Cardiopulmonary exercise test to detect cardiac dysfunction from pulmonary vascular disease.

BACKGROUND: Cardiac dysfunction from pulmonary vascular disease causes characteristic findings on cardiopulmonary exercise testing (CPET). We tested the accuracy of CPET for detecting inadequate stroke volume (SV) augmentation during exercise, a pivotal manifestation of cardiac limitation in patients with pulmonary vascular disease. METHODS: We reviewed patients with suspected pulmonary vascular disease in whom CPET and right heart catheterization (RHC) measurements were taken at rest and at anaerobic threshold (AT). We correlated CPET-determined O2·pulseAT/O2·pulserest with RHC-determined SVAT/SVrest. We evaluated the sensitivity and specificity of O2·pulseAT/O2·pulserest to detect SVAT/SVrest below the lower limit of normal (LLN). For comparison, we performed similar analyses comparing echocardiographically-measured peak tricuspid regurgitant velocity (TRVpeak) with SVAT/SVrest. RESULTS: From July 2018 through February 2023, 83 simultaneous RHC and CPET were performed. Thirty-six studies measured O2·pulse and SV at rest and at AT. O2·pulseAT/O2·pulserest correlated highly with SVAT/SVrest (r = 0.72, 95% CI 0.52, 0.85; p < 0.0001), whereas TRVpeak did not (r = -0.09, 95% CI -0.47, 0.33; p = 0.69). The AUROC to detect SVAT/SVrest below the LLN was significantly higher for O2·pulseAT/O2·pulserest (0.92, SE 0.04; p = 0.0002) than for TRVpeak (0.69, SE 0.10; p = 0.12). O2·pulseAT/O2·pulserest of less than 2.6 was 92.6% sensitive (95% CI 76.6%, 98.7%) and 66.7% specific (95% CI 35.2%, 87.9%) for deficient SVAT/SVrest. CONCLUSIONS: CPET detected deficient SV augmentation more accurately than echocardiography. CPET-determined O2·pulseAT/O2·pulserest may have a prominent role for noninvasive screening of patients at risk for pulmonary vascular disease, such as patients with persistent dyspnea after pulmonary embolism.

Multidisciplinary Approach to Chronic Thromboembolic Pulmonary Hypertension: Role of Radiologists.

Management of chronic thromboembolic pulmonary hypertension (CTEPH) should be determined by a multidisciplinary team, ideally at a specialized CTEPH referral center. Radiologists contribute to this multidisciplinary process by helping to confirm the diagnosis of CTEPH and delineating the extent of disease, both of which help determine a treatment decision. Preoperative assessment of CTEPH usually employs multiple imaging modalities, including ventilation-perfusion (V/Q) scanning, echocardiography, CT pulmonary angiography (CTPA), and right heart catheterization with pulmonary angiography. Accurate diagnosis or exclusion of CTEPH at imaging is imperative, as this remains the only form of pulmonary hypertension that is curative with surgery. Unfortunately, CTEPH is often misdiagnosed at CTPA, which can be due to technical factors, patient-related factors, radiologist-related factors, as well as a host of disease mimics including acute pulmonary embolism, in situ thrombus, vasculitis, pulmonary artery sarcoma, and fibrosing mediastinitis. Although V/Q scanning is thought to be substantially more sensitive for CTEPH compared with CTPA, this is likely due to lack of recognition of CTEPH findings rather than a modality limitation. Preoperative evaluation for pulmonary thromboendarterectomy (PTE) includes assessment of technical operability and surgical risk stratification. While the definitive therapy for CTEPH is PTE, other minimally invasive or noninvasive therapies also lead to clinical improvements including greater survival. Complications of PTE that can be identified at postoperative imaging include infection, reperfusion edema or injury, pulmonary hemorrhage, pericardial effusion or hemopericardium, and rethrombosis. ©RSNA, 2022 Online supplemental material is available for this article.

Atrial arrhythmias after pulmonary thromboendarterectomy.

BACKGROUND AND OBJECTIVES: Atrial arrhythmias (AAs) are common after cardiac surgeries including pulmonary thromboendarterectomy (PTE). This study was done to identify patients at highest risk of developing post-PTE AA and their length of stay (LOS). METHODS: We reviewed 521 consecutive patients referred to University of California San Diego (UCSD) for PTE and examined their demographics as well as their baseline pulmonary hemodynamics to determine risk factors for AA. RESULTS: Overall, 24.2% of patients developed an AA after PTE. Patients who developed AA had a significantly longer Intensive Care Unit (ICU) LOS (median: 5 vs 3 days, P < 0.001) and postoperative LOS (median: 14 vs 9 days; P < 0.001). Patients who developed AA were more frequently male (63.2% male, P = 0.003), older (mean age 60.8 vs 50.7 years, P < 0.001), had a prior history of atrial fibrillation (80.2% of those who developed AA) and were more likely to have undergone concomitant Coronary Artery Bypass Graft (12.7% vs 6.6%, P = 0.028). Compared to those who did not develop AA, the cardiopulmonary bypass time was longer among those who developed AA (261.6 vs 253.8 minutes, P = 0.027). In a multivariate logistic regression model, the preoperative variables that predicted AA were age (odds ratio [OR], 1.058 per year, 95% confidence interval [CI]: 1.038-1.078), male sex (OR, 1.68, 95% CI: 1.06-2.64), prior AA (OR, 2.52, 95% CI: 1.23-5.15) and baseline right atrial pressure (OR, 1.039 per mm Hg, 95% CI: 1.000-1.079). While mortality rates were similar, patients who developed AA had more bleeding complications and more postoperative delirium. CONCLUSIONS: AA is common after PTE surgery. The strongest risk factors for AA after PTE included the previous history of AA, age and male sex. Development of AA was associated with longer lengths of stay and more postoperative complications.

Advances in the management of chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH), a potentially curable form of pulmonary hypertension with pulmonary thromboendarterectomy surgery, has been the focus of significant medical advances. In addition to new imaging modalities that are now used to help recognize and diagnose CTEPH, additional treatment options have emerged for inoperable cases. These include a newly approved medical therapy for inoperable disease or persistent/recurrent CTEPH as well as percutaneous balloon angioplasty of the pulmonary arteries. In this article, we summarize these recent advances in the field and review the related literature.

NT-pro-BNP is predictive of morbidity and mortality after pulmonary thromboendarterectomy and is independent of preoperative hemodynamics.

Current predictors of clinical outcomes after pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) are largely limited to preoperative clinical characteristics. N-terminal-pro-brain natriuretic peptide (NT-pro-BNP), a biomarker of right ventricular dysfunction, has not yet been well described as one such predictor. From 2017 to 2021, 816 patients with CTEPH referred to the University of California, San Diego for PTE were reviewed for differences in NT-pro-BNP to predict preoperative characteristics and postoperative outcomes up to 30 days post-PTE. For analysis, NT-pro-BNP was dichotomized to less than/equal to or greater than 1000 pg/mL based on the mean of the study population. Mean NT-pro-BNP was 1095.9 ±1783.4 pg/mL and median was 402.5 pg/mL (interquartile range: 119.5-1410.8). Of the 816 patients included, 250 had NT-pro-BNP > 1000 pg/mL. Those with NT-pro-BNP > 1000 pg/mL were significantly more likely to have worse preoperative functional class (III-IV) and worse preoperative hemodynamics. Patients with NT-pro-BNP > 1000 pg/mL also tended to have more postoperative complications including reperfusion pulmonary edema (22% vs. 5.1%, p < 0.001), airway hemorrhage (8.4% vs. 4.9%, p = 0.075), residual pulmonary hypertension (11.9% vs. 3.1%, p < 0.001), and 30-day mortality (4.8% vs. 1.1%, p = 0.001). Even after adjusting for confounders, patients with NT-pro-BNP > 1000 pg/mL had a 2.48 times higher odds (95% confidence interval: 1.45-4.00) of reaching a combined endpoint that included the above complications. Preoperative NT-pro-BNP > 1000 pg/mL is a strong predictor of more severe preoperative hemodynamics and identifies patients at higher risk for postoperative complications.

Tricuspid annular plane systolic excursion to pulmonary artery systolic pressure ratio in chronic thromboembolic pulmonary hypertension improves with balloon pulmonary angioplasty.

Right ventricle (RV)-to-pulmonary artery (PA) coupling measured by the ratio of echocardiography-derived tricuspid annular plane systolic excursion (TAPSE) and pulmonary artery systolic pressure (PASP) is a meaningful prognostic marker in pulmonary hypertension (PH). It's unclear if balloon pulmonary angioplasty (BPA) treatment of chronic thromboembolic pulmonary hypertension (CTEPH) alters RV-PA coupling measured by TAPSE/PASP. We reviewed CTEPH patients treated with BPA at our institution who had a transthoracic echocardiogram (TTE) before BPA and a follow-up TTE at any point during BPA. TAPSE was obtained from the initial and lattermost TTE; hemodynamics were obtained before each BPA session. Between March 2015 to October 2023, there were 228 patients treated with BPA. After excluding post-PTE patients and those without PH, 67 were included. Initial TAPSE/PASP was 0.39 ± 0.21 mm/mmHg. Using previously defined TAPSE/PASP tertiles in PH (<0.19, 0.19-0.32, >0.32 mm/mmHg), there were 6 patients (9%) in low, 30 (45%) in middle, and 31 (46%) in the high tertiles at baseline. The lower TAPSE/PASP tertiles had more severe baseline hemodynamics (p < 0.001) compared to the high TAPSE/PASP cohort. At follow-up, TAPSE/PASP improved to 0.47 ± 0.20 mm/mmHg (p = 0.023), with 2 (3%), 13 (19%), and 52 (78%) patients in the low, middle, high TAPSE/PASP tertiles, respectively. As patients progress through BPA sessions, the TAPSE/PASP ratio increases, possibly reflecting improved RV mechanics and RV-PA coupling. TAPSE/PASP ratio as a marker of RV-PA coupling can improve with BPA treatment and may be an important measure to follow during treatment of CTEPH.

Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs.

Exposure to chronic hypoxia during gestation predisposes infants to neonatal pulmonary hypertension, but the underlying mechanisms remain unclear. Here, we test the hypothesis that moderate continuous hypoxia during gestation causes changes in the rho-kinase pathway that persist in the newborn period, altering vessel tone and responsiveness. Lambs kept at 3,801 m above sea level during gestation and the first 2 wk of life were compared with those with gestation at low altitude. In vitro studies of isolated pulmonary arterial rings found a more forceful contraction in response to KCl and 5-HT in high-altitude compared with low-altitude lambs. There was no difference between the effects of blockers of various pathways of extracellular Ca(2+) entry in low- and high-altitude arteries. In contrast, inhibition of rho-kinase resulted in significantly greater attenuation of 5-HT constriction in high-altitude compared with low-altitude arteries. High-altitude lambs had higher baseline pulmonary artery pressures and greater elevations in pulmonary artery pressure during 15 min of acute hypoxia compared with low-altitude lambs. Despite evidence for an increased role for rho-kinase in high-altitude arteries, in vivo studies found no significant difference between the effects of rho-kinase inhibition on hypoxic pulmonary vasoconstriction in intact high-altitude and low-altitude lambs. We conclude that chronic hypoxia in utero results in increased vasopressor response to both acute hypoxia and serotonin, but that rho-kinase is involved only in the increased response to serotonin.

Repeat pulmonary thromboendarterectomy outcomes: A 15-year single-center retrospective review.

OBJECTIVE: Chronic thromboembolic pulmonary hypertension is potentially curable via pulmonary thromboendarterectomy. A minority of patients experience recurrence of their symptoms and are eligible for repeat pulmonary thromboendarterectomy. However, little data exist regarding risk factors and outcomes for this patient population. METHODS: We performed a retrospective review of the University of California San Diego chronic thromboembolic pulmonary hypertension quality improvement database, including all patients who underwent pulmonary thromboendarterectomy from December 2005 to December 2020. Of the 2019 cases performed during this period, 46 were repeat pulmonary thromboendarterectomy procedures. Demographics, preoperative and postoperative hemodynamics, and surgical complications were compared between the repeat pulmonary thromboendarterectomy group and 1008 first pulmonary thromboendarterectomy group. RESULTS: Repeat pulmonary thromboendarterectomy recipients were more likely to be younger, to have an identified hypercoagulable state, and to have higher preoperative right atrial pressure. Etiologies of recurrent disease include incomplete initial endarterectomy, discontinuation of anticoagulation (noncompliance or for medical reasons), and anticoagulation treatment failure. Patients who received repeat pulmonary thromboendarterectomy had significant hemodynamic improvement, but less pronounced compared with patients who received first pulmonary thromboendarterectomy. Repeat pulmonary thromboendarterectomy was associated with an increased risk of postoperative bleeding, reperfusion lung injury, residual pulmonary hypertension, and increased ventilator, intensive care unit, and hospital days. However, hospital mortality was similar between the groups (2.2% vs 1.9%). CONCLUSIONS: This is the largest reported series of repeat pulmonary thromboendarterectomy surgery. Despite an increase in postoperative complications, this study demonstrates that repeat pulmonary thromboendarterectomy surgery can result in significant hemodynamic improvement with acceptable surgical mortality in an experienced center.

Distal vessel pulmonary thromboendarterectomy: Results from a single institution.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is primarily managed by pulmonary thromboendarterectomy (PTE). As advanced surgical techniques permit resection at the segmental and subsegmental level, PTE can now be curative for CTEPH mostly involving the distal pulmonary arteries. METHODS: Between January 2017 and June 2021, consecutive patients undergoing PTE were categorized according to the most proximal level of chronic thrombus resection: Level I (main pulmonary artery), Level II (lobar), Level III (segmental) and Level IV (subsegmental). Proximal disease patients (any Level I or II) were compared to distal disease (Level III or IV bilaterally) patients. Demographics, medical history, preoperative pulmonary hemodynamics, and immediate postoperative outcomes were obtained for each group. RESULTS: During the study period, 794 patients underwent PTE, 563 with proximal disease and 231 with distal disease. Patients with distal disease more frequently had a history of an indwelling intravenous device, splenectomy, upper extremity thrombosis or use thyroid replacement and less often had prior lower extremity thrombosis or hypercoagulable state. Despite more use of PAH-targeted medications in the distal disease group (63.2% vs 50.1%, p < 0.001), preoperative hemodynamics were similar. Both patient groups exhibited significant improvements in pulmonary hemodynamics postoperatively with comparable in-hospital mortality rates. Compared to proximal disease, a lower percentage of patients with distal disease showed residual pulmonary hypertension (3.1% vs 6.9%, p = 0.039) and airway hemorrhage (3.0% vs 6.6%, p = 0.047) postoperatively. CONCLUSIONS: Thromboendarterectomy for distal (segmental and subsegmental) CTEPH is technically feasible and may result in favorable pulmonary hemodynamic outcomes, without increased mortality or morbidity.

Airway Hemorrhage Complicating Pulmonary Thromboendarterectomy: Risk Factors and Outcomes.

BACKGROUND: Airway hemorrhage is a known complication of pulmonary thromboendarterectomy (PTE) in patients with chronic thromboembolic pulmonary hypertension. Predisposing factors for postoperative airway hemorrhage have not been well described. The aims of this study were to determine the incidence and outcomes of airway hemorrhage after PTE and to identify potential risk factors. METHODS: This was a retrospective chart review of subjects undergoing PTE between 2015 and 2019. Postoperative airway hemorrhage was defined as significant endobronchial bleeding requiring withholding anticoagulation, bronchial blocker placement, and/or extracorporeal membrane oxygenation (ECMO). RESULTS: Of 877 subjects who underwent PTE, 58 subjects (6.6%) developed postoperative airway hemorrhage. Subjects with hemorrhage were more likely to be women (60% vs 45%, P = .03), to be older (57.8 vs 54.0 years, P = .04), and to have a higher incidence of preoperative hemoptysis (19.0% vs 7.6%, P = .006) compared with control subjects (subjects without airway hemorrhage). Those with hemorrhage had significantly higher preoperative right atrial pressure (P = .002) and pulmonary vascular resistance (P < .001) and a higher incidence of residual pulmonary hypertension (P = .005). Airway hemorrhage management included ECMO with bronchial blocker (n = 2), bronchial blocker without ECMO (n = 26), or withholding anticoagulation alone until bleeding subsided (n = 30). Mortality was significantly higher in those with airway hemorrhage compared with control subjects (13.8% vs 1.2%, P < .001). CONCLUSIONS: The incidence of postoperative airway hemorrhage is low but associated with significant mortality. Older age, female sex, preoperative hemoptysis, and worse preoperative pulmonary hypertension were associated with an increased risk of developing postoperative airway hemorrhage.

Outcomes of cardiopulmonary resuscitation in patients with pulmonary arterial hypertension.

Over the past 20 years, despite significant advancements in pulmonary arterial hypertension (PAH) medical therapy, many patients require admission to the hospital and are at risk for in-hospital cardiac arrest (IHCA). Prior data found poor survival in PAH patients after cardiac arrest. The purpose of this study was to explore post-IHCA outcomes in PAH patients receiving advanced medical therapies. This is a single-center retrospective study of PAH patients who underwent cardiopulmonary resuscitation for IHCA between July 2005 and May 2021. Patients were identified through an internal cardiac arrest database. Twenty six patients were included. Half of the cohort had idiopathic PAH, with 54% of patients on combination therapy, 27% on monotherapy, and 19% of patients on no therapy. Mean right atrial pressure, mean pulmonary artery pressure, cardiac index, and pulmonary vascular resistance were 13 ± 6 mmHg, 57 ± 13 mmHg, 2.0 ± 0.7 L/min/m2, and 14.5 ± 7.6 Wood units, respectively. Most common etiology of cardiac arrest was circulatory collapse. Initial arrest rhythm in all but one patient was pulseless electrical activity. Six patients (23%) achieved return of spontaneous circulation (ROSC) and one patient (4%) survived to hospital discharge. Rates of ROSC and survival to discharge after IHCA are poor in patients with PAH. Even patients with mild hemodynamics had low likelihood of survival. In patients who are lung transplant candidates, there should be early consideration of extracorporeal support before cardiac arrest.

Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension.

The management of pulmonary arterial hypertension (PAH) has become more complex in recent years because of increased pharmacotherapy options and longer patient survival with increasing numbers of comorbidities. As such, more opportunities exist for drug-drug interactions between PAH-targeted medications and medications potentially used to treat comorbid conditions. In this review, we provide an overview of pharmaceutical metabolism by cytochrome P450 and discuss important drug-drug interactions for the 14 Food and Drug Administration-approved medications for PAH in the nitric oxide (NO), endothelin, and prostacyclin pathways. Among the targets in the NO pathway (sildenafil, tadalafil, and riociguat), important interactions with nitrates, protease inhibitors, and other phosphodiesterase inhibitors can cause profound hypotension. In the endothelin pathway, bosentan is associated with more drug interactions via CYP3A4 inhibition; macitentan and ambrisentan have fewer interactions of note. Although the parenteral therapies in the prostacyclin pathway bypass significant liver metabolism and avoid drug interactions, selexipag and oral treprostinil may exhibit interactions with CYP2C8 inhibitors such as gemfibrozil and clopidogrel, which can raise drug levels. Finally, we provide a framework for identifying potential drug-drug interactions and avoiding errors.

Evolution of randomized, controlled studies of medical therapy in chronic thromboembolic pulmonary hypertension.

Although pulmonary endarterectomy (PEA) is the treatment of choice for chronic thromboembolic pulmonary hypertension (CTEPH), many patients have inoperable disease, and some have persistent or recurrent pulmonary hypertension (PH) after surgery. Alternative options (balloon pulmonary angioplasty (BPA) and PH-targeted medical therapy) are, therefore, required. Studies of medical therapies for CTEPH have evolved since Aerosolized Iloprost Randomized (AIR), the first randomized, controlled study of a PH-targeted therapy (inhaled iloprost) to include patients with CTEPH. Key learnings from these studies include the need to evaluate CTEPH separately from other types of PH, the importance of prospective operability adjudication as part of the protocol, and the need for sufficient duration to allow treatment benefits to become apparent. The 16-week Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Study 1 (CHEST-1) study was the first to operationalize these learnings, demonstrating a significant mean improvement in 6-minute walk distance (+46 m) and improvements in hemodynamic endpoints with riociguat versus placebo. Findings from previous studies will inform the design of future studies to address key issues related to combination medical therapy. Data on combinations of macitentan with phosphodiesterase type 5 inhibitors or oral prostanoids are available from MERIT, the first study to allow such regimens. No data on combinations including riociguat, the only licensed medical therapy for CTEPH, are available. Studies are also needed for multimodality treatment, including medical therapy plus BPA, and medical therapy as a bridge to PEA in selected operable patients. To address these issues and improve patient outcomes, it is vital that we learn from current studies to improve future trial design.

Pregnancy and pulmonary arterial hypertension: a case series and literature review.

BACKGROUND: Despite the development of advanced therapies for pulmonary arterial hypertension, pregnancy remains contraindicated in these patients owing to high maternal and fetal morbidity and mortality. Limited data exist regarding pregnancy management and outcome in this unique patient population. We describe a series of pregnant patients diagnosed as having pulmonary arterial hypertension before or during pregnancy who delivered at a tertiary center with a comprehensive and established pulmonary vascular disease program. OBJECTIVE: This study aimed to describe a single institution's experience and review the existing literature for pregnancy management and outcomes in patients with pulmonary arterial hypertension. STUDY DESIGN: A review of all patients with pulmonary arterial hypertension who were admitted for delivery between 2005 and 2019 at our institution was performed. All data were extracted from the electronic health record and included patient demographics, pulmonary arterial hypertension subtype, pulmonary arterial hypertension-targeted therapies, and mode of delivery and anesthesia. RESULTS: A total of 7 patients were identified; 5 patients had a prepartum diagnosis of pulmonary arterial hypertension, whereas 2 patients were diagnosed as having pulmonary arterial hypertension during the third trimester. All patients were started on prostacyclins and the majority were on combination pulmonary arterial hypertension-targeted therapy. The maternal mortality rate was 29%. Elective cesarean delivery was performed in more than 70% of cases, whereas 1 patient required an urgent cesarean delivery and 1 patient had a successful vaginal delivery. Most patients had epidural anesthesia. Notably, 2 patients required extracorporeal membrane oxygenation after delivery and both died. There were no cases of neonatal mortality. CONCLUSION: Our cases series and the published literature to date show that pregnancy in pulmonary arterial hypertension remains poorly tolerated despite marked advancements in pulmonary arterial hypertension-targeted therapies and postpartum care. A multidisciplinary team approach remains essential for the management of these patients.

Chronic Thromboembolic Pulmonary Hypertension: JACC Focus Seminar.

Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of pulmonary arterial obstruction by organized thrombotic material stemming from incompletely resolved acute pulmonary embolism. The exact incidence of CTEPH is unknown but appears to approximate 2.3% among survivors of acute pulmonary embolism. Although ventilation/perfusion scintigraphy has been supplanted by computed tomographic pulmonary angiography in the diagnostic approach to acute pulmonary embolism, it has a major role in the evaluation of patients with suspected CTEPH, the presence of mismatched segmental defects being consistent with the diagnosis. Diagnostic confirmation of CTEPH is provided by digital subtraction pulmonary angiography, preferably performed at a center familiar with the procedure and its interpretation. Operability assessment is then undertaken to determine if the patient is a candidate for potentially curative pulmonary endarterectomy surgery. When pulmonary endarterectomy is not an option, pulmonary arterial hypertension-targeted pharmacotherapy and balloon pulmonary angioplasty represent potential therapeutic alternatives.

Long-Term High-Altitude Hypoxia and Alpha Adrenoceptor-Dependent Pulmonary Arterial Contractions in Fetal and Adult Sheep.

Autonomic innervation of the pulmonary vasculature triggers vasomotor contractility predominately through activation of alpha-adrenergic receptors (α-ARs) in the fetal circulation. Long-term hypoxia (LTH) modulates pulmonary vasoconstriction potentially through upregulation of α1-AR in the vasculature. Our study aimed to elucidate the role of α-AR in phenylephrine (PE)-induced pulmonary vascular contractility, comparing the effects of LTH in the fetal and adult periods on α-AR subtypes and PE-mediated Ca2+ responses and contractions. To address this, we performed wire myography, Ca2+ imaging, and mRNA analysis of pulmonary arteries from ewes and fetuses exposed to LTH or normoxia. Postnatal maturation depressed PE-mediated contractile responses. α2-AR activation contracted fetal vessels; however, this was suppressed by LTH. α1A- and α1B-AR subtypes contributed to arterial contractions in all groups. The α1D-AR was also important to contractility in fetal normoxic vessels and LTH mitigated its function. Postnatal maturity increased the number of myocytes with PE-triggered Ca2+ responses while LTH decreased the percentage of fetal myocytes reacting to PE. The difference between myocyte Ca2+ responsiveness and vessel contractility suggests that fetal arteries are sensitized to changes in Ca2+. The results illustrate that α-adrenergic signaling and vascular function change during development and that LTH modifies adrenergic signaling. These changes may represent components in the etiology of pulmonary vascular disease and foretell the therapeutic potential of adrenergic receptor antagonists in the treatment of pulmonary hypertension.

Relationship between travoprost and central corneal thickness in ocular hypertension and open-angle glaucoma.

PURPOSE: To evaluate whether treatment with travoprost, an F2a prostaglandin analog, affects central corneal thickness (CCT) and whether intraocular pressure (IOP) response to the medication is related to baseline CCT. METHODS: This was a prospective, interventional, nonrandomized, nonconsecutive, clinical trial. In this multicenter study, 379 total patients, 220 with newly or previously diagnosed open-angle glaucoma (OAG), 141 with ocular hypertension (OHT), and 18 unspecified, were recruited from 15 Canadian sites. IOP and CCT assessments were performed at baseline and 6 weeks after treatment with travoprost. Patients on IOP-lowering therapy at the time of enrollment were washed out for 4 weeks before baseline examinations. IOP was measured with Goldmann tonometers and CCT with Accutome IV pachymeters. Statistical analysis was performed with S-PLUS software. RESULTS: Posttherapy mean IOP decreased by 6.31 mm Hg or 24.4% (P < 0.001), and regression analysis indicated relatively greater IOP reduction in patients with higher pretherapy IOP (slope = 0.64; 95% CI, 0.54-0.76). Mean CCT decreased by 6.9 microm (P < 0.001). IOP reduction was not related to CCT reduction (slope = 0.253; 95% CI, -0.232 to 0.739; P = 0.305). Percent IOP decrease was not related to baseline CCT (slope = -0.02; 95% CI, -0.06 to 00.02; P = 0.33) in the total study sample. When OHT and OAG groups were considered separately, the OAG patients had less percent IOP decrease with thicker baseline CCT (slope = -0.067; 95% CI, -0.13 to -0.004; P = 0.037). CONCLUSIONS: Treatment with travoprost decreased IOP significantly and was associated with CCT thinning, which had little or no effect on actual IOP decrease. In the OAG group, IOP decrease was found to be statistically smaller in patients with thicker corneas.

Chronic angle-closure glaucoma secondary to a suprachoroidal effusion induced by central retinal vein occlusion.

A 68-year-old woman presented to the ophthalmology emergency clinic with a painful left eye of a few hours' duration. One month prior, the patient had presented with a central retinal vein occlusion in the same eye. Examination revealed an intraocular pressure of 32 mm Hg in the left eye with 360 degree angle closure unaltered by indentation, a patent iridectomy from a previous combined phacoemulsification and trabeculectomy surgery, and no evident iris or angle neovascularization. Ultrasound biomicroscopic examination revealed a large suprachoroidal effusion with anterior rotation of the ciliary body and secondary angle closure in the left eye. The patient underwent successful pars plana vitrectomy, radial optic neurotomy, intra-vitreal triamcinolone acetonide injection, and goniosynechialysis.

Muscarinic Receptor Activation Affects Pulmonary Artery Contractility in Sheep: The Impact of Maturation and Chronic Hypoxia on Endothelium-Dependent and Endothelium-Independent Function.

Giang, Michael, Demosthenes G. Papamatheakis, Dan Nguyen, Ricardo Paez, Carla Blum Johnston, Joon Kim, Alexander Brunnell, Quintin Blood, Ravi Goyal, Lawrence D. Longo, and Sean M. Wilson. Muscarinic receptor activation affects pulmonary artery contractility in sheep: the impact of maturation and chronic hypoxia on endothelium-dependent and endothelium-independent function. High Alt Med Biol. 17:122-132, 2015.-Muscarinic receptor activation in the pulmonary vasculature can cause endothelium-dependent vasodilation and smooth muscle-dependent vasoconstriction. Chronic hypoxia (CH) can modify both of these responses. This study aimed to assess the combined influence of CH and maturation on endothelium-dependent and endothelium-independent muscarinic-induced vasoreactivity. This was accomplished by performing wire myography on endothelium-intact or endothelium-disrupted pulmonary arterial rings isolated from normoxic or CH fetal and adult sheep. In endothelium-intact arteries, vasodilation was evaluated using cumulative bradykinin doses in phenylephrine and carbachol precontracted pulmonary arterial segments; and vasoconstriction was examined using cumulative doses of carbachol following bradykinin predilation. Effects of nonselective (atropine) and selective M1 (pirenzepine), M2 (AFDX116), and M3 (4-DAMP and Dau5884) muscarinic receptor antagonists were assessed in disrupted arteries. In normoxic arteries, bradykinin relaxation was twofold greater in the adult compared to fetus, while carbachol contraction was fourfold greater. In adult arteries, CH increased bradykinin relaxation and carbachol contraction. In vessels with intact endothelium, maturation and CH augmented maximal response and efficacy for carbachol constriction and bradykinin relaxation. Approximately 50%-80% of adult normoxic and CH endothelium-disrupted arteries contracted to acetylcholine, while ∼50% of fetal normoxic and ∼10% of CH arteries responded. Atropine reduced carbachol-induced contraction in all vessels. Adult normoxic vessels were most responsive to M3 antagonism, fetal to M2 antagonism, while M1 inhibition had no effect. Overall, muscarinic-induced pulmonary arterial contraction is partially endothelium dependent and appears to develop after birth. Fetuses are more reliant on M3 receptors while M2 receptors predominate in adults, whereas CH augments muscarinic-dependent pulmonary vasoconstriction in both.

Validity of screening for glaucomatous optic nerve damage using confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph II) in high-risk populations: a pilot study.

PURPOSE: To evaluate whether confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph II [HRT II], Heidelberg Engineering, Heidelberg, Germany) is a valid tool for the detection of glaucomatous optic nerve damage. DESIGN: Observational, cross-sectional, nonconsecutive study in Montreal, Canada. PARTICIPANTS: Three hundred three nonconsecutive, high-risk persons were enrolled during a 6-month period. METHODS: Participants underwent HRT II testing and a standard ophthalmologic examination, including gonioscopy, intraocular pressure measurement, and optic disc grading. MAIN OUTCOME MEASURES: Positive likelihood ratio (PLR) and negative likelihood ratio (NLR), sensitivities and specificities, positive predictive value (PPV) and negative predictive value (NPV), and kappa coefficients of agreement of Moorfields regression analysis (MRA), cup shape measure (CSM), height variation contour (HVC), and mean retinal nerve fiber layer thickness (MRNFL). RESULTS: Three hundred three participants were enrolled, and 291 were examined clinically; 21 (7.2%) were found to have glaucoma. Heidelberg Retina Tomograph II testing was performed successfully and was of acceptable quality in 531 of 601 eyes (88%). When MRA was compared with the clinically based diagnosis, the weighted kappa coefficient was kappa = 0.567 (95% confidence interval [CI], 0.42-0.71) for the right eye and kappa = 0.516 (95% CI, 0.37-0.66) for the left eye. Best kappa coefficient of agreement was seen when normals were grouped with suspects in both clinical and MRA diagnosis (kappa = 0.604; 95% CI, 0.409-0.799 in the right eye). Depending on the gold standard and test-positive definitions for glaucoma, specificity ranged from 87% to 97%, sensitivity from 25% to 100%, PPV from 28% to 68%, NPV from 84% to 100%, PLR from 5.0 to 19.2, and NLR from 1.3 to 6.2. When CSM, HVC, and MRNFLT were compared with clinical diagnosis, all outcome measures were found to have lower ranges: specificity from 46.9% to 83.7%, sensitivity from 36.5% to 76.9%, PPV from 6% to 36%, NPV from 80% to 99%, PLR from 0.8 to 4.0, NLR from 0.9 to 3.0. CONCLUSIONS: The results of this study suggest that a glaucoma screening program may be effective in detecting glaucoma when targeting high-risk populations. Heidelberg Retina Tomograph II testing may prove to be a useful tool in detecting glaucomatous optic nerve damage and could be used as part of a complete glaucoma screening protocol.