Meredith E. Pugh

High Prevalence of Occult Pulmonary Venous Hypertension Revealed by Fluid Challenge in Pulmonary Hypertension

Background— Determining the cause for pulmonary hypertension is difficult in many patients. Pulmonary arterial hypertension (PAH) is differentiated from pulmonary venous hypertension (PVH) by a wedge pressure (PWP) >15 mm Hg in PVH. Patients undergoing right heart catheterization for evaluation of pulmonary hypertension may be dehydrated and have reduced intravascular volume, potentially leading to a falsely low measurement of PWP and an erroneous diagnosis of PAH. We hypothesized that a fluid challenge during right heart catheterization would identify occult pulmonary venous hypertension (OPVH). Methods and Results— We reviewed the results of patients undergoing fluid challenge in our pulmonary hypertension database from 2004 to 2011. Baseline hemodynamics were obtained and repeated after infusion of 0.5 L of normal saline for 5 to 10 minutes. Patients were categorized as OPVH if PWP increased to >15 mm Hg after fluid challenge. Baseline hemodynamics in 207 patients met criteria for PAH. After fluid challenge, 46 patients (22.2%) developed a PWP >15 mm Hg and were reclassified as OPVH. Patients with OPVH had a greater increase in PWP compared with patients with PAH, P<0.001, and their demographics and comorbid illnesses were similar to patients with PVH. There were no adverse events related to fluid challenge. Conclusions— Fluid challenge at the time of right heart catheterization is easily performed, safe, and identifies a large group of patients diagnosed initially with PAH, but for whom OPVH contributes to pulmonary hypertension. These results have implications for therapeutic trials in PAH and support the routine use of fluid challenge during right heart catheterization in patients with risk factors for PVH.

Unrecognized glucose intolerance is common in pulmonary arterial hypertension

BACKGROUND Animal and human data suggest insulin resistance is common in pulmonary arterial hypertension (PAH). Although routine assessment of insulin resistance is difficult, hemoglobin A(1c) (HbA(1c)) is a sensitive test to detect diabetes mellitus (DM) and those at high risk for DM. We aimed to define the prevalence of elevated HbA(1c) in PAH patients and to correlate HbA(1c) levels with functional assessment. METHODS HbA(1c) was measured in 41 PAH patients without a diagnosis of DM, along with demographic, functional, and hemodynamic data. Using published criteria, HbA(1c) ≤ 5.9% defined normal, 6.0% to 6.4% was glucose intolerance, and ≥ 6.5% was DM. RESULTS Twenty-three patients (56%) had HbA(1c) ≥ 6.0%, and 6 (15%) had unrecognized DM (HbA(1c) ≥ 6.5%). Age and body mass index were similar in patients with HbA(1c) ≥ 6.0% vs < 6.0%. There was a trend towards lower mean 6-minute walk distance in patients with elevated HbA(1c) (331.0 ± 126.6 vs 413.6 ± 74.9 meters, p = 0.07). The 6-month event-free survival was not significantly different in patients with elevated HbA(1c). CONCLUSIONS Unrecognized glucose intolerance as assessed by HbA(1c) is common in PAH. Further studies are needed to discern if glucose or insulin dysregulation mediates PAH pathogenesis or is secondary to advanced PAH.

The Index Case for the Fungal Meningitis Outbreak in the United States

Persistent neutrophilic meningitis presents a diagnostic challenge, because the differential diagnosis is broad and includes atypical infectious causes. We describe a case of persistent neutrophilic meningitis due to Aspergillus fumigatus in an immunocompetent man who had no evidence of sinopulmonary or cutaneous disease. An epidural glucocorticoid injection was identified as a potential route of entry for this organism into the central nervous system, and the case was reported to the state health department.

A potential role for insulin resistance in experimental pulmonary hypertension

Patients with pulmonary arterial hypertension have increased prevalence of insulin resistance. We aimed to determine whether metabolic defects are associated with bone morphogenic protein receptor type 2 (Bmpr2) mutations in mice, and whether these may contribute to pulmonary vascular disease development. Metabolic phenotyping was performed on transgenic mice with inducible expression of Bmpr2 mutation, R899X. Phenotypic penetrance in Bmpr2R899X was assessed in a high-fat diet model of insulin resistance. Alterations in glucocorticoid responses were assessed in murine pulmonary microvascular endothelial cells and Bmpr2R899X mice treated with dexamethasone. Compared to controls, Bmpr2R899X mice showed increased weight gain and demonstrated insulin resistance as assessed by the homeostatic model assessment insulin resistance (1.0±0.4 versus 2.2±1.8) and by fat accumulation in skeletal muscle and decreased oxygen consumption. Bmpr2R899X mice fed a high-fat diet had strong increases in pulmonary hypertension penetrance (seven out of 11 versus three out of 11). In cell culture and in vivo experiments, Bmpr2 mutation resulted in a combination of constitutive glucocorticoid receptor activation and insensitivity. Insulin resistance is present as an early feature of Bmpr2 mutation in mice. Exacerbated insulin resistance through high-fat diet worsened pulmonary phenotype, implying a possible causal role in disease. Impaired glucocorticoid responses may contribute to metabolic defects.

Fatty Acid Metabolic Defects and Right Ventricular Lipotoxicity in Human Pulmonary Arterial Hypertension

Background— The mechanisms of right ventricular (RV) failure in pulmonary arterial hypertension (PAH) are poorly understood. Abnormalities in fatty acid (FA) metabolism have been described in experimental models of PAH, but systemic and myocardial FA metabolism has not been studied in human PAH. Methods and Results— We used human blood, RV tissue, and noninvasive imaging to characterize multiple steps in the FA metabolic pathway in PAH subjects and controls. Circulating free FAs and long-chain acylcarnitines were elevated in PAH patients versus controls. Human RV long-chain FAs were increased and long-chain acylcarnitines were markedly reduced in PAH versus controls. With the use of proton magnetic resonance spectroscopy, in vivo myocardial triglyceride content was elevated in human PAH versus controls (1.4±1.3% triglyceride versus 0.22±0.11% triglyceride, P=0.02). Ceramide, a mediator of lipotoxicity, was increased in PAH RVs versus controls. Using an animal model of heritable PAH, we demonstrated reduced FA oxidation via failure of palmitoylcarnitine to stimulate oxygen consumption in the PAH RV. Conclusions— Abnormalities in FA metabolism can be detected in the blood and myocardium in human PAH and are associated with in vivo cardiac steatosis and lipotoxicity. Murine data suggest that lipotoxicity may arise from reduction in FA oxidation.

Percutaneous Vascular Stent Implantation as Treatment for Central Vascular Obstruction Due to Fibrosing Mediastinitis

Background— Fibrosing Mediastinitis (FM) is a rare complication of infection with Histoplasma capsulatum that can lead to obstruction of pulmonary and systemic vasculature and large airways, often resulting in significant morbidity and mortality. Medical therapy is ineffective, and surgical intervention is often not feasible. Stent implantation offers a potential treatment for vascular obstruction due to FM, but this has not been well studied. Methods and Results— We conducted a retrospective review of all patients undergoing cardiac catheterization for FM. Anatomic site of stenosis and hemodynamic information before and after intervention, as well as clinical presentation and follow-up data, were recorded. From 1996 to 2008, 58 patients underwent cardiac catheterization for FM, with intervention performed in 40 (69%). A total of 77 stents were used to relieve 59 lesions (pulmonary artery=26, pulmonary vein=21, and superior vena cava=12). Significant reduction in pressure gradients (P<0.001) and increase in vessel caliber (P<0.001) were seen at all locations. Symptomatic recurrent stenosis requiring further intervention occurred in 11 patients (28%). Median time to recurrence was 115 months. Thirty-two (87%) of 37 patients for whom follow-up was available reported symptomatic improvement after stent placement. Procedure-related complications occurred in 14 patients (24%). Overall mortality was 19%, with the majority of deaths in patients with bilateral disease. Among patients with bilateral disease, intervention was associated with improved survival at 5 years. Conclusion— Percutaneous vascular stent implantation is an effective therapy for central vascular obstruction due to FM, providing significant relief of anatomic obstruction and sustained clinical improvement.

Physical Activity Limitation as Measured by Accelerometry in Pulmonary Arterial Hypertension

BACKGROUND The 6-min walk test, commonly used to assess exercise capacity and response to therapy in pulmonary arterial hypertension (PAH), has many well-described limitations. Sedentary time is associated with adverse cardiovascular outcomes and reduced quality of life, and measuring sedentary time and physical activity using accelerometry is another potential way to quantify exercise capacity in PAH. Whether sedentary time is different in patients with PAH vs control subjects is unknown. METHODS Physical activity was measured in 20 patients with PAH and 30 matched healthy control subjects using accelerometry for 7 consecutive days. Patients with PAH completed standard 6-min walk testing, and baseline demographics were recorded for all study participants. Total daily activity counts, sedentary time, and proportion of time at various activity levels were compared between groups. RESULTS Sedentary time was significantly higher in patients with PAH (mean, 92.1% daily activity; 95% CI, 89.5-94.8%) than in control subjects (mean, 79.9% daily activity; 95% CI, 76.4%-83.5%; P < .001), and all levels of physical activity were reduced in the PAH group compared with the control group ( P < .01 for all). Daily moderate to vigorous physical activity was reduced in the PAH group (7.5 min; 95% CI; 0.8-15.6 min) compared with the control group (mean, 64.7 min; 95% CI, 51.1-78.2 min; P < .001). Activity counts correlated with 6-min walk distance in the PAH group (Spearman rank correlation 5 0.72, P < .001). CONCLUSIONS Sedentary time is increased in patients with PAH and may lead to increased risk for metabolic and cardiovascular morbidity. Quantitation of daily activity and sedentary time using accelerometry may be a novel end point for PAH management and clinical trials.

Pulmonary hypertension in women.

Female predominance in pulmonary arterial hypertension (PAH) has been known for several decades and recent interest in the effects of sex hormones on the development of disease has substantially increased our understanding of this epidemiologic observation. Basic science data suggest a beneficial effect of estrogens in the pulmonary vasculature both acutely and chronically, which seems to contradict the known predilection in women. Recent human and rodent data have suggested that altered levels of estrogen, differential signaling and altered metabolism of estrogens in PAH may underlie the gender difference in this disease. Studies of the effects of sex hormones on the right ventricle in animal and human disease will further aid in understanding gender differences in PAH. This article focuses on the effects of sex hormones on the pulmonary vasculature and right ventricle on both a basic science and translational level.

Prostanoids But Not Oral Therapies Improve Right Ventricular Function in Pulmonary Arterial Hypertension

OBJECTIVES This study hypothesized that right ventricular stroke work index (RVSWI) and pulmonary capacitance (PC) would increase after treatment for pulmonary arterial hypertension (PAH) and that prostanoids would have a stronger effect than oral therapy. BACKGROUND Right ventricular (RV) function is a major determinant of outcome in patients with PAH. Little is known about the response of RV function or its hemodynamic determinants to PAH-specific therapy. METHODS We reviewed hemodynamic and health data on 58 patients from an institutional registry and analyzed changes in hemodynamic status between diagnostic and first repeat catheterization after initiation of therapy for PAH. RESULTS The RVSWI and PC increased significantly after therapy (p = 0.007 and p = 0.02, respectively). Improvement in RV function was limited to patients treated with prostanoid-only therapy (p = 0.04); no improvement was found in patients treated with oral therapy (p = 0.25). Patients with the poorest baseline RV function (lowest tertile) had the greatest improvement post-therapy (p = 0.005 and p < 0.001 vs. middle and highest tertiles). The major determinant of RVSWI was change in stroke volume (r(s) = 0.54, p < 0.001), indicating RVSWI is an accurate reflection of RV function. CONCLUSIONS Right ventricular function improves after therapy with regimens including prostanoids but not oral-only regimens. Patients with the least compensated RV function at diagnosis might derive the most benefit from therapy. Larger studies are needed to determine whether changes in RVSWI after therapy are associated with outcomes.

Impact of diabetes on survival and right ventricular compensation in pulmonary arterial hypertension.

Insulin resistance is highly prevalent in pulmonary arterial hypertension (PAH) patients. However, the long-term impact of diabetes mellitus (DM) on survival in PAH is unclear. Insulin resistance and DM are associated with left ventricular steatosis and dysfunction, but whether the right ventricle (RV) might be affected by DM in PAH is unknown. We hypothesized that PAH patients with DM would have worse survival than PAH patients without DM and that this would be due to impaired RV compensation. From a large registry of PAH patients at our institution, we analyzed the effect of DM on survival in patients with idiopathic or heritable PAH. Clinical and hemodynamic differences were compared between PAH patients with DM and those without DM. Twenty-nine patients with DM and 84 without DM were included. Gender, body mass index, PAH type and duration, and 6-minute walk distance were similar between groups. PAH patients with DM had significantly lower survival at 10 years than PAH patients without DM. Right atrial pressure, pulmonary arterial pressure, and cardiac output did not differ significantly between the two groups. However, right ventricular stroke work index (RVSWI) was lower in the PAH DM group than in the no-DM patients. Among PAH patients with DM, patients who died had a lower RVSWI than survivors. In conclusion, survival in PAH patients with DM was reduced compared to that of patients without DM; impaired RV compensation may underlie this finding. Further study is needed to understand this effect.