Methods

The 135 study subjects represented a cohort of clinically stable patients with SCD followed in the Sickle Cell Clinic at University of North Carolina hospitals from 2004 to 2010. Each clinic patient was offered enrollment, with the exclusion of those with evidence of heart failure, acute painful episodes, or episodes of acute chest syndrome within 4 weeks. Enrolled subjects were not required to have symptoms attributable to PH, allowing prospective screening without a referral bias. The institutional review board at the University of North Carolina approved the study, and all participants provided written informed consent.

The demographic and clinical characteristics of the study subjects were determined by interview and review of the medical records. Height, weight, blood pressure, and laboratory studies were measured at a single clinic visit. The body mass index (BMI) was calculated as the weight in kilograms divided by the height in meters squared. The seated blood pressure was measured with an automated device (Dinamap, GE Healthcare, Waukesha, Wisconsin) after a minimum of 10 minutes of rest, and the pulse pressure was calculated as the difference between systolic and diastolic pressures. Blood specimens were acquired for creatinine, hemoglobin, N-terminal probrain natriuretic peptide, and lactate dehydrogenase. The glomerular filtration rate was estimated using the abbreviated Modification of Diet in Renal Disease formula.

Echocardiograms were performed by 1 sonographer, using a protocol that included ≥3 cardiac cycles for each image. All studies were acquired with a Philips Sonos 5500 imaging platform and were stored in a digital format for subsequent analysis. In 2006, tissue Doppler imaging was added to the protocol after a software upgrade.

All echocardiographic measurements were made in triplicate and averaged from the representative beats, using off-line echocardiographic analysis software. To minimize temporal drift in measurement tendencies, all measurements were batched and quantified at the study close by 1 analyst who was unaware of the clinical characteristics of the study subjects. The measurements of the TRVs were made separately by a single experienced cardiologist. The following echocardiographic parameters were measured. First, the TRV was measured by continuous wave Doppler signals acquired from the parasternal short axis, right ventricular inflow, and apical 4-chamber views. Only waveforms with well-defined “envelopes” were measured. Pulmonary arterial systolic pressure was estimated using the modified Bernoulli equation and an assumed right atrial pressure of 10 mm Hg (pulmonary arterial systolic pressure = 4 × TRV ² + 10). Second, the velocity-time integral of systolic flow through the right ventricular outflow tract, a surrogate for the right ventricular stroke volume, was measured by pulsed wave Doppler with the sample volume positioned to obtain the “closing click” of the pulmonic valve. Third, the PVR was estimated using the noninvasive PVR index developed by Abbas et al : PVR index = 10 × (TRV/right ventricular outflow tract time-velocity integral). An index >1.75 was considered evidence of an elevated PVR. Fourth, the left and right ventricular areas were measured by planimetry from the apical 4-chamber view at end-diastole, tracing the endocardial borders and carefully avoiding papillary muscles and trabeculae. The right atrial area was traced by planimetry at midsystole. Fifth, the ratio of mitral inflow to mitral annular early diastolic velocities (E/e′) was calculated as an index of the left atrial pressure. The E-wave peak velocity was measured by pulsed wave Doppler of the transmitral diastolic flow, with the sample volume placed at the mitral leaflet tips. The e′ peak velocity was measured using tissue Doppler imaging with the sample volume placed in the lateral mitral annulus. Finally, the tricuspid annulus s′ velocity, an indicator of right ventricular function, was obtained by placing the tissue Doppler sample volume in the lateral tricuspid annulus and measuring the peak systolic velocity.

Because the expected upper limits of pulmonary arterial systolic pressure are influenced by age and obesity, we based the diagnosis of PH on gender-, age-, and BMI-specific normal reference ranges derived from a large clinical database of echocardiographically normal subjects. A patient was classified as having “suspected PH” if the TRV resulted in a calculated pulmonary arterial systolic pressure that exceeded the 95% confidence interval for both the gender- and age-specific reference range and the gender- and BMI-specific reference range. This approach minimizes the tendency to overestimate the prevalence of PH owing to marginally elevated TRVs in overweight and older patients. Because the TRV can usually be quantified in patients with significantly elevated pulmonary arterial pressure, we categorized patients with unmeasureable TRV as having “no PH.”

All statistical analyses were performed using SAS, version 9.2 (SAS Institute, Cary, North Carolina), with significance at the α = 0.05 level (2-sided). The mean values for PVR were calculated after dichotomizing PH, using the normal gender-, age-, and BMI-specific reference ranges for the calculated pulmonary arterial systolic pressure. Significance of the stratified analysis was determined using Wilcoxon rank sum testing. Linear correlations between TRV and echocardiographic, clinical, and laboratory variables were tested with Spearman regression analysis. Relationships between TRV and all 2-diminsional echocardiographic measurements were tested by Spearman partial correlation, after controlling for body surface area. Spearman partial correlation controlling for the glomerular filtration rate was used to test the relation between N-terminal probrain natriuretic peptide and TRV. The predictors of TRV were modeled using stepwise linear regression analysis, with gender, age, and BMI forced into the model and all parameter estimates standardized. Hemoglobin, lactate dehydrogenase, glomerular filtration rate, smoking, the E/e′ ratio, pulse pressure, and the right ventricular outflow tract velocity-time integral were entered into the model, along with the interaction terms. To meet the assumptions of normality, the TRV was log transformed.

Results

The characteristics of the study sample are summarized in Tables 1 and 2 . Despite the relatively young sample, significant chronic co-morbidities were observed in some subjects. Eighteen patients (13%) had stage 3 or 4 chronic kidney disease (glomerular filtration rate 15 to 59 ml/min/1.73 m ² ). Nineteen subjects (14%) were hypertensive, with a blood pressure measurement >140/90 mm Hg in the clinic.

Tricuspid regurgitation could be detected and the velocity quantified for 104 (77%) of the 135 screening echocardiograms; none of the remaining patients had echocardiographic findings (septal flattening or marked right ventricular enlargement and dysfunction) suggestive of PH. Of the 104 patients with quantifiable TRVs, 34 had a peak TRV suggesting PH, using the gender-, age-, and BMI-specific reference ranges for calculated pulmonary arterial systolic pressure. Thus, PH was suspected in 25% of patients. The distributions of the TRV values in the patients with and without suspected PH are illustrated in Figure 1 . Ten subjects were classified as “no PH” despite a TRV of ≥2.5 m/s, the partition value sometimes used to define PH. Most patients with suspected PH had mild TRV elevations; 20 (59%) had a TRV <3.0 m/s. The average PVR index was significantly greater in patients with suspected PH than in those without (1.4 ± 0.2 vs 1.2 ± 0.2, p = 0.0001) but was still well below the 1.75 cutoff for elevated PVR. Only 2 subjects with suspected PH (6%), with TRV values of 3.0 and 3.9 m/s, respectively, had an elevated PVR index.

Distributions of TRVs, stratified by “suspected PH” and “no PH” classification.

Invasive measurements of pulmonary hemodynamics were examined in a convenience sample of 12 subjects who had suspected PH (mean TRV of 3.1 m/s) and who underwent right heart catheterization as a part of their clinical evaluation within 3 years of the screening echocardiogram. PH (defined as a mean pulmonary arterial pressure of ≥25 mm Hg) was confirmed in all but 1 of the 12 patients, and only 1 patient had an elevated PVR (defined as PVR >3 Wood units).

The linear relations between TRV and a priori selected variables are listed in Table 3 . TRV correlated positively with age, BMI, E/e′ ratio, and right ventricular outflow tract velocity-time integral and negatively with hemoglobin and glomerular filtration rate. A trend was seen toward a linear association between TRV and lactate dehydrogenase that did not reach statistical significance. The left atrial pressure, right ventricular stroke volume, and hemoglobin (at a borderline level of statistical significance) were predictors of TRV in a multivariate regression model that explained 49% of the variability ( Table 4 ). For every 1.0-U increase in E/e′, the TRV increased by 12%. For every 1.0-g/dl increase in hemoglobin, the TRV decreased by 13%. Also, for every 1.0-cm increase in the right ventricular outflow tract velocity-time integral, the TRV increased by 6%.

Table 3

Simple correlations of tricuspid regurgitation jet velocity (TRV) with selected clinical and echocardiographic variables

Variable	Patients (n)	r Value	p Value
Age (years)	104	0.35	0.0003
Body mass index (kg/m 2 )	104	0.26	0.007
Hemoglobin (g/dl)	104	−0.22	0.02
Lactate dehydrogenase (U/L)	102	0.17	0.08
Glomerular filtration rate (ml/min/1.73 m 2 )	104	−0.47	<0.0001
E/e′ ratio	76	0.60	<0.0001
Right ventricular outflow tract velocity-time integral (cm)	103	0.39	<0.0001
Pulse pressure (mm Hg)	104	0.13	0.2

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