Michael G. Risbano

Altered Immune Phenotype in Peripheral Blood Cells of Patients with Scleroderma‐Associated Pulmonary Hypertension

Pulmonary arterial hypertension is a common and fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. Our goal is to identify differentially expressed genes in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension as biomarkers of disease.

Increased expression of growth differentiation factor-15 in systemic sclerosis-associated pulmonary arterial hypertension

BACKGROUND Growth differentiation factor (GDF)-15 is a secreted member of the transforming growth factor-β cytokine superfamily. GDF-15 levels are elevated in the serum of patients with cardiovascular diseases. We hypothesized that GDF-15 levels would also be increased in the plasma and lung tissue of patients with systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH). METHODS GDF-15 levels were measured in plasma in subjects with SSc-PAH (n = 30) and compared with subjects with systemic sclerosis (SSc) without pulmonary arterial hypertension (PAH) (n = 24). Patients with idiopathic PAH (IPAH) (n = 44) and normal individuals (n = 13) served as control subjects. Immunohistochemistry and immunofluorescence assay identified GDF-15 protein in lung tissue from patients with SSc-PAH and IPAH. RESULTS Patients with SSc-PAH had significantly higher mean circulating levels of GDF-15 in plasma compared with patients with SSc without PAH (422.3 ± 369.5 pg/mL vs 108.1 ± 192.8 pg/mL, P = .004). GDF-15 levels correlated positively with estimated right ventricular systolic pressure on echocardiogram and plasma levels of the amino terminal propeptide form of brain natriuretic peptide. There was an inverse correlation between circulating GDF-15 and diffusing capacity of the lung for carbon monoxide (Dlco) and a positive correlation with the FVC to Dlco ratio on pulmonary function test. GDF-15 levels > 125 pg/mL were associated with reduced survival. GDF-15 protein expression was increased in lung tissue from patients with SSc-PAH. CONCLUSIONS GDF-15 may be a useful biomarker in PAH associated with SSc. Its presence in lung tissue may suggest a role in the pathology of the disease.

Overview of current therapeutic approaches for pulmonary hypertension.

There have been tremendous strides in the management of pulmonary hypertension over the past 20 years with the introduction of targeted medical therapies and overall improvements in surgical treatment options and general supportive care. Furthermore, recent data shows that the survival of those with pulmonary arterial hypertension is improving. While there has been tremendous progress, much work remains to be done in improving the care of those with secondary forms of pulmonary hypertension, who constitute the majority of patients with this disorder, and in the optimal treatment approach in those with pulmonary arterial hypertension. This article will review general and targeted medical treatment, along with surgical interventions, of those with pulmonary hypertension.

A Rare Presentation of Ischemic Pseudomembranous Colitis Due to Escherichia coli

Escherichia coli Ol57:H7 infection ranges from mild diarrheal illness to severe hemorrhagic colitis but may rarely be complicated by pseudomembranous colitis and/or necrosis. Herein, we report a sporadic case of ischemic E. coli Ol57:H7 pseudomembranous colitis in an adult that occurred during a national outbreak of E. coli Ol57:H7 in the United States.

Ambrisentan: a review of its use in pulmonary arterial hypertension:

Pulmonary arterial hypertension (PAH) is a progressive disease defined by an elevation in pulmonary arterial pressure that can lead to right heart failure and death. Ambrisentan is a selective endothelin receptor antagonist approved for the treatment of idiopathic, heritable PAH and connective tissue disease-associated PAH. Ambrisentan has been shown to improve exercise capacity and hemodynamics with an acceptable side-effect profile. It has also proven to be safely used in combination with other PAH-specific medications, especially with phosphodiesterase-5 inhibitors. In the recent randomized trial, AMBITION, it was shown that upfront combination therapy of ambrisentan and tadalafil significantly decreased the risk of clinical failure compared with monotherapy. This review describes the drug profile of ambrisentan and its safety and efficacy in the treatment of PAH.

Impact of four times daily dosing of oral treprostinil on tolerability and daily dose achieved in pulmonary hypertension

Oral treprostinil (TRE) is a prostacylin that is approved for the treatment of patients with pulmonary arterial hypertension (PAH). Dosing is approved for two or three times daily (t.i.d.); however, adverse effects, including gastrointestinal-related symptoms, may limit the ability to reach optimal doses. We report our experience with a four times daily (q.i.d.) regimen of oral TRE for goal-directed therapy of PAH. We describe three patients that were transitioned from infusion or inhaled TRE to oral TRE with initial t.i.d. dosing over a four-day hospital stay. All patients were subsequently further dose-adjusted in the outpatient setting; however, adverse effects limited additional up-titration despite persistent dyspnea. In a carefully monitored outpatient setting, patients were switched from t.i.d. to q.i.d. dosing of oral TRE. All three patients were successfully dosed q.i.d., having achieved a higher total daily dose compared with a t.i.d. dose regimen. Furthermore, patients were able to maintain functional class II symptoms with mitigation of adverse effects using the q.i.d. dose regimen.

Timed response to inhaled nitric oxide in pulmonary hypertension

Pulmonary arterial hypertension (PAH) is a progressive, debilitating, and frequently terminal disease of the pulmonary vasculature.1 Over the past 20 years, the introduction of medications including calcium channel blockers (CCBs), phosphodiesterase-5 inhibitors (PDE5i), endothelin receptor antagonists (ERA), and prostacyclin therapies have significantly improved the treatment and prognosis of PAH.2 Despite these advancements, however, many patients continue to suffer unacceptably high morbidity and mortality.3 In light of this fact, it is notable that a subset (∼5%–10%) of patients with idiopathic pulmonary arterial hypertension (IPAH) can respond to oral CCBs and have a significantly improved prognosis.4 The initiation of CCBs in patients with PAH, however, must be done with caution; unresponsive patients can experience dangerous and even fatal hemodynamic compromise.5 In order to identify those patients in whom CCBs will be safe and potentially effective, it is essential that an acute vasodilator challenge be performed with a short-acting vasoactive agent such as adenosine, epoprostenol, or inhaled nitric oxide (iNO), iNO being the most common agent.6-9 During this challenge, the patient’s hemodynamic responses are carefully monitored with the aid of right heart catheterization (RHC). Under current recommendations, a patient is considered an acute vasodilator responder and appropriate for CCBs if the mean pulmonary arterial pressure (mPAP) falls by ≥10 mmHg to an absolute value <40 mmHg without a degradation in cardiac output (CO).3 Although the use of RHC with an acute vasodilator challenge is an accepted part of the evaluation in patients with PAH, little has been published with regard to its standardization and protocolization.10 For instance, most investigations have focused on patients categorized into World Health Organization (WHO) group I disease with IPAH. However, recent publications suggest that patients with pulmonary hypertension (PH) diagnoses other than IPAH may benefit from acute vasodilator testing and the use of CCBs.11,12 Other details regarding the protocolization of acute vasodilator challenge, such as the optimal length of time to adequately observe a patient for an acute vasodilatory response, are likewise unknown or unclear in the literature. In the timed response to inhaled nitric oxide study, we examined, in patients with diverse PH diagnoses, the effect of iNO administered for acute vasoreactivity testing at 5 and 10 minutes. We performed a single-center, retrospective analysis of patients with suspected PH prospectively enrolled in a quality control initiative entailing RHC with acute vasodilator challenge and hemodynamic measurements recorded at 5 and 10 minutes. Our goal is to better define the length of time necessary for vasoreactivity testing in patients with PH.

Treatment of exercise pulmonary hypertension improves pulmonary vascular distensibility

Exercise pulmonary hypertension (ePH) is an underappreciated form of exertional limitation. Despite normal resting pulmonary artery pressures, patients with ePH demonstrate early pulmonary vascular changes with reduced pulmonary arterial compliance (PAC) and vascular distensibility (α). Recent data suggest that targeted vasodilator therapy may improve hemodynamics in ePH, but it is not well-known whether such medications alter pulmonary vascular distensibility. Thus, we sought to evaluate if vasodilator therapy improved α a marker of early pulmonary vascular disease in ePH. Ten patients performed supine exercise right heart catheterization (exRHC) with bicycle ergometer to peak exercise. Patients diagnosed with ePH were treated with pulmonary vasodilators. A repeat symptom-limited exercise RHC was performed at least six months after therapy. Patients with ePH had evidence of early pulmonary vascular disease, as baseline PAC and α were reduced. After pulmonary vasodilator therapy, a number of peak exercise hemodynamics statistically improved, including a decrease of total pulmonary resistance and pulmonary vascular resistance, while cardiac output increased. Importantly, vasodilator therapy partially reversed the pathogenic decreases of α at the time of repeat exRHC. Pulmonary vascular distensibility, α, a marker of early pulmonary vascular disease, improves in ePH after therapy with pulmonary vasodilators.

Acute respiratory failure mimicking acute respiratory distress syndrome due to parenchymal infiltration by metastatic melanoma.

Malignant melanoma is the most aggressive form of skin cancer and carries a predisposition for metastasis to many different organs. Pulmonary dissemination is common, most often presenting as multiple discrete pulmonary nodules. While a variety of other intrathoracic patterns can occur, diffuse parenchymal infiltration causing acute respiratory failure is an extremely rare manifestation of metastatic disease. We present a case of an otherwise healthy man who developed rapidly progressive respiratory failure mimicking acute respiratory distress syndrome due to melanomatous infiltration of the lung parenchyma and airways.