Improvement Of Cardiac Dysfunction Research Articles

The role of TREM-1 in septic myocardial pyroptosis and septic cardiomyopathy in vitro and in vivo.

Septic cardiomyopathy (SCM) is an acute cardiac dysfunction involving myocardial cell pyroptosis. TREM-1 is a known receptor on cell membrane that can amplify the inflammatory response. Our previous studies have shown that TREM-1 in cardiomyocytes is involved in the activation of NLRP3 through the SMC4/NEMO pathway. Here, we aimed to use Trem-1 and Nlrp3 knockout mice to verify the effect of TREM-1 through NLRP3 on cardiac function in septic mice. The results showed that TREM-1 knockout resulted in a decrease in the release of downstream cell signals, including SMC4 and NLRP3, resulting in a decrease in cytokine release and improvement of cardiac dysfunction. Knockout of NLRP3 also reduced cardiomyocyte pyroptosis and increased survival rate. The therapeutic targeting of TREM-1 activation of NLRP3 and its pathway may contribute to the treatment or prevention of SCM.

Neocryptotanshinone ameliorates insufficient energy production in heart failure by targeting retinoid X receptor alpha

Retinoid X receptor alpha (RXRα) is a nuclear transcription factor that extensively regulates energy metabolism in cardiovascular diseases. Identification of targeted RXRα drugs for heart failure (HF) therapy is urgently needed. Neocryptotanshinone (NCTS) is a component derived from Salvia miltiorrhiza Bunge, the effect and mechanism of which for treating HF have not been reported. The goal of this study was to explore the pharmacological effects of NCTS on energy metabolism to protect against HF post-acute myocardial infarction (AMI) via RXRα. We established a left anterior descending artery ligation-induced HF post-AMI model in mice and an oxygen-glucose deprivation-reperfusion-induced H9c2 cell model to investigate the cardioprotective effect of NCTS. Component–target binding techniques, surface plasmon resonance (SPR), microscale thermophoresis (MST) and small interfering RNA (siRNA) transfection were applied to explore the potential mechanism by which NCTS targets RXRα. The results showed that NCTS protects the heart against ischaemic damage, evidenced by improvement of cardiac dysfunction and attenuation of cellular hypoxic injury. Importantly, the SPR and MST results showed that NCTS has a high binding affinity for RXRα. Meanwhile, the critical downstream target genes of RXRα/PPARα, which are involved in fatty acid metabolism, including Cd36 and Cpt1a, were upregulated under NCTS treatment. Moreover, NCTS enhanced TFAM levels, promoted mitochondrial biogenesis and increased myocardial adenosine triphosphate levels by activating RXRα. In conclusion, we confirmed that NCTS improves myocardial energy metabolism, including fatty acid oxidation and mitochondrial biogenesis, by regulating the RXRα/PPARα pathway in mice with HF post-AMI.

Effect of Gallic Acid Pretreatment and SGK1 Enzyme Inhibition on Cardiac Function and Inflammation in a Rat Model of Ischemia-Reperfusion Injury.

Serum and glucocorticoid-induced kinase 1 (SGK1) is an enzyme that may play an important role in ischemic-reperfusion (I/R) injury and myocardial dysfunction. Although many studies have been conducted on individual antioxidants, little attention has been paid to the effects of co-administration of an antioxidant with an SGK1 inhibitor on cardiac function after I/R. This study aimed to determine the effects of gallic acid (as an antioxidant) combined with an SGK1 inhibitor on I/R-induced cardiac dysfunction and inflammation. Sixty male Wistar rats were randomized into 6 groups, pretreated with gallic acid or vehicle for 10 days. Subsequently, the heart was isolated and exposed to I/R. In groups that received the SGK1 inhibitor, the heart was perfused with the SGK1 inhibitor GSK650394, 5 min before induction of ischemia. After that, cardiac function, inflammatory factors, and myocardial damage were evaluated. The combination of these two compounds improved cardiac contractility, heart rate, rate pressure product, left ventricular developed pressure, left ventricular systolic pressure, perfusion pressure, and QRS voltage significantly (P < 0.05). In addition, concomitant therapy of these two agents reduced tumor necrosis factor-alpha and interleukin-6, and the activity of creatine kinase-MB, lactate dehydrogenase, and troponin-I (P < 0.05). The results indicated that administration of gallic acid with the SGK1 inhibitor may have a potentiating effect on the improvement of cardiac dysfunction and I/R-induced inflammation.

Cardiac dysfunction in active pulmonary tuberculosis: Mysterious facts of TB’s pandora

&lt;b&gt;Introduction&lt;/b&gt;: Cardiac dysfunction in pulmonary tuberculosis is relatively more common and underestimated due to lack of suspicion. We have studied prevalence of cardiac dysfunction in pulmonary tuberculosis with special emphasis on echocardiography, serum cortisol and its correlation in cases with unstable cardiorespiratory parameters.&lt;br /&gt; &lt;b&gt;Methods:&lt;/b&gt; Prospective, observational, complete workup, and one year follow up study conducted during January 2016 to December 2020 included 800 cases of active pulmonary tuberculosis with specified inclusion criteria of disproportionate tachycardia, tachypnea with or without hypoxia and shock. Cases with known risk factor for cardiac disease and taking cardiac medicines, and cases with pericardial effusion were excluded from study. All study cases were undergone protocolized analysis such as chest radiograph, pulse oximetry, ECG, sputum examination, cardiac enzymes (CPK-MB, NT-Pro-BNP, and cardiac troponins), serum cortisol, and echocardiography at entry point, at two and six months of treatment with anti-tuberculosis medicines as per NTEP. Statistical analysis was carried out by Chi-square test.&lt;br /&gt; &lt;b&gt;Observations and analysis: &lt;/b&gt;In a study of 800 pulmonary tuberculosis cases, 56.00% (448/800) cases were males, and 44.00% (352/800) cases were females. Cases with BMI&amp;lt;18 was 41.62% (333/800) and BMI&amp;gt;18 was 58.37% (467/800). Radiological patterns as unilateral disease in 33.62% (269/800) &amp;amp; bilateral disease in 66.37% (531/800). Hemoglobin less than 10 gm% were documented in 85.12% (681/800) and above 10 gm% were in 14.87% (119/800) cases. Serum albumin less than 3.5 gm% and more than 3.5 gm% were observed in 48.12% (385/800) and 51.12% (415/800) cases respectively. Hypoxia was documented 26.12% (209/800) cases and normal oxygen saturation in 73.87% (591/800) cases. cases with normal and abnormal serum cortisol were 61.37% (491/800) &amp;amp; 38.62% (309/800) respectively. Sputum examination for AFB observed in 30.00% (240/800) and gene Xpert MTB/RIF documented in 51.37% (411/800) cases respectively. Bronchoscopy guided techniques were used in 149 cases and BAL smear AFB in 44.96% (67/149) cases, gene Xpert MTB/RIF in 97.31% (145/149) cases and MGIT culture in four cases (positive in 100% cases subjected to MGIT culture). We have observed global hypokinesia is predominant cardiac dysfunction documented in 82.21% (171/208) cases, followed by left heart systolic dysfunction in 16.34% (34/208) cases and left heart diastolic dysfunction in 75% (156/208) cases. Right heart dysfunction as dilated right atrium and right ventricle documented in 52.88% (110/208) cases and pulmonary hypertension in 40.38% (84/208) cases. Covariates such as age, gender, hemoglobin, BMI, serum cortisol, serum albumin, oxygen saturation and radiological involvement has significant association with cardiac dysfunction. (p&amp;lt;0.00001) Response to treatment with antituberculosis medicines and steroids has documented as improved in 77.40% cases (161/208) cases, persistent in 13.46% (28/2028) cases and progressive in 9.13% (19/208) cases. Final outcome of cardiac dysfunction in Pulmonary tuberculosis cases has significant association with serum cortisol level (p&amp;lt;0.00086).&lt;br /&gt; &lt;b&gt;Conclusion:&lt;/b&gt; Cardiac dysfunction is active pulmonary tuberculosis needs prompt workup in presence of disproportionate tachypnea, tachycardia with or without hypoxia and shock. Echocardiography is basic tool to evaluate these cases and global hypokinesis is most common abnormality. Serum cortisol abnormality documented in fair number of cases and very well correlated with left ventricular dysfunction abnormalities. Steroids with antituberculosis treatment backup is mainstay protocol during management of these cases. Cardiac dysfunction is reversible in majority of cases and proportionate number shown complete improvement in cardiac dysfunction.

Potential Impact of Non-Steroidal Mineralocorticoid Receptor Antagonists in Cardiovascular Disease.

Inappropriate mineralocorticoid receptor (MR) activation in different cardiovascular cell types has deleterious effects on cardiac remodeling and function. Therefore, MR inhibition is a crucial pharmacological strategy to overcome cardiovascular dysfunction. Despite efficient blockade of MR with steroidal MR antagonists (MRAs), their clinical application is unsatisfactory due to the adverse effects. Newer non-steroidal MRAs with greater potency could be suitable for clinical application, especially in patients with type 2 diabetes mellitus and chronic kidney disease. Although clinical evidence has shown the beneficial effects of non-steroidal MRAs on cardiovascular outcomes in patients with heart failure with reduced ejection fraction, clinical trials are ongoing to evaluate the efficacy of heart failure with preserved ejection fraction. Therefore, comparative pharmacological characterization of non-steroidal MRAs over classic steroidal MRAs is crucial. Here, we summarize the pre-clinical evidence of non-steroidal MRAs, which suggests an improvement in cardiac dysfunction, as well as the underlying molecular mechanisms in animal models mimicking different clinical conditions. In addition, we discuss up-to-date information from clinical trials regarding the beneficial effects of non-steroidal MRAs on meaningful cardiovascular outcomes. Both pre-clinical and clinical evidence support treatment with non-steroidal MRAs in patients with cardiovascular disease.

Community-acquired pneumonia in patients with chronic heart failure: clinical manifestation and a diagnostic role of biomarkers

The aims of this study were to evaluate clinical course of community-acquired pneumonia (CAP) in patients with chronic heart failure (CHF) and to assess the time course of serum biomarkers, such as C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and brain natriuretic peptide (BNP), at baseline and after treatment in patients with CAP and CHF. Methods. This was a prospective observational study. Adult patients with CHF admitted to a hospital due to suspected CAP were recruited in the study. The diagnosis of CAP was confirmed by chest computed tomography (CT). Subsequently, patients were assigned to the group 1 (with confirmed CAP) or the group 2 (with respiratory infections other than CAP). Echocardiography was performed in all patients at baseline and in follow-up visits. In addition to the routine clinical examination and laboratory tests, serum biomarkers were measured in all patients at admission (Visit 1), at days 10 to 14 (Visit 2), and at days 28 to 42 (Visit 3). Standard statistical methods were used for data analysis. Results. Seventy patients who met the inclusion criteria were enrolled in this study; of them, 35 patients had confirmed CAP and 35 patients had respiratory infections other than CAP. Both groups were similar for demographic and clinical characteristics, as well as for laboratory, echocardiographic and radiological findings. CAP did not affect the clinical course of CHF and echocardiographic parameters did not differ significantly between the groups. Clinical signs of both diseases improved after the treatment in majority of patients. Echocardiographic parameters also improved in both groups that indicates the improvement in cardiac dysfunction under the treatment. During the follow-up, the most prominent changes were seen in CRP level which was significantly higher at baseline in CAP patients compared to patients with other respiratory infections. CRP level decreased at Visit 2 in both groups and in Visit 3 in CAP group. CRP levels differed significantly between the groups both at Visits 1 and 2. Other biomarkers, such as PCT, IL-6, and BNP, were significantly higher at Visit 1 compares to Visit 2. TNF-α level did not change significantly neither in any group during the study nor between the groups at any study time. Conclusion. CAP did not affect the clinical course of CHF. Inflammatory biomarkers, such as CRP, PCT, and IL-6, could be used additionally to the routine diagnostic procedures to differentiate between CAP and other respiratory infections in patients with CHF. CRP is the most promising biomarker. Serum levels of the biomarkers decreased significantly under the standard hospital treatment of CAP and CHF; this could be considered to evaluate treatment success and prognosis.

Abstract 489: CC Chemokine Receptor 5 Protects the Heart from Inflammation in Pressure Overload-induced Cardiac Dysfunction

Objective: Sustained inflammation is a key pathological process in the development of heart failure and thus suppression of inflammation possibly leads to improvement of cardiac dysfunction. It has been suggested that CC chemokine receptor 5 (CCR5) scavenges pro-inflammatory mediators and resolves inflammation. The aim of this study is to uncover the role of CCR5 in the pathogenesis of heart failure. Methods: Pressure overload heart failure was induced by transverse aortic constriction (TAC). Sham or TAC operation was performed in male 10-week-old CCR5 knockout (KO) mice and wild-type (WT) controls. Cardiac function and morphology were examined by echocardiography 1 week and 4 weeks after TAC surgery. After euthanization, the heart was extracted and embedded in paraffin for the measurements of cardiac fibrosis and cardiomyocyte hypertrophy with EVG stain and immunohistochemistry using WGA, respectively. The extent of inflammation was evaluated by the immunostaining against CD45 and F4/80 antigens, and by qRT-PCR for inflammatory cytokines and chemokines. Results: We found that heart weight was significantly larger and fractional shortening was significantly lower in CCR5 KO mice than those in WT 4 weeks after TAC, indicating CCR5-induced protective effects on heart failure development. Whilst there was no difference observed in the extent of fibrosis, the size of cardiomyocytes from CCR5 KO heart tended to be increased compared to WT. The number of CD45-positive inflammatory cells and F4/80-positive macrophage infiltration was increased 1 week after TAC in KO mice. The RNA expression levels of monocyte chemotactic protein-1, transforming growth factor-β and tumor necrosis factor-α were significantly higher and NFκB p65 was more phosphorylated in KO mice. Conclusions: We revealed that the inflammation in pressure overload-induced heart failure was exacerbated by the deletion of CCR5 and, therefore, CCR5 could contribute to resolution of inflammation and be a potential therapeutic target for the heart failure treatment.

Correction: Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial.

[This corrects the article DOI: 10.1371/journal.pone.0188551.].

Adeno-associated Virus Vector-mediated Interleukin-10 Induction Prevents Vascular Inflammation in a Murine Model of Kawasaki Disease

Kawasaki disease (KD), which is the leading cause of pediatric heart disease, is characterized by coronary vasculitis and subsequent aneurysm formation. Although intravenous immunoglobulin therapy is effective for reducing aneurysm formation, a certain number of patients are resistant to this therapy. Because interleukin-10 (IL-10) was identified as a negative regulator of cardiac inflammation in a murine model of KD induced by Candida albicans water-soluble fraction (CAWS), we investigated the effect of IL-10 supplementation in CAWS-induced vasculitis. Mice were injected intramuscularly with adeno-associated virus (AAV) vector encoding IL-10, then treated with CAWS. The induction of AAV-mediated IL-10 (AAV-IL-10) significantly attenuated the vascular inflammation and fibrosis in the aortic root and coronary artery, resulting in the improvement of cardiac dysfunction and lethality. The predominant infiltrating inflammatory cells in the vascular walls were Dectin-2+CD11b+ macrophages. In vitro experiments revealed that granulocyte/macrophage colony-stimulating factor (GM-CSF) induced Dectin-2 expression in bone marrow-derived macrophages and enhanced the CAWS-induced production of tumor necrosis factor-α (TNF-α) and IL-6. IL-10 had no effect on the Dectin-2 expression but significantly inhibited the production of cytokines. IL-10 also inhibited CAWS-induced phosphorylation of ERK1/2, but not Syk. Furthermore, the induction of AAV-IL-10 prevented the expression of TNF-α and IL-6, but not GM-CSF and Dectin-2 at the early phase of CAWS-induced vasculitis. These findings demonstrate that AAV-IL-10 may have therapeutic application in the prevention of coronary vasculitis and aneurysm formation, and provide new insights into the mechanism underlying the pathogenesis of KD.

Improvement in cardiac dysfunction with a novel circuit training method combining simultaneous aerobic-resistance exercises. A randomized trial.

IntroductionExercise is considered a valuable nonpharmacological intervention modality in cardiac rehabilitation (CR) programs in patients with ischemic heart disease. The effect of aerobic interval exercise combined with alternating sets of resistance training (super-circuit training, SCT) on cardiac patients' with reduced left ventricular function, post-myocardial infarction (MI) has not been thoroughly investigated.Aim of studyto improve cardiac function with a novel method of combined aerobic-resistance circuit training in a randomized control trial by way of comparing the effectiveness of continuous aerobic training (CAT) to SCT on mechanical cardiac function. Secondary to compare their effect on aerobic fitness, manual strength, and quality of life in men post MI. Finally, to evaluate the safety and feasibility of SCT.Methods29 men post-MI participants were randomly assigned to either 12-weeks of CAT (n = 15) or SCT (n = 14). Both groups, CAT and SCT exercised at 60%-70% and 75–85% of their heart rate reserve, respectively. The SCT group also engaged in intermittently combined resistance training. Primary outcome measure was echocardiography. Secondary outcome measures were aerobic fitness, strength, and quality of life (QoL). The effectiveness of the two training programs was examined via paired t-tests and Cohen's d effect size (ES).ResultsPost-training, only the SCT group presented significant changes in echocardiography (a reduction in E/e' and an increase in ejection fraction, P<0.05). Similarly, only the SCT group presented significant changes in aerobic fitness (an increase in maximal metabolic equivalent, P<0.05). In addition, SCT improvement in the physical component of QoL was greater than this observed in the CAT group. In both training programs, no adverse events were observed.ConclusionMen post-MI stand to benefit from both CAT and SCT. However, in comparison to CAT, as assessed by echocardiography, SCT may yield greater benefits to the left ventricle mechanical function as well as to the patient's aerobic fitness and physical QoL. Moreover, the SCT program was found to be feasible as well as safe.

Improvement of cardiac dysfunction by bilateral surgical renal denervation in animals with diabetes induced by high fructose and high fat diet

AimsInsulin resistance (IR) and sympathetic over-activation play a critical role in diabetic cardiomyopathy (DCM). Percutaneous renal sympathetic denervation (RDN) was tested to treat refractory hypertension. However, the benefits of RDN for DCM and IR still remain unknown. The present study aimed to investigate the effect and associated mechanisms of bilateral surgical RDN (bsRDN) on cardiac function and glucose metabolism in animals with diabetes. MethodsThirty-two male New Zealand white rabbits were randomly assigned to Chow (n=8, normal diet) and TEST (n=24, high-fructose fat diet [HFD]) groups. At 48 weeks after HFD feeding, animals in the TEST group were randomized to the Sham, HFD, and RDN subgroups and were fed a HFD for an additional 8 weeks. Repeated measurements of cardiac function, IR, apoptosis/autophagy, and histopathological assessment were performed at 48 and 56 weeks. ResultsHFD feeding for 56 weeks induced IR and diastolic cardiac dysfunction with hypertrophy in septum but well preserved eject fraction in the animals. Impaired IR further deteriorated over the time in the RDN group, featured by a more profound reduction in GLUT4 mRNA and its translocation to the plasma membrane. Successful denervation was associated with improvement of cardiac function via preventing myocardial fibrosis and over-expression of procollagen III, mammalian target of rapamycin, and cardiac apoptosis. Cardiac autophagy, assessed by either electron microscopy or Western blot, was enhanced by bsRDN. ConclusionsRenal sympathetic denervation led to a significant improvement of HFD-induced cardiac dysfunction by shifting the cardiac apoptosis to autophagy, but worsening IR. Further study is required to identify the clinical benefits of RDN.

Neovascularization induced by hypoxia inducible transcription factor is associated with the improvement of cardiac dysfunction in experimental autoimmune myocarditis

Objective: Mechanisms of cardiac dysfunction in myocarditis have not been fully elucidated. Though it remains controversial whether angiogenesis is beneficial or harmful in inflammatory disease, significant vascular destruction might possibly impair cardiac function in myocarditis. The prolyl hydroxylase domain-containing protein (PHD) inhibitor is a potential drug for promoting angiogenesis as it stabilizes hypoxia inducible transcription factor (HIF). The authors examine whether the PHD inhibitor TM6008 could affect cardiac function by promoting angiogenesis in experimental autoimmune myocarditis (EAM).Methods: EAM was induced on BALB/c mice by immunizing them with a synthesized α myosin heavy-chain peptide. Every day, 200 mg/kg of TM6008 or vehicle was administered orally.Results: TM6008 improved left ventricular ejection fraction significantly on the 21st day of EAM. Though TM6008 did not affect the severity of myocardial cell infiltration, it tended to reduce cardiac fibrosis. Immunohistochemistry showed that CD31-positive blood vessels were preserved in the TM6008 group compared to the control group. Immunoblotting revealed that TM6008 increased the expression of HIF-1α, HIF-2α and vascular endothelial growth factor in myocarditis.Conclusion: Inhibition of PHD could ameliorate cardiac dysfunction in EAM, partially through promoting neovascularization. Relief of tissue hypoxia via neovascularization could improve cardiac function in myocarditis.

Circulation: Cardiovascular Interventions Editors’ Picks

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Alpha lipoic acid protects heart against myocardial ischemia–reperfusion injury through a mechanism involving aldehyde dehydrogenase 2 activation

Recent studies demonstrate that alpha lipoic acid can prevent nitroglycerin tolerance by restoring aldehyde dehydrogenase 2 (ALDH2) activity and ALDH2-mediated detoxification of aldehydes is thought as an endogenous mechanism against ischemia–reperfusion injury. This study was performed to explore whether the cardioprotective effect of alpha lipoic acid was related to activation of ALDH2 and the underlying mechanisms. In a Langendorff model of ischemia–reperfusion in rats, cardiac function, activities of creatine kinase (CK) and ALDH2, contents of 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) were measured. In a cell model of hypoxia–reoxygenation, the apoptosis, ALDH activity, reactive oxygen species level, 4-HNE and MDA contents were examined. In the isolated hearts, ischemia–reperfusion treatment led to cardiac dysfunction accompanied by an increase in 4-HNE and MDA contents. Pretreatment with lipoic acid significantly up-regulated myocardial ALDH2 activity concomitantly with an improvement of cardiac dysfunction and a decrease in 4-HNE and MDA contents, these effects were blocked by the inhibitor of ALDH2. Similarly, in the cultured cardiomyocytes, hypoxia–reoxygenation treatment induced apoptosis accompanied by an increase in the production of reactive oxygen species, 4-HNE and MDA. Administration of lipoic acid significantly up-regulated cellular ALDH2 activity concomitantly with a reduction in apoptosis, production of reactive oxygen species, 4-HNE and MDA, these effects were reversed in the presence of ALDH2 or PKCε inhibitors. Our results suggest that the cardioprotective effects of lipoic acid on ischemia–reperfusion injury are through a mechanism involving ALDH2 activation. The regulatory effect of lipoic acid on ALDH2 activity is dependent on PKCε signaling pathway.

Molecular targets for PDE inhibitor-mediated improvement of cardiac dysfunction in the mdx mouse?

Recent results show that the classic PDE5 inhibitor, Viagra® (sildenafil), can ameliorate much of the cardiac pathology resulting from several different forms of cardiac damage. These results have elicited great interest in the use of this drug as a therapeutic agent, particularly for treatment of diastolic cardiac dysfunction. In fact several clinical trials are now enrolling and one published trial shows promising results. Unfortunately, it is not clear how this drug works at a molecular level to improve cardiac function and not even clear what the initial molecular target(s) are for Viagra® in any of these studies. Recent data from our group and others strongly suggest that sildenafil, a “classical” PDE5 inhibitor, ameliorates much of the diastolic dysfunction seen in older mdx mice, animals having a disruption in the dystrophin gene. However, our preliminary data suggests that tadalafil does not cause this effect. Moreover, the usual accepted target for sildenafil, PDE5, is not even expressed in adult mouse cardiomyocyes; but an alternate or additional target, PDE1C is highly expressed in this cell type. Since PDE1C, also can be substantially inhibited by sildenafil (but not by tadalafil) we feel that the most likely molecular target for Viagra® is a direct effect on PDE1C in the cardiomyocyte itself. There also may be additional effects on PDE5, but probably in another cell type. These topics will be discussed in this talk.

Contribution of Nitric Oxide in Big Endothelin-1–induced Cardioprotective Effects on Ischemia/Reperfusion Injury in Rat Hearts

We have recently shown that an appropriate amount of exogenous big endothelin-1 (ET-1) has beneficial effects on ischemia-/reperfusion-induced norepinephrine overflow and cardiac dysfunction in rat hearts and that these effects occur through a conversion to ET-1 by endothelin-converting enzyme and following stimulation of ETB receptor. In this study, we examined the possible involvement of nitric oxide (NO) in the big ET-1-induced cardioprotective effects. According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. Exogenous big ET-1 (0.3 nM) significantly increased NOx (NO2/NO3) level in the coronary effluent after onset of reperfusion. This effect was markedly attenuated by treatment with SM-19712 (selective endothelin-converting enzyme inhibitor), A-192621 (selective ETB receptor antagonist), or NG-nitro-l-arginine (nonselective NO synthase inhibitor), respectively. In addition, N-nitro-l-arginine blunted big ET-1-induced suppression of norepinephrine overflow and improvement of cardiac dysfunction after ischemia/reperfusion. These findings suggest that NO produced by ETB receptor activation plays an important role in exogenous big ET-1-induced actions.

Cardiac and autonomic nerve function after reduced-intensity stem cell transplantation for hematologic malignancy in patients with pre-transplant cardiac dysfunction

Recent reports have shown that cardiomyopathy caused by hemochromatosis in severe aplastic anemia is reversible after reduced-intensity allogeneic stem-cell transplantation (RIST). We comprehensively evaluated cardiac and autonomic nerve function to determine whether cardiac dysfunction due to causes other than hemochromatosis is attenuated after RIST. In five patients with cardiac dysfunction before transplant, we analyzed the changes in cardiac and autonomic nerve function after transplant, using electrocardiography (ECG), echocardiography, radionuclide angiography (RNA), serum markers, and heart rate variability (HRV), before and up to 100 days after transplant. There was no significant improvement in cardiac function in any patient and no significant alteration in ECG, echocardiogram, RNA, or serum markers. However, on time-domain analysis of HRV, the SD of normal-to-normal RR intervals (SDNN) and the coefficient of variation of the RR interval (CVRR) decreased significantly 30 and 60 days after transplant (P = 0.04 and 0.01, respectively). Similarly, on frequency-domain analysis of HRV, low and high frequency power (LF and HF) significantly and temporarily decreased (P = 0.003 and 0.03, respectively). Notably, in one patient who had acute heart failure after transplantation, the values of SDNN, CVRR, r-MSSD, LF, and HF at 30 and 60 days after transplantation were the lowest of all the patients. In conclusion, this study suggests that (a) RIST is well-tolerated in patients with cardiac dysfunction, but we cannot expect improvement in cardiac dysfunction due to causes other than hemochromatosis; and (b) monitoring HRV may be useful in predicting cardiac events after RIST.

Novel Mechanisms of Valsartan on the Treatment of Acute Myocardial Infarction Through Inhibition of the Antiadhesion Molecule Periostin

Our previous study demonstrated that periostin, an extracellular matrix protein, plays an important role in left ventricular remodeling through the inhibition of cell-cell interactions. Because the gene regulation of periostin has not yet been examined, we focused on the effects of angiotensin (Ang) II and mechanical stretch, because Ang II and mechanical stretch are related to cardiac remodeling after myocardial infarction. First, we examined the effects of Ang II on periostin in myocytes and fibroblasts in vitro. Ang II significantly increased periostin through phosphatidylinositol 3-kinase, c-Jun N-terminal kinase, p38, and extracellular signal-regulated kinase 1/2 pathways in myocytes and fibroblasts (P<0.05). On the other hand, mechanical stretch also significantly increased periostin expression (P<0.05). This increase was inhibited partially, but significantly, by an Ang II receptor blocker, valsartan, and inhibited almost completely by valsartan with the neutralization antibodies for transforming growth factor-beta and platelet-derived growth factor-BB (P<0.05). Therefore, we further examined periostin expression in vivo. Periostin expression was significantly increased in infarcted myocardium (P<0.05), and treatment with valsartan significantly attenuated it at 4 weeks after myocardial infarction (P<0.05), accompanied by a significant improvement in cardiac dysfunction (P<0.05). Overall, the present study demonstrated that Ang II, as well as mechanical stretch, stimulated periostin expression in both cardiac myocytes and fibroblasts, whereas valsartan significantly attenuated the increase in periostin expression. The inhibition of periostin by valsartan might especially contribute to its beneficial effects on cardiac remodeling after myocardial infarction.

Growth hormone and the heart.

GH exerts direct effects on myocardial growth and function. Evidence from laboratory models shows that GH (or IGF-I) induces mRNA expression for specific contractile proteins and myocyte hypertrophy. Furthermore, GH increases the force of contraction and determines myosin phenoconversion toward the low ATPase activity V3 isoform. These data provide plausible explanations for the cardiac abnormalities observed in clinical settings of excessive or defective GH production. In acromegaly, the functional consequences of GH excess initially prevail (hyperkinetic syndrome), followed by alterations of cardiac function when myocardial hypertrophy develops. This involves both ventricles and is purposeless because it occurs without increased wall stress. Hypertrophy also entails proliferation of the myocardial fibrous tissue that leads to interstitial remodeling. The functional consequence is an impaired ventricular relaxation that causes a diastolic dysfunction, followed by impairment of systolic function. In untreated disease, cardiac performance slowly but inexorably deteriorates and heart failure eventually develops. Several lines of evidence support the specificity of heart disease in acromegaly. Particularly demonstrative are the recent studies in which GH production was suppressed by octreotide, with a consequent significant regression of hypertrophy and improvement of cardiac dysfunction. It is not yet established whether full recovery of normal cardiac morphology and function is possible after correction of GH excess. The point is not a minor one since the possibility to revert, albeit partially, myocardial fibrosis is of great relevance to the control of cardiac hypertrophy in general. GHD leads to a reduced mass of both ventricles and to impaired cardiac performance with low heart rate (hypokinetic syndrome). These alterations are particularly evident during physical exercise and might provide an important contribution to the reduced exercise capacity of GHD patients, in addition to the reduced muscle mass and strength. The data also support a role of GH in the maintenance of a normal cardiac structure and performance. The hypokinetic syndrome is well documented in young patients in whom GHD began very early in their childhood. In contrast, the data in adult-onset GHD are less consistent. This suggests that the consequences of GHD are more relevant if the disorder starts during early heart development. As observed with other abnormalities associated with GHD, cardiac dysfunction is also susceptible to marked improvement by hrGH. This observation lends further support to the proposal to treat these patients with replacement therapy.