Person:

Maron, Bradley

Abstract The extent to which pulmonary arterial hypertension (PAH) experts share common practice patterns that are in alignment with published expert consensus recommendations is unknown. Our objective was to characterize the clinical management strategies used by an international cohort of self-identified PAH experts. A 32-item questionnaire composed mainly of rank order or Likert scale questions was distributed via the Internet (August 5, 2013, through January 20, 2014) to four international pulmonary vascular disease organizations. The survey respondents (N = 105) were field experts reporting 11.6 ± 8.7 years of PAH experience. Likert scale responses (1 = disagree, 7 = agree) were 3.0–5.0, indicating a disparity in opinions, for 78% of questions. Respondent (dis)agreement scores were 4.4 ± 2.2 for use of expert recommendations to determine catheterization timing in PAH. For PAH patients without cardiogenic shock or known vasoreactivity status, the most and least preferred first-line therapies (1 = most preferred, 5 = least preferred) were phosphodiesterase type 5 inhibitors (PDE-Vi) and subcutaneous prostacyclin analogues, respectively (1.4 ± 0.8 vs. 4.0 ± 1.1; P < 0.05). Compared with US-practicing clinicians (N = 46), non-US-practicing clinicians (N = 57) favored collaboration between cardiology and pulmonary medicine for clinical decision making (1 = disagree, 7 = agree; 3.1 ± 2.2 vs. 4.8 ± 2.2; P < 0.0001) and PDE-Vi (6.5% vs. 22.4%) as first-line therapy for PAH patients with cardiogenic shock but were less likely to perform vasoreactivity testing in patients with lung disease–induced pulmonary hypertension (4.3 ± 2.1 vs. 2.2 ± 1.6; P < 0.0001). In conclusion, practice patterns among PAH experts diverge from consensus recommendations and differ by practice location, suggesting that opportunity may exist to improve care quality for this highly morbid cardiopulmonary disease.

Abstract Despite the importance of preserved right ventricular structure and function with respect to outcome across the spectrum of lung, cardiac, and pulmonary vascular diseases, only recently have organized efforts developed to consider the pulmonary vascular–right ventricular apparatus as a specific unit within the larger context of cardiopulmonary pathophysiology. The Third International Right Heart Failure Summit (Boston, MA) was a multidisciplinary event dedicated to promoting a dialogue about the scientific and clinical basis of right heart disease. The current review provides a synopsis of key discussions presented during the section of the summit titled “Emerging Hemodynamic Signatures of the Right Heart.” Specifically, topics emphasized in this element of the symposium included (1) the effects of pulmonary vascular dysfunction at rest or provoked by exercise on the right ventricular pressure-volume relationship, (2) the role of pressure-volume loop analysis as a method to characterize right ventricular inefficiency and predict right heart failure, and (3) the importance of a systems biology approach to identifying novel factors that contribute to pathophenotypes associated with pulmonary arterial hypertension and/or right ventricular dysfunction. Collectively, these concepts frame a forward-thinking paradigm shift in the approach to right heart disease by emphasizing factors that regulate the transition from adaptive to maladaptive right ventricular–pulmonary vascular (patho)physiology.

Abstract In patients with chronic obstructive pulmonary disease (COPD), moderate or severe pulmonary hypertension (COPD-PH) is associated with increased rates of morbidity and mortality. Despite this, approaches to treatment and the efficacy of phosphodiesterase type 5 inhibition (PDE-5i) in COPD-PH are unresolved. We present the clinical rationale and study design to assess the effect of oral tadalafil on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome measures in COPD-PH patients. Male and female patients 40–85 years old with GOLD stage 2 COPD or higher and pulmonary hypertension diagnosed on the basis of invasive cardiac hemodynamic assessment (mean pulmonary artery pressure [mPAP] >30 mmHg, pulmonary vascular resistance [PVR] >2.5 Wood units, and pulmonary capillary wedge pressure ≤18 mmHg at rest) will be randomized at a 1∶1 ratio to receive placebo or oral PDE-5i with tadalafil (40 mg daily for 12 months). The primary end point is change from baseline in 6-minute walk distance at 12 months. The secondary end points are change from baseline in PVR and mPAP at 6 months and change from baseline in peak volume of oxygen consumption () during exercise at 12 months. Changes in systemic blood pressure and/or oxyhemoglobin saturation (Sao2) at rest and during exercise will function as safety outcome measures. TADA-PHiLD (TADAlafil for Pulmonary Hypertension assocIated with chronic obstructive Lung Disease) is the first sufficiently powered randomized clinical trial testing the effect of PDE-5i on key clinical and drug safety outcome measures in patients with at least moderate PH due to COPD.

Objective: We aimed to identify the echocardiographic measures associated with survival in a patient population with a high prevalence of co-morbid cardiovascular and pulmonary disease that have significantly elevated estimated pulmonary artery systolic pressures (ePASP). Background: Pulmonary hypertension (PH) is a clinical feature of several cardiopulmonary diseases that are prevalent among elderly. While certain echocardiographic parameters have been shown to be important in the prognosis in specific PH groups, the prognostic relevance of echocardiographic characteristics in a cohort with multiple cardiopulmonary comorbidities is unclear. Methods: We retrospectively identified 152 patients with ePASP > 60 mmHg by echocardiography over a five year period (6/2006–11/2011) and followed until 4/2013. Candidate clinical and echocardiographic characteristics suggestive of PH severity were compared between deceased and surviving subpopulations. Cox proportional hazard modeling was used to identify echocardiographic predictors of death adjusted for age and clinical characteristics. Results: This was a predominantly elderly (age 78.8 ± 10.2 years), male (98.7%) cohort with several cardiopulmonary comorbidities. Overall mortality was high (69.7%, median survival 129 days). After adjusting for age and clinical characteristics, decreased right ventricular (RV) systolic function assessed by tricuspid annular plane systolic excursion (HR 0.56, 95% CI 0.33–0.96, p = 0.034) and increased RV thickness (HR: 4.34, 95% CI: 1.49–12.59, p = 0.007) were independently associated with mortality. In contrast, left ventricular systolic function, left ventricular diastolic parameters, ePASP, or echo-derived pulmonary vascular resistance (PVR) were not associated with increased mortality. Conclusion: In a cohort of patients with PH and high prevalence of cardio-pulmonary comorbidities, RV systolic function and hypertrophy are associated with mortality and may be the most relevant echocardiographic markers for prognosis.

Pulmonary arterial hypertension (PAH) is a devastating disease that is precipitated by hypertrophic pulmonary vascular remodeling of distal arterioles to increase pulmonary artery pressure and pulmonary vascular resistance in the absence of left heart, lung parenchymal, or thromboembolic disease. Despite available medical therapy, pulmonary artery remodeling and its attendant hemodynamic consequences result in right ventricular dysfunction, failure, and early death. To limit morbidity and mortality, attention has focused on identifying the cellular and molecular mechanisms underlying aberrant pulmonary artery remodeling to identify pathways for intervention. While there is a well-recognized heritable genetic component to PAH, there is also evidence of other genetic perturbations, including pulmonary vascular cell DNA damage, activation of the DNA damage response, and variations in microRNA expression. These findings likely contribute, in part, to dysregulation of proliferation and apoptosis signaling pathways akin to what is observed in cancer; changes in cellular metabolism, metabolic flux, and mitochondrial function; and endothelial-to-mesenchymal transition as key signaling pathways that promote pulmonary vascular remodeling. This review will highlight recent advances in the field with an emphasis on the aforementioned molecular mechanisms as contributors to the pulmonary vascular disease pathophenotype.

Women have an increased risk of pulmonary hypertension (PH) but better survival compared to men. Few studies have explored sex-based differences in population-based cohorts with PH. We sought to determine whether sex was associated with hemodynamics and survival in US veterans with PH (mean pulmonary artery pressure [mPAP] ≥ 25 mm Hg) from the Veterans Affairs Clinical Assessment, Reporting, and Tracking database. The relationship between sex and hemodynamics was assessed with multivariable linear mixed modeling. Cox proportional hazards models were used to compare survival by sex for those with PH and precapillary PH (mPAP ≥ 25 mm Hg, pulmonary artery wedge pressure [PAWP] ≤ 15 mm Hg and pulmonary vascular resistance [PVR] > 3 Wood units) respectively. The study population included 15,464 veterans with PH, 516 (3%) of whom were women; 1,942 patients (13%) had precapillary PH, of whom 120 (6%) were women. Among those with PH, women had higher PVR and pulmonary artery pulse pressure, and lower right atrial pressure and PAWP (all p <0.001) compared with men. There were no significant differences in hemodynamics according to sex in veterans with precapillary PH. Women with PH had 18% greater survival compared to men with PH (adjusted HR 0.82, 95% CI 0.69–0.97, p = 0.020). Similarly, women with precapillary PH were 29% more likely to survive as compared to men with PH (adjusted HR 0.71, 95% CI 0.52–0.98, p = 0.040). In conclusion, female veterans with PH have better survival than males despite higher pulmonary afterload.

Reductionist theory proposes that analyzing complex systems according to their most fundamental components is required for problem resolution, and has served as the cornerstone of scientific methodology for more than four centuries. However, technological gains in the current scientific era now allow for the generation of large datasets that profile the proteomic, genomic, and metabolomic signatures of biological systems across a range of conditions. The accessibility of data on such a vast scale has, in turn, highlighted the limitations of reductionism, which is not conducive to analyses that consider multiple and contemporaneous interactions between intermediates within a pathway or across constructs. Systems biology has emerged as an alternative approach to analyze complex biological systems. This methodology is based on the generation of scale-free networks and, thus, provides a quantitative assessment of relationships between multiple intermediates, such as protein-protein interactions, within and between pathways of interest. In this way, systems biology is well positioned to identify novel targets implicated in the pathogenesis or treatment of diseases. In this review, the historical root and fundamental basis of systems biology, as well as the potential applications of this methodology are discussed with particular emphasis on integration of these concepts to further understanding of cardiovascular disorders such as coronary artery disease and pulmonary hypertension.

Borderline resting mean pulmonary arterial pressure (mPAP) is associated with adverse outcomes and affects the exercise pulmonary vascular response. However, the pathophysiological mechanisms underlying exertional intolerance in borderline mPAP remain incompletely characterized. In the current study, we sought to evaluate the prevalence and functional impact of exercise pulmonary hypertension (ePH) across a spectrum of resting mPAP’s in consecutive patients with contemporary resting right heart catheterization (RHC) and invasive cardiopulmonary exercise testing. Patients with resting mPAP <25 mmHg and pulmonary arterial wedge pressure ≤15 mmHg (n = 312) were stratified by mPAP < 13, 13–16, 17–20, and 21–24 mmHg. Those with ePH (n = 35) were compared with resting precapillary pulmonary hypertension (rPH; n = 16) and to those with normal hemodynamics (non-PH; n = 224). ePH prevalence was 6%, 8%, and 27% for resting mPAP 13–16, 17–20, and 21–24 mmHg, respectively. Within each of these resting mPAP epochs, ePH negatively impacted exercise capacity compared with non-PH (peak oxygen uptake 70 ± 16% versus 92 ± 19% predicted, P < 0.01; 72 ± 13% versus 86 ± 17% predicted, P < 0.05; and 64 ± 15% versus 82 ± 19% predicted, P < 0.001, respectively). Overall, ePH and rPH had similar functional limitation (peak oxygen uptake 67 ± 15% versus 68 ± 17% predicted, P > 0.05) and similar underlying mechanisms of exercise intolerance compared with non-PH (peak oxygen delivery 1868 ± 599 mL/min versus 1756 ± 720 mL/min versus 2482 ± 875 mL/min, respectively; P < 0.05), associated with chronotropic incompetence, increased right ventricular afterload and signs of right ventricular/pulmonary vascular uncoupling. In conclusion, ePH is most frequently found in borderline mPAP, reducing exercise capacity in a manner similar to rPH. When borderline mPAP is identified at RHC, evaluation of the pulmonary circulation under the stress of exercise is warranted.