Rajive Tandon

A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension.

Background: Plexiform lesions comprising proliferative endothelial cells are hallmarks of pulmonary arterial hypertension. Results: Granzyme B cleaves intersectin-1s and generates a fragment with endothelial cell proliferative potential via phosphorylation of p38MAPK and Elk-1 transcription factor. Conclusion: Granzyme B cleavage of intersectin-1s and subsequent p38MAPK/Elk-1 activation are critical for endothelial cell proliferation. Significance: The novel pathogenic p38MAPK/Elk-1 signaling may explain the formation of plexiform lesions. Plexiform lesions (PLs), the hallmark of plexogenic pulmonary arterial hypertension (PAH), contain phenotypically altered, proliferative endothelial cells (ECs). The molecular mechanism that contributes to EC proliferation and formation of PLs is poorly understood. We now show that a decrease in intersectin-1s (ITSN-1s) expression due to granzyme B (GrB) cleavage during inflammation associated with PAH and the high p38/Erk1/2MAPK activity ratio caused by the GrB/ITSN cleavage products lead to EC proliferation and selection of a proliferative/plexiform EC phenotype. We used human pulmonary artery ECs of PAH subjects (ECPAH), paraffin-embedded and frozen human lung tissue, and animal models of PAH in conjunction with microscopy imaging, biochemical, and molecular biology approaches to demonstrate that GrB cleaves ITSN-1s, a prosurvival protein of lung ECs, and generates two biologically active fragments, an N-terminal fragment (GrB-EHITSN) with EC proliferative potential and a C-terminal product with dominant negative effects on Ras/Erk1/2. The proliferative potential of GrB-EHITSN is mediated via sustained phosphorylation of p38MAPK and Elk-1 transcription factor and abolished by chemical inhibition of p38MAPK. Moreover, lung tissue of PAH animal models and human specimens and ECPAH express lower levels of ITSN-1s compared with controls and the GrB-EHITSN cleavage product. Moreover, GrB immunoreactivity is associated with PLs in PAH lungs. The concurrent expression of the two cleavage products results in a high p38/Erk1/2MAPK activity ratio, which is critical for EC proliferation. Our findings identify a novel GrB-EHITSN-dependent pathogenic p38MAPK/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH.

COPD exacerbation care bundle improves standard of care, length of stay, and readmission rates

Introduction COPD is the third leading cause of death in the world. Utilizing care bundles during acute COPD exacerbations results in fewer complications and lower costs. Our aim was to construct a COPD exacerbation care bundle and evaluate the effects on patient care. Methods We conducted a prospective analysis of 44 patients admitted with a COPD exacerbation to a single tertiary care facility. Primary outcomes included length of stay, readmission rates, and hospital costs. Secondary outcomes included patient education, pulmonologist follow-up, and timeliness of medication administration. Two cohorts were analyzed: those treated with an electronic COPD care bundle (cases; N=22) versus those treated without the care bundle (controls; N=22). Results Mean length of stay (51.2 vs 101.1 hours in controls; P-value =0.001), 30-day readmission rates (9.1% vs 54.4% in controls; P-value =0.001), and 60-day readmission rates (22.7% vs 77% in controls; P-value =0.0003) decreased in the care bundle group. Ninety-day hospital costs had a significant difference in the care bundle group (US

Early detection of right ventricular dysfunction using transthoracic echocardiography in ARDS: a more objective approach.

7,652 vs US

Echocardiographic parameters of right ventricular function predict mortality in acute respiratory distress syndrome: A pilot study

19,954 in controls; P-value =0.044). Secondary outcomes included a 100% rate of COPD inhaler teaching (vs 27.3% in controls; P-value <0.001), 59.1% rate of pulmonologist follow-up after discharge (vs 18.2% in controls; P-value =0.005), and a mean reduction in time to steroid administration (7.0 hours; P-value =0.015) seen in the care bundle cases. Conclusion Our significant findings coupled with the recent success of standardized algorithms in managing COPD exacerbations stress the importance of enforcing clinical guidelines that can enhance patient care. We demonstrated improved care for COPD exacerbation patients during hospitalizations, thereby decreasing morbidity and the financial burden hospitals face in regard to this increasingly prevalent disease.

Intersectin-1s: an important regulator of cellular and molecular pathways in lung injury

Right ventricular (RV) dysfunction is an independent predictor of morbidity and mortality in acute respiratory distress syndrome (ARDS). Our goal was to describe morphologic changes in the RV using objective measures on transthoracic echocardiography (TTE) that occur following ARDS.

A Novel Expression of Exercise Induced Pulmonary Hypertension in Human Immunodeficiency Virus Patients: A Pilot Study

Right ventricular (RV) dysfunction in acute respiratory distress syndrome (ARDS) contributes to increased mortality. Our aim is to identify reproducible transthoracic echocardiography (TTE) parameters of RV dysfunction that can be used to predict outcomes in ARDS. We performed a retrospective single-center cohort pilot study measuring tricuspid annular plane systolic excursion (TAPSE), Tei index, RV-fractional area change (RV-FAC), pulmonary artery systolic pressure (PASP), and septal shift, reevaluated by an independent blinded cardiologist (JK). Thirty-eight patients were included. Patients were divided on the basis of 30-day survival. Thirty-day mortality was 47%. Survivors were younger than nonsurvivors. Survivors had a higher pH, PaO2: FiO2 ratio, and TAPSE. Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Sequential Organ Failure Assessment (SOFA) scores were lower in survivors. TAPSE has the strongest association with increased 30-day mortality from date of TTE. Accordingly, TAPSE has a strong positive correlation with PaO2: FiO2 ratios, and Tei index has a strong negative correlation with PaO2: FiO2 ratios. Septal shift was associated with lower PaO2: FiO2 ratios. Decrease in TAPSE, increase in Tei index, and septal shift were seen in the severe ARDS group. In multivariate logistic regression models, TAPSE maintained a significant association with mortality independent of age, pH, PaO2: FiO2 ratios, positive end expiratory pressure, PCO2, serum bicarbonate, plateau pressures, driving pressures, APACHE II, SAPS II, and SOFA scores. In conclusion, TAPSE and other TTE parameters should be used as novel predictive indicators for RV dysfunction in ARDS. These parameters can be used as surrogate noninvasive RV hemodynamic measurements to be manipulated to improve mortality in patients with ARDS and contributory RV dysfunction.

Transition From Subcutaneous or Inhaled Treprostinil to Oral Treprostinil at Home in Patients With Pulmonary Arterial Hypertension: A Retrospective Case Series

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe syndromes resulting from the diffuse damage of the pulmonary parenchyma. ALI and ARDS are induced by a plethora of local or systemic insults, leading to the activation of multiple pathways responsible for injury, resolution, and repair or scarring of the lungs. Despite the large efforts aimed at exploring the roles of different pathways in humans and animal models and the great strides made in understanding the pathogenesis of ALI/ARDS, the only viable treatment options are still dependent on ventilator and cardiovascular support. Investigation of the pathophysiological mechanisms responsible for initiation and resolution or advancement toward lung scarring in ALI/ARDS animal models led to a better understanding of the diseases complexity and helped in elucidating the links between ALI and systemic multiorgan failure. Although animal models of ALI/ARDS have pointed out a variety of new ideas for study, there are still limited data regarding the initiating factors, the critical steps in the progression of the disease, and the central mechanisms dictating its resolution or progression to lung scarring. Recent studies link deficiency of intersectin-1s (ITSN-1s), a prosurvival protein of lung endothelial cells, to endothelial barrier dysfunction and pulmonary edema as well as to the repair/recovery from ALI. This review discusses the effects of ITSN-1s deficiency on pulmonary endothelium and its significance in the pathology of ALI/ARDS.

Increased mortality from complications of pulmonary hypertension in patients undergoing transcatheter aortic valve replacement

Background: Patients with the human immunodeficiency virus (HIV) are at risk for multiple pulmonary complications including pulmonary hypertension. Exercise induced pulmonary hypertension (EIPH) has been previously described in patients with scleroderma, sickle cell disease and chronic obstructive pulmonary disease, yet has not been associated with the HIV population. Methods: A prospective case-control study design was implemented. Four HIV patients with unexplained dyspnea and four healthy controls underwent symptom-limited stationary bicycle exercise. Transthoracic Doppler Echocardiography was used to measure tricuspid regurgitation velocity which was used to calculate the right ventricular to right atrial pressure (RV-RA) gradient at rest and at peak exercise using the simplified Bernoulli’s equation. Change in RV-RA gradient between rest and peak exercise was calculated and considered to represent change in pulmonary arterial systolic pressure. Results: The mean age was 41.25 years (±8.7) for patients and 33.5 years (±6.0) for controls. The mean CD4 count of patients was 191.5 cells/μL (±136.2). Patients had a significantly higher increase in RV-RA gradient as compared to controls (180.2% vs. 27.5%, p = 0.03). Discussion: This pilot study suggests that it is feasible to use recumbent bicycle and transthoracic Doppler echocardiography for the evaluation of EIPH among HIV patients with dyspnea of unknown etiology. The study is too small to draw any broad conclusion. Further evaluation of this concept with a larger study is warranted.

In Acute Right Ventricular Failure, What are the Effects of Preload and Afterload?

Pulmonary arterial hypertension (PAH) is a progressive condition that can lead to right ventricular failure and death. Treprostinil is a prostacyclin analogue that has proven clinical efficacy in patients with PAH. Difficulties in the administration of inhaled and parenteral prostacyclins led to the development of extended-release treprostinil diolamine for oral use. Limited data exist on the transition to oral treprostinil. The purpose of this case series is to describe the transition from subcutaneous or inhaled treprostinil to oral treprostinil in the outpatient setting. With the current availability of oral prostacyclins and prostacyclins analogues, most transitions to oral therapy are done in the hospital setting resulting in increased cost and risk of hospital-acquired infections. Four patients on background phosphodiesterase type 5 therapy with baseline World Health Organization functional class (WHO FC) II PAH were transitioned at home. Three of the 4 patients were safely transitioned as outpatients and maintained WHO FC II status at 10 and 12 months. The fourth patient had worsening right heart failure and was admitted within 2 months of the transition and started back on parenteral prostacyclin therapy. The 6-minute walk distance (6MWD) increased in patients transitioning from inhaled therapy and decreased in the patient transitioning from subcutaneous therapy. The most common adverse event was nausea.

Erratum: A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension (Journal of Biological Chemistry (2013) 288 (25701-25716))

Aortic stenosis (AS) leads to pulmonary hypertension (PH) and right ventricle (RV) failure. Our goal was to describe mortality related to postoperative complications in PH patients undergoing transcatheter aortic valve replacement (TAVR). Ninety-three TAVR patients were analyzed (controls, sPAP < 50 mmHg; cases, sPAP ≥ 50 mmHg). Significant findings in cases included increased mortality (365 days), post-TAVR atrioventricular block (AVB) and acute kidney injury (AKI), and increased mean length of stay (LOS). This novel study highlights complications of PH as independent risk factors for death and significant morbidity post TAVR. Optimization of preoperative volume status and RV afterload reduction, while addressing AVB and AKI, may play a vital role in reducing mortality and LOS.