Development Of Secondary Pulmonary Hypertension Research Articles

1109 PULMONARY PRESSUR TREND ANALYSIS IN PATIENTS UNDERGOING MITRACLIP

Abstract Mitral regurgitation (MR) is the second most frequent valve heart disease in Europe and its underlying mechanism primary-organic (due to disease of the mitral leaflets), or secondary-functional (where valve leaflets and chordae are structurally normal and MR results from alterations in left ventricle and left atrium geometry), determines the therapeutic approach. Transcatheter Edge-to-Edge Repair (TEER) with MitraClip implantation is a minimal-invasive treatment that according to 2021 ESC Guidelines should be considered (class of recomandation IIa) in selected symptomatic patients with severe MR despite optimal medical therapy, not eligible for surgery and fulfilling COAPT trial inclusion criteria, suggesting an increased chance of responding to treatment. Optimal valve morphology features for TEER are central pathology (second scallop), no leaflet calcifications, mitral valve area >4cm2, mobile length of posterior leaftel >10 mm, coaptation depth <11mm, normal leaflet strength and mobility, flail width <15 mm, flail gap <10 mm. TEER may be considered (class IIb) only in selected cases when the COAPT criteria are not fulfilled with the aim of improving symptoms and quality of life. MR occurs during systole, that at normal heart rates represents 30-50% of the cardiac cycle. As such, marked left atrial (LA) pressure elevation is present only transiently, representing less of a drive to development of secondary pulmonary hypertension compared to chronic LA pressure elevation seen in severe mitral stenosis. Anyway, in patients with severe MR echocardiography often reveals elevated systolic pulmonary artery pressure (PAPs) and MitraClip implantation usually is associated with a slight increase of the trans-mitral gradient with possible repercussions on pulmonary pressures. To better describe the effect of MitraClip implantation on pulmonary pressures and clinical outcomes we did a retrospective study enrolling in the period 2012-2022 thirty-six patients with severe mitral regurgitation treated with TEER. Compared to the last year presentation, we add eleven patients. The target was still to evaluate the clinical outcomes (symptoms, signs of heart failure, NYHA functional class) and the pulmonary pressures assessed by an echocardiographic examination before and after the intervention. At 6-month follow-up we observed in all patients with repaired mitral regurgitation an improvement in the NYHA class (from IV to II) without re-hospitalization. In addition we notice a more pronounced trend in the reduction of the mean sistolic pulmonary arterial pressure, estimated at around 2.86 mmHg ± 14 mmHg (p 0.24, 95% C.I. -7.69 to 1.94) with an unchanged left ventricle ejection fraction. Moreover, the echocardiographic exam showed a normalization of the S and D waves pattern in the pulmonary veins at the PW Doppler evaluation. These new data reinforced the idea that the clinical improvement and the reduction of dyspnea in these patients underwent TEER is related to a reduction of pressures in the pulmonary circulation regardless of the ejection fraction. This finding could be used as a tool that the cardiologist has to evaluate in the echocardiography lab to reveal a new mitral valve disfunction. Despite the addition of the new patients, the sample is still relatively small. However, considering the improvement of the results with the enlargement of the sample, the goal is to enroll additional patients to make the study even more meaningful.

733 Evaluation of pulmonary pressures in patients underwent to MitraClip

Abstract Mitral regurgitation (MR) is the second most frequent valve heart disease in Europe and its underlying mechanism primary-organic (due to disease of the mitral leaflets), or secondary-functional (where valve leaflets and chordae are structurally normal and MR results from alterations in left ventricle and left atrium geometry), determines the therapeutic approach. Transcatheter Edge-to-Edge Repair (TEER) with MitraClip implantation is a minimal-invasive treatment that according to 2021 ESC Guidelines should be considered (class indication IIa) in selected symptomatic patients with severe MR despite optimal medical therapy, not eligible for surgery and fulfilling COAPT trial inclusion criteria, suggesting an increased chance of responding to treatment. Optimal valve morphology features for TEER are central pathology (second scallop), no leaflet calcifications, mitral valve area >4 cm2, mobile length of posterior leaftel >10 mm, coaptation depth <11mm, normal leaflet strength and mobility, flail width <15 mm, flail gap <10 mm. TEER may be considered (class IIb) only in selected cases when the COAPT criteria are not fulfilled with the aim of improving symptoms and quality of life. MR occurs during systole, that at normal heart rates represents 30–50% of the cardiac cycle. As such, marked left atrial (LA) pressure elevation is present only transiently, representing less of a drive to development of secondary pulmonary hypertension compared to chronic LA pressure elevation seen in severe mitral stenosis. Anyway, in patients with severe MR echocardiography often reveals elevated systolic pulmonary artery pressure (PAPs) and MitraClip implantation usually is associated with a slight increase of the trans-mitral gradient with possible repercussions on pulmonary pressures. To better describe the effect of MitraClip implantation on pulmonary pressures and clinical outcomes we did a retrospective study enrolling in the period 2012–2021 25 patients with severe mitral regurgitation treated with TEER. We aimed to evaluate the clinical outcomes (symptoms, signs of heart failure, NYHA functional class) and the pulmonary pressures assessed by an echocardiographic examination before and after the intervention. At 6-month follow-up all patients with repaired mitral regurgitation showed an improvement in the NYHA class (from IV to II) and no need for re-hospitalization. We observed a trend in the reduction of the mean sistolic pulmonary arterial pressure of 2.68 mmHg ± 15 mmHg (P 0.39, 95% C.I. −9.03 to 3.67) with an unchanged left ventricle ejection fraction. Moreover, the echocardiographic exam showed a normalization of the S and D waves pattern in the pulmonary veins at the PW Doppler evaluation. We can assume that the clinical improvement and the reduction of dyspnoea in these patients underwent TEER is related to a reduction of pressures in the pulmonary circulation regardless of the ejection fraction. This finding could be used as a tool that the cardiologist has to evaluate in the echocardiography lab to reveal a new mitral valve disfunction. Considering the small sample, a greater number of patients will be enrolled to highlight the statistical significance.

"A small leak will sink a great ship": hypoxia-inducible factor and group III pulmonary hypertension.

Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) – a regulatory protein that is vital in adaptation to hypoxic conditions – in the development of secondary pulmonary hypertension. HIF influences development of hypoxia-induced pulmonary hypertension through alteration in voltage-gated potassium channels and homeostatic calcium regulation, resulting in disruption of endothelial cell-cell communication, and eventual vascular remodeling. This article summarizes salient literature related to HIF and secondary pulmonary hypertension, in addition to proposing a final common pathway in known mechanistic pathways that result in endothelial barrier integrity loss – vascular “leak” – primarily through a shared endothelial-epithelial signaling protein family, CCN.

Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodeling.

Interstitial lung disease is a devastating disease in humans that can be further complicated by the development of secondary pulmonary hypertension. Accumulating evidence indicates that the oxidant superoxide can contribute to the pathogenesis of both interstitial lung disease and pulmonary hypertension. We used a model of pulmonary hypertension secondary to bleomycin-induced pulmonary fibrosis to test the hypothesis that an imbalance in extracellular superoxide and its antioxidant defense, extracellular superoxide dismutase, will promote pulmonary vascular remodeling and pulmonary hypertension. We exposed transgenic mice overexpressing lung extracellular superoxide dismutase and wild-type littermates to a single dose of intratracheal bleomycin, and evaluated the mice weekly for up to 35 days. We assessed pulmonary vascular remodeling and the expression of several genes critical to lung fibrosis, as well as pulmonary hypertension and mortality. The overexpression of extracellular superoxide dismutase protected against late remodeling within the medial, adventitial, and intimal layers of the vessel wall after the administration of bleomycin, and attenuated pulmonary hypertension at the same late time point. The overexpression of extracellular superoxide dismutase also blocked the early up-regulation of two key genes in the lung known to be critical in pulmonary fibrosis and vascular remodeling, the transcription factor early growth response-1 and transforming growth factor-β. The overexpression of extracellular superoxide dismutase attenuated late pulmonary hypertension and significantly improved survival after exposure to bleomycin. These data indicate an important role for an extracellular oxidant/antioxidant imbalance in the pathogenesis of pulmonary vascular remodeling associated with secondary pulmonary hypertension attributable to bleomycin-induced lung fibrosis.

VEGF ameliorates pulmonary hypertension through inhibition of endothelial apoptosis in experimental lung fibrosis in rats

Idiopathic pulmonary fibrosis (IPF) can lead to the development of secondary pulmonary hypertension (PH) and ultimately death. Despite this known association, the precise mechanism of disease remains unknown. Using a rat model of IPF, we explored the role of the proangiogenic and antiapoptotic growth factor VEGF in the vascular remodeling that underlies PH. In this model, adenoviral delivery of active TGF-beta1 induces pulmonary arterial remodeling, loss of the microvasculature in fibrotic areas, and increased pulmonary arterial pressure (PAP). Immunohistochemistry and mRNA analysis revealed decreased levels of VEGF and its receptor, which were inversely correlated with PAP and endothelial cell apoptosis in both the micro- and macrovasculature. Treatment of IPF rats with adenoviral delivery of VEGF resulted in reduced endothelial apoptosis, increased vascularization, and improved PAP due to reduced remodeling but worsened PF. These data show that experimental pulmonary fibrosis (PF) leads to loss of the microvasculature through increased apoptosis and to remodeling of the pulmonary arteries, with both processes resulting in PH. As administration of VEGF ameliorated the PH in this model but concomitantly aggravated the fibrogenic process, VEGF-based therapies should be used with caution.

578: The Development of Secondary Pulmonary Hypertension in Heart Failure Patients Is a Predictor of Poor Response to Cardiac Resynchronization Therapy

Cardiac resynchronization therapy (CRT) has been shown to be of benefit in patients with chronic heart failure who meet defined criteria, but approximately one third of patients fail to show a clinical response. In this study, response to CRT was defined by strict criteria, and characteristics of responders and non-responders were investigated.

Atypical manifestations of feline inflammatory polyps in three cats

Inflammatory polyps of the feline middle ear and nasopharynx are non-neoplastic masses that are presumed to originate from the epithelial lining of the tympanic bulla or Eustachian tube. The exact origin and cause are unknown, however, it is thought that inflammatory polyps arise as a result of a prolonged inflammatory process. It is unclear whether this inflammation initiates or potentiates the development and growth of inflammatory polyps. Cats with inflammatory polyps typically present with either signs of otitis externa and otitis media or with signs consistent with upper airway obstruction. Traditional diagnostics involve imaging of the tympanic bulla either with skull radiographs or computed topography (CT). Treatment consists of traction and avulsion of the polyp with or without ventral bulla osteotomy (VBO) to remove the epithelial lining of the tympanic bulla. The three cases described here are unusual manifestations or presentations of feline inflammatory polyps that address the following issues: (1) concurrent otic and nasopharyngeal polyps, (2) potential association with chronic viral infection, (3) polyp development in the contralateral middle ear, (4) CT appearance of the skull following VBO, and (5) development of secondary pulmonary hypertension.

Inhaled iloprost as a bridge to transplant in advanced pulmonary fibrosis and secondary pulmonary hypertension

The development of secondary pulmonary hypertension is a poor prognostic factor in patients with pulmonary fibrosis. An acute challenge of inhaled iloprost, a chemically stable derivative of prostacyclin, has previously been shown to cause selective pulmonary vasodilatation in secondary pulmonary hypertension. We assessed its short-term efficacy in patients with advanced pulmonary fibrosis and secondary pulmonary hypertension as a bridge to transplantation. We studied seven patients (4 with UIP, and 3 with advanced sarcoidosis) all in New York Heart Association functional class IV. Iloprost was nebulized using a Schill multisonic nebulizer, and administered 3 hourly in increasing daily doses to a maintenance of 90mcg/day. The effects of inhaled iloprost were assessed by echocardiography, shuttle walk test and right heart catheterization (n 2). Inhalation of iloprost was well tolerated, and administered for a mean (SEM) of 2.4 (0.9) months. Two of 4 UIP patients and 1 of 2 sarcoid patients died during the follow up. There was a fall in pulmonary artery pressure, 73mmHg (19) before iloprost, versus 40mmHg (9) after iloprost therapy (p 0.26). There was a non significant improvement in pulmonary artery pressure when assessed by echo, 60mmHg (8) before versus 48mmHg (7) after iloprost therapy (p 0.28). Shuttle walk distance improved, but not significantly, 86m (34) before, versus 104m (48) after iloprost therapy (p 0.77). Inhaled iloprost therapy with terminal pulmonary fibrosis may only benefit selected (sarcoid) patients.

The structural basis of pulmonary hypertension in chronic lung disease: remodelling, rarefaction or angiogenesis?

Chronic lung disease in humans is frequently complicated by the development of secondary pulmonary hypertension, which is associated with increased morbidity and mortality. Hypoxia, inflammation and increased shear stress are the primary stimuli although the exact pathways through which these initiating events lead to pulmonary hypertension remain to be completely elucidated. The increase in pulmonary vascular resistance is attributed, in part, to remodelling of the walls of resistance vessels. This consists of intimal, medial and adventitial hypertrophy, which can lead to encroachment into and reduction of the vascular lumen. In addition, it has been reported that there is a reduction in the number of blood vessels in the hypertensive lung, which could also contribute to increased vascular resistance. The pulmonary endothelium plays a key role in mediating and modulating these changes. These structural alterations in the pulmonary vasculature contrast sharply with the responses of the systemic vasculature to the same stimuli. In systemic organs, both hypoxia and inflammation cause angiogenesis. Furthermore, remodelling of the walls of resistance vessels is not observed in these conditions. Thus it has been generally stated that, in the adult pulmonary circulation, angiogenesis does not occur. Prompted by previous observations that chronic airway inflammation can lead to pulmonary vascular remodelling without hypertension, we have recently shown, using quantitative stereological techniques, that angiogenesis can occur in the adult pulmonary circulation. Pulmonary angiogenesis has also been reported in some other conditions including post-pneumonectomy lung growth, metastatic disease of the lung and in biliary cirrhosis. Such angiogenesis may serve to prevent or attenuate increased vascular resistance in lung disease. In view of these more recent data, the role of structural alterations in the pulmonary vasculature in the development of pulmonary hypertension should be carefully reconsidered.

Flow-Induced Pressure Differentially Regulates Endothelin-1, Urotensin II, Adrenomedullin, and Relaxin in Pulmonary Vascular Endothelium

We hypothesized that increased pulmonary vascular pressure—one of the characteristics of congestive heart failure—directly regulates pulmonary endothelial vasoconstrictors (endothelin-1, urotensin II) and vasodilators (adrenomedullin, relaxin). To this end, we subjected pulmonary artery endothelial cells in a novel flow-chamber model to different shear stresses (17, 29, and 46 dyn/cm2) at low and elevated levels of downstream pressure (10 and 30 mm Hg). Application of elevated pressure over 16 h increased gene expression and peptide secretion of endothelin-1 at all shear levels, whereas secretion of adrenomedullin rose via decreased expression of its clearance receptor. In contrast, preprourotensin II mRNA and urotensin II peptide decreased in response to elevated pressure, and relaxin remained unaffected. This is the first study to identify pressure as key regulator of mediator synthesis by pulmonary vascular endothelium. Pressure-induced mediator regulation may represent an early event in the development of secondary pulmonary hypertension.

Hypoxia modifies the effect of PDGF on glycosaminoglycan synthesis by primary human lung cells.

Hypoxia, a consequence of interstitial lung diseases, may lead to secondary pulmonary hypertension and pulmonary vascular remodeling. Hypoxia induces activation and proliferation of lung cells and enhances the deposition of extracellular matrix including glycosaminoglycans (GAGs). To elucidate the cell biological mechanisms underlying the development of secondary pulmonary hypertension, we studied the effect of hypoxia on GAG synthesis by human lung cells. GAG synthesis was measured by incorporation of [(3)H]glucosamine; GAGs were isolated, purified, and characterized with GAG-degrading enzymes. Fibroblasts and vascular smooth muscle cells (VSMCs) synthesized hyaluronic acid, heparan sulfate, and chondroitin sulfates, whereas dermatan sulfate was found only in fibroblasts. Hypoxia did not influence the size or charge of the individual GAGs. However, hypoxia inhibited platelet-derived growth factor-induced [(3)H]glucosamine incorporation in secreted GAGs, especially hyaluronic acid, in VSMCs. In contrast, it stimulated GAG secretion, specifically heparan sulfate, by fibroblasts. Our results indicate that hypoxia induces modifications in GAG synthesis by human lung VSMCs and fibroblasts that may be correlated to pathophysiological manifestations in lung diseases causing hypoxia.

Differential roles of endothelin-1 in the development of secondary pulmonary hypertension in patients with left heart failure with or without acute exacerbation

Background: The aim of this study was to investigate the contribution of endothelin-1 (ET-1) to the development of secondary pulmonary hypertension (PH) in patients with left heart failure (HF). Methods and Results: The subjects were 40 patients with left HF with (group 1; n = 20) and without (group 2; n = 20) acute exacerbation. Before treatment, the ET-1 level in the pulmonary capillary wedge region was three times greater in patients of group 2 than group 1, although there was no significant difference in mean pulmonary artery pressure (mPAP) or pulmonary vascular resistance index (PVRI) between the two groups. Also, the ET-1 level significantly correlated with mPAP and PVRI for both groups, but with different slopes of the regression lines. After treatment of group 1, the extent of reduction in the ET-1 level significantly correlated with that in mPAP and in PVRI, whereas the ET-1 level itself correlated with mPAP, with the regression lines approximating those of group 2. Conclusions: Our findings suggest that ET-1 may have differential roles in the development of secondary PH in patients with left HF with or without acute exacerbation.