Marked Improvement In Cardiac Function Research Articles

Enhancing miR-19a/b induced cardiomyocyte proliferation in infarcted hearts by alleviating oxidant stress and controlling miR-19 release

Fully restoring the lost population of cardiomyocytes and heart function remains the greatest challenge in cardiac repair post myocardial infarction. In this study, a pioneered highly ROS-eliminating hydrogel was designed to enhance miR-19a/b induced cardiomyocyte proliferation by lowering the oxidative stress and continuously releasing miR-19a/b in infarcted myocardium in situ. In vivo lineage tracing revealed that ∼20.47 % of adult cardiomyocytes at the injected sites underwent cell division in MI mice. In MI pig the infarcted size was significantly reduced from 40 % to 18 %, and thereby marked improvement of cardiac function and increased muscle mass. Most importantly, our treatment solved the challenge of animal death--all the treated pigs managed to live until their hearts were harvested at day 50. Therefore, our strategy provides clinical conversion advantages and safety for healing damaged hearts and restoring heart function post MI, which will be a powerful tool to battle cardiovascular diseases in patients.

Pheochromocytoma Presenting With Cardiomyopathy in an Otherwise Healthy Young Patient: A Rare Case Report

Background: Pheochromocytomas are rare neuroendocrine tumors. The classic triad of symptoms includes diaphoresis, episodic headache, and tachycardia. Rarely, patients may develop cardiomyopathy associated with pheochromocytoma. It is uncommon for cardiomyopathy to be the initial presenting symptom of pheochromocytoma and can lead to a delayed diagnosis.Clinical Case: The patient is a 30-year old female with no significant medical history who presented with complaints of dyspnea, fever and malaise. The patient had no known prior history of hypertension and did not report complaints of headache, diaphoresis or palpitations. Patient was hypertensive and tachycardic on admission. Upon treatment with intravenous fluids, the patient acutely decompensated and developed respiratory failure requiring emergent intubation. CT of the chest, abdomen and pelvis was performed which showed diffuse bilateral pulmonary edema as well as a circumscribed, heterogeneously enhancing 4.4 cm mass involving the right adrenal gland. An echocardiogram was performed which showed significant left ventricular dysfunction with ejection fraction of 5%. Patient had wide fluctuations in her blood pressure during admission ranging from hypotension to extreme hypertension. She did require the use of epinephrine and milrinone when hypotensive. Due to the use of vasopressors, plasma fractionated metanephrines and 24-hour urine fractionated metanephrines and catecholamines were not recommended to be obtained as these medications may contribute to false positive testing. A dedicated CT of the abdomen with and without contrast was performed to further assess the patient’s right adrenal mass; this revealed a 3.9 x 2.4 x 4.9 cm right adrenal mass with 33% absolute washout and 17% relative washout concerning for pheochromocytoma. The patient underwent an open right adrenalectomy during admission. Surgical pathology results were consistent with a pheochromocytoma measuring 5.2 cm at greatest dimension; the tumor was confined to the adrenal gland and completely excised. Following her surgery, the patient’s clinical status improved significantly over the next several days. She was discharged home in stable condition on hospital day #18. An echocardiogram was repeated 2 months after her hospitalization with ejection fraction improved to 58%.Conclusion: Catecholamine-induced cardiomyopathy in pheochromocytoma is rare, occurring in approximately 8–11% of patients with pheochromocytoma. Cardiomyopathy as the initial presentation of pheochromocytoma is very uncommon. It is important to accurately diagnose pheochromocytoma-related cardiomyopathy as early detection and resection can lead to marked improvement in cardiac function and prevent catastrophic consequences including death.

Long-term benefits of high-intensity atorvastatin therapy in Chinese acute coronary syndrome patients undergoing percutaneous coronary intervention: A retrospective study.

There is lack of long-term data on high-intensity statin therapy of Chinese acute coronary syndrome (ACS) patients scheduled to undergo percutaneous coronary intervention (PCI). In this retrospective study, we compared the long-term efficacy and safety of high-intensity and conventional atorvastatin therapy in reducing low-density lipoprotein cholesterol (LDL-C) and plaque size, and improving cardiac function of ACS patients who underwent PCI.We retrospectively analyzed the clinical records of 120 consecutive ACS patients who underwent PCI at our hospital. Group I received a loading dose of atorvastatin (80 mg/day) prior to PCI, followed by a maintenance dose of 40 mg/day for 3 months post-PCI. Group II received a regular dose of atorvastatin (20 mg/day) from the date of admission until 1 year post-PCI. The composite primary efficacy end point was the mean percent change in calculated LDL-C from baseline to week 48 in both groups and percentage of patients achieving the LDL-C target of ≤1.81 mmol/L.Group I had significantly higher mean baseline LDL-C than group II. Moreover, 8.3% of group I patients had an LDL-C ≤1.81 mmol/L versus 43.3% for group II. At week 24, 75.0% and 90.0% of group I and II patients, respectively, achieved the LDL-C target. At week 48, 85.0% and 96.7% of group I and II patients, respectively, achieved the LDL-C target. Additionally, the mean percent changes at week 4 from baseline in LDL-C were −33.6% ± 20.0% for group I versus −12.8% ± 19.6% for group II, and −47.0% ± 25.5% at week 48 for group I versus −36.4% ± 20.2% for group II. Meanwhile, significant reduction in plaque size and marked improvement in cardiac function were seen in patients receiving high-intensity atorvastatin therapy.Compared to conventional therapy, high-intensity statin therapy is more effective in reducing LDL-C and improving cardiac function of ACS patients, with a general benign safety profile over a period of 48 weeks. Our findings support the use of high-intensity statin therapy for Chinese ACS patients to improve the proportion of patients attaining the LDL-C target and reduction in plaque size and improvement cardiac function.

MicroRNA-29b Regulates the Mitochondria-Dependent Apoptotic Pathway by Targeting Bax in Doxorubicin Cardiotoxicity

Background/Aims: Myocardial apoptosis plays an important role in doxorubicin (Dox) cardiotoxicity. MicroRNA-29 (miR-29) is suggested to function as an anti-fibrotic factor with potential therapeutic effects on cardiac fibrosis. However, it has not been shown whether there is an association between miR-29b and myocardial apoptosis. Methods: Male Wistar rats were transfected with miR-29b agomir by local delivery to the myocardium prior to Dox treatment. Rat cardiomyocytes were pretreated with miR-29b mimics or inhibitor followed by Dox incubation in vitro. Cardiac function and underlying mechanisms were evaluated by echocardiography, immunofluorescence, flow cytometry, real-time PCR, and western blotting. Results: Our results revealed that miR-29b is the only member of the miR-29 family that was significantly downregulated in myocardium from Dox-treated rats. Delivery of miR-29b agomir to myocardium resulted in a marked improvement of cardiac function. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining showed that rescue of miR-29b expression inhibited Dox-induced myocardial apoptosis, concomitantly with increased Bcl-2 expression and decreased Bax expression and caspase-3 activity. In vitro, miR-29b overexpression mitigated, whereas inhibition of miR-29b promoted, Dox-induced cardiomyocyte apoptosis. Mechanistically, miR-29b negatively regulated Bax expression by directly targeting the 3′ untranslated region of Bax. In Dox-treated cardiomyocytes, upregulation of miR-29b resulted in a significant decrease in Bax expression, with an increase in Bcl-2 expression, accompanied by inhibition of mitochondrial membrane depolarization, cytochrome c release, and caspase activation. However, inhibition of miR-29b produced the opposite effects by further augmenting the effects of Dox. Conclusions: These data demonstrate that miR-29b prevents Dox-induced myocardial apoptosis through inhibition of the mitochondria-dependent pathway by directly targeting Bax, suggesting that miR-29b is a potential novel therapeutic target for the treatment of Dox cardiotoxicity.

Long-term administration of pyridostigmine attenuates pressure overload-induced cardiac hypertrophy by inhibiting calcineurin signalling.

Cardiac hypertrophy is associated with autonomic imbalance, characterized by enhanced sympathetic activity and withdrawal of parasympathetic control. Increased parasympathetic function improves ventricular performance. However, whether pyridostigmine, a reversible acetylcholinesterase inhibitor, can offset cardiac hypertrophy induced by pressure overload remains unclear. Hence, this study aimed to determine whether pyridostigmine can ameliorate pressure overload‐induced cardiac hypertrophy and identify the underlying mechanisms. Rats were subjected to either sham or constriction of abdominal aorta surgery and treated with or without pyridostigmine for 8 weeks. Vagal activity and cardiac function were determined using PowerLab. Cardiac hypertrophy was evaluated using various histological stains. Protein markers for cardiac hypertrophy were quantitated by Western blot and immunoprecipitation. Pressure overload resulted in a marked reduction in vagal discharge and a profound increase in cardiac hypertrophy index and cardiac dysfunction. Pyridostigmine increased the acetylcholine levels by inhibiting acetylcholinesterase in rats with pressure overload. Pyridostigmine significantly attenuated cardiac hypertrophy based on reduction in left ventricular weight/body weight, suppression of the levels of atrial natriuretic peptide, brain natriuretic peptide and β‐myosin heavy chain, and a reduction in cardiac fibrosis. These effects were accompanied by marked improvement of cardiac function. Additionally, pyridostigmine inhibited the CaN/NFAT3/GATA4 pathway and suppressed Orai1/STIM1 complex formation. In conclusion, pressure overload resulted in cardiac hypertrophy, cardiac dysfunction and a significant reduction in vagal discharge. Pyridostigmine attenuated cardiac hypertrophy and improved cardiac function, which was related to improved cholinergic transmission efficiency (decreased acetylcholinesterase and increased acetylcholine), inhibition of the CaN/NFAT3/GATA4 pathway and suppression of the interaction of Orai1/STIM1.

Abstract 18312: In vivo Selection of Ghrelin as a Powerful Cardioprotective Factor After Myocardial Infarction

Introduction: By applying an innovative selection procedure based on in vivo gene transfer of AAV libraries coding for the entire mouse secretome, we discovered that the neurohormone ghrelin exerts a powerful protective effect against skeletal muscle damage. In particular, an AAV9 expressing ghrelin protected muscle fibers from severe hind limb ischemia and promoted muscle regeneration. Hypothesis: Based on the established similarities between biology and functional regulation of cardiomyocytes and muscle cells, we wanted to assess the hypothesis that ghrelin was also an effective protective factor in a mouse model of myocardial infarction (MI). Methods: A group of CD1 mice (n=20 per group) underwent permanent left descendent coronary artery ligation and were immediately injected into the peri-infarcted area with 1x10^11 viral particles of an AAV9 vector expressing ghrelin or a control AAV9 empty vector. Cardiac function after MI was monitored by echocardiography, morphometric, histological and molecular analysis. Results: Cardiac gene delivery of AAV9-Ghrelin after MI determined a marked improvement of cardiac function (LVEF: 51±3% vs. 31±3% for AAV9-Ghrelin vs. AAV9-Control vector; LVFS: 26±1% vs. 15±2%) at day 90 after MI (p<0.001 in both cases), while significantly reducing infarct size (27±2 vs. 51±5%; p<0.001). The marked improvement in cardiac contractility was paralleled by a reduced apoptotic rate at early times after MI (31±5% vs 8±4%, p<0.005) and reduced inflammatory cells infiltration in the peri-infarctual region. Moreover, ghrelin counteracted the induction of markers of cardiac damage (in particular, miR21 and MMP-2) and prevented the deregulated expression of pathological left ventricle remodelling markers, such ad bMHC, BNP and others. Conclusions: In conclusion, these results demonstrate the efficacy of ghrelin as a powerful molecule conferring protection from skeletal muscle degeneration and providing benefit upon cardiac damage.

The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia–reperfusion injury

Nucleotide-binding oligomerization domain-Like Receptor with a Pyrin domain 3 (NLRP3) is considered necessary for initiating a profound sterile inflammatory response. NLRP3 forms multi-protein complexes with Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC) and Caspase-1, which activate pro-interleukin-1β (IL-1β) and pro-IL-18. The role of NLRP3 in cardiac cells is not known. Thus, we investigated the expression and function of NLRP3 during myocardial ischaemia. Myocardial infarction (MI) was induced in adult C57BL/6 mice and Wistar rats by ligation of the coronary artery. A marked increase in NLRP3, IL-1β, and IL-18 mRNA expression was found in the left ventricle after MI, primarily located to myocardial fibroblasts. In vitro studies in cells from adult mice showed that myocardial fibroblasts released IL-1β and IL-18 when primed with lipopolysaccharide and subsequently exposed to the danger signal adenosine triphosphate, a molecule released after tissue damage during MI. When hearts were isolated from NLRP3-deficient mice, perfused and subjected to global ischaemia and reperfusion, a marked improvement of cardiac function and reduction of hypoxic damage was found compared with wild-type hearts. This was not observed in ASC-deficient hearts, potentially reflecting a protective role of other ASC-dependent inflammasomes or inflammasome-independent effects of NLRP3. This study shows that the NLRP3 inflammasome is up-regulated in myocardial fibroblasts post-MI, and may be a significant contributor to infarct size development during ischaemia-reperfusion.

Cardiac magnetic resonance imaging in children with chronic kidney disease and renal transplantation

CV disease is the major cause of death in patients with CKD. Recently, CMR imaging emerges as a complementary method providing advantages in cardiac assessment; however, data on CMR in pediatric CKD are scarce. We performed CMR in 15 children: two with CKD, six on peritoneal dialysis, seven on hemodialysis, and in 18 children 5.1 (0.4-15.4) yr after kidney Tx. Eight children underwent CMR six months before and after Tx. Results are presented as mean z score ± SD. LV EF was higher and in the normal range in Tx patients compared with CKD (-0.3 ± 1 vs. -2.1 ± 1.6, respectively, p < 0.05), whereas RV EF was similar (-0.9 ± 1.4 vs. -0.9 ± 1.8, p = n.s.). End-diastolic and end-systolic LV volume index (0 ± 1.7 vs. 2.1 ± 3.1; 0.2 ± 1.2 vs. 3.1 ± 3.7, both p < 0.05) and LV mass index (1.4 ± 1.5 vs. 3.4 ± 2.9, p < 0.05) were lower in Tx children. All parameters improved in the eight children after Tx. In conclusion, our CMR analysis suggests marked improvement of cardiac function and morphology in children after kidney Tx. CMR might be an appropriate complementary method for measuring detailed cardiac status in children with CKD.

Inhibition of Protein Phosphatase 2A Activity by PI3Kγ Regulates β-Adrenergic Receptor Function

Phosphoinositide 3-kinase γ (PI3Kγ) is activated by Gprotein-coupled receptors (GPCRs). We show here that PI3Kγ inhibits protein phosphatase 2A (PP2A) at the β-adrenergic receptor (βAR, a GPCR) complex altering G protein coupling. PI3Kγ inhibition results in significant increase of βAR-associated phosphatase activity leading to receptor dephosphorylation and resensitization preserving cardiac function. Mechanistically, PI3Kγ inhibits PP2A activity at the βAR complex by phosphorylating an intracellular inhibitor of PP2A (I2PP2A) on serine residues 9 and 93, resulting in enhanced binding to PP2A. Indeed, enhanced phosphorylation of β2ARs is observed with a phosphomimetic I2PP2A mutant that was completely reversed with a mutant mimicking dephosphorylated state. siRNA depletion of endogenous I2PP2A augments PP2A activity despite active PI3K resulting in β2AR dephosphorylation and sustained signaling. Our study provides the underpinnings of a PI3Kγ-mediated regulation of PP2A activity that has significant consequences on receptor function with broad implications in cellular signaling.

Silencing Nox4 in the Paraventricular Nucleus Improves Myocardial Infarction–Induced Cardiac Dysfunction by Attenuating Sympathoexcitation and Periinfarct Apoptosis

Myocardial infarction (MI)-induced heart failure is characterized by central nervous system-driven sympathoexcitation and deteriorating cardiac function. The paraventricular nucleus (PVN) of the hypothalamus is a key regulator of sympathetic nerve activity and is implicated in heart failure. Redox signaling in the PVN and other central nervous system sites is a primary mechanism of neuro-cardiovascular regulation, and excessive oxidant production by activation of NADPH oxidases (Noxs) is implicated in some neuro-cardiovascular diseases. We tested the hypothesis that Nox-mediated redox signaling in the PVN contributes to MI-induced sympathoexcitation and cardiac dysfunction in mice. Real-time PCR revealed that Nox4 was the most abundantly expressed Nox in PVN under basal conditions. Coronary arterial ligation (MI) caused a selective upregulation of this homolog compared to Nox1 and Nox2. Adenoviral gene transfer of Nox4 (AdsiNox4) to PVN (bilateral) attenuated MI-induced superoxide formation in this brain region (day 14) to the same level as that produced by PVN-targeted gene transfer of cytoplasmic superoxide dismutase (AdCu/ZnSOD). MI mice treated with AdsiNox4 or AdCu/ZnSOD in the PVN showed marked improvement in cardiac function as assessed by echocardiography and left ventricular hemodynamic analysis. This was accompanied by significantly diminished sympathetic outflow and apoptosis in the periinfarct region of the heart. These results suggest that MI causes dysregulation of Nox4-mediated redox signaling in the PVN, which leads to sympathetic overactivation and a decline in cardiac function. Targeted inhibition of oxidant signaling in the PVN could provide a novel treatment for MI-induced heart failure.

Cardiomyocyte VEGFR‐1 activation by VEGF‐B induces compensatory hypertrophy and preserves cardiac function after myocardial infarction

Mounting evidence indicates that the function of members of the vascular endothelial growth factor (VEGF) family extends beyond blood vessel formation. Here, we show that the prolonged intramyocardial expression of VEGF-A(165) and VEGF-B(167) on adeno-associated virus-mediated gene delivery determined a marked improvement in cardiac function after myocardial infarction in rats, by promoting cardiac contractility, preserving viable cardiac tissue, and preventing remodeling of the left ventricle (LV) over time. Consistent with this functional outcome, animals treated with both factors showed diminished fibrosis and increased contractile myocardium, which were more pronounced after expression of the selective VEGF receptor-1 (VEGFR-1) ligand VEGF-B, in the absence of significant induction of angiogenesis. We found that cardiomyocytes expressed VEGFR-1, VEGFR-2, and neuropilin-1 and that, in particular, VEGFR-1 was specifically up-regulated in hypoxia and on exposure to oxidative stress. VEGF-B exerted powerful antiapoptotic effect in both cultured cardiomyocytes and after myocardial infarction in vivo. Finally, VEGFR-1 activation by VEGF-B was found to elicit a peculiar gene expression profile proper of the compensatory, hypertrophic response, consisting in activation of alphaMHC and repression of betaMHC and skeletal alpha-actin, and an increase in SERCA2a, RYR, PGC1alpha, and cardiac natriuretic peptide transcripts, both in cultured cardiomyocytes and in infarcted hearts. The finding that VEGFR-1 activation by VEGF-B prevents loss of cardiac mass and promotes maintenance of cardiac contractility over time has obvious therapeutic implications.

Lupus myocarditis: marked improvement in cardiac function after intravenous immunoglobulin therapy

Intravenous immunoglobulin (IVIg) is emerging as the mainstay in the treatment of many autoimmune diseases, including systemic lupus erythematosus. IVIg has been found to be beneficial in myocarditis due to dermatomyositis/polymyositis, Kawasaki disease, and viral myocarditis in children. We report an 18-year-old man of active lupus with worsening cardiac systolic function who did not respond to pulse methylprednisolone and cyclophosphamide, but subsequently showed an improvement in his cardiac function after IVIg administration.

腎移植は尿毒症性心の低心機能を著明に改善する

尿毒症性心の低心機能を伴う腹膜透析患者の外科治療においては，その適応や管理に未だ議論がある．今回，心房内腫瘤摘出術前に透析法を腹膜透析から血液透析に変更することで心機能が改善し，手術を安全に行い得て，その後に生体腎移植を施行し，さらに心機能の改善をみた症例を経験したので報告する．症例は71歳の男性で，慢性腎不全に対し6年前より腹膜透析を行っていた．このたび，配偶者をドナーとした生体間腎移植を希望して来院した．術前の心超音波検査でLVEF 25%の低心機能と，同時に右房内に浮遊する腫瘤を指摘され，急処生体間腎移植を延期し，まず右房内腫瘤摘出術を行うこととした．低心機能の原因は尿毒症性，虚血性の両因子が考えられた．右房内腫瘤摘出術の前に，腹膜透析から血液透析に変更すると，2カ月後にLVEF 48%と心機能の改善を認めた．そこで，人工心肺補助・心拍動下で右房内腫瘤摘出術を施行した．病理組織学的に摘出腫瘤は壊死組織と線維化血栓からなり，治癒期心内膜炎と診断された．術後状態は安定して心不全症状を来すことなく回復し，その5カ月後に生体間腎移植を施行し，腎機能の改善とともに，さらにLVEF 56%と著明な改善を認めた．低心機能を伴う腹膜透析患者における外科治療では，手術に先立って透析方法を適切に変更することにより心機能の改善を図ることができ，より安全な外科治療が可能であり，本病態を有する場合の考慮すべき戦略になりえると思われる．

Implication of QRS Prolongation and Its Relation to Mechanical Dyssynchrony in Idiopathic Dilated Cardiomyopathy in Childhood

We explored the role of QRS prolongation (>or=120 ms) and its relation to mechanical dyssynchrony and outcomes in childhood idiopathic dilated cardiomyopathy (IDC). A total of 89 patients <or=18 years old diagnosed as having IDC (21 days to 26 years of follow-up) were investigated. In 20 survivors with residual left ventricular (LV) dysfunction, mechanical (interventricular and intra-LV) dyssynchrony was assessed. The SD of time from the beginning of QRS prolongation to peak systolic contraction was measured in 12 LV segments by tissue Doppler imaging. A cut-off value >32.6 ms was used to define intra-LV dyssynchrony. The 1- and 5-year survivals were 70% and 53%, respectively. Requirement of intravenous inotropes at follow-up (hazard ratio 3.10) and initial LV ejection fraction (hazard ratio 0.95) were major prognostic factors. QRS prolongation, primarily left bundle branch block, was identified in 16 patients (18%) and tended to increase the risk of requiring inotropes. Moreover, none of those with QRS prolongation regained normal cardiac function at follow-up. Two patients with QRS prolongation showed marked improvement in cardiac function after cardiac resynchronization therapy. Mechanical dyssynchrony was noted in all patients with QRS prolongation and in 8% (interventricular) or 38% (intra-LV) of those without. In conclusion, QRS prolongation was common in childhood IDC and was possibly associated with persistent LV dysfunction and worse cardiac outcome. Mechanical (inter- and intraventricular) dyssynchrony was highly prevalent in those with QRS prolongation and was still often observed in those without.

Abstract 3905: MSCs Wnt11 Derived Paracrine Factors Are Critical to the Repair of Infarcted Myocardium

Genetically engineered MSCs have been shown to serve as an effective vehicle for the delivery of protective proteins. We hypothesized that Wnt11 enhanced MSCs induced cardioprotection of ischemic myocardium via paracrine effect. We have successfully transfected Wnt11 into MSCs. Method: Conditioned medium (con-M) was obtained from various MSCs which were exposed to normoxia or hypoxia for 24 hours and was concentrated 100 times by ultrafiltration. Con-M (50μl) was injected into the border zone of infarcted myocardium immediately after rat underwent left anterior descending coronary artery (LAD) occlusion. Cultured cardiomyocytes (CM) were also treated with Con-M before cells were exposed to hypoxia. Result: A marked improvement in cardiac function was observed in the con-M from MSCs Wnt11 compared to the con-M from MSCs GFP (Table 1 ). Microarray analysis revealed that Wnt11 was 204 fold higher in MSCs Wnt11 than that in MSCs GFP . Moreover, many growth factors and cytokines were upregulated when MSCs Wnt11 were exposed to hypoxia for 24 hours (e.g. BMP4, 1.64; FGF1, 1.61 and TGFμ2, 2.21 fold higher than that in MSCs GFP , respectively; all p&lt;0.05). Con-M significantly improved the survival of CM as expressed by an increased intake of MTT when CM were exposed to hypoxia. Neutralizing antibodies, including anti-Wnt11 (6 and 12 μg/ml) (Fig. 1 ), anti-BMP4 (3μg/ml), anti-FGF-1 (6μg/ml) and anti-TGFβ-2 (12μg/ml), abrogated the protection of CM induced by con-M, especially anti-FGF-1 (Fig. 2 ). It is concluded that MSCs Wnt11 protect cardiomyocytes by releasing cytoprotective factors in their environment. Table 1. Effects of condition medium on cardiac function Figure 1. Anti-Wnt11 antibody increased CM injury and abrogated the protective effect of conditioned medium against hypoxic damage. N = 4 in each group Figure 2. Neutralizing antibodies abolished the CM protection on cultured CM. #, p&lt;0.05 vs normal control; *, p&lt;0.05 vs hypoxia; †, p&lt;0.05 vs Con-M-MSC GFP , ‡, p&lt;0.05 vs Con-M-MSC Wnt11 respectively.

Calcitonin gene-related peptide-mediated cardioprotection of postconditioning in isolated rat hearts

Previous studies have demonstrated that endogenous calcitonin gene-related peptide (CGRP) plays an important role in mediation of ischemic preconditioning. In the present study, we tested whether CGRP is also involved in mediation of the protective effects of postconditioning in isolated rat hearts. Sixty minutes of left coronary artery occlusion and followed by 60 min of reperfusion caused a significant decrease in cardiac function and a significant increase in creatine kinase (CK) release and infarct size. Postconditioning with three cycles of 1-min ischemia and 1-min reperfusion produced a marked improvement of cardiac function and decreased CK release and infarct size, concomitantly with an increase in the release of CGRP release in coronary effluent. However, the cardioprotection afforded by postconditioning was abolished by CGRP 8-37 (10−7 M), a selective CGRP receptor antagonist, or pretreatment with capsaicin (50 mg/kg, s.c.), which depletes transmitters in sensory nerves. Exogenous CGRP (5×10−9 M) administration of CGRP reappeared postconditioning-like cardioprotection in the rats pretreated with capsaicin. These results suggest that the protective effects of ischemic postconditioning are related to stimulation of endogenous CGRP release in rat hearts.

Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure

Marked improvement of cardiac function early after non-myeloablative BMT in a heavily transfused patient with severe aplastic anemia and heart failure

Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats

Cardiac remodeling of viable myocardium occurs after acute myocardial infarction (AMI) and further contributes to cardiac dysfunction. The present study explored whether thyroid hormone (TH) administered shortly after AMI in rats can attenuate cardiac remodeling and improve cardiac function. TH regulates important structural and regulatory proteins in the myocardium including myosin isoform expression and calcium cycling proteins. AMI was induced in Wistar male rats by ligating left coronary artery (AMI, n=10), while sham-operated rats were used as controls (SHAM, n=10). Animals with acute myocardial infarction were also treated with 0.05% thyroid powder in food (AMI-THYR, n=10). Within 2 weeks, cardiac function was impaired as assessed by echocardiography and under isometric conditions in Langendorff preparations. Ejection fraction (EF%) was 71.5 (SEM, 2.7) in SHAM versus 30.0 (2.0) in AMI, P<0.05. +dp/dt was 3886 (566) in SHAM versus 2266 (206) in AMI hearts, P<0.05 and -dp/dt was 1860 (46) in SHAM versus 1633 (120) in AMI hearts, P=ns. Such changes were associated with alterations in myosin isoform expression in the non-infarcted area; AMI hearts expressed 34% alpha-MHC and 66% beta-MHC versus 52% alpha-MHC and 48% beta-MHC in SHAM, P<0.05, while the expression of SERCA and phospholamban (PLB) remained unchanged. Furthermore, a mismatch of left ventricular size and cardiac mass (2*Posterior Wall thickness/LVIDd was decreased) was observed. After TH treatment, AMI-THYR hearts expressed 71% alpha-MHC and 29% beta-MHC, P<0.05 versus SHAM and AMI and the ratio of SERCA/PLB was increased by 2.0-fold, P<0.05 versus SHAM and AMI. These changes corresponded to a marked improvement in cardiac function; EF% was raised to 45.8 (1.7), P<0.05 versus AMI while +dp/dt and -dp/dt were 3800 (435) and 2600 (200), respectively, in AMI-THYR hearts, P<0.05 versus AMI. The ratio of 2*Posterior Wall thickness/LVIDd was normalized. Thyroid hormone administration early after infarction attenuates cardiac remodeling and significantly improves myocardial performance.

Targeted Inhibition of β-Adrenergic Receptor Kinase-1–Associated Phosphoinositide-3 Kinase Activity Preserves β-Adrenergic Receptor Signaling and Prolongs Survival in Heart Failure Induced by Calsequestrin Overexpression

Desensitization and down-regulation of beta-adrenergic receptors (betaARs) are prominent features of heart failure largely mediated by increased levels of betaAR kinase-1 (betaARK1). beta-adrenergic receptor kinase 1 interacts with phosphoinositide-3 kinase (PI3K), and upon agonist stimulation, the betaARK1/PI3K complex is recruited to agonist-stimulated betaARs. Here we tested the hypothesis that in vivo selective inhibition of betaARK1-associated PI3K activity would preserve betaAR signaling and, therefore, improve cardiac function and survival in experimental heart failure. We used a murine model of heart failure induced by calsequestrin (CSQ) cardiac-specific overexpression; CSQ mice were crossed with mice overexpressing in the heart a catalytically inactive PI3Kgamma (PI3Kgamma(inact)) to competitively displace endogenous PI3K from betaARK1. Catalytically inactive PI3KgammaPI3K overexpression in CSQ mice inhibited betaARK1-associated PI3K activity, normalized betaAR levels, and preserved betaAR responsiveness to isoproterenol (ISO). Restoration of betaAR signaling via PI3Kgamma(inact) overexpression resulted in marked improvement of cardiac function and a significant prolongation of survival. Importantly, the effects of PI3Kgamma(inact) overexpression were restricted to betaAR signaling, because cellular PI3K signaling was unaltered, as shown by the similar activation of multiple downstream signaling pathways in both CSQ and CSQ/PI3Kgamma(inact) mice. These data in the CSQ model of cardiac dysfunction indicate that membrane-targeted PI3K activity plays a detrimental role in heart failure, and its inhibition represents a novel therapeutic approach to ameliorate cardiac dysfunction and improve survival.

Chronic Administration of an Endothelin-A Receptor Antagonist Improves Exercise Capacity in Rats with Myocardial Infarction-induced Congestive Heart Failure

The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. At weeks 20 and 24 the treadmill test was performed. YM598 prolonged running time, which had been shortened as a result of heart failure. The weights, relative to the body weight, of the left and right ventricles and lungs of surviving rats with CHF were significantly greater than those of sham-operated rats, suggesting hypertrophy of the ventricles and congestion of the lungs. Administration of YM598 markedly reduced ventricular hypertrophy and pulmonary congestion. Examination of cardiac function revealed that, in surviving CHF rats, the peak positive first derivative of left ventricular pressure was significantly lower, and left ventricular end-diastolic pressure, right ventricular systolic pressure and central venous pressure were significantly higher in comparison to sham-operated rats. These data demonstrate that, in rats with CHF, the contractile and diastolic capacity of the left ventricle decreased and pulmonary hypertension and systemic congestion occurred. Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.