Pulmonary Circulation

Over the past decade, the importance of non-coding RNA such as microRNA has been established in numerous processes that drive human pathogenesis. These crucial molecular regulators modulate networks of target gene transcripts that, in turn, orchestrate cellular phenotypes such as cell survival, differentiation, proliferation, and metabolism among others and thus affect cardiopulmonary vascular disease conditions. Many of these same pathophenotypes figure prominently in the complex pathogenesis of pulmonary hypertension, an enigmatic vascular disorder characterized by a histological panvasculopathy and driven by disparate upstream triggers such as hypoxia, inflammation, and bone morphogenetic protein signaling. Yet, the importance of just a few microRNAs in pulmonary hypertension has been recognized, and we are only beginning to understand the integrative functions of these molecules in this disease. By combining systems biology with traditional experimental approaches, more direct insight into the pleiotropy of microRNA should not only further reveal the spectrum of molecular pathways that cause pulmonary hypertension, but also offer novel and much needed diagnostic and therapeutic strategies.

Almost a trillion platelets pass through the pulmonary circulation every minute, yet little is known about how they support pulmonary physiology or contribute to the pathogenesis of lung diseases. When considering this conundrum, three questions jump out: Does platelet production in the lungs occur? Why does severe thrombocytopenia—which undercuts the principal physiological role of platelets to effect hemostasis—not lead to pulmonary hemorrhage? Why does atherothrombosis—which platelets initiate, maintain, and trigger is other critically important arterial beds—not develop in the pulmonary artery? The purpose of this review is to explore these and derivative questions by providing data within a conceptual framework that begins to organize a subject that is largely unassembled.

Right ventricular (RV) function is a strong independent predictor of outcome in a number of distinct cardiopulmonary diseases. The RV has a remarkable ability to sustain damage and recover function which may be related to unique anatomic, physiologic, and genetic factors that differentiate it from the left ventricle. This capacity has been described in patients with RV myocardial infarction, pulmonary arterial hypertension, and chronic thromboembolic disease as well as post-lung transplant and post-left ventricular assist device implantation. Various echocardiographic and magnetic resonance imaging parameters of RV function contribute to the clinical assessment and predict outcomes in these patients; however, limitations remain with these techniques. Early diagnosis of RV function and better insight into the mechanisms of RV recovery could improve patient outcomes. Further refinement of established and emerging imaging techniques is necessary to aid subclinical diagnosis and inform treatment decisions.

Increased pulmonary blood flow (PBF) is widely thought to provoke pulmonary vascular obstructive disease (PVO), but the impact of wall shear stress in the lung is actually poorly defined. We examined information from patients having cardiac lesions which impact the pulmonary circulation in distinct ways, as well as experimental studies, asking how altered hemodynamics impact the risk of developing PVO. Our results are as follows: (1) with atrial septal defect (ASD; increased PBF but low PAP), shear stress may be increased but there is little tendency to develop PVO; (2) with normal PBF but increased pulmonary vascular resistance (PVR; mitral valve disease) shear stress may also be increased but risk of PVO still low; (3) with high PVR and PBF (e.g., large ventricular septal defect), wall shear stress is markedly increased and the likelihood of developing PVO is much higher than with high PBF or PAP only; and (4) with ASD, experimental and clinical observations suggest that increased PBF plus another stimulus (e.g., endothelial inflammation) may be required for PVO. We conclude that modestly increased wall shear stress (e.g., ASD) infrequently provokes PVO, and likely requires other factors to be harmful. Likewise, increased PAP seldom causes PVO. Markedly increased wall shear stress may greatly increase the likelihood of PVO, but we cannot discriminate its effect from the combined effects of increased PAP and PBF. Finally, the age of onset of increased PAP may critically impact the risk of PVO. Some implications of these observations for future investigations are discussed.

The pathogenesis of idiopathic pulmonary hypertension is poorly understood. This paper utilized histology-based Matrix-Assisted Laser Desorption Ionization Mass Spectrometry (MALDI MS) to identify as-yet unknown proteins that may be associated with the structural changes in the pulmonary arterial walls of patients with IPAH. The technology identified significant increases in two fragments of histone H1 in the IPAH cases compared to controls. This finding was further examined using immunofluorescence techniques applied to sections from IPAH and control pulmonary arteries. In addition, cultured pulmonary artery smooth muscle cells (PASMCs) were utilized for Western analysis of histone H1 and importin β and importin 7, immunoprecipitation and assessment of nucleosomal repeat length (NRL). Immunofluorescence techniques revealed that nuclear expression of histone H1 was decreased and the chromatin was less compact in the IPAH cases than in the controls; furthermore, some cases showed a marked increase in cytoplasmic histone H1 expression. Using nuclear and cytoplasmic fractions of cultured PASMCs, we confirmed the reduction in histone H1 in the nucleus and an increase in the cytoplasm in IPAH cells compared to controls. Immunoprecipitation demonstrated a decreased association of histone H1 with importin β while importin 7 was unchanged in the IPAH cells compared to controls. The assessment of NRL revealed that the distance between nucleosomes was increased by ∼20 bp in IPAH compared to controls. We conclude that at least two factors contribute to the reduction in nuclear histone H1—fragmentation of the protein and decreased import of histone H1 into the nucleus by importins. We further suggest that the decreased nuclear H1 contributes the less compact nucleosomal pattern in IPAH and this, in turn, contributes to the increase in NRL.

Right ventricular (RV) function is the major determinant of mortality in pulmonary arterial hypertension and male sex is a strong predictor of mortality in this disease. The effects of testosterone on RV structure and function in load stress are presently unknown. We tested whether testosterone levels affect RV hypertrophic responses, fibrosis, and function. Male C57BL/6 mice underwent castration or sham followed by pulmonary artery banding (PAB) or sham. After recovery, testosterone pellets were placed in a subset of the castrated mice and mice were maintained for at least two weeks, when they underwent hemodynamic measurements and tissues were harvested. Plasma levels of testosterone were reduced by castration and repleted by testosterone administration. In PAB, castration resulted in lower right ventricle/left ventricle + septum (RV/LV+S), and myocyte diameter (P < 0.05). Replacement of testosterone normalized these parameters and increased RV fibrosis (P < 0.05). Two weeks of PAB resulted in increased RV systolic pressure in all groups with decreased markers of RV systolic and diastolic function, specifically reduced ejection fraction and increased time constant, and dPdt minimum (P < 0.05), though there was minimal effect of testosterone on hemodynamic parameters. Survival was improved in mice that underwent castration with PAB compared with PAB alone (P < 0.05). Testosterone affects RV hypertrophic response to load stress through increased myocyte size and increased fibrosis in mice. Castration and testosterone replacement are not accompanied by significant alterations in RV in vivo hemodynamics, but testosterone deprivation appears to improve survival in PAB. Further study of the role of testosterone in RV dysfunction is warranted to better understand these findings in the context of human disease.

The objective of this study was to report the outcome of pulmonary endarterectomy (PEA) surgery performed for chronic thromboembolic pulmonary hypertension (CTEPH) at a single tertiary center. The prospective study consisted of 35 patients with surgically amenable CTEPH undergoing PEA between September 2004 and September 2010. The main outcome measures were Functional (New York Heart Association [NYHA] class, 6-Minute Walk Distance), hemodynamic (echocardiography, right heart catheterization, and cardiac MRI), and outcome data (morbidity and mortality). Following PEA, there were significant improvements in NYHA class (pre 2.9±0.7 vs. post 1.3±0.5, P < 0.0001), right ventricular systolic pressure (pre 77.4±24.8 mmHg vs. post 45.1±24.9 mmHg, P = 0.0005), 6-Minute Walk Distance (pre 419.6±109.4 m vs. post 521.6±83.5 m, P = 0.0017), mean pulmonary artery pressure (pre 41.8±15.3 mmHg vs. post 24.7±8.8 mmHg, P = 0.0006), and cardiac MRI indices (end diastolic volume pre 213.8±49.2 mL vs. post 148.1±34.5 mL, P < 0.0001; ejection fraction pre 40.7±9.8 mL vs. post 48.1±8.9 mL, P = 0.0069). The mean cardiopulmonary bypass time was 258.77±26.16 min, with a mean circulatory arrest time of 43.83 ±28.78 min, a mean ventilation time of 4.7±7.93 days (range 0.2–32.7), and a mean intensive care unit stay of 7.22±8.71 days (range 1.1–33.8). Complications included reperfusion lung injury (20%), persistent pulmonary hypertension (17.1%), slow respiratory wean (25.7%), pericardial effusion (11.4%), and cardiac tamponade (5.7%). 1-year mortality post-procedure was 11.4%. Pulmonary endarterectomy can be performed safely with relatively low mortality.

This study measured glucose uptake in the right ventricle (RV) of patients with pulmonary hypertension and investigated the relationship to hemodynamics and survival. Myocardial 18F-fluorodeoxy-glucose (FDG) uptake was measured using single-photon positron emission tomography (SPECT) in 24 patients with idiopathic pulmonary arterial hypertension (IPAH) and 43 patients with congenital heart disease (CHD). In both IPAH and CHD-PAH, RV FDG uptake (RV/LV ratio) was associated with pulmonary vascular resistance (PVR). A second SPECT scan was performed in nine patients after 6 months treatment with sildenafil. PVR decreased from 1683±426 to 1207±383 dyn s⁻¹ cm⁻⁵ (P < 0.05) and cardiac index improved from 2.2±0.2 to 2.8±0.5 L/min/m² (P < 0.01). RV/LV FDG uptake decreased from 1.28±0.32 before treatment to 0.99±0.23 (P < 0.05). Survival in the IPAH group with a baseline RV/LV FDG uptake greater than the median value of 1.20 was significantly lower than that of the group with RV/LV FDG uptake below 1.20 (log-rank test, P < 0.05). In contrast, baseline RV/LV FDG was of little informative value in CHD. FDG uptake by the RV reflects the severity of PVR in PAH. Increased RV FDG uptake is a marker of poor prognosis in IPAH and is reduced in patients receiving effective therapy. It could prove useful in the early clinical assessment of novel therapies for PAH.

The survival rates of Chinese patients with idiopathic pulmonary arterial hypertension (IPAH) and familial pulmonary arterial hypertension (PAH) on conventional therapy at 1 and 3 years were 68.0% and 38.9%, respectively. Our aim was to update recent knowledge on the demographics, clinical course, hemodynamic features, disease management, and survival of adult patients with IPAH. This retrospective and observational study was conducted at the largest tertiary referral center in China. Ninety patients with IPAH who underwent initial evaluation at Fu Wai Hospital from January 2006 through November 2009 were retrospectively enrolled. The primary outcome was death. Statistical analyses used included independent sample t test, nonparametric test, Kaplan-Meier method, and Cox proportional hazards analysis. Of the 90 patients enrolled, the median age was 32 years with female predominance. The median interval from onset of symptoms to diagnosis was 14 months. Patients exhibited severe exercise limitation and hemodynamic abnormalities at diagnosis. Only 10.6% had a positive vasoreactivity test, while calcium channel blockers were given to 22.2% of patients. Fifty-nine patients (65.6%) received PAH-targeted therapies during follow-up. Our survival rates of 84.1%, 73.7%, and 70.6% at 1-, 2-, and 3-years compared favorably with predicted survival based on the National Institutes of Health equation which showed 1-, 2-, and 3-years survival rates of 67.7%, 55.9%, and 47%, respectively. For the patients receiving conventional therapy solely, the 1- and 3-years survival rates were 67.0% and 49.3%, respectively. Younger age, lower body mass index, presence of pericardial effusion, and absence of PAH-targeted therapy were independently associated with mortality. We concluded that patients with IPAH were still diagnosed too late, and while survival rates have improved in the modern treatment era, there is still room for improvement.

The pulmonary vasculature is an important site of renin-angiotensin metabolism. While angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (collectively AIABs) have a role in left ventricular (LV) disease, the impact of AIABs on right ventricular (RV) function is unknown. AIAB use was determined by medication inventory during the Multi-Ethnic Study of Atherosclerosis baseline examination. RV measures were obtained via cardiac magnetic resonance imaging. The relationship between AIAB use and RV measures was assessed using multivariable linear regression, stratified by race/ethnicity, and adjusted for multiple covariates. AIAB use was associated with lower RV mass (−0.7 g, 95% confidence interval [CI] −1.3 to −0.1, P=0.03) in African Americans (N=1012) after adjustment for multiple covariates including LV mass. Among Caucasians (N=1591), AIAB use was associated with larger RV end-diastolic volume (3.7 mL, 95% CI 0.7–6.8, P=0.02) after adjustment for LV volume. No significant associations were seen between AIAB use and other RV measures or in Hispanic or Chinese American participants. AIAB use was associated with RV morphology in a race-specific and LV-independent manner, suggesting the renin-angiotensin system may play a unique role in RV structure and function. The use of AIABs in those with RV dysfunction warrants further study.

Patients affected by pulmonary arterial hypertension (PAH) show a typical pattern of abnormalities on cardiopulmonary exercise testing (CPET). However, CPET is not routinely used as a screening method. We discuss a patient with hereditary PAH in whom CPET revealed onset of disease. Furthermore, we show that the abnormalities observed can improve in part by PAH-specific treatment.

Pulmonary arterial hypertension is a fatal disease. Intravenous prostanoids are often utilized for long-term management of patients. The therapy requires a significant commitment and change in lifestyle for both the patient and family. Takotsubo cardiomyopathy, transient apical ballooning syndrome, has been reported in association with emotional and physical stress. This case report describes a patient with pulmonary arterial hypertension who developed Takotsubo cardiomyopathy after treatment initiation with intravenous treprostinil. Over time, the syndrome resolved and the patient had return of normal left ventricular function. Takotsubo cardiomyopathy should be recognized as a potential, rare complication of therapy initiation due to the severity of the illness and the emotional stress of the disease.

Pulmonary Circulation, April-June, 2012; Vol 2; Issue 2

Title: Clinical perspectives with long-term pulsed inhaled nitric oxide for the treatment of pulmonary arterial hypertension

The sentences pertaining should be read as follows

“Conflict of Interest: None declared”

Should read as

“Conflict of Interest: Dr. Barst has been a member of the speakers' bureau for Actelion Pharmaceuticals US, Inc. and Gilead; has been a consultant and has received honoraria for speaking engagements as an invited speaker for Actelion Pharmaceuticals US, Inc.; Bayer HealthCare Pharmaceuticals; Eli Lilly and Company; Gilead; Ikaria, Inc.; Merck & Co., Inc.; Novartis Pharmaceuticals Corporation; Pfizer Inc; and VentriPoint, Inc.; and is a shareholder of VentriPoint, Inc. stock. Dr. Channick has received grant/research support from and has been a consultant for Ikaria, Inc. and Actelion Pharmaceuticals US, Inc. He has participated in formal advisory activities for Ikaria, Inc.; Actelion Pharmaceuticals US, Inc.; and United Therapeutics Corporation. The University of Colorado receives fees for Dr. Ivy to be a consultant for Actelion Pharmaceuticals US, Inc.; Gilead; Pfizer Inc; and United Therapeutics Corporation. Dr. Goldstein is an employee of Ikaria, Inc.”

The error is regretted

—Chief Editor, PC