Mark T. Gladwin, MD
Chief, Pulmonary, Allergy and Critical Care Medicine Department, University of Pittsburgh
Director, Vascular Medicine Institute, University of Pittsburgh School of Medicine
Mark Gladwin, MD has a long history of leadership of translational projects and programs, having served as a principal or associate investigator on more than 25 human subjects protocols and holding seven FDA INDs for the use of investigational therapeutic medications, including nitrite, carbon monoxide, L-NMMA, and sildenafil.
Serving for more than 5 years as an Intramural Research Division Branch Chief, he was PI on two major phase II clinical trials, the DeNOVO trial of NO therapy for acute pain crisis in patients with sickle cell disease, which successfully enrolled 154 patients at 13 Centers and the Walk-PHASST trial of sildenafil for pulmonary hypertension secondary to sickle cell disease. Dr. Gladwin’s research activities have led to four fundamental scientific hypotheses: (1) The discovery that the nitrite anion is a circulating storage pool for NO bioactivity (PNAS 2000) that regulates hypoxic vasodilation (Nature Medicine 2003) and the cellular resilience to low oxygen and ischemia (JCI 2005). (2) The discovery of a novel physiological function for hemoglobin as an electronically and allosterically-regulated nitrite reductase (Nature Medicine 2003; Huang JCI 2005).
These studies reveal that nitrite is a potent vasodilator in humans and is bioactivated by reaction with deoxyhemoglobin (and myoglobin) to generate NO preferentially under hypoxic conditions; they also suggest that hemoglobin has an “enzymatic” property as a nitrite reductase that participates in hypoxic vasodilation. In related translational studies, Dr. Gladwin has demonstrated that inhaled nitrite reverses hypoxic neonatal pulmonary hypertension in sheep (Nature Medicine 2004), and that infused nitrite solutions prevent post-subarachnoid hemorrhage-induced vasospasm in primates (JAMA 2005) and prevent hepatic and cardiac ischemia-reperfusion injury and infarction in mice (JCI 2005). (3) The characterization of a novel mechanism of disease, hemolysis-associated endothelial dysfunction (Nature Medicine 2002; JAMA 2005; JCI 2005).
This work has described a state of resistance to NO in patients with sickle cell disease caused by scavenging of nitric oxide by hemoglobin that is released into plasma during hemolysis. (4) The mechanistic, clinical, and epidemiological description of a human disease syndrome, hemolysis-associated pulmonary hypertension (NEJM 2004). He has found that pulmonary hypertension occurs in 10% of patients with sickle cell disease, is a major cause of mortality in this population, and is strongly associated with high hemolytic rate, iron overload, and kidney disease.
B. Positions and Honors
1991-1995 Internship, Residency, Chief Residency, Department of Internal Medicine, Oregon Health Sciences University (OHSU), Portland, OR
1995-1996 Critical Care Fellow, Critical Care Medicine Department, NIH
1996-1998 Pulmonary-Critical Care Fellow, Pulmonary Division, University of Washington. Seattle, WA
1998-2000 Senior Research Fellow, Critical Care Medicine Department, NIH
1995-2000 Commander, US Public Health Service (0-5)
2000-2004 Section Head, Sickle Cell/Nitric Oxide Therapeutics Section, Critical Care Medicine Department, Clinical Center, Cardiovascular Branch, NHLBI, NIH, Bethesda, MD
2004-2005 Section Head, Vascular Therapeutics Section, Cardiovascular Branch, NHLBI, NIH
2005-2008 Chief, Pulmonary and Vascular Medicine Branch, NHLBI, NIH
2008-Present Chief, Pulmonary, Allergy and Critical Care Medicine Department, University of Pittsburgh and Director, Vascular Medicine Institute, University of Pittsburgh School of Medicine
Abstract: Hemolytic anemia as a mechanism for vasculopathy and pulmonary hypertension in sickle cell disease
Large screening studies of patients with sickle cell disease (SCD) for the presence of pulmonary hypertension (PH) have been performed using non-invasive Doppler-echocardiography, screening biomarkers such as N-terminal brain natriuretic peptide and right heart catheterization. These studies have reported a high prevalence of PH in this population, a significant association of increasing pulmonary pressures with more severe hemolytic anemia, cutaneous leg ulcerations, systemic systolic hypertension and renal dysfunction, and a high prospective associated risk of death. The mechanistic linkage between hemolytic anemia and vasculopathy has been the subject of extensive study in pre-clinical animal models, in vascular studies in patients, and in large human cohort studies. Three new large screening studies of patients with sickle cell disease evaluating the prevalence of pulmonary hypertension, associated risk factors and relationship to outcome have now been published and will be reviewed. In aggregate, these studies show that pulmonary hypertension, defined by a mean pulmonary artery pressure greater than or equal to 25 mm Hg, occurs in 6-11% of all adult SCD patients, and is associated with risk factors previously reported, including more intense hemolytic anemia, higher prevalence of cutaneous leg ulcers, systemic hypertension, hypoxemia, renal insufficiency and reduced exercise capacity, and represents a significant and independent risk factor for prospective mortality.