Biomedical subjects

Alessandra Manes

Publications and source records attributed to Alessandra Manes.

13 recordsLinked to original sources

PubMed2006

Prognostic implications of serial assessments of pulmonary hypertension in severe chronic heart failure.

BACKGROUND: It is unknown whether time-related changes of pulmonary hypertension (PH) have prognostic relevance in severe chronic heart failure (CHF). METHODS: All CHF patients referred for follow-up from 1996 through 2003 were screened for this study. Eligibility depended on availability of a concomitant clinical, laboratory, electrocardiographic (ECG), echocardiographic and right-heart catheterization (RHC) assessment at index evaluation, as well as absence of pre-capillary PH. RESULTS: One hundred ninety-six patients (age 54 +/- 9 years; 27% women, 73% men; 50% in New York Heart Association [NYHA] Class III or IV) were included. PH at index evaluation was an independent predictor of acute heart failure or cardiovascular death (AHF/CD), with adjusted risk ratio (RR) = 2.30, 95% confidence interval (CI) 1.42 to 3.73 and p < 0.001. A pre-study (> or =6 months) RHC was available for 174 of the 196 patients. Worsening of mean pulmonary artery pressure (mPAP) of > or =30% (a pre-specified cut-off corresponding to the 75th percentile of DeltamPAP%) provided prognostic information independent of all index-evaluation parameters (adjusted RR = 2.60, 95% CI 1.45 to 4.67, p = 0.001), and from time-related changes in the other hemodynamic parameters (p < or = 0.033). CONCLUSIONS: PH retains independent prognostic significance even after adjusting for a large set of clinical/laboratory/instrumental parameters. Furthermore, serial measurements of mPAP seem to provide additional prognostic information as compared with a single assessment. These findings indicate that serial evaluations of PAP may help identify a sub-set of high-risk CHF patients deserving a particularly close follow-up to facilitate timely indications for non-pharmacologic strategies, including (when appropriate) heart transplantation.

Acute Disease↗

PubMed2006

BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension.

Mutations of the BMPR2 gene predispose to pulmonary arterial hypertension (PAH), a serious, progressive disease of the pulmonary vascular system. However, despite the fact that most PAH families are consistent with linkage to the BMPR2 locus, sequencing only identifies mutations in some 55% of familial cases and between 10% and 40% of cases without a family history (idiopathic or IPAH). We therefore conducted a systematic analysis for larger gene rearrangements in panels of both familial and idiopathic PAH cases that were negative on sequencing of coding regions. Analysis of exon dosage across the entire gene using Multiplex Ligation-dependent Probe Amplification identified nine novel rearrangements and enabled full characterization at the exon level of previously reported deletions. Overall, BMPR2 rearrangements were identified in 7 of 58 families and 6 of 126 IPAH cases, suggesting that gross rearrangements underlie around 12% of all FPAH cases and 5% of IPAH. Importantly, two deletions encompassed all functional protein domains and are predicted to result in null mutations, providing the strongest support yet that the predominant molecular mechanism for disease predisposition is haploinsufficiency. Dosage analysis should now be considered an integral of part of the molecular work-up of PAH patients.

Bone Morphogenetic Protein Receptors, Type II↗

PubMed2005

Pulmonary hypertension: classification and diagnostic algorithm.

Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and premature death. Recently, the diagnostic approach has been more clearly defined according to the new clinical classification and with consensus reached on algorithms of various investigative tests and procedures that exclude other causes and ensure an accurate diagnosis of PAH. The diagnostic procedures include clinical history and physical examination, ECG, chest X-ray, transthoracic Doppler echocardiography, pulmonary function tests, arterial blood gas analysis, ventilation and perfusion lung scan, high-resolution computed tomography of the lungs, contrast-enhanced spiral computed tomography of the lungs and pulmonary angiography, blood tests and immunology, abdominal ultrasound scan, exercise capacity assessment, and hemodynamic evaluation. Invasive and non-invasive markers of disease severity, either biomarkers or physiological parameters and tests that can be widely applied, have been proposed to reliably monitor the clinical course.

Algorithms↗

PubMed2004

Antiproliferative effect of sildenafil on human pulmonary artery smooth muscle cells.

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and by obstructive changes of the pulmonary vasculature including smooth muscle cell proliferation which leads to medial hypertrophy and subsequent luminal narrowing. Sildenafil, an orally active inhibitor of cGMP phosphodiesterase-type-5, exerts pulmonary vasodilator activity in PAH patients. We evaluated the effects of sildenafil on growth of cultured human pulmonary artery smooth muscle cells (PASMC). The results indicate that sildenafil reduced DNA synthesis stimulated by PDGF and dose dependently inhibited PASMC proliferation. These effects were paralleled by a progressive increase in cGMP content, followed by an accumulation of cAMP. The treatment with 8-bromo-cGMP or dibutyryl-cAMP mimicked all the effects of sildenafil. On the other hand, treatment of PASMC with inhibitors of cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) reversed the antiproliferative effect of sildenafil. In addition, sildenafil inhibited the phosphorylation of ERK, a converging point for several pathways leading to cell proliferation. This effect was partially reduced by PKG inhibition and completely abolished by PKA inhibition.We conclude that sildenafil exerts an antiproliferative effect on human PASMC that is mediated by an interaction between the cGMP-PKG and the cAMP-PKA activated pathways, leading to inhibition of PDGF-mediated activation of the ERK.

Cell Proliferation↗

PubMed2004

Endothelin receptor antagonists in pulmonary arterial hypertension.

Endothelin receptor antagonism has emerged as an important therapeutic strategy in pulmonary arterial hypertension (PAH). Laboratory and clinical investigations have clearly shown that endothelin (ET)-1 is overexpressed in several forms of pulmonary vascular disease and likely plays a significant pathogenetic role in the development and progression of pulmonary vasculopathy. Oral endothelin receptor antagonists (ERAs) have been shown to improve pulmonary hemodynamics, exercise capacity, functional status, and clinical outcome in several randomized placebo-controlled trials. Bosentan, a dual-receptor antagonist, is approved by the U.S. Food and Drug Administration for class III and IV patients with PAH, based on two phase III trials. In addition to its efficacy as sole therapy, bosentan may have a role as part of a combination of drugs such as a prostanoid or sildenafil. The selective endothelin receptor-A antagonists sitaxsentan and ambrisentan are currently undergoing investigation.

Endothelin Receptor Antagonists↗

PubMed2004

The endothelin system in pulmonary arterial hypertension.

Endothelin-1 (ET-1), a peptide produced primarily by vascular endothelial cells, was discovered in 1980 and it was characterized as a powerful vasoconstrictor and mitogen for smooth muscle. ET-1 binds to two types of receptors, ETA and ETB: ETA-receptors are found in smooth muscle cells, whereas ETB-receptors are localized on both endothelial cells and in smooth muscle cells. Activation of ETA- and ETB-receptors on smooth muscle cells mediates the vasoconstrictive and mitogenic effects of ET-1. Stimulation of endothelial ETB-receptors promotes ET-1 clearance and activation of NO and prostacyclin release. Pulmonary arterial hypertension (PAH) is a severe condition characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. An activation of the ET-1 system has been demonstrated in both plasma and lung tissues of PAH patients as well as in animal models of PAH. The most efficient way to antagonize the ET-1 system is the use of ET-1 receptor antagonists that can block either ETA- or ETA- and ETB-receptors. These drugs are effective in animal models of PAH and have been tested in multiple clinical trials in patients with PAH. Bosentan, an orally active, dual ET-1 receptor antagonist has been shown to improve symptoms, exercise capacity, hemodynamics, echocardiographic parameters and the outcome of patients with severe PAH, and it has been approved for clinical use in many countries. The selective ETA-receptor antagonist sitaxentan has improved exercise capacity and hemodynamics of PAH patients in two preliminary studies. The main side effect of ET-1 antagonists is the increase of liver enzymes likely due to an accumulation of bile salts cytotoxic to hepatocytes. Additional trials with these drugs are currently ongoing. In conclusion, the hypothesis that the ET-1 system over-activation can be successfully antagonised in patients with PAH has been clearly demonstrated.

Animals↗

PubMed2004

Evaluation of pulmonary arterial hypertension.

PURPOSE OF REVIEW: Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase of pulmonary vascular resistance leading to right ventricular failure and premature death. The purpose of this review is to analyze the current knowledge of the evaluation of PAH patients. RECENT FINDINGS: Recently, the diagnostic approach has been more clearly defined according to the new clinical classification and with consensus reached on algorithms of various investigative tests and procedures that exclude other causes and ensure an accurate diagnosis of PAH. The diagnostic procedures include clinical history and physical examination, ECG, chest radiography, transthoracic Doppler echocardiography, pulmonary function tests, arterial blood gases, ventilation and perfusion lung scan, high-resolution CT of the lung, contrast-enhanced spiral CT of the lung and pulmonary angiography, blood tests and immunology, abdominal ultrasound scan, exercise capacity assessment, and hemodynamic evaluation. SUMMARY: Invasive and noninvasive markers of disease severity, either biomarkers or physiologic parameters and tests that can be widely applied, have been proposed to reliably diagnose PAH and monitor the clinical course.

Electrocardiography↗

PubMed2004

[New insights on pulmonary arterial hypertension].

The 3rd World Symposium on Pulmonary Arterial Hypertension has been a forum for the presentation and discussion of overviews on several aspects of this devastating disease, including pathology and pathobiology, genetics, epidemiology, nomenclature and classification, diagnosis and assessment, medical treatments, interventional and surgical treatments and future directions. This editorial will provide a brief overview of the new findings emerging in this field including new pathologic and pathobiologic concepts, changes in the clinical classification and in the diagnostic definitions. In addition, new treatment strategies and future perspectives will be discussed.

Humans↗

PubMed2003

Effects of the oral endothelin-receptor antagonist bosentan on echocardiographic and doppler measures in patients with pulmonary arterial hypertension.

OBJECTIVES: The purpose of this study was to investigate the effects of bosentan (125 or 250 mg twice daily) on echocardiographic and Doppler variables in 85 patients with World Health Organization class III or IV pulmonary arterial hypertension (PAH). BACKGROUND: Bosentan, an orally active dual endothelin-receptor antagonist, improves symptoms, exercise capacity, and hemodynamics in patients with PAH. METHODS: Patients had primary pulmonary hypertension (84%) or PAH associated with connective tissue disease. Of these, 29 patients received placebo and 56 received bosentan (1:2 randomization). Six-minute walk tests and echocardiograms were performed at baseline and after 16 weeks of treatment. RESULTS: Baseline characteristics were similar in the placebo and bosentan groups, and echocardiographic and Doppler findings were consistent with marked abnormalities of right ventricular (RV) and left ventricular (LV) structure and function that were due to PAH. The treatment effect on 6-min walking distance was 37 m in favor of bosentan (p = 0.036). Treatment effects of bosentan compared with placebo on other parameters were as follows: Doppler-derived cardiac index = +0.4 l/min/m(2) (p = 0.007), LV early diastolic filling velocity = +10.5 cm/s (p = 0.003), LV end-diastolic area = +4.2 cm(2) (p = 0.003), LV systolic eccentricity index = -0.12 (p = 0.047), RV end-systolic area = -2.3 cm(2) (p = 0.057), RV:LV diastolic areas ratio = -0.64 (p = 0.007), Doppler RV index = -0.06 (p = 0.03), and percentage of patients with an improvement in pericardial effusion score = 17% (p = 0.05). CONCLUSIONS: Bosentan improves RV systolic function and LV early diastolic filling and leads to a decrease in RV dilation and an increase in LV size in patients with PAH.

Administration, Oral↗

PubMed2003

Prostanoids for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a severe condition that markedly reduces exercise capacity and survival in the affected patient population. PAH includes primary pulmonary hypertension (PPH) and pulmonary hypertension associated with collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension and HIV infection. All these conditions share virtually identical obstructive pathologic changes of the pulmonary microcirculation and probably similar pathobiologic processes. The pathophysiology is characterized by a progressive increase in pulmonary vascular resistance, leading to right ventricular failure and death. Prostacyclin is an endogenous substance that is produced by vascular endothelial cells and induces vasodilatation, inhibition of platelet activity, and antiproliferative effects. A dysregulation of prostacyclin metabolic pathways has been shown in patients with PAH and this represents the rationale for the exogenous therapeutic administration of this substance. The clinical use of prostacyclin in patients with PAH has been made possible by the synthesis of stable analogs that possess different pharmacokinetic properties but share similar pharmacodynamic effects. Experience in humans has been initially collected with epoprostenol, which is a synthetic salt of prostacyclin. Epoprostenol has a short half-life in the circulation and requires continuous administration by the intravenous route by means of infusion pumps and permanent tunnelized catheters. In addition, epoprostenol is unstable at room temperature, and the complex delivery system required is associated with several adverse effects and potentially serious complications. For these reasons, alternatives to intravenous epoprostenol have been sought and this has led to the development of analogs that can be administered subcutaneously (treprostinil), orally (beraprost sodium) or by inhalation (iloprost). Three unblinded clinical trials and several uncontrolled trials have shown that treatment with epoprostenol improved symptoms and exercise capacity in New York Heart Association (NYHA) class III and IV PAH patients and also survival in patients with PPH. Subcutaneous treprostinil improved symptoms, exercise, hemodynamics and clinical events in the largest clinical trial ever performed in PAH, but local infusion site reactions limited efficacy in a proportion of patients. Oral beraprost sodium improved exercise capacity only in patients with PPH and is the only prostacyclin analog that has also been tested in NYHA class II patients. Inhaled iloprost has improved symptoms, exercise capacity and clinical events in patients with PAH and inoperable chronic thromboembolic pulmonary hypertension. The favorable effects of prostanoids observed in all studies coupled with different profiles of adverse events and tolerability for each prostacyclin analog allow the unique opportunity to select the most appropriate compound for the individual patient with PAH.

Adult↗

PubMed2002

Inhaled iloprost for severe pulmonary hypertension.

BACKGROUND: Uncontrolled studies suggested that aerosolized iloprost, a stable analogue of prostacyclin, causes selective pulmonary vasodilatation and improves hemodynamics and exercise capacity in patients with pulmonary hypertension. METHODS: We compared repeated daily inhalations of 2.5 or 5.0 microg of iloprost (six or nine times per day; median inhaled dose, 30 microg per day) with inhalation of placebo. A total of 203 patients with selected forms of severe pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (New York Heart Association [NYHA] functional class III or IV) were included. The primary end point was met if, after week 12, the NYHA class and distance walked in six minutes were improved by at least one class and at least 10 percent, respectively, in the absence of clinical deterioration according to predefined criteria and death. RESULTS: The combined clinical end point was met by 16.8 percent of the patients receiving iloprost, as compared with 4.9 percent of the patients receiving placebo (P=0.007). There were increases in the distance walked in six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8 m in the subgroup of patients with primary pulmonary hypertension. Overall, 4.0 percent of patients in the iloprost group (including one who died) and 13.7 percent of those in the placebo group (including four who died) did not complete the study (P=0.024); the most common reason for withdrawal was clinical deterioration. As compared with base-line values, hemodynamic values were significantly improved at 12 weeks when measured after iloprost inhalation (P<0.001), were largely unchanged when measured before iloprost inhalation, and were significantly worse in the placebo group. Further significant beneficial effects of iloprost treatment included an improvement in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life (P=0.026). Syncope occurred with similar frequency in the two groups but was more frequently rated as serious in the iloprost group, although this adverse effect was not associated with clinical deterioration. CONCLUSIONS: Inhaled iloprost is an effective therapy for patients with severe pulmonary hypertension.

Administration, Inhalation↗

PubMed2002

Effects of beraprost sodium, an oral prostacyclin analogue, in patients with pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: The purpose of this study was to assess the efficacy and safety of beraprost sodium, an orally active prostacyclin analogue, in New York Heart Association (NYHA) functional class II and III patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous infusion of prostacyclin has been proven effective. However, this treatment is associated with serious complications arising from the complex delivery system. METHODS: In this double-blind, placebo-controlled study, 130 patients with PAH were randomized to the maximal tolerated dose of beraprost (median dose 80 microg four times a day) or to placebo for 12 weeks. The primary end point was the change in exercise capacity assessed by the 6-min walk test. Secondary end points included changes in Borg dyspnea index, cardiopulmonary hemodynamics and NYHA functional class. RESULTS: Patients treated with beraprost improved exercise capacity and symptoms. The difference between treatment groups in the mean change of 6-min walking distance at week 12 was 25.1 m (95% confidence interval [CI]: 1.8 to 48.3, p = 0.036). The difference in the mean change of Borg dyspnea index was -0.94 (95% CI: -1.63 to -0.24, p = 0.009). In the sub-group of patients with primary pulmonary hypertension, the difference in the mean change of 6-min walking distance was 46.1 m (95% CI: 3.0 to 89.3, p = 0.035). Cardiopulmonary hemodynamics and NYHA functional class had no statistically significant changes. Drug-related adverse events were common in the titration phase and decreased in the maintenance period. CONCLUSIONS: Beraprost improves exercise capacity and symptoms in NYHA functional class II and III patients with PAH and, in particular, in those with primary pulmonary hypertension.

Administration, Oral↗

PubMedDate not supplied

Emerging medical therapies for pulmonary arterial hypertension.

Until a few years ago, "conventional" treatment for pulmonary arterial hypertension (PAH) included oral anticoagulants, calcium channel blockers, diuretics, digoxin, and oxygen. In the 1990s, 3 randomized studies demonstrated that the continuous intravenous infusion of epoprostenol improved functional capacity, cardiopulmonary hemodynamics, and survival in patients with severe PAH. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost, and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in more than 1,100 patients. Except for terbogrel, all compounds have improved by different degrees the mean exercise capacity as assessed by 6 minutes walking distance. Conversely, these trials differ for the severity and etiology of included PAH patients as well as for the effects on combined clinical events, on quality of life, and on hemodynamics. No trials have shown effects on mortality, and each new compound presents different side effects that seem unpredictable in the individual patient. At present, additional new compounds such as sitaxentan, ambisentan, L-arginine, and sildenafil are studied in clinical trials. The new therapeutic options are currently in different phases of approval by regulatory agencies, and when they will become available we will have the opportunity to select the most appropriate treatment for the single patient, according to an individualized benefit-to-risk ratio.

Arginine↗