Ali Sadoughi

Macrophage Migration Inhibitory Factor Mediates Hypoxia-Induced Pulmonary Hypertension

Pulmonary hypertension (PH) is a devastating disease leading to progressive hypoxemia, right ventricular failure, and death. Hypoxia can play a pivotal role in PH etiology, inducing pulmonary vessel constriction and remodeling. These events lead to increased pulmonary vessel wall thickness, elevated vascular resistance and right ventricular hypertrophy. The current study examined the association of the inflammatory cytokine macrophage migration inhibitory factor (MIF) with chronic lung disease and its role in the development of hypoxia-induced PH. We found that plasma MIF in patients with primary PH or PH secondary to interstitial lung disease (ILD) was significantly higher than in the control group (P = 0.004 and 0.007, respectively). MIF involvement with hypoxia-induced fibroblast proliferation was examined in both a human cell-line and primary mouse cells from wild-type (mif+/+) and MIF-knockout (mif−/−) mice. In vitro, hypoxia-increased MIF mRNA, extracellular MIF protein accumulation and cell proliferation. Inhibition of MIF inflammatory activity reduced hypoxia-induced cell proliferation. However, hypoxia only increased proliferation of mif−/− cells when they were supplemented with media from mif+/+ cells. This growth increase was suppressed by MIF inhibition. In vivo, chronic exposure of mice to a normobaric atmosphere of 10% oxygen increased lung tissue expression of mRNA encoding MIF and accumulation of MIF in plasma. Inhibition of the MIF inflammatory active site, during hypoxic exposure, significantly reduced pulmonary vascular remodeling, cardiac hypertrophy and right ventricular systolic pressure. The data suggest that MIF plays a critical role in hypoxia-induced PH, and its inhibition may be beneficial in preventing the development and progression of the disease.

Use of Selective Serotonin Reuptake Inhibitors and Outcomes in Pulmonary Arterial Hypertension

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) have been suggested to offer therapeutic benefit in patients with pulmonary arterial hypertension (PAH). We conducted two analyses to explore the association between SSRI use and PAH outcomes using the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL Registry). METHODS First, new users (SSRI-naive patients who initiated treatment after enrollment, incident use analysis, n = 220) were matched (1:2) with non-SSRI users (nonusers, n = 440) by enrollment center, sex, date of most recent visit, age, and 6-min walk distance. Second, a cross-sectional design was used to compare nonusers (n = 2,463), high-affinity SSRI users (n = 430), and non-high-affinity SSRI users (n = 125) at enrollment. Mortality and a composite end point defined by events indicative of clinical worsening were evaluated. RESULTS New users had a higher risk of death (unadjusted hazard ratio [HR], 1.74; 95% CI, 1.19-2.54; P = .004) and were less likely to be free from the composite end point 2 years after enrollment vs nonusers (25.7% vs 43.2%, respectively; P < .001). Similarly, among prevalent SSRI users (patients with a history of SSRI use at enrollment), high-affinity SSRI users were less likely to be free from the composite end point vs nonusers (unadjusted HR, 1.20; 95% CI, 1.07-1.36; P = .003). In both analyses, differences in outcome were maintained after adjustment for clinical variables previously associated with PAH outcomes. CONCLUSIONS In a large population of patients with PAH, incident SSRI use was associated with increased mortality and a greater risk of clinical worsening, although we could not adjust for all potential confounders.

Measurement and Management of Increased Intracranial Pressure

Increased intracranial pressure (ICP) is a serious complication of a variety of neurologic injuries and is a major challenge in intensive care units. The most common causes of increased ICP are: traumatic brain injury (TBI), stroke, neoplasms, hydrocephalus, hepatic encephalopathy, CNS venous return impairment, encephalitis, and abscesses. Prompt diagnosis and intensive monitoring and therapy of this condition are essential for successful management of this potentially devastating condition. Recent technical innovations in neuromonitoring may allow for improvement in morbidity and mortality rates attributable to elevated ICP. Normal ICP ranges from 3-15 mmHg. In routine intensive care unit (ICU) practice, the goal of ICP management is to maintain levels below 20 mmHg. Noninvasive and metabolic monitoring of ICP including imaging-clinical examination has been studied and suggested to be as efficient as the care based on invasive ICP monitoring; however its application in clinical practice is to be established. Raised intracranial pressure correlates with decreased survival and is often the only remediable element of brain pathology. While elimination of the cause of elevated ICP remains the definitive approach, there are maneuvers that should be used to decrease ICP urgently. Surgical decompression of mass effect may rapidly improve ICP elevation. Osmolar therapy, maintenance of euvolemia, cerebral metabolic suppression, and temperature control are part of the advanced management of elevated ICP.

A 77-Year-Old Woman With Dyspnea and Raynaud Phenomenon

A 77-year-old black woman who was a lifelong nonsmoker presented to our office for evaluation of worsening dyspnea over the last year that had severely limited her activities of daily living. Her medical history included type 2 diabetes, hypertension, and pacemaker placement. She reported paroxysmal nocturnal dyspnea and dry cough. She denied fevers, chills, chest pain, hemoptysis, or weight loss. She also reported whitening of her fingers with cold temperatures, suggestive of Raynaud phenomenon (RP). However, this symptom was not apparent on the initial visit, and she did not complain of it at that time.