SNPs for Genes Encoding the Mitochondrial Proteins Sirtuin3 and Uncoupling Protein 2 Are Associated With Disease Severity, Type 2 Diabetes, and Outcomes in Patients With Pulmonary Arterial Hypertension and This Is Recapitulated in a New Mouse Model Lacking Both Genes.

Background Isolated loss-of-function single nucleotide polymorphisms (SNPs) for SIRT3 (a mitochondrial deacetylase) and UCP2 (an atypical uncoupling protein enabling mitochondrial calcium entry) have been associated with both pulmonary arterial hypertension (PAH) and insulin resistance, but their collective role in animal models and patients is unknown. Methods and Results In a prospective cohort of patients with PAH (n=60), we measured SNPs for both SIRT3 and UCP2, along with several clinical features (including invasive hemodynamic data) and outcomes. We found SIRT3 and UCP2 SNPs often both in the same patient in a homozygous or heterozygous manner, correlating positively with PAH severity and associated with the presence of type 2 diabetes and 10-year outcomes (death and transplantation). To explore this mechanistically, we generated double knockout mice for Sirt3 and Ucp2 and found increasing severity of PAH (mean pulmonary artery pressure, right ventricular hypertrophy/dilatation and extensive vascular remodeling, including inflammatory plexogenic lesions, in a gene dose-dependent manner), along with insulin resistance, compared with wild-type mice. The suppressed mitochondrial function (decreased respiration, increased mitochondrial membrane potential) in the double knockout pulmonary artery smooth muscle cells was associated with apoptosis resistance and increased proliferation, compared with wild-type mice. Conclusions Our work supports the metabolic theory of PAH and shows that these mice exhibit spontaneous severe PAH (without environmental or chemical triggers) that mimics human PAH and may explain the findings in our patient cohort. Our study offers a new mouse model of PAH, with several features of human disease that are typically absent in other PAH mouse models.

Reducing electronic health record-related burnout in providers through a personalized efficiency improvement program.

OBJECTIVE: To give providers a better understanding of how to use the electronic health record (EHR), improve efficiency, and reduce burnout. MATERIALS AND METHODS: All ambulatory providers were offered at least 1 one-on-one session with an "optimizer" focusing on filling gaps in EHR knowledge and lack of customization. Success was measured using pre- and post-surveys that consisted of validated tools and homegrown questions. Only participants who returned both surveys were included in our calculations. RESULTS: Out of 1155 eligible providers, 1010 participated in optimization sessions. Pre-survey return rate was 90% (1034/1155) and post-survey was 54% (541/1010). 451 participants completed both surveys. After completing their optimization sessions, respondents reported a 26% improvement in mean knowledge of EHR functionality (P < .01), a 19% increase in the mean efficiency in the EHR (P < .01), and a 17% decrease in mean after-hours EHR usage (P < .01). Of the 401 providers asked to rate their burnout, 32% reported feelings of burnout in the pre-survey compared to 23% in the post-survey (P < .01). Providers were also likely to recommend colleagues participate in the program, with a Net Promoter Score of 41. DISCUSSION: It is possible to improve provider efficiency and feelings of burnout with a personalized optimization program. We ascribe these improvements to the one-on-one nature of our program which provides both training as well as addressing the feeling of isolation many providers feel after implementation. CONCLUSION: It is possible to reduce burnout in ambulatory providers with personalized retraining designed to improve efficiency and knowledge of the EHR.

Sequential Latent Structure Analysis of Segregated System Material in the Doll Play of Maltreated Children.

A range of assessment methodologies pertaining to attachment in children have been developed and validated during the past decades. The present study examined the validity of a sequential, profile-centered approach to the assessment of attachment disorganization using a doll play methodology developed by George and Solomon (1990). The sample was composed of sixty-two children between the age of 5 and 12 who had been removed from their family of origin due to abuse or neglect. Latent Markov Models performed on markers of defensive dysregulation (Frightening, Chaos, Constriction) yielded three distinct states, characterized respectively by themes of fear or chaos, presence of at least partial constriction, and absence of segregated system markers across doll play stories. The states generally showed a high degree of stability across scenarios. The Frightening-Chaotic state was positively associated with sexual abuse, placement in a specialized setting and caregiver-reported externalizing problems whereas the Constricted state was associated with placement in a specialized setting and self-reported hyperactivity and attention problems. These results provide support for the validity and clinical utility of this approach to assessing attachment disorganization on the doll play.

Inhibition of pyruvate dehydrogenase kinase improves pulmonary arterial hypertension in genetically susceptible patients.

Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of SIRT3 and UCP2 that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.

Aggressive Drive Derivatives in the Rorschachs of Maltreated Children and Adolescents: Latent Structure and Clinical Correlates.

Psychological assessment can play an important role in informing the intervention process with child and adolescent victims of maltreatment. This study investigated the validity of the Rorschach in assessing aggressive drive derivatives using a profile-based approach, with a sample of 108 children and adolescents in foster care. Aggression indicators were derived from the work of Gacono and Meloy ( 1994 ). Latent class analysis yielded a 4-class model including gender and age as covariates. The first 2 classes were characterized by low prevalence rates across all indicators of aggression, and were distinguished primarily on the basis of participant's age. The 3rd class was characterized by the presence of Aggressive Vulnerability (AgV) responses, whereas the 4th showed higher occurrence of all markers except AgV. Modest associations were found between characteristics of abuse, select classes, and behavior problems. The 4th class showed the strongest link with behavior problems, albeit only in the presence of ego impairment. These findings support a contextualized, developmentally informed use of aggression markers on the Rorschach in the context of child maltreatment.

Sirtuin 3 deficiency is associated with inhibited mitochondrial function and pulmonary arterial hypertension in rodents and humans.

Suppression of mitochondrial function promoting proliferation and apoptosis suppression has been described in the pulmonary arteries and extrapulmonary tissues in pulmonary arterial hypertension (PAH), but the cause of this metabolic remodeling is unknown. Mice lacking sirtuin 3 (SIRT3), a mitochondrial deacetylase, have increased acetylation and inhibition of many mitochondrial enzymes and complexes, suppressing mitochondrial function. Sirt3KO mice develop spontaneous PAH, exhibiting previously described molecular features of PAH pulmonary artery smooth muscle cells (PASMC). In human PAH PASMC and rats with PAH, SIRT3 is downregulated, and its normalization with adenovirus gene therapy reverses the disease phenotype. A loss-of-function SIRT3 polymorphism, linked to metabolic syndrome, is associated with PAH in an unbiased cohort of 162 patients and controls. If confirmed in large patient cohorts, these findings may facilitate biomarker and therapeutic discovery programs in PAH.

Endothelin axis is upregulated in human and rat right ventricular hypertrophy.

RATIONALE: Right ventricular (RV) function is the most important determinant of morbidity and mortality in pulmonary arterial hypertension (PAH). Endothelin (ET)-1 receptor antagonists (ERAs) are approved therapies for PAH. It is not known whether ERAs have effects on the RV, in addition to their vasodilating/antiproliferative effects in pulmonary arteries. OBJECTIVE: We hypothesized that the ET axis is upregulated in RV hypertrophy (RVH) and that ERAs have direct effects on the RV myocardium. METHODS AND RESULTS: RV myocardial samples from 34 patients with RVH were compared with 16 nonhypertrophied RV samples, and from rats with normal RV versus RVH attributable to PAH. Confocal immunohistochemistry showed that RVH myocardial ET type A (but not type B) receptor and ET-1 protein levels were increased compared with the nonhypertrophied RVs and positively correlated with the degree of RVH (RV thickness/body surface area; r(2)=0.838 and r(2)=0.818, respectively; P<0.01). These results were recapitulated in the rat model. In modified Langendorff perfusions, ERAs (BQ-123 and bosentan 10(-7,-6,-5) mol/L) decreased contractility in the hypertrophied, but not normal RV, in a dose-dependent manner (P<0.01). CONCLUSIONS: Patients and rats with PAH have an upregulation of the myocardial ET axis in RVH. This might be a compensatory mechanism to preserve RV contractility, as the afterload increases. ERAs use might potentially worsen RV function, and this could explain some of the peripheral edema noted clinically with these agents. Further studies are required to evaluate the effects of ERAs on the RV in patients with RVH and PAH.

Qualitative evaluation of suicide and overdose risk assessment procedures among veterans in substance use disorder treatment clinics.

The objective of this study was to examine risk assessment practices for suicide and unintentional overdose to inform ongoing care in substance use disorder clinics. Focus groups were conducted via telephone among a random sample of treatment providers (N = 19) from Veterans Health Administration substance use disorder clinics across the nation. Themes were coded by research staff. Treatment providers reported consistent and clear guidelines for risk assessment of suicide among patients. Unintentional overdose questions elicited dissimilar responses which indicated a lack of cohesion and uniformity in risk assessment practices across clinics. Suicide risk assessment protocols are cohesively implemented by treatment providers. Unintentional overdose risk, however, may be less consistently assessed in clinics.

Unresolved attachment status and trauma-related symptomatology in maltreated adolescents: an examination of cognitive mediators.

Attachment Theory has received increasing interest as a framework allowing for a more refined understanding of the potential consequences of early relational trauma on psychological and social adjustment. Research has provided support for the role of disorganized attachment, both as a sequela of traumatic experiences and as a risk factor for subsequent maladjustment. This study investigated the associations between unresolved/disorganized attachment, cognitive functioning, and dissociative symptomatology in a sample of 60 adolescents with a history of maltreatment. A model with cognitive efficiency as a mediator variable was tested using hierarchical multiple regression analysis, with a bootstrapping procedure to examine indirect effects. Results provided support for the association between unresolved attachment, cognitive efficiency (but not verbal or thinking ability), and dissociation. Working memory was a strong mediator of the link between attachment and dissociation. These results highlight the importance of assessing attachment status and cognitive functioning in the context of clinical work with maltreated youth. In addition, it is proposed that greater attention be paid to internal models of attachment relationships and how they impact psychosocial functioning at different levels in maltreated populations.

Use of the Adult Attachment Projective Picture System in an assessment of an adolescent in foster care.

Child maltreatment has been associated with a host of negative outcomes including impaired social relationships (Rogosch, Cicchetti, & Aber, 1995), depression (Toth, Manly, & Cicchetti, 1992), poor self-concept and motivation (Vondra, Barnett, & Cicchetti, 1990), and delinquency and conduct problems (Cook et al., 2005; Grotevant et al., 2006; McCabe, Lucchini, Hough, Yeh, & Hazen, 2005; Ryan & Testa, 2005). An assessment of the mental representation of attachment relationships could offer additional relevant and useful information to the evaluation of youth in foster care, and could inform treatment and placement considerations. The Adult Attachment Projective Picture System (AAP) is a relatively new measure of internal representations of attachment based on the analysis of a set of stimuli designed to systematically activate the attachment system (George, West, & Pettem, 1997). This article considers the use of the AAP with a maltreated adolescent in a clinical setting and uses a case study to illustrate the components of the AAP that are particularly relevant to case conceptualization and interventions.

Measuring pain medication expectancies in adults treated for substance use disorders.

BACKGROUND: The U.S. prevalence of misuse of prescription opioid analgesics has increased substantially over the past decade but research on the factors influencing misuse of these medications remains preliminary. In the literature on alcohol, marijuana and stimulants, substance-related expectancies have been found to predict level of substance use. A similar line of research is needed to better understand reasons for misusing pain medications. METHODS: This study utilized a sample of adults presenting to a large residential addictions treatment program (N=351). Participants were administered a new instrument, the Pain Medication Expectancy Questionnaire (PMEQ) as well as questions about current alcohol, illegal drug and pain medication misuse. Exploratory factor analysis was used to determine underlying factors of the PMEQ. RESULTS: Results of the factor analysis supported a three-factor solution focusing on pleasure/social enhancement, pain reduction and negative experience reduction. In general, greater perceived expectancy of the positive effects of Prescription Opiate Analgesics (POAs) in all three domains were correlated with greater frequency of substance use and poorer mental health functioning. Expectancies directly related to the pain-reducing properties of POAs were also related to greater pain and poorer physical functioning. CONCLUSIONS: This new measure of pain medication expectancies had sound psychometric properties and the resulting factors were associated with other clinically important aspects of patient functioning. The results highlight the need to assess for and address perceptions related to pain medication use in patients presenting to addictions treatment.

Sleep-disordered breathing and chronic opioid therapy.

OBJECTIVE: To assess the relation between medications prescribed for chronic pain and sleep apnea. DESIGN: An observational study of chronic pain patients on opioid therapy who received overnight polysomnographies. Generalized linear models determined whether a dose relation exists between methadone, nonmethadone opioids, and benzodiazepines and the indices measuring sleep apnea. SETTING: A private clinic specializing in the treatment of chronic pain. PATIENTS: Polysomnography was sought for all consecutive (392) patients on around-the-clock opioid therapy for at least 6 months with a stable dose for at least 4 weeks. Of these, 147 polysomnographies were completed (189 patients declined, 56 were directed to other sleep laboratories by insurance companies, and data were incomplete for seven patients). Available data were analyzed on 140 patients. OUTCOME MEASURES: The apnea-hypopnea index to assess overall severity of sleep apnea and the central apnea index to assess central sleep apnea. RESULTS: The apnea-hypopnea index was abnormal (> or =5 per hour) in 75% of patients (39% had obstructive sleep apnea, 4% had sleep apnea of indeterminate type, 24% had central sleep apnea, and 8% had both central and obstructive sleep apnea); 25% had no sleep apnea. We found a direct relation between the apnea-hypopnea index and the daily dosage of methadone (P = 0.002) but not to other around-the-clock opioids. We found a direct relation between the central apnea index and the daily dosage of methadone (P = 0.008) and also with benzodiazepines (P = 0.004). CONCLUSIONS: Sleep-disordered breathing was common in chronic pain patients on opioids. The dose-response relation of sleep apnea to methadone and benzodiazepines calls for increased vigilance.

Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of phosphodiesterase type 5 improves contractility.

BACKGROUND: Sildenafil was recently approved for the treatment of pulmonary arterial hypertension. The beneficial effects of phosphodiesterase type 5 (PDE5) inhibitors in pulmonary arterial hypertension are thought to result from relatively selective vasodilatory and antiproliferative effects on the pulmonary vasculature and, on the basis of early data showing lack of significant PDE5 expression in the normal heart, are thought to spare the myocardium. METHODS AND RESULTS: We studied surgical specimens from 9 patients and show here for the first time that although PDE5 is not expressed in the myocardium of the normal human right ventricle (RV), mRNA and protein are markedly upregulated in hypertrophied RV (RVH) myocardium. PDE5 also is upregulated in rat RVH. PDE5 inhibition (with either MY-5445 or sildenafil) significantly increases contractility, measured in the perfused heart (modified Langendorff preparation) and isolated cardiomyocytes, in RVH but not normal RV. PDE5 inhibition leads to increases in both cGMP and cAMP in RVH but not normal RV. Protein kinase G activity is suppressed in RVH, explaining why the PDE5 inhibitor-induced increase in cGMP does not lead to inhibition of contractility. Rather, it leads to inhibition of the cGMP-sensitive PDE3, explaining the increase in cAMP and contractility. This is further supported by our findings that, in RVH protein kinase A, inhibition completely inhibits PDE5-induced inotropy, whereas protein kinase G inhibition does not. CONCLUSIONS: The ability of PDE5 inhibitors to increase RV inotropy and to decrease RV afterload without significantly affecting systemic hemodynamics makes them ideal for the treatment of diseases affecting the RV, including pulmonary arterial hypertension.

The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted.

In pulmonary arterial hypertension (PAH), antiapoptotic, proliferative, and inflammatory diatheses converge to create an obstructive vasculopathy. A selective down-regulation of the Kv channel Kv1.5 has been described in human and animal PAH. The resultant increase in intracellular free Ca(2+) ([Ca(2+)](i)) and K(+) ([K(+)](i)) concentrations explains the pulmonary artery smooth muscle cell (PASMC) contraction, proliferation and resistance to apoptosis. The recently described PASMC hyperpolarized mitochondria and increased bcl-2 levels also contribute to apoptosis resistance in PAH. The cause of the Kv1.5, mitochondrial, and inflammatory abnormalities remains unknown. We hypothesized that these abnormalities can be explained in part by an activation of NFAT (nuclear factor of activated T cells), a Ca(2+)/calcineurin-sensitive transcription factor. We studied PASMC and lungs from six patients with and four without PAH and blood from 23 PAH patients and 10 healthy volunteers. Compared with normal, PAH PASMC had decreased Kv current and Kv1.5 expression and increased [Ca(2+)](i), [K(+)](i), mitochondrial potential (Delta Psi m), and bcl-2 levels. PAH but not normal PASMC and lungs showed activation of NFATc2. Inhibition of NFATc2 by VIVIT or cyclosporine restored Kv1.5 expression and current, decreased [Ca(2+)](i), [K(+)](i), bcl-2, and Delta Psi m, leading to decreased proliferation and increased apoptosis in vitro. In vivo, cyclosporine decreased established rat monocrotaline-PAH. NFATc2 levels were increased in circulating leukocytes in PAH versus healthy volunteers. CD3-positive lymphocytes with activated NFATc2 were seen in the arterial wall in PAH but not normal lungs. The generalized activation of NFAT in human and experimental PAH might regulate the ionic, mitochondrial, and inflammatory remodeling and be a therapeutic target and biomarker.

Aetiology and management of male erectile dysfunction and female sexual dysfunction in patients with cardiovascular disease.

The historical basis for understanding erectile function as a neurovascular phenomenon and the advance from fanciful to effective treatment of erectile dysfunction (ED) are reviewed, with emphasis on patients with cardiovascular disease (CVD). ED occurs in 60% of CVD patients by 40 years of age. Male ED and female sexual dysfunction (FSD) diminish quality of life and often warn of occult CVD. ED is often unrecognised but is readily diagnosed during a 5-minute interview using a truncated International Index of Erectile Function questionnaire. Erection of the penis and clitoral engorgement result from local, arousal-induced release of neuronal and endothelial-derived nitric oxide (NO). Arterial vasodilatation and relaxation of cavernosal smooth muscle cells cause arterial blood to flood trabecular spaces, compressing venous drainage, resulting in tumescence. Cyclic guanosine monophosphate (cGMP)-induced activation of protein kinase G mediates the effects of NO by enhancing calcium sequestration and activating large-conductance, calcium-sensitive K+ channels. Future treatment strategies will likely enhance these pathways. Phosphodiesterase-5 inhibitors (sildenafil, tadalafil and vardenafil) increase cGMP levels in erectile tissue. These agents are effective in 80% of CVD patients with ED and can be used safely, even in the presence of stable coronary disease or congestive heart failure, provided nitrates are avoided and patients do not have hypotension, severe aortic stenosis or evocable myocardial ischaemia. Second-line therapies (vacuum constrictor device and transurethral or intracavernosal prostaglandin E1) can also be used in CVD patients. Treatment of FSD and its relationship to CVD are less well established, but similarities to ED exist. ED can be prevented by reduction of CVD risk factors, exercise, weight loss and abstinence from smoking.

Use of sildenafil for safe improvement of erectile function and quality of life in men with New York Heart Association classes II and III congestive heart failure: a prospective, placebo-controlled, double-blind crossover trial.

BACKGROUND: Erectile dysfunction (ED) is common in patients with congestive heart failure (CHF) and is often associated with symptoms of depression. Although sildenafil citrate, a phosphodiesterase 5 inhibitor, is effective in treating ED, its use is considered a relative contraindication in CHF. We hypothesized that sildenafil is a safe and effective treatment for ED in patients with New York Heart Association classes II and III CHF and that treatment of ED will improve symptoms of depression and enhance perceived of quality of life. METHODS: We studied 35 patients in a prospective, placebo-controlled, crossover trial for 12 weeks. Inclusion required a history of chronic ED and absence of ischemia (negative results from exercise stress test or nuclear perfusion scan) or nitrate use. The tolerability of sildenafil citrate was established by monitoring the ambulatory blood pressure for 4 hours after a single 50-mg dose. Improvement in ED, the primary end point, was assessed using the International Index of Erectile Function survey. The effect of improved erectile function on quality of life and mood was assessed using the Minnesota Living With Heart Failure Questionnaire, the Beck Depression Index, and the Center for Epidemiological Studies-Depression Scale. RESULTS: Sildenafil caused a mean +/- SEM asymptomatic decrease in blood pressure of 6 +/- 3 mm Hg, and no patient experienced symptomatic hypotension or other significant adverse effects. Sildenafil improved the International Index for Erectile Function (P<.001) and both sets of depression scores. The Living With Heart Failure Questionnaire index also improved with sildenafil (P =.02). CONCLUSION: Sildenafil is a safe and effective treatment for ED in men with New York Heart Association classes II and III CHF and provides relief of depressive symptoms, explaining an improvement in the perception of quality of life.

Long-term treatment with oral sildenafil is safe and improves functional capacity and hemodynamics in patients with pulmonary arterial hypertension.

BACKGROUND: The prognosis and functional capacity of patients with pulmonary arterial hypertension (PAH) is poor, and there is a need for safe, effective, inexpensive oral treatments. A single dose of sildenafil, an oral phosphodiesterase type-5 (PD-5) inhibitor, is an effective and selective pulmonary vasodilator in PAH. However, the long-term effects of PD-5 inhibition and its mechanism of action in human pulmonary arteries (PAs) are unknown. METHODS AND RESULTS: We hypothesized that 3 months of sildenafil (50 mg orally every 8 hours) added to standard treatment would be safe and improve functional capacity and hemodynamics in PAH patients. We studied 5 consecutive patients (4 with primary pulmonary hypertension, 1 with Eisenmenger's syndrome; New York Heart Association class II to III). Functional class improved by > or =1 class in all patients. Pretreatment versus posttreatment values (mean+/-SEM) were as follows: 6-minute walk, 376+/-30 versus 504+/-27 m, P<0.0001; mean PA pressure, 70+/-3 versus 52+/-3 mm Hg, P<0.007; pulmonary vascular resistance index 1702+/-151 versus 996+/-92 dyne x s x cm(-5) x m(-2), P<0.006. The systemic arterial pressure was unchanged, and no adverse effects occurred. Sildenafil also reduced right ventricular mass measured by MRI. In 7 human PAs (6 cardiac transplant donors and 1 patient with PAH on autopsy), we showed that PD-5 is present in PA smooth muscle cells and that sildenafil causes relaxation by activating large-conductance, calcium-activated potassium channels. CONCLUSIONS: This small pilot study suggests that long-term sildenafil therapy might be a safe and effective treatment for PAH. At a monthly cost of 492 dollars Canadian, sildenafil is more affordable than most approved PAH therapies. A large multicenter trial is indicated to directly compare sildenafil with existing PAH treatments.

Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide.

BACKGROUND: The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO. METHODS AND RESULTS: We studied 13 consecutive patients (mean+/-SEM, 44+/-2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (-19+/-5%) and sildenafil (-27+/-3%), whereas sildenafil+iNO was more effective than iNO alone (-32+/-5%, P<0.003). Sildenafil and sildenafil+iNO increased cardiac index (17+/-5% and 17+/-4%, respectively), whereas iNO did not (-0.2+/-2.0%, P<0.003). iNO increased, whereas sildenafil tended to decrease, pulmonary capillary wedge pressure (+15+/-6 versus -9+/-7%, P<0.0007). Systemic arterial pressure was similar among groups and did not decrease with treatment. cGMP levels increased similarly with iNO and sildenafil, and their combination synergistically elevated cGMP (P<0.0001). CONCLUSIONS: A single oral dose of sildenafil is as effective and selective a pulmonary vasodilator as iNO. Sildenafil may be superior to iNO in that it increases cardiac output and does not increase wedge pressure. Future studies are indicated to establish whether sildenafil could be effective over a longer duration.