Isabel Blanco

Hemodynamic and gas exchange effects of sildenafil in patients with chronic obstructive pulmonary disease and pulmonary hypertension.

RATIONALE Sildenafil, a phosphodiesterase-5 inhibitor, could be useful for treating pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD). However, vasodilators may inhibit hypoxic pulmonary vasoconstriction and impair gas exchange in this condition. OBJECTIVES To assess the acute hemodynamic and gas exchange effects of sildenafil in patients with COPD-associated PH. METHODS We conducted a randomized, dose comparison trial in 20 patients with COPD-associated PH. Eleven patients were assigned to 20 mg, and 9 patients to 40 mg, of sildenafil. Pulmonary hemodynamics and gas exchange, including ventilation-perfusion (V(A)/Q) relationships, were assessed at rest and during constant-work rate exercise, before and 1 hour after sildenafil administration. MEASUREMENTS AND MAIN RESULTS Both sildenafil doses reduced the mean pulmonary arterial pressure (PAP) at rest and during exercise, without differences between them. Overall, PAP decreased -6 mm Hg (95% confidence interval [95% CI], -7 to -4) at rest and -11 mm Hg (95% CI, -14 to -8) during exercise. After sildenafil, Pa(O(2)) decreased -6 mm Hg (95% CI, -8 to -4) at rest because of increased perfusion in units with low V(A)/Q ratio, without differences between doses. No change in Pa(O(2)) (95% CI, -3 to 0.2 mm Hg) or V(A)/Q relationships occurred during exercise after sildenafil. Changes induced by sildenafil in Pa(O(2)) and V(A)/Q distributions at rest correlated with their respective values at baseline. CONCLUSIONS In patients with COPD-associated PH, sildenafil improves pulmonary hemodynamics at rest and during exercise. This effect is accompanied by the inhibition of hypoxic vasoconstriction, which impairs arterial oxygenation at rest. The use of sildenafil in COPD should be done cautiously and under close monitoring of blood gases. Clinical trial registered with www.clinicaltrials.gov (NCT00491803).

Survival in pulmonary hypertension in Spain: insights from the Spanish registry

A pulmonary hypertension (PH) registry (Spanish Registry of Pulmonary Arterial Hypertension) was undertaken to analyse prevalence, incidence and survival of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in Spain, and to assess the applicability of recent survival prediction equations. Voluntary reporting of previously diagnosed and incident PAH or CTEPH cases (July 2007–June 2008) was performed. Demographic, functional and haemodynamic variables were evaluated. 866 patients with PAH and 162 with CTEPH were included. PAH associated with toxic oil syndrome and pulmonary veno-occlusive disease were reported for the first time in a PAH registry. Estimated prevalences were as follows: PAH, 16 and CTEPH, 3.2 cases per million adult inhabitants (MAI). Estimated incidences were as follows: PAH, 3.7 and CTEPH, 0.9 cases per MAI per yr. 1-, 3- and 5-yr survival was 87%, 75% and 65%, respectively, with no differences between PAH and CTEPH. Male sex, right atrial pressure and cardiac index were independent predictors of death. Matching between observed survival and that predicted by different equations was closer when the characteristics of the cohorts were similar. Epidemiology and survival of PAH patients in the Spanish registry are similar to recent registries. Characteristics of the population from which survival prediction equations are derived influence their applicability to a different cohort. CTEPH is much less prevalent than PAH, although has a similar survival rate.

Pregnancy outcomes in pulmonary arterial hypertension in the modern management era

Previous studies have reported mortality rates of up to 56% associated with pregnancy in pulmonary arterial hypertension (PAH) but the management of this disease has changed considerably in recent years. We compiled a multinational, prospective registry to examine the contemporary outcome of pregnancies in patients with PAH. During a 3-yr period, the 13 participating centres reported 26 pregnancies. Three (12%) females died and one (4%) developed right heart failure requiring urgent heart–lung transplantation. There were eight abortions; two spontaneous and six induced. 16 (62%) pregnancies were successful, i.e. the females delivered healthy babies without complications. These females had well controlled PAH (pulmonary vascular resistance (PVR) 500±352 dyn·s·cm−5); eight of them were long-term responders to calcium channel blockers. In contrast, the females who died or required transplantation had poorly controlled PAH (PVR 1,667±209 dyn·s·cm−5). Pregnancy remains associated with a substantial mortality rate in PAH. However, our results indicate that the outcome of pregnancy in PAH has improved, at least when PAH is well controlled, and particularly in long-term responders to calcium channel blockers. These data must be confirmed by larger series before the general recommendation to avoid pregnancy in all patients with PAH is reconsidered.

Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial

Pulmonary hypertension is a serious complication of chronic obstructive pulmonary disease (COPD) that currently has no established pharmacological treatment. This study aimed to assess whether concomitant treatment with sildenafil would enhance the results of pulmonary rehabilitation in patients with COPD and increased pulmonary arterial pressure (PAP). In this double-blind, randomised controlled trial patients received 20 mg sildenafil or placebo three times daily and underwent pulmonary rehabilitation for 3 months. The primary end-point was the gain in the cycle endurance time at a constant work-rate. Secondary end-points included performance in the incremental exercise test, 6-min walk distance and quality of life. 63 patients with severe COPD and moderately increased PAP were randomised. Cycle endurance time increased by 149 s (95% CI 26–518 s) in the sildenafil group and by 169 s (95% CI 0–768 s) in the placebo group (median change difference -7 s, 95% CI -540–244 s; p=0.77). Gains in the incremental exercise test, 6-min walk distance and quality of life at the end of the study did not differ between groups. Measurements of arterial oxygenation and adverse events were similar in both groups. In patients with severe COPD and moderately increased PAP, concomitant treatment with sildenafil does not improve the results of pulmonary rehabilitation in exercise tolerance. Sildenafil did not improve respiratory rehabilitation outcomes in patients with severe COPD and moderately increased PAP http://ow.ly/lh7cb

A large-scale meta-analysis to refine colorectal cancer risk estimates associated with MUTYH variants

Background:Defective DNA repair has a causal role in hereditary colorectal cancer (CRC). Defects in the base excision repair gene MUTYH are responsible for MUTYH-associated polyposis and CRC predisposition as an autosomal recessive trait. Numerous reports have suggested MUTYH mono-allelic variants to be low penetrance risk alleles. We report a large collaborative meta-analysis to assess and refine CRC risk estimates associated with bi-allelic and mono-allelic MUTYH variants and investigate age and sex influence on risk.Methods:MUTYH genotype data were included from 20 565 cases and 15 524 controls. Three logistic regression models were tested: a crude model; adjusted for age and sex; adjusted for age, sex and study.Results:All three models produced very similar results. MUTYH bi-allelic carriers demonstrated a 28-fold increase in risk (95% confidence interval (CI): 6.95–115). Significant bi-allelic effects were also observed for G396D and Y179C/G396D compound heterozygotes and a marginal mono-allelic effect for variant Y179C (odds ratio (OR)=1.34; 95% CI: 1.00–1.80). A pooled meta-analysis of all published and unpublished datasets submitted showed bi-allelic effects for MUTYH, G396D and Y179C (OR=10.8, 95% CI: 5.02–23.2; OR=6.47, 95% CI: 2.33–18.0; OR=3.35, 95% CI: 1.14–9.89) and marginal mono-allelic effect for variants MUTYH (OR=1.16, 95% CI: 1.00–1.34) and Y179C alone (OR=1.34, 95% CI: 1.01–1.77).Conclusions:Overall, this large study refines estimates of disease risk associated with mono-allelic and bi-allelic MUTYH carriers.

Acute and long‐term effects of inhaled iloprost in portopulmonary hypertension

Portopulmonary hypertension (PoPH) is a serious condition without an established treatment. Drugs used to treat pulmonary hypertension may have detrimental effects on portal hypertension. This study was designed to assess in patients with PoPH the acute effects of inhaled iloprost (iILO) on pulmonary and hepatic hemodynamics and to evaluate the clinical outcome after 12 months of treatment. We conducted 2 separate studies. In the first one, 21 patients with PoPH were acutely tested with 2.8 μg of iILO. Pulmonary and hepatic hemodynamics were assessed at the baseline and through 60 minutes after iILO. In the second one, we retrospectively evaluated 12 patients treated with iILO (30 μg/day) for more than 1 year. The 6‐minute walk distance (6MWD), functional class (FC), and echocardiogram were analyzed at the baseline and after 12 months of treatment. In the acute study, iILO rapidly reduced pulmonary artery pressure (PAP; −16% ± 8%, P < 0.001) and pulmonary vascular resistance (−18% ± 14%, P < 0.001). The cardiac output did not change initially but decreased after 30 minutes. The hepatic venous pressure gradient (HVPG) and hepatic blood flow did not vary through the study. Pulmonary vasodilation induced by iILO was inversely related to HVPG. In the long‐term evaluation, iILO improved FC by 1 or more in 7 patients (P = 0.04) and increased 6MWD by 67 ± 59 m at 12 months (P < 0.001). No change in systolic PAP was observed. Two patients died because of hepatic complications, and 4 additional patients presented clinically significant events that were related to hepatic disease in 2 and worsening of pulmonary hypertension in 2. We conclude that in patients with PoPH, iILO produces rapid and selective pulmonary vasodilation without altering the hepatic hemodynamics. Its long‐term use may provide sustained improvements in symptoms and exercise tolerance in some patients with PoPH. A randomized, controlled trial is warranted to establish its clinical role in this serious condition. Liver Transpl 16:348–356, 2010.

Stimulation of soluble guanylate cyclase prevents cigarette smoke-induced pulmonary hypertension and emphysema.

RATIONALE Chronic obstructive pulmonary disease (COPD) is a major cause of death worldwide. No therapy stopping progress of the disease is available. OBJECTIVES To investigate the role of the soluble guanylate cyclase (sGC)-cGMP axis in development of lung emphysema and pulmonary hypertension (PH) and to test whether the sGC-cGMP axis is a treatment target for these conditions. METHODS Investigations were performed in human lung tissue from patients with COPD, healthy donors, mice, and guinea pigs. Mice were exposed to cigarette smoke (CS) for 6 hours per day, 5 days per week for up to 6 months and treated with BAY 63-2521. Guinea pigs were exposed to CS from six cigarettes per day for 3 months, 5 days per week and treated with BAY 41-2272. Both BAY compounds are sGC stimulators. Gene and protein expression analysis were performed by quantitative real-time polymerase chain reaction and Western blotting. Lung compliance, hemodynamics, right ventricular heart mass alterations, and alveolar and vascular morphometry were performed, as well as inflammatory cell infiltrate assessment. In vitro assays of cell adhesion, proliferation, and apoptosis have been done. MEASUREMENTS AND MAIN RESULTS The functionally essential sGC β1-subunit was down-regulated in patients with COPD and in CS-exposed mice. sGC stimulators prevented the development of PH and emphysema in the two different CS-exposed animal models. sGC stimulation prevented peroxynitrite-induced apoptosis of alveolar and endothelial cells, reduced CS-induced inflammatory cell infiltrate in lung parenchyma, and inhibited adhesion of CS-stimulated neutrophils. CONCLUSIONS The sGC-cGMP axis is perturbed by chronic exposure to CS. Treatment of COPD animal models with sGC stimulators can prevent CS-induced PH and emphysema.

Personalised Prehabilitation in High-risk Patients Undergoing Elective Major Abdominal Surgery: A Randomized Blinded Controlled Trial

Objective: The aim of this study was to assess the impact of personalized prehabilitation on postoperative complications in high-risk patients undergoing elective major abdominal surgery. Summary Background Data: Prehabilitation, including endurance exercise training and promotion of physical activity, in patients undergoing major abdominal surgery has been postulated as an effective preventive intervention to reduce postoperative complications. However, the existing studies provide controversial results and show a clear bias toward low-risk patients. Methods: This was a randomized blinded controlled trial. Eligible candidates accepting to participate were blindly randomized (1:1 ratio) to control (standard care) or intervention (standard care + prehabilitation) groups. Inclusion criteria were: i) age >70 years; and/or, ii) American Society of Anesthesiologists score III/IV. Prehabilitation covered 3 actions: i) motivational interview; ii) high-intensity endurance training; and promotion of physical activity. The main study outcome was the proportion of patients suffering postoperative complications. Secondary outcomes included the endurance time (ET) during cycle-ergometer exercise. Results: We randomized 71 patients to the control arm and 73 to intervention. After excluding 19 patients because of changes in the surgical plan, 63 controls and 62 intervention patients were included in the intention-to-treat analysis. The intervention group enhanced aerobic capacity [&Dgr;ET 135 (218) %; P < 0.001), reduced the number of patients with postoperative complications by 51% (relative risk 0.5; 95% confidence interval, 0.3–0.8; P = 0.001) and the rate of complications [1.4 (1.6) and 0.5 (1.0) (P =  0.001)] as compared with controls. Conclusion: Prehabilitation enhanced postoperative clinical outcomes in high-risk candidates for elective major abdominal surgery, which can be explained by the increased aerobic capacity.

Echocardiographic assessment of pulmonary arterial pressure in the follow-up of patients with pulmonary embolism

BACKGROUND Echocardiography remains a clinically useful screening test for chronic thromboembolic pulmonary hypertension (CTEPH) in patients with a history of pulmonary embolism (PE). To devise an effective screening strategy, the definition of a high-risk group is necessary. METHODS We examined a total of 744 patients with acute symptomatic pulmonary embolism (PE) who were enrolled in a Spanish multicenter study. Patients were monitored every 6months during the first two years, and then once a year thereafter. Transthoracic echocardiography was used to screen patients with a clinical suspicion of CTEPH during follow-up. Pulmonary arterial hypertension was defined as an estimated pulmonary artery systolic pressure (PAP)>50mm Hg. The index thromboembolic episode was considered severe if: (a) the patient was immobilized for medical reasons; or (b) systolic blood pressure was less than 90mm Hg; or (c) troponin T values were above the reference range. RESULTS The incidence of PAP>50mm Hg at 36months was 8.3% (95% confidence interval=4.6%-14.5%). Statistical analysis showed a highly significant association between a severe index thromboembolic episode and the subsequent detection of PAP>50mm Hg on echocardiography, with high positive likelihood ratio (2.40) and negative predictive value (>0.97). CONCLUSIONS Patients with a severe index thromboembolic episode would constitute a high-risk group for the development of CTEPH. This group of patients should be subjected to a strict follow-up protocol.

Pulmonary Hypertension Is Related to Peripheral Endothelial Dysfunction in Heart Failure With Preserved Ejection Fraction

Background—Pulmonary hypertension (PH) and collagen metabolism abnormalities are prevalent in patients with heart failure with preserved ejection fraction (HFpEF). Peripheral endothelial dysfunction (PED) has been described in HF and in pulmonary arterial hypertension. Our aim is to determine whether PH is associated with PED and impaired collagen metabolism in patients with HFpEF.; Methods and Results—Flow-mediated dilation of the brachial artery, matrix metalloproteinase-2 and matrix metalloproteinase-9, tissue metalloproteinase inhibitor 1, and C-terminal propeptide of type I procollagen were determined in 28 patients with HFpEF and 42 hypertensive controls. Patients with systolic pulmonary artery pressure >35 mm Hg on echocardiogram underwent a right heart catheterization. Patients with HFpEF had more severe PED than controls: flow-mediated dilation 1.95% (−0.81 to 4.92) versus 5.02% (3.90 to 10.12), P=0.002. Twenty patients with PH underwent right heart catheterization: mean pulmonary artery pressure 38 (27–52) mm Hg, wedge capillary pressure 18 (16–22) mm Hg, pulmonary vascular resistance 362 (235–603) dyn s cm-5. There was a significant inverse correlation between flow-mediated dilation and pulmonary vascular resistance in patients with HFpEF and PH (r=−0.679; P=0.002). Patients with HFpEF showed higher matrix metalloproteinase-2 and C-terminal propeptide of type I procollagen values than hypertensive controls. Patients with HFpEF and higher C-terminal propeptide of type I procollagen values also had higher mean pulmonary artery pressure (r=0.553; P=0.014), transpulmonary gradient (r=0.560; P=0.013), and pulmonary vascular resistance (r=0.626; P=0.004). Conclusions—In patients with HFpEF, there is a significant correlation between PED and pulmonary vascular resistance. Collagen metabolism was more impaired in patients with HFpEF and PH. PED and collagen metabolism assessment could be useful tools to identify patients with HFpEF at risk of developing PH.