PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-21 (21)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
more »
Document Types
1.  A Simple Echocardiographic Method To Estimate Pulmonary Vascular Resistance 
The American journal of cardiology  2013;112(6):873-882.
Pulmonary hypertension is comprised of heterogeneous diagnoses with distinct hemodynamic pathophysiology. Identifying elevated pulmonary vascular resistance (PVR) is critical for appropriate treatment. We reviewed data for patients seen at referral PH clinics who underwent echocardiography and right heart catheterization within 1 year. We derived equations to estimate PVR based on the ratio of estimated pulmonary artery (PA) systolic pressure (PASPDoppler) to RVOT VTI. We validated these equations in a separate sample and compared them to a published model based on the ratio of transtricuspid flow velocity to RVOT VTI (Model 1, Abbas et al 2003). The derived models were: (Model 2)PVR=1.2×PASPRVOT VTI (Model 3)PVR=PASPRVOT VTI+3if notch present
The cohort included 217 patients with mean PA pressure=45.3±11.9mmHg, PVR=7.3±5.0WU and PA wedge pressure=14.8±8.1mmHg; just over 1/3rd had PA wedge pressure >15mmHg (35.5%) and 82.0% had PVR>3WU. Model 1 systematically underestimated PVR, especially with high PVR. The derived models demonstrated no systematic bias. Model 3 correlated best with PVR (r=0.80 vs. 0.73 and 0.77 for Models 1 and 2 respectively). Model 3 had superior discriminatory power for PVR>3WU (AUC=0.946) and PVR>5WU (AUC=0.924), though all models discriminated well. Model 3 estimated PVR>3 was 98.3% sensitive and 61.1% specific for PVR>3WU (PPV=93%; NPV=88%). In conclusion, we present an equation to estimate PVR, using the ratio of PASPDoppler to RVOT VTI and a constant designating presence of RVOT VTI mid-systolic notching, which provides superior agreement with PVR across a wide range of values.
doi:10.1016/j.amjcard.2013.05.016
PMCID: PMC4317360  PMID: 23735649
pulmonary hypertension; hemodynamics; echocardiography
2.  The Inflammasome Mediates Hyperoxia-Induced Alveolar Cell Permeability 
A hallmark of hyperoxic acute lung injury is the influx of inflammatory cells to lung tissue and the production of proinflammatory cytokines, such as IL-1β; however, the mechanisms connecting hyperoxia and the inflammatory response to lung damage is not clear. The inflammasome protein complex activates caspase-1 to promote the processing and secretion of proinflammatory cytokines. We hypothesized that hyperoxia-induced K+ efflux activates the inflammasome via the purinergic P2X7 receptor to cause inflammation and hyperoxic acute lung injury. To test this hypothesis, we characterized the expression and activation of inflammasome components in primary murine alveolar macrophages exposed to hyperoxia (95% oxygen and 5% CO2) in vitro, and in alveolar macrophages isolated from mice exposed to hyperoxia (100% oxygen). Our results showed that hyperoxia increased K+ efflux, inflammasome formation, release of proinflammatory cytokines, and induction of caspase-1 and IL-1β cleavage both in vitro and in vivo. The P2X7 agonist ATP enhanced hyperoxia-induced inflammasome activation, whereas the P2X7 antagonist, oxidized ATP, inhibited hyperoxia induced inflammasome activation. In addition, when ATP was scavenged with apyrase, hyperoxia-induced inflammasome activation was significantly decreased. Furthermore, short hairpin RNA silencing of inflammasome components abrogated hyperoxia-induced secretion of proinflammatory cytokines in vitro. These results suggest that hyperoxia induces K+ efflux through the P2X7 receptor, leading to inflammasome activation and secretion of proinflammatory cytokines. These events would affect the permeability of the alveolar epithelium and ultimately lead to epithelial barrier dysfunction and cell death.
doi:10.4049/jimmunol.0902766
PMCID: PMC3780794  PMID: 20375306
3.  Effectiveness of Spironolactone Plus Ambrisentan for Treatment of Pulmonary Arterial Hypertension (from the [ARIES] Study 1 and 2 Trials) 
The American journal of cardiology  2013;112(5):720-725.
In translational models of pulmonary arterial hypertension (PAH), spironolactone improves cardiopulmonary hemodynamics by attenuating the adverse effects of hyperaldosteronism on endothelin type-B receptor function in pulmonary endothelial cells. This observation suggests that coupling spironolactone with inhibition of endothelin type-A receptor—mediated pulmonary vasoconstriction may be a useful treatment strategy for patients with PAH. We examined clinical data from patients randomized to placebo or the selective endothelin type-A receptor antagonist ambrisentan (10 mg/day) and in whom spironolactone use was reported during ARIES-1 and -2, which were randomized, double-blind, placebo-controlled trials assessing the effect of ambrisentan for 12 weeks on clinical outcome in PAH. From patients randomized to placebo (n = 132) or ambrisentan (n = 67), we identified concurrent spironolactone use in 21 (15.9%) and 10 (14.9%) patients, respectively. Compared with patients treated with ambrisentan alone (n = 57), therapy with ambrisentan D spironolactone improved change in 6-minute walk distance by 94% at week 12 (mean ± SE, +38.2 ± 8.1 vs +74.2 ± 27.4 m, p = 0.11), improved plasma B-type natriuretic peptide concentration by 1.7-fold (p = 0.08), and resulted in a 90% relative increase in the number of patients improving ≥1 World Health Organization functional class (p = 0.08). Progressive illness, PAH-associated hospitalizations, or death occurred as an end point for 5.3% of ambrisentan-treated patients; however, no patient treated with ambrisentan + spironolactone reached any of these end points. In conclusion, these pilot data suggest that coupling spironolactone and endothelin type-A receptor antagonism may be clinically beneficial in PAH. Prospective clinical trials are required to further characterize our findings.
doi:10.1016/j.amjcard.2013.04.051
PMCID: PMC3906683  PMID: 23751938
4.  Safety and efficacy of transition from inhaled treprostinil to parenteral treprostinil in selected patients with pulmonary arterial hypertension 
Pulmonary Circulation  2014;4(3):456-461.
Guidelines for the treatment of pulmonary arterial hypertension (PAH) recommend sequential add-on therapy for patients who deteriorate or fail to improve clinically. However, it is not known whether these patients also benefit from transitioning from inhaled prostacyclins to parenteral prostacyclins. We sought to characterize PAH patients receiving inhaled treprostinil who were transitioned to parenteral treprostinil. We conducted a multicenter retrospective study at 7 PAH centers and collected reasons, methods, safety, and outcome of patients transitioned from inhaled treprostinil to parenteral treprostinil. Twenty-six patients with pulmonary hypertension in group 1, 4, or 5 transitioned from inhaled treprostinil to parenteral treprostinil (10 intravenous, 16 subcutaneous). Twenty-four patients were also on one or two oral therapies. Reasons for transition were clinical deterioration, lack of clinical improvement, and pregnancy (19, 6, and 1 patients, respectively). Transitions occurred in hospital, clinic, or home (17, 7, and 2 patients, respectively). Parenteral infusion was started after the last inhaled treatment at maintenance dose (13 patients), after the inhaled therapy was downtitrated to 18 g (6 patients), or with an overlap of inhaled downtitration with parenteral uptitration (7 patients). The transition was safe; side effects included symptoms of prostacyclin overdose. Patients were followed for 3–18 months. At 3 months, 8 patients improved, 17 maintained their functional class, and 1 continued to deteriorate. In conclusion, selected PAH patients can be safely transitioned from inhaled treprostinil to parenteral treprostinil using a variety of methodologies in different settings with the expectation that patients will improve or at least remain clinically stable.
doi:10.1086/677360
PMCID: PMC4278605  PMID: 25621159
prostacyclin analogues; goal-oriented therapy; multicenter study
5.  Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension 
The Journal of Clinical Investigation  2014;124(8):3514-3528.
Development of the vascular disease pulmonary hypertension (PH) involves disparate molecular pathways that span multiple cell types. MicroRNAs (miRNAs) may coordinately regulate PH progression, but the integrative functions of miRNAs in this process have been challenging to define with conventional approaches. Here, analysis of the molecular network architecture specific to PH predicted that the miR-130/301 family is a master regulator of cellular proliferation in PH via regulation of subordinate miRNA pathways with unexpected connections to one another. In validation of this model, diseased pulmonary vessels and plasma from mammalian models and human PH subjects exhibited upregulation of miR-130/301 expression. Evaluation of pulmonary arterial endothelial cells and smooth muscle cells revealed that miR-130/301 targeted PPARγ with distinct consequences. In endothelial cells, miR-130/301 modulated apelin-miR-424/503-FGF2 signaling, while in smooth muscle cells, miR-130/301 modulated STAT3-miR-204 signaling to promote PH-associated phenotypes. In murine models, induction of miR-130/301 promoted pathogenic PH-associated effects, while miR-130/301 inhibition prevented PH pathogenesis. Together, these results provide insight into the systems-level regulation of miRNA-disease gene networks in PH with broad implications for miRNA-based therapeutics in this disease. Furthermore, these findings provide critical validation for the evolving application of network theory to the discovery of the miRNA-based origins of PH and other diseases.
doi:10.1172/JCI74773
PMCID: PMC4109523  PMID: 24960162
6.  IL-6 Protects against Hyperoxia-Induced Mitochondrial Damage via Bcl-2–Induced Bak Interactions with Mitofusions 
Overexpression of IL-6 markedly diminishes hyperoxic lung injury, hyperoxia-induced cell death, and DNA fragmentation, and enhances Bcl-2 expression. We hypothesized that changes in the interactions between Bcl-2 family members play an important role in the IL-6–mediated protective response to oxidative stress. Consistent with this hypothesis, we found that IL-6 induced Bcl-2 expression, both in vivo and in vitro, disrupted interactions between proapoptotic and antiapoptotic factors, and suppressed H2O2-induced loss of mitochondrial membrane potential in vitro. In addition, IL-6 overexpression in mice protects against hyperoxia-induced lung mitochondrial damage. The overexpression of Bcl-2 in vivo prolonged the survival of mice exposed to hyperoxia and inhibited alveolar capillary protein leakage. In addition, apoptosis-associated DNA fragmentation was substantially reduced in these animals. This IL-6–mediated protection was lost when Bcl-2 was silenced, demonstrating that Bcl-2 is an essential mediator of IL-6 cytoprotection. Finally, Bcl-2 blocked the dissociation of Bak from mitofusion protein (Mfn) 2, and inhibited the interaction between Bak and Mfn1. Taken together, our results suggest that IL-6 induces Bcl-2 expression to perform cytoprotective functions in response to oxygen toxicity, and that this effect is mediated by alterations in the interactions between Bak and Mfns.
doi:10.1165/rcmb.2008-0302OC
PMCID: PMC2746985  PMID: 19168699
lung injury; mitochondria; apoptosis; cytochrome c; Bax
7.  IL-6 Cytoprotection in Hyperoxic Acute Lung Injury Occurs via Suppressor of Cytokine Signaling-1–Induced Apoptosis Signal–Regulating Kinase-1 Degradation 
Hyperoxic acute lung injury (HALI) is characterized by a cell death response that is inhibited by IL-6. Suppressor of cytokine signaling-1 (SOCS-1) is an antiapoptotic negative regulator of the IL-6–mediated Janus kinase–signal transducer and activator of transcription signaling pathway. We hypothesized that SOCS-1 is a critical regulator and key mediator of IL-6–induced cytoprotection in HALI. To test this hypothesis, we characterized the expression of SOCS-1 and downstream apoptosis signal–regulating kinase (ASK)-1–Jun N-terminal kinase signaling molecules in small airway epithelial cells in the presence of H2O2, which induces oxidative stress. We also examined these molecules in wild-type and lung-specific IL-6 transgenic (Tg+) mice exposed to 100% oxygen for 72 hours. In control small airway epithelial cells exposed to H2O2 or in wild-type mice exposed to 100% oxygen, a marked induction of ASK-1 and pJun N-terminal kinase was observed. Both IL-6–stimulated endogenous SOCS-1 and SOCS-1 overexpression abolished H2O2-induced ASK-1 activation. In addition, IL-6 Tg+ mice exposed to 100% oxygen exhibited reduced ASK-1 levels and enhanced SOCS-1 expression compared with wild-type mice. Interestingly, no significant changes in activation of the key ASK-1 activator, tumor necrosis factor receptor-1/tumor necrosis factor receptor–associated factor-2 were observed between wild-type and IL-6 Tg+ mice. Furthermore, the interaction between SOCS-1 and ASK-1 promotes ubiquitin-mediated degradation both in vivo and in vitro. These studies demonstrate that SOCS-1 is an important regulator in IL-6–induced cytoprotection against HALI.
doi:10.1165/rcmb.2007-0287OC
PMCID: PMC2645529  PMID: 18776134
IL-6; apoptosis signal–regulating kinase-1; suppressor of cytokine signaling-1; lung injury; tumor necrosis factor receptor-1
8.  Plasma aldosterone levels are elevated in patients with pulmonary arterial hypertension in the absence of left ventricular heart failure: a pilot study 
European Journal of Heart Failure  2012;15(3):277-283.
Aims
Elevated levels of the mineralocorticoid hormone aldosterone are recognized as a modifiable contributor to the pathophysiology of select cardiovascular diseases due to left heart failure. In pulmonary arterial hypertension (PAH), pulmonary vascular remodelling induces right ventricular dysfunction and heart failure in the absence of left ventricular (LV) dysfunction. Hyperaldosteronism has emerged as a promoter of pulmonary vascular disease in experimental animal models of PAH; however, the extent to which hyperaldosteronism is associated with PAH in patients is unknown. Thus, the central aim of the current study is to determine if hyperaldosteronism is an unrecognized component of the PAH clinical syndrome.
Methods and results
Plasma aldosterone levels and invasive cardiopulmonary haemodynamic measurements were obtained for 25 patients referred for evaluation of unexplained dyspnoea or pulmonary hypertension. Compared with controls (n = 5), patients with PAH (n = 18) demonstrated significantly increased plasma aldosterone levels (1200.4 ± 423.9 vs. 5959.1 ± 2817.9 pg/mL, P < 0.02), mean pulmonary artery pressure (21.4 ± 5.0 vs. 45.5 ± 10.4 mmHg, P < 0.002), and pulmonary vascular resistance (PVR) (1.41 ± 0.6 vs. 7.3 ± 3.8 Wood units, P < 0.003) without differences in LV ejection fraction or pulmonary capillary wedge pressure between groups. Among patients not prescribed PAH-specific pharmacotherapy prior to cardiac catheterization, a subgroup of the cohort with severe pulmonary hypertension, aldosterone levels correlated positively with PVR (r = 0.72, P < 0.02) and transpulmonary gradient (r = 0.69, P < 0.02), but correlated inversely with cardiac output (r = –0.79, P < 0.005).
Conclusions
These data demonstrate a novel cardiopulmonary haemodynamic profile associated with hyperaldosteronism in patients: diminished cardiac output due to pulmonary vascular disease in the absence of LV heart failure.
doi:10.1093/eurjhf/hfs173
PMCID: PMC3576899  PMID: 23111998
Aldosterone; Pulmonary hypertension; Right ventricle; Heart failure
9.  Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation 
PLoS Medicine  2013;10(12):e1001577.
In this paper, Choi and colleagues analyzed levels of mitochondrial DNA in two prospective observational cohort studies and found that increased mtDNA levels are associated with ICU mortality, and improve risk prediction in medical ICU patients. The data suggests that mtDNA could serve as a viable plasma biomarker in MICU patients.
Background
Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.
Methods and Findings
Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women's Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10−7) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10−5) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10−4) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.
Conclusions
Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Intensive care units (ICUs, also known as critical care units) are specialist hospital wards that provide care for people with life-threatening injuries and illnesses. In the US alone, more than 5 million people are admitted to ICUs every year. Different types of ICUs treat different types of problems. Medical ICUs treat patients who, for example, have been poisoned or who have a serious infection such as sepsis (blood poisoning) or severe pneumonia (inflammation of the lungs); trauma ICUs treat patients who have sustained a major injury; cardiac ICUs treat patients who have heart problems; and surgical ICUs treat complications arising from operations. Patients admitted to ICUs require constant medical attention and support from a team of specially trained nurses and physicians to prevent organ injury and to keep their bodies functioning. Monitors, intravenous tubes (to supply essential fluids, nutrients, and drugs), breathing machines, catheters (to drain urine), and other equipment also help to keep ICU patients alive.
Why Was This Study Done?
Although many patients admitted to ICUs recover, others do not. ICU specialists use scoring systems (algorithms) based on clinical signs and physiological measurements to predict their patients' likely outcomes. For example, the APACHE II scoring system uses information on heart and breathing rates, temperature, levels of salts in the blood, and other signs and physiological measurements collected during the first 24 hours in the ICU to predict the patient's risk of death. Existing scoring systems are not perfect, however, and “biomarkers” (molecules in bodily fluids that provide information about a disease state) are needed to improve risk prediction for ICU patients. Here, the researchers investigate whether levels of circulating cell-free mitochondrial DNA (mtDNA) are associated with ICU deaths and whether these levels can be used as a biomarker to improve risk prediction in ICU patients. Mitochondria are cellular structures that produce energy. Levels of mtDNA in the plasma (the liquid part of blood) increase in response to trauma and infection. Moreover, mtDNA activates molecular processes that lead to inflammation and organ injury.
What Did the Researchers Do and Find?
The researchers measured mtDNA levels in the plasma of patients enrolled in two prospective observational cohort studies that monitored the outcomes of ICU patients. In the Brigham and Women's Hospital Registry of Critical Illness study, blood was taken from 200 patients within 24 hours of admission into the hospital's medical ICU. In the Molecular Epidemiology of Acute Respiratory Distress Syndrome study (acute respiratory distress syndrome is a life-threatening inflammatory reaction to lung damage or infection), blood was taken from 243 patients within 48 hours of admission into medical and non-medical ICUs at two other US hospitals. Patients admitted to medical ICUs with a raised mtDNA level (3,200 or more copies of a specific mitochondrial gene per microliter of plasma) had a 7- to 8-fold increased risk of dying within 28 days of admission compared to patients with mtDNA levels of less than 3,200 copies/µl plasma. There was no evidence of an association between raised mtDNA levels and death among patients admitted to non-medical ICUs. The addition of an elevated mtDNA level to a clinical model for risk prediction that included the APACHE II score and biomarkers that are already used to predict ICU outcomes improved the net reclassification index (an indicator of the improvement in risk prediction algorithms offered by new biomarkers) of 28-day mortality among medical ICU patients in both studies.
What Do These Findings Mean?
These findings indicate that raised mtDNA plasma levels are associated with death in medical ICUs and show that, among patients in medical ICUs, measurement of mtDNA plasma levels can improve the prediction of the risk of death from the APACHE II scoring system, even when commonly measured biomarkers are taken into account. These findings do not indicate whether circulating cell-free mtDNA increased because of the underlying severity of illness or whether mtDNA actively contributes to the disease process in medical ICU patients. Moreover, they do not provide any evidence that raised mtDNA levels are associated with an increased risk of death among non-medical (mainly surgical) ICU patients. These findings need to be confirmed in additional patients, but given the relative ease and rapidity of mtDNA measurement, the determination of circulating cell-free mtDNA levels could be a valuable addition to the assessment of patients admitted to medical ICUs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001577.
The UK National Health Service Choices website provides information about intensive care
The Society of Critical Care Medicine provides information for professionals, families, and patients about all aspects of intensive care
MedlinePlus provides links to other resources about intensive care (in English and Spanish)
The UK charity ICUsteps supports patients and their families through recovery from critical illness; its booklet Intensive Care: A Guide for Patients and Families is available in English and ten other languages; its website includes patient experiences and relative experiences of treatment in ICUs
Wikipedia has a page on ICU scoring systems (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001577
PMCID: PMC3876981  PMID: 24391478
10.  A review of sitaxsentan sodium in patients with pulmonary arterial hypertension 
Pulmonary arterial hypertension (PAH) is a life threatening, progressive condition which eventually leads to fatal right heart failure. Endothelin-1 (ET-1), a potent vasoconstrictor peptide, is increased in the pulmonary arteries of patients with pulmonary hypertension. Endothelin-1 acts through the stimulation of 2 subtypes of receptors (endothelin receptor subtypes A [ETA] and B [ETB]). In PAH patients, ETRAs block the deleterious vasoconstrictor effects of ET-1, and ETRA treatment in PAH patients has been shown to be safe and efficacious. Sitaxsentan is an orally active, highly ETA selective ETRA that, in clinical trials, has demonstrated improvements in exercise capacity, functional class and hemodynamics in PAH patients. Sitaxsentan has been shown to be safe, well tolerated, and associated with a lower incidence of liver toxicity than other approved ETRAs.
PMCID: PMC1994033  PMID: 17583185
endothelin receptor antagonist; endothelin receptor inhibitor; endothelin A; sitaxsentan; pulmonary hypertension; endothelin
11.  Right heart failure: toward a common language 
Pulmonary Circulation  2013;3(4):963-967.
In this guideline, the International Right Heart Foundation Working Group moves a step forward to develop a common language to describe the development and defects that exemplify the common syndrome of right heart failure. We first propose fundamental definitions of the distinctive components of the right heart circulation and provide consensus on a universal definition of right heart failure. These definitions will form the foundation for describing a uniform nomenclature for right heart circulatory failure with a view to foster collaborative research initiatives and conjoint education in an effort to provide insight into mechanisms of disease unique to the right heart.
doi:10.1086/674750
PMCID: PMC4070823  PMID: 25006413
right heart failure; pulmonary hypertension; pulmonary circulation; right ventricle; etiology; physiology; anatomy; classification
12.  MicroRNA-21 Integrates Pathogenic Signaling to Control Pulmonary Hypertension: Results of a Network Bioinformatics Approach 
Circulation  2012;125(12):1520-1532.
Background
Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA (miRNA) are potential candidates for coordinated regulation of these disease stimuli.
Methods and Results
Using a network biology approach, we identify miRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying miRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haplo insufficiency of the BMP Receptor Type 2 (BMPRII). To validate these predictions, we have found that hypoxia and BMPRII signaling independently up-regulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 down-regulates BMPRII expression. Furthermore, miR-21 directly represses RhoB expression and Rho kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is up-regulated in pulmonary tissue from several rodent models of PH and in humans with PH. Upon induction of disease in miR-21-null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH.
Conclusions
A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying miRNA in PH.
doi:10.1161/CIRCULATIONAHA.111.060269
PMCID: PMC3353408  PMID: 22371328
Pulmonary Heart Disease; microRNA; Network Biology; Molecular Biology; Vasculature
13.  Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension 
Pulmonary circulation  2011;1(2):250-258.
Background
Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established.
Methods
Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O2 for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years).
Results
Five-year survival was 56%. Baseline PVR (mean ± SD 850±580 dyne-sec/cm5) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO & O2 was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O2 had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O2 had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O2 were independent predictors of survival.
Conclusions
Reduction in PVR or mPAP during short-term administration of inhaled NO and O2 predicts survival in PAH patients.
doi:10.4103/2045-8932.83449
PMCID: PMC3183738  PMID: 22020367
pulmonary arterial hypertension; vasodilator testing; nitric oxide; vasoreactivity
14.  Vasoreactivity to inhaled nitric oxide with oxygen predicts long-term survival in pulmonary arterial hypertension 
Pulmonary Circulation  2011;1(2):250-258.
Pulmonary vasodilator testing is currently used to guide management of patients with pulmonary arterial hypertension (PAH). However, the utility of the pulmonary vascular response to inhaled nitric oxide (NO) and oxygen in predicting survival has not been established. Eighty patients with WHO Group I PAH underwent vasodilator testing with inhaled NO (80 ppm with 90% O2 for 10 minutes) at the time of diagnosis. Changes in right atrial (RA) pressure, mean pulmonary artery pressure (mPAP), pulmonary capillary wedge pressure, Fick cardiac output, and pulmonary vascular resistance (PVR) were tested for associations to long-term survival (median follow-up 2.4 years). Five-year survival was 56%. Baseline PVR (mean±SD 850±580 dyne-sec/cm5) and mPAP (49±14 mmHg) did not predict survival, whereas the change in either PVR or mPAP while breathing NO and O2 was predictive. Patients with a ≥30% reduction in PVR with inhaled NO and O2 had a 53% relative reduction in mortality (Cox hazard ratio 0.47, 95% confidence interval (CI) 0.23-0.99, P=0.047), and those with a ≥12% reduction in mPAP with inhaled NO and O2 had a 55% relative reduction in mortality (hazard ratio 0.45, 95% CI 0.22-0.96, P=0.038). The same vasoreactive thresholds predicted survival in the subset of patients who never were treated with calcium channel antagonists (n=66). Multivariate analysis showed that decreases in PVR and mPAP with inhaled NO and O2 were independent predictors of survival. Reduction in PVR or mPAP during short-term administration of inhaled NO and O2 predicts survival in PAH patients.
doi:10.4103/2045-8932.83449
PMCID: PMC3183738  PMID: 22020367
pulmonary arterial hypertension; vasodilator testing; nitric oxide; vasoreactivity
15.  Exercise-induced pulmonary arterial hypertension 
Circulation  2008;118(21):2183-2189.
Background
The clinical relevance of exercise-induced pulmonary arterial hypertension (EIPAH) is uncertain, and its existence has never been well-studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that EIPAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal.
Methods and Results
406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of EIPAH (n=78) was compared to resting PAH (n=15), and normals (n=16). Log-log plots of mean pulmonary artery pressure vs. oxygen uptake (VO2) were obtained, and a “join-point” for a least residual sum-of-squares for two straight-line segments (slopes m1, m2) was determined; m2 < m1 = “plateau”, and m2 > m1 = “takeoff” pattern. At maximum exercise, VO2 (55.8±20.3 vs. 66.5±16.3 vs. 91.7±13.7 % predicted) was lowest in resting PAH, intermediate in EIPAH, and highest in normals, whereas mean pulmonary artery pressure (48.4±11.1 vs. 36.6±5.7 vs. 27.4+3.7 mmHg) and pulmonary vascular resistance (294±158 vs. 161±60 vs. 62±20 dynes-sec/cm5, respectively, p<0.05) followed an opposite pattern. An EIPAH plateau (n=32) was associated with lower VO2max (60.6±15.1 vs. 72.0±16.1 %predicted) and maximum cardiac output (78.2±17.1 vs. 87.8±18.3 %predicted), and a higher resting pulmonary vascular resistance (247±101 vs. 199±56 dynes-sec/cm5, p<0.05) than takeoff (n=40). The plateau pattern was most common in resting PAH, while the takeoff pattern was present in nearly all normals.
Conclusions
EIPAH is an early, mild, and clinically relevant phase of the PAH spectrum.
doi:10.1161/CIRCULATIONAHA.108.787101
PMCID: PMC2767322  PMID: 18981305
Circulation; Physiology; Hemodynamics; Pulmonary hypertension; Exercise
16.  Portopulmonary Hypertension: Challenges in Diagnosis and Management 
Portopulmonary hypertension is defined as the combination of pulmonary arterial hypertension with portal hypertension and presents management complications in patients awaiting liver transplantation. The combination of these vascular disorders has a marked impact on mortality. At present the recommendations for management are limited because of the paucity of definitive clinical trials. We have reviewed the available data on prevalence, diagnosis and treatment. It is clearly time to more formally approach the study of this patient population.
doi:10.1177/1756283X09338431
PMCID: PMC3002535  PMID: 21180556
pulmonary hypertension; portal hypertension; liver disease; portopulmonary hypertension; vasodilators
17.  Plasma Gelsolin Depletion and Circulating Actin in Sepsis—A Pilot Study 
PLoS ONE  2008;3(11):e3712.
Background
Depletion of the circulating actin-binding protein, plasma gelsolin (pGSN) has been described in septic patients and animals. We hypothesized that the extent of pGSN reduction correlates with outcomes of septic patients and that circulating actin is a manifestation of sepsis.
Methodology/Principal Findings
We assayed pGSN in plasma samples from non-surgical septic patients identified from a pre-existing database which prospectively enrolled patients admitted to adult intensive care units at an academic hospital. We identified 21 non-surgical septic patients for the study. Actinemia was detected in 17 of the 21 patients, suggesting actin released into circulation from injured tissues is a manifestation of sepsis. Furthermore, we documented the depletion of pGSN in human clinical sepsis, and that the survivors had significantly higher pGSN levels than the non-survivors (163±47 mg/L vs. 89±48 mg/L, p = 0.01). pGSN levels were more strongly predictive of 28-day mortality than APACHE III scores. For every quartile reduction in pGSN, the odds of death increased 3.4-fold.
Conclusion
We conclude that circulating actin and pGSN deficiency are associated with early sepsis. The degree of pGSN deficiency correlates with sepsis mortality. Reversing pGSN deficiency may be an effective treatment for sepsis.
doi:10.1371/journal.pone.0003712
PMCID: PMC2577888  PMID: 19002257
18.  DNA Damage Induced by Hyperoxia 
Inspired oxygen, an essential therapy for cardiorespiratory disorders, has the potential to generate reactive oxygen species that damage cellular DNA. Although DNA damage is implicated in diverse pulmonary disorders, including neoplasia and acute lung injury, the type and magnitude of DNA lesion caused by oxygen in vivo is unclear. We used single-cell gel electrophoresis (SCGE) to quantitate two distinct forms of DNA damage, base adduction and disruption of the phosphodiester backbone, in the lungs of mice. Both lesions were induced by oxygen, but a marked difference between the two was found. With 40 h of oxygen exposure, oxidized base adducts increased 3- to 4-fold in the entire population of lung cells. This lesion displayed temporal characteristics (a progressive increase over the first 24 h) consistent with a direct effect of reactive oxygen species attack upon DNA. DNA strand breaks, on the other hand, occurred in < 10% of pulmonary cells, which acquired severe levels of the lesion; dividing cells were preferentially affected. Characteristics of these cells suggested that DNA strand breakage was secondary to cell death, rather than a primary effect of reactive oxygen species attack on DNA. By analysis of IL-6– and IL-11–overexpressing transgenic animals, which are resistant to hyperoxia, we found that DNA strand breaks, but not base damage, correlated with acute lung injury. Analysis of purified alveolar type 2 preparations from hyperoxic mice indicated that strand breaks preferentially affected this cell type.
doi:10.1165/rcmb.2005-0340OC
PMCID: PMC2643280  PMID: 16574945
8-oxoguanine; acute lung injury; apoptosis; DNA damage; hyperoxia
19.  Bcl-2–related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury 
Journal of Clinical Investigation  2005;115(4):1039-1048.
Hyperoxic acute lung injury (HALI) is characterized by a cell death response with features of apoptosis and necrosis that is inhibited by IL-11 and other interventions. We hypothesized that Bfl-1/A1, an antiapoptotic Bcl-2 protein, is a critical regulator of HALI and a mediator of IL-11–induced cytoprotection. To test this, we characterized the expression of A1 and the oxygen susceptibility of WT and IL-11 Tg(+) mice with normal and null A1 loci. In WT mice, 100% O2 caused TUNEL+ cell death, induction and activation of intrinsic and mitochondrial-death pathways, and alveolar protein leak. Bcl-2 and Bcl-xl were also induced as an apparent protective response. A1 was induced in hyperoxia, and in A1-null mice, the toxic effects of hyperoxia were exaggerated, Bcl-2 and Bcl-xl were not induced, and premature death was seen. In contrast, IL-11 stimulated A1, diminished the toxic effects of hyperoxia, stimulated Bcl-2 and Bcl-xl, and enhanced murine survival in 100% O2. In A1-null mice, IL-11–induced protection, survival advantage, and Bcl-2 and Bcl-xl induction were significantly decreased. VEGF also conferred protection via an A1-dependent mechanism. In vitro hyperoxia also stimulated A1, and A1 overexpression inhibited oxidant-induced epithelial cell apoptosis and necrosis. A1 is an important regulator of oxidant-induced lung injury, apoptosis, necrosis, and Bcl-2 and Bcl-xl gene expression and a critical mediator of IL-11– and VEGF-induced cytoprotection.
doi:10.1172/JCI200523004
PMCID: PMC1070412  PMID: 15841185
20.  Roundtable debate: Controversies in the management of the septic patient – desperately seeking consensus 
Critical Care  2004;9(1):E1.
Despite continuous advances in technologic and pharmacologic management, the mortality rate from septic shock remains high. Care of patients with sepsis includes measures to support the circulatory system and treat the underlying infection. There is a substantial body of knowledge indicating that fluid resuscitation, vasopressors, and antibiotics accomplish these goals. Recent clinical trials have provided new information on the addition of individual adjuvant therapies. Consensus on how current therapies should be prescribed is lacking. We present the reasoning and preferences of a group of intensivists who met to discuss the management of an actual case. The focus is on management, with emphasis on the criteria by which treatment decisions are made. It is clear from the discussion that there are areas where there is agreement and areas where opinions diverge. This presentation is intended to show how experienced intensivists apply clinical science to their practice of critical care medicine.
doi:10.1186/cc2940
PMCID: PMC1065094  PMID: 15693960
sepsis; septic shock; resuscitation; pneumonia
21.  IL-13 stimulates vascular endothelial cell growth factor and protects against hyperoxic acute lung injury 
Hyperoxia is an important cause of acute lung injury. To determine whether IL-13 is protective in hyperoxia, we compared the survival in 100% O2 of transgenic mice that overexpress IL-13 in the lung and of nontransgenic littermate controls. IL-13 enhanced survival in 100% O2. One hundred percent of nontransgenic mice died in 4–5 days, whereas 100% of IL-13–overexpressing mice lived for more than 7 days, and many lived 10–14 days. IL-13 also stimulated VEGF accumulation in mice breathing room air, and it interacted with 100% 2 to increase VEGF accumulation further. The 164–amino acid isoform was the major VEGF moiety in bronchoalveolar lavage from transgenic mice in room air, whereas the 120– and 188–amino acid isoforms accumulated in these mice during hyperoxia. In addition, antibody neutralization of VEGF decreased the survival of IL-13–overexpressing mice in 100% 2. These studies demonstrate that IL-13 has protective effects in hyperoxic acute lung injury. They also demonstrate that IL-13, alone and in combination with 100% 2, stimulates pulmonary VEGF accumulation, that this stimulation is isoform-specific, and that the protective effects of IL-13 are mediated, in part, by VEGF.
PMCID: PMC381393  PMID: 10995789

Results 1-21 (21)