September 2004

Abnormal pericyte recruitment as a cause for pulmonary hypertension in Adams-Oliver syndrome.

Am J Med Genet. 2004 Sep 1;129A(3):294-9

Patel MS, Taylor GP, Bharya S, Al-Sanna'a N, Adatia I, Chitayat D, Suzanne Lewis ME, Human DG.

Department of Pediatrics, Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

Adams-Oliver syndrome (AOS) consists of congenital scalp defects with variable limb defects of unknown pathogenesis. We report on two children with AOS plus additional features including intrauterine growth retardation (IUGR), cutis marmorata telangiectatica congenita (CMTC), pulmonary hypertension (PH), intracranial densities shown in one case to be sites of active bleeding and osteopenia. Autopsy in one case revealed defective vascular smooth muscle cell/pericyte coverage of the vasculature associated with two blood vessel abnormalities. Pericyte absence correlated with vessel dilatation while hyperproliferation of pericytes correlated with vessel stenosis. These findings suggest a unifying pathogenic mechanism for the abnormalities seen in AOS. These and previously reported cases establish that a subset of AOS patients is at high risk for PH.

New approaches for persistent pulmonary hypertension of newborn.

Clin Perinatol. 2004 Sep;31(3):591-611

Konduri GG.

Division of Neonatology, Medical College of Wisconsin and Children's Research Institute of Children's Hospital of Wisconsin, CHW Office Building, MS 213 A, Milwaukee, WI 53226, USA.

Modulating the pulmonary circulation: an update.

Minerva Anestesiol. 2004 Apr;70(4):239-43

Dembinski R, Henzler D, Rossaint R.

Department of Anesthesiology, University Hospital, RWTH, Aachen, Germany. Rolf.Dembinski@post.rwth-aachen.de

Pulmonary hypertension is a common finding in pulmonary circulatory disorders of different origin. Chronic pulmonary hypertension may develop due to either cardiopulmonary or systemic diseases whereas acute and acute-on-chronic pulmonary hypertension often occur in the course of cardiothoracic surgery. Right heart failure is the major risk particularly in the course of acute pulmonary hypertension. Thus, besides basic treatment of the underlying disease the use of vasodilators is a valuable therapeutic option to decrease right ventricular afterload, but intravenous vasodilators may provoke systemic arterial hypotension and impair gas exchange due to vasodilation of pulmonary shunt areas. Therefore, inhaled vasodilators such as nitric oxide and prostacyclin have been suggested for the treatment of pulmonary hypertension especially when concomitant hypoxemia is present due to a ventilation-perfusion mismatch. However, randomised controlled trials performed to evaluate long-term effects revealed different results: thus, in chronic pulmonary hypertension inhaled vasodilators improved outcome whereas the results for the treatment of the acute respiratory distress syndrome revealed beneficial effects only when used as a rescue and/or bridging therapy in severe hypoxemia. In cardiothoracic surgery, inhaled vasodilators have been shown to improve pulmonary circulation when severe pulmonary hypertension is present. Although effective in experimental studies no clear recommendation can be made in view to the use of other vasodilators such as phosphodiesterase inhibitors or endothelin antagonists. Likewise, the combination of different vasodilators merit further investigations to prove efficacy in randomised controlled trials.

Publication Types:

· Review

· Review, Tutorial

Endogenous production of ghrelin and beneficial effects of its exogenous administration in monocrotaline-induced pulmonary hypertension.

Am J Physiol Heart Circ Physiol. 2004 Aug 26 [Epub ahead of print

Henriques-Coelho T, Correia-Pinto J, Roncon-Albuquerque Jr R, Baptista MJ, Lourenco AP, Oliveira SM, Brandao-Nogueira A, Teles A, Fortunato JM, Leite-Moreira AF.

We investigated endogenous production of ghrelin, as well as, cardiac and pulmonary vascular effects of its administration in a rat model of monocrotaline (MCT) induced pulmonary hypertension (PH). Adult Wistar rats randomly received a sc injection of MCT (60 mg/Kg) or an equal volume of vehicle. One week later, animals were randomly assigned to receive a sc injection of ghrelin (100 micro g/Kg, BID for 2 weeks) or saline. Four groups were analyzed: normal rats treated with ghrelin (n=7), normal rats injected with saline (n=7), MCT rats treated with ghrelin (n=9) and MCT rats injected with saline (n=9). At 22-25 days, right (RV) and left ventricular (LV) pressures were measured; heart and lungs weighted and samples collected for histologic and molecular analysis. Endogenous production of ghrelin was almost abolished in normal rats treated with ghrelin. In MCT treated animals, pulmonary expression of ghrelin was preserved and RV myocardial expression was increased more than 20 times. In these animals, exogenous administration of ghrelin attenuated PH, RV hypertrophy, wall thickening of peripheral pulmonary arteries, RV diastolic disturbances and ameliorated LV dysfunction, without affecting its endogenous production. In conclusion, decreased tissular expression of ghrelin in healthy animals but not in PH, suggests a negative feedback in the former that is lost in the latter. Selective increase of ghrelin mRNA levels in the RV of animals with PH might indicate distinct regulation of its cardiac expression. Finally, ghrelin administration attenuated MCT-induced PH, pulmonary vascular remodeling and RV hypertrophy, indicating that it may modulate PH.

Ann Intern Med. 2004 Aug 3;141(3):169-77

Comment in:

· Ann Intern Med. 2004 Aug 3;141(3):233-5.

· Ann Intern Med. 2004 Aug 3;141(3):I12.

Sildenafil increased exercise capacity during hypoxia at low altitudes and at Mount Everest base camp: a randomized, double-blind, placebo-controlled crossover trial.

Ghofrani HA, Reichenberger F, Kohstall MG, Mrosek EH, Seeger T, Olschewski H, Seeger W, Grimminger F.

University Hospital Giessen and Justus-Liebig University, Giessen, Germany.

BACKGROUND: Alveolar hypoxia causes pulmonary hypertension and enhanced right ventricular afterload, which may impair exercise tolerance. The phosphodiesterase-5 inhibitor sildenafil has been reported to cause pulmonary vasodilatation. OBJECTIVE: To investigate the effects of sildenafil on exercise capacity under conditions of hypoxic pulmonary hypertension. DESIGN: Randomized, double-blind, placebo-controlled crossover study. SETTING: University Hospital Giessen, Giessen, Germany, and the base camp on Mount Everest. PARTICIPANTS: 14 healthy mountaineers and trekkers. MEASUREMENTS: Systolic pulmonary artery pressure, cardiac output, and peripheral arterial oxygen saturation at rest and during assessment of maximum exercise capacity on cycle ergometry 1) while breathing a hypoxic gas mixture with 10% fraction of inspired oxygen at low altitude (Giessen) and 2) at high altitude (the Mount Everest base camp). INTERVENTION: Oral sildenafil, 50 mg, or placebo. RESULTS: At low altitude, acute hypoxia reduced arterial oxygen saturation to 72.0% (95% CI, 66.5% to 77.5%) at rest and 60.8% (CI, 56.0% to 64.5%) at maximum exercise capacity. Systolic pulmonary artery pressure increased from 30.5 mm Hg (CI, 26.0 to 35.0 mm Hg) at rest to 42.9 mm Hg (CI, 35.6 to 53.5 mm Hg) during exercise in participants taking placebo. Sildenafil, 50 mg, significantly increased arterial oxygen saturation during exercise (P = 0.005) and reduced systolic pulmonary artery pressure at rest (P < 0.001) and during exercise (P = 0.031). Of note, sildenafil increased maximum workload (172.5 W [CI, 147.5 to 200.0 W]) vs. 130.6 W [CI, 108.8 to 150.0 W]); P < 0.001) and maximum cardiac output (P < 0.001) compared with placebo. At high altitude, sildenafil had no effect on arterial oxygen saturation at rest and during exercise compared with placebo. However, sildenafil reduced systolic pulmonary artery pressure at rest (P = 0.003) and during exercise (P = 0.021) and increased maximum workload (P = 0.002) and cardiac output (P = 0.015). At high altitude, sildenafil exacerbated existing headache in 2 participants. LIMITATIONS: The study did not examine the effects of sildenafil on normoxic exercise tolerance. CONCLUSIONS: Sildenafil reduces hypoxic pulmonary hypertension at rest and during exercise while maintaining gas exchange and systemic blood pressure. To the authors' knowledge, sildenafil is the first drug shown to increase exercise capacity during severe hypoxia both at sea level and at high altitude.

Publication Types:

· Clinical Trial

· Randomized Controlled Trial

Prognosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):78S-92S

McLaughlin VV, Presberg KW, Doyle RL, Abman SH, McCrory DC, Fortin T, Ahearn G; American College of Chest Physicians.

University of Michigan, 1500 East Medical Center Dr, Women's Hospital-Room L3119, Ann Arbor, MI 48109-0273, USA. vmclaugh@umich.edu

Although idiopathic pulmonary arterial hypertension is perceived as a progressive disease with a uniformly poor outcome, the natural history of disease is heterogeneous, with some patients dying within months of diagnosis and others living for decades. The course of the disease has also been altered by advances in medical therapies. The outcome of patients with other types of pulmonary arterial hypertension (PAH) has been less well characterized. Assessment of prognosis of such patients is important, as it influences both medical therapy and referral for transplantation. This chapter will provide evidence based recommendations to assess the prognosis of patients with PAH.

Publication Types:

· Guideline

· Practice Guideline

· Review

· Review, Tutorial

Pulmonary artery hypertension and sleep-disordered breathing: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):72S-77S

Atwood CW Jr, McCrory D, Garcia JG, Abman SH, Ahearn GS; American College of Chest Physicians.

Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center and the VA Pittsburgh Healthcare System, Pittsburgh, PA 15213, USA. atwoodcw@upmc.edu

The objective of this article is to review the available data on the relationship between sleep-disordered breathing (SDB) and pulmonary arterial hypertension (PAH), with a focus on the prevalence of SDB in patients with idiopathic PAH (IPAH); the prevalence of PAH in patients with SDB; and the effects of SDB treatment on PAH. The evidence to date suggests that PAH may occur in the setting of SDB, although the prevalence is low. However, pulmonary hypertension (PH) in SDB is most strongly associated with other risk factors, such as left-sided heart disease, parenchymal lung disease, nocturnal desaturation, and obesity. The limited data available also suggest that SDB is uncommon in patients with IPAH. Treatment of SDB with continuous positive airway pressure may lower pulmonary artery pressures when the degree of PH is mild.

Publication Types:

· Guideline

· Review

· Review, Tutorial

Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):63S-71S

Doyle RL, McCrory D, Channick RN, Simonneau G, Conte J; American College of Chest Physicians.

Pulmonary and Critical Care Medicine, H3147 Stanford University School of Medicine, Palo Alto, CA 94305, USA. rldoyle@stanford.edu

While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.

Publication Types:

· Guideline

· Practice Guideline

Medical therapy for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):35S-62S

Badesch DB, Abman SH, Ahearn GS, Barst RJ, McCrory DC, Simonneau G, McLaughlin VV; American College of Chest Physicians.

University of Colorado Health Sciences Center, Denver, CO 80262, USA. David.Badesch@UCHSC.edu

Pulmonary arterial hypertension (PAH) is often difficult to diagnose and challenging to treat. Untreated, it is characterized by a progressive increase in pulmonary vascular resistance leading to right ventricular failure and death. The past decade has seen remarkable improvements in therapy, driven largely by the conduct of randomized controlled trials. Still, the selection of most appropriate therapy is complex, and requires familiarity with the disease process, evidence from treatment trials, complicated drug delivery systems, dosing regimens, side effects, and complications. This chapter will provide evidence-based treatment recommendations for physicians involved in the care of these complex patients. Due to the complexity of the diagnostic evaluation required, and the treatment options available, it is strongly recommended that consideration be given to referral of patients with PAH to a specialized center.

Publication Types:

· Guideline

· Practice Guideline

Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):14S-34S

McGoon M, Gutterman D, Steen V, Barst R, McCrory DC, Fortin TA, Loyd JE; American College of Chest Physicians.

Mayo Clinic, Rochester, USA.

Pulmonary arterial hypertension (PAH) occurs as an idiopathic process or as a component of a variety of disease processes, including chronic thromboembolic disease, connective tissue diseases, congenital heart disease, and exposure to exogenous factors including appetite suppressants or infectious agents such as HIV. This article reviews evidence for screening in susceptible patient groups and the approach to diagnosing PAH when it is suspected, and provides specific recommendations for applying this evidence to clinical practice.

Publication Types:

· Guideline

· Practice Guideline

Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):7S-10S

Rubin LJ; American College of Chest Physicians.

Division of Pulmonary and Critical Care Medicine, University of California, San Diego School of Medicine, La Jolla, USA. ljrubin@ucsd.edu

Publication Types:

· Guideline

· Practice Guideline

Diagnosis and management of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.

Chest. 2004 Jul;126(1 Suppl):4S-6S

· Guideline

· Practice Guideline

Differential expression of mitochondrial electron transport chain proteins in cardiac tissues of broilers from pulmonary hypertension syndrome-resistant and -susceptible lines.

Poult Sci. 2004 Aug;83(8):1420-6

Cisar CR, Balog JM, Anthony NB, Iqbal M, Bottje WG, Donoghue AM.

Poultry Production and Product Safety Research Unit, Agricultural Research Service, USDA, Center of Excellence for Poultry Science, University of Arkansas, Fayetteville, Arkansas, 72701, USA.

Pulmonary hypertension syndrome (PHS) is a metabolic disease associated with the rapid growth rate of modern broilers. Broilers susceptible to PHS experience sustained elevation of pulmonary arterial pressure leading to right ventricular hypertrophy and ultimately heart failure. Previous studies have shown that mitochondrial function is defective in broilers with PHS; they use oxygen less efficiently than broilers without PHS. In this study mitochondrial electron transport chain (ETC) protein levels were compared in cardiac tissues from PHS resistant and susceptible line broilers using quantitative immunoblots. Seven of 9 anti-mammalian mitochondrial ETC protein antibodies tested exhibited cross-species reactivity. Six ETC proteins were differentially expressed in the right ventricles of broilers raised under simulated high altitude conditions (2,900 m above sea level). Four ETC proteins were present at higher levels in resistant line birds without PHS than in resistant line birds with PHS or in susceptible line birds with or without PHS. One ETC protein was present at higher levels in broilers without PHS than in broilers with PHS in both lines, and one ETC protein was present at lower levels in susceptible line birds without PHS than in susceptible line birds with PHS or in resistant line birds with or without PHS. Interestingly, differential expression of mitochondrial ETC proteins was not observed in the right ventricles of broilers raised at local altitude (390 m above sea level) nor was it observed in the left ventricles of broilers exposed to simulated high altitude. These results suggest that higher levels of mitochondrial ETC proteins in right ventricle cardiac muscle may be correlated with resistance to PHS in broilers.

Nitric oxide and pulmonary arterial pressures in pulmonary hypertension.

Free Radic Biol Med. 2004 Oct 1;37(7):1010-7

Machado RF, Londhe Nerkar MV, Dweik RA, Hammel J, Janocha A, Pyle J, Laskowski D, Jennings C, Arroliga AC, Erzurum SC.

Department of Pulmonary and Critical Care Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.

Decreased production of vasodilator substances such as nitric oxide (NO) has been proposed as important in development of pulmonary arterial hypertension (PAH). We hypothesize that NO measured over time serves as a non invasive marker of severity of PAH and response to therapy. We prospectively and serially measured exhaled NO and carbon monoxide (CO), a vasodilator and anti-inflammatory product of heme oxygenases, in 17 PAH patients in conjunction with hemodynamic parameters over 2 years. Although pulmonary artery pressures and NO were similar in all patients at entry to the study, NO increased in the 12 individuals who survived to complete the study, and correlated with change in pulmonary artery pressures. In contrast, CO did not change or correlate with hemodynamic parameters. Investigation of NO-oxidant reaction products in PAH in comparison to controls suggests that NO synthesis is impaired in the lung and that reactive oxygen species may be involved in the pathophysiology of pulmonary hypertension. Endogenous NO is inversely related to pulmonary artery pressure in PAH, with successful therapy of PAH associated with increase in NO.

Safety and hemodynamic effects of pulmonary angiography in patients with pulmonary hypertension: 10-year single-center experience.

AJR Am J Roentgenol. 2004 Sep;183(3):779-86

Hofmann LV, Lee DS, Gupta A, Arepally A, Sood S, Girgis R, Eng J.

Division of Vascular and Interventional Radiology, Johns Hopkins Medical Institutions, 600 N Wolfe St., Blalock 545, Baltimore, MD 21287, USA. lhofmann@jhmi.edu

OBJECTIVE: We sought to examine the incidence of complications and change in pulmonary artery pressure in patients with pulmonary hypertension who were undergoing pulmonary angiography. MATERIALS AND METHODS: A retrospective review was performed for all patients who underwent pulmonary angiography over a 10-year period at a single institution. Patients with moderate pulmonary hypertension (pulmonary artery pressure, 30-59 mm Hg) and severe pulmonary hypertension (pulmonary artery pressure, >/= 60 mm Hg) served as the study population. Demographic data, clinical indication, pre- and postcontrast pulmonary artery pressure measurements, type of pulmonary hypertension, contrast agent volume, complications, and American Society of Anesthesiologists (ASA) classification were recorded for all patients and compared. RESULTS: Two hundred two of 612 patients who underwent pulmonary angiography had pulmonary hypertension. Moderate pulmonary hypertension was present in 155 patients (77%) and severe pulmonary hypertension, in 47 patients (23%). Three (2.0%) of four complications were fatal. The complication rate was higher in patients with severe pulmonary hypertension compared with patients with moderate pulmonary hypertension but not statistically significant (6.3% vs 0.6%, p = 0.63). Patients with complications had a higher mean ASA score than those without complications (4.0 vs 3.0, p = 0.03). Patients with lung transplants had the greatest increase in pulmonary artery pressure after pulmonary angiography compared with all other clinical indications (16.75 +/- 12.97 mm Hg vs 5.46 +/- 6.86 mm Hg, p = 0.003). CONCLUSION: The complication rate of pulmonary angiography in patients with pulmonary hypertension is low. However, in severely ill patients with acute pulmonary hypertension, pulmonary angiography should be undertaken with extreme caution.

C-Type Natriuretic Peptide Ameliorates Monocrotaline-induced Pulmonary Hypertension in Rats.

Am J Respir Crit Care Med. 2004 Aug 27 [Epub ahead of print]

Itoh T, Nagaya N, Murakami S, Fujii T, Iwase T, Ishibashi-Ueda H, Yutani C, Yamagishi M, Kimura H, Kangawa K.

Department of Regenerative Medicine and Tissue Engineering, National Cardiovascular Center Research Institute, Suita, Osaka, Japan; Second Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.

C-type natriuretic peptide has been shown to act as a local regulator of vascular tone and remodeling. We investigated whether C-type natriuretic peptide ameliorates monocrotaline-induced pulmonary hypertension in rats. Rats received continuous infusion of C-type natriuretic peptide or placebo. Significant pulmonary hypertension developed three weeks after monocrotaline. However, infusion of C-type natriuretic peptide significantly attenuated the development of pulmonary hypertension and vascular remodeling. Neither systemic arterial pressure nor heart rate was altered. Interestingly, C-type natriuretic peptide enhanced Ki-67 expression, a marker for cell proliferation, in pulmonary endothelial cells and augmented lung tissue content of endothelial nitric oxide synthase. C-type natriuretic peptide significantly suppressed apoptosis of pulmonary endothelial cells, decreased the number of monocytes/macrophages, and inhibited expression of plasminogen activator inhibitor type 1, a marker for fibrinolysis impairment, in the lung. In addition, C-type natriuretic peptide significantly increased the survival rate in monocrotaline rats. Finally, infusion of C-type natriuretic peptide after establishment of pulmonary hypertension also had beneficial effects on hemodynamics and survival. In conclusion, infusion of C-type natriuretic peptide ameliorated monocrotaline-induced pulmonary hypertension and improved survival. These beneficial effects may be mediated by regeneration of pulmonary endothelium, inhibition of endothelial cell apoptosis, and prevention of monocyte/macrophage infiltration and fibrinolysis impairment.