Introduction

Familial Mediterranean fever (FMF) is an autosomal recessive disease manifested by recurrent attacks of peritonitis, pleuritis, pericarditis, synovitis/arthritis, fever, and arthritis and characterized by clinical, histological, and laboratory evidence for localized and systemic inflammation. Although FMF presents with exacerbations and attack-free periods, we along with others have demonstrated the presence of sustained inflammation during attack-free periods of FMF patients [1–4]. In the contrary to other rheumatologic disorders, there have been a limited number of studies investigating the cardiac involvement in patients with FMF, although the disease may carry a potential for cardiovascular disorders because of sustained inflammation during its course [1–3]. With respect to previous literature, cardiac involvement of FMF was limited by pericardial manifestation. In a cohort study, the frequency of pericarditis was reported in a ratio of 1.4% [5]. Until now, there is no data interrogating cardiac function changes in patients with FMF.

Recent developments in cardiac ultrasound permitted more precise echocardiographic assessment of cardiac functions. Tissue Doppler imaging (TDI) is a recently developed technique for the quantization of myocardial contraction and relaxation in the left ventricle using low-velocity pulsed wave Doppler interrogation of the myocardium [6, 7]. Particularly, tissue Doppler-derived myocardial performance index (MPI), which has been shown to have important clinical use as a predictor of morbidity and mortality in patients with heart failure, was also used. MPI is superior to conventional methods because it is relatively unaffected by significant changes in preload and afterload. Besides, MPI might be more accurate and reflective of overall cardiac dysfunction than systolic and diastolic measures alone. Therefore, new modality may be more sensitive for detecting subclinical abnormalities [8, 9]. For this reason, these methods were preferred to assess overall cardiac functions.

In the present study, we used high usefulness TDI for detailed analysis of cardiac changes in FMF patients.

Materials and methods

The study population included 30 patients with FMF (11 men, 19 women; mean age, 35 ± 7 years, mean disease duration, 15.4 ± 7.6 years) and 30 healthy subjects as controls (12 men, 18 women; mean age, 33 ± 7 years). The diagnosis of FMF was established according to the Tell–Hashomer criteria [4]. The demographic characteristics of the patients and the controls are given in Table 1, and clinical features of the patients are given in Table 2.

Table 1 The demographic of patients with familial Mediterranean fever (FMF) and healthy controls
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Table 2 Clinical features of patients with familial Mediterranean fever (n = 30)
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All patients were using regular colchicine 1–1.5 mg/day, and all of them were in the attack-free period during echocardiographic evaluation. None of the patients had hypertension, renal failure, diabetes mellitus, left ventricle (LV) ejection fraction lower than 60%, severe valvular regurgitation and moderate or severe valvular stenosis, coronary artery disease, chronic obstructive pulmonary disease, atrial fibrillation, or aortic disease.

Echocardiography

All patients underwent complete transthoracic echocardiographic studies including two-dimensional, color flow, and spectral Doppler as well as TDI with a GE-Vingmed Vivid 7 system (GE-Vingmed Ultrasound AS, Horten, Norway) using a 2.5–3.5-MHz transducer. Echocardiographic measurements were taken with patients in the left lateral decubitus position. M-mode traces were recorded at the speed of 50 mm/s and the Doppler signals at 100 mm/s. Three consecutive cycles were averaged for every parameter. LV diameters, LV ejection fraction, and the left ventricular mass index were also determined from M-mode traces recorded from the parasternal long-axis view according to the established standard [10]. The LV function was also evaluated by the apical displacement of the mitral annulus by M-mode echocardiography in terms of excursion [11]. By this method, mitral lateral annular plane systolic excursion (MLAPSE) is calculated. Furthermore, tissue Doppler systolic velocity of the lateral (S m) annulus was measured for the assessment of the LV systolic function [12].

To measure the diastolic function of LV, transmitral diastolic flow Doppler tracing was imaged in the apical four-chamber view by using pulsed Doppler echocardiography with the sample volume sited at the tip of the mitral leaflets. The peak early transmitral-filling velocity during early diastole (E), peak transmitral atrial filling velocity during late diastole (A), deceleration time of E velocity, and relaxation time were used as left ventricular diastolic function parameters. Diastolic function was also evaluated by tissue Doppler indices. Peak early (E′m) and atrial velocities (A′m) were measured by using the sample volume that was placed at the lateral annulus of the mitral leaflets (E′m, A′m) in the apical four-chamber view [13, 14]. The LV MPI was calculated as (a − b)/b, where a being equal to the sum of contraction time, the Systolic ejection time, and the relaxation time, and b was measured as the duration of the systolic annular velocity [6, 7].

Right ventricle (RV) systolic function was assessed by two methods; The first one is tricuspid annular plane systolic excursion (TAPSE), by two-dimensional difference of end-diastolic and end-systolic lines (in mm) traced between the center of the ultrasound fan origin and the junction of right ventricular lateral tricuspid annulus, in apical four-chamber view, as described by Kaul et al. [15]. The tissue Doppler systolic velocity at tricuspid lateral annulus (S t) was used as second method. RV diastolic function was measured by the method that is described as LV regarding the sample volume of Doppler that was symmetrically set at the tricuspid valve instead of the mitral valve (tricuspid E velocity, tricuspid A velocity S t, E′t, A′t). The intraobserver variability of echocardiographic measurements was less than 5%, and all examinations were performed by an experienced cardiologist (Tavil) who had no knowledge of the patient’s clinical information.

Statistical analysis

Continuous variables were given as mean ± SD; categorical variables were defined as percentage. Independent-sample t test was used to compare the study variables between FMF patients and control subjects. Correlation analyses were performed using the Pearson coefficient of correlation. A probability value of p < 0.05 was considered significant, and two-tailed p values were used for all statistics. All statistical analyses were carried out using a statistical software (SPSS, version 10.0 for Windows; SPSS, Chicago, IL).

Results

According to the basic clinical characteristics, both groups of the study were similar with regard to age, body mass index, heart rate, cholesterol level, and smoking status (Table 1).

The results of conventional echocardiographic examinations are summarized in Table 3. The LV diameters, ejection fraction, LV diastolic filling velocities (mitral E and A), and MLAPSE values were comparable in FMF patients and healthy controls except for the increased mitral relaxation time in FMF patients. RV diameters, TAPSE, and tricuspid diastolic velocities were also similar in both groups.

Table 3 Two-dimensional and Doppler echocardiographic measurements
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Tissue Doppler characteristics of the study groups are shown in Table 4. Systolic velocities of the both ventricles (S m, S t) were not different between the groups. Likewise, E′t, A′t, and E′t/A′t values were also comparable between the groups. On the other hand, there were statistically significant differences regarding E′m, A′m, and E′m/A′m values. LV MPI, which was calculated from tissue Doppler systolic time intervals, was found similar between two groups.

Table 4 Pulsed wave Doppler tissue imaging measurements
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There were no significant correlations between the disease duration, clinical features, and echocardiographic parameters.

Discussion

In this study, we have investigated the cardiac functions in FMF patients by using high usefulness TDI. We have demonstrated that although systolic functions were comparable in the patients and controls, left ventricular diastolic function indices were impaired in FMF patients.

Previous studies have suggested the potential for chronic inflammatory diseases to impair vascular and cardiac function [16, 17]. Patients with rheumatoid arthritis have cardiac systolic and diastolic abnormalities despite absence of clinical evidences of cardiovascular disease [18]. Likewise, similar cardiac disturbances have been demonstrated in subjects with systemic lupus erythematosus and Behcet disease. In these diseases, systolic dysfunction and cardiac failure are often preceded by alterations in LV diastolic function [17, 19]. The main pathophysiologic mechanism, accused for developing cardiac deteriorations in those disorders, is the inflammation, which may accelerate the development of atherogenesis, thrombosis, and congestive heart disease.

Despite the presence of recurrent and sustained inflammation in FMF, the effects of inflammation on cardiovascular system remained unclear in those patients. There is only one study that evaluated the prevalence of cardiac disorders in FMF patients. The prevalence of ischemic heart disease in 290 FMF patients was comparable with their spouses and with the matched general population in Israel [20]. However, more recently, a number of studies raised the possibility of increased risk for heart diseases in FMF patients. We demonstrated that various markers of endothelial activation and/or injury including soluble vascular endothelial growth factor receptor 1 and thrombomodulin were increased in patients with FMF [21, 22]. It was reported that FMF was a significant risk factor for both increased intima media thickness of carotid arteries and decreased endothelium-dependent flow-mediated dilation of the brachial artery [23]. Aortic pulse wave velocity was higher in patients with FMF than in control subjects [24]. Carrying the FMF-associated mutation M694V may increase the risk to develop acute myocardial infarction [25]. Different ethnic groups vary in the frequency of Mediterranean fever (known as MEFV) gene mutations, the extent of severity of the disease, and the rates of amyloidosis [26]. Hence, cardiovascular risk because of FMF might differ in different populations. Moreover, there is no data regarding the prevalence of congestive heart disease in FMF. In this study, we investigated cardiac involvement in those patients with sophisticated echocardiography. Our findings are in accordance with those abovementioned previous studies in systemic lupus erythematosus and rheumatoid arthritis. Left ventricular diastolic function was abnormal in subjects with FMF, although systolic function was normal. These differences were determined by tissue Doppler velocities, while the majority of conventional Doppler parameters were normal apart from myocardial relaxation, which was longer in FMF patients supporting diastolic dysfunction in those patients. Additionally, MPI has the trend to be impaired, but this difference has not reached significant level.

Several mechanisms may be responsible for diastolic dysfunction in FMF. One of the main possible mechanisms is systemic inflammation that is an important factor in the development of early atherosclerosis. The presence of sustained inflammation in patients with FMF might have a role in the chronic development of atherosclerosis. There is evidence for the presence of subclinical atherosclerosis in FMF patients, demonstrated with increased intima media thickness of carotid arteries and decreased endothelium-dependent flow-mediated dilation of the brachial artery [23]. Several lines of experimental evidence are suggesting that elevated levels of C-reactive protein (CRP) and serum amyloid A (SAA) are strongly associated with the development of atherosclerosis and its complications. It was previously shown that a sustained long-term elevation level of SAA reflects subclinical inflammation with high sensitivity, a prerequisite for the development of AA amyloidosis [27, 28]. Thus, subclinical amyloidosis might be another factor in the etiology of diastolic dysfunction in this disease. It is widely accepted that FMF may be complicated by AA-type (secondary) amyloidosis, which mainly affects the kidneys, causing proteinuria and leading to renal failure [29]. Amyloidosis was not thought of in the differentiation of etiology for the reason that the involvement of the heart may not be seen in this type of amyloidosis. Furthermore, increased levels of CRP have a causative and predictive role in progressing future myocardial ischemia. Briefly, induction of the atherosclerotic process may cause the diastolic abnormality.

The other possible pathophysiological link is elevated levels of circulating cytokines such as tumor necrosis factor alpha, soluble interleukin 2 receptor, interleukin 1β, interleukin 6, interleukin 8, and interleukin 12, which may cause endothelial dysfunction that inversely affects arterial vasculature to accommodate the increased afterload. Those cytokines remain elevated in FMF patients, even in the attack-free periods [30–34]. This mechanism might explain the presence of diastolic dysfunction. Moreover, reduced nitric oxide (NO) production in FMF may have a contributory effect on impaired endothelial function [35]. This possibility is in agreement with the findings of Panossian et al. [36] in which they have reported that the level of NO in the blood of FMF patients decreased significantly during inflammatory attacks. They have also indicated the beneficial effect of the increase in NO blood levels in reducing the severity of inflammatory attacks in FMF patients.

Because of these two reasons, our results may have underestimated the cardiac involvement in FMF. First, our study population was quite younger for the appearance of heart disease and atherosclerosis. Relevant studies that are related to cardiac disturbances in rheumatologic disorder have often older subjects compared to us. Second, most of our patients are under the treatment of colchicines, which cause to conceal or delay any findings of inverse effects on the heart.

Conclusion

In this study we have demonstrated the presence of diastolic abnormality in FMF patients. We cannot explain the exact mechanism of diastolic dysfunction because the present study had not been planned to clarify its etiopathogenesis. Future investigations are needed to clarify this association. Additionally, impaired LV diastolic functions in echocardiography are not always associated with clinically important cardiac trouble. Therefore, further studies with prospective follow-up of FMF patients with or without impaired diastolic functions are needed to shed light on the clinical implications of our findings and to answer the question whether systematic echocardiographic screening is appropriate in those patients.