POEMS syndrome is a rare clonal plasma cell disease. Patients with POEMS syndrome are at risk of developing pulmonary hypertension, but the data on its incidence and impact on outcome are limited. We reviewed retards of 154 POEMS syndrome patients with complete duplex echocardiography data for estimation of pulmonary artery systolic pressure (sPAP) at the time of diagnosis. Forty-two (27%) of 154 patients with pulmonary hypertension (estimated sPAP >= 50mmHg) were identified. Median age was 46 years (range 31-71 years). Patients with pulmonary hypertension were more likely to have peripheral edema (P=0.04), ascites (P=0.02), pleural effusion (P=0.005), and have longer time from onset to diagnosis (P=0.004) when compared with those without pulmonary hypertension. Restrictive abnormalities and decreased diffusion capacity of carbon monoxide were observed in 83% and 96% patients with pulmonary hypertension, compared with 50% and 72% in patients without pulmonary hypertension, respectively. Reversibility of pulmonary hypertension was observed after treatment of POEMS syndrome. After median follow of 32 months, survival of patients with pulmonary hypertension was worse than those without (median overall survival 54 months vs. median not reached, P=0.021). In conclusion, pulmonary hypertension is a common feature of POEMS syndrome, and is associated with signs of extravascular volume overload. Although active treatment of POEMS syndrome can reverse pulmonary hypertension, survival of these patients is worse than those without pulmonary hypertension.
Pulmonary hypertension is one of the problems that can be encountered before liver transplantation. It is not expected in cases with no additional disease in postoperative period. Herein, we report on a 43-year-old woman who developed idiopathic pulmonary hypertension in the early postoperative period. Further investigation both pathologically and clinically is needed in patients undergoing living donor liver transplantation that may help to solve the problems such as pulmonary arterial hypertension before it occurs and manage complex hemodynamic changes successfully in the future.
Remodeling of the distal pulmonary artery wall is a characteristic feature of pulmonary hypertension (PH). In hypoxic PH, the most substantial pathologic changes occur in the adventitia. Here, there is marked fibroblast proliferation and profound macrophage accumulation. These PH fibroblasts (PH-Fibs) maintain a hyperproliferative, apoptotic-resistant, and proinflammatory phenotype in ex vivo culture. Considering that a similar phenotype is observed in cancer cells, where it has been associated, at least in part, with specific alterations in mitochondrial metabolism, we sought to define the state of mitochondrial metabolism in PH-Fibs. In PH-Fibs, pyruvate dehydrogenase was markedly inhibited, resulting in metabolism of pyruvate to lactate, thus consistent with a Warburg-like phenotype. In addition, mitochondrial bioenergetics were suppressed and mitochondrial fragmentation was increased in PH-Fibs. Most importantly, complex I activity was substantially decreased, which was associated with down-regulation of the accessory subunit nicotinamide adenine dinucleotide reduced dehydrogenase (ubiquinone) Fe-S protein 4 (NDUFS4). Owing to less-efficient ATP synthesis, mitochondria were hyperpolarized and mitochondrial superoxide production was increased. This pro-oxidative status was further augmented by simultaneous induction of cytosolic nicotinamide adenine dinucleotide phosphate reduced oxidase 4. Although acute and chronic exposure to hypoxia of adventitial fibroblasts from healthy control vessels induced increased glycolysis, it did not induce complex I deficiency as observed in PH-Fibs. This suggests that hypoxia alone is insufficient to induce NDUFS4 down-regulation and constitutive abnormalities in complex I. In conclusion, our study provides evidence that, in the pathogenesis of vascular remodeling in PH, alterations in fibroblast mitochondrial metabolism drive distinct changes in cellular behavior, which potentially occur independently of hypoxia.
Chronic pulmonary hypertension (PH) is characterized by the accumulation of persistently activated cell types in the pulmonary vessel exhibiting aberrant expression of genes involved in apoptosis resistance, proliferation, inflammation and extracellular matrix (ECM) remodelling. Current therapies for PH, focusing on vasodilatation, do not normalize these activated phenotypes. Furthermore, current approaches to define additional therapeutic targets have focused on determining the initiating signals and their downstream effectors that are important in PH onset and development. Although these approaches have produced a large number of compelling PH treatment targets, many promising human drugs have failed in PH clinical trials. Herein, we propose that one contributing factor to these failures is that processes important in PH development may not be good treatment targets in the established phase of chronic PH. We hypothesize that this is due to alterations of chromatin structure in PH cells, resulting in functional differences between the same factor or pathway in normal or early PH cells versus cells in chronic PH. We propose that the high expression of genes involved in the persistently activated phenotype of PH vascular cells is perpetuated by an open chromatin structure and multiple transcription factors (TFs) via the recruitment of high levels of epigenetic regulators including the histone acetylases P300/CBP, histone acetylation readers including BRDs, the Mediator complex and the positive transcription elongation factor (Abstract figure). Thus, determining how gene expression is controlled by examining chromatin structure, TFs and epigenetic regulators associated with aberrantly expressed genes in pulmonary vascular cells in chronic PH, may uncover new PH therapeutic targets. Hypothetical representation of chromatin structure, transcription factors (TFs) and TF co‐regulators in normal (top panel), and persistently “activated” PH vascular cells (lower panel) of genes involved in proliferation, apoptosis‐resistance and pro‐inflammation. We posit that the persistently high expression of these genes in PH vascular cells is due to their “open” chromatin structure, allowing binding of multiple stress‐related TFs and pioneer TF(s), which help maintain an active chromatin structure and high levels of gene expression by recruiting and maintaining high levels of TF co‐factors including epigenetic regulators such as HATs, BRDs and the Mediator Complex (lower panel). Abbreviations: Ac, acetylation; EGR1, early growth response 1; p‐TEFb, positive transcription elongation factor B; Pol II, RNA polymerase II.
Optimal right ventricular (RV) function in pulmonary hypertension (PH) requires structural and functional coupling between the RV cardiomyocyte and its adjacent capillary network. Prior investigations have indicated that RV vascular rarefaction occurs in PH, which could contribute to RV failure by reduced delivery of oxygen or other metabolic substrates. However, it has not been determined if rarefaction results from relative underproliferation in the setting of tissue hypertrophy or from actual loss of vessels. It is also unknown if rarefaction results in inadequate substrate delivery to the RV tissue. In the present study, PH was induced in rats by SU5416-hypoxia-normoxia exposure. The vasculature in the RV free wall was assessed using stereology. Steady-state metabolomics of the RV tissue was performed by mass spectrometry. Complementary studies were performed in hypoxia-exposed mice and rats. Rats with severe PH had evidence of RV failure by decreased cardiac output and systemic hypotension. By stereology, there was significant RV hypertrophy and increased total vascular length in the RV free wall in close proportion, with evidence of vessel proliferation but no evidence of endothelial cell apoptosis. There was a modest increase in the radius of tissue served per vessel, with decreased arterial delivery of metabolic substrates. Metabolomics revealed major metabolic alterations and metabolic reprogramming; however, metabolic substrate delivery was functionally preserved, without evidence of either tissue hypoxia or depletion of key metabolic substrates. Hypoxia-treated rats and mice had similar but milder alterations. There is significant homeostatic vascular adaptation in the right ventricle of rodents with PH.
Right heart failure is the cause of death of most patients with severe pulmonary arterial hypertensive (PAH) disorders, yet little is known about the cellular and molecular causes of right ventricular failure (RVF). We first showed a differential gene expression pattern between normal rat right and left ventricles, and postulated the existence of a molecular right heart failure program that distinguishes RVF from adaptive right ventricular hypertrophy (RVH), and that may differ in some respects from a left heart failure program. By means of microarrays and transcriptional sequencing strategies, we used two models of adaptive RVH to characterize a gene expression pattern reflective of growth and the maintenance of myocardial structure. Moreover, two models of RVF were associated with fibrosis, capillary rarefaction, the decreased expression of genes encoding the angiogenesis factors vascular endothelial growth factor, insulin-like growth factor 1, apelin, and angiopoeitin-1, and the increased expression of genes encodinga set of glycolytic enzymes. The treatment of established RVF with a beta-adrenergic receptor blocker reversed RVF, and partly reversed the molecular RVF program. We conclude that normal right and left ventricles demonstrate clearly discernable differences in the expression of mRNA and microRNA, and that RVH and RVF are characterized by distinct patterns of gene expression that relate to cell growth, angiogenesis, and energy metabolism.
The authors demonstrated that CX3CR1 deficiency is protective against hypoxia-induced pulmonary hypertension (PH) by modulating monocyte recruitment, macrophage polarization, and pulmonary artery smooth muscle cell proliferation. [...]its importance in many neuroinflammatory diseases, including hypertension, is well appreciated (2-6). In view of these observations and the study by Amsellem and colleagues (1), we explored the role of microglial cells in hypoxia-induced PH in wild-type (WT) and CX3CR1 knockout (CX3CR1gfp/gfp) mice. Altered inflammatory response is associated with an impaired autonomic input to the bone marrow in the spontaneously hypertensive rat.
BACKGROUND: Chronic thromboembolic pulmonary hypertension after pulmonary embolism is associated with high morbidity and mortality. Understanding the incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism is important for evaluating the need for screening but is also a subject of debate because of different inclusion criteria among previous studies. We determined the incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism and the utility of a screening program for this disease. DESIGN AND METHODS: We conducted a cohort screening study in an unselected series of consecutive patients (n=866) diagnosed with acute pulmonary embolism between January 2001 and July 2007. All patients who had not been previously diagnosed with pulmonary hypertension (PH) and had survived until study inclusion were invited for echocardiography. Patients with echocardiographic suspicion of PH underwent complete work-up for chronic thromboembolic pulmonary hypertension, including ventilation-perfusion scintigraphy and right heart catheterization. RESULTS: After an average follow-up of 34 months of all 866 patients, PH was diagnosed in 19 patients by routine clinical care and in 10 by our screening program; 4 patients had chronic thromboembolic pulmonary hypertension, all diagnosed by routine clinical care. The cumulative incidence of chronic thromboembolic pulmonary hypertension after all cause pulmonary embolism was 0.57% (95% confidence interval [CI] 0.02-1.2%) and after unprovoked pulmonary embolism 1.5% (95% CI 0.08-3.1%). CONCLUSIONS: Because of the low incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism and the very low yield of the echocardiography based screening program, wide scale implementation of prolonged follow-up including echocardiography of all patients with pulmonary embolism to detect chronic thromboembolic pulmonary hypertension does not seem to be warranted.
Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are causally linked to pulmonary arterial hypertension (PAH) pathogenesis. Carbonic anhydrase inhibition (CAI) induces mild metabolic acidosis and exerts protective effects in hypoxic pulmonary hypertension (PH). Carbonic anhydrases and metabolic acidosis are further known to modulate immune cell activation. To evaluate if CAI modulates macrophage activation, inflammation, and VSMC phenotypic switching in severe experimental PH. PH was assessed in Sugen 5416/hypoxia (SU/Hx) rats after treatment with acetazolamide or ammonium chloride (NH4Cl). We evaluated pulmonary and systemic inflammation and characterized the effect of CAI and metabolic acidosis in alveolar and bone marrow-derived macrophages (BMDM). We further evaluated the treatment effects on VSMC phenotypic switching in pulmonary arteries (PAs) and pulmonary artery smooth muscle cells (PASMC) and corroborated some of our findings in lungs and PAs of PAH patients. Both idiopathic PAH patients and SU/Hx rats had increased expression of lung inflammatory markers and signs of PASMC de-differentiation in PAs. Acetazolamide and NH4Cl ameliorated SU/Hx-induced PH and blunted pulmonary and systemic inflammation. Expression of CA isoform 2 (Car2, CA2) was increased in alveolar macrophages from SU/Hx animals, classically (M1) and alternatively (M2) activated BMDMs, and PAH patient lungs. CAIs and acidosis had distinct effects on M1 and M2 markers in BMDMs. Inflammatory cytokines drove PASMC de-differentiation and this was inhibited by acetazolamide and acidosis. The protective anti-inflammatory effect of acetazolamide in PH is mediated by a dual mechanism of macrophage CAI and systemic metabolic acidosis.