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R J Barst

Publications and source records attributed to R J Barst.

At least 19 recordsLinked to original sources
PubMed2001

Novel therapeutics for the treatment of paediatric pulmonary arterial hypertension.

The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.

Child↗
PubMed2000

Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene.

Familial primary pulmonary hypertension is a rare autosomal dominant disorder that has reduced penetrance and that has been mapped to a 3-cM region on chromosome 2q33 (locus PPH1). The phenotype is characterized by monoclonal plexiform lesions of proliferating endothelial cells in pulmonary arterioles. These lesions lead to elevated pulmonary-artery pressures, right-ventricular failure, and death. Although primary pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs, including phentermine-fenfluramine. We genotyped 35 multiplex families with the disorder, using 27 microsatellite markers; we constructed disease haplotypes; and we looked for evidence of haplotype sharing across families, using the program TRANSMIT. Suggestive evidence of sharing was observed with markers GGAA19e07 and D2S307, and three nearby candidate genes were examined by denaturing high-performance liquid chromatography on individuals from 19 families. One of these genes (BMPR2), which encodes bone morphogenetic protein receptor type II, was found to contain five mutations that predict premature termination of the protein product and two missense mutations. These mutations were not observed in 196 control chromosomes. These findings indicate that the bone morphogenetic protein-signaling pathway is defective in patients with primary pulmonary hypertension and may implicate the pathway in the nonfamilial forms of the disease.

Amino Acid Sequence↗
PubMed2000

Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial.

BACKGROUND: Pulmonary hypertension is a progressive and often fatal complication of the scleroderma spectrum of disease for which no treatment has been proven effective in a randomized trial. OBJECTIVE: To determine the effect of epoprostenol on pulmonary hypertension secondary to the scleroderma spectrum of disease. DESIGN: Randomized, open-label, controlled trial. SETTING: 17 pulmonary hypertension referral centers. PATIENTS: 111 patients with moderate to severe pulmonary hypertension. INTERVENTION: Epoprostenol plus conventional therapy or conventional therapy alone. MEASUREMENTS: The primary outcome measure was exercise capacity. Other measures were cardiopulmonary hemodynamics, signs and symptoms of pulmonary hypertension and scleroderma, and survival. RESULTS: Exercise capacity improved with epoprostenol (median distance walked in 6 minutes, 316 m at 12 weeks compared with 270 m at baseline) but decreased with conventional therapy (192 m at 12 weeks compared with 240 m at baseline). The difference between treatment groups in the median distance walked at week 12 was 108 m (95% CI, 55.2 m to 180.0 m) (P < 0.001). Hemodynamics improved at 12 weeks with epoprostenol. The changes in mean pulmonary artery pressure for the epoprostenol and conventional therapy groups were -5.0 and 0.9 mm Hg, respectively (difference, -6.0 mm Hg [CI, -9.0 to -3.0 mm Hg), and the mean changes in pulmonary vascular resistance were -4.6 and 0.9 mm Hg/L per minute, respectively (difference, -5.5 mm Hg/L per minute [CI, -7.3 to -3.7 mm Hg/L per minute). Twenty-one patients treated with epoprostenol and no patients receiving conventional therapy showed improved New York Heart Association functional class. Borg Dyspnea Scores and Dyspnea-Fatigue Ratings improved in the epoprostenol group. Trends toward greater improvement in severity of the Raynaud phenomenon and fewer new digital ulcers were seen in the epoprostenol group. Four patients in the epoprostenol group and five in the conventional therapy group died (P value not significant). Side effects of epoprostenol therapy included jaw pain, nausea, and anorexia. Adverse events related to the epoprostenol delivery system included sepsis, cellulitis, hemorrhage, and pneumothorax (4% incidence for each condition). CONCLUSIONS: Continuous epoprostenol therapy improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension due to the scleroderma spectrum of disease.

Adult↗
PubMed2000

Fine mapping of PPH1, a gene for familial primary pulmonary hypertension, to a 3-cM region on chromosome 2q33.

Familial primary pulmonary hypertension (PPH) is a rare autosomal dominant disease characterized by distinctive changes in pulmonary arterioles that lead to increased pulmonary artery pressures, right ventricular failure, and death. Our previous studies had mapped the disease locus, PPH1, to a 27-cM region on chromosome 2q31-q33, with a maximum multipoint logarithm of the odds favoring genetic linkage score of 3.87 with markers D2S350 and D2S364. To narrow the minimal genetic region for PPH, we physically mapped 33 highly polymorphic microsatellite markers and used them to genotype 44 affected individuals and 133 unaffected individuals from 17 families with PPH. We observed recombination events that substantially reduced the interval for PPH1 to the approximately 3-cM region that separates D2S311 and D2S1384. This entire region lies within chromosome 2q33. A maximum two-point lod score of 7.23 at a recombination fraction of zero was obtained for marker D2S307. A maximum multipoint lod score of 7.41 was observed close to marker D2S1367. The current minimal genetic region contains multiple candidate genes for PPH, including a locus thought to play a role in lung cancer.

Chromosome Aberrations↗
PubMed1999

Continuous infusion of epoprostenol improves the net balance between pulmonary endothelin-1 clearance and release in primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension results from progressive narrowing of the precapillary pulmonary vasculature. A variety of endothelial abnormalities have been identified, including a net reduction in pulmonary clearance of the vasoconstrictor and smooth muscle mitogen endothelin-1. In many patients, net pulmonary release of endothelin-1 is observed. Chronic infusions of epoprostenol (prostacyclin) improve functional capacity, survival, and hemodynamics in patients with advanced primary pulmonary hypertension. We hypothesized that the epoprostenol infusions, as compared with conventional therapy, might alter the abnormal pulmonary endothelin-1 homeostasis. METHODS AND RESULTS: Using a subset of patients from a larger randomized study comparing epoprostenol plus conventional therapy (n=11 in the present study) with conventional therapy alone (n=7 in the present study), we determined the ratio of plasma endothelin-1 levels in systemic arterial blood leaving the lung to levels in mixed venous blood entering the lung both before randomization and after 88 days of continuous therapy. There were no differences between the 2 groups before therapy, but by day 88, the epoprostenol-treated group had a greater proportion of patients (82%) with an arterial/venous ratio <1 than did the conventional therapy group, in which only 29% of patients had a ratio <1 (P<0.05). CONCLUSIONS: These results suggest that continuous epoprostenol therapy may have a beneficial effect on the balance between endothelin-1 clearance and release in many patients with primary pulmonary hypertension and may provide one explanation for the salutary effect of epoprostenol in this disease.

Antihypertensive Agents↗
PubMed1999

Long-term prostacyclin for pulmonary hypertension with associated congenital heart defects.

BACKGROUND: Although long-term prostacyclin (PGI2) has been shown to improve hemodynamics, quality of life, and survival in patients with primary pulmonary hypertension, its use in patients with pulmonary hypertension (PHT) and associated congenital heart defects (CHD) has not been evaluated. METHODS AND RESULTS: Twenty patients (15+/-14 years) with PHT and associated CHD (9 atrial septal defect, 7 ventricular septal defect, 4 transposition of the great vessels, 3 patient ductus arteriosus, 3 partial anomalous pulmonary venous return, and 1 aortopulmonary window) who failed conventional therapy (including digitalis; diuretics; oxygen; warfarin; calcium channel blockade, if indicated; and surgery, if operable) were treated with chronic PGI2. Eleven patients had previous cardiac surgery at a median age of 3 years (range, 5 days to 47 years). Eleven of 20 patients had residual systemic to pulmonary shunts. Hemodynamics, NYHA functional class, and exercise capacity were measured at baseline and after 1 year of PGI2 therapy. None of the patients acutely responded to PGI2 administration. Despite lack of an acute response, mean pulmonary artery pressure decreased 21% on chronic PGI2: 77+/-20 to 61+/-15 mm Hg (P<0.01, n=16). Cardiac index and pulmonary vascular resistance also improved on long-term PGI2: 3. 5+/-2.0 to 5.9+/-2.7 L. min-1. m-2 (P<0.01, n=16), and 25+/-13 to 12+/-7 U.m2 (P<0.01, n=16), respectively. NYHA functional class improved from 3.2+/-0.7 to 2.0+/-0.9 (P<0.0001, n=19). Exercise capacity increased from 408+/-149 to 460+/-99 m (P=0.13, n=14) on long-term PGI2. CONCLUSIONS: Chronic PGI2 improves hemodynamics and quality of life in patients with PHT and associated CHD who fail conventional therapy. As previously demonstrated in patients with primary pulmonary hypertension, long-term PGI2 may have an important role in the treatment of patients with PHT and associated CHD.

Adult↗
PubMed1999

Vasodilator therapy for primary pulmonary hypertension in children.

BACKGROUND: This report presents 13 years of experience with vasodilator therapy for primary pulmonary hypertension (PPH) in children. Two eras were involved: between 1982 and 1987, oral calcium channel blockers were the only agents available for long-term therapy; after 1987, prostacyclin (PGI2) has been available for long-term intravenous use. METHODS AND RESULTS: Seventy-four children underwent short-term vasodilator testing with intravenous PGI2. Those who manifested pulmonary vasodilation ("acute responders") were treated with oral calcium channel blockers. Until 1987, "acute nonresponders" were treated in the same way as long as they had no serious side effects. When PGI2 became available for long-term administration, all nonresponders, as well as those who failed to improve clinically and hemodynamically on calcium channel blockers, were treated with long-term PGI2. In the 31 responders, calcium channel blockers improved survival compared with the 43 nonresponders (P=0.0002). Survival was also better in 24 PGI2-treated nonresponders compared with 22 nonresponders for whom PGI2 was unavailable (P=0.0005) as well as in all children who failed conventional therapy (n=31; P=0.002). CONCLUSIONS: Long-term vasodilator therapy improves survival in children with PPH. In acute responders, oral calcium channel blockers generally suffice. In both nonresponders to short-term testing and responders who fail to improve on calcium channel blockers, continuous intravenous infusion of PGI2 improves survival.

Adolescent↗
PubMed1999

Recent advances in the treatment of pediatric pulmonary artery hypertension.

As our understanding of the pathogenesis of PAH evolves, newer strategies for its treatment are being developed and implemented. Based on studies with adult PPH patients, anticoagulation is now regarded as a mainstay of therapy and is associated with prolonged survival. Before the era of vasodilator therapy, which began in the late 1970s, most children with PPH died within 1 year of diagnosis. Now with chronic calcium channel blockade, survival and QOL are improved in children who acutely respond to vasodilator drug testing. In the author's experience, the 5-year survival rate for patients treated with chronic oral calcium channel blockade who respond acutely to vasodilator testing is 97% versus 35% for those who do not respond acutely. Continuous i.v. prostacyclin has also been used successfully, with a 5-year survival rate of 92% in children in whom oral calcium channel blockade failed (although in some patients the prostacyclin therapy was used as a bridge to transplantation) versus 29% in children in whom oral calcium channel blockade also failed and for whom chronic prostacyclin was unavailable. Before the availability of long-term prostacyclin therapy, 30% to 40% of patients with PPH died while waiting for transplantation. Prostacyclin has virtually eliminated this situation. The results of lung transplantation for adult patients with PPH at 3 years are similar to the results of those on continuous i.v. prostacyclin. Ultimately, the best therapy for an individual child depends on the results of longer follow-up studies. Inhaled nitric oxide has also been used to treat PAH in newborns and other forms of acute and chronic PAH. Although less experience exists with long-term inhaled nitric oxide than with long-term prostacyclin, the preliminary results of long-term inhaled nitric oxide are promising and await further study. The "optimal" vasodilator for long-term therapy, (e.g., calcium channel blockade), prostacyclin, nitric oxide, or potential future therapies, such as prostacyclin analogs, endothelin receptor blockers and thromboxane synthase inhibitors or receptor blockers, must be based on a thorough evaluation with acute vasodilator testing and overall risk-benefit considerations for the various therapeutic regimens. Further clarification of the mechanisms of the development and perpetuation of the PAH process will undoubtedly lead to a refinement in treatment strategies for patients with PAH, which not too long ago was often considered untreatable and fatal. By increasing our understanding of the pathogenesis and pathophysiology of primary and secondary PAH disorders, one day we may be able to prevent or cure these diseases as opposed to providing only palliative therapy. Despite this, therapeutic advances have significantly improved the outcome for children with PAH.

Adolescent↗
PubMed1999

Effects of long-term infusion of prostacyclin on exercise performance in patients with primary pulmonary hypertension.

STUDY OBJECTIVES: To determine whether long-term IV prostacyclin (PGI(2)) use improves exercise capacity in patients with primary pulmonary hypertension (PPH). DESIGN: Cycle ergometry and the 6-min walk was used to evaluate the exercise performance of patients with PPH. The patients underwent serial exercise testing after starting continuous IV PGI(2) and were followed up for 19.5 +/- 7.5 months. Peak work, peak oxygen consumption (f1.gif" BORDER="0">O(2)), peak O(2) pulse, and distance walked in 6 min were used to evaluate performance. BACKGROUND: PPH is characterized by medial hypertrophy and intimal proliferation of the pulmonary arterioles, leading to elevation of pulmonary artery pressure, right ventricular failure, and death. Palliative treatment consists of vasodilators, anticoagulants, cardiac glycosides, diuretics, and transplantation. PGI(2), a potent vasodilator and inhibitor of platelet aggregation, has been used for long-term treatment when conventional therapy has been unsuccessful. PATIENTS: Sixteen patients with PPH (10 women, 6 men; mean age, 24 years). RESULTS: At the initiation of PGI(2), peak work (+/- SD) was 35.5 +/- 11% of predicted; peak f1.gif" BORDER="0">O(2), 39 +/- 10.4%; peak O(2) pulse, 5.0 +/- 1.7 mL/min; and distance on the 6-min walk, 428 +/- 78 feet. At 18 to 27 months, peak work increased to 58.8 +/- 23% of predicted (p = 0.001), peak f1.gif" BORDER="0">O(2) increased to 52 +/- 15% of predicted (p = 0. 02), peak O(2) pulse increased to 7.1 +/- 3.0 mL/beat (p = 0.004), and performance on the 6-min walk increased to 526 +/- 62 feet (p = 0.001). There was a positive correlation between peak f1.gif" BORDER="0">O(2) and peak 6-min walk of 0.6 (p < 0.005) and between peak work and peak 6-min walk of 0.6 (p < 0.005). CONCLUSIONS: Exercise capacity improved in our patients at up to 27 months of follow-up. Exercise testing is helpful in assessing the functional capacity of patients with PPH and may be useful in guiding therapy. Patients who deteriorate while receiving optimal conventional therapy should be considered for IV PGI(2) therapy.

Adolescent↗
PubMed1999

Do no harm.

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Calcium Channel Blockers↗