Search PubMed⌕ Search

Biomedical subjects

R J Barst

Publications and source records attributed to R J Barst.

At least 37 records · Page 2Linked to original sources
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.

Explore the source record for details and available documents.

Calcium Channel Blockers↗
PubMed1998

Genetics and immunogenetic aspects of primary pulmonary hypertension.

Primary pulmonary hypertension (PPH), also referred to as unexplained or idiopathic pulmonary hypertension, is the clinical term used to describe a condition in patients for which we can find no underlying cause. Patients with PPH not uncommonly also have evidence of immune dysregulation: autoimmune disorders, drug therapy, or HIV infections. We will review these associations and possible relevant abnormalities in immune regulation with regard to how they may play a role in the pathogenesis of PPH. Autoantibody-HLA correlations have been observed in several subsets of PPH patients. In addition, a familial form of PPH has been described and characterized with linkage to chromosome 2q31-q32. The identification of a specific gene for PPH and the subsequent understanding of its effects will help us identify the basic cause of PPH. Furthering our understanding regarding the role(s) and significance of immunogenetic as well as genetic aspects of the pathogenesis and pathophysiology of PPH should also lead to improved therapeutic modalities for PPH.

Autoimmune Diseases↗
PubMed1997

Continuous infusion of prostacyclin normalizes plasma markers of endothelial cell injury and platelet aggregation in primary pulmonary hypertension.

BACKGROUND: Primary pulmonary hypertension (PPH) is characterized by vascular injury of pulmonary arterioles, in which endothelial dysfunction may play a major role. Although continuous infusion of prostacyclin (prostaglandin I2, a potent vasodilator released by vascular endothelial cells) improves the clinical status and survival in PPH, its mechanism or mechanisms of action remain unclear. METHODS AND RESULTS: We measured endothelium-derived clotting factors and assayed platelet aggregation in 64 patients (26 adults and 38 children) with PPH before long-term PGI2 therapy. Repeat studies were performed in 42 patients (18 adults, 24 children) after one year of PGI2 therapy. At baseline, 87% of adults and 79% of children had abnormal platelet aggregation. In addition, factor VIII, von Willebrand (vW) antigen, and ristocetin cofactor levels were abnormally high in 92%, 72%, and 52%, respectively, of the adults versus 29%, 16%, and 16%, respectively, of the children (P<.005 adults versus children). With long-term PGI2, platelet aggregation normalized in 83% of the adults and 80% of the children who had platelet aggregation abnormalities at baseline (P<.01). Factor VIII, vW antigen, and ristocetin cofactor also decreased with long-term PGI2 in both groups (P<.02). The ratio of ristocetin cofactor to vW antigen, which may reflect biological activity of vW factor, increased with long-term PGI2 in adults from an abnormally low level (0.6+/-0.2) to normal level (1.10+/-0.4), and in children the ratio increased from 0.8+/-0.3 to 1.3+/-0.4 (normal, 0.8 to 1.4). CONCLUSIONS: Alterations in the coagulation system may contribute to the pathogenesis of PPH; the normalization of these endothelial markers concomitant with improvement in hemodynamic parameters with long-term PGI2 suggests that long-term PGI2 remodels the pulmonary vascular bed with subsequent decreases in endothelial cell injury and hypercoagulability.

Adolescent↗
PubMed1997

Common cardiovascular problems in the young: Part I. Murmurs, chest pain, syncope and irregular rhythms.

Cardiovascular signs and symptoms in young people are common and usually represent variants of normal physiology. However, these signs and symptoms can also indicate the presence of important cardiovascular disorders. Innocent heart murmurs can be distinguished from pathologic murmurs by the lack of associated symptoms, as well as their loudness, timing and location. Although most chest pain in this age group is of musculoskeletal or psychogenic origin, cardiac causes can include pericarditis, aortic stenosis and coronary anomalies. Syncope is usually vasovagal in origin and has a benign prognosis. Sinus arrhythmia and isolated extrasystoles are the most common causes of irregular cardiac rhythms in the young. Multiform premature ventricular contractions, couplets and ventricular tachycardia may indicate underlying cardiac disease.

Adolescent↗