Background
The aim of this work was to evaluate myocardial strain analysis as a tool for the early detection of left ventricular functional changes in patients with cystic fibrosis.
Methods
A total of 42 consecutive patients (mean age, 24 ± 7.5 years; 52% men) diagnosed with cystic fibrosis and referred for echocardiographic cardiac function assessment were prospectively enrolled. A group of healthy age-matched and gender-matched volunteers ( n = 42) formed the reference population for echocardiographic comparisons.
Results
Left ventricular ejection fraction was conserved in both groups but was significantly lower in the cystic fibrosis group. Cardiac function assessment using Doppler tissue imaging parameters revealed that both systolic and diastolic measurements differed between the two groups: mitral peak systolic and diastolic velocities, as well as septal and lateral wall strain rates, were decreased in patients with cystic fibrosis, as was longitudinal strain of both the septal and lateral walls.
Conclusions
Using strain measurements, subclinical changes in left ventricular function were found in patients with cystic fibrosis. These parameters were correlated with the degree of pulmonary involvement severity. These findings have potentially significant clinical implications for the outcomes and follow-up of patients with cystic fibrosis, meriting further studies.
Cystic fibrosis is a life-threatening autosomal recessive disorder primarily affecting the Caucasian population. This systemic disease is responsible for multiple-organ dysfunction, possibly affecting the heart. Most studies focusing on cardiac function and cystic fibrosis pertain to right ventricular function. The effects of cystic fibrosis on the right ventricle have in fact been extensively studied by previous investigators, who have found abnormal right ventricular function and structure. Besides the negative effect of pulmonary hypertension on right ventricular function, other potential mechanisms have been proposed to explain right ventricular dysfunction in cystic fibrosis, including chronic hypoxemia, myocardial fibrosis, and recurrent infection. In case of such mechanisms, one would also expect left ventricular function to be impaired. Postmortem studies of the heart in cystic fibrosis have reported abnormalities of structure for both ventricles in 20% to 47% of patients, and several histologic studies have reported that myocardial fibrosis could affect the left ventricle. Nevertheless, left ventricular function has not been well investigated. Previous echocardiographic studies using standard two-dimensional and Doppler echocardiography have reported contradictory results in patients with cystic fibrosis. More recently, strain and strain rate derived from Doppler tissue imaging (DTI) have been proposed as parameters for the early detection of myocardial dysfunction. These measurements may help identify patients likely to develop left ventricular dysfunction. The longevity of patients with cystic fibrosis has extended, and the proportion of patients with cystic fibrosis who are middle-aged is increasing. A progressive process of left-heart dysfunction may have functional significance and could generate heart failure in this new population of patients. To establish whether adult patients with cystic fibrosis would develop impairment of left ventricular function, we compared myocardial strain and strain rate analysis in these patients with these parameters in a control population.
Methods
Study Population
We prospectively recruited patients with cystic fibrosis followed up at the Cystic Fibrosis Center of Basse-Normandie. Diagnoses had been confirmed using sweat chloride tests or molecular biology. To qualify for inclusion in the study, patients were required to be ≥16 years old, to be ambulatory and without signs of respiratory symptom worsening (no exacerbations requiring antibiotic therapy and no change in symptoms in the months before echocardiography), not to be on a lung transplantation waiting list, and to have no history of concurrent heart issues. Patients provided consent personally or through legal representatives. Forty-two healthy, age-matched and gender-matched volunteers formed the reference group for echocardiographic comparisons. These subjects were recruited from our institutional medicine and nursing schools. The inclusion criteria for healthy volunteers were no history of cardiovascular or pulmonary disease, no smoking habit, no drug intake, normal results on physical examination, normal oxygen saturation and arterial blood pressure, and normal routine echocardiographic findings.
Echocardiography Measurements
Echocardiographic studies were performed using an iE33 (Philips Medical Systems, Best, The Netherlands) equipped with a 3-MHz phased-array transducer and tissue Doppler technology. Each subject was examined in a semisupine left lateral position. The electrocardiogram was recorded continuously.
Global left ventricular function was assessed from an apical four-chamber view by measuring left ventricular ejection fraction (LVEF) using the modified monoplane Simpson’s rule. Left ventricular end-diastolic diameter, right ventricular end-diastolic dimension, and right ventricular anterior wall thickness were measured from the M mode from a left parasternal view. Left atrial area and right atrial area were measured from the apical four-chamber view. Left ventricular end-diastolic diameter, right ventricular end-diastolic dimension, right ventricular anterior wall thickness, and left and right atrial areas were normalized to body surface area. The mitral Doppler signal was recorded in the apical four-chamber view, with the Doppler sample volume placed at the tip of the mitral valve. The peak velocities of early (E) and late (A) filling waves and early/late filling ratios of peak velocities (E/A) were measured on the basis of transmitral flow velocities. Pulmonary systolic artery pressure was estimated from continuous-wave Doppler of tricuspid regurgitation using the Bernoulli equation. Tricuspid regurgitation velocity was recorded from the apical view and the parasternal short-axis view. Right atrial pressure was estimated by assessing the diameter of the inferior vena cava and the percentage decrease in its diameter during inspiration.
Myocardial systolic and diastolic velocities were recorded using the pulsed-wave DTI technique from an apical four-chamber view. The sample volume (4 mm thick) was placed at the basal level of the right ventricular and left ventricular free walls to measure tricuspid peak systolic velocity (St), mitral peak systolic velocity (Sm), and early mitral peak diastolic velocity (Em). For longitudinal strain and strain rate measurements, narrow sector angle acquisitions of the septal and lateral left ventricular walls were obtained in the apical four-chamber view with color DTI (minimum frame rate, 90 Hz) during brief apnea after expiration. Probe movements were maximally limited. Three consecutive beats were stored digitally and analyzed offline using dedicated research software (QLAB; Philips Medical Systems) capable of extracting strain and strain rate from tissue velocity data sets. During processing, manual tagging was performed, and curved M-mode lines (10-mm-thick area of interest) were drawn on the septal and lateral left ventricular walls to obtain the mean strain and strain rate values of both basal and medium myocardial segments. A tracking of the myocardial region of interest was activated to avoid blood flow artifacts. The peak systolic strain in each wall was determined as the nadir of the strain curves. The peak systolic and early peak diastolic strain rates were measured ( Figure 1 ).
Functional Respiratory Exploration and Genotype Assessment
Patients with cystic fibrosis underwent spirometry to measure the forced expired volume in 1 sec (FEV 1 ), which was expressed as a percentage of the predicted value for sex, age, and height. All patients with cystic fibrosis underwent genotyping.
Statistical Analysis
Nonparametric Mann-Whitney U tests were used to compare echocardiographic measurements between patients and controls and to assess the association with the F508del mutation among patients. The ability of echocardiographic parameters to discriminate diseased and healthy subjects was evaluated using receiver operating characteristic curve analyses. The receiver operating characteristic curve is a graphical method of assessing the characteristic of a diagnostic test. The area under the curve indicates the discriminant value of this test. Pearson’s correlation coefficients were calculated to assess any associations between FEV 1 and echocardiography measurements. To limit α error inflation due to the analysis of multiple echocardiographic parameters, P values were corrected using the Hochberg adjustment for multiple comparisons. Intraobserver and interobserver variability for septal and lateral strain and strain rate parameters were assessed using Bland-Altman analysis for a randomly chosen sample of 10 study patients. Observers were blinded to the results. In addition, intraclass correlation coefficients and their 95% confidence intervals were calculated to assess the reliability of the measurements of different DTI parameters. Statistical significance was defined as P < .05. Data were analyzed using SPSS version 15.0 for Windows (SPSS, Inc., Chicago, IL).
Results
Patients
Overall, 42 consecutive patients (mean age, 24 ± 7.5 years; 52% men) diagnosed with cystic fibrosis and referred for echocardiographic assessment of cardiac function were enrolled in this prospective cohort. At the time of echocardiography, all patients were in stable respiratory condition and showed no signs of heart failure. Severe lung disease, defined as FEV 1 < 30%, was present in 10 patients (23.8%), and oxygen supplementation was necessary in four patients (9.5%) with desaturation. The study population’s mean body mass index was 19.7 ± 2.3 kg/m 2 compared with 21.1 ± 2.3 kg/m 2 in the control group. Seven patients had diabetes (16.7%), and three had cirrhosis (7.1%).
Echocardiographic Measurements
Echocardiography was successfully performed in 41 patients with cystic fibrosis. One patient was excluded from analysis because of image quality unsuitable for quantitative echocardiography. The mean LVEF was lower in patients with cystic fibrosis than in the control group ( Table 1 ), though LVEF was conserved in both groups, and only one patient with cystic fibrosis had an LVEF < 55% ( Figure 2 ). Left ventricular end-diastolic diameter and left atrial area were higher in patients with cystic fibrosis, without reaching statistical significance; right ventricular anterior walls were thicker in patients with cystic fibrosis; and right ventricular end-diastolic dimension and right atrial area were significantly higher in the cystic fibrosis group ( Table 1 ). Pulmonary systolic artery pressure was significantly higher in the cystic fibrosis group, but no patient had severe pulmonary hypertension (cystic fibrosis group, 25 ± 6.2 mm Hg; control group, 19.6 ± 2.8 mm Hg; P < .001). St was significantly lower in the cystic fibrosis group ( Table 1 ).
| Variable | Patients with cystic fibrosis ( n = 41) | Normal controls ( n = 42) | P ∗ |
|---|---|---|---|
| Standard parameters | |||
| LVEF (%) | 61.5 ± 5.5 | 65.2 ± 3.6 | .005 |
| LVEDD (mm/m 2 ) | 28 ± 2 | 28 ± 1.8 | .075 |
| LA area (cm 2 /m 2 ) | 9.8 ± 2,7 | 8.8 ± 2 | .065 |
| E/A ratio | 1.4 ± 0.4 | 1.5 ± 0.4 | .27 |
| RVEDD (mm/m 2 ) | 14 ± 3 | 10 ± 4 | .005 |
| RVAW thickness (mm/m 2 ) | 0.4 ± 0.1 | 0.3 ± 0.1 | .02 |
| RA area (cm 2 /m 2 ) | 9 ± 2 | 8 ± 1.5 | .04 |
| DTI parameters | |||
| Systolic function | |||
| Septal wall | |||
| Strain (%) | −11.4 ± 3.7 | −18.8 ± 3.7 | <.001 |
| Ssr (1/sec) | −0.9 ± 0.5 | −1.2 ± 0.6 | .069 |
| Lateral wall | |||
| Strain (%) | −10.2 ± 4.4 | −17.2 ± 4.6 | <.001 |
| Ssr (1/sec) | −0.7 ± 0.4 | −0.9 ± 0.4 | .036 |
| Sm (cm/sec) | 11.0 ± 2.1 | 11.9 ± 1.6 | .069 |
| St (cm/sec) | 11.8 ± 2.2 | 14.5 ± 1.2 | <.001 |
| Diastolic function | |||
| Septal wall | |||
| Esr (1/sec) | 1.2 ± 0.7 | 1.5 ± 0.6 | .003 |
| Lateral wall | |||
| Esr (1/sec) | 1.4 ± 0.7 | 1.8 ± 0.8 | .036 |
| Em (cm/sec) | −16.5 ± 3.3 | −19.4 ± 2.7 | <.001 |
For cardiac function assessment using DTI parameters, both systolic and diastolic measurements differed between the two groups: Sm and Ea ( Figure 3 ), as well as septal and lateral wall strain rates (peak systolic strain rate and early peak diastolic strain rate), were decreased in patients with cystic fibrosis ( Table 1 ). Longitudinal strain for the septal ( Figure 4 A) and lateral ( Figure 5 A) walls was also decreased in patients with cystic fibrosis compared with control patients. The diagnostic performance of longitudinal strain for both the septal and lateral walls, along with the proposed cutoff values, is presented as receiver operating characteristic curves ( Figures 4 B and 5 B, respectively).
Relationship Between Myocardial Strain Parameters and FEV 1
Among longitudinal strain parameters, septal ( Figure 6 A) and lateral ( Figure 6 B) wall peak systolic strain rates were moderately correlated, early peak diastolic strain rate was not correlated (results not shown), and septal wall strain was weakly correlated ( r = −0.39, P = .01) with FEV 1 .
Strain and Strain Rate in Relation to the F508del Mutation
Strain parameters did not differ in relation to the F508del mutation (21 patients [50% of the sample population]).
Reproducibility and Repeatability
Ten patients were randomly selected for the analysis of interobserver and intraobserver reproducibility. With our method of measure, strain and strain rate for the septal and lateral walls were reliable parameters for both reproducibility and repeatability. The results are shown in Table 2 and Figures 7 and 8 .
