Roberto F. Machado

Inhaled nebulized nitrite is a hypoxia-sensitive NO-dependent selective pulmonary vasodilator

The blood anion nitrite contributes to hypoxic vasodilation through a heme-based, nitric oxide (NO)–generating reaction with deoxyhemoglobin and potentially other heme proteins. We hypothesized that this biochemical reaction could be harnessed for the treatment of neonatal pulmonary hypertension, an NO-deficient state characterized by pulmonary vasoconstriction, right-to-left shunt pathophysiology and systemic hypoxemia. To test this, we delivered inhaled sodium nitrite by aerosol to newborn lambs with hypoxic and normoxic pulmonary hypertension. Inhaled nitrite elicited a rapid and sustained reduction (∼65%) in hypoxia-induced pulmonary hypertension, with a magnitude approaching that of the effects of 20 p.p.m. NO gas inhalation. This reduction was associated with the immediate appearance of NO in expiratory gas. Pulmonary vasodilation elicited by aerosolized nitrite was deoxyhemoglobin- and pH-dependent and was associated with increased blood levels of iron-nitrosyl-hemoglobin. Notably, from a therapeutic standpoint, short-term delivery of nitrite dissolved in saline through nebulization produced selective, sustained pulmonary vasodilation with no clinically significant increase in blood methemoglobin levels. These data support the concept that nitrite is a vasodilator acting through conversion to NO, a process coupled to hemoglobin deoxygenation and protonation, and evince a new, simple and inexpensive potential therapy for neonatal pulmonary hypertension.

Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension

Pulmonary hypertension is a frequent complication of sickle cell disease that is associated with haemolysis, impaired nitric oxide bioavailability and high mortality. We sought to evaluate the safety and efficacy of selective pulmonary vasodilators and antiproliferative agents in this at‐risk population. After optimising sickle cell disease therapy to stabilise haemoglobin and fetal haemoglobin levels, we evaluated the safety and efficacy of sildenafil in 12 patients with sickle cell disease and pulmonary hypertension. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure [50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% confidence interval (CI): 0·3–17, P = 0·043] and increased the 6‐min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI: 40–117, P = 0·0012). Transient headaches occurred in two patients and transient eye‐lid oedema in four patients. No episodes of priapism occurred in the three men in the study; two of them were on chronic exchange transfusions and one had erectile dysfunction. In conclusion: (1) sickle cell disease patients with anaemia and pulmonary hypertension have significant exercise limitation; (2) the 6‐min walk distance may be a valid endpoint in this population; (3) therapy with sildenafil appears safe and improves pulmonary hypertension and exercise capacity. Additional phase I studies in males with sickle cell disease followed by phase II/III placebo controlled trials evaluating the safety and efficacy of sildenafil therapy in sickle cell disease patients with pulmonary hypertension are warranted.

Hospitalization for pain in patients with sickle cell disease treated with sildenafil for elevated TRV and low exercise capacity

In adults with sickle cell disease (SCD), an increased tricuspid regurgitation velocity (TRV) by Doppler echocardiography is associated with increased morbidity and mortality. Although sildenafil has been shown to improve exercise capacity in patients with pulmonary arterial hypertension, it has not been evaluated in SCD. We therefore sought to determine whether sildenafil could improve exercise capacity in SCD patients with increased TRV and a low exercise capacity. A TRV ≥ 2.7 m/s and a 6-minute walk distance (6MWD) between 150 and 500 m were required for enrollment in this 16-week, double-blind, placebo-controlled sildenafil trial. After 74 of the screened subjects were randomized, the study was stopped early due to a higher percentage of subjects experiencing serious adverse events in the sildenafil arm (45% of sildenafil, 22% of placebo, P = .022). Subject hospitalization for pain was the predominant cause for this difference: 35% with sildenafil compared with 14% with placebo (P = .029). There was no evidence of a treatment effect on 6MWD (placebo-corrected effect -9 m; 95% confidence interval [95% CI] -56-38; P = .703), TRV (P = .503), or N-terminal pro-brain natriuretic peptide (P = .410). Sildenafil appeared to increase hospitalization rates for pain in patients with SCD. This study is registered at www.clinicaltrials.gov as NCT00492531.

Mortality in adults with sickle cell disease and pulmonary hypertension

To the Editor: Dr Olshansky’s research letter on the accelerated aging of US presidents concluded that presidents do not age faster than other men. That may be true, but this study cannot demonstrate it due to a faulty comparison. Olshansky compared presidents’ actual age at death (adjusted for aging by subtracting 2 days for every day in office) against average life expectancy for men matched to the date of inauguration. However, the correct comparison is with men who have the same profile of risk factors for premature death. For example, as Olshansky notes, education, wealth, and access to medical care strongly influence life expectancy, and these factors undoubtedly contributed to longer lives for many presidents. The real question is if, despite these advantages, presidents’ lives were shortened. That requires comparison with other men of similar education, wealth, and access to medical care, and possibly with similar risk factors, such as smoking and alcohol consumption. Absent data permitting proper restriction, stratification, or control for confounding, the only conclusion that can be drawn is that presidents tend to be blessed with certain advantages that allow them to outlive men without those advantages.

Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension

Pulmonary hypertension is a common complication of sickle cell disease (SCD). In spite of the mild elevations in pulmonary artery pressures in these patients, the associated morbidity and mortality is high. In fact, in adult patients with SCD, pulmonary hypertension is emerging as the major independent risk factor for death. The aetiology of pulmonary hypertension is probably multifactorial, including haemolysis, impaired nitric oxide bioavailability, chronic hypoxaemia, thromboembolism, parenchymal and vascular injury because of sequestration of sickle erythrocytes, chronic liver disease and asplenia. Interestingly, pulmonary hypertension is emerging as a common, and probably, invariant sequella of lifelong haemolytic anaemia in other hereditary and acquired haemolytic diseases, such as thalassaemia, stomatocytosis and spherocytosis. There are currently limited specific data on the effects of any treatment modality for pulmonary hypertension in patients with SCD. It is likely that maximization of SCD therapy, in all patients, and treatment with selective pulmonary vasodilators and antiproliferative agents, in patients with severe disease, would be beneficial. A large trial evaluating the effects of therapy for pulmonary hypertension in the SCD population is clearly indicated.

An Official American Thoracic Society Clinical Practice Guideline: Diagnosis, Risk Stratification, and Management of Pulmonary Hypertension of Sickle Cell Disease

BACKGROUND In adults with sickle cell disease (SCD), an increased tricuspid regurgitant velocity (TRV) measured by Doppler echocardiography, an increased serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) level, and pulmonary hypertension (PH) diagnosed by right heart catheterization (RHC) are independent risk factors for mortality. METHODS A multidisciplinary committee was formed by clinician-investigators experienced in the management of patients with PH and/or SCD. Clinically important questions were posed, related evidence was appraised, and questions were answered with evidence-based recommendations. Target audiences include all clinicians who take care of patients with SCD. RESULTS Mortality risk stratification guides decision making. An increased risk for mortality is defined as a TRV equal to or greater than 2.5 m/second, an NT-pro-BNP level equal to or greater than 160 pg/ml, or RHC-confirmed PH. For patients identified as having increased mortality risk, we make a strong recommendation for hydroxyurea as first-line therapy and a weak recommendation for chronic transfusions as an alternative therapy. For all patients with SCD with elevated TRV alone or elevated NT-pro-BNP alone, and for patients with SCD with RHC-confirmed PH with elevated pulmonary artery wedge pressure and low pulmonary vascular resistance, we make a strong recommendation against PAH-specific therapy. However, for select patients with SCD with RHC-confirmed PH who have elevated pulmonary vascular resistance and normal pulmonary capillary wedge pressure, we make a weak recommendation for either prostacyclin agonist or endothelin receptor antagonist therapy and a strong recommendation against phosphodiesterase-5 inhibitor therapy. CONCLUSIONS Evidence-based recommendations for the management of patients with SCD with increased mortality risk are provided, but will require frequent reassessment and updating.

The relationship between the severity of hemolysis, clinical manifestations and risk of death in 415 patients with sickle cell anemia in the US and Europe

The intensity of hemolytic anemia has been proposed as an independent risk factor for the development of certain clinical complications of sickle cell disease, such as pulmonary hypertension, hypoxemia and cutaneous leg ulceration. A composite variable derived from several individual markers of hemolysis could facilitate studies of the underlying mechanisms of hemolysis. In this study, we assessed the association of hemolysis with outcomes in sickle cell anemia. A hemolytic component was calculated by principal component analysis from reticulocyte count, serum lactate dehydrogenase, aspartate aminotransferase and total bilirubin concentrations in 415 hemoglobin SS patients. Association of this component with direct markers of hemolysis and clinical outcomes was assessed. As primary validation, both plasma red blood cell microparticles and cell-free hemoglobin concentration were higher in the highest hemolytic component quartile compared to the lowest quartile (P≤0.0001 for both analyses). The hemolytic component was lower with hydroxyurea therapy, higher hemoglobin F, and alpha-thalassemia (P≤0.0005); it was higher with higher systemic pulse pressure, lower oxygen saturation, and greater values for tricuspid regurgitation velocity, left ventricular diastolic dimension and left ventricular mass (all P<0.0001). Two-year follow-up analysis showed that a high hemolytic component was associated with an increased risk of death (hazard ratio, HR 3.44; 95% confidence interval, CI: 1.2–9.5; P=0.02). The hemolytic component reflects direct markers of intravascular hemolysis in patients with sickle cell disease and allows for adjusted analysis of associations between hemolytic severity and clinical outcomes. These results confirm associations between hemolytic rate and pulse pressure, oxygen saturation, increases in Doppler-estimated pulmonary systolic pressures and mortality (Clinicaltrials.gov identifier: NCT00492531).

Severity of pulmonary hypertension during vaso‐occlusive pain crisis and exercise in patients with sickle cell disease

Pulmonary hypertension is associated with sudden death and is a risk factor for mortality in adult patients with sickle cell disease. The high mortality despite only mild‐to‐moderate increases in pulmonary vascular resistance remains an unresolved paradox. Accordingly, little is known about the cardiovascular effects of stressors, such as vaso‐occlusive pain crisis (VOC) and exercise, which may acutely increase pulmonary pressures and impair right heart function. We therefore evaluated pulmonary artery pressures by echocardiogram in 25 patients with sickle cell disease in steady‐state and during VOC, and by right heart catheterisation with exercise in a second cohort of 21 patients to determine whether pulmonary hypertension worsens during acute cardiopulmonary stress. TRV increased during VOC (P < 0·001), and the increased pulmonary pressures during VOC were associated with decreases in haemoglobin levels (P < 0·001), and increases in lactate dehydrogenase (P < 0·001) and plasma haemoglobin levels (P = 0·03). During exercise stress performed during cardiac catheterisation, mean pulmonary artery pressures (P < 0·001) and pulmonary vascular resistance increased (P < 0·001) in all subjects. These data suggest that acute elevations in pulmonary pressures during VOC or exercise may contribute to morbidity and mortality in patients with sickle cell disease.

Exercise capacity and haemodynamics in patients with sickle cell disease with pulmonary hypertension treated with bosentan: results of the ASSET studies

Doppler‐defined pulmonary hypertension (PH) in sickle cell disease (SCD) is associated with 40% mortality at 40 months. To assess the effect of bosentan in SCD‐PH, two randomized, double‐blind, placebo‐controlled, 16‐week studies were initiated. Safety concerns are particularly relevant in SCD due to comorbid conditions. ASSET‐1 and ‐2 enrolled patients with pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PH), respectively. Haemodynamics and 6‐min walk distance (6MWD) were obtained at baseline and week 16. The studies were terminated due to slow site initiation and patient enrolment (n = 26). Bosentan appeared to be well tolerated. Although sample sizes were limited, in ASSET‐1 at baseline, 6MWD correlated with cardiac output (CO; P = 0·006) with non‐significant inverse correlations between 6MWD and pulmonary vascular resistance (PVR; P = 0·07) and between 6MWD and right atrial pressure (P = 0·08). In ASSET‐2 at baseline, there was a non‐significant correlation between 6MWD and CO (P = 0·06). Due to limited sample sizes, efficacy endpoints were not analysed. However, in both studies, non‐significant increases in CO were observed with bosentan compared to placebo. Similarly, non‐significant decreases in PVR were observed with bosentan. Limited data in SCD‐PH suggest that a low 6MWD predicts a low CO. Standard‐dose bosentan appears to be well tolerated. Further investigation is warranted. Clinicaltrials.gov registration numbers NCT00310830, NCT00313196, NCT00360087.

Pulmonary Hypertension: An Increasingly Recognized Complication of Hereditary Hemolytic Anemias and HIV Infection

Modern health care has greatly increased longevity for patients with congenital hemolytic anemias (such as sickle cell disease and thalassemia) and human immunodeficiency virus (HIV) infection. It is estimated that 10% of patients with hemoglobinopathies and 0.5% of patients with HIV infection develop moderate to severe pulmonary hypertension. Pulmonary hypertension is a relentlessly progressive disease leading to right heart failure and death. Worldwide, there are an estimated 30 million patients with sickle cell disease or thalassemia and 40 million patients with HIV disease. Considering the prevalence of pulmonary vascular disease in these populations, sickle cell disease and HIV disease may be the most common causes of pulmonary hypertension worldwide. In this review, the available data on epidemiology, hemodynamics, mechanisms, and therapeutic strategies for these diseases are summarized. Because therapy is likely to reduce morbidity and prolong survival, efforts to screen, diagnose, and treat these patients represent a global health opportunity.