Restoration of Foxp3+ Regulatory T Cells by HDAC-Dependent Epigenetic Modulation Plays a Pivotal Role in Resolving Pulmonary Arterial Hypertension Pathology.

Rationale: Immune dysregulation is a common feature of pulmonary arterial hypertension (PAH). Histone deacetylase (HDAC)-dependent transcriptional reprogramming epigenetically modulates immune homeostasis and is a novel disease-oriented approach in modern times. Objectives: To identify a novel functional link between HDAC and regulatory T cells (Tregs) in PAH, aiming to establish disease-modified biomarkers and therapeutic targets. Methods: Peripheral blood mononuclear cells were isolated from patients with idiopathic PAH (IPAH) and rodent models of pulmonary hypertension (PH): monocrotaline rats, Sugen5416-hypoxia rats, and Treg-depleted mice. HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) was used to examine the immune modulatory effects in vivo, ex vivo, and in vitro. Measurements and Main Results: Increased HDAC expression was associated with reduced Foxp3+ Tregs and increased PD-1 (programmed cell death-1) signaling in peripheral blood mononuclear cells from patients with IPAH. SAHA differentially modified a cluster of epigenetic-sensitive genes and induced Foxp3+ Treg conversion in IPAH T cells. Rodent models recapitulated these epigenetic aberrations and T-cell dysfunction. SAHA attenuated PH phenotypes and restored FOXP3 transcription and Tregs in PH rats; interestingly, the effects were more profound in female rats. Selective depletion of CD25+ Tregs in Sugen5416-hypoxia mice neutralized the effects of SAHA. Furthermore, SAHA inhibited endothelial cytokine/chemokine release upon stimulation and subsequent immune chemotaxis. Conclusions: Our results indicated HDAC aberration was associated with Foxp3+ Treg deficiency and demonstrated an epigenetic-mediated mechanism underlying immune dysfunction in PAH. Restoration of Foxp3+ Tregs by HDAC inhibitors is a promising approach to resolve pulmonary vascular pathology, highlighting the potential benefit of developing epigenetic therapies for PAH.

Cardiac tamponade secondary to haemopericardium in a patient on warfarin.

Acute cardiac tamponade requires urgent diagnosis and treatment. We report a case involving a 70-year-old man who was receiving warfarin treatment for 12 years following mitral valve replacement. The international normalised ratio (INR) was checked and echocardiography performed regularly in the clinic. The last INR was 2.1, checked 2 weeks before admission to the emergency department. The last echocardiography performed 3 months previously revealed no pericardial effusion. The patient suffered from progressive dyspnoea and orthopnoea for several days. Cardiac tamponade was diagnosed, and the INR at that time was 7.52. Urgent pericardiocentesis and pericardiotomy were undertaken and 1300 ml of pericardial blood was drained. Following surgery the patient's recovery was uneventful. An intravenous vitamin K injection and fresh frozen plasma transfusion were administered to reverse the patient's over-anticoagulated state. The final pathology revealed chronic inflammation and there was no malignancy, and no bacteria or mycobacterium were seen. Emergency physicians should remember that over-anticoagulation with warfarin may contribute to certain complications, including haemopericardium, and that strict control of target INR should be the goal for patients who require continuous warfarin treatment.