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The right ventricle (RV) differs developmentally, anatomically and functionally from the left ventricle (LV). Therefore, characteristics of LV adaptation to chronic pressure overload cannot easily be extrapolated to the RV. Mitochondrial abnormalities are considered a crucial contributor in heart failure (HF), but have never been compared directly between RV and LV tissues and cardiomyocytes. To identify ventricle-specific mitochondrial molecular and functional signatures, we established rat models with two slowly developing disease stages (compensated and decompensated) in response to pulmonary artery banding (PAB) or ascending aortic banding (AOB). Genome-wide transcriptomic and proteomic analyses were used to identify differentially expressed mitochondrial genes and proteins and were accompanied by a detailed characterization of mitochondrial function and morphology. Two clearly distinguishable disease stages, which culminated in a comparable systolic impairment of the respective ventricle, were observed. Mitochondrial respiration was similarly impaired at the decompensated stage, while respiratory chain activity or mitochondrial biogenesis were more severely deteriorated in the failing LV. Bioinformatics analyses of the RNA-seq. and proteomic data sets identified specifically deregulated mitochondrial components and pathways. Although the top regulated mitochondrial genes and proteins differed between the RV and LV, the overall changes in tissue and cardiomyocyte gene expression were highly similar. In conclusion, mitochondrial dysfuntion contributes to disease progression in right and left heart failure. Ventricle-specific differences in mitochondrial gene and protein expression are mostly related to the extent of observed changes, suggesting that despite developmental, anatomical and functional differences mitochondrial adaptations to chronic pressure overload are comparable in both ventricles.

Right ventricular (RV) function determines prognosis in pulmonary arterial hypertension (PAH). We hypothesize that ischemia causes RV dysfunction in PAH by triggering dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. RV function was compared in control rats ( n  = 50) versus rats with monocrotaline-induced PAH (MCT-PAH; n  = 60) both in vivo (echocardiography) and ex vivo (RV Langendorff). Mitochondrial membrane potential and morphology and RV function were assessed before or after 2 cycles of ischemia-reperfusion injury challenge (RV-IR). The effects of Mdivi-1 (25 μM), a Drp1 GTPase inhibitor, and P110 (1 μM), a peptide inhibitor of Drp1-Fis1 interaction, were studied. We found that MCT caused RV hypertrophy, RV vascular rarefaction, and RV dysfunction. Prior to IR, the mitochondria in MCT-PAH RV were depolarized and swollen with increased Drp1 content and reduced aconitase activity. RV-IR increased RV end diastolic pressure (RVEDP) and mitochondrial Drp1 expression in both control and MCT-PAH RVs. IR depolarized mitochondria in control RV but did not exacerbate the basally depolarized MCT-PAH RV mitochondria. During RV IR mdivi-1 and P110 reduced Drp1 translocation to mitochondria, improved mitochondrial structure and function, and reduced RVEDP. In conclusion, RV ischemia occurs in PAH and causes Drp1-Fis1-mediated fission leading to diastolic dysfunction. Inhibition of mitochondrial fission preserves RV function in RV-IR. Key messages Right ventricular ischemia reperfusion (RV-IR) causes RV diastolic dysfunction. IR-induced mitochondrial fission causes RV diastolic dysfunction. In RV-IR Drp1 translocates to mitochondria, binds Fis1 and causes fission and injury. A baseline RV mitochondriopathy in MCT PAH resembles IR-induced mitochondrial injury. Drp1 inhibitors (Mdivi-1 and P110) preserve RV diastolic function post RV-IR.

Increased mitochondrial reactive oxygen species (ROS) formation is important for the development of right ventricular (RV) hypertrophy (RVH) and failure (RVF) during pulmonary hypertension (PH). ROS molecules are produced in different compartments within the cell, with mitochondria known to produce the strongest ROS signal. Among ROS-forming mitochondrial proteins, outer-mitochondrial-membrane-located monoamine oxidases (MAOs, type A or B) are capable of degrading neurotransmitters, thereby producing large amounts of ROS. In mice, MAO-B is the dominant isoform, which is present in almost all cell types within the heart. We analyzed the effect of an inducible cardiomyocyte-specific knockout of MAO-B (cmMAO-B KO) for the development of RVH and RVF in mice. Right ventricular hypertrophy was induced by pulmonary artery banding (PAB). RV dimensions and function were measured through echocardiography. ROS production (dihydroethidium staining), protein kinase activity (PamStation device), and systemic hemodynamics (in vivo catheterization) were assessed. A significant decrease in ROS formation was measured in cmMAO-B KO mice during PAB compared to Cre-negative littermates, which was associated with reduced activity of protein kinases involved in hypertrophic growth. In contrast to littermates in which the RV was dilated and hypertrophied following PAB, RV dimensions were unaffected in response to PAB in cmMAO-B KO mice, and no decline in RV systolic function otherwise seen in littermates during PAB was measured in cmMAO-B KO mice. In conclusion, cmMAO-B KO mice are protected against RV dilatation, hypertrophy, and dysfunction following RV pressure overload compared to littermates. These results support the hypothesis that cmMAO-B is a key player in causing RV hypertrophy and failure during PH.

Our previous studies have shown that continuous infusion of angiotensin II (Ang II) in C57BL/6J mice causes dysfunction and a cachexia-like pathogenesis in both skeletal muscle and the left ventricle, which is significantly reduced by withaferin A (WFA), a steroidal lactone. However, it remains unknown whether WFA can reverse right ventricular (RV) dysfunction induced by Ang II. To determine the effects of WFA in attenuating Ang II-induced RV dysfunction, we employed a model in which continuous Ang II infusion via an osmotic pump in C57BL/6J mice induced cardiac remodeling. We then focused on investigating RV performance and structural changes using echocardiography and histopathological examination, as well as quantitative real-time PCR (qRT-PCR) for mRNA expression. Echocardiographic analysis demonstrated that Ang II significantly increased RV wall thickness and impaired RV systolic and diastolic function, as indicated by reductions in tricuspid annular plane systolic excursion, TV E/E′ ratio, RV S′, and RVOT VTI. The qRT-PCR analysis revealed marked upregulation of pro-fibrotic markers, including TGF-β, fibronectin, and collagen. WFA treatment restored RV functions and significantly attenuated Ang II-induced RV dysfunction and fibrosis. Our findings provide the first evidence that WFA attenuates Ang II-induced cachexia-like remodeling and dysfunction of the RV. These results position WFA as a compelling therapeutic candidate for cardiac cachexia, offering direct anti-fibrotic and cardioprotective benefits that warrant further translational development.

Right ventricular (RV) fibrosis is associated with RV dysfunction in a variety of RV pressure-loading conditions in which RV mechanical stress is increased, but the underlying mechanisms driving RV fibrosis are incompletely understood. In pulmonary and cardiovascular diseases characterized by elevated mechanical stress and transforming growth factor-β1 signaling, myocardin-related transcription factor A (MRTF-A) is a mechanosensitive protein critical to driving myofibroblast transition and fibrosis. In this study, we investigated whether MRTF-A inhibition improves RV profibrotic remodeling and function in response to a pulmonary artery banding (PAB) model of RV pressure loading. Rats were assigned into either sham or PAB groups. MRTF-A inhibitor CCG-1423 was administered daily at 0.75 mg/kg in a subset of PAB animals. Echocardiography and pressure–volume hemodynamics were obtained at a terminal experiment 6 weeks later. RV myocardial samples were analyzed for fibrosis, cardiomyocyte hypertrophy, and profibrotic signaling. MRTF-A inhibition slightly reduced systolic dysfunction in PAB rats reflected by increased lateral tricuspid annulus peak systolic velocity, whereas diastolic function parameters were not significantly improved. RV remodeling was attenuated in PAB rats with MRTF-A inhibition, displaying reduced fibrosis. This was accompanied with a reduction in PAB-induced upregulation of Yes-associated protein (YAP) and its paralog transcriptional coactivator with PDZ-binding motif (TAZ). We also confirmed, using a second-generation MRTF-A inhibitor CCG-203971, that MRTF-A is critical in driving RV fibroblast expression of TAZ and markers of myofibroblast transition in response to transforming growth factor-β1 stress and RhoA activation. These studies identify RhoA, MRTF-A, and YAP/TAZ as interconnected regulators of profibrotic signaling in RV pressure loading and as potential targets to improve RV profibrotic remodeling.

Heart failure is a multifaceted syndrome addressing for a high rate of death among the general population. The common approach to this disease has been always based on the evaluation of the left ventricular ejection fraction by two-dimensional echocardiography with Simpson’s method. Mounting evidences have demonstrated the pitfalls of this method and have suggested that the management of heart failure requires a deep knowledge of the pathophysiological insights of the disease and cannot rely only on the evaluation of the left ventricular ejection fraction. Several advanced imaging technologies overwhelm the evaluation of ejection fraction and could provide a better understanding of the myocardial abnormalities underlying heart failure. Considering the limitation of left ventricular ejection fraction and the systemic involvement of heart failure, classifications of heart failure based on ejection fraction should be substituted with a comprehensive “staging” of multiorgan damage, not only considering the heart but also the lungs, kidneys, and liver, such as the HLM staging system. Such a holistic approach based on the HLM staging system and multimodality imaging can provide a global assessment of patient features allowing for targeted therapies and better heart failure management.

Background Pulmonary hypertension (PH) is a frequent complication in obese patients showing heart failure with preserved ejection fraction (HFpEF) and correlates with poor prognosis. PH associated with cardiometabolic HFpEF (PH-cHFpEF) is characterized by inflammation and metabolic dysregulation. Alterations in the immune landscape, particularly activation of alveolar macrophages (AMs), may propagate the inflammatory response and lead to endothelial damage and vascular remodeling in the lung. Whether AMs contribute to PH in cardiometabolic HFpEF remains elusive. Purpose The present study investigates the role of alveolar macrophages in PH-cHFpEF. Methods Mice subjected to high-fat diet and L-NAME treatment for 15 weeks were used as experimental model of PH-cHFpEF. At the end of the treatment, echocardiography and treadmill exhaustion tests were performed. Single nucleus RNA-sequencing (snRNA-seq) was employed to study the AMs transcriptional landscape and cell-cell interactions. In vitro experiments were performed to study the mechanisms underlying metabolic stress-induced macrophage dysfunction using palmitic acid (PA), co-culture experiments were used to investigate the crosstalk between macrophages and endothelial cells. Results Compared with control mice, PH-cHFpEF animals displayed right ventricular dysfunction, vascular remodeling and increased pulmonary pressure. SnRNA-seq of mouse lungs revealed transcriptional alterations in AMs, with a significant reduction in their abundance in PH-cHFpEF mice. These changes were associated with dysregulation of transcriptional programs involved in pyroptosis, defective autophagy and inflammation in AMs from PH-cHFpEF vs. control mice, as shown by the upregulation of c-Fos , Dusp1 , Pim-1 and Ccn1 . STRING analysis revealed a molecular link between these partners and highlighted c-Fos/Dusp-1 as a central axis of AMs cell death and inflammation. Metabolic stress induced by PA in isolated murine macrophages recapitulated c-Fos/Dusp-1 activation as well as IL-1β, TNF-α, and Caspase-1 upregulation resulting in inflammation, impaired autophagy and enhanced pyroptosis. Moreover, c-Fos/Dusp1 activation in macrophages promoted secretion of pro-inflammatory chemokines leading to endothelial dysfunction in a paracrine manner. Dusp1 knockdown rescued autophagy and pyroptosis while mitigating macrophage-driven inflammation and endothelial damage. Conclusions PH-cHFpEF is characterized by AMs activation, upregulation of the cFos/Dusp-1 pathway and subsequent pyroptosis and inflammation in alveolar macrophages. Our findings highlight the role of AMs as putative targets for preventing endothelial damage in experimental PH-cHFpEF.

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.

With pulmonary arterial hypertension (PAH), right ventricular (RV) function is a major determinant of survival. Despite current therapies, maladaptive changes ensue in the RV muscle of PAH patients, culminating in RV dysfunction and failure. The aims of the study were to evaluate the impact of intra-coronary (IC) cardiosphere-derived cells (CDCs) in attenuating the maladaptive pathobiology in the RV muscle and evaluating mechanisms underlying improvements in RV function. Two groups of the Sugen/Hypoxia rat model of PAH, exhibiting significantly reduced RV function, via TAPSE measurements, received either intracoronary infusion of CDCs or PBS placebo. Immunohistochemistry methods were used to assess RV pathobiological changes. Additionally, advanced proteomics were employed to examine protein signaling pathways and upstream regulators. RV muscle capillarity was significantly reduced in the PAH rats while RV muscle fibrosis was increased. IC CDCs significantly increased RV muscle capillarity back to levels noted in healthy rats and reduced RV free wall fibrosis. Further, a significant reduction in iNOS+ (M1) macrophages was also observed within the RV free wall in CDC-treated animals. Proteomic analysis of RV muscle in CDC- or PBS-treated PAH rats showed alterations in protein pathways related to inflammation, fibrosis, autophagy, cell vitality, and angiogenesis. These changes were consistent with putative coordination by a small number of key upstream regulators (MYC, TP53, HNF4A, TGFB1, and KRAS). TAPSE was significantly reduced in PBS-treated animals but was maintained at or above baseline levels in CDC-treated animals. CDC therapy can significantly impact the maladaptive milieu of the RV myocardium in advanced PAH, by altering several pathobiological pathways. Such adjunctive therapy, in addition to those employed to reduce pulmonary vascular resistance, would be a great advance in managing RV failure, for which no effective current approved therapies exist.

Pulmonary artery hypertension (PAH) is a rare chronic disease with high impact on patients’ quality of life and currently no available cure. PAH is characterized by constant remodeling of the pulmonary artery by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), fibroblasts (FBs) and endothelial cells (ECs). This remodeling eventually leads to increased pressure in the right ventricle (RV) and subsequent right ventricle hypertrophy (RVH) which, when left untreated, progresses into right ventricle failure (RVF). PAH can not only originate from heritable mutations, but also develop as a consequence of congenital heart disease, exposure to drugs or toxins, HIV, connective tissue disease or be idiopathic. While much attention was drawn into investigating and developing therapies related to the most well understood signaling pathways in PAH, in the last decade, a shift towards understanding the epigenetic mechanisms driving the disease occurred. In this review, we reflect on the different epigenetic regulatory factors that are associated with the pathology of RV remodeling, and on their relevance towards a better understanding of the disease and subsequently, the development of new and more efficient therapeutic strategies.