David D. Ralph

Echocardiographic predictors of adverse outcomes in primary pulmonary hypertension

OBJECTIVES The aim of this study was to evaluate the relationships between echocardiographic findings and clinical outcomes in patients with severe primary pulmonary hypertension (PPH). BACKGROUND Primary pulmonary hypertension is associated with abnormalities of right heart structure and function that contribute to the poor prognosis of the disease. Echocardiographic abnormalities associated with PPH have been described, but the prognostic significance of these findings remains poorly characterized. METHODS Echocardiographic studies, invasive hemodynamic measurements and 6-min walk tests were performed and outcomes prospectively followed in 81 patients with severe PPH. Subjects were participants in a 12-week randomized trial examining the effects of prostacyclin plus conventional therapy compared with conventional therapy alone. RESULTS During the mean follow-up period of 36.9 +/- 15.4 months, 20 patients died and 21 patients underwent transplantation. Pericardial effusion (p = 0.003) and indexed right atrial area (p = 0.005) were predictors of mortality. Pericardial effusion (p = 0.017), indexed right atrial area (p = 0.012) and the degree of septal shift in diastole (p = 0.004) were predictors of a composite end point of death or transplantation. In multivariable analyses incorporating clinical, hemodynamic and echocardiographic variables, pericardial effusion and an enlarged right atrium remained predictors of adverse outcomes. Six-minute walk results, mixed venous oxygen saturation and initial treatment randomization were also independently associated with a poor prognosis. CONCLUSIONS Pericardial effusion, right atrial enlargement and septal displacement are echocardiographic abnormalities that reflect the severity of right heart failure and predict adverse outcomes in patients with severe PPH. These characteristics may help identify patients appropriate for more intensive medical therapy or earlier transplantation.

Pulmonary hypertension in pregnancy: treatment with pulmonary vasodilators.

OBJECTIVE To describe the clinical course of pregnancies complicated by pulmonary hypertension and treated with the pulmonary vasodilators nifedipine and prostacyclin. METHODS Four pregnant women with pulmonary hypertension were treated with pulmonary vasodilators. Therapy with oral nifedipine and intravenous prostacyclin was guided by right pulmonary artery catheterization and Doppler measurements of cardiac output. RESULTS Three of four women responded to vasodilator therapy and successfully completed their pregnancies. Two who conceived at least 1 year after successful treatment and normalized right ventricle function carried three uncomplicated pregnancies. The woman who did not respond died. Delay in diagnosis contributed to her outcome. Noninvasive measurement of cardiac output helped diagnosis of right ventricular failure and offered reassurance in women who remained compensated. Postpartum decompensation in one woman was characterized by a negative Starling response as central venous pressure increased from 4 to 11 mmHg. She responded positively to diuresis. CONCLUSION Early diagnosis of pulmonary hypertension is critical. Volume overload postpartum might significantly contribute to decompensation. We recommend a year of successful therapy after a response to vasodilator therapy and near-normal right ventricular function before pregnancy is considered. In complicated pregnancies, women must balance the best estimate of risk with the value they put on pregnancy.

Frequency and Severity of Tricuspid Regurgitation Determined by Doppler Echocardiography in Primary Pulmonary Hypertension

W previously described a high prevalence of functional tricuspid regurgitation (TR) in patients with severely symptomatic primary pulmonary hypertension (PPH).1 We report the relations of TR to right ventricular (RV) size and geometry, tricuspid annulus diameter, tricuspid leaflet displacement, hemodynamics, and exercise capacity in these patients. • • • The study group consisted of 78 patients enrolled in a multicenter trial of epoprostenol (Flolan, GlaxoSmithKline, Research Triangle Park, North Carolina) for the treatment of severe PPH.2 The study consisted of 56 women and 32 men (mean age 40 15 years). Most (74%) had New York Heart Association class III symptoms; their average mean pulmonary arterial pressure was 60 12 mm Hg. All participants met the criteria for PPH as defined by the National Institutes of Health Patient Registry,3 and all had New York Heart Association class III or class IV symptoms. The study was approved by the institutional review committee of each participating center, and informed consent was acquired from each patient before enrollment. Baseline echocardiograms of all participants were obtained using a defined imaging protocol and recorded on videotape. All studies were analyzed using an off-line quantification system by a single observer from the core echocardiographic laboratory. Measurements were obtained on 3 representative beats, and the results averaged. Details of the imaging and quantification protocols, including reproducibility data, have been described previously.1 The severity of TR was determined from 2-dimensional and Doppler color flow images in the apical 4-chamber view. Frame-by-frame analysis of each cardiac cycle was used to identify the maximum area of the Doppler color flow jet. The outline of the regurgitant signal, including aliased signals and contiguous velocities moving in the same direction, was traced and the area determined by computerized planimetry. The area of the right atrium was similarly measured on the same frame. The severity of TR was quantified as the ratio of the Doppler regurgitant jet area to the right atrial (RA) area (the TR/RA ratio). Previous investigators have demonstrated that this ratio is correlated closely with the severity of TR measured by a double thermodilution technique.4 Severe TR was defined as a TR/RA ratio 0.34, a ratio that corresponds to severe TR as judged by thermodilution4 or intraoperative digital palpation.5 TR was considered moderate if the TR/RA ratio was 0.20 and 0.34, and mild if the TR/RA ratio was 0.20. The tricuspid valve was examined in the apical 4-chamber view for thickening or doming, and for abnormal closure. The apical displacement of the tricuspid leaflets, an index of abnormal closure due to chordal tension, was measured as the distance from the coaptation point to the plane of the tricuspid annulus at the time of maximal systolic closure. Loss of coaptation was defined as a visible separation of the septal and anterior leaflets throughout systole. The following echocardiographic measures of RV structure were obtained in the apical 4-chamber view at end-diastole and at end-systole. (1) The tricuspid annulus diameter was measured from the point of attachment of the septal leaflet to the attachment of the anterior leaflet. This diameter was corrected for differences in body size by dividing by height. (2) The RV remodeling index was calculated as the ratio of RV short and long axes; the short axis was defined as the distance between the septal and free wall endocardial surfaces of the right ventricle at the midventricular level. The long axis was measured from the endocardial surface at the tip of the RV apex to the midpoint of the annular plane. (3) RV area was measured by planimetry, tracing the endocardial edge of the right ventricle and the plane of the tricuspid valve, and corrected for height. From the Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; University of Washington, Seattle, Washington; Maine Medical Center, Portland, Maine; Washington University, St. Louis, Missouri; Rhode Island Hospitals, Providence, Rhode Island; Louisiana State Medical Center, New Orleans, Louisiana; Cato Research Ltd., Durham, North Carolina; Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina; GlaxoSmithKline, Research Triangle Park, North Carolina; and United Therapeutics Inc., Chapel Hill, North Carolina. This study was supported by Burroughs Wellcome Co., Research Triangle Park, North Carolina. Dr. Hinderliter’s address is: Division of Cardiology, University of North Carolina, CB 7075, Chapel Hill, North Carolina, 27599. E-mail: hinderli@med.unc.edu. Manuscript received July 29, 2002; revised manuscript received and accepted December 20, 2002.

Dynamics of heat, water, and soluble gas exchange in the human airways: 1. A model study

In order to provide a means for analysis of heat, water, and soluble gas exchange with the airways during tidal ventilation, a one dimensional theoretical model describing heat and water exchange in the respiratory airways has been extended to include soluble gas exchange with the airway mucosa and water exchange with the mucous layer lining the airways. Not only do heat, water, and gas exchange occur simultaneously, but they also interact. Heating and cooling of the airway surface and mucous lining affects both evaporative water and soluble gas exchange. Water evaporation provides a major source of heat exchange. The model-predicted mean airway temperature profiles agree well with literature data for both oral and nasal breathing validating that part of the model. With model parameters giving the best fit to experimental data, the model shows: (a) substantial heat recovery in the upper airways, (b) minimal respiratory heat and water loss, and (c) low average mucous temperatures and maximal increases in mucous thickness. For resting breathing of room air, heat and water conservation appear to be more important than conditioning efficiency. End-tidal expired partial pressures of very soluble gases eliminated by the lungs are predicted to be lower than the alveolar partial pressures due to the absorption of the expired gases by the airway mucosa. The model may be usable for design of experiments to examine mechanisms associated with the local hydration and dehydration dynamics of the mucosal surface, control of bronchial perfusion, triggering of asthma, mucociliary clearance and deposition of inhaled pollutant gases.

Three-dimensional analysis of right ventricular shape and function in pulmonary hypertension

Right ventricular (RV) failure is a key determinant of morbidity and mortality in pulmonary hypertension (PH). The present study aims to add to existing descriptions of RV structural and functional changes in PH through a comprehensive three-dimensional (3D) shape analysis. We performed 3D echocardiography on 53 subjects with PH and 19 normal subjects. Twenty short-axis slices from apex to tricuspid centroid were measured to characterize regional shape: apical angle, basal bulge, eccentricity, and area. Transverse shortening was assessed by fractional area change (FAC) in each short-axis slice, longitudinal contraction was assessed by tricuspid annular plane systolic excursion (TAPSE) and global function by RV ejection fraction. Multivariate logistic analysis was used to compare the association of RV parameters with New York Heart Association (NYHA) class. Compared to normal, RV function in PH is characterized by decreased stroke volume index (SVi), fractional area change and ejection fraction. Increased eccentricity, apical rounding and bulging at the base characterize the shape of the RV in PH. Increased SVi, ejection fraction and mid-ventricular FAC were associated with less severe NYHA class in adjusted analyses. The RV in idiopathic PH (iPAH) was observed to have a larger end-diastolic volume and decreased function compared with connective tissue disease associated PH (ctd-PH). This work describes increased eccentricity and decreased systolic function in subjects with PH. Functional parameters were associated with NYHA class and heterogeneity in the phenotype was noted between subjects with iPAH and ctd-PH.

H2 Receptor Antagonists and Right Ventricular Morphology: The MESA Right Ventricle Study

RATIONALE H2 receptor antagonist (H2RA) use is common and may act directly on the heart through myocardial H2 receptors or indirectly through changes in pulmonary vascular resistance. OBJECTIVES To determine the relationship between histamine H2RA use and right ventricular (RV) morphology. METHODS We studied 4,122 participants in the Multi-Ethnic Study of Atherosclerosis without clinical cardiovascular disease who had magnetic resonance imaging assessment of RV morphology and ascertainment of medication use. Multivariable linear regression estimated cross-sectional associations between H2RA use and RV morphology after adjusting for demographics, anthropometrics, smoking status, diabetes mellitus, and hypertension. Further adjustments for co-medication use, left ventricular parameters, lung structure and function, renal function, or inflammatory markers were considered in separate models. Analyses in a subcohort restricted to H2RA or proton pump inhibitor users accounted for confounding by the indication of gastroesophageal reflux disease. MEASUREMENTS AND MAIN RESULTS H2RA use was associated with lower RV mass (-0.7 g; 95% confidence interval, -1.2 to -0.2 g; P = 0.004) and smaller RV end-diastolic volume (-4.2 ml; 95% confidence interval, -7.2 to -1.2 ml; P = 0.006). This relationship was unchanged with adjustment for co-medication use, lung structure and function, renal function, and inflammation. The relationship with RV mass was independent of left ventricular mass. Results were similar in the smaller cohort restricted to proton pump inhibitor and H2RA users. CONCLUSIONS H2RA use was associated with lower RV mass and smaller RV end-diastolic volume. Additional study of histamine and H2 receptors in cardiopulmonary diseases affecting the RV may have direct clinical relevance.

Influence of Gas Physical Properties on Pulmonary Gas Exchange

Overall, the exchange of gas by the lung is strongly dependent on the blood-gas partition coefficient of that gas and weakly dependent on the molecular weight of the gas. The exchange of very soluble inert gases is dependent on interaction with the airway surface during inspiration and expiration.

H2 Receptor Antagonist Use and Mortality in Pulmonary Hypertension: Insight from the VA-CART Program

Accuracy of immunofluorescence in the diagnosis of primary ciliary dyskinesia. Am J Respir Crit Care Med 2017;196:94–101. 7. Bolte S, Cordelières FP. A guided tour into subcellular colocalization analysis in light microscopy. J Microsc 2006;224:213–232. 8. Lee TWR, Brownlee KG, Conway SP, Denton M, Littlewood JM. Evaluation of a new definition for chronic Pseudomonas aeruginosa infection in cystic fibrosis patients. J Cyst Fibros 2003;2:29–34. 9. Ortori CA, Dubern JF, Chhabra SR, Cámara M, Hardie K, Williams P, et al. Simultaneous quantitative profiling of N-acyl-L-homoserine lactone and 2-alkyl-4(1H)-quinolone families of quorum-sensing signaling molecules using LC-MS/MS. Anal Bioanal Chem 2011;399:839–850. 10. Shah AS, Ben-Shahar Y, Moninger TO, Kline JN, Welsh MJ. Motile cilia of human airway epithelia are chemosensory. Science 2009;325:1131–1134. 11. Yan CH, Hahn S, McMahon D, Bonislawski D, Kennedy DW, Adappa ND, et al. Nitric oxide production is stimulated by bitter taste receptors ubiquitously expressed in the sinonasal cavity. Am J Rhinol Allergy 2017;31:85–92. 12. Yang J, Liu X, Yue G, Adamian M, Bulgakov O, Li T. Rootletin, a novel coiled-coil protein, is a structural component of the ciliary rootlet. J Cell Biol 2002;159:431–440. 13. Kerem E, Viviani L, Zolin A, MacNeill S, Hatziagorou E, Ellemunter H, et al.; ECFS Patient Registry Steering Group. Factors associated with FEV1 decline in cystic fibrosis: analysis of the ECFS patient registry. Eur Respir J 2014;43:125–133.

What’s in a side effect? The association between pulmonary vasodilator adverse drug events and clinical outcomes in patients with pulmonary arterial hypertension ☆

BACKGROUND Adverse drug events (ADEs) with pulmonary vasodilator use in pulmonary arterial hypertension (PAH) are common. ADEs may contribute to worse quality of life; however, their relationship to prognosis is unknown. The objective of this study was to determine whether common ADEs after initiating subcutaneous treprostinil were associated with prognosis in PAH. METHODS We assembled a retrospective cohort of participants from four clinical trials of treprostinil for PAH, including 908 participants who received subcutaneous treprostinil and 243 who received placebo at the time ADEs were ascertained. The occurrences of four common early ADEs (infusion reactions, headaches, jaw pain, or gastrointestinal side effects) were assessed during the eight weeks after starting the infusion. We used Cox proportional hazards to estimate associations between ADEs and mortality. RESULTS No ADEs related to placebo were associated with mortality. In participants who received treprostinil, infusion reactions, headaches, and jaw pain were not associated with mortality. Gastrointestinal side effects occurring during the first eight weeks following treprostinil infusion were associated with a 57% increase in the hazard of mortality (95% CI: 14-118%). This relationship was unchanged after adjusting for demographic differences and differences in baseline PAH severity. CONCLUSIONS Gastrointestinal ADEs after starting subcutaneous treprostinil were associated with an increased risk for mortality. Increased mortality was not observed with other early ADEs or with gastrointestinal symptoms in participants who were not receiving treprostinil at the time. This hypothesis-generating association suggests ADEs may identify different phenotypes in PAH.