Cardiac Dilatation Research Articles

Distinctive neck swelling in a patient with a vein of Galen arteriovenous malformation.

A vein of Galen arteriovenous malformation (VGAM) is a rare intracranial shunt lacking a capillary bed and resulting in subsequent aneurysmal enlargement. VGAM has been previously reported to present as cardiovascular abnormalities, including increased right-sided cardiac load and pressure, cardiac dilatation, pulmonary hypertension and retrograde flow into the aortic arch. We report the first case of VGAM presenting as a gross right-sided neck swelling in a 39-week-old immediately at birth. Transthoracic echocardiography detected dilatation of the superior vena cava and innominate vein, increased right ventricular and pulmonary arterial pressure, and retrograde flow into the aortic arch. Follow-up neck ultrasound revealed tortuous carotid artery and bilateral dilatation of neck veins. Transcranial ultrasound revealed abnormally dilated vessels posterior to the third ventricle, confirming VGAM. Our case demonstrates that while the differential diagnoses of neck swelling are extensive, such a presentation upon Doppler and echocardiographic investigation, may be suggestive of extracardiac causes such as VGAM. The management of such a condition remains critical due to risk of hemorrhage and extensive cerebral involvement.

Allogeneic cardiospheres delivered via percutaneous transendocardial injection increase viable myocardium, decrease scar size, and attenuate cardiac dilatation in porcine ischemic cardiomyopathy.

BackgroundEpicardial injection of heart-derived cell products is safe and effective post-myocardial infarction (MI), but clinically-translatable transendocardial injection has never been evaluated. We sought to assess the feasibility, safety and efficacy of percutaneous transendocardial injection of heart-derived cells in porcine chronic ischemic cardiomyopathy.Methods and ResultsWe studied a total of 89 minipigs; 63 completed the specified protocols. After NOGA-guided transendocardial injection, we quantified engraftment of escalating doses of allogeneic cardiospheres or cardiosphere-derived cells in minipigs (n = 22) post-MI. Next, a dose-ranging, blinded, randomized, placebo-controlled (“dose optimization”) study of transendocardial injection of the better-engrafting product was performed in infarcted minipigs (n = 16). Finally, the superior product and dose (150 million cardiospheres) were tested in a blinded, randomized, placebo-controlled (“pivotal”) study (n = 22). Contrast-enhanced cardiac MRI revealed that all cardiosphere doses preserved systolic function and attenuated remodeling. The maximum feasible dose (150 million cells) was most effective in reducing scar size, increasing viable myocardium and improving ejection fraction. In the pivotal study, eight weeks post-injection, histopathology demonstrated no excess inflammation, and no myocyte hypertrophy, in treated minipigs versus controls. No alloreactive donor-specific antibodies developed over time. MRI showed reduced scar size, increased viable mass, and attenuation of cardiac dilatation with no effect on ejection fraction in the treated group compared to placebo.ConclusionsDose-optimized injection of allogeneic cardiospheres is safe, decreases scar size, increases viable myocardium, and attenuates cardiac dilatation in porcine chronic ischemic cardiomyopathy. The decreases in scar size, mirrored by increases in viable myocardium, are consistent with therapeutic regeneration.

Telomerase expression confers cardioprotection in the adult mouse heart after acute myocardial infarction.

Coronary heart disease is one of the main causes of death in the developed world, and treatment success remains modest, with high mortality rates within 1 year after myocardial infarction (MI). Thus, new therapeutic targets and effective treatments are necessary. Short telomeres are risk factors for age-associated diseases, including heart disease. Here we address the potential of telomerase (Tert) activation in prevention of heart failure after MI in adult mice. We use adeno-associated viruses for cardiac-specific Tert expression. We find that upon MI, hearts expressing Tert show attenuated cardiac dilation, improved ventricular function and smaller infarct scars concomitant with increased mouse survival by 17% compared with controls. Furthermore, Tert treatment results in elongated telomeres, increased numbers of Ki67 and pH3-positive cardiomyocytes and a gene expression switch towards a regeneration signature of neonatal mice. Our work suggests telomerase activation could be a therapeutic strategy to prevent heart failure after MI.

A G613A missense in the Hutchinson’s progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block

BackgroundLMNA/C mutations have been linked to the premature aging syndrome Hutchinson’s progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease.One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype–phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies.ResultsDNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members.In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype–phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB.ConclusionsScreening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12979-014-0019-3) contains supplementary material, which is available to authorized users.

Resveratrol ameliorates cardiac dysfunction induced by pressure overload in rats via structural protection and modulation of Ca(2+) cycling proteins.

BackgroundCardiac hypertrophy is a compensatory stage of the heart in response to stress such as pressure overload (PO), which can develop into heart failure (HF) if left untreated. Resveratrol has been reported to prevent the development of hypertrophy and contractile dysfunction induced by PO. However, other studies found that resveratrol treatment for a longer period of time failed to regress cardiac hypertrophy. The aim of this study is to determine the timing of resveratrol treatment to achieve antihypertrophic effect and investigate whether resveratrol prevents the development of HF through preservation of myocardium structure and modulation of Ca2+ handling proteins.MethodsTo generate rats with cardiac hypertrophy, male Sprague–Dawley rats were subjected to PO (aortic banding procedure) for 4 weeks. Sham-operated animals served as controls. Rats with cardiac hypertrophy were given resveratrol (4 mg/kg/day) for 4, 6, and 8 weeks, respectively. Histological and echocardiographic analysis and transmission electron microscopy were performed to assess cardiac structure and function. The levels of Ca2+ handling proteins were measured by western blot analysis.ResultsHistological analysis showed that resveratrol treatment regressed developed cardiac hypertrophy at 8 and 10 weeks postsurgery, but not at 12 weeks. However, resveratrol strongly and continuously prevented the development of cardiac dysfunction and dilation of cardiac chamber as evaluated by echocardiography and H&E staining of heart cross-sections. In addition, PO-induced cardiac fibrosis was completely inhibited by resveratrol treatment. Resveratrol markedly prevented the disrupted myocardium but partially rescued mitochondrial abnormality in banded rats. Moreover, resveratrol prevented the alteration of Ca2+ handling proteins induced by aortic banding, including downregulation of sarcoplasmic reticulum Ca2+ ATPase 2 (SERCA2) and ryanodine receptor 2 (RyR2), hypophosphorylated phospholamban (PLB), upregulation of Na+/Ca2+-exchangers (NCX1) and increased expression and phosphorylation of Ca2+/calmodulin -dependent protein kinase II (CaMKII). Moreover, resveratrol alleviated the decreased SERCA activity induced by aortic banding.ConclusionsResveratrol effectively prevented the transition from compensatory to decompensatory stage of cardiac hypertrophy induced by PO, but this effect is dependent on the timing of treatment. We suggest that resveratrol may exert beneficial effects on cardiac hypertrophy through protection of cardiac structure and modulation of Ca2+ handling proteins.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-014-0323-x) contains supplementary material, which is available to authorized users.

Abstract 19049: CASK Regulates Sodium Channels Distribution and Function in Costameric Microdomain

Introduction: Proteins of the MAGUK family have emerged as key components in ion channels organization and regulation within specialized submembrane domains of cardiomyocytes. In this context, we investigated for the first time the expression, localization and function in the heart of the MAGUK protein CASK. Methods and Results: Surprisingly, no signal was detectable for CASK at intercalated discs, making CASK the first MAGUK to be excluded from these structures. On the contrary, CASK was located at the lateral membrane where it belonged specifically to the costameric dystrophin/glycoproteins complex (DGC). Since a lateral sub-population of Nav1.5 channels have been reported to interact with syntrophin, a member of DGC, we hypothesized that CASK could modulate Nav1.5 channels. Using high resolution 3-D deconvolution microscopy, we observed a co-localization of CASK and Nav1.5 in cardiomyocytes and co-IP experiments confirmed that the two proteins are in the same complex. Whole-cell patch-clamp recordings revealed a negative regulation by CASK of the sodium current INa carried by Nav1.5 channels in cardiomyocytes. Using super resolution scanning coupled to conventional cell-attached patch-clamp, we investigated the involvement of CASK on Nav1.5 function and localization in highly confined microdomains of the lateral membrane. INa was recorded in crests and T-tubules on freshly isolated cardiomyocytes obtained from adult rats injected with Adeno Associated Virus (eGFP-AAV-ShCASK or eGFP-AAV-ShScr). CASK silencing caused a drastic reduction of INa at the crest whereas it increased the current at the T-tubules suggesting that CASK retains Nav1.5 channels at the crest and prevents their clustering in T-tubules. In vivo CASK silencing in rat using an eGFP-AAV-ShCASK-injected was associated with a conduction slowing as indicated by the prolongation of the QRS duration, cardiac dilation and left ventricle systolic dysfunction. Conclusion: Taken together these results indicate that CASK is a major determinant of the organization of a subpopulation of Nav1.5 at the costamere of cardiomyocytes and that CASK-silencing induces electrical and morphological remodeling.

Abstract 16892: Beneficial Effect of miR-25 Decoy Overexpression in a Murine Model of Heart Failure

Introduction: Recently, our group found that miR-25 is a key microRNA that regulates SERCA2a and we showed anti-miR25 treatment enhanced cardiac contractility and function through SERCA2a restoration in murine heart failure model. However, the strong and stable suppression of specific microRNA activity would be essential to evaluate the therapeutic potential of such an approach. In this study, we constructed a miR-25 decoy t using TuD RNA (tough decoy RNAs) and miR-25 decoy activity was evaluated in various settings. Methods: First, miR-25 decoy construct was applied to both isolated adult cardiomyocytes and H9C2 cardiomyoblasts. A pMirTarget vector containing SERCA2a 3’-UTR under luciferase was used to evaluate this decoy specificity. Second, we generated pressure-overload heart failure models in mouse by TAC operation. In the HF mice, AAV9-GFP (control) and AAV9-miR-25 decoy were delivered by tail vein injection. Two months following gene transfer, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of SERCA2a and miR-25 expression level were confirmed by qRT-PCR analysis. Results: First, we observed that we were able to achieve about 2-3 fold increase of SERCA2a expression by miR-25 decoy transfection in both H9C2 and in isolated adult cardiomyocytes. Also, similar expression pattern was confirmed in the heart of miR-25 decoy injected normal mice. Second, the HF model by TAC surgery was confirmed with echocardiography. Overall average FS (%) in HF was 37.77+/- 8.75 (n=10) and in non-surgery control mice was 62.51 +/- 3.42(n=4). After AAV9 injection, cardiac function of AAV9-miR-25 decoy injected mice was enhanced but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (n=6) vs AAV-miR-25 decoy (n=4)). Third, western blot analysis showed that SERCA2a expression was significantly restored in miR-25 decoy injected mice. In addition, we confirmed that miR-25 expression level was kept low by qRT-PCR analysis. Taken together, our data would indicate that using miR-25 decoy is an effective strategy for the long-term suppression of miR-25 and it may be a promising therapeutic target to restore SERCA2a and reverse the HF phenotype.

Can intensive exercise harm the heart? You can get too much of a good thing.

Can intensive exercise harm the heart? You can get too much of a good thing.

Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII.

Cardiac β-adrenergic receptors (β-AR) are key regulators of cardiac haemodynamics and size. The scaffolding protein A-kinase anchoring protein 79/150 (AKAP5) is a key regulator of myocardial signalling by β-ARs. We examined the function of AKAP5 in regulating cardiac haemodynamics and size, and the role of β-ARs and Ca(2+)-regulated intracellular signalling pathways in this phenomenon. We used echocardiographic, histological, genetic, and biochemical methods to examine the effect of ablation of AKAP5 on cardiac haemodynamics, size, and signalling in mice. AKAP5(-/-) mice exhibited enhanced signs of cardiac dilatation and dysfunction that progressed with age. Infusions of isoprenaline worsened cardiac haemodynamics in wild-type (WT) mice only, but increased the ratio of heart-to-body weight equally in WT and in AKAP5(-/-) mice. Mechanistically, loss of AKAP5 was associated with enhanced activity of cardiac calmodulin kinase II (CaMKII) and calcineurin (CaN) as indexed by nuclear factor of activated T-cell-luciferase activity. Loss of AKAP5 interfered with the recycling of cardiac β1-ARs, which was mediated in part by CaN binding to AKAP5. Carvedilol reversed cardiac hypertrophy and haemodynamic deficiencies in AKAP5(-/-) mice by normalizing the activities of cardiac CaN and CaMKII. These findings identify a novel cardioprotective role for AKAP5 that is mediated by regulating the activities of cardiac CaN and CaMKII and highlight a significant role for cardiac β-ARs in this phenomenon.

Abstract 487: Cardiac Sympathetic Afferent Denervation Improves Cardiac Inflammation and Ameliorates Cardiac Remodeling in Post-MI Rats

A recent study from our laboratory demonstrated that chronic and selective cardiac sympathetic afferent denervation at the time of myocardial infarction (MI) by epicardial application of resiniferatoxin (RTX), a neuronal toxin capable of inducing rapid degeneration of transient receptor potential vanilloid 1 (TRPV1)-expressing afferent neurons and fibers, largely prevented the deleterious cardiac remodeling process 9-11 weeks post-MI. This included reduced cardiac hypertrophy, fibrosis and apoptosis. Here, we further investigated the effect of epicardial application of RTX during MI on cardiac extracellular matrix (ECM) remodeling at 10 weeks post-MI. Echocardiographic and morphologic data demonstrated that, compared to MI+vehicle, MI+RTX exhibited a significantly slower LV chamber dilation (6-week echocardiographic data: left ventricular end-diastolic diameter, 10.7 ± 0.2 vs. 9.6 ± 0.3 mm; left ventricular end-systolic diameter: 8.8 ± 0.2 vs. 7.8 ± 0.3 mm; MI+vehicle vs. MI+RTX, n=18, P<0.05). To further explore its molecular mechanism, we used zymography to evaluate the effect of RTX application on the matrix metalloproteinase (MMP) activity, which is responsible for degrading ECM and cardiac dilation after MI. Our preliminary data show that MMP9 activity was increased by 3.9 times in the peri-infarct myocardium post-MI compared to sham. This was largely abolished by RTX application (peri-infarct area: 3.9 ± 0.5 vs. 1.7 ± 0.4, MI+vehicle vs. MI+RTX, n=3, p=0.03). We further investigated the effect of RTX application on MI-induced cardiac inflammation, which has been reported as an upstream mechanism triggering MMP activation post-MI. Our data show that cardiac TNF alpha levels are markedly increased in the peri-infarct or remote myocardium of post-MI rats, which was largely abolished by RTX application during MI (TNF alpha levels in peri-infarct area: 214.2 ± 13.1 vs. 647.5 ± 45.1 vs. 357.3 ± 25.4 pg/mg protein, sham+vehicle vs. MI+vehicle vs. MI+RTX, n=5/each, p<0.05). These data suggest that cardiac sympathetic afferent denervation during MI exerts a local anti-inflammatory effect and reduces the ECM remodeling by preventing excessive MMP activation in post-MI rats.

Establishment and Evaluation of Isoproterenol Induced Chronic Heart Failure and Cardiac Remodeling Model in Rats: An Experimental Study

Objective: To assess the efficacy of isoproterenol (ISO) in the establishment of chronic heart failure (CHF) and cardiac remodeling model in rats. Methods: Twelve Wistar rats were randomly divided into two groups: control group (n=3) and model group (n=9). Rats in model group were hypodermic injected with ISO 5mg/kg/d for 10 days. Ultrasonic cardiogram, HE staining, immunohistochemistry of collagen Ⅰ and Masson staining were performed to evaluate the cardiac function and myocardial fibrosis. Besides, ventricular mass/body mass ratio, collagen volume fraction (CVF), perivascular collagen area (PVCA), hydroxyproline (HYP) concentration and relative expression of transforming growth factor β1 (TGF-β1) mRNA were also detected. Results: Compared to the controls, rats in model group had a marked enlargement of cardiac dilatation and reduction of ejection fraction (57.00±3.61% vs. 44.67±3.06%, P=0.011). Ventricular mass/body mass ratio (3.60±0.31 vs. 4.88±0.34, P=0.020), CVF (5.65±0.68% vs. 27.62±4.89%, P=0.020), PVCA (11.22±3.40% vs. 28.50±4.52%, p=0.001) and HYP level (0.24±0.08μg/mg wet weight vs. 0.62±0.11μg/mg wet weight, P=0.001) were significantly increased in model group. Remarkably cardiac fibrosis were also observed in the Masson staining and immunohistochemistry. The expression of TGF-β1 mRNA was increased significantly in the model group (P=0.003). The mortality rate in the model group was 33.3% during the whole procedure. Conclusion: ISO can successfully induce a CHF and cardiac remodeling rat model with a low mortality rate.

Two cases of placental mesenchymal dysplasia: Case reports

Two cases of placental mesenchymal dysplasia: Case reports

The consequences of contracting early and often

Frequent premature ventricular contractions (PVCs) are associated with structural heart disease and an increase in sudden and overall mortality. PVCs themselves, if in sufficient numbers, may be associated with the development of a reversible form of cardiomyopathy (CM). A number of small series have suggested that PVC density and features, such as QRS duration, location of origin, and coupling, may increase the predilection to cause CM in structurally normal and diseased hearts. Moreover, elimination of PVCs by catheter ablation has improved ventricular function. Thus, frequent PVCs are a previously underappreciated target for therapeutic intervention in CM. However, the fundamental triggers for the development of myopathy and the details of structural and electrical remodeling have been impeded by the development of a suitable model system. Pacing has been exploited to generate reversible forms of tachycardia-induced CM. Huizar et al have used a premature pacing algorithm to create a model of PVC-induced CM in structurally normal hearts. The algorithm generates a high PVC burden, in this case in a bigeminal pattern pacing from the right ventricular apex. PVC pacing increased the heart rate, on average, from 80 bpm to approximately 130 bpm over 4 months of pacing. Previous characterization of this model demonstrated reversible cardiac dilation and reduced ejection fraction with a compromise in repolarizing reserve evidenced by an increase in ventricular refractory periods. This occurred in the absence of inflammation, fibrosis, increased programmed cell death, or compromised oxidative phosphorylation. In a study reported in this issue of HeartRhythm, Wang et al describe heterogeneously prolonged action potential durations (APD) in myocytes isolated from the left ventricular free wall, associated with reductions in the transient outward (Ito) and inward rectifier (IK1) potassium currents without significant changes in the delayed rectifier (IKr, IKs) currents. The decrease in repolarizing reserve is associated

Cardiac fibroblasts support cardiac inflammation in heart failure.

Cardiac remodeling and inflammation are hallmarks of cardiac failure and correlate with outcome in patients. However, the basis for the development of both remains unclear. We have previously reported that cardiac inflammation triggers transdifferentiation of fibroblasts to myofibroblasts and therefore increase accumulation of cardiac collagen, one key pathology in cardiac remodeling. Hence, identifying key pathways for inflammation would be beneficial for patients suffering from heart failure also. Besides their well-characterized function in matrix regulation, we here investigate the role of fibroblasts in the inflammatory process. We address for the first time the role of fibroblasts as inflammatory supporter cells in heart failure. Using endomyocardial biopsies from patients with heart failure and dilated cardiomyopathy, we created a primary human cardiac fibroblast cell culture system. We found that mechanical stretch mimicking cardiac dilation in heart failure induces activation of fibroblasts and not only stimulates production of extracellular matrix but more interestingly up-regulates chemokine production and triggers typical inflammatory pathways in vitro. Moreover, the cell culture supernatant of stretched fibroblasts activates inflammatory cells and induces further recruitment of monocytes by allowing transendothelial migration into the cardiac tissue. Our findings reveal that cardiac fibroblasts provide pro-inflammatory mediators and may act as sentinel cells activated by mechanical stress. Those cells are able to recruit inflammatory cells into the cardiac tissue, a process known to aggravate outcome of patients. This might be important in different forms of heart failure and therefore may be one general mechanism specific for fibroblasts.

RP105 deficiency aggravates cardiac dysfunction after myocardial infarction in mice

BackgroundToll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signaling, would lead to aggravated cardiac dysfunction after MI. Methods and resultsFirst, whole blood from RP105−/− and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105−/− mice. Then, baseline heart function was assessed by left ventricular pressure–volume relationships which were not different between RP105−/− and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analyzed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105−/− mice had significantly higher heart rate (+21%, P<0.01), end systolic volume index (+57%, P<0.05), end systolic pressure (+22%, P<0.05) and lower relaxation time constant tau (−12%, P<0.05), and a tendency for increased end diastolic volume index (+42%, P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups. ConclusionDeficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodeling.

The impact of juvenile coxsackievirus infection on cardiac progenitor cells and postnatal heart development.

Coxsackievirus B (CVB) is an enterovirus that most commonly causes a self-limited febrile illness in infants, but cases of severe infection can manifest in acute myocarditis. Chronic consequences of mild CVB infection are unknown, though there is an epidemiologic association between early subclinical infections and late heart failure, raising the possibility of subtle damage leading to late-onset dysfunction, or chronic ongoing injury due to inflammatory reactions during latent infection. Here we describe a mouse model of juvenile infection with a subclinical dose of coxsackievirus B3 (CVB3) which showed no evident symptoms, either immediately following infection or in adult mice. However following physiological or pharmacologically-induced cardiac stress, juvenile-infected adult mice underwent cardiac hypertrophy and dilation indicative of progression to heart failure. Evaluation of the vasculature in the hearts of adult mice subjected to cardiac stress showed a compensatory increase in CD31+ blood vessel formation, although this effect was suppressed in juvenile-infected mice. Moreover, CVB3 efficiently infected juvenile c-kit+ cells, and cardiac progenitor cell numbers were reduced in the hearts of juvenile-infected adult mice. These results suggest that the exhausted cardiac progenitor cell pool following juvenile CVB3 infection may impair the heart's ability to increase capillary density to adapt to increased load.

Abstract 65: Regulation of Cardiac Hypertrophy and Dilated Cardiomyopathy by CIP

Cardiac hypertrophy is one of the primary responses of the heart to pathophysiological stress. However, the mechanism of the transition from compensative hypertrophic growth to cardiac dilation is poor understood. Recently, we identified a cardiac-specific expressed gene CIP. The expression of CIP is unchanged in hypertrophic heart but significantly down-regulated in dilated hearts, suggesting CIP may play an important role in the transition from cardiac hypertrophy to dilated cardiomyopathy. We generated CIP knockout mice and found that CIP is dispensable for cardiac development. Interestingly, CIP-null mutant mice developed severe cardiac dilation 4 weeks after TAC (transverse aortic constriction) surgery, while control mice were still at the stage of compensative hypertrophic growth. Echocardiography and histological examinations showed that mutant hearts had enlarged chamber with thinner ventricle wall and decreased cardiac performance compared to controls. The expression of marker genes of cardiac disease, BNP and Myh7, was elevated. Consistently, deletion of CIP in Myh6-CnA transgenic mice result in premature death, displaying severe left ventricle dilation. Conversely, cardiac-specific CIP overexpression inhibited pressure overload-induced cardiac hypertrophy. CIP transgenic mice exhibit decreased ventricle weight/body weight ratio, decreased cardiomyocyte cross-section area and repressed expression of hypertrophic related marker genes. CIP overexpression also protected the heart from developing cardiac dilation and preserved the cardiac function after prolonged pressure overload. We performed unbiased microarray assay to document the transcriptome in CIP knockout and control mice which were subjected to pressure overload (TAC). The analysis of Gene Ontology term indicated the Negative Regulation of Apoptosis was down-regulated while the Collagen/Extracellular Structure Organization was up-regulated in CIP-null hearts under TAC condition. In summary, our studies established CIP as a key regulator of the transition from cardiac hypertrophy to dilated cardiomyopathy. The protective effect of CIP in cardiac remodeling indicates that CIP could become a therapeutic target for cardiac diseases.

Effects of candesartan on electrical remodeling in the hearts of inherited dilated cardiomyopathy model mice.

Inherited dilated cardiomyopathy (DCM) is characterized by dilatation and dysfunction of the ventricles, and often results in sudden death or heart failure (HF). Although angiotensin receptor blockers (ARBs) have been used for the treatment of HF, little is known about the effects on postulated electrical remodeling that occurs in inherited DCM. The aim of this study was to examine the effects of candesartan, one of the ARBs, on cardiac function and electrical remodeling in the hearts of inherited DCM model mice (TNNT2 ΔK210). DCM mice were treated with candesartan in drinking water for 2 months from 1 month of age. Control, non-treated DCM mice showed an enlargement of the heart with prolongation of QRS and QT intervals, and died at t1/2 of 70 days. Candesartan dramatically extended the lifespan of DCM mice, suppressed cardiac dilatation, and improved the functional parameters of the myocardium. It also greatly suppressed prolongation of QRS and QT intervals and action potential duration (APD) in the left ventricular myocardium and occurrence of ventricular arrhythmia. Expression analysis revealed that down-regulation of Kv4.2 (Ito channel protein), KChIP2 (auxiliary subunit of Kv4.2), and Kv1.5 (IKur channel protein) in DCM was partially reversed by candesartan administration. Interestingly, non-treated DCM heart had both normal-sized myocytes with moderately decreased Ito and IKur and enlarged cells with greatly reduced K+ currents (Ito, IKur IK1 and Iss). Treatment with candesartan completely abrogated the emergence of the enlarged cells but did not reverse the Ito, and IKur in normal-sized cells in DCM hearts. Our results indicate that candesartan treatment suppresses structural remodeling to prevent severe electrical remodeling in inherited DCM.

Isolated Partial Anomalous Pulmonary Venous Connection

BACKGROUND: Isolated partial anomalous pulmonary venous connection (PAPVC) is a very rare variant of PAPVC, and involves the anomalous drainage of the right upper pulmonary vein into the superior vena cava (SVC) with no associated inter-atrial septal defect. CASE: We present a case of an isolated PAPVC occurring in 26-year old female patient who presented with palpitations, exertional dyspnea and easy fatigability. Physical examination revealed a dynamic precordium, a right ventricular heave, and a tricuspid regurgitation murmur. Transthoracic echocardiogram showed right atrial, ventricular, and main pulmonary artery dilatation with moderate pulmonary hypertension. Hemodynamic studies revealed an isolated PAPVC with severe pulmonary hypertension. She underwent Warden’s procedure (superior vena cava translocation with atriocaval anastomosis), which remarkably improved her symptoms. CONCLUSION: This case report shows a very rare case of isolated PAPVC presenting with heart failure symptoms and right-sided chamber enlargement. The clinical presentation is not specific and may mimic more common diseases, such as acyanotic atrial septal defect and primary pulmonary hypertension. A high index of suspicion is important in diagnosing the disease in patients with right-sided cardiac chamber dilatation.

Therapeutic efficacy of cardiosphere-derived cells in a transgenic mouse model of non-ischaemic dilated cardiomyopathy.

Cardiosphere-derived cells (CDCs) produce regenerative effects in the post-infarct setting. However, it is unclear whether CDCs are beneficial in non-ischaemic dilated cardiomyopathy (DCM). We tested the effects of CDC transplantation in mice with cardiac-specific Gαq overexpression, which predictably develop progressive cardiac dilation and failure, with accelerated mortality. Wild-type mouse CDCs (10(5) cells) or vehicle only were injected intramyocardially in 6-, 8-, and 11-week-old Gαq mice. Cardiac function deteriorated in vehicle-treated mice over 3 months of follow-up, accompanied by oxidative stress, inflammation and adverse ventricular remodelling. In contrast, CDCs preserved cardiac function and volumes, improved survival, and promoted cardiomyogenesis while blunting Gαq-induced oxidative stress and inflammation in the heart. The mechanism of benefit is indirect, as long-term engraftment of transplanted cells is vanishingly low. Cardiosphere-derived cells reverse fundamental abnormalities in cell signalling, prevent adverse remodelling, and improve survival in a mouse model of DCM. The ability to impact favourably on disease progression in non-ischaemic heart failure heralds new potential therapeutic applications of CDCs.