How do we explain unexplained pulmonary hypertension in the elderly?
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Aged↗
Biomedical subjects
Stuart Rich
Publications and source records attributed to Stuart Rich.
Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension.
BACKGROUND: Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-beta type II receptor gene, BMPR2, predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. METHODS AND RESULTS: We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations (P=0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. CONCLUSIONS: Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.
Adolescent↗
Temporal trends and drug exposures in pulmonary hypertension: an American experience.
BACKGROUND: Reports have linked anorexigen intake to an increased risk of pulmonary arterial hypertension (PAH). With the rise in anorexigen use in the latter half of the last decade, we established a surveillance network within the United States to monitor temporal trends in the number of reported cases of PAH. We also studied whether use of anorexigens and other drugs differed among patients with pulmonary hypertension of different etiologies. METHODS: Newly diagnosed subjects (N = 1335) at 13 tertiary pulmonary hypertension centers were enrolled between January 1998 and June 2001. Patient-reported medication use was obtained by a telephone interview. Patients were classified as to the type of pulmonary hypertension. Poisson regression models were fitted to monthly case counts, and logistic regression methods were used to assess the association between type of pulmonary hypertension and medication use. RESULTS: The average monthly number of reported cases of PAH and other categories of pulmonary hypertension did not change over the study period. Fenfluramine or dexfenfluramine use during the 5 years before the time of the interview was preferentially associated with PAH. Fenfluramine/dexfenfluramine use was particularly common in cases referred but found not to have pulmonary hypertension. CONCLUSIONS: No epidemic of anorexigen-related PAH was evident during the study period. As persons who had taken fenfluramine or dexfenfluramine were particularly likely to be referred for evaluation of pulmonary hypertension, it is unlikely that the failure to detect an anorexigen-induced rise in primary pulmonary hypertension was because of underascertainment. The association between fenfluramine derivatives and PAH is consistent with the risk elevations previously reported.
Adolescent↗
The current treatment of pulmonary arterial hypertension: time to redefine success.
In the past decade, three classes of medications have been approved for the treatment of pulmonary arterial hypertension. A review of the clinical trial data for the prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors has shown that all agents have similar efficacy on the 6-min walk distance over 12 to 16 weeks, which was the primary end point in the randomized clinical trials. However, little is known about their long-term efficacy or about how these drugs affect the underlying disease, if at all. Successful therapy is currently defined as an improvement in exercise tolerance over a 4-month period. Future trials need to better characterize how therapies affect the pulmonary vasculature pathologically, biologically, and hemodynamically, and whether survival is actually improved.
Bosentan↗
Efficacy and safety of sildenafil added to treprostinil in pulmonary hypertension.
Pulmonary arterial hypertension (PAH) is characterized by abnormalities in endothelial and smooth muscle cell function. Prostacyclin released by endothelial cells is a potent vasodilator by increasing cyclic adenosine monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic guanosine monophosphate in the lungs, producing vasodilation. To test for a therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous treprostinil, and sildenafil, a proof-of-concept, open-label investigational trial was initiated. Subjects with PAH in World Health Organization (WHO) functional classes II to IV receiving subcutaneous treprostinil for > or =6 months were evaluated with an exercise treadmill test using the Naughton-Balke protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was added to the treprostinil. Mean treadmill times in seconds were compared before and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women (mean age 35 years). At baseline, 3 subjects were in WHO functional class II and 6 subjects were in WHO functional class III. The mean treadmill time at baseline was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42% improvement, p = 0.049). All patients had symptomatic improvement. In conclusion, this pilot study of subcutaneous treprostinil with sildenafil for PAH suggests additive beneficial effects.
3',5'-Cyclic-GMP Phosphodiesterases↗
Matrix metalloproteinases in the urine of patients with pulmonary arterial hypertension.
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Humans↗
Clinical classification of pulmonary hypertension.
In 1998, during the Second World Symposium on Pulmonary Hypertension (PH) held in Evian, France, a clinical classification of PH was proposed. The aim of the Evian classification was to individualize different categories sharing similarities in pathophysiological mechanisms, clinical presentation, and therapeutic options. The Evian classification is now well accepted and widely used in clinical practice, especially in specialized centers. In addition, this classification has been used by the U.S. Food and Drug Administration and the European Agency for Drug Evaluation for the labeling of newly approved medications in PH. In 2003, during the Third World Symposium on Pulmonary Arterial Hypertension held in Venice, Italy, it was decided to maintain the general architecture and philosophy of the Evian classification. However, some modifications have been proposed, mainly to abandon the term "primary pulmonary hypertension" and to replace it with "idiopathic pulmonary hypertension"; to reclassify pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis; to update risk factors and associated conditions for pulmonary arterial hypertension and to propose guidelines in order to improve the classification of congenital systemic-to-pulmonary shunts.
Genetic Predisposition to Disease↗
Pulmonary hypertension.
Pulmonary hypertension, in its simplest sense, is elevation of the pulmonary artery pressure above normal. A multitude of diseases may increase the pulmonary artery pressure and result in right ventricular dysfunction. The treatments of pulmonary hypertension are as varied as its causes. The past decade has realized remarkable growth in knowledge of the mechanisms of pulmonary arterial hypertension and, concurrently, therapies for this once uniformly fatal disease. In addition to continuous intravenous epoprostenol, subcutaneous treprostinil and oral bosentan are now FDA approved for the treatment of pulmonary arterial hypertension. Other forms of pulmonary hypertension, such as pulmonary venous hypertension, pulmonary hypertension related to diseases of the respiratory system, and thromboembolic pulmonary hypertension will be discussed.
Cardiotonic Agents↗
Treprostinil, a prostacyclin analogue, in pulmonary arterial hypertension associated with connective tissue disease.
STUDY OBJECTIVES: To assess the efficacy and safety of continuous subcutaneous infusion of treprostinil, a stable prostacyclin analogue, for treating pulmonary arterial hypertension (PAH) in patients with connective tissue disease (CTD). DESIGN: Two multicenter, randomized, double-blind, placebo-controlled, prospective trials of treprostinil vs placebo in 470 patients with PAH. PATIENTS: A subset of 90 patients with PAH and CTD, including systemic lupus erythematosus, diffuse scleroderma, limited scleroderma, and mixed CTD/overlap syndrome. INTERVENTIONS: Patients received either treprostinil (initiated at 1.25 ng/kg/min, and titrated upward) or placebo via continuous subcutaneous infusion. The maximum dose of treprostinil allowed was 22.5 ng/kg/min. MEASUREMENTS: Six-minute walk (6MW) distance and dyspnea-fatigue scores were determined at baseline, and at 6 weeks and 12 weeks. Hemodynamic measures were obtained at baseline and at 12 weeks. RESULTS: At baseline, most patients had New York Heart Association class III symptoms. The mean baseline 6MW distance was 289 m (range, 60 to 448 m). The mean dose of treprostinil at week 12 was 8.4 ng/kg/min (range, 1.25 to 17.5 ng/kg/min). After 12 weeks, the change in cardiac index from baseline was + 0.2 +/- 0.08 L/min/m(2) in the treprostinil group and - 0.07 +/- 0.07 L/min/m(2) in the placebo group (p = 0.007). The pulmonary vascular resistance index decreased by 4 +/- 2 U x m(2) in the treprostinil group and increased by 1 +/- 1 U x m(2) in the placebo group (p = 0.006). The placebo-corrected median improvement from baseline in 6MW distance was 25 m in treprostinil-treated patients (p = 0.055); this improvement appeared to be dose related. Dyspnea fatigue scores also improved in the treprostinil group compared with the placebo group (p = 0.014). Adverse events included infusion site pain and typical side effects related to prostaglandins, and were tolerated by most patients. CONCLUSIONS: Continuous subcutaneous infusion of treprostinil in patients with PAH associated with CTD improved exercise capacity, symptoms of PAH, and hemodynamics.
Adolescent↗
Elevated basic fibroblast growth factor levels in patients with pulmonary arterial hypertension.
STUDY OBJECTIVES: Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation. DESIGN: Case-control study. SETTING: Multicenter, tertiary care hospitals. PARTICIPANTS: We studied 117 patients with PAH and 60 control subjects. MEASUREMENTS: We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay. RESULTS: Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects. CONCLUSION: Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.
Adolescent↗
Comparison of survival in patients with pulmonary hypertension associated with fenfluramine to patients with primary pulmonary hypertension.
To test whether the clinical presentation and prognosis of fenfluramine-induced pulmonary hypertension (PH) differs from primary PH (PPH), we compared the clinical profile and outcome of 10 patients with fenfluramine-induced PH with that of 70 patients with PPH referred to our center over the same time frame and treated identically. Patients with diet pill PH were similar to those with PPH with respect to hemodynamics. However, patients with fenfluramine-induced PH had poorer survival: 1-year survival 50% versus 88%, and 3-year survival 17% versus 60%.
Adult↗
Endothelin receptor blockers in cardiovascular disease.
The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. The selective ET A receptor antagonist sitaxsentan also improves hemodynamics and exercise capacity in patients with pulmonary arterial hypertension. Results with ET receptor antagonists in congestive heart failure have been disappointing. Although some studies have suggested benefit, larger studies have been neutral. The use of ET receptor antagonists for other conditions has not been fully explored. Future studies with the use of ET receptor antagonists as part of a multidrug regimen are also needed.
Animals↗
Beraprost therapy for pulmonary arterial hypertension.
OBJECTIVES: The purpose of this study was to assess the safety and efficacy of the oral prostacyclin analogue beraprost sodium during a 12-month double-blind, randomized, placebo-controlled trial in patients with pulmonary arterial hypertension (PAH). BACKGROUND: Pulmonary arterial hypertension is a progressive disease that ultimately causes right heart failure and death. Despite the risks from its delivery system, continuous intravenous epoprostenol remains the most efficacious treatment currently available. METHODS: A total of 116 patients with World Health Organization (WHO) functional class II or III primary pulmonary hypertension or PAH related to either collagen vascular diseases or congenital systemic to pulmonary shunts were enrolled. Patients were randomized to receive the maximal tolerated dose of beraprost sodium (median dose 120 microg four times a day) or placebo for 12 months. The primary end point was disease progression; i.e., death, transplantation, epoprostenol rescue, or >25% decrease in peak oxygen consumption (VO(2)). Secondary end points included exercise capacity assessed by 6-min walk test and peak VO(2), Borg dyspnea score, hemodynamics, symptoms of PAH, and quality of life. RESULTS: Patients treated with beraprost exhibited less evidence of disease progression at six months (p = 0.002), but this effect was not evident at either shorter or longer follow-up intervals. Similarly, beraprost-treated patients had improved 6-min walk distance at 3 months by 22 m from baseline and at 6 months by 31 m (p = 0.010 and 0.016, respectively) compared with placebo, but not at either 9 or 12 months. Drug-related adverse events were common and were related to the disease and/or expected prostacyclin adverse events. CONCLUSIONS: These data suggest that beneficial effects may occur during early phases of treatment with beraprost in WHO functional class II or III patients but that this effect attenuates with time.
Administration, Oral↗
Efficacy and safety of treprostinil: an epoprostenol analog for primary pulmonary hypertension.
Intravenous epoprostenol is currently FDA approved for management of primary pulmonary hypertension, but it requires intravenous infusion and is associated with adverse effects. The objective of this study was to evaluate the effects of an epoprostenol analog, treprostinil, for management of pulmonary hypertension. Ten tertiary care academic institutions with pulmonary hypertension programs participated in these pilot trials. In the first trial, intravenous epoprostenol and intravenous treprostinil were compared. In the second trial, intravenous treprostinil and subcutaneous treprostinil were compared. In the third trial, subcutaneous treprostinil was compared with placebo infusion during an 8-week period. Intravenous epoprostenol and intravenous treprostinil resulted in a similar reduction in pulmonary vascular resistance acutely (22% and 20%, respectively). Intravenous treprostinil and subcutaneous treprostinil also demonstrated comparable short-term decrease in pulmonary vascular resistance (23% and 28%, respectively). The placebo-controlled 8-week trial demonstrated a mean improvement of 37 +/- 17 m as measured by the 6-minute walk distance in patients receiving treprostinil compared with a 6 +/- 28 m reduction in those receiving placebo. There were trends toward an improvement in cardiac index and pulmonary vascular resistance index in the treprostinil group. Subcutaneous treprostinil has favorable hemodynamic effects when given acutely and in the short term. Treprostinil can be given safely to an ambulatory patient with a novel subcutaneous delivery pump system.
Adolescent↗
Hormone replacement therapy is associated with less coronary atherosclerosis in postmenopausal women.
Most observational studies indicate that hormone replacement therapy (HRT) protects women from cardiovascular disease. Two recent randomized trials, however, showed no reduction in coronary events with HRT in postmenopausal women. A randomized study evaluating subclinical atherosclerosis showed a beneficial effect of estrogen. In the current study we evaluated the association between HRT and coronary artery atherosclerosis, as quantified by coronary artery calcium score. Current users of HRT were significantly more likely to have a coronary artery calcium score less than 100 and were less likely to have a score greater than 400 than non-HRT users. After adjustment for cardiac risk factors, current use of HRT was associated with a significant reduction of coronary artery calcium score (-28; 95% confidence interval, -48 to -10). The average age of users was 59 yr, the mean duration of use was 9 yr, and the duration of HRT use was significantly associated with a reduction in coronary artery calcium. These results suggest that HRT suppresses atherosclerosis in the coronary arteries. The failure to modify the cardiovascular event rate in clinical trials could result from the adverse effect of HRT on complicated lesions. Additional mechanistic studies may help identify therapeutic strategies that could maximize a potential benefit of HRT on early atherogenesis while minimizing adverse proinflammatory and procoagulant effects on complicated plaque lesions.
Aged↗
Survival in primary pulmonary hypertension: the impact of epoprostenol therapy.
BACKGROUND: Primary pulmonary hypertension (PPH) is a severe and progressive disease. Without treatment, the median survival is 2.8 years, with survival rates of 68%, 48%, and 34% at 1, 3, and 5 years, respectively. Intravenous epoprostenol was the first Food and Drug Administration-approved therapy for PPH. The long-term impact that epoprostenol has made on PPH remains to be defined. METHODS AND RESULTS: One hundred sixty-two consecutive patients diagnosed with PPH and treated with epoprostenol were followed for a mean of 36.3 months (median, 31 months). Data including functional class, exercise tolerance, and hemodynamics were recorded in a customized database. Vital status was verified in each patient. Observed survival with epoprostenol therapy at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8% and was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4% based on historical data. Baseline predictors of survival included exercise tolerance, functional class, right atrial pressure, and vasodilator response to adenosine. Predictors of survival after the first year of therapy included functional class and improvement in exercise tolerance, cardiac index, and mean pulmonary artery pressure. CONCLUSIONS: Intravenous epoprostenol improves long-term survival in PPH.
Adult↗
Electron beam computed tomography for assessment of coronary artery disease in HIV-infected men receiving antiretroviral therapy.
Hyperlipidemia has been seen in patients receiving protease inhibitor-based antiretroviral therapy, prompting concern that such patients are at risk for accelerated coronary artery disease (CAD). To assess the risk of CAD in antiretroviral-treated HIV-infected men, we quantified coronary artery calcium (CAC), a sensitive and established marker of subclinical CAD, using electron beam computed tomography (EBCT) of coronary vessels. Sixty HIV-infected men who met the following criteria (cases) were enrolled in the study: age of 40 years or older; naive to antiretroviral therapy or use of a stable antiretroviral regimen for >or=6 months (mean duration, 25.9 months; 41 patients were receiving protease inhibitor therapy); and no known CAD or no use of lipid-lowering agents. EBCT-derived CAC scores, serum lipid levels, history of antiretroviral therapy, and risk factors for CAD were obtained. Each case was compared with three age-, sex-, and race-matched HIV-negative controls randomly selected from a database including >9000 patients who had undergone EBCT. We determined differences in the proportion of cases and controls with CAC scores of >0 (detectable calcium) and clinically significant CAC for age range. There were no statistically significant differences between the number of cases and controls with detectable CAC (33% and 39%, respectively) and clinically significant CAC (18% and 17%, respectively). This study suggests that the rate of coronary atherosclerosis among HIV-infected patients who receive short-term antiretroviral therapy with or without protease inhibitors is not higher than that among age-, sex-, and race-matched HIV-negative controls. These results need to be confirmed in larger long-term studies, with controls well matched for coronary risk factors.
Adult↗
Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.
Pulmonary arterial hypertension is a life-threatening disease for which continuous intravenous prostacyclin has proven to be effective. However, this treatment requires a permanent central venous catheter with the associated risk of serious complications such as sepsis, thromboembolism, or syncope. Treprostinil, a stable prostacyclin analogue, can be administered by a continuous subcutaneous infusion, avoiding these risks. We conducted a 12-week, double-blind, placebo-controlled multicenter trial in 470 patients with pulmonary arterial hypertension, either primary or associated with connective tissue disease or congenital systemic-to-pulmonary shunts. Exercise capacity improved with treprostinil and was unchanged with placebo; the between treatment group difference in median six-minute walking distance was 16 m (p = 0.006). Improvement in exercise capacity was greater in the sicker patients and was dose-related, but independent of disease etiology. Concomitantly, treprostinil significantly improved indices of dyspnea, signs and symptoms of pulmonary hypertension, and hemodynamics. The most common side effect attributed to treprostinil was infusion site pain (85%) leading to premature discontinuation from the study in 8% of patients. Three patients in the treprostinil treatment group presented with an episode of gastrointestinal hemorrhage. We conclude that chronic subcutaneous infusion of treprostinil is an effective treatment with an acceptable safety profile in patients with pulmonary arterial hypertension.
Adult↗