Increased QT dispersion: a negative prognostic finding in chronic obstructive pulmonary disease

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a highly prevalent syndrome, deeply affecting the cardiovascular system as well as the lungs. We investigated the prognostic role of the QT interval and QT dispersion (QTD) in predicting all-cause, respiratory and cardiovascular mortality in COPD, and the relationship between these electrocardiographic parameters and pulmonary function in a prospective longitudinal study. METHODS: We studied 246 COPD patients without significant co-morbidities, with a mild to moderate functional impairment, admitted to the Department of Internal Medicine from January 1995 to December 2001, performing a 5-year mean follow-up (5-116 months) up to August 2004. After clinical stabilisation, an electrocardiogram and functional respiratory tests were obtained, allowing measurement of the QT interval and QTD, forced vital capacity (FVC), forced expiratory volume at 1 s (FEV1), inspiratory capacity, FEV1/FVC ratio, partial oxygen pressure and partial carbon dioxide pressure in arterial blood. RESULTS: At the end of the follow-up period, 81 patients were dead, 165 still alive; 36 died because of respiratory causes, 23 because of cardio-cerebrovascular events, 21 because of cancer (mainly lung cancer). A significant high incidence of sudden cardiac death was observed. QTD and QTcD showed a significant relationship with respiratory functional parameters. Maximal QT interval, QTcD and QTD appear to be independent predictors of all-cause, cardiovascular and respiratory mortality (relative risk 1.94, 3.22, 2.88, respectively). Age > 65 years, partial oxygen pressure < 60 mmHg and inspiratory capacity < 80% of the predicted value were the only other independent predictive parameters. CONCLUSIONS: Maximal QT interval, QTD and QTcD are independent predictors of mortality. A significant incidence of cardiac sudden death was observed. These findings suggest the need for a global and multidisciplinary risk assessment in COPD patients. Intriguing relationships between the QTD and functional respiratory parameters were also observed.     

Hemolytic anemia-associated pulmonary hypertension in sickle cell disease

Pulmonary hypertension is one of the leading causes of death in adult sickle cell patients, with a prevalence of 20% to 40%. Although these patients have lower pulmonary pressures than patients with primary pulmonary hypertension, both groups suffer high 2-year mortality rates. Pulmonary hypertension may go undetected until the disease is advanced. Therefore, all adult patients with sickle cell disease should be screened with transthoracic Doppler echocardiogram and the tricuspid regurgitant jet (TRJ) velocity measured to estimate pulmonary artery pressures. A regurgitant jet (RJ) velocity of 2.5 m/s or higher establishes diagnosis and suggests a high risk of death (rate ratio of 10.1; CI= 2.2-47). Basic and epidemiologic studies suggest that pulmonary hypertension in sickle cell disease is mechanistically linked to chronic hemolytic anemia. Hemolysis results in the release of hemoglobin and arginase from the erythrocyte, increasing the consumption and decreasing the production of nitric oxide (NO), respectively. NO is a critical regulator of vasodilation and vascular homeostasis whose inactivation produces vasoconstriction and proliferative vasculopathy. Finally, we review suggested therapies including the established treatments and new pulmonary vasodilator and remodeling agents in the management of pulmonary hypertension in hemolytic anemias.     

Cerebrovascular disease associated with sickle cell pulmonary hypertension

In patients with sickle cell disease, anemia is a recognized risk factor for stroke, death, and the development of pulmonary hypertension. We have proposed that hemolytic anemia results in endothelial dysfunction and vascular instability and can ultimately lead to a proliferative vasculopathy leading to pulmonary hypertension. Consistent with this mechanism of disease, we now report a case series of six patients with obliterative central nervous system vasculopathy who also have pulmonary hypertension and high hemolytic rate. These patients, identified in the course of a prospective screening study for pulmonary hypertension, presented with neurological symptoms prompting neuroimaging studies. Compared to 164 other patients of similar age in the screened population, those with newly diagnosed or clinically active cerebrovascular disease have significantly lower hemoglobin levels and higher levels of lactate dehydrogenase. A review of the literature suggests that many clinical, epidemiological, and physiological features of the arteriopathy of pulmonary hypertension closely overlap with those of stroke in sickle cell disease, both known to involve proliferative vascular intimal and smooth muscle hypertrophy and thrombosis. These cases suggest that cerebrovascular disease and pulmonary hypertension in sickle cell disease share common mechanisms, in particular, reduced nitric oxide bioactivity associated with particularly high-grade hemolysis. Clinicians should suspect occult cerebrovascular disease in sickle cell patients with pulmonary hypertension.     

Fatal small-bowel necrosis and pulmonary hypertension in sickle cell disease

Initial enthusiasm for the use of vasodilators to improve pulmonary hemodynamics and symptomatic status in pulmonary hypertension of diverse etiologies has been tempered by the high incidence of serious complications, especially hypotension. However, the unrelenting hypoxia of pulmonary hypertension without treatment and the improved pulmonary hemodynamics and symptomatic states of some patients during vasodilator therapy provide the rationale for a therapeutic test of vasodilators in hemodynamically monitored patients. We report that vasodilator therapy in a patient with severe hypoxia due to pulmonary hypertension and sickle cell crisis was fatally complicated by hypotension and extensive small-bowel infarction.     

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.     

肺动脉高压患者心率校正QT间期和QT离散度的研究

目的:检测肺动脉高压(pulmonary hypertension,PH)患者的心率校正的QT间期(heartrate-corrected QT interval,QTc)和QTc离散度(QTc dispersion,QTcd),并评价其与肺动脉压力的关系。方法:入选2003年12月至2008年7月因初步诊断为PH而进行右心导管术的患者。记录静息12导联心电图,手工测量QT间期并用Bazett公式进行校正。根据平均肺动脉压,将患者分为对照组,轻-中度PH组和重度PH组。结果:共入选201例患者。男性患者的QTc和QTcd在3组间差异无统计学意义。女性患者中,重度PH组的QTc比对照组高〔(436.1±39.4)msvs.(407.6±24.8)ms,P=0.037〕,重度PH组的QTcd(68.5±20.9)ms高于对照组(45.1±12.6)ms和轻-中度组(58.6±14.7)ms(P=0.002;P=0.003)。此外,女性患者的QTc和QTcd与平均肺动脉压正相关(r=0.207,P=0.03;r=0.236,P=0.012)。结论:本组资料中女性PH患者的QTc和QTcd与平均肺动脉压正相关,且在重度PH患者中显著增高,有待于进一步探讨。     

Pulmonary hypertension in sickle cell disease

BACKGROUND: Recurrent vaso-occlusive episodes lead to progressive end-organ damage in patients with sickle cell disease. We sought to determine the prevalence of pulmonary hypertension in adult patients with sickle cell disease and to identify factors associated with this life-threatening complication. METHODS: Sixty patients (> or =18 years of age; mean [+/- SD] age, 37 +/- 13 years) followed at a University Medical Center were evaluated. They were selected by a systematic sampling of patients presenting to the clinic for routine follow-up visits. All enrolled subjects underwent a clinical examination, Doppler echocardiography, pulmonary function tests, and hematologic tests during a single visit. Pulmonary hypertension was defined using an age- and body mass index-adjusted nomogram. RESULTS: The prevalence of pulmonary hypertension was 30% (18/60). Ten patients had mild pulmonary hypertension (up to 44 mm Hg), 5 had moderate pulmonary hypertension (45 to 74 mm Hg), and 2 had severe pulmonary hypertension (> or =75 mm Hg). In a logistic regression model, both lower fetal hemoglobin level and lower systolic blood pressure were associated with the presence of pulmonary hypertension. CONCLUSION: We found that the prevalence of pulmonary hypertension in adult patients with sickle cell disease was substantial, particularly in those with lower levels of fetal hemoglobin and lower systolic blood pressure.     

Hemodynamic characteristics and predictors of pulmonary hypertension in patients with sickle cell disease

Pulmonary hypertension is a common co-morbidity of sickle cell disease with an associated increased mortality risk, but its etiology is not well-understood. To evaluate the hemodynamic characteristics, clinical predictors, and cardiovascular manifestations of elevated pulmonary arterial pressure in this population, we performed noninvasive hemodynamic assessments of 135 patients with sickle cell disease using Doppler echocardiography. A diagnosis of pulmonary hypertension was determined by gender-, age-, and body mass index-specific normal reference ranges for tricuspid regurgitation jet velocities (TRVs). A high TRV was noted in 34 patients (25%). Pulmonary vascular resistance was elevated in only 2 (6%) of the 34 patients with suspected pulmonary hypertension but was significantly greater than in those with normal TRV. On univariate regression, the TRV correlated with age, body mass index, left atrial pressure, and right ventricular stroke volume and was negatively associated with hemoglobin and glomerular filtration rate. The left atrial pressure, right ventricular stroke volume, and hemoglobin remained independent predictors of TRV in a multivariate model. A greater TRV was also associated with larger right ventricular and right atrial chamber sizes and greater N-terminal probrain natriuretic peptide levels. In conclusion, our results suggest that the mild elevation in TRV often observed in patients with sickle cell disease is rarely associated with a high pulmonary vascular resistance and that multiple factors-including the compensatory high output state associated with anemia, pulmonary venous hypertension, and pulmonary vasculopathy-can contribute to an elevated pulmonary arterial pressure in these patients.     

Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease

Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 ± 22 to 398 ± 18 m at 5–6 months, P  < 0·05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44–38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD.     

Increased adhesive properties of eosinophils in sickle cell disease

OBJECTIVE: A role for leukocytes in vasoocclusion is becoming increasingly recognized. Here we investigate a possible role for the eosinophil in sickle cell anemia (SCA). PATIENTS AND METHODS: Eosinophils were isolated from whole blood samples of 59 steady-state SCA homozygous SS and control individuals using Percoll gradient separation, followed by immunomagnetic sorting. Adhesion of cells to FN was evaluated using static adhesion assays (60 min, 37 degrees C, 5% CO2) and eosinophil adhesion molecular expression was observed by flow cytometry. RESULTS: SCA patients presented significantly elevated absolute eosinophil numbers. Furthermore, eosinophils isolated from these individuals demonstrated a significantly greater adhesion ( approximately 70% increased) to fibronectin (FN) than normal eosinophils in static adhesion assays. Coincubation of eosinophils with integrin-blocking monoclonal antibodies in adhesion assays showed that an association of the VLA-4, LFA-1, and Mac-1 integrins mediate the adhesion of SCA eosinophils to FN. Flow cytometry demonstrated that the expression of these integrins, however, was unaltered on the surface of SCA eosinophils, suggesting that the increased SCA eosinophil adhesion is a consequence of increased integrin affinity or avidity. SCA eosinophil adhesion to FN was further increased by the cytokine, GM-CSF, indicating that inflammation processes may further stimulate eosinophil adhesion in these patients. CONCLUSION: We report that eosinophil numbers may be significantly increased in SCA individuals and that these cells appear to exist in an activated state. Such alterations may indicate a role for the eosinophil in the vasooclusive process.     

Identification of genetic polymorphisms associated with risk for pulmonary hypertension in sickle cell disease

Up to 30% of adult patients with sickle cell disease (SCD) will develop pulmonary hypertension (pHTN), a complication associated with significant morbidity and mortality. To identify genetic factors that contribute to risk for pHTN in SCD, we performed association analysis with 297 single nucleotide polymorphisms (SNPs) in 49 candidate genes in patients with sickle cell anemia (Hb SS) who had been screened for pHTN by echocardiography (n = 111). Evidence of association was primarily identified for genes in the TGFβ superfamily, including activin A receptor, type II–like 1 (ACVRL1), bone morphogenetic protein receptor 2 (BMPR2), and bone morphogenetic protein 6 (BMP6). The association of pHTN with ACVRL1 and BMPR2 corroborates the previous association of these genes with primary pHTN. Moreover, genes in the TGFβ pathway have been independently implicated in risk for several sickle cell complications, suggesting that this gene pathway is important in overall sickle cell pathophysiology. Genetic variation in the β-1 adrenergic receptor (ADRB1) was also associated with pHTN in our dataset. A multiple regression model, which included age and baseline hemoglobin as covariates, retained SNPs in ACVRL1, BMP6, and ADRB1 as independently contributing to pHTN risk. These findings may offer new promise for identifying patients at risk for pHTN, developing new therapeutic targets, and reducing the occurrence of this life-threatening SCD complication.     

Hemodynamic and functional assessment of patients with sickle cell disease and pulmonary hypertension

RATIONALE: Although pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) associated with high mortality, there exist few data characterizing hemodynamics and cardiopulmonary function in this population. OBJECTIVES: To characterize hemodynamics and cardiopulmonary function in patients with SCD with and without PH. METHODS: Patients with SCD with PH (n = 26) were compared with control subjects with SCD but without PH (n = 17), matched for age, hemoglobin levels, and fetal hemoglobin levels. MEASUREMENTS AND MAIN RESULTS: Upon catheterization, 54% of the patients with PH had pulmonary arterial hypertension, and 46% had pulmonary venous hypertension. When compared with control subjects, patients with PH exhibited lower six-minute-walk distance (435 +/- 31 vs. 320 +/- 20 m, p = 0.002) and oxygen consumption (50 +/- 3% vs. 41 +/- 2% of predicted, p = 0.02), and also had mild restrictive lung disease and more perfusion abnormalities on radionuclide lung scans. The six-minute-walk distance in this population inversely correlated with tricuspid regurgitant jet velocity (r = -0.55, p < 0.001), and mean pulmonary artery pressure (r = -0.57, p < 0.001), and directly correlated with maximal oxygen consumption (r = 0.49, p = 0.004), even after adjustment for hemoglobin, supporting an independent contribution of increasing pulmonary artery pressures to loss of exercise capacity. CONCLUSIONS: Patients with SCD-associated PH have both pulmonary arterial and venous PH associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia. These data support the use of the six-minute-walk distance as an index of PH and cardiopulmonary function in patients with SCD.     

Cardiopulmonary imaging, functional and laboratory studies in sickle cell disease associated pulmonary hypertension

Pulmonary hypertension (PHT) occurs in approximately 30% of adults with sickle cell disease (SCD) and is an independent risk factor for early death. In this study, we aimed to determine the value of general laboratory testing, plain chest radiography, electrocardiography (ECG), high-resolution computer tomography (HRCT) of the thorax, pulmonary function testing, and plasma N-terminal brain natriuretic peptide (NT-proBNP) and brain natriuretic peptide (BNP) in patients with SCD-related PHT. A cohort of 85 ambulatory sickle cell patients were prospectively screened for PHT with echocardiography (defined as a tricuspid regurgitation flow velocity of > or =2.5 m/sec). All patients were systematically evaluated by the aforementioned diagnostic tests comparing patients with and without PHT. The prevalence of PHT was 41% in HbSS/HbSbeta(0)-thalassemia patients and 13% in HbSC/HbSbeta(+)-thalassemia patients. No statistically significant differences were detected in ECG, chest radiography, HRCT, and pulmonary function testing between patients with and without PHT. The degree of anemia and renal dysfunction, but not the presence of PHT, were the most important determinants of plasma (NT-pro)BNP levels. The performed imaging and functional studies do not seem to be of value in identifying etiological conditions (such as airflow obstruction or parenchymal lung disease) nor do they offer clues to the presence of mild PHT in SCD.     

Clinical differences between children and adults with pulmonary hypertension and sickle cell disease

Pulmonary hypertension (PHT) is an important co-morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at the Children's Hospital & Research Center Oakland were reviewed to determine clinical variables associated with obtaining echocardiographic screening for PHT, clinical associations of PHT, and associated mortality following diagnosis in adults and children with SCD. In this cohort, patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms, however the diagnosis of PHT was often unrecognized. A different clinical phenotype for PHT in adults versus children was identified. Associations with PHT for adults included age, renal and lung disease, hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective. Surprisingly, for children, a history of sepsis, along with a history of ACS, or obstructive lung disease were associated with PHT. Survival analysis found significant mortality for PHT, with a hazard ratio of 17·3 (95% confidence interval 4·9–60·4). The divergent clinical spectrum for PHT between adults and children may point to different age-specific mechanisms or biological expression of PHT.