Ovarian hormones do not mediate protection against pulmonary hypertension and right ventricular remodeling in female mice exposed to chronic, inhaled nicotine.

Electronic cigarette use has increased globally prompting calls for improved understanding of nicotine's cardiovascular health effects. Our group has previously demonstrated that chronic, inhaled nicotine induces pulmonary hypertension and right ventricular (RV) remodeling in male mice, but not female mice, suggesting sex differences in nicotine-related pathology. Clinically, biological females develop pulmonary hypertension more often but have less severe disease than biological males, likely because of the cardiopulmonary protective effects of estrogen. Nicotine is also metabolized more rapidly in biological females because of differences in cytochrome-P450 activity, which are thought to be mediated by female sex hormones. These findings led us to hypothesize that female mice are protected against nicotine-induced pulmonary hypertension by an ovarian hormone-dependent mechanism. In this study, intact and ovariectomized (OVX) female mice were exposed to chronic, inhaled nicotine or room air for 12 h/day for 10-12 wk. We report no differences in serum cotinine levels between intact and OVX mice. In addition, we found no structural (RV or left ventricular dimensions and Fulton index) or functional (RV systolic pressure, pulmonary vascular resistance, cardiac output, ejection fraction, and fractional shortening) evidence of cardiopulmonary dysfunction in intact or OVX mice. We conclude that ovarian hormones do not mediate cardiopulmonary protection against nicotine-induced pulmonary hypertension. Due to profound sex differences in clinical pulmonary hypertension pathogenesis and nicotine metabolism, further studies are necessary to elucidate mechanisms underlying protection from nicotine-induced pathology in female mice.NEW & NOTEWORTHY The emergence of electronic cigarettes poses a threat to cardiovascular and pulmonary health, but the direct contribution of nicotine to these disease processes is largely unknown. Our laboratory has previously shown that chronic, inhaled nicotine induces pulmonary hypertension and right ventricular remodeling in male mice, but not female mice. This study using a bilateral ovariectomy model suggests that the cardiopulmonary protection observed in nicotine-exposed female mice may be independent of ovarian hormones.

Right ventricular and atrial strain in patients with advanced melanoma undergoing immune checkpoint inhibitor therapy.

AIMS: While immune checkpoint inhibitor (ICI) therapy significantly improves survival rates in advanced melanoma, ICI can evoke severe immune-related cardiovascular adverse events. Right ventricular (RV) dysfunction negatively impacts the outcomes in cardiovascular diseases and may be an early sign for overall cardiotoxicity. We aimed to assess RV function in melanoma patients undergoing ICI therapy using conventional echocardiographic and strain imaging techniques. METHODS AND RESULTS: We retrospectively examined 30 patients (40% women, age 59 ± 13 years) with advanced melanoma (stage III/IV) before and 4 weeks after the start of ICI therapy (follow-up at 39 ± 15 days); n = 15 of the patients received nivolumab, and n = 15 received the combination therapy nivolumab/ipilimumab. Two-dimensional echocardiography with assessment of RV longitudinal strain of the free wall (RV-LSFW) and assessment of right atrial (RA) strain from speckle tracking was performed at baseline and after the start of ICI therapy. Short-term ICI therapy caused a reduction of RV-LSFW (-25.5 ± 6.4% vs. -22.4 ± 4.3%, P = 0.002) and of RA strain during contraction phase (-10.6 ± 3.5% vs. -7.7 ± 3.1%, P = 0.001). Conventional parameters including tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC), and pulmonary artery systolic pressure were not different between the two time points (TAPSE 26 ± 5 vs. 25 ± 5 mm, P = 0.125; FAC 38 ± 13% vs. 38 ± 14%, P = 0.750; and pulmonary artery systolic pressure 27 ± 10 vs. 25 ± 8 mmHg, P = 0.268). CONCLUSIONS: Analysis of RV and RA strain shows alterations even in a short-term follow-up, while changes in RV function are not visible by conventional RV parameters. Alterations in RV and RA strain could be early signs of cardiotoxicity and therefore should be assessed in patients undergoing ICI therapy.

Xbp1s-Ddit3 promotes MCT-induced pulmonary hypertension.

Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling. Exploring new therapy target is urgent. The purpose of the present study is to investigate whether and how spliced x-box binding protein 1 (xbp1s), a key component of endoplasmic reticulum stress (ERS), contributes to the pathogenesis of PH. Forty male SD rats were randomly assigned to four groups: Control, Monocrotaline (MCT), MCT+AAV-CTL (control), and MCT+AAV-xbp1s. The xbp1s protein levels were found to be elevated in lung tissues of the MCT group. Intratracheal injection of adeno-associated virus serotype 1 carrying xbp1s shRNA (AAV-xbp1s) to knock down the expression of xbp1s effectively ameliorated the MCT-induced elevation of right ventricular systolic pressure (RVSP), total pulmonary resistance (TPR), right ventricular hypertrophy and medial wall thickness of muscularized distal pulmonary arterioles. The abnormally increased positive staining rates of proliferating cell nuclear antigen (PCNA) and Ki67 and decreased positive staining rates of terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) in pulmonary arterioles were also reversed in the MCT+AAV-xbp1s group. For mechanistic exploration, bioinformatics prediction of the protein network was performed on the STRING database, and further verification was performed by qRT-PCR, Western blots and co-immunoprecipitation (Co-IP). DNA damage-inducible transcript 3 (Ddit3) was identified as a downstream protein that interacted with xbp1s. Overexpression of Ddit3 restored the decreased proliferation, migration and cell viability caused by silencing of xbp1s. The protein level of Ddit3 was also highly consistent with xbp1s in the animal model. Taken together, our study demonstrated that xbp1s-Ddit3 may be a potential target to interfere with vascular remodeling in PH.

Right ventricular dysfunction in patients with diffuse large B-cell lymphoma undergoing anthracycline-based chemotherapy: a 2D strain and 3D echocardiography study.

To investigate whether 2D strain and 3D echocardiography could early identify the impaired right ventricular (RV) function after anthracycline exposure. Sixty-one patients with diffuse large B-cell lymphoma treated with anthracycline were studied. Echocardiography was conducted at baseline, after the third cycle of the chemotherapy, after the completion of the chemotherapy, and follow-up at 10 months after the initiation of chemotherapy. RV global longitudinal strain (RV GLS) and RV free wall longitudinal strain (RV FWLS) were calculated using speckle tracking echocardiography. RV ejection fraction (RVEF) was analyzed by 3D echocardiography. RV systolic dysfunction was defined by ≥ 2 RV parameters below the threshold value, and cardiotoxicity was defined as a reduction in left ventricular EF > 10 to < 53%. After the third cycle of chemotherapy, only RV GLS was significantly decreased, while after the completion of the chemotherapy, RV GLS, RV FWLS, and RVEF were all significantly decreased compared with baseline measurements. At the end of follow-up, 9 patients (14.8%) were diagnosed with RV systolic dysfunction, and 16 patients (26.2%) had at least 1 abnormal RV function parameter. The proportion of RV systolic dysfunction was significantly higher in patients with cardiotoxicity than in patients without cardiotoxicity, yielding an odds ratio of 5.143. A percentage decrease in RV FWLS and RVEF were independent predictors of RV systolic dysfunction. Two-dimensional strain and 3D echocardiography are valuable methods for evaluating anthracycline-related impairment of RV function in DLBCL patients receiving chemotherapy. RV FWLS and RVEF are reliable predictors of RV systolic dysfunction.

Chronic cardiac structural damage, diastolic and systolic dysfunction following acute myocardial injury due to bromine exposure in rats.

Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600 ppm for 45 min) and the survivors were sacrificed at 14 or 28 days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.

Combination therapy improves vascular volume in female rats with pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.

PI3Kα Pathway Inhibition With Doxorubicin Treatment Results in Distinct Biventricular Atrophy and Remodeling With Right Ventricular Dysfunction.

Background Cancer therapies inhibiting PI 3Kα (phosphoinositide 3-kinase-α)-dependent growth factor signaling, including trastuzumab inhibition of HER 2 (Human Epidermal Growth Factor Receptor 2), can cause adverse effects on the heart. Direct inhibition of PI 3Kα is now in clinical trials, but the effects of PI 3Kα pathway inhibition on heart atrophy, remodeling, and function in the context of cancer therapy are not well understood. Method and Results Pharmacological PI 3Kα inhibition and heart-specific genetic deletion of p110α, the catalytic subunit of PI 3Kα, was characterized in conjunction with anthracycline (doxorubicin) treatment in female murine models. Biventricular changes in heart morphological characteristics and function were analyzed, with molecular characterization of signaling pathways. Both PI 3Kα inhibition and anthracycline therapy promoted heart atrophy and a combined effect of distinct right ventricular dilation, dysfunction, and cardiomyocyte remodeling in the absence of pulmonary arterial hypertension. Congruent findings of right ventricular dilation and dysfunction were seen with pharmacological and genetic suppression of PI 3Kα signaling when combined with doxorubicin treatment. Increased p38 mitogen-activated protein kinase activation was mechanistically linked to heart atrophy and correlated with right ventricular dysfunction in explanted failing human hearts. Conclusions PI 3Kα pathway inhibition promotes heart atrophy in mice. The right ventricle is specifically at risk for dilation and dysfunction in the setting of PI 3K inhibition in conjunction with chemotherapy. Inhibition of p38 mitogen-activated protein kinase is a proposed therapeutic target to minimize this mode of cardiotoxicity.

Longitudinal changes of right ventricular deformation mechanics during trastuzumab therapy in breast cancer patients.

BACKGROUND: Trastuzumab improves dramatically the prognosis of HER2-positive breast cancer patients, but it may lead to cardiotoxicity with left ventricular (LV) systolic dysfunction. Its effects on right ventricular (RV) function have not however been elucidated. We sought to assess LV and RV deformation mechanics during treatment with trastuzumab in breast cancer patients. METHODS AND RESULTS: We studied 101 consecutive women (mean age 54.3 ± 11.4 years) receiving trastuzumab for 12 months; 62 of them (61.4%) had previously received anthracyclines and 26 (25.7%) were receiving taxanes concurrently with trastuzumab. Comprehensive two-dimensional echocardiography with speckle tracking imaging of LV and RV global longitudinal strain (GLS) and RV free wall longitudinal strain (FWLS) analyses were performed at baseline and every 3 months up to treatment completion. Cardiotoxicity was defined as a decrease of baseline LV ejection fraction > 10 percentage units to a value < 50%. At 3 months, only LV GLS was significantly reduced (-19.5 ± 2.7 to -18.7 ± 2.8, P = 0.0410), while at 6 months, LV GLS, RV GLS and RV FWLS had significantly declined reaching their lowest values (-17.9 ± 6.1, P = 0.002, -19.6 ± 5.2, P = 0.003 and -19.7 ± 5.6, P = 0.004, respectively). Ten women (9.9%) developed cardiotoxicity. A RV GLS percent change of -14.8% predicted cardiotoxicity with 66.7% sensitivity and 70.8% specificity (area under the curve 0.68, 95% confidence interval 0.54-0.81), classifying correctly 90% of women with cardiotoxicity. This cut-off is quite similar to the 15% change of LV GLS previously suggested as predictive of cardiotoxicity. CONCLUSIONS: Deformation mechanics of both the left and right ventricle follow similar temporal pattern and degree of impairment during trastuzumab therapy, confirming the global and uniform effect of trastuzumab on myocardial function.

Copaiba Oil Attenuates Right Ventricular Remodeling by Decreasing Myocardial Apoptotic Signaling in Monocrotaline-Induced Rats.

There is an increase in oxidative stress and apoptosis signaling during the transition from hypertrophy to right ventricular (RV) failure caused by pulmonary arterial hypertension (PAH) induced by monocrotaline (MCT). In this study, it was evaluated the action of copaiba oil on the modulation of proteins involved in RV apoptosis signaling in rats with PAH. Male Wistar rats (±170 g, n = 7/group) were divided into 4 groups: control, MCT, copaiba oil, and MCT + copaiba oil. PAH was induced by MCT (60 mg/kg intraperitoneally) and, 7 days later, treatment with copaiba oil (400 mg/kg by gavage) was given for 14 days. Echocardiographic and hemodynamic measurements were performed, and the RV was collected for morphometric evaluations, oxidative stress, apoptosis, and cell survival signaling, and eNOS protein expression. Copaiba oil reduced RV hypertrophy (24%), improved RV systolic function, and reduced RV end-diastolic pressure, increased total sulfhydryl levels and eNOS protein expression, reduced lipid and protein oxidation, and the expression of proteins involved in apoptosis signaling in the RV of MCT + copaiba oil as compared to MCT group. In conclusion, copaiba oil reduced oxidative stress, and apoptosis signaling in RV of rats with PAH, which may be associated with an improvement in cardiac function caused by this compound.

A Case of Cardiomyopathy Due to Premature Ductus Arteriosus Closure: The Flip Side of Paracetamol.

Paracetamol (acetaminophen or N-acetyl-p-aminophenol) is considered a safe analgesic and antipyretic nonsteroidal antiinflammatory drug commonly used during pediatric ages and during pregnancy. We report on a term neonate with closed ductus arteriosus, severe cardiomyopathy, right ventricular dysfunction, and functional stenosis of pulmonary arteries at birth after maternal self-medication with paracetamol and consumption of polyphenol-rich foods in late pregnancy. This drug, especially when associated with other vasoconstrictors (such as polyphenols), interferes with prostaglandin metabolism, which seriously accentuates the intrauterine ductus arteriosus constriction and leads to pharmacologic adverse events. We suggest maternal educational programs to avoid risky self-medications and provide training for the best diets.

Longitudinal assessment of right ventricular structure and function by cardiovascular magnetic resonance in breast cancer patients treated with trastuzumab: a prospective observational study.

BACKGROUND: There are limited data on the effects of trastuzumab on the right ventricle (RV). Therefore, we sought to evaluate the temporal changes in right ventricular (RV) structure and function as measured by cardiovascular magnetic resonance (CMR), and their relationship with left ventricular (LV) structure and function in breast cancer patients treated with trastuzumab. METHODS: Prospective, longitudinal, observational study involving 41 women with HER2+ breast cancer who underwent serial CMR at baseline, 6, 12, and 18 months after initiation of trastuzumab. A single blinded observer measured RV parameters on de-identified CMRs in a random order. Linear mixed models were used to investigate temporal changes in RV parameters. RESULTS: Of the 41 women (age 52 ± 11 years), only one patient experienced trastuzumab-induced cardiotoxicity. Compared to baseline, there were small but significant increases in the RV end-diastolic volume at 6 months (p = 0.002) and RV end-systolic volume at 6 and 12 months (p < 0.001 for both), but not at 18 months (p = 0.82 and 0.13 respectively). RV ejection fraction (RVEF), when compared to baseline (58.3%, 95% CI 57.1-59.5%), showed corresponding decreases at 6 months (53.9%, 95% CI 52.5-55.4%, p < 0.001) and 12 months (55%, 95% CI 53.8-56.2%, p < 0.001) that recovered at 18 months (56.6%, 95% CI 55.1-58.0%, p = 0.08). Although the temporal pattern of changes in LVEF and RVEF were similar, there was no significant correlation between RVEF and LVEF at baseline (r = 0.29, p = 0.07) or between their changes at 6 months (r = 0.24, p = 0.17). CONCLUSION: In patients receiving trastuzumab without overt cardiotoxicity, there is a subtle but significant deleterious effect on RV structure and function that recover at 18 months, which can be detected by CMR. Furthermore, monitoring of LVEF alone may not be sufficient in detecting early RV injury. These novel findings provide further support for CMR in monitoring early cardiotoxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01022086 . Date of registration: November 27, 2009.

Altered mTOR and Beclin-1 mediated autophagic activation during right ventricular remodeling in monocrotaline-induced pulmonary hypertension.

BACKGROUND: Right ventricular structure and function is a major predictor of outcomes in pulmonary hypertension (PH), yet the underlying mechanisms remain poorly understood. Growing evidence suggests the importance of autophagy in cardiac remodeling; however, its dynamics in the process of right ventricle(RV) remodeling in PH has not been fully explored. We sought to study the time course of cardiomyocyte autophagy in the RV in PH and determine whether mammalian target of rapamycin (mTOR) and Beclin-1 hypoxia-related pro-autophagic pathways are underlying mechanisms. METHODS: Rats were studied at 2, 4, and 6 weeks after subcutaneous injection of 60 mg/kg monocrotaline (MCT) (MCT-2 W, 4 W, 6 W) or vehicle (CON-2 W, 4 W, 6 W). Cardiac hemodynamics and RV function were assessed in rats. Autophagy structures and markers were assessed using transmission electron microscope, RT-qPCR, immunohistochemistry staining, and western blot analyses. Western blot was also used to quantify the expression of mTOR and Beclin-1 mediated pro-autophagy signalings in the RV. RESULTS: Two weeks after MCT injection, pulmonary artery systolic pressure increased and mild RV hypertrophy without RV dilation was observed. RV enlargement presented at 4 weeks with moderately decreased function, whereas typical characteristics of RV decompensation and failure occurred at 6 weeks thus demonstrating the progression of RV remodeling in the MCT model. A higher LC3 (microtubule- associated protein light chain 3) II/I ratio, upregulated LC3 mRNA and protein levels, as well as accumulation of autophagosomes in RV of MCT rats indicated autophagy induction. Autophagy activation was coincident with increased pulmonary artery systolic pressure. Pro-autophagy signaling pathways were activated in a RV remodeling stage-dependent manner since phospho-AMPK (adenosine monophosphate-activated protein kinase)-α were primarily upregulated and phospho-mTOR suppressed in the RV at 2 and 4 weeks post-MCT injection, whearas, BNIP3 (Bcl2-interacting protein 3) and beclin-1 expression were relatively low during these stages, they were significantly upregulated after 6 weeks in this model. CONCLUSIONS: Our findings provide evidence of sustained activation of autophagy in RV remodeling of MCT induced PH model, while pro-autophagic signaling pathways varied depending on the phase.

The influence of chemotherapy on the right ventricle: did we forget something?

BACKGROUND: A large number of chemotherapy-induced cardiovascular complications were discovered in studies over the last several decades. The focus of the majority of these studies was left ventricular (LV) remodeling. The aim of this article was to provide a comprehensive overview of potential mechanisms of chemotherapy-induced right ventricular (RV) remodeling and summarize clinical studies on this topic. HYPOTHESIS: Chemotherapy induces RV structural, functional, and mechanical changes. METHODS: We searched PubMed, MEDLINE, Ovid and Embase databases for studies published from January 1990 up to September 2016 in the English language using the following keyword "chemotherapy," "heart," "right ventricle," "anthracyclines," and "trastuzumab." RESULTS: The existing research show that RV remodeling occurs simultaneously with LV remodeling, which is why RV remodeling should not be neglected in the overall cardiac assessment of patients treated with chemotherapy, and especially those protocols that involve anthracyclines and trastuzumab. Investigations showed that these agents could significantly impact RV structure, function, and mechanics. These medications induce fibrosis of the RV myocardium, RV dilatation, decline in RV systolic function, worsening of its diastolic function, and finally impairment of RV mechanics (strain). The mechanisms of chemotherapy-induced RV remodeling are still not entirely clear, but it is considered that direct destructive influence of chemotherapy on myocardium, oxidative stress, endothelial dysfunction, and negative impact on pulmonary circulation could significantly contribute to RV impairment. CONCLUSIONS: Chemotherapy induces the impairment of RV structure, function, and mechanics by different complex mechanisms.

Alterations in the echocardiographic variables of the right ventricle in asymptomatic patients with breast cancer during anthracycline chemotherapy.

BACKGROUND: Anthracycline-induced cardiotoxicity can reach an irreversible phase; therefore great efforts are made to diagnose it early. As the right ventricle (RV) is smaller than the left, the right side of the heart is probably influenced by anthracycline to a greater extent and in a shorter time. The purpose of the present study was to investigate the early effects of chemotherapy on the right side of the heart. METHODS: This cross-sectional study was performed in Isfahan University hospitals from August 2014 to December 2015. Subjects were 67 patients with breast cancer who were planned to receive anthracycline for the first time. Echocardiography was performed before administration of anthracycline and 6 months later. Variables included right heart measures (RV end-diastolic dimensions, right atrium length and diameter), RV fractional area change (RVFAC), index of myocardial performance (Tei index), tricuspid annular plane systolic excursion (TAPSE), pulmonary artery systolic pressure, lateral tricuspid annular early and late diastolic velocities, and tissue Doppler diastolic and systolic velocities. RESULTS: Forty-nine of the subjects completed the study. RV end-diastolic diameters and Tei index (0.31 to 0.37) were significantly increased (p<0.001). RVFAC (49.83% to 43.59%) and TAPSE (18.8 to 17.7 mm) were significantly decreased (p<0.001). There was a significant reduction in E (57.06 to 46.59 cm/s, p<0.001), E/A ratio (1.42 to 1.18, p<0.001), E' (16.73 to 12.4 cm/s, p<0.001), E'/A' ratio (1.21 to 0.9, p<0.001) and S' (12.59 to 10.57 cm/s, p<0.001). Systolic pulmonary arterial pressure (20.63 to 22.24 mm Hg, p=0.04) was significantly increased. CONCLUSIONS: This study shows a significant decrease in RV systolic and diastolic function during chemotherapy for 6 months. These reductions are in the normal range and can probably be considered an early indicator of anthracycline-induced cardiotoxicity.

Evaluation and Treatment of Endoplasmic Reticulum (ER) Stress in Right Ventricular Dysfunction during Monocrotaline-Induced Rat Pulmonary Arterial Hypertension.

PURPOSE: Endoplasmic reticulum (ER) stress contributes to pulmonary artery hypertension (PAH). However, the exact roles of ER stress in right ventricular (RV) dysfunction, which is strongly associated with PAH, are largely unknown. Here, we aimed to explore how ER stress affects RV function in a rat PAH model and evaluated the effects of an ER stress inhibitor on RV dysfunction. METHODS: We examined expression changes of an ER marker: chaperone glucose-regulated protein 78 (GRP78), three ER stress sensor proteins: activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and protein kinase RNA-like endoplasmic reticulum kinase (PERK), and a key ER stress-induced apoptosis indicator: CCAAT/enhancer-binding protein homologous protein (CHOP), with inflammation indicators: interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinases (MMPs) in RV at 3, 7, 14 and 28 days following a single dose of monocrotaline (MCT) injection, with or without a preventive treatment [4-phenylbutyric acid (PBA)]. RV function was evaluated by histological, molecular and echocardiographic analysis. RESULTS: 1) GRP78 protein expression started to increase (1.5 ± 0.06 fold change) at 3d post MCT injection, even before the formation of PAH. 2) ATF6, IRE1, and PERK showed distinctive expression patterns post MCT injection. 3) CHOP expression remained low at day 3 & 7, but significantly increased at day 14 (p < 0.05), along with the peak of RV cardiomyocytes apoptosis. 4) PBA inhibited ER stress and alleviated remodeling and dysfunction in the RV. CONCLUSIONS: The early phase of ER stress might benefit RV function, whereas the extended phase led to RV cardiomyocyte apoptosis and dysfunction. Inhibition of ER stress by PBA during PAH directly improved RV function.

Speckle tracking echocardiography detects decreased cardiac longitudinal function in anthracycline-exposed survivors of childhood cancer.

UNLABELLED: Longitudinal motion significantly contributes to the contraction of the ventricles. We studied the left (LV) and right ventricular (RV) longitudinal functions in 75 anthracycline-exposed, long-term childhood cancer survivors and 75 healthy controls with conventional echocardiography, tissue Doppler imaging (TDI), speckle tracking echocardiography (STE) of the mitral and tricuspid annular motion, and real-time three-dimensional echocardiography (RT-3DE). Cardiac magnetic resonance (CMR) imaging was performed on 61 of the survivors. The survivors had lower systolic myocardial velocities in the LV and lower diastolic velocities in both ventricles by TDI than did their healthy peers. The STE-based tissue motion annular displacement (TMAD) values describing the LV and RV systolic longitudinal function (MAD and TAD mid%, respectively) were also lower among the survivors (15.4 ± 2.4 vs. 16.1 ± 2.2 %, p = 0.049 and 22.5 ± 3.0 vs. 23.5 ± 3.0 %, p = 0.035). MAD and TAD mid in millimeters correlated with the respective ventricular volumes measured with RT-3DE or CMR. CONCLUSION: Childhood cancer survivors exposed to low to moderate anthracycline doses had decreased longitudinal systolic and diastolic functions (TDI or STE) compared with healthy controls. The STE-based TMAD is a fast and reproducible method to assess cardiac longitudinal function. What is Known? • High anthracycline doses cause LV dysfunction as evidenced by a decreased ejection fraction. What is new? • Low to moderate anthracycline doses also have a negative impact on the LV and RV longitudinal systolic and diastolic function. • TMAD is a new and fast method to assess the cardiac longitudinal function after anthracycline exposure.

Comparison of Right Ventricle Systolic Function between Long-Term Anabolic-Androgenic Steroid User and Nonuser Bodybuilder Athletes: A Study of Two-Dimensional Speckle Tracking Echocardiography.

BACKGROUND: Right ventricular (RV) effects of long-term use of anabolic-androgenic steroids (AAS) are not clearly known. The aim of this study was to assess RV systolic functions by two-dimensional speckle tracking echocardiography (2DSTE) in AAS user and nonuser bodybuilders. METHODS: A total of 33 competitive male bodybuilders (15 AAS users, 18 AAS nonusers) were assessed. To assess RV systolic functions, all participants underwent standard two-dimensional and Doppler echocardiography, and 2DSTE. RESULTS: Interventricular septal thickness, left ventricle posterior wall thickness, relative wall thickness, and left ventricle mass index were significantly higher in AAS users than nonusers. While standard diastolic parameters were not statistically different between the groups, tissue Doppler parameters including RV E' and E'/A' were lower in AAS users than nonusers (10.1 ± 2.0 vs. 12.7 ± 2.1; P = 0.001, 1.1 ± 0.1 vs. 1.5 ± 0.4; P = 0.009, respectively). Tricuspid annular plane systolic excursion, RV fractional area change, and RV S' were in normal ranges. However, RV S' was found to be lower in users than nonusers (12.2 ± 2.2 vs. 14.6 ± 2.8, P = 0.011). RV free wall longitudinal strain and strain rate were decreased in AAS users in comparison with nonusers (-20.2 ± 3.1 vs. -23.3 ± 3.5; P = 0.012, -3.2 ± 0.1 vs. -3.4 ± 0.1; P = 0.022, respectively). In addition, there were good correlations between 2DSTE parameters and RV S', E', and E'/A'. CONCLUSION: Despite normal standard systolic echo parameters, peak systolic RV free wall strain and strain rate were reduced in AAS user bodybuilders in comparison with nonusers. Strain and strain rate by 2DSTE may be useful for early determination of subclinical RV dysfunction in AAS user bodybuilders.

Exercise preconditioning prevents MCT-induced right ventricle remodeling through the regulation of TNF superfamily cytokines.

BACKGROUND: Exercise training has been recognized as a non-pharmacological therapeutic approach in several chronic diseases; however it remains to be tested if exercise preconditioning can positively interfere with the natural history of pulmonary arterial hypertension (PAH). This is important since the majority of these patients are diagnosed at advanced stages of the disease, when right ventricle (RV) impairment is already present. OBJECTIVES: In the current study, we evaluated the preventive effect of exercise preconditioning on RV failure secondary to PAH, with a focus on the signaling pathways modulated by pro-inflammatory cytokines from TNF superfamily. METHODS: We analyzed the RV muscle from adult male Wistar rats exposed to a 4-week treadmill exercise training or sedentary regime, prior to the administration of monocrotaline (MCT) to induce PAH or with saline solution (controls). RESULTS: Data indicate that exercise preconditioning prevented cardiac hypertrophy and RV diastolic dysfunction. At a molecular level, exercise modulated the TWEAK/NF-κB signaling axis and prevented the shift in MHC isoforms towards an increased expression of beta-MHC. Exercise preconditioning also prevented the increase of atrogin-1 expression, and induced a shift of MMP activity from MMP-9 to MMP-2 activity. CONCLUSIONS: Altogether, data support exercise as a preventive strategy for the management of PAH, which is of particular relevance for the familial form of PAH that is manifested by greater severity or earlier onset.