g BW and 0.12 ± 0.03 mL/100 g BW after treatment, P < .01). Cardiac output index also improved after 5 months of treatment, although it did not reach statistical significance. These results suggest that antioxidant therapy alone decreases ventricular dilatation and improves cardiovascular function in this animal model of dilated cardiomyopathy, but it does not prevent the appearance of HF.

Enhancement of shortening velocity, power, and acto‐myosin crossbridge (CB) kinetics following long‐term treatment with propionyl‐L‐carnitine, coenzyme Q10, and omega‐3 fatty acids in BIO TO‐2 cardiomyopathic Syrian hamsters papillary muscle

Impaired functions of myocardial muscle cells in human and animals, is a primary defect associated with idiopathic dilated cardiomyopathy (DCM). The pathophysiological mechanisms implicated in the DCM are yet to be clarified and an effective therapy is still not available. The BIO TO-2 cardiomyopathic Syrian Hamsters (CMSHs) represent an animal model of idiopathic DCM. The aim of this study was to investigate the effect of long-term treatment (2 months) with propionyl-L-carnitine (PLC), coenzyme Q(10), omega-3 fatty acids and a combination of these three agents (formulation HS12607) on mechanical properties and acto-myosin crossbridges (CBs) kinetics of left ventricular (LV) papillary muscle from control and treated 10 month old BIO TO-2 CMSHs. Isometric and isotonic contractile properties of isolated papillary muscle from control and treated CMSHs were investigated, and acto-myosin CB number, force and kinetics were calculated using Huxley's equations. Mechanical parameter values were higher in treated than in control hamsters, particularly when substances were administered together in a coformulation (HS12607). Compared to control, HS12607-treated papillary muscles showed a significant increase of maximum peak isometric tension (P(o)) (30.06 +/- 4.91 vs. 19.74 +/- 5.00 mN/mm(2)), maximum extent of muscle shortening (0.13 +/- 0.03 vs. 0.07 +/- 0.02 L/L(max)), maximum unloaded shortening velocity (1.18 +/- 0.24 vs. 0.53 +/- 0.13 L/L(max) s(-1)) and maximum peak of power output (5.52 +/- 1.61 vs. 1.58 +/- 0.83). The curvature of the hyperbolic force-velocity relationships did not differ between control and treated hamsters. When compared to controls, acto-myosin CB number increased in treated hamsters [(6.67 +/- 1.91) 10(10)/mm(2) vs. (3.55 +/- 2.08) 10(10)/mm(2)], whereas the unitary force of single CB was similar in control and treated animals. The peak value of the rate constant for CB attachment (f(1)) and detachment (g(2)) was higher in treated animals when compared to control. (93.87 +/- 25.82 vs.47.28 +/- 10.88 s(-1) and 214.40 +/- 44.64 vs. 95.56 +/- 23.49 s(-1), respectively). In conclusion, the present study illustrates that supplementation with PLC, CoQ(10) and omega-3 fatty acids improved motor parameters, energetic, and CB kinetics of BIO TO-2 CMSH papillary muscle indicating that these naturally occurring substances may be a valid adjuvant to conventional therapy in DCM.

Vascular ACE and eNOS Expression in Syrian Cardiomyopathic Hamsters

Angiotensin Converting Enzyme (ACE) and endothelial Nitric Oxide Synthase (eNOS) have been implicated in the pathophysiology of heart failure. We evaluated the time‐course expression of ACE and eNOS in aortic tissue from 1‐ to 4‐month‐old Syrian cardiomyopathic hamsters (SCH) to correlate these variables with vascular status. The expression of both genes in 2‐month‐old SCH after one month of treatment with the antioxidant N‐acetylcysteine (NAC, 1g/kg/d) and the β‐blocker‐antioxidant carvedilol (1mg/kg/d) was also evaluated. Age‐matched golden hamsters were used as controls (CT). Total RNA was extracted and gene expression was quantified by Real‐Time RT‐PCR. Our results showed up‐regulation in ACE (1.5 fold) and eNOS (4‐fold) expression in 2‐month‐old SCH when compared to 1‐, 3‐ and 4‐month‐old SCH and to CT. In 2‐month‐old SCH, carvedilol down‐regulated eNOS and ACE gene expressions, whereas NAC down‐regulated eNOS expression without modifying ACE expression. These results suggest that the improvements in CV function observed previously in SCH after early administration of NAC or carvedilol may involve modifications in the expression of ACE and eNOS genes. Supported by NIH‐SCORE S06‐RR 08224.

Cerebral Malaria: A Vasculopathy

Cerebral Malaria: A Vasculopathy

Circadian Body Temperature Variability is an Indicator of Poor Prognosis in Cardiomyopathic Hamsters

BackgroundLow body temperature is an independent predictor of poor prognosis in patients with congestive heart failure. The cardiomyopathic hamster develops progressive biventricular dysfunction, resulting in heart failure death at 9 months to 1 year of life. Our goal was to use cardiomyopathic hamsters to examine the relationship between body temperature and heart failure decompensation and death. Methods and ResultsTo this end, we implanted temperature and activity transducers with telemetry into the peritoneal space of 46 male Bio-TO-2 Syrian cardiomyopathic hamsters. Multiple techniques, including computing mean temperature, frequency domain analysis, and nonlinear analysis, were used to determine the most useful method for predicting poor prognosis. Data from 44 hamsters were included in our final analysis. We detected a decline in core body temperature in 98% of the hamsters 8±4 days before death (P < .001). We examined the dominant frequency of temperature variation (ie, the circadian rhythm) by using cosinor analysis, which revealed a significant decrease in the amplitude of the body temperature circadian rhythm 8 weeks before death (0.28°C; 95% CI, 0.26-0.31) compared to baseline (0.36°C; 95% CI, 0.34-0.39; P=.005). The decline in the circadian temperature variation preceded all other evidence of decompensation. ConclusionsWe conclude that a decrease in the amplitude of the body temperature circadian rhythm precedes fatal decompensation in cardiomyopathic hamsters. Continuous temperature monitoring may be useful in predicting preclinical decompensation in patients with heart failure and in identifying opportunities for therapeutic intervention.

Influence of Enalapril Therapy Schedule on the Progression of the Disease in Dilated Cardiomyopathic Syrian Hamsters (Bio TO-2 strain)

The influence of enalapril therapy schedule on the progression of the disease in terms of hemodynamics, cardiac remodeling and survival was assessed in cardiomyopathic Syrian hamsters (CMHs). CMHs (Bio TO-2 dilated strain) were treated orally with enalapril at 20 mg/kg/day from 60 to 200 (early treatment), from 120 to 200 (late treatment) or 120 to 250 (prolonged treatment) days of age. In survival studies, CMHs were treated until 90% of controls are death. Early, late and prolonged treatments significantly decreased mean arterial blood pressure (-23%, -27% and -22%, respectively), but had no effects on cardiac output and stroke volume. Late and prolonged treatments significantly decreased total peripheral resistance (-38% and -24%, respectively), but not early treatment. Only, prolonged treatment significantly decreased left ventricle (LV) end diastolic blood pressure (-60%). Early, late and prolonged treatments significantly decreased LV collagen density (-44%, -31% and -54%, respectively) and LV cavity area (-26%, -21% and -29%, respectively). Survival was significantly improved when enalapril was administered from 120 days of age, but not significantly when administered earlier. In conclusion, enalapril exerted beneficial effects (improvement of cardiac function and prolonged survival) more marked when the treatment was begun late in the evolution of congestive heart failure.

Hemodynamic Alterations in the Coronary Circulation of Cardiomyopathic Hamsters: Age and Ang II–dependent Mechanisms

Background Coronary vasospasms have been reported in the early stages of cardiomyopathy in the Syrian cardiomyopathic hamster (CM; BIO-TO2 strain). It has been proposed these alterations could lead to ischemic heart disease and heart failure. However, the cause of these coronary abnormalities has not been established. In this study, we evaluated coronary hemodynamic to assess the role of Ang-II, reactive oxygen species, and nitric oxide (NO) in the development of these alterations in CM of 1, 2, and 6 months of age. Methods and Results Excised hearts from control (CT) and CM were retroperfused with Krebs-Ringer bicarbonate solution (KRB), and coronary resistance (CR) was determined. The experimental protocol involved sequential infusions of the thromboxane analog U46619 (THX, 0.1 μmol/L), bradykinin (BKN, 10 μmol/L), and sodium nitroprusside (SNP, 10 μmol/L). Similar experiments were conducted after treatment of hearts with N ω -nitro-L-arginine methyl ester (L-NAME, 10 μmol/L). Basal CR increased with age, but no significant differences were observed between CT and CM. Reactivity to THX was increased (69%, P < .05) in 2-month-old CM when compared with CT. This effect was observed concomitantly with a significant reduction (53%, P < .05) in BKN-induced relaxation. The reduction in BKN-dependent relaxation was prevented by treatment for 1 month with the antioxidant N-acetylcysteine (1 g·kg·day), or losartan, an Ang II type 1 receptor blocker (10 mg·kg·day). Losartan also prevented the THX-induced increased reactivity in 2-month-old CM. The BKN-induced relaxation occurred through an L-NAME–sensitive pathway that was impaired with age. SNP dilation was preserved in all animal groups. Conclusions Our results strongly implicate vascular renin-angiotensin-system (RAS) and oxidative stress in endothelial dysfunction and increased reactivity in the early stages of cardiomyopathy in CM. These findings could be relevant to understand the etiology of cardiovascular disorders, in particular, in patients with sarcoglycanopathies.

Ex vivo diffusion tensor MRI reflects microscopic structural remodeling associated with aging and disease progression in normal and cardiomyopathic Syrian hamsters

Dilated cardiomyopathy (DCM) is a major cause of mortality and morbidity in cardiac patients. Aging is often an ignored etiology of pathological conditions. Quantification of DCM and aging associated cardiac structural remodeling is important in guiding and evaluating therapeutic interventions. Diffusion tensor magnetic resonance imaging (DTMRI) has recently been used for nondestructive characterization of three-dimensional myofiber structure. In this study, we explored the potential of DTMRI in delineating microscopic structural remodeling in aging and DCM hearts. Six month (n = 10) and nine month old (n = 11) DCM (TO-2) hamsters and their age-matched controls (F1 beta) were characterized. Both aging and DCM hearts showed increased diffusivity and decreased diffusion anisotropy. DTMRI images of DCM hearts also revealed a subgroup of imaging pixels characterized by decreased radial diffusivity and increased FA. The location of these pixels showed qualitative agreement with regions of calcium deposition determined by X-ray CT imaging. Histological analysis confirmed expanded extracellular space in aging and DCM hearts as well as substantial calcium deposition in DCM hearts. These results suggest that DTMRI may provide a noninvasive technique to delineate structural remodeling associated with aging and DCM progression at the tissue and cellular level without the use of an exogenous contrast agent.

N‐acetylcysteine (NAC) Improves but does not Prevent the Appearance of Heart Failure in Syrian Cardiomyopathic Hamsters.

Oxidative stress has been postulated to contribute to the etiology of heart failure (HF). The efficacy of antioxidant therapy in HF, however, remains controversial. This study evaluates the effect of the antioxidant N‐acetylcysteine (NAC, 1g/kg/day) on cardiovascular function in 2‐ and 6‐month‐old Bio‐TO2 Syrian cardiomyopathic hamsters (SCH) after 1‐month and 5‐month treatment with this drug. Endothelial function, systolic blood pressure (SBP), and echocardiographic parameters were evaluated. One month of NAC administration normalized the increased SBP observed in 2‐month‐old SCH (n=5, P&lt;0.05). Five‐month treatment with NAC, improved 24% (P&lt;0.05) the EMax value from the Ach‐induced relaxation (from 45.8± 4 % to 56.1 ± 2 % n= 7) while did not modify EC50 or SBP. Ejection fraction increased 39±4 % (n=11, P&lt;0.05) and cardiac output index improved but did not reach statistical significance. In addition, LVEDV and LVESV were significantly reduced by NAC (P&lt;0.05), These results suggest that antioxidant therapy alone improves cardiovascular function in this animal model of dilated cardiomyopathy. The treatment, however, does not prevent the appearance of HF. Supported by NIH‐SCORE S06‐RR 08224.

Cardiomyopathic Syrian Hamster as a Model of Congestive Heart Failure

Cardiomyopathic Syrian hamsters (Bio TO-2 dilated strain) constitute an animal model of congestive heart failure, which progressively develops an alteration of cardiac function leading to decreased arterial blood pressure and musculo-cutaneous blood flow associated with a complex process of cardiac remodeling including left ventricle dilation, wall thinning, and greater collagen density. The protocols described in this unit are designed to assess the pharmacological effects of new therapeutic strategies on cardiac and systemic hemodynamics, morphometry (body and target organs weight), cardiac remodeling (left ventricle dilation and collagen density), and survival in this model of dilated cardiomyopathy. Examples of results obtained with enalapril, an angiotensin I converting enzyme inhibitor, are provided for illustrative purposes.