Discussion

CF is known to affect cardiac function. Systolic and diastolic LV dysfunction in CF patients has been well characterized. TTE evaluation in M-mode and Doppler echocardiography generally shows normal results in the early stages of cardiac involvement. This cardiac dysfunction in its subclinical stage may be characterized using methods such as TDI and STE. While TDI provides global parameters of ventricular function, STE may be used to selectively evaluate areal ventricular function. STE thus provides superior evaluation quality compared to TDI (10,11,12).
The baseline assessment in our study used physical examination, ECG and TTE. Systolic and diastolic LV functions were evaluated by TTE, Doppler, TDI and STE. While ventricular function as assessed by TTE appeared to be normal in all cases, pathologic findings of systolic and diastolic function were revealed by TDI and STE. Three recently published reports evaluate ventricular function in CF patients using STE. Two of these studied LV and RV function in adults; the third reports RV function in children as measured by TDI, strain and strain rate. All three studies compared TDI to STE. While ventricular function appeared to be normal in TTE, both techniques gave results confirming subclinical ventricular dysfunction (5,8,10).
PAPs as measured based on the tricuspit regurgitation (TR) jet was higher in the CF patients group than in controls. In their study of 35 adult CF patients with a mean age of 27.14 years, Thomas et al.found similarly high PAPs values (1). In this study, 13 patients diagnosed with pulmonary hypertension were found to have a PAPs higher than 35 mmHg. In our study, 6 of the CF patients had a PAPs value exceeding 35 mmHg. Özçelik et al. found the PAPs of pediatric CF patients (n=18, mean age 7.7) to be normal (8). LV compression by RV pressure elevation and an abnormal interventricular septal motion may also affect LV function (5).
In their report of an evaluation by TDI of the LV function of 8 patients with an average age of 35, Sellers et al . find a higher IVRT in CF patients compared to controls (10). While S-wave velocities may appear to be reduced in the patient group relative to the controls, no statistical significance was detected. The IVRT increase and S-wave velocity reduction in our CF patients was similarly not confirmed as statistically significant. TDI studies in CF patients have often been conducted in adult populations. The studies focused mainly on the IVRT increase and reduction in S-wave velocities. Özçelik et al. , who also evaluated LV function by TDI, could not detect a statistically significant difference between CF patients and controls with regard to E/A and E/e’ ratios and the MPI. While our results were similar for E/A and E/e’, a clear difference between patients and control subjects was evidenced for MPI, which was higher in the CF patients. MPI is a global indicator of LV function. It increases with the development of LV dysfunction. We interpreted it as an indicator of LV dysfunction.
STE is a new technique for evaluating ventricular function. The use of strain and strain rate parameters to evaluate regional deformation is an alternative to conventional echocardiography. Strain here expresses the percent dimensional deformation occurring in the object, while strain rate is the velocity of such deformation. Published reports have shown the superiority of these parameters over TTE and TDI in identifying ventricular dysfunction. This technique also seems superior to others in evaluating local ventricular function in addition to the global one (15,16,17).
In 41 patients with a mean age of 24, Labombarda et al. used strain and strain rate to evaluate LV free wall and septal function (5). They found free wall strain and strain rate and septal strain values to be significantly lower in patients compared to control subjects. While also appearing lower, the septal strain rate values were not significantly different than those of the controls. Sellers et al. compared peak systolic strain and strain rates in LV STE studies of adult CF patients to reference values and found them to be lower (10). We did a similar evaluation of LV strain and strain rate. While the two published STE reports evaluated ventricular function globally, our study was different in that it additionally measured local LV function. Of longitudinal myocardial strain measurements, APS and apex segments in A4C view, MIL and BAS in A3C, MI, API and MA in A2C were significantly reduced compared to controls. As for circumferential myocardial strain measurements, the API segment in the apical, the MI segment in the medial and the BI segment in the basal view were also significantly lower than in control subjects. While global and total global strain values appeared to be lower in 6 windows, this difference was not confirmed by a detected statistical significance. A statistically significant reduction was established in CF patients in five segments (MAL, BIL, MI, apex, APA) in the longitudinal, and five (BAS, BAL, MA, MIL, MIS) in the circumferential strain rate measurements.
LV dysfunction detected by TDI and STE in CF patients is attributed to different causes, primarily chronic hypoxia, chronic inflammation, myocardial fibrosis and RV dysfunction (5,18,19). LV compression by a dilated RV and interventricular septal motion abnormalities may also be counted as additional causes of this LV dysfunction. Elevated plasma angiotensin II and aldosterone levels may also be observed in CF patients. As a result, myositis with fibroblastic cell proliferation and an increased protein synthesis leading directly to myocardial fibrosis may develop. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists may thus be included in treatment plans (5,18,19). The CFTR has been characterized in myositis; it has a regulatory function on resting potentials, calcium-mediated depolarization and beta-adrenergic stimulation. Disruption of regulation mechanisms at the cellular level due to CFTR gene defects creates a favorable background for cardiac dysfunction (9,22). Hyperglycemia, which develops in 32% of CF patients over age 25 as a result of pancreatic beta-cell damage, may lead to myocardial function impairment through an increase in myocardial stiffness and impaired contractility caused by the increased protein glycosylation (20,21).
As CF patients benefit from an increased life expectancy thanks to effective treatment and lung transplantation, problems of myocardial dysfunction may be expected to be increase in frequency. Myocardial dysfunction in its subclinical stage may be characterized using methods such as TDI and STE. The ease of use of both these techniques and the availability of reference values may suggest their possible use in the follow-up of CF patients. Further studies are needed to determine whether these findings have clinical significance.

Study Limitations

Our study has several limitations. The first was the impossibility of using the STE software available to us to evaluate the three-dimensional structure of RV geometry, while RV dysfunction is the main focus in CF. The second was that the number of subjects was small. Finally, invasive hemodynamic data, exercise testing and cardiac MRI were not available at the same time for correlation with the echocardiographic measurements.
Contributors TD,SI is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. OK wrote the manuscript and researched data. NU, NY and NU reviewed/edited the manuscript. OK and MK performed the echocardiographic evaluation.