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Objective: We studied the clinical presentation and management of acute pulmonary arterial hypertension (PAH) in healthy young infants, and the effect of thiamine therapy., Methods: Review of hospital records was conducted for 56 healthy infants (aged below 6 month) who developed sudden onset of pulmonary arterial hypertension as diagnosed on 2D echocardiography, and were admitted at our institution., Results: All patients received supportive care and pulmonary vasodilator therapy, whereas those admitted after Sep-tember, 2019 (n=28) received thiamine in addition, as per the institute's protocol. Overall, complete recovery was seen in 80% (n=45). Infants who died had significantly lower mean pH (7.05 vs 7.27; P=0.001) and serum bicarbonate (9.1 vs 14.9; P=0.007), higher arterial lactate (72.7 vs 61.5; P=0.92), ventricular dysfunction (16 vs 10; P=0.01) and shock (7 vs 9; P=0.008) when compared to those who survived. Baseline characteristics, severity of acidosis and pulmonary hypertension, time taken to recover from PAH, presence of ventricular dysfunction were comparable among those who received thiamine and those who did not receive it. Similarly, recovery (89% vs 71%; P=0.17) and mortality (11% vs 29%) were also comparable between the two groups., Conclusions: A significant proportion of infants with PAH improve with supportive treatment and pulmonary vasodilator therapy. Thiamine supplementation may not give any additional benefit in these patients.

Aims: Sinus tachycardia potentially leads to a deterioration of cardiac function in critically ill infants. The ultrashort-acting beta-blocker landiolol hydrochloride is a new pharmacological option for a selective heart rate (HR) control in patients with sinus tachycardia and heart failure., Methods and Results: This study was a monocentric retrospective medical chart review study at the University Children's Hospital Bonn (Germany) from 01 January 2018 until 30 June 2020. This study included a cohort of 62 term and preterm infants with a diagnosis of ventricular dysfunction and/or pulmonary hypertension (PH), in combination with preexisting tachycardia and treatment with landiolol hydrochloride. Infants were allocated to subgroups according to weeks of gestational age (GA): born at <35 weeks of GA (Group A) and born at >35 weeks of GA (Group B). Tachycardia was defined depending on GA (<35 weeks of GA: >170 b.p.m.; ≥ 35 weeks of GA: >150 b.p.m.). The primary endpoint was defined as percentage of patients achieving HR normalization during the first 24 h of landiolol treatment. Twenty-nine infants were allocated to Group A and 33 infants to Group B. The overall median GA of the infants was 35.3 (23.3/41.3), with 53% female infants. The primary endpoint was achieved in 57 patients (91.9%). The median time to reach target HR was 1.8 (0.3-24) h. The median starting dose of landiolol was 8.8 (3.9-25.3) μk/kg/min, with a median dosing during the first 24 h of landiolol treatment of 9.9 (2.8-35.4) μk/kg/min. The median landiolol dose while achieving the target HR was 10 (2.4-44.4) μk/kg/min. The right ventricular dysfunction improved significantly in both groups 24 h after onset of landiolol infusion (P = 0.001 in Group A and P = 0.045 in Group B). The left ventricular and biventricular dysfunction improved significantly 24 h after onset of landiolol infusion in infants of Group B (P = 0.004 and P = 0.006, respectively). The severity of PH improved significantly after 24 h in infants of Group A (P < 0.001). During landiolol treatment, no severe drug-related adverse event was noted., Conclusions: The use of landiolol hydrochloride for HR control of non-arrhythmic tachycardia in critically ill infants is well tolerated. Reduction of HR can be guided quickly and landiolol treatment is associated with an improvement of ventricular dysfunction and PH., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: The aim of this study was to evaluate outcome measures between our standard multidose cardioplegia protocol and a del Nido cardioplegia protocol in congenital heart surgery patients., Methods: Retrospective single-center study including 250 consecutive patients that received del Nido cardioplegia (DN group) with a mandatory reperfusion period of 30% of cross clamp time and 250 patients that received a modified St. Thomas' solution (ST group). Groups were matched by age, weight, gender, and Risk Adjustment for Congenital Heart Surgery (RACHS-1) scores. Preoperative hematocrit and oxygen saturation were also recorded. Outcomes analyzed were the vasoactive inotropic score (VIS), lactate, ventilation time, ventricular dysfunction with low cardiac output syndrome (LCOS), intensive care unit (ICU) length of stay (LOS), hospital LOS, bypass and aortic cross-clamp times, and in-hospital mortality., Results: Both groups were comparable demographically. Statistically significant differences (p ⩽ 0.05) were noted for cardiac dysfunction with LCOS, hematocrit at end of surgery (p = 0.0038), VIS on ICU admission and at end of surgery (p = 0.0111), and ICU LOS (p = 0.00118) with patients in the DN group having more desirable values for those parameters. Other outcome measures did not reach statistical significance., Conclusion: In our congenital cardiac surgery population, del Nido cardioplegia strategy was associated with less ventricular dysfunction with LCOS, a lower VIS and decreased ICU LOS compared with patients that received our standard myocardial protection using a modified St. Thomas' solution. Despite the limitation of this study, including its retrospective nature and cohort size, these data supported our transition to incorporate del Nido cardioplegia solution with a mandatory reperfusion period as the preferred myocardial protection method in our program.

LCZ696, an angiotensin receptor-neprilysin inhibitor, has shown promising clinical efficacy in patients with heart failure (HF) with reduced ejection fraction. However, its potential effects on heart failure with preserved ejection fraction (HFpEF) are still not fully understood. We evaluated the effect of LCZ696 on HFpEF in transverse aortic constriction mice and compared it with the effect of the angiotensin receptor blocker, valsartan. We found that LCZ696 improved cardiac diastolic function by reducing ventricular hypertrophy and fibrosis in mice with overload-induced diastolic dysfunction. In addition, there was superior inhibition of LCZ696 than stand-alone valsartan. As a potential underlying mechanism, we demonstrated that LCZ696 behaves as a potent suppressor of calcium-mediated calcineurin-nuclear factor of activated T cells (NFAT) signalling transduction pathways. Hence, we demonstrated the protective effects of LCZ696 in overload-induced HFpEF and provided a pharmaceutical therapeutic strategy for related diseases., (© 2022 John Wiley & Sons Australia, Ltd.)

Many Fontan patients with and without systolic ventricular dysfunction are being treated with angiotensin-converting enzyme (ACE) inhibitors, despite its effectiveness remaining unclear. In the present study, we evaluated the short-term effect of enalapril on exercise capacity, vascular and ventricular function in pediatric Fontan patients with moderate-good systolic ventricular function. Fontan patients between 8 and 18 years with moderate-good systolic ventricular function and without previous ACE inhibitor treatment were included and were treated with enalapril for 3 months. During the first 2 weeks, the dosage was titrated according to systolic blood pressure (SBP). Exercise tests, ventricular function assessed by echocardiography, arterial stiffness measurements, and plasma levels of N-terminal pro-B-type natriuretic peptide assessed before and after a 3-month enalapril treatment period was compared. A total of 28 Fontan patients (median age 13.9 years, 6 to 15 years after Fontan operation) completed the study with a mean dosage of 0.3 ± 0.1 mg/kg/d. A total of 6 patients (21%) experienced a significant drop in SBP and 6 others (21%) experienced other adverse events. Enalapril treatment lowered the SBP (from 110 to 104 mmHg, p = 0.003) and levels of N-terminal pro-B-type natriuretic peptide (from 80 to 72 ng/L, p = 0.036). However, enalapril treatment did not improve exercise capacity, ventricular function, or arterial stiffness. In conclusion, short-term ACE inhibition has no beneficial effect in Fontan patients with moderate-good systolic ventricular function., Competing Interests: Disclosures The authors have no conflicts of interest to declare., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Intrahepatic cholestasis of pregnancy (ICP) is associated with an increased risk of stillbirth. This study aimed to assess the relationship between bile acid concentrations and fetal cardiac dysfunction in patients with ICP who were or were not treated with ursodeoxycholic acid (UDCA)., Methods: Bile acid profiles and NT-proBNP, a marker of ventricular dysfunction, were assayed in umbilical venous serum from 15 controls and 76 ICP cases (36 untreated, 40 UDCA-treated). Fetal electrocardiogram traces were obtained from 43 controls and 48 ICP cases (26 untreated, 22 UDCA-treated). PR interval length and heart rate variability (HRV) parameters were measured in 2 behavioral states (quiet and active sleep)., Results: In untreated ICP, fetal total serum bile acid (TSBA) concentrations (r = 0.49, p = 0.019), hydrophobicity index (r = 0.20, p = 0.039), glycocholate concentrations (r = 0.56, p = 0.007) and taurocholate concentrations (r = 0.44, p = 0.039) positively correlated with fetal NT-proBNP. Maternal TSBA (r = 0.40, p = 0.026) and alanine aminotransferase (r = 0.40, p = 0.046) also positively correlated with fetal NT-proBNP. There were no significant correlations between maternal or fetal serum bile acid concentrations and fetal HRV parameters or NT-proBNP concentrations in the UDCA-treated cohort. Fetal PR interval length positively correlated with maternal TSBA in untreated (r = 0.46, p = 0.027) and UDCA-treated ICP (r = 0.54, p = 0.026). Measures of HRV in active sleep and quiet sleep were significantly higher in untreated ICP cases than controls. HRV values in UDCA-treated cases did not differ from controls., Conclusions: Elevated fetal and maternal serum bile acid concentrations in untreated ICP are associated with an abnormal fetal cardiac phenotype characterized by increased NT-proBNP concentration, PR interval length and HRV. UDCA treatment partially attenuates this phenotype., Lay Summary: The risk of stillbirth in intrahepatic cholestasis of pregnancy (ICP) is linked to the level of bile acids in the mother which are thought to disrupt the baby's heart rhythm. We found that babies of women with untreated ICP have abnormally functioning hearts compared to those without ICP, and the degree of abnormality is closely linked to the level of harmful bile acids in the mother and baby's blood. Babies of women with ICP who received treatment with the drug UDCA do not have the same level of abnormality in their hearts, suggesting that UDCA could be a beneficial treatment in some ICP cases, although further clinical trials are needed to confirm this., Competing Interests: Conflict of interest BHG has previously served as a director for Monica Healthcare Limited and has no commercial or financial connections in the company. CW and HUM are consultants with Mirum Pharmaceuticals and CW is a consultant for GlaxoSmithKline. The remaining authors have no conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

There is increasing evidence that cardiac dysfunction is a key contributor to CDH pathophysiology. Dysfunction in both right and left ventricles is common in the early neonatal period, contributes to clinical disease severity, and is associated with adverse outcomes including death and ECMO use. Early and routine assessment of ventricular function and pulmonary artery pressure may guide individualized clinical decision-making, including use of pulmonary vasodilators, cardiotropes, ECMO, and timing of surgical repair. Minimizing cardiac dysfunction, whether by prenatal, postnatal or perinatal treatment strategies, may lead to improved outcome in CDH., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives: Sacubitril/valsartan reduces cardiovascular morbidity and mortality in patients with systolic dysfunction. The aim of the present study was to assess the evolution of chronic kidney disease (CKD) patients after initiating sacubitril/valsartan., Material and Methods: We included 66 consecutive CKD patients with systolic dysfunction followed up in outpatient care. Patients had to meet the inclusion criteria of having a New York Heart Association class ii to iv, receiving maximum tolerated doses of optimal medical therapy and CKD stages 1 to 4. At baseline, comorbidities and epidemiological data were collected and low doses of sacubitril/valsartan were initiated. At month 1 and 3, doses of sacubitril/valsartan were increased up to the maximum doses if tolerated. In each visit, renal function and cardiac biomarkers were recorded. All the data were analyzed at the end of follow up (6 months)., Results: Of the 66 patients, 42 (63%) were men, with a mean age of 73±15 years. Mean creatinine at baseline was 1.42±0.5 mg/dL (glomerular filtration rate estimated by CKD-EPI was 50±19 mL/min/1.73 m 2 ) and mean left ventricular ejection fraction (LVEF) was 31±9%. At the end of follow up, LVEF improved from 31±9% to 39±15% (P <0.001). After one month of treatment, renal function improved up to 53±21 mL/min/1.73 m 2 , P=0.005. For the remaining follow-up time, glomerular filtration rate remained stable (mean at end of follow-up 51±18 mL/min/1.73 m 2 ). Seven patients (10.6%) withdrew from treatment., Conclusion: In our experience, sacubitril/valsartan is safe in CKD, offering stability in CKD progression after 6 months., (Copyright © 2019 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)

Aims: Sepsis is a leading cause of death and disability worldwide. Autophagy may play a protective role in sepsis-induced myocardial dysfunction (SIMD). The present study investigated whether valproic acid (VPA), a class I histone deacetylase (HDAC) inhibitor, can attenuate SIMD by accelerating autophagy., Main Methods: A sepsis model was established via the cecum ligation and puncture of male Sprague-Dawley rats. Cardiac injuries were measured using serum markers, echocardiographic cardiac parameters, and hematoxylin and eosin staining. Cardiac mitochondria injuries were detected with transmission electron microscopy, adenosine triphosphate (ATP) and cardiac mitochondrial DNA (mtDNA) contents. Cardiac oxidative levels were measured using redox markers in the cardiac homogenate. Real-time polymerase chain reaction (RT-PCR) and Western blot were performed to detect the expression levels of relative genes and proteins. HDAC binding to the phosphatase and tensin homolog deleted on chromosome ten (PTEN) promoters and histone acetylation levels of the PTEN promoters were analyzed via chromatin immunoprecipitation and quantitative RT-PCR., Key Findings: VPA can ameliorate SIMD by enhancing the autophagy level of the myocardium to reduce mitochondrial damage, oxidative stress, and myocardial inflammation in septic rats. Moreover, this study demonstrated that VPA induces autophagy by inhibiting HDAC1- and HDAC3-mediated PTEN expression in the myocardial tissues of septic rats., Significance: This study found that VPA attenuates SIMD through myocardial autophagy acceleration by increasing PTEN expression and inhibiting the AKT/mTOR pathway. These findings preliminarily suggest that VPA may be a potential approach for the intervention and treatment of SIMD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Purpose: Hypertension is a multifactorial disease, manifested by vascular dysfunction, increased superoxide production, and perivascular inflammation. In this study, we have hypothesized that 1,2,3,4,6-penta-O-galloyl-β-d-glucose (PGG) would inhibit vascular inflammation and protect from vascular dysfunction in an experimental model of hypertension., Experimental Approach: PGG was administered to mice every 2 days at a dose of 10 mg·kg -1 i.p during 14 days of Ang II infusion. It was used at a final concentration of 20 μM for in vitro studies in cultured cells., Key Results: Ang II administration increased leukocyte and T-cell content in perivascular adipose tissue (pVAT), and administration of PGG significantly decreased total leukocyte and T-cell infiltration in pVAT. This effect was observed in relation to all T-cell subsets. PGG also decreased the content of T-cells bearing CD25, CCR5, and CD44 receptors and the expression of both monocyte chemoattractant protein 1 (CCL2) in aorta and RANTES (CCL5) in pVAT. PGG administration decreased the content of TNF + and IFN-γ + CD8 T-cells and IL-17A + CD4 + and CD3 + CD4 - CD8 - cells. Importantly, these effects of PGG were associated with improved vascular function and decreased ROS production in the aortas of Ang II-infused animals independently of the BP increase. Mechanistically, PGG (20 μM) directly inhibited CD25 and CCR5 expression in cultured T-cells. It also decreased the content of IFN-γ + CD8 + and CD3 + CD4 - CD8 - cells and IL-17A + CD3 + CD4 - CD8 - cells., Conclusion and Implication: PGG may constitute an interesting immunomodulating strategy in the regulation of vascular dysfunction and hypertension., Linked Articles: This article is part of a themed section on Immune Targets in Hypertension. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.12/issuetoc., (© 2019 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg -1 ·wk -1 ), or 3) SNT (40 mg·kg -1 ·day -1 ) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Diminazene aceturate (DIZE) has been reported to enhance the catalytic efficiency of ACE-2 and presumably increases angiotensin 1-7 generation, interfering with cardiac remodeling after myocardial infarction (MI). Our aim was to investigate the chronic effects of DIZE on cardiac dysfunction post-MI. Male Wistar rats underwent myocardial infarction (MI) or SHAM surgery (SO) and were divided into groups treated with DIZE 15 mg/kg/day, s.c. or vehicle (Control). After 4 weeks, the hemodynamic variables were recorded by cardiac catheterism. Hearts were then arrested to obtain the left ventricular (LV) pressure-volume curves in situ. Cardiomyocyte hypertrophy and collagen content were determined by histology. DIZE prevented LV end-diastolic pressure increases in MI rats (MI: 26 ± 3.3 vs. MI-DIZE: 15 ± 1.6 mmHg, P < 0.001) without a significant effect on LV systolic pressure (LVSP). Moreover, DIZE improved LV contractility (+dP/dt, MI: 3014 ± 161 vs. MI-DIZE: 3884 ± 104 mmHg/s, P < 0.001) and relaxation (-dP/dt, MI: -2333 ± 91 vs. MI-DIZE: -2798 ± 120 mmHg/s, P < 0.05). Right ventricular SP was increased in the MI compared to that in the SO group (40 ± 0.6 vs. 30 ± 1.2 mmHg; P < 0.01), and DIZE partially prevented this augmentation. LV stiffness was reduced in MI-DIZE compared with that in MI (0.64 ± 0.01 vs. 0.78 ± 0.02 mmHg/mL; P < 0.01). DIZE treatment reduced the interstitial collagen content by 18% in the surviving LV myocardium. Cardiomyocyte hypertrophy remained unaffected by DIZE treatment. Our findings show that chronic DIZE treatment post-MI attenuates the morphofunctional changes induced by MI in rats. The effects on LV -dP/dt, chamber stiffness and collagen content suggest this drug can be used as a therapeutic agent to reduce interstitial fibrosis and diastolic dysfunction after MI., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases.

Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias., Competing Interests: The authors declare no conflict of interest.

Cardiovascular disease (CVD) is a key cause of deaths worldwide, comprising 15-17% of healthcare expenditure in developed countries. Current records estimate an annual global average of 30 million cardiac dysfunction cases, with a predicted escalation by two-three folds for the next 20-30years. Although β-blockers and angiotensin-converting-enzymes are commonly prescribed to control CVD risk, hepatotoxicity and hematological changes are frequent adverse events associated with these drugs. Search for alternatives identified endogenous cofactor l-carnitine, which is capable of promoting mitochondrial β-oxidation towards a balanced cardiac energy metabolism. l-Carnitine facilitates transport of long-chain fatty acids into the mitochondrial matrix, triggering cardioprotective effects through reduced oxidative stress, inflammation and necrosis of cardiac myocytes. Additionally, l-carnitine regulates calcium influx, endothelial integrity, intracellular enzyme release and membrane phospholipid content for sustained cellular homeostasis. Carnitine depletion, characterized by reduced expression of "organic cation transporter-2" gene, is a metabolic and autosomal recessive disorder that also frequently associates with CVD. Hence, exogenous carnitine administration through dietary and intravenous routes serves as a suitable protective strategy against ventricular dysfunction, ischemia-reperfusion injury, cardiac arrhythmia and toxic myocardial injury that prominently mark CVD. Additionally, carnitine reduces hypertension, hyperlipidemia, diabetic ketoacidosis, hyperglycemia, insulin-dependent diabetes mellitus, insulin resistance, obesity, etc. that enhance cardiovascular pathology. These favorable effects of l-carnitine have been evident in infants, juvenile, young, adult and aged patients of sudden and chronic heart failure as well. This review describes the mechanism of action, metabolism and pharmacokinetics of l-carnitine. It specifically emphasizes upon the beneficial role of l-carnitine in cardiomyopathy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation. In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways. Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aims: To test the hypothesis that treatment with a sodium-glucose co-transporter-2 inhibitor would reverse ventricular repolarization heterogeneity, a predictor of cardiovascular mortality, in people with Type 2 diabetes., Methods: We retrospectively analysed changes in indices of ventricular repolarization before and after treatment with a sodium-glucose co-transporter-2 inhibitor in 46 people with Type 2 diabetes., Results: Sodium-glucose co-transporter-2 inhibitor treatment reduced HbA 1c concentration [62±13 mmol/mol (7.7±1.2%) vs 59±16 mmol/mol (7.5±1.4%)], body weight (77.8±13.9 vs 74.7±12.5 kg) and systolic blood pressure (133±18 vs 126±12 mmHg) in the study participants. Heart rate and QTc interval were not changed by sodium-glucose co-transporter-2 inhibitor treatment, but QTc dispersion was significantly reduced (median, 48.8 vs 44.2 ms). Sodium-glucose co-transporter-2 inhibitor treatment reversed QTc dispersion more in participants who had larger QTc dispersion before the treatment. Changes in systolic blood pressure (Spearman's ρ= 0.319; P=0.031), but not in HbA 1c concentration, were correlated with changes in QTc dispersion after sodium-glucose co-transporter-2 inhibitor treatment., Conclusions: The findings suggest that sodium-glucose co-transporter-2 inhibitor treatment reverses ventricular repolarization heterogeneity in people with Type 2 diabetes, independently of its effect on glycaemic control. The favourable effect on ventricular repolarization heterogeneity could be the mechanism by which empaglifozin reduced cardiovascular events in a recent study., (© 2017 Diabetes UK.)

The I f channel inhibitor ivabradine is recommended for treatment of chronic heart failure. However, ivabradine also inhibits human ether-a-go-go (hERG) mediated potassium currents. The aim of the present study was to assess the electrophysiologic effects of ivabradine in an experimental model of short-QT-syndrome. Twelve rabbit hearts were isolated and Langendorff-perfused. After obtaining baseline data, pinacidil, an I K-ATP channel opener, was infused (1 μmol/L). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a significant abbreviation of QT interval (-32 ms, P<.05) and shortening of action potential duration at 90% of repolarization (APD90; -22 ms, P<.05). The shortening of ventricular repolarization was accompanied by a reduction of effective refractory period (ERP; -20 ms, P<.05). Thereafter, hearts were additionally treated with ivabradine (5 μmol/L) leading to an increase of QT interval (+31 ms, P<.05), APD90 (+15 ms, P<.05) as well as of ERP (+38 ms, P<.05) and post-repolarization refractoriness (PRR, +33 ms, P<.05) as compared with sole pinacidil infusion. Under baseline conditions, ventricular fibrillation (VF) was inducible by a standardized pacing protocol including programmed stimulation and burst stimulation in 3 of 12 hearts (6 episodes). After application of 1 μmol/L pinacidil, 6 of 12 hearts were inducible (22 episodes). Additional infusion of 5 μmol/L ivabradine led to a significant suppression of VF. Only two episodes could be induced in 1 of 12 hearts. In the present study ivabradine reversed the electrophysiologic effects of pharmacologically simulated short-QT syndrome. Ivabradine demonstrated antiarrhythmic properties based on an increase of both ERP and PRR., (© 2017 John Wiley & Sons Australia, Ltd.)

Potentiation of glucagon-like peptide-1 (GLP-1) action through selective GLP-1 receptor (GLP-1R) agonism or by prevention of enzymatic degradation by inhibition of dipeptidyl peptidase-4 (DPP-4) promotes glycemic reduction for the treatment of type 2 diabetes mellitus by glucose-dependent control of insulin and glucagon secretion. GLP-1R agonists also decelerate gastric emptying, reduce body weight by reduction of food intake and lower circulating lipoproteins, inflammation, and systolic blood pressure. Preclinical studies demonstrate that both GLP-1R agonists and DPP-4 inhibitors exhibit cardioprotective actions in animal models of myocardial ischemia and ventricular dysfunction through incompletely characterized mechanisms. The results of cardiovascular outcome trials in human subjects with type 2 diabetes mellitus and increased cardiovascular risk have demonstrated a cardiovascular benefit (significant reduction in time to first major adverse cardiovascular event) with the GLP-1R agonists liraglutide (LEADER trial [Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Ourcome Results], -13%) and semaglutide (SUSTAIN-6 trial [Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide], -24%). In contrast, cardiovascular outcome trials examining the safety of the shorter-acting GLP-1R agonist lixisenatide (ELIXA trial [Evaluation of Lixisenatide in Acute Coronary Syndrom]) and the DPP-4 inhibitors saxagliptin (SAVOR-TIMI 53 trial [Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus-Thrombolysis in Myocardial Infarction 53]), alogliptin (EXAMINE trial [Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care in Patients With Type 2 Diabetes Mellitus and Acute Coronary Syndrome]), and sitagliptin (TECOS [Trial Evaluating Cardiovascular Outcomes With Sitagliptin]) found that these agents neither increased nor decreased cardiovascular events. Here we review the cardiovascular actions of GLP-1R agonists and DPP-4 inhibitors, with a focus on the translation of mechanisms derived from preclinical studies to complementary findings in clinical studies. We highlight areas of uncertainty requiring more careful scrutiny in ongoing basic science and clinical studies. As newer more potent GLP-1R agonists and coagonists are being developed for the treatment of type 2 diabetes mellitus, obesity, and nonalcoholic steatohepatitis, the delineation of the potential mechanisms that underlie the cardiovascular benefit and safety of these agents have immediate relevance for the prevention and treatment of cardiovascular disease., (© 2017 American Heart Association, Inc.)

Importance: The natriuretic peptides are biochemical markers of heart failure (HF) severity and predictors of adverse outcomes. Smaller studies have evaluated adjusting HF therapy based on natriuretic peptide levels ("guided therapy") with inconsistent results., Objective: To determine whether an amino-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided treatment strategy improves clinical outcomes vs usual care in high-risk patients with HF and reduced ejection fraction (HFrEF)., Design, Settings, and Participants: The Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) study was a randomized multicenter clinical trial conducted between January 16, 2013, and September 20, 2016, at 45 clinical sites in the United States and Canada. This study planned to randomize 1100 patients with HFrEF (ejection fraction ≤40%), elevated natriuretic peptide levels within the prior 30 days, and a history of a prior HF event (HF hospitalization or equivalent) to either an NT-proBNP-guided strategy or usual care., Interventions: Patients were randomized to either an NT-proBNP-guided strategy or usual care. Patients randomized to the guided strategy (n = 446) had HF therapy titrated with the goal of achieving a target NT-proBNP of less than 1000 pg/mL. Patients randomized to usual care (n = 448) had HF care in accordance with published guidelines, with emphasis on titration of proven neurohormonal therapies for HF. Serial measurement of NT-proBNP testing was discouraged in the usual care group., Main Outcomes and Measures: The primary end point was the composite of time-to-first HF hospitalization or cardiovascular mortality. Prespecified secondary end points included all-cause mortality, total hospitalizations for HF, days alive and not hospitalized for cardiovascular reasons, the individual components on the primary end point, and adverse events., Results: The data and safety monitoring board recommended stopping the study for futility when 894 (median age, 63 years; 286 [32%] women) of the planned 1100 patients had been enrolled with follow-up for a median of 15 months. The primary end point occurred in 164 patients (37%) in the biomarker-guided group and 164 patients (37%) in the usual care group (adjusted hazard ratio [HR], 0.98; 95% CI, 0.79-1.22; P = .88). Cardiovascular mortality was 12% (n = 53) in the biomarker-guided group and 13% (n = 57) in the usual care group (HR, 0.94; 95% CI; 0.65-1.37; P = .75). None of the secondary end points nor the decreases in the NT-proBNP levels achieved differed significantly between groups., Conclusions and Relevance: In high-risk patients with HFrEF, a strategy of NT-proBNP-guided therapy was not more effective than a usual care strategy in improving outcomes., Trial Registration: clinicaltrials.gov Identifier: NCT01685840.

We hypothesised that infants with ventricular dysfunction after cardiac surgery have impaired haemodynamic response to arginine-vasopressin therapy. We retrospectively reviewed the medical records of neonates and infants treated with arginine-vasopressin within 48 hours of corrective or palliative cardiac surgery who underwent echocardiographic assessment of ventricular function before initiation of therapy. Patients were classified as "responders" if their systolic blood pressure increased by ⩾10% without increase in catecholamine score or if it was maintained with decreased catecholamine score. Response was assessed 1 hour after maximum upward titration of arginine-vasopressin. A total of 36 children (15 neonates) were reviewed (17 male). The median (interquartile) age was 10.4 weeks (1.1-26.9), and the median weight was 4.3 kg (3.2-5.8). Diagnoses included single ventricle (eight), arch abnormalities (five), atrioventricular septal defect (four), double-outlet right ventricle (three), tetralogy of Fallot (three), and others (13). In all, 12 patients (33%) had ventricular dysfunction. Only 15 (42%) responded favourably according to our definition 1 hour after the "target" arginine-vasopressin dose was achieved. Ventricular dysfunction was not associated with poor response. The overall mortality was 25%, but mortality in patients with ventricular dysfunction was 42%. Favourable response was associated with shorter ICU stay (9.5 days versus 19.5 days, p=0.01). We conclude that arginine-vasopressin fails to increase blood pressure in ~50% of hypotensive children after cardiac surgery. The response rate does not increase with duration of therapy. Ventricular function does not predict haemodynamic response. The mortality in this group is very high. Prospective comparison of vasopressin with other vasoactive agents and/or inotropes is warranted.

Aims: LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin-related protein 1 (Drp1)., Methods and Results: In human study, we found that myocardial fission protein Drp1 expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients. Male Balb/c mice and H9c2 cardiomyocytes were randomized into three groups: saline, DOX, DOX plus LCZ696. Reduced cardiac function, mitochondrial morphology disturbance, reduced activity of mitochondrial respiration complex I and lowered adenosine triphosphate (ATP) content were detected post DOX stimulation in mice, which could be significantly improved by LCZ696. Fission protein Drp1 and its ser 616 phosphorylation were also increased post DOX and which could be reduced by LCZ696. In vitro, increased cardiomyocyte apoptosis, Drp1 ser 616 phosphorylation post DOX stimulation could be significantly attenuated by LCZ696 or Drp1 specific inhibitor Midivi-1. Furthermore, over-expression of Drp1 abrogated the protection effect of LCZ696 against DOX-induced cardiotoxicity in H9c2 cells., Conclusion: The protective effect of LCZ696 against DOX-induced cardiac dysfunction is at least partly associated with alleviating Drp1-mediated mitochondrial dysfunction., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic stimulation leads to coupling of the β-adrenergic receptor/Gs/adenylyl cyclase, a membrane-bound enzyme that catalyzes the conversion of ATP to cAMP, thereby stimulating protein kinase A (PKA) and ultimately compensating for cardiac dysfunction. The mechanism of such compensation by catecholamine has been traditionally understood as PKA-mediated enforcement of cardiac contractility. We hypothesized that exchange protein activated by cyclic AMP (Epac), a new target of cAMP signaling that functions independently of protein kinase A, also plays a key role in protection against acute stresses or changes in hemodynamic overload. Lipopolysaccharide injection induced cytokine release and severe cardiac dysfunction in mouse. In mouse overexpressing Epac1 in the heart, however, the magnitude of such dysfunction was significantly smaller. Epac1 overexpression inhibited the Jak-STAT pathway, as indicated by decreased phosphorylation of STAT3 and increased SOCS3 expression, with subsequent inhibition of iNOS expression. In cultured cardiomyocytes treated with isoproterenol or forskolin, the increase of SOCS3 expression was blunted when Epac1 or PKCα was silenced with siRNA. Activation of the cAMP/Epac/PKCα pathway protected the heart against cytokine-induced cardiac dysfunction, suggesting a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac1 and its downstream pathways may be novel targets for treating cardiac dysfunction in endotoxemia., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: For acute myocardial infarction (AMI) without heart failure (HF), it is unclear if β-blockers are associated with reduced mortality., Objectives: The goal of this study was to determine the association between β-blocker use and mortality in patients with AMI without HF or left ventricular systolic dysfunction (LVSD)., Methods: This cohort study used national English and Welsh registry data from the Myocardial Ischaemia National Audit Project. A total of 179,810 survivors of hospitalization with AMI without HF or LVSD, between January 1, 2007, and June 30, 2013 (final follow-up: December 31, 2013), were assessed. Survival-time inverse probability weighting propensity scores and instrumental variable analyses were used to investigate the association between the use of β-blockers and 1-year mortality., Results: Of 91,895 patients with ST-segment elevation myocardial infarction and 87,915 patients with non-ST-segment elevation myocardial infarction, 88,542 (96.4%) and 81,933 (93.2%) received β-blockers, respectively. For the entire cohort, with >163,772 person-years of observation, there were 9,373 deaths (5.2%). Unadjusted 1-year mortality was lower for patients who received β-blockers compared with those who did not (4.9% vs. 11.2%; p < 0.001). However, after weighting and adjustment, there was no significant difference in mortality between those with and without β-blocker use (average treatment effect [ATE] coefficient: 0.07; 95% confidence interval [CI]: -0.60 to 0.75; p = 0.827). Findings were similar for ST-segment elevation myocardial infarction (ATE coefficient: 0.30; 95% CI: -0.98 to 1.58; p = 0.637) and non-ST-segment elevation myocardial infarction (ATE coefficient: -0.07; 95% CI: -0.68 to 0.54; p = 0.819)., Conclusions: Among survivors of hospitalization with AMI who did not have HF or LVSD as recorded in the hospital, the use of β-blockers was not associated with a lower risk of death at any time point up to 1 year. (β-Blocker Use and Mortality in Hospital Survivors of Acute Myocardial Infarction Without Heart Failure; NCT02786654)., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Different arrhythmias are cause of sudden death in many patients with heart failure. Amiodarone is usually used for prevent this arrhythmias, but it is not drug of choice for treatment the patients with heart failure. We retrospectively analyzed 142 patients with moderate and severe heart failure and history of myocardial infarction. These patients have received amiodarone, carvedilol or combination of these two medications together with standard therapy. In our retrospective analysis, the combination therapy with Amiodarone and Carvedilol had highly significant decrease arrhythmic death compare with carvedilol and amiodarone groups. This therapy is more effective in recovering of sinus rhythm in patients with atrial fibrillation and for control ventricular arrhythmias. The effects of carvedilol on left ventricular remodeling, systolic function and symptomatic status are not affected adversly by concurrent treatment with amiodarone. Carvedilol is an effective additional therapy for the patients with chronic heart failure already receiving Amiodarone. Carvedilol can be added to Amiodarone in patients with severe ventricular rhythm disorders and increased risk of sudden death without expecting of increase adverse events (than either drug alone) or loss of clinical efficacy.

The aim of the present study was to investigate whether cyclosporine A (CSA) improved cardiac dysfunction at an early stage of sepsis. Male Wistar rats were randomly divided into the following three groups: the sham‑operated control group, the cecal ligation puncture (CLP) procedure‑induced sepsis group and the CSA intervention group. Cecal ligation was performed to generate a sepsis model. At different time points (2, 6, 12, 24 and 72 h) following sepsis induction, blood pressure, cardiac function, and non‑esterified free fatty acid (NEFA) levels in the plasma and myocardia were measured, and the expression levels of components associated with the AMP‑activated protein kinase (AMPK)‑acetyl CoA carboxylase (ACC)‑carnitine palmitoyl transferase 1 (CPT1) signaling pathway were compared among the three groups. Sepsis induced a decrease in blood pressure and cardiac function at 24 h following sepsis induction in the CLP group, and CSA treatment ameliorated these pathophysiological alterations. In addition, rats in the CLP group exhibited significant increases in calcineurin activity and NEFA accumulation in the heart when compared with those in the sham group. These effects were attenuated by CSA treatment. Mechanistically, the activity of the AMPK‑ACC‑CPT1 pathway was enhanced by CSA treatment. The present study revealed that CSA treatment increases cardiac function at an early stage of sepsis in rats. This treatment partially suppresses calcineurin activity while activating the AMPK‑TCC‑CPT1 pathway.

Nonthyroidal illness syndrome (NTIS) affects patients with myocardial infarction (MI). Oxidative stress has been implicated as a causative factor of NTIS, and reversed via N-acetylcysteine (NAC). Male Wistar rats submitted to left anterior coronary artery occlusion received NAC or placebo. Decreases in triiodothyronine (T3) levels were noted in MI-placebo at 10 and 28 days post-MI, but not in MI-NAC. Groups exhibited similar infarct areas whereas MI-NAC exhibited higher ejection fraction than did MI-placebo. Left ventricular systolic and diastolic diameters were also preserved in MI-NAC, but not in MI-placebo. Ejection fraction was positively correlated with T3 levels. Oxidative balance was deranged only in MI-placebo animals. Increased type 3 iodothyronine deiodinase expression was detected in the cardiomyocytes of MI-placebo compared with normal heart tissue. NAC was shown to diminish type 3 iodothyronine deiodinase expression and activity in MI-NAC. These results show that restoring redox balance by NAC treatment prevents NTIS- related thyroid hormone derangement and preserves heart function in rats subjected to MI., (Copyright © 2017 Endocrine Society.)

Neuregulins are important growth factors involved in cardiac development and response to stress. Certain isoforms and fragments of neuregulin have been found to be cardioprotective. The effects of a full-length neuregulin-1β isoform, glial growth factor 2 (GGF2; USAN/INN; also called cimaglermin) were investigated in vitro. Various dosing regimens were then evaluated for their effects on left ventricular (LV) function in rats with surgically-induced myocardial infarction. In vitro, GGF2 bound with high affinity to erythroblastic leukemia viral oncogene (ErbB) 4 receptors, potently promoted Akt phosphorylation, as well as reduced cell death following doxorubicin exposure in HL1 cells. Daily GGF2 treatment beginning 7-14 days after left anterior descending coronary artery ligation produced improvements in LV ejection fraction and other measures of LV function and morphology. The improvements in LV function (e.g. 10% point increase in absolute LV ejection fraction) with GGF2 were dose-dependent. LV performance was substantially improved when GGF2 treatment was delivered infrequently, despite a serum half-life of less than 2h and could be maintained for more than 10 months with treatment once weekly or once every 2 weeks. These studies confirm previous findings that GGF2 may improve contractile performance in the failing rat heart and that infrequent exposure to GGF2 may improve LV function and impact remodeling in the failing myocardium. GGF2 is now being developed for the treatment of heart failure in humans., (Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cinnamaldehyde (CA), a major bioactive compound extracted from the essential oil of Cortex Cinnamomi, exhibits anti-inflammatory activity on endotoxemia. Accumulating evidence indicates reactive oxygen species (ROS) and autophagy play a vital role in the cardiac dysfunction during endotoxemia. The aim of this study was to unveil the mechanism of CA on ROS production and autophagy during endotoxemia. Male Sprague-Dawley rats were stimulated by LPS (20mg/kg i.v.) with or without treatment of CA. Cardiac function and histopathological staining were preformed 4h after LPS stimulation. The levels of TNF-α, IL-1β and IL-6 were detected by ELISA. The expression of p-JNK, p-ERK, p-p38, TLR4, NOX4, NOX2, ATG5 and LC3 proteins were determined by Western blot. The results showed that CA inhibited cardiac dysfunction, inflammatory infiltration and the levels of TNF-α, IL-1β and IL-6 in LPS stimulated rats by blocking the TLR4, NOX4, MAPK and autophagy signalings. In order to obtain further confirmation of the mechanism of CA on endotoxemia in vitro, a limited time-course study was firstly performed by Western blot. TLR4, NOX4 and LC3 were significantly increased after 4h LPS stimulation. CA reversed the intracellular ROS production and MAPK signaling activation induced by LPS. Electron microscopy, mRFP-GFP-LC3 transfection and western blot results revealed autophagic flux were attenuated after CA treatment. The siRNA and molecular docking results suggest that CA can suppress both TLR4 and NOX4 during endotoxemia. Our data revealed that CA ameliorated LPS-induced cardiac dysfunction by inhibiting ROS production and autophagy through TLR4-NOX4 pathway., (Copyright © 2016. Published by Elsevier Ltd.)

Rationale: Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart., Objective: To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart., Methods and Results: We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer + mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities., Conclusion: These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Aims: Macrophages are of key importance for tissue repair after myocardial infarction (MI). Hydrogen sulfide (H2S) has been shown to exert cardioprotective effects in MI. However, the mechanisms by which H2S modulates cardiac remodeling and repair post-MI remain to be clarified., Results: In our current study, we showed that H2S supplementation ameliorated pathological remodeling and dysfunction post-MI in wild-type (WT) and CSE KO mice, resulting in decreased infarct size and mortality, accompanied by an increase in the number of M2-polarized macrophages at the early stage of MI. Strikingly, adoptive transfer of NaHS-treated bone marrow-derived macrophages into WT and CSE KO mice with depleted macrophages also ameliorated MI-induced cardiac functional deterioration. Further mechanistic studies demonstrated that NaHS-induced M2 polarization was achieved by enhanced mitochondrial biogenesis and fatty acid oxidation., Innovation and Conclusion: Our study shows (for the first time) that H2S may have the potential as a therapeutic agent for MI via promotion of M2 macrophage polarization. Rebound Track: This work was rejected during standard peer review and rescued by Rebound Peer Review (Antioxid Redox Signal 16:293-296, 2012) with the following serving as open reviewers: Hideo Kimura, Chaoshu Tang, Xiaoli Tian, and Kenneth Olson. Antioxid. Redox Signal. 25, 268-281.

Background: Diastolic dysfunction (DD) is associated with exercise intolerance. To evaluate mechanisms of exercise intolerance in patients with DD, we performed bicycle stress echocardiography., Method and Results: Doppler measurements were performed at baseline, during exercise and recovery in 26 patients (58 ± 11 years) with DD and normal left ventricular ejection fraction and 6 normal controls (53 ± 5 years). Compared to controls, patients achieved similar target heart rates but lower METs (5.5 ± 2 vs. 9.8 ± 3, P < 0.01) and a higher peak pulmonary artery pressure (PAP) at peak exercise (50 ± 13 vs. 32 ± 7 mmHg, P < 0.01) despite similar PAP at rest and similar mean blood pressure at peak exercise (110.4 ± 18.0 vs. 106.9 ± 11.4 mmHg, P = NS). In patients versus controls, mitral E/E' was similar at baseline (10 ± 3 vs. 8 ± 1.3, P = NS) but higher at recovery (11 ± 2 vs. 7 ± 2, P < 0.05), % mitral filling time was shorter at baseline, onset, and peak exercise, whereas % LV and RV ejection time was similar to controls throughout exercise. Compared to controls, lateral mitral annular S' (11.8 ± 2.5 cm/sec vs. 14.9 ± 1.9 cm/sec, P < 0.02) and tricuspid annular S' (14.8 ± 4.1 cm/sec vs. 19.4 ± 4.0 cm/sec, P < 0.05) were lower at peak exercise in patients., Conclusion: Diastolic filling time is reduced at rest and stress while LV ejection time increases normally during exercise in DD. There is a reduced systolic reserve in LV and RV during exercise in DD. These mechanisms contribute to exercise intolerance and elevation of left atrial and PAP in patients with DD., (© 2016, Wiley Periodicals, Inc.)

Background: Angiotensin-converting enzyme inhibitors (ACEIs) are a mainstay of medical management in pediatric cardiology. However, there are no data defining how best to initiate and uptitrate the dose of these medications in children., Methods and Results: Retrospective chart review revealed only 24% of our pediatric cardiology inpatients were discharged on predefined optimal doses of ACEIs and few underwent further dose uptitration in the 8 weeks after hospital discharge. Therefore, 2 alternative protocols for initiation of captopril were compared in a prospective randomized clinical trial. A "rapid uptitration" protocol reached an optimal dose on day 3, whereas the alternative, "prolonged uptitration" protocol, reached an optimal dose on day 9. Forty-6 patients (54% male) were recruited to the trial, with a median age of 0.7 year (IQR 0.5-2.3 years). Captopril was initiated while in intensive care in 39% of patients and on the cardiology ward in 61%. There were no differences between the protocols in episodes of hypotension, symptomatic hypotension, or indices of renal function. Patients following the rapid protocol reached higher doses of captopril (0.93±0.24 versus 0.57±0.38 mg/kg per dose, P<0.0001) and were more likely to have achieved the predefined target (88% versus 43%, P=0.002) and optimal ACEI doses (80% versus 29%, P=0.001) before discharge., Conclusions: A protocol of rapid ACEI dose uptitration for infants and children with cardiovascular disease can be introduced safely, even in patients receiving intensive care therapy. Compared with standard clinical practice or with a more prolonged protocol, rapid ACEI dose uptitration achieves a higher dosage in this population with no evident disadvantages., Clinical Trial Registration: URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00742040., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Alterations in energetic state of the myocardium are associated with decompensated heart failure in humans and in animal models. However, the functional consequences of the observed changes in energetic state on mechanical function are not known. The primary aim of the study was to quantify mechanical/energetic coupling in the heart and to determine if energetic dysfunction can contribute to mechanical failure. A secondary aim was to apply a quantitative systems pharmacology analysis to investigate the effects of drugs that target cross-bridge cycling kinetics in heart failure-associated energetic dysfunction. Herein, a model of metabolite- and calcium-dependent myocardial mechanics was developed from calcium concentration and tension time courses in rat cardiac muscle obtained at different lengths and stimulation frequencies. The muscle dynamics model accounting for the effect of metabolites was integrated into a model of the cardiac ventricles to simulate pressure-volume dynamics in the heart. This cardiac model was integrated into a simple model of the circulation to investigate the effects of metabolic state on whole-body function. Simulations predict that reductions in metabolite pools observed in canine models of heart failure can cause systolic dysfunction, blood volume expansion, venous congestion, and ventricular dilation. Simulations also predict that myosin-activating drugs may partially counteract the effects of energetic state on cross-bridge mechanics in heart failure while increasing myocardial oxygen consumption. Our model analysis demonstrates how metabolic changes observed in heart failure are alone sufficient to cause systolic dysfunction and whole-body heart failure symptoms., (Copyright © 2016. Published by Elsevier Ltd.)

Selective pharmacological treatments targeting reperfusion injury produced modest protective effects and might be associated with immunosuppression. In order to identify novel and better-tolerated approaches, we focused on the neutralization of receptor activator of nuclear factor kappa-B ligand [RANKL], a cytokine recently shown to activate inflammatory cells (i.e. neutrophils) orchestrating post-infarction injury and repair. Myocardial ischemia (60min) and reperfusion injury was surgically induced in C57Bl/6 mice. In hearts and serum, RANKL was early upregulated during reperfusion. A "one-shot" injection with neutralizing anti-RANKL IgG during ischemia ameliorated myocardial infarct size and function, but not adverse remodeling (determined by Magnetic Resonance Imaging [MRI]) as compared to Vehicle or control IgG. These beneficial effects were accompanied in vivo by reduction in cardiac neutrophil infiltration, reactive oxygen species (ROS) and MMP-9 release. Anti-RANKL IgG treatment suppressed sudden peak of neutrophil granule products in mouse serum early after reperfusion onset. In vitro, RANK mRNA expression was detected in isolated mouse neutrophils. Co-incubation with neutralizing anti-RANKL IgG abrogated RANKL-induced mouse neutrophil degranulation and migration, suggesting a critical role of RANKL in neutrophil-mediated injury. Conversely, anti-RANKL IgG did not affect salvage pathways in cardiac cells (i.e. ERK p42/p44, Akt and STAT-3) or macrophage cardiac infiltration. Finally, treatment with anti-RANKL IgG showed no effect on B and T lymphocyte polarization (in serum, spleen and infarcted myocardium) and circulating chemokines as compared with Vehicle or control IgG. In conclusion, acute treatment with anti-RANKL IgG improved cardiac infarct size and function by potentially impacting on neutrophil-mediated injury and repair., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Although nesiritide has been used in adults with left heart failure, the experience in the paediatric population is limited. We reviewed and analysed our experience with continuous nesiritide infusion as adjunct therapy in children with biventricular dysfunction due to diverse aetiologies and suffering from oliguria despite intravenous diuretics and inotropic therapies for heart-failure management.

Ebstein&#039;s anomaly is a rare form of congenital malformation of the heart, characterized by apical displacement of the septal and posterior tricuspid valve leaflets, leading to atrialisation of the right ventricle with a variable degree of malformation and displacement of the anterior leaflet. It may not be detected until late in adolescence or adulthood. The clinical manifestations of Ebstein&#039;s anomaly vary greatly. We are reporting a case of 35-year male who presented with generalized fatigue, palpitation and effort intolerance. Laboratory investigations confirmed the diagnosis of diabetes ketosis. Transthoracic echocardiography showed severe Ebstein&#039;s anomaly with severe tricuspid regurgitation, no residual atrial septal defect, but with severe right ventricular dysfunction. Though only few studies showed the high prevalence of abnormal glucose metabolism in young adult patients with complex congenital heart disease, but Epstein&#039;s anomaly with diabetes ketosis was nowhere mentioned.

Background: Ventricular arrhythmias induced by ischemic heart disease are the main cause of sudden cardiac death. Ischemia can cause life-threatening arrhythmias by modulating connexin 43 (Cx43), a principal cardiac gap junction channel protein. The present study investigates whether nitrite can attenuate ischemia-induced ventricular arrhythmias and dephosphorylation of Cx43 in a rat model., Methods: Rats were medicated with normal saline (control, n = 10), nitrite (0.015, 0.15, and 1.5 mg/kg, n = 9 or 10 each), and 0.15 mg/kg nitrite with either the nitric oxide scavenger 2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, sodium salt (cPTIO; n = 9) or allopurinol (xanthine oxidoreductase inhibitor, n = 9). We determined the severity of ventricular arrhythmias based on arrhythmia scores and levels of phosphorylated Cx43., Results: The median arrhythmia score may have been lower in the group given 0.15 mg/kg nitrite (4 [interquartile range {IQR}, 4-5]) than that in the control group (7.5 [IQR, 5.25-8]; P = 0.013). There was no difference among the control, the given 0.015 mg/kg nitrite (7 [IQR, 5-8]), and 1.5 mg/kg nitrite (7 [IQR, 5.5-7.75]; P = 0.95). The arrhythmia scores in the cPTIO (6 [IQR, 5-8]; P = 0.030) and allopurinol (7 [IQR, 5-8]; P = 0.005) groups may have been higher than that in 0.15 mg/kg nitrite group. Immunoblotting revealed that the level of phosphorylated Cx43 in the group given 0.15 mg/kg nitrite, but not in the other treated groups, was significantly higher compared with the control group (P = 0.007)., Conclusions: Nitrite may have attenuated acute ischemia-induced ventricular arrhythmias and Cx43 dephosphorylation in rats. Nitric oxide, which might be generated by xanthine oxidoreductase via nitrite reduction, appears to play a crucial role in this antiarrhythmic effect.

Cardiac remodeling is defined as a group of molecular, cellular and interstitial changes that manifest clinically as changes in size, mass, geometry and function of the heart after injury. The process results in poor prognosis because of its association with ventricular dysfunction and malignant arrhythmias. Here, we discuss the concepts and clinical implications of cardiac remodeling, and the pathophysiological role of different factors, including cell death, energy metabolism, oxidative stress, inflammation, collagen, contractile proteins, calcium transport, geometry and neurohormonal activation. Finally, the article describes the pharmacological treatment of cardiac remodeling, which can be divided into three different stages of strategies: consolidated, promising and potential strategies.

This study characterized the antiarrhythmic effects of the opioid receptor antagonist naloxone in rats subject to electrically induced and ischemic arrhythmias. Naloxone (2, 8 and 32 μmol/kg/min) was examined on heart rate, blood pressure, and the electrocardiogram (EKG) as well as for effectiveness against arrhythmias produced by occlusion of the left anterior descending coronary artery or electrical stimulation of the left ventricle. Naloxone reduced blood pressure at the highest dose tested while heart rate was dose-dependently reduced. Naloxone dose-dependently prolonged the P-R and QRS intervals and increased the RSh amplitude indicative of effects on cardiac sodium (Na) channels. Naloxone prolonged the Q-T interval suggesting a delay in repolarization. Naloxone effects were comparable to the comparator quinidine. Naloxone (32 μmol/kg/min) reduced ventricular fibrillation (VF) incidence to 38% (from 100% in controls). This same dose significantly increased the threshold for induction of ventricular fibrillation (VFt), prolonged the effective refractory period (ERP) and reduced the maximal following frequency (MFF). The patterns of ECG changes, reduction in ischemic arrhythmia (VF) incidence and changes in electrically induced arrhythmia parameters at high doses of naloxone suggest that it directly blocks cardiac Na and potassium (K) ion channels., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Despite key advances in the clinical management of life-threatening ventricular arrhythmias, culminating with the development of implantable cardioverter-defibrillators and catheter ablation techniques, pharmacologic/biologic therapeutics have lagged behind. The fundamental issue is that biological targets are molecular factors. Diseases, however, represent emergent properties at the scale of the organism that result from dynamic interactions between multiple constantly changing molecular factors. For a pharmacologic/biologic therapy to be effective, it must target the dynamic processes that underlie the disease. Here we propose a classification of ventricular arrhythmias that is based on our current understanding of the dynamics occurring at the subcellular, cellular, tissue and organism scales, which cause arrhythmias by simultaneously generating arrhythmia triggers and exacerbating tissue vulnerability. The goal is to create a framework that systematically links these key dynamic factors together with fixed factors (structural and electrophysiological heterogeneity) synergistically promoting electrical dispersion and increased arrhythmia risk to molecular factors that can serve as biological targets. We classify ventricular arrhythmias into three primary dynamic categories related generally to unstable Ca cycling, reduced repolarization, and excess repolarization, respectively. The clinical syndromes, arrhythmia mechanisms, dynamic factors and what is known about their molecular counterparts are discussed. Based on this framework, we propose a computational-experimental strategy for exploring the links between molecular factors, fixed factors and dynamic factors that underlie life-threatening ventricular arrhythmias. The ultimate objective is to facilitate drug development by creating an in silico platform to evaluate and predict comprehensively how molecular interventions affect not only a single targeted arrhythmia, but all primary arrhythmia dynamics categories as well as normal cardiac excitation-contraction coupling., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The development of diabetic cardiomyopathy is a key contributor to heart failure and mortality in obesity and type 2 diabetes (T2D). Current therapeutic interventions for T2D have limited impact on the development of diabetic cardiomyopathy. Clearly, new therapies are urgently needed. A potential therapeutic target is protein kinase D (PKD), which is activated by metabolic insults and implicated in the regulation of cardiac metabolism, contractility and hypertrophy. We therefore hypothesised that PKD inhibition would enhance cardiac function in T2D mice. We first validated the obese and T2D db/db mouse as a model of early stage diabetic cardiomyopathy, which was characterised by both diastolic and systolic dysfunction, without overt alterations in left ventricular morphology. These functional characteristics were also associated with increased PKD2 phosphorylation in the fed state and a gene expression signature characteristic of PKD activation. Acute administration of the PKD inhibitor CID755673 to normal mice reduced both PKD1 and 2 phosphorylation in a time and dose-dependent manner. Chronic CID755673 administration to T2D db/db mice for two weeks reduced expression of the gene expression signature of PKD activation, enhanced indices of both diastolic and systolic left ventricular function and was associated with reduced heart weight. These alterations in cardiac function were independent of changes in glucose homeostasis, insulin action and body composition. These findings suggest that PKD inhibition could be an effective strategy to enhance heart function in obese and diabetic patients and provide an impetus for further mechanistic investigations into the role of PKD in diabetic cardiomyopathy.

The incretin hormone glucagon-like peptide-1 (Glp1) is cardioprotective in models of ischemia-reperfusion injury, myocardial infarction and gluco/lipotoxicity. Inflammation is a factor in these models, yet it is unknown whether Glp1 receptor (Glp1r) agonists are protective against cardiac inflammation. We tested the hypothesis that the Glp1r agonist Exendin-4 (Ex4) is cardioprotective in mice with cardiac-specific monocyte chemoattractant protein-1 overexpression. These MHC-MCP1 mice exhibit increased cardiac monocyte infiltration, endoplasmic reticulum (ER) stress, apoptosis, fibrosis and left ventricular dysfunction. Ex4 treatment for 8 weeks improved cardiac function and reduced monocyte infiltration, fibrosis and apoptosis in MHC-MCP1 mice. Ex4 enhanced expression of the ER chaperone glucose-regulated protein-78 (GRP78), decreased expression of the pro-apoptotic ER stress marker CCAAT/-enhancer-binding protein homologous protein (CHOP) and increased expression of the ER calcium regulator Sarco/Endoplasmic Reticulum Calcium ATPase-2a (SERCA2a). These findings suggest that the Glp1r is a viable target for treating cardiomyopathies associated with stimulation of pro-inflammatory factors., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The protective role of etanercept in myocardial ischemia/reperfusion is not well understood. The aim of this study was to investigate whether etanercept modulates neutrophil accumulation, TNF-α induction and oxidative stress in an ischemia/reperfusion injured rat heart model. Rats were randomly exposed to sham operation, myocardial ischemia/reperfusion (MI/R) alone, MI/R+ etanercept. The results demonstrated that compared to MI/R, etanercept reduced myocardial infarction area, myocardial myeloperoxidase (MPO) levels, serum creatinine kinase (CK) and lactate dehydrogenase (LDH) levels, and both serum and myocardial TNF-α production. Etanercept also markedly enhanced the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-PX), and reduced the level of malondialdehyde (MDA) in MI/R rats. In summary, our data suggested that etanercept has protective effects against MI/R injury in rats, which may be attributed to attenuating inflammation and oxidative stress.

Excessive dietary salt intake induces extensive cardiovascular and renal damage in spontaneously hypertensive rats (SHR) that may be prevented by antihypertensive agents. This study examines whether salt-induced cardiac damage may be reversed by angiotensin II (type 1) receptor blockade (telmisartan). Eight-week-old male SHRs were divided into four groups; Group 1 (NS) was fed regular rat chow, and Group 2 (HS) received high-salt diet (HS; 8% NaCl). After 8 weeks on their respective diets, systemic hemodynamics and indices of left ventricular (LV) function were determined. Group 3 (HSnoT) was given HS for 8 weeks and then switched to a regular chow (0.6% NaCl) diet with no other treatment, and Group 4 (HSArb) received HS for 8 weeks and was then given regular diet plus telmisartan. Rats from these latter two groups were monitored for the ensuing 30 days. Compared with the NS group, rats in the HS group exhibited increased mean arterial pressure (161 ± 7 vs. 184 ± 8 mm Hg) and LV diastolic dysfunction, as evidenced by a decreased rate of LV pressure decline (-8754 ± 747 vs. -4234 ± 754 mmHg/sec) at the end of the 8 weeks of their respective treatment. After switching to regular chow, only one of 11 rats in the HSnoT group survived for the 30 days, whereas 10 died within 18 days; in the HSArb group only one of nine rats died; eight survived 30 days (P < .01). Telmisartan significantly improved LV function and survival in those SHR rats having extensive cardiovascular damage induced by dietary salt excess., (Copyright © 2014 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.)

Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

Background: Secondhand smoke (SHS) impairs cardiac function and resveratrol is cardioprotective, possibly via antioxidant and anti-inflammatory capabilities. Previously, it was shown that resveratrol protects against SHS-induced cardiac dysfunction, but the molecular mechanism is not clear., Methods: We measured cardiac function in pigs exposed to SHS alone in a first experiment or with and without resveratrol (5 mg/kg/day) in a second experiment using echocardiography and compared this with proteomic changes., Results: In the first experiment after 28 days, end-diastolic volume, end-systolic volume, and stroke volume were all impaired in SHS pigs compared with control pigs, with cardiac output significantly depressed as early as 14 days. Depressed function corresponded to increased inflammation, oxidative stress, and matrix metalloproteinase-2, but decreased intact myosin light chain 1 in SHS compared with control pigs at 28 days. In our second study after 14 days, two-dimensional electrophoresis detected 6 significantly increased protein spots in SHS compared with control pigs. Mass spectrometry identified 4 spots as fragments of sarcomeric protein (1 myosin light chain 1, 1 β-myosin heavy chain, and 2 myosin-7), and 2 spots as glucose metabolism enzymes (lactate and pyruvate dehydrogenases). Resveratrol normalized the fragmented protein levels, but not the metabolic enzymes. At 14 days, matrix metalloproteinase-2 activity almost doubled in cardiac tissue from SHS compared with control pigs, and resveratrol appeared to normalize it., Conclusions: Thus, the ventricular differences in protein expression might explain the mechanism by which SHS reduces critical hemodynamic parameters through the degradation of sarcomeres, appearing to be prevented by resveratrol administration., (Copyright © 2013 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Background: Chagas disease is a tropical parasitic disease caused by the flagellate protozoan Trypanosoma cruzi. Chagasic cardiomyopathy is characterized by disorders of autonomic regulation and action potential conduction in the acute and chronic phases of infection. Although tumor necrosis factor alpha (TNF-α) has been linked to cardiomyopathy in experimental models and in patients with Chagas disease, other reports suggest that TNF-α may exert anti-parasitic actions during the acute phase of infection., Objectives: This study aimed to determine the effects of a soluble TNF-α agonist, etanercept, on electrocardiographic parameters in the acute phase of experimental infection with Trypanosoma cruzi., Methods: Electrocardiograms were obtained from untreated infected mice and infected mice who were treated with etanercept 7 days after infection. ECG wave and heart rate variability parameters were determined using Chart for Windows., Results: Etanercept treatment resulted in a low QRS voltage and decreased heart rate variability compared with no treatment. However, the treated mice exhibited a delay in the fall of the survival curve during the acute phase., Conclusion: The results of this study suggest that although etanercept treatment promotes survival in mice infected with a virulent T. cruzi strain, TNF-α blockade generates a low voltage complex and autonomic dysfunction during the acute phase of infection. These findings indicate that mortality during the acute phase can be attributed to a systemic inflammatory response rather than cardiac dysfunction.

Current therapy of pulmonary arterial hypertension (PAH) is inadequate. Dehydroepiandrosterone (DHEA) effectively treats experimental pulmonary hypertension in chronically hypoxic and monocrotaline-injected rats. Contrary to these animal models, SU5416/hypoxia/normoxia-exposed rats develop a more severe form of occlusive pulmonary arteriopathy and right ventricular (RV) dysfunction that is indistinguishable from the human disorder. Thus, we tested the effects of DHEA treatment on PAH and RV structure and function in this model. Chronic (5 wk) DHEA treatment significantly, but moderately, reduced the severely elevated RV systolic pressure. In contrast, it restored the impaired cardiac index to normal levels, resulting in an improved cardiac function, as assessed by echocardiography. Moreover, DHEA treatment inhibited RV capillary rarefaction, apoptosis, fibrosis, and oxidative stress. The steroid decreased NADPH levels in the RV. As a result, the reduced reactive oxygen species production in the RV of these rats was reversed by NADPH supplementation. Mechanistically, DHEA reduced the expression and activity of Rho kinases in the RV, which was associated with the inhibition of cardiac remodeling-related transcription factors STAT3 and NFATc3. These results show that DHEA treatment slowed the progression of severe PAH in SU5416/hypoxia/normoxia-exposed rats and protected the RV against apoptosis and fibrosis, thus preserving its contractile function. The antioxidant activity of DHEA, by depleting NADPH, plays a central role in these cardioprotective effects.