Study design and rationale for investigating phosphodiesterase type 5 inhibition for the treatment of pulmonary hypertension due to chronic obstructive lung disease: the TADA-PHiLD (TADAlafil for Pulmonary Hypertension associated with chronic obstructive Lung Disease) trial

Abstract In patients with chronic obstructive pulmonary disease (COPD), moderate or severe pulmonary hypertension (COPD-PH) is associated with increased rates of morbidity and mortality. Despite this, approaches to treatment and the efficacy of phosphodiesterase type 5 inhibition (PDE-5i) in COPD-PH are unresolved. We present the clinical rationale and study design to assess the effect of oral tadalafil on exercise capacity, cardiopulmonary hemodynamics, and clinical outcome measures in COPD-PH patients. Male and female patients 40–85 years old with GOLD stage 2 COPD or higher and pulmonary hypertension diagnosed on the basis of invasive cardiac hemodynamic assessment (mean pulmonary artery pressure [mPAP] >30 mmHg, pulmonary vascular resistance [PVR] >2.5 Wood units, and pulmonary capillary wedge pressure ≤18 mmHg at rest) will be randomized at a 1∶1 ratio to receive placebo or oral PDE-5i with tadalafil (40 mg daily for 12 months). The primary end point is change from baseline in 6-minute walk distance at 12 months. The secondary end points are change from baseline in PVR and mPAP at 6 months and change from baseline in peak volume of oxygen consumption () during exercise at 12 months. Changes in systemic blood pressure and/or oxyhemoglobin saturation (Sao2) at rest and during exercise will function as safety outcome measures. TADA-PHiLD (TADAlafil for Pulmonary Hypertension assocIated with chronic obstructive Lung Disease) is the first sufficiently powered randomized clinical trial testing the effect of PDE-5i on key clinical and drug safety outcome measures in patients with at least moderate PH due to COPD

Prevalence and Clinical Characteristics Associated with Pulmonary Hypertension in African-Americans

<div><p>Background</p><p>Pulmonary hypertension (PH) is associated with increased mortality and morbidity. It is frequently associated with cardiopulmonary diseases that are prevalent in African Americans (AAs). However, the prevalence or determinants of PH in the AA population is not known. </p> <p>Methods</p><p>We conducted a cross-sectional study to estimate the prevalence of PH (defined as trans-tricuspid gradient ≥ 35 mm Hg) and associated clinical characteristics in AAs using the Jackson Heart Study cohort (n=3,282) who underwent echocardiography and had a measurable trans-tricuspid regurgitant jet. Echocardiography is frequently used for screening for PH despite its limitations in estimating accurate PA systolic pressures. Overall and age-adjusted gender-specific prevalence were estimated and modified Poisson regression was used to identify independent clinical, spirometric, and echocardiographic characteristics associated with PH.</p> <p>Results</p><p>The mean age of the study population was 56.1 ± 12.6 years with 67.5% female. The prevalence of PH was 6.8%, with higher prevalence in female AAs (age-adjusted prevalence: Men 4.9%, 95% CI 3.6-6.2%; Women 7.7%, 95% CI 6.6-8.8%). Pulmonary hypertension prevalence increased with age (Prevalence Ratio: 10.0, 95%CI 4.0-25.1, >65 versus <45 years old), presence of obesity, higher pulse pressure, diabetes, obstructive or restrictive spirometry pattern, and severe left heart valvular disease. Also, PH was significantly associated with left atrial size and left ventricular ejection fraction.</p> <p>Conclusions</p><p>Pulmonary hypertension is prevalent in AAs, more in women than in men. The identified cardiopulmonary risk factors that increase the prevalence of PH may assist in diagnosis and management of these at-risk subjects in the AA population.</p> </div

Cognitive Biases in the Era of COVID-19 : A Case of Clostridium sporogenes Bacteremia in a Patient with Small Bowel Obstruction

Clostridium sporogenes bacteremia in immunocompetent patients is rare with very few reported cases in the literature. We present a case of Clostridium sporogenes bacteremia in an 81-year-old immunocompetent man with small bowel obstruction and hypoxemia during the COVID-19 pandemic. Routine monitoring of prognostic inflammatory markers for COVID-19 created a unique challenge in the management of our patient who developed sepsis with respiratory symptoms. Upon review, bacteremia from Clostridium sporogenes was associated with high mortality rates and could produce similar elevations in the inflammatory markers observed in COVID-19 pneumonia. Further, we reviewed the cognitive biases encountered when monitoring these inflammatory markers during the management of our patient with Clostridium sporogenes bacteremia, who was initially thought to have COVID-19 disease. While our patient ultimately tested negative for COVID-19, early administration of empiric antimicrobial therapy without source control failed to prevent clinical decompensation

Prevalence of pulmonary hypertension based on age groups and gender.

<p>Prevalence of pulmonary hypertension based on age groups and gender.</p

Distribution of trans-tricuspid gradients in study cohort.

<p>Vertical line indicates a gradient of 35 mm of Hg that was used as a cut-off for definition of pulmonary hypertension.</p

Inhibition of ICMT Induces Endothelial Cell Apoptosis through GRP94

Isoprenylcysteine-O-carboxyl methyltransferase (ICMT) catalyzes methylation of proteins containing a C-terminal CAAX motif. We have previously shown that chemical inhibition of ICMT caused endothelial cell apoptosis, an effect correlated with decreased Ras and RhoA carboxyl methylation and GTPase activities. In the current study, proteomic analysis of pulmonary artery endothelial cells (PAEC) exposed to the ICMT inhibitor, N-acetyl-geranylgeranyl-cysteine (AGGC), demonstrated a shift in the isoelectric points (pI) of the glucose-regulated protein (GRP) 94. Two-dimensional PAGE and immunoblot analysis further documented that ICMT inhibition caused multiple changes in the pI of GRP94. GRP94 is an endoplasmic reticulum molecular chaperone, a component of the unfolded protein response (UPR), and is involved in apoptosis. Immunofluorescence analyses revealed redistribution and aggregation of GRP94 after 3 h exposure to AGGC. A similar finding was noted with calnexin. In addition, GRP94 protein levels were significantly diminished upon 18 h AGGC exposure or ICMT suppression. The effects of ICMT inhibition on changes in GRP94 subcellular localization and protein content were blunted by overexpression of constitutively active RhoA or a caspase inhibitor. Furthermore, GRP94 depletion augmented endothelial cell apoptosis induced by ICMT inhibition. These results indicate that ICMT inhibition leads to GRP94 relocalization, aggregation, and degradation; effects were dependent upon the activities of RhoA and caspases. We speculate that changes in the pI, subcellular localization, and protein level of GRP94 cause endothelial cell apoptosis, possibly through UPR dysfunction. These studies suggest a novel link between RhoA GTPases and the UPR