Experimental Dilated Cardiomyopathy Research Articles

Knockdown of HDAC6 alleviates ventricular remodeling in experimental dilated cardiomyopathy via inhibition of NLRP3 inflammasome activation and promotion of cardiomyocyte autophagy.

Histone deacetylases (HDACs) has been implicated in cardiac diseases, while the role of HDAC6 in dilated cardiomyopathy (DCM) remains obscure. The in silico analyses predicted potential association of HDAC6 with autophagy-related genes and DCM. Thus, we evaluated the functional relevance of HDAC6 in DCM in vivo and in vitro. We developed a rat model in vivo and a cell model in vitro by doxorubicin (DOX) induction to simulate DCM. HDAC6 expression was determined in myocardial tissues of DCM rats. DCM rats exhibited elevated HDAC6 mRNA and protein expression as compared to sham-operated rats. We knocked HDAC6 down and/or overexpressed NLRP3 in vivo and in vitro to characterize their roles in cardiomyocyte autophagy. It was established that shRNA-mediated HDAC6 silencing augmented cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation, thus ameliorating cardiac injury in myocardial tissues of DCM rats. Besides, in DOX-injured cardiomyocytes, HDAC6 silencing also diminished NLRP3 inflammasome activation and cell apoptosis but enhanced cell autophagy, whereas ectopic NLRP3 expression negated the effects of HDAC6 silencing. Since HDAC6 knockdown correlates with enhanced cardiomyocyte autophagy and suppressed NLRP3 inflammasome activation through an interplay with NLRP3, it is expected to be a potential biomarker and therapeutic target for DCM. 1. HDAC6 was up-regulated in DCM rats. 2. HDAC6 knockdown promoted cardiomyocyte autophagy to relieve cardiac dysfunction. 3. HDAC6 knockdown inhibited NLRP3 inflammasome and promoted cardiomyocyte autophagy. 4. Silencing HDAC6 promoted autophagy and repressed apoptosis in cardiomyocytes. 5. This study provides novel therapeutic targets for DCM.

A Low-Sodium Diet Boosts Ang (1-7) Production and NO-cGMP Bioavailability to Reduce Edema and Enhance Survival in Experimental Heart Failure.

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1–7) levels, promoting nitric oxide bioavailability and stimulating 3′-5′-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1–7) levels, nitric oxide bioavailability and cGMP production.

Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

BackgroundAutophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).MethodsWe explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.ResultsAutophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82% vs 14.38 ± 1.24%, P < 0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48% vs 45.29 ± 6.68%, P < 0.01; 26.89 ± 4.04% vs 22.17 ± 2.82%, P < 0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.ConclusionsThe study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

Cardiac-Specific Overexpression of Catalytically Inactive Corin Reduces Edema, Contractile Dysfunction, and Death in Mice with Dilated Cardiomyopathy.

Humans with dilated cardiomyopathy (DCM) and heart failure (HF) develop low levels of corin, a multi-domain, cardiac-selective serine protease involved in natriuretic peptide cleavage and sodium and water regulation. However, experimental restoration of corin levels markedly attenuates HF progression. To determine whether the beneficial effects of corin in HF require catalytic activity, we engineered cardiac overexpression of an enzymatically inactive corin transgene (corin-Tg(i)). On a wild-type (WT) background, corin-Tg(i) had no evident phenotypic effects. However, in a well-established genetic model of DCM, corin-Tg(i)/DCM mice had increased survival (p < 0.01 to 0.001) vs. littermate corin-WT/DCM controls. Pleural effusion (p < 0.01), lung edema (p < 0.05), systemic extracellular free water (p < 0.01), and heart weight were decreased (p < 0.01) in corin-Tg(i)/DCM vs. corin-WT/DCM mice. Cardiac ejection fraction and fractional shortening improved (p < 0.01), while ventricular dilation decreased (p < 0.0001) in corin-Tg(i)/DCM mice. Plasma atrial natriuretic peptide, cyclic guanosine monophosphate, and neprilysin were significantly decreased. Cardiac phosphorylated glycogen synthase kinase-3β (pSer9-GSK3β) levels were increased in corin(i)-Tg/DCM mice (p < 0.01). In summary, catalytically inactive corin-Tg(i) decreased fluid retention, improved contractile function, decreased HF biomarkers, and diminished cardiac GSK3β activity. Thus, the protective effects of cardiac corin on HF progression and survival in experimental DCM do not require the serine protease activity of the molecule.

Abstract 16743: Targeting Renin Activity in Heart Failure: Precision Therapy With Aliskiren Improves Systolic Function and Prolongs Survival in Female Experimental Dilated Cardiomyopathy

Introduction: Patients with heart failure (HF) are treated according to general therapy guidelines, without precise consideration for the individual’s sex and biomarker profile. Renin activation has been implicated in the pathophysiology of HF progression, but studies of the direct renin inhibitor aliskiren in general HF patients have not shown benefits. Mice with experimental dilated cardiomyopathy (DCM) develop progressive HF with reduced ejection fraction that progresses through all stages (A-D) of human HF. Female DCM mice specifically show an elevation of plasma renin activity with a decline in systolic function, severe HF and enhanced mortality (median survival 103 days). We used aliskiren to determine whether renin activity is critical for HF outcomes. Methods and Results: Untreated female DCM mice were compared to female DCM littermate mice given aliskiren (100 mg/kg orally, drinking water) starting at 50 days, Stage B HF (n=20-27/group). When evaluated at 90-100 days, Stage C-D HF, aliskiren suppressed renin activity to normal levels ( P &lt;0.001) and improved cardiac function (ejection fraction, %: 15±1 vs. 11±1, P &lt;0.05; cardiac output, mL/min: 7.5±0.7 vs. 4.6±0.5, P &lt;0.01) compared to untreated DCM littermates. Aliskiren also reduced the development of systemic edema (extracellular water, g: 0.36±0.06 vs. 1.25±0.35, P &lt;0.0001). Treatment with aliskiren delayed loss of body fat and lean muscle mass consistent with cardiac cachexia and sarcopenia. The strongest predictors of survival were fat mass ( r p =0.61, P &lt;0.0001), free water ( r p =-0.55, P &lt;0.0001), and cardiac output ( r p =0.53, P &lt;0.001). Overall, aliskiren treatment resulted in a 7% improvement in median survival ( P &lt;0.05). Conclusion: In females with experimental DCM, targeted treatment of elevated plasma renin activity with aliskiren slowed the development of edema, decreased cachexia, enhanced systolic function, reduced the progression of HF and prolonged survival. These data suggest that more complete biomarker analysis of HF patients may enhance the precision of HF treatment to better address sex-related and individual differences, in order to improve outcomes.

Serelaxin and augmented L‐arginine transport attenuates renal fibrosis and inflammation in experimental dilated cardiomyopathy

IntroductionHeart failure (HF) often leads to secondary renal dysfunction. Morbidity and mortality in HF patients worsens steeply when concomitant renal injury is present and current treatments fail to rescue renal function in these patients. Reduced nitric oxide (NO) levels are associated with both heart and renal failure. We hypothesised that reduced NO bioavailability is central to the development of renal inflammation, fibrosis and ultimate failure of the kidney in HF. L‐arginine is the sole substrate for NO formation and increasing cellular L‐arginine transport can increase NO levels. Serelaxin can also increase NO levels in HF.MethodsAdult male transgenic mice (18–26 weeks of age) that develop cardiomyopathy as a result of cardiac specific overexpression of MST‐1 (DCM mice) were used. NO levels in DCM mice were increased via endothelial specific overexpression of the predominant L‐arginine transporter, cationic amino acid transporter‐1 (CAT1), and by administration of serelaxin.There were five treatment groups; wild type mice (WT; n=8), DCM mice (n=8), DCM mice overexpressing CAT1 (n=8), DCM mice administered serelaxin vehicle (20 mM sodium acetate, pH 5.0; n=8) and DCM mice administered serelaxin (500μg/kg/day; 8 weeks; subcutaneous minipumps; n=8). In all mice, cardiac structure and function were assessed via echocardiography, renal fibrosis was assessed via Masson's Trichrome staining, plasma nitrate and nitrite levels (an index of NO levels) were assessed via a commercially available ELISA kit and mRNA expression of inflammatory markers was assessed via PCR.ResultsEjection fraction was 33% less in 18 week old DCM mice than in 18 week old WT (P = 0.01). Plasma nitrate and nitrite levels were 78% less in 18 week old DCM mice than in 18 week old WT (P&lt;0.05). Plasma nitrate and nitrite levels were normalised in 18 week old DCM mice overexpressing CAT1. Renal tubulointerstitial and glomerular fibrosis were 89% and 76% greater respectively, in 18 week old DCM mice than in age matched WT (P≤0.05). Renal tubulointerstitial and glomerular fibrosis were less (by 77 and 54% respectively; P ≤ 0.05) in 18 week old DCM mice overexpressing CAT1 compared 18 week old DCM mice that do not overexpress CAT1. Renal expression of inflammatory markers, Il6 and Il1β were less while renal expression of anti‐inflammatory marker Il‐10 was greater in the former genotype compared to the latter (all P&lt;0.05).Renal tubulointerstitial and glomerular fibrosis were less by 46% and 45% respectively, in serelaxin treated 26 week old DCM mice compared to age matched vehicle treated DCM mice (P≤0.01). Renal mRNA expression of inflammatory marker Tnfα was 75% greater in 26 week old DCM mice compared to 26 week old WT (P&lt;0.01). Renal Tnfα mRNA expression was 57% less in serelaxin treated 26 week old DCM mice than in 26 week old DCM mice treated with vehicle (P=0.05).ConclusionThese data indicate that augmented L‐arginine transport and serelaxin can reduce renal inflammation and fibrosis in chronic HF potentially by restoring NO levels.Support or Funding InformationNHMRC Program Grant to DK, Investigator led project grant from Novartis to NR and DKThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Enhanced heart failure, mortality and renin activation in female mice with experimental dilated cardiomyopathy.

Dilated cardiomyopathy (DCM) is the major cause of heart failure affecting both women and men. Limited clinical studies show conflicting data in sex-related differences in the progression of dilated cardiomyopathy and heart failure (HF) outcomes. We examined the comparative sex-related progression of cardiomyopathy and the development of HF (at 4, 7, 13 weeks of age) in a well-established, transgenic mouse model of DCM that recapitulates the progressive stages of human HF. By 13 weeks of age, female mice with DCM had more severe left ventricular systolic dysfunction, left ventricular dilation and wall thinning (P<0.001 for all) than age-matched male mice with DCM. Female mice also had greater lung edema (P<0.001), cardiac fibrosis (P<0.01) and pleural effusions, which were not rescued by ovariectomy. By comparison to DCM male mice at 13 weeks, these pathological changes in female mice with DCM, were associated with significant increases in plasma active renin (P<0.01), angiotensin II (P<0.01) and aldosterone levels (P<0.001). In comparison to DCM male mice, DCM female mice also showed differential expression of the natriuretic peptide system with lower corin and higher ANP, BNP and cGMP levels at 13 weeks of age. We conclude, that female mice with experimental DCM have an accelerated progression of cardiomyopathy and HF, which was not corrected by early ovariectomy. These alterations are associated with early renin activation with increased angiotensin II and aldosterone levels, and altered expression of the natriuretic peptide system.

N-Acetylcysteine Attenuates\xa0the Development of Renal Fibrosis in Transgenic Mice with Dilated Cardiomyopathy

Mechanisms underlying the renal pathology in cardiorenal syndrome (CRS) type 2 remain elusive. We hypothesised that renal glutathione deficiency is central to the development of CRS type 2. Glutathione precursor, N-acetylcysteine (NAC;40 mg/kg/day; 8 weeks) or saline were administered to transgenic mice with dilated cardiomyopathy (DCM) and wild-type (WT) controls. Cardiac structure, function and glutathione levels were assessed at the end of this protocol. Renal fibrosis, glutathione content, expression of inflammatory and fibrotic markers, and function were also evaluated. In both genotypes, NAC had minimal effect on cardiac glutathione, structure and function (P ≥ 0.20). In NAC treated DCM mice, loss of glomerular filtration rate (GFR), tubulointerstitial and glomerular fibrosis and renal oxidised glutathione levels were attenuated by 38%, 99%, 70% and 52% respectively, compared to saline treated DCM mice (P ≤ 0.01). Renal expression of PAI-1 was greater in saline treated DCM mice than in WT mice (P < 0.05). Renal PAI-1 expression was less in NAC treated DCM mice than in vehicle treated DCM mice (P = 0.03). Renal IL-10 expression was greater in the former cohort compared to the latter (P < 0.01). These data indicate that normalisation of renal oxidized glutathione levels attenuates PAI-1 expression and renal inflammation preventing loss of GFR in experimental DCM.

Depressed Corin Levels Indicate Early Systolic Dysfunction Before Increases of Atrial Natriuretic Peptide/B-Type Natriuretic Peptide and Heart Failure Development

Dilated cardiomyopathy is a major cause of heart failure (HF) that affects millions. Corin cleaves and biologically activates pro-atrial natriuretic peptide (pro-ANP) and pro-B-type natriuretic peptide (pro-BNP). High corin levels reduce the development of systolic dysfunction and HF in experimental dilated cardiomyopathy. Yet, patients with significant HF unexpectedly show low corin levels with high plasma ANP/BNP levels. Therefore, we examined the relationship between cardiac corin expression, ANP/BNP levels, and the stages of HF. We used a well-established, dilated cardiomyopathy model to evaluate gene and protein expression as mice longitudinally developed Stages A-D HF. Cardiac systolic function (ejection fraction) continuously declined over time (P<0.001). Cardiac corin transcripts were decreased at early Stage B HF and remained low through Stages C and D (P<0.001). Cardiac corin levels were positively correlated with systolic function (r=0.96, P=0.003) and inversely with lung water (r=-0.92, P=0.001). In contrast, cardiac pro-ANP/BNP transcripts increased later (Stages C and D) and plasma levels rose only with terminal HF (Stage D, P<0.001). Immunoreactive plasma ANP and BNP levels were positively associated with plasma cyclic guanosine monophosphate levels (r=0.82, P=0.01 and r=0.8, P=0.02, respectively). In experimental dilated cardiomyopathy, corin levels declined early with progressive systolic dysfunction before the development of HF, whereas significant increases in plasma ANP, BNP, and cyclic guanosine monophosphate levels were found only in later stage (C and D) HF. This dyssynchrony in expression of corin versus ANP/BNP may impair cleavage activation of pro-natriuretic peptides, and thereby promote the transition from earlier to later stage HF.

Комплекс препаратов тестостерона, АТФ и экстракта миокарда в качестве коррекционной схемы при экспериментальной дилатационной кардиомиопатии

Комплекс препаратов тестостерона, АТФ и экстракта миокарда в качестве коррекционной схемы при экспериментальной дилатационной кардиомиопатии

Atrial Natriuretic Peptide Affects Cardiac Remodeling, Function, Heart Failure, and Survival in a Mouse Model of Dilated Cardiomyopathy

Dilated cardiomyopathy is a frequent cause of heart failure and death. Atrial natriuretic peptide (ANP) is a biomarker of dilated cardiomyopathy, but there is controversy whether ANP modulates the development of heart failure. Therefore, we examined whether ANP affects heart failure, cardiac remodeling, function, and survival in a well-characterized, transgenic model of dilated cardiomyopathy. Mice with dilated cardiomyopathy with normal ANP levels survived longer than mice with partial ANP (P<0.01) or full ANP deficiency (P<0.001). In dilated cardiomyopathy mice, ANP protected against the development of heart failure as indicated by reduced lung water, alveolar congestion, pleural effusions, etc. ANP improved systolic function and reduced cardiomegaly. Pathological cardiac remodeling was diminished in mice with normal ANP as indicated by decreased ventricular interstitial and perivascular fibrosis. Mice with dilated cardiomyopathy and normal ANP levels had better systolic function (P<0.001) than mice with dilated cardiomyopathy and ANP deficiency. Dilated cardiomyopathy was associated with diminished cardiac transcripts for NP receptors A and B in mice with normal ANP and ANP deficiency, but transcripts for NP receptor C and C-type natriuretic peptide were selectively altered in mice with dilated cardiomyopathy and ANP deficiency. Taken together, these data indicate that ANP has potent effects in experimental dilated cardiomyopathy that reduce the development of heart failure, prevent pathological remodeling, preserve systolic function, and reduce mortality. Despite the apparent overlap in physiological function between the NPs, these data suggest that the role of ANP in dilated cardiomyopathy and heart failure is not compensated physiologically by other NPs.

Activin-A, Transforming Growth Factor-β, and Myostatin Signaling Pathway in Experimental Dilated Cardiomyopathy

Background The pathogenic mechanisms of dilated cardiomyopathy are still uncertain. A number of cytokines and growth factors participate in the remodeling process of the disease. Methods We investigated the cardiac myostatin, transforming growth factor (TGF)β, and activin-A/Smad growth inhibitory signaling pathway in experimental dilated cardiomyopathy. Transvenous endomyocardial biopsies of the interventricular septum were taken weekly in 15 beagle dogs during the development of heart failure (HF) induced by rapid pacing over a period of 7 weeks. Genes involved in the myostatin-TGFβ-activin-A/Smad signaling pathway and the cardiac hypertrophic process were quantified by real-time quantitative polymerase chain reaction. Left ventricular volume, function, and mass were evaluated by echocardiography. Results Overpacing was associated with increased left ventricular volumes and decreased ejection fraction, whereas the left ventricular mass remained unchanged. TGFβ was increased in moderate HF. Activin-A mRNA expression was 4-fold higher in overt congestive HF than at baseline. A 2-fold decrease of activin type II receptors and activin receptor interacting protein 2 gene expressions were observed, as well as a transient decrease of follistatin. Activin type I receptors, activin receptor interacting protein 1, follistatin-related gene, and myostatin remained unchanged. The inhibitory Smad 7, a negative feedback loop regulator of the Smad pathway, was overexpressed in severe HF. Gene expression of the cyclin-dependent kinase inhibitor p21, a direct target gene of the Smad pathway, was 8-fold up-regulated in HF, whereas cyclin D1 was down-regulated. Conclusion We conclude that tachycardia-induced dilated cardiomyopathy is characterized by gene overexpression of the TGFβ-activin-A/Smad signaling pathway and their target gene p21 and by the absence of ventricular hypertrophy.

Ventricular constraint in dilated cardiomyopathy: A new, compliant textile mesh exerts prophylactic and therapeutic properties

Dilated cardiomyopathy is associated with a progressive decrease in cardiac function, leading to end-stage heart failure. We aimed to stop this process by mechanically constraining the heart with a new, compliant textile mesh. In 16 male Munich minipigs (50 +/- 7 kg), dilated cardiomyopathy with congestive heart failure was induced through 4 weeks of rapid ventricular pacing (220 beats/min). In the early-mesh group (n = 8), a polyvinylidene fluoride mesh was positioned around both ventricles before pacing was started. In the other group (n = 8), experimental dilated cardiomyopathy through rapid pacing was induced (no mesh). After mesh grafting, rapid pacing was continued (late mesh). Rapid pacing in the no-mesh group (control group) significantly decreased both systolic (cardiac output, peak systolic pressure, and the derivative of pressure increase [dP/dt(max)]) and diastolic (minimum rate of pressure rise [dP/dt(min)] and left ventricular end-diastolic pressure) variables, whereas these variables remained almost unchanged in the early-mesh group. In the late-mesh group the passive-elastic constraint not only prevented further deterioration but even exerted reverse remodeling to some extent (dP/dt(max) and left ventricular end-diastolic pressure, P < .05). Ventricular constraint with the new mesh seems to be a prophylactic and therapeutic option in cardiac insufficiency caused by ventricular dilation. This passive-elastic cardioplasty induced reverse remodeling of dilated hearts and significantly improved diastolic and systolic ventricular function.

Ventricular containment in the prophylaxis of experimental dilated cardiomyopathy

End-stage heart failure is an increasing clinical problem with only a few satisfactory therapeutic options. Dilated cardiomyopathy (DCM) is associated with a progressive decline in cardiac function. Our hypothesis was to arrest this worsening of cardiac function by mechanical containment of the dilating heart. In 16 pigs (50+/-7 kg) DCM with congestive heart failure was initiated by rapid ventricular pacing (220 beats/m) for at least 4 weeks. In group I (n=8) an elastic net was placed around both ventricles before pacing was induced, whereas in group II (n=8) only the catheters for hemodynamic measurements were implanted. Comparing hemodynamic data the decrease of cardiac output (CO) and dp/dt(max) during the period of stimulation was significantly lower in group I than in group II (CO: gr. I: -1.4 l/min; gr. 2: -4.1 l/min/dp/dt(max): gr. II: +288 mmHg/s; gr. 2: -1350 mmHg/s). This observation could also be made concerning the maximal left ventricular pressure (LVP(max): gr. I: +8.6 mmHg; gr. II: -39.4 mmHg). Ventricular containment with an elastic net seems to be a prophylactic option in cardiac insufficiency caused by ventricular dilation. This 'cardioplasty' is able to reduce the development of such a dilation with concomitant heart failure.

Ventricular constraint in severe heart failure halts decline in cardiovascular function associated with experimental dilated cardiomyopathy

Background We have shown that passive ventricular constraint during moderate heart failure can halt progressive deterioration in cardiac function in an experimental model of ovine pacing induced heart failure (HF). We report on ventricular constraint in severe heart failure. Methods Eighteen adult merino sheep were used. Severe heart failure was induced in two stages, ie, high rate ventricular pacing for 21 days to produce moderate HF and then for 42 days to induce severe HF. A custom-made polyester mesh cardiac support device ([CSD] Acorn Cardiovascular, St Paul, MN) was implanted snugly around both ventricles through a lower partial sternotomy in 9 sheep (group 1). Rapid ventricular pacing was continued for a further 28 days in all animals to induce advanced HF. Cardiovascular functional indicators were determined using echocardiography and a submaximal treadmill exercise protocol at base line, moderate, severe, and advanced stages. The 9 sheep in group 2 were used as controls. Results Cardiovascular function was significantly depressed in all animals in advanced heart failure compared with base line, with left ventricular ejection fraction (LVEF) falling from 50% to 25% ( p < 0.05) and LV +dp/dt (max) declining from 1,777 to 1,243 ( p < 0.05). However after CSD implantation cardiovascular function during exercise improved significantly despite ongoing rapid pacing, with LVEF increasing to 30% and LV +dp/dt to 1,499 ( p < 0.05) in group 1. There were no significant changes in left ventricular long axis area (157 to 151 cm 2) and short axis (6.8 to 6.1 cm) dimensions at the termination of pacing compared with those at time of CSD implant. Mitral regurgitation improved slightly from 2.5 to 2.19 after containment ( p < 0.05) in group 1 but increased to 2.83 in group 2. Conclusions Ventricular constraint in advanced heart failure with a custom-made polyester mesh device halted the decline in cardiac function seen in untreated animals with this pacing-induced animal model of heart failure. These results indicate potential clinical implications for ventricular containment in the treatment of end-stage heart failure.

Rescue of cardiomyocyte dysfunction by phospholamban ablation does not prevent ventricular failure in genetic hypertrophy.

Cardiac hypertrophy, either compensated or decompensated, is associated with cardiomyocyte contractile dysfunction from depressed sarcoplasmic reticulum (SR) Ca(2+) cycling. Normalization of Ca(2+) cycling by ablation or inhibition of the SR inhibitor phospholamban (PLN) has prevented cardiac failure in experimental dilated cardiomyopathy and is a promising therapeutic approach for human heart failure. However, the potential benefits of restoring SR function on primary cardiac hypertrophy, a common antecedent of human heart failure, are unknown. We therefore tested the efficacy of PLN ablation to correct hypertrophy and contractile dysfunction in two well-characterized and highly relevant genetic mouse models of hypertrophy and cardiac failure, Galphaq overexpression and human familial hypertrophic cardiomyopathy mutant myosin binding protein C (MyBP-C(MUT)) expression. In both models, PLN ablation normalized the characteristically prolonged cardiomyocyte Ca(2+) transients and enhanced unloaded fractional shortening with no change in SR Ca(2+) pump content. However, there was no parallel improvement in in vivo cardiac function or hypertrophy in either model. Likewise, the activation of JNK and calcineurin associated with Galphaq overexpression was not affected. Thus, PLN ablation normalized contractility in isolated myocytes, but failed to rescue the cardiomyopathic phenotype elicited by activation of the Galphaq pathway or MyBP-C mutations.

Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy.

Clinical interest in xenon has been rekindled recently by new recycling systems that have decreased its relative cost. The cardiovascular effects of xenon were examined in isoflurane-anesthetized dogs before and after the development of rapid left ventricular (LV) pacing-induced cardiomyopathy. Dogs (n = 10) were chronically instrumented to measure aortic and LV pressure, LV subendocardial segment length, and aortic blood flow. Hemodynamics were recorded, and indices of LV systolic and diastolic function and afterload were determined in the conscious state and during 1.5 minimum alveolar concentration isoflurane anesthesia alone and combined with 0.25, 0.42, and 0.55 minimum alveolar concentration xenon in dogs with and without cardiomyopathy. Administration of xenon to healthy dogs anesthetized with isoflurane decreased heart rate and increased the time constant (tau) of isovolumic relaxation but did not alter arterial and LV pressures, preload recruitable stroke work slope, and indices of LV afterload. Chronic rapid LV pacing increased the baseline heart rate and LV end-diastolic pressure, decreased arterial and LV systolic pressures, and produced LV systolic and diastolic dysfunction. Administration of xenon to isoflurane-anesthetized, cardiomyopathic dogs did not alter heart rate, arterial and LV pressures, myocardial contractility, and indices of early LV filling and regional chamber stiffness. More pronounced increases in tau were accompanied by increases in total arterial resistance during administration of xenon to isoflurane-anesthetized cardiomyopathic compared with healthy dogs. The results indicate that xenon produces minimal cardiovascular actions in the presence of isoflurane in dogs with and without experimental dilated cardiomyopathy.

Ultrasonic tissue characterization of end-stage dilated cardiomyopathy

The clinical use of angiotensin-converting enzyme (ACE) inhibitors now represents the standard of care for the treatment of chronic congestive heart failure. We utilized ultrasonic tissue characterization to define potentially salutary effects of treatment with ACE inhibitors on the material properties of the heart and its potential influence on cardiac remodeling at the cellular level. Ten 1-month-old cardiomyopathic (CM) Syrian hamsters were treated with captopril (2 g/L water ad libitum), and 10 CM and 5 normal hamsters were maintained untreated for 9 months. Hearts were excised, and backscattered radiofrequency data were acquired from 1200 independent sites from each specimen with a high-resolution 50-MHz acoustic microscope for calculation of integrated backscatter. Treatment with captopril elicited relative decreases in left ventricular (LV) wet weight, LV calcium concentration and integrated backscatter (IB) in treated as compared with untreated cardiomyopathic hearts without affecting LV collagen concentration. The IB from hearts of treated cardiomyopathic hamsters was significantly less in both grossly normal regions of myocardium ( P < 0.02) and scar tissue regions ( P = 0.0005) as compared with IB from hearts of untreated hamsters. The reduced integrated backscatter from hearts of treated cardiomyopathic hamsters indicates direct alterations in the material properties of cardiomyopathic hearts after captopril therapy. The lower IB from scar tissue in the treated animals was associated with decreased scar tissue calcification, which represents a novel therapeutic effect of captopril. This is the first report that delineates direct effects of ACE inhibitors on the material properties of both scar tissue and grossly normal myocardium at the cellular level in experimental dilated cardiomyopathy. Quantitative ultrasonic tissue characterization may ultimately play a role in initiating and monitoring the effects ACE inhibitors on cardiac remodeling, calcium deposition and tissue stiffness in patients with dilated cardiomyopathy.

The Dilated Cardiomyopathies: Experimental Aspects

Dilated cardiomyopathy is characterized by the primacy of systolic dysfunction. Experimental animal models have contributed greatly to our current knowledge and promise to continue to expand our understanding, especially as methods of cellular and molecular biology are increasingly applied. Although specific etiologies dominate in some forms of dilated cardiomyopathy, the cause is generally multifactorial--that is, the full expression results from the interplay of a number of etiologic and enhancing factors. Recognition of these factors paves the way for therapy as well as primary and secondary prevention. This article has focused chiefly on experimental models of dilated cardiomyopathy associated with congestive heart failure and on interventions producing or aggravating heart failure. Many factors associated with the production or aggravation of experimental myocardial necroses have not been considered here. Even so, this overview reaffirms the concept that dilated cardiomyopathies are pluricausal. In Table 3, the major processes identifies as pathogenetic in experimental dilated cardiomyopathy are listed. Table 4 presents a list of major categories of enhancing factors. The evidence offered in this article indicates that in most models many pathogenetic mechanisms and enhancing factors may be operative, and this is also believed to be the case in human dilated cardiomyopathy Recognition of the multifactorial etiologies of the dilated cardiomyopathies is an important first step in therapeutic and preventive interventions. Experimental work in human dilated cardiomyopathy has not been included in this article, but some recent studies provide challenging insights.