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Assessment of aortic stiffness and ventricular functions in familial Mediterranean fever/Ailevi Akdeniz atesinde aortik sertlesme parametrelerinin ve ventrikul fonksiyonlarinin degerlendirilmesi.

ABSTRACT

Objective: To investigate systolic and diastolic ventricular functions, aortic elastic properties and the presence of pericardial effusion in familial Mediterranean fever (FMF) patients.

Methods: A case-controlled, cross-sectional study was performed on 44 FMF patients and 27 controls. Subjects with hypertension, diabetes mellitus and hyperlipidemia were excluded. Left and right ventricular functions were measured using echocardiography including two-dimensional, M-mode, and conventional Doppler as well as pulsed wave tissue Doppler imaging (TDI). Aortic elasticity was analyzed using M-mode tracing guided by the two-dimensional echocardiography. Statistical analysis was performed using Mann Whitney U, Spearman rho correlation and Fisher's exact tests.

Results: Age, sex, body mass index, smoking status and lipids were comparable in patients and controls (p>0.05). None of the subjects had pericarditis and/or pericardial effusion. Aortic wall properties were similar between groups (p>0.05). The TDI parameters of mitral lateral annulus revealed significantly lower Em/Am ratios in patients compared to controls [1.77 (0.6-3.4) vs. 1.79 (0.9-4.8), p=0.02]. Mitral flow propagation velocity was significantly lower in patients than healthy subjects [63 (39-100) vs. 74 (40-94) cm/s, p=0.008]. Tricuspid annular plane systolic excursion (TAPSE) was significantly reduced in FMF group than in controls [2 (1.3-2.5) vs. 2.5 (1.7-3.2) cm; p<0.001]. Eight of the patients and one control had impaired TAPSE (<2 cm; p=0.025). There was no difference regarding right ventricular diastolic dysfunction (RVDD) as assessed by using standard Doppler echocardiography (p>0.05). However, pronounced RVDD was observed in FMF patients documented by TDI (Em/Am<l;19 patients vs. 0 controls, p<0.001).

Conclusion: Subclinical myocardial involvement is present in a cohort of relatively young FMF patients who were also free of classical cardiovascular risk factors. Pericardium and aorta seem to be spared during attack free periods of FMF. (Anadolu Kardiyol Derg 2008, & 271-8)

Key words: Aortic stiffness, cardiac disease, Doppler echocardiography, familial Mediterranean fever, ventricular dysfunction

OZET

Amac: Bu calismada Ailevi Akdeniz Atesi (AAA) hastalarinda aortun elastik ozelliklerinin, ventrikul fonksiyonlarinin ve perikardiyal efuzyon varliginin degerlendirilmesini amacladik.

Yontemler: Bu vaka-kontrollu, enine-kesitsel calismada 44 AAA hastasi ve 27 saglikli birey yer aldi. Hipertansiyon, diyabet ve dislipidemisi olan bireyler calismada almmadi. Sag ve sol ventrikul fonksiyonlarinin degerlendirilmesinde 2-boyutlu, M-mod, standartve doku Doppler ekokardiyografi incelemeleri kullanildi. Aortun elastik ozelliklerinin incelenmesinde 2-boyutlu ve M-mod ekokardiyografi kullanildi. Istatistiksel degerlendirmede Mann Whitney U, Fisher testi ve Spearman korelasyonu kullanildi.

Bulgular: Hasta ve kontrol grubu yas, cins, sigara kullanma durumu, vucut kitle indeksi- ve serum lipid duzeyleri acisindan benzer ozellikteydi (p>0.05). Calisma grubundaki hicbir bireyde perikardit ve/veya perikardiyal efuzyonla iliskin bulguya rastlanmadi. Aortik elastik fonksiyon parametreleri hasta ve kontrol guruplan arasinda benzerdi (p>0.05). Doku Doppler ile elde edilen sol ventrikul mitral annuler Em/Am oram hasta grubunda kontrollere gore anlamli olarak dusuktu [1.77 (0.6-3.4) karsi 1.79 (0.9-4.8) p=0.02]. Ote yandan mitral renkli M-mod akim yayilma hizi (Vp) hasta grubunda anlamli olarak kisa bulundu [63 (39-100) karsi 74 (40-94) cm/s, p=0.008]. Tricuspid annuler duzlem sistolik hareketi (TAPSE) degeri AAA hastalarinda kontrollere gore belirgin dusuktu [2 (1.3-2.5) vs. 2.5 (1.7-3.2) cm; p<0.001]. Sekiz AAA hastasi ve bir kontrolde TAPSE degeri <2 cm bulundu (p=0.025). Standart Doppler degerlendirmesi ile sag ventrikul fonksiyonlarinda hasta ve kontrol grubu arasinda fark izlenmezken doku Doppler ile elde edilen degerlendirmede AAA hastalarinda artmis sag ventrikul diyastolik disfonksiyonu vardi (Em/Am<l;19 AAA vs. 0 kontrol, p<0.001).

Sonuc: Bu calismadaki bulgular klasik kardiyovaskuler risk faktoru olmayan ve nispeten genc yastaki AAA hastalarinda subklinik bir miyokardiyal tutulumu dusundurtmektedir. Ote yandan aort ve perikardiyumun bu hastalarda etkilenmedigi gozlenmistir. (Anadolu Kardiyol Derg 2008, & 271-8)

Anahtar kelimeler: Aortik sertlesme, kalp hastaligi, Doppler ekokardiyografi, ailevi Akdeniz atesi, ventrikul fonksiyon bozuklugu

Introduction

Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease that occurs worldwide and predominantly affects populations of Mediterranean basin (1). Clinically, FMF is characterized by recurrent, acute, self-limiting attacks of fever and serositis, lasting at average 24-72 hours (2). Current evidence indicates that subclinical inflammation continues during attack-free periods of FMF (3, 4).

Clinical and subclinical cardiovascular involvement have been reported in several inflammatory rheumatic diseases including rheumatoid arthritis (RA) (5), ankylosing spondylitis (6), systemic lupus erythematosus (SLE) (7), and Behcet's disease (8). However, there is considerable lack of evidence regarding cardiac involvement in FMF patients.

As echocardiography is a reliable, cost-effective, non-invasive and reproducible diagnostic tool to evaluate aortic wall functional and anatomical alterations, cardiac function and structures, we aimed to investigate systolic and diastolic ventricular functions, aortic elastic properties and the presence of pericardial effusion in FMF patients by using conventional echocardiography and pulsed wave tissue Doppler imaging (TDI) methods.

Methods

This cross-sectional and case-control study was conducted between February and July 2006. Fifty-two out of 453 adult FMF patients, diagnosed in accordance with Tel-Hashomer criteria (9), registered in the computer files of our department all over the country, were included in the study. The patients living in city of Izmir who did not have a record regarding history of cardiac and pulmonary disease, diabetes mellitus, hypertension, hyperlipidemia and amyloidosis in the computer files were contacted for the study. We were able to contact 55 subjects and invited them to participate in the study. Thirty-three volunteers, with a similar age and sex distribution to the FMF patients, recruited from hospital staff. Same exclusion criteria were applied to controls as well as patients. None of the patients refused to join to the study. Eight of the FMF patients were excluded because of hypertension (four patients), hyperlipidemia (two patients) and diabetes mellitus according to the two-hour oral glucose tolerance test (OGTT) after our clinical evaluation. Six of the controls were also excluded because of hypertension (four subjects) and hyperlipidemia (two subjects). This study was approved by the local ethical committee and all participants gave written informed consents.

Echocardiographic studies were performed on the remaining 44 FMF patients [21 males/23 females; median age: 30 (19-47) years] and 27 healthy controls [12 males/15 females; median age: 29.5 (22-38) years]. All patients fulfilled the Tel-Hashomer criteria for FMF (9). All were on regular daily colchicine treatment and measurements of the study were performed during the attack free period (at least seven days). None of the participants had impaired glucose tolerance according to the OGTT and none of the patients had proteinuria on dipstick urinalysis. The median disease duration for FMF patients was 15.5 (1-45) years.

Blood pressure was measured by using mercury sphygmomanometer after 5 minutes of resting period and in the sitting position. Two readings were taken half an hour apart and the average value was calculated. Hypertension was defined as the mean systolic blood pressure [greater than or equal to]140 mmHg, and/or mean diastolic blood pressure [greater than or equal to]90 mmHg or if the subject was on antihypertensive medication.

Hyperlipidemia was defined as the total cholesterol level [greater than or equal to]240 mg/dl or low-density lipoprotein (LDL) cholesterol [greater than or equal to]160 mg/dl or triglyceride level [greater than or equal to]200 or the use of lipid lowering medication.

The diagnostic criterion of the American Diabetes Association based on the 75-g OGTT was used to define diabetes mellitus and glucose intolerance (10).

Participants who reported smoking at least one cigarette per day during the year before the study were classified as smokers.

Laboratory evaluation

In the morning, after an overnight fast, venous blood was sampled for the measurement of serum concentrations of glucose, total cholesterol, high-density lipoprotein (HDL) cholesterol, LDL cholesterol, triglycerides, standard C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Thereafter, a 75-g oral glucose load was administered to whole group and venepuncture was repeated 2 hours later for measurement of post-challenge serum glucose.

Echocardiographic Examination

The echocardiographic examinations were obtained by using Sonos 4500 (Hewlett Packard, USA) with a multifrequency transducer (2.5-4 MHz) equipped with TDI technology. Images were taken with subjects in left lateral decubitus position and Doppler measurements were obtained during end-expiration. All echocardiographic measurements were performed by a single experienced cardiologist throughout the whole study using the same device blinded to the study groups. M-mode traces were recorded at a speed of 50 mm/s and the Doppler signals at 100 mm/s and measurements of at least three cardiac cycles were averaged in sinus rhythm. The recorded echocardiography tracings were analyzed by another experienced cardiologist.

M-mode, two-dimensional and standard Doppler echocardiography

M-mode measurements were done according to the recommendations of the American Society of Echocardiography (11). Presence of pericardial effusion was evaluated from the posterior wall of the left ventricle at end-diastole and pericardial effusion was defined as [greater than or equal to]2 mm echo-free space between the pericardial layers of the left ventricle posterior wall. Valvular regurgitation was assessed qualitatively and graded as none, trace, mild, moderate, or severe by using color-coded Doppler imaging (12). Left ventricular ejection fraction was measured using the modified Simpson's method (13).

The sample volume (size 2 mm) of the pulsed wave Doppler was placed between the tips of the mitral leaflets in the apical four-chamber view. The mitral inflow velocity was traced and the following variables derived: peak velocity of early (E) and late (A) filling and deceleration time (DT) of the E wave velocity. Left ventricular isovolumic relaxation time (IVRT) was measured as the interval between aortic valve closure and the onset of mitral flow. The ratio of early to late peak velocities (E/A) was calculated. Peak velocities of E and A wave and E/A ratio were also obtained for right ventricle in the apical four-chamber view, placing the sample volume at the tips of the tricuspid valve.

The propagation velocity of early flow into the left ventricle cavity (Vp) and tricuspid annular plane systolic excursion (TAPSE) were measured from the apical four-chamber view. The Vp was measured using color M-mode Doppler after aligning the cursor in the direction of inflow jet from the mitral annulus in the early diastole to 4 cm distally into the left ventricle cavity. To determine TAPSE, the M-mode cursor was oriented to the junction of the tricuspid valve plane with the right ventricle free wall using the apical 4-chamber view. The echoes generated were received and registered as motion of the right ventricle base. Maximal TAPSE was determined by the total excursion of the tricuspid annulus from its highest position after atrial ascent to the peak descent during ventricular systole.

Diameter of the ascending aorta was measured from the same view on the M-mode tracing at a level of 3 cm above the aortic valve. The systolic aortic diameter (ADS) was measured at the maximal anterior motion of the aorta, whereas the diastolic aortic diameter (ADD) was measured at the peak of the (IRS complex on the simultaneously recorded electrocardiogram. Following parameters of the aortic elasticity were calculated according to the following formulas: The aortic strain (AOST) = [(ADS - AOD)/AOD], aortic stiffness ([beta]) index=ln (systolic blood pressure/diastolic blood pressure)/AOST and aortic distensibility= 2xAOST/pulse pressure

Tissue Doppler echocardiography

The TDI was performed by activating the tissue Doppler function in the same echocardiography machine. In the apical four chamber view, a 5 mm pulsed Doppler sample volume was placed at the level of the lateral mitral and tricuspid valves. For each ventricle, myocardial systolic wave (Sm) velocity and the diastolic indices, myocardial early (Em) and atrial contraction (Am) peak velocities, were measured and Em/Am ratio was calculated.

The following parameters were used to define ventricular systolic and diastolic function:

1- Preserved left ventricular systolic function: LVEF[greater than or equal] 55% (14).

2-Left ventricular diastolic dysfunction (conventional Doppler): E/A<50 years<1, or E/A>50 years<0.5, or IVRT<30 years>92 ms, or IVRT30-50 years>100 ms, or IVRT>50 years>105 (15).

3-Left ventricular diastolic dysfunction (TDI and conventional Doppler methods): Em/Am<l (16), Vp<50 cm/s (17) or E/Em>15 (18, 19).

4-Right ventricular diastolic dysfunction (conventional Doppler): E/A<1.

5-Right ventricular diastolic dysfunction (TDI): Em/Am<l.

Reproducibility

To examine the reproducibility, ten healthy subjects were examined on two different occasions within a week. Intra-class correlation coefficients were substantial for right ventricular Em/Am, left ventricular E/A and right ventricular E/A ratios (0.74, 0.73 and 0.76, respectively). On the other hand, intra-class correlation coefficients of the left ventricular Em/Am ratio, Vp, TAPSE, systolic and diastolic aortic diameter measurements were excellent (0.85, 0.87, 0.84, 0.99 and 0.99 respectively).

Statistical analysis

The statistical analysis was carried out by using Statistical Package of Social Science (SPSS), version 13.0 (Chicago, IL, USA). Comparison between groups of continuous variables was performed by using the Mann-Whitney U test. Fisher's exact test was performed for the comparison of categorical variables. The Spearman rho correlation was used to determine relationships between parameters. The average intra-class correlation was used to assess the reproducibility of the echocardiographic assessment. A p value of <0.05 was considered as statistically significant.

Results

Clinical characteristics of the study group are presented in Table 1. There were 44 FMF patients (21 males/23 females) and 27 healthy controls (12 males/15 females). Age, sex, body mass index (BMI), smoking status and serum lipids were similar in FMF patients and control subjects (p>0.05). However, acute phase reactants (ESR and CRP) were significantly higher in the FMF patients compared to controls (p=0.04 and p=0.002, respectively). The median disease duration for FMF patients was 15.5 (1-45) years. The number of attacks before and after colchicine treatment was 15 (2-100) and 2 (0-36) per year respectively (p<0.001). Median daily colchicine use was 1.5 (0.5-2) grams.

Echocardiographic examination

None of the subjects had significant pericardial effusion or had moderate or severe valve abnormalities. Cardiac dimensions, left ventricular mass index, fractional shortening percentage and left ventricular ejection fraction values were similar in FMF patients and controls (p>0.05). The data obtained from the M- mode and standard Doppler echocardiography (SDE) is summarized in Table 2 and TDI examination results are given in Table 3.

Left ventricle

Four subjects (two in FMF patients and two in controls; p>0.05) had left ventricular diastolic dysfunction (LVDD) diagnosed by standard Doppler echocardiography (15).

Color M-mode Doppler study revealed significantly lower values of Vp in the FMF patients compared to healthy subjects (p<0.008). On the other hand, when Vp < 50 cm/s accepted as a cut-off for LVDD (17), seven FMF patients and one control subject had LVDD (p>0.05) (Table 2).

Tissue Doppler imaging- parameters of mitral lateral annulus revealed significantly lower Em/Am ratios in the FMF patients group compared to controls (p=0.02). Six subjects (5 FMF patients vs. one control; p>0.05) had LVDD with Em/Am ratio of the mitral lateral valve <1 (Table 3).

Another index of LVDD, E/Em ratio, was not different between FMF patients and controls (p>0.05). In addition, there were no subjects who had E/Em ratio greater than 15.

Figure 1 represents diastolic dysfunction indices of left ventricle either obtained from TDI or color M -mode techniques.

Right ventricle

Right ventricular E/A ratio was similar between FMF patients and controls. Ten subjects had right ventricular diastolic dysfunction (RVDD) by SDE method according to the criteria E/A ratio <1; however, significance was not seen between the groups (7 FMF patients and 3 controls; p>0.05).

Tissue Doppler imaging examination of the tricuspid lateral valve indices in the patients including Em and Am peak velocities and Em/Am ratio were significantly different in FMF patients and controls (p=0.02, p=0.01, and p<0.001, respectively). There were 19 patients who had RVDD with Em/Am ratio <1. However, none of the controls had RVDD according to those criteria. When only the cases under the age of 50 were re-analyzed, Em/Am ratio <1 was present in 18 out of 41 patients (p<0.001) (Table 3).

The TAPSE was significantly reduced in the FMF patients (p<0.001) as compared with controls. Eight of the FMF patients and one healthy subject (p<0.025) had impaired TAPSE (<2 cm). The cases under the age of 50 years demonstrated similar findings (Table 2).

Box plot graphic of the right ventricular Em/Am ratio and TAPSE is given in Figure 2.

Aortic elasticity

The systolic and diastolic diameters of the aorta, aortic elastic properties and aortic distensibility were similar in FMF patients and controls (p>0.05) (Table 2).

Correlation analysis

Correlation analysis of the right ventricular Em/Am, representing RVDD, yielded significant correlations with TAPSE, CRP, triglyceride, BMI, Vp, left ventricular Em/Am ratio and left ventricular E/A ratio (p<0.001, r=0.5; p=0.01, r=-0.4; p=0.04, r= -0.3; p=0.007, r=-0.3; p=0.02, r=0.3; p<0.001, r=0.5 and, p=0.009, r=0.3 respectively).

Right ventricular systolic function index TAPSE was significantly correlated with right ventricular Em/Am ratio, ESR, CRP, AOST, aortic distensibility, FS% and Vp (p<0.001, r=0.5; p=0.01, r=-0.3; p=0.03, r=-0.3; p=0.04, r=-0.3; p=0.03, r= -0.3; p=0.005, r=0.4 and, p<0.001, r=0.6, respectively).

Left ventricular Em/Am ratio, representing LVDD, showed significant correlations with left ventricular E/A ratio, right ventricular Em/Am ratio, age, fasting blood glucose, BMI, triglyceride, Vp and colchicine dose (p<0.001, r=0.5; p<0.001, r=0.5; p<0.001, r=-0.4; p=0.04, r=-0.2; p=0.03, r=-0.3; p=0.02, r=-0.3; p=0.03, r=0.3, and p=0.03, r=0.3, respectively).

Mitral flow propagation velocity, representing LVDD, was correlated significantly with left ventricular E/A ratio, left ventricular Em/Am ratio, pulse pressure and right ventricular Em/Am ratio (p=0.02, r=0.3; p=0.03, r= 0.3; p=0.04, r=0.4, and p=0.02, r=0.3, respectively).

Other parameters including disease duration, numbers of attacks before and after colchicine treatment were not correlated with left and right ventricular Em/Am ratio, TAPSE and Vp.

Discussion

The results of our study demonstrate that systolic and diastolic functions of right ventricle and diastolic function of left ventricle are impaired in patients with FMF when compared to healthy controls. On the other hand aortic elastic properties and pericardium showed no significant difference between groups.

There are several anatomic sites such as the pericardium, aorta, myocardium and the cardiac conduction system, which may be involved in various rheumatic diseases. However, there is a considerable lack of evidence regarding cardiac involvement in FMF patients. The disease of pericardium, although it is a double-layered serous membrane, is a rare manifestation of FMF. In a series of 2468 patients, only 34 subjects (1.4%) had pericarditis (20). In another study, the incidence of pericardial effusion was 3.6% during attacks of FMF (21). The present study, which investigates pericardial effusion during attack free period of FMF shows that pericardium is not affected in FMF patients during the attack free periods.

[FIGURE 1 OMITTED]

Myocardial involvement, especially LVDD, is a relatively common problem among patients with inflammatory rheumatic conditions. Up to 44% of ankylosing spondylitis (22), 66% of RA (23), 40% of Behget's disease (24), and 64% of SLE patients (25) may have LVDD. In addition, right ventricular diastolic impairment has also been reported in the above disorders (2629). Several mechanisms have been proposed as a cause of diastolic dysfunction in inflammatory rheumatic diseases such as the fibrous scarring of the heart muscle, abnormal myocardial collagen deposition, myocardial infarcts, focal inflammation, vasculitis, myocarditis, arteritis and amyloidosis (7, 26, 27, 3O, 31). The presence of asymptomatic diastolic dysfunction in RA and SLE patients is believed to be partly responsible for the increased cardiovascular mortality (23, 25).

Diastolic dysfunction can be identified by standard echocardiography and/or recently introduced methods such as TDI. Standard echocardiography has several limitations; one major limitation is its dependence of loading conditions and heart rate for the assessment of diastolic ventricular function (32). In case of worsening left ventricular diastolic function there is a compensatory increase in left atrial pressure resulting in an increase in E wave velocity of the mitral inflow and therefore pseudo-normalization of the filling pattern (normal E/A ratio and DT) (33). The TDI is a new technique, which offers useful information about ventricular functions (19). Myocardial or annular velocities are easy to obtain, volume-load independent and offer a rapid way to differentiate normal from pseudo-normal pattern and constrictive from restrictive pathology (16, 19, 33). Another preferred method for assessing left ventricular diastolic function is the measurement of Vp by color M-mode echocardiography (34). This method is also volume independent and decreased Vp (<50 cm/s) could reliably detect all grades of diastolic dysfunction (17).

In this study, standard echocardiography revealed similar results for FMF patients and controls regarding LVDD. However, TDI study and color M-mode investigations of the left ventricle showed significant difference between the FMF patients and control groups regarding Em/Am and Vp values but not in E/Em values. The number of subjects who had Em/Am<1, Vp<50 cm/s and E/Em>15 were similar in the groups. Although these criteria of LVDD were not completely met in FMF patients; the significantly lower values of Em/Am and significantly reduced Vp values suggest the LVDD in a cohort of relatively young FMF patients who were free of classical cardiovascular risk factors.

[FIGURE 2 OMITTED]

Measurements of right ventricular functions are difficult due to the complex three-dimensional structure and nonconcentric contraction of this ventricle (35). In addition, conventional Doppler studies conducted for RVDD have the same limitations for left ventricle, like its dependence of preload, afterload and heart rate (32). The TDI method has been shown to be superior when compared to standard Doppler in assessing RVDD (36). In the present study, we found no difference regarding RVDD by using standard Doppler echocardiography. In FMF patients, there was a pronounced right ventricular diastolic dysfunction detected with TDI method. Both the number of FMF patients with Em/Am<1 and Em/Am ratio were significantly different from healthy subjects. The TAPSE is a simple, reproducible and accurate index of right ventricular systolic function (37) and a cut-off value of TAPSE< 2 cm could identify patients with some degree of either right or left ventricular systolic dysfunction (38). In this study, FMF patients also exhibited a significantly depressed TAPSE value. Furthermore, the number of FMF patients with TAPSE< 2 cm was also significantly higher than the healthy controls. As none of the patients and controls had impaired left ventricular systolic function described by a normal ejection fraction, the depressed values of TAPSE may indicate a subclinical right ventricular systolic dysfunction in FMF.

There are a few of studies investigating cardiac and vascular functions in adult patients with FMF. An impaired endothelial function, a key early event in atherosclerosis (39), has been reported in FMF patients (40). However, another study investigating early atherosclerosis in adult patients with FMF did not report endothelial dysfunction (41). There are also two recent studies investigating cardiac functions in FMF (42, 43). Tavil et al. (43) studied 30 cases and showed significantly reduced left ventricular Em/Am ratio in FMF patients. However, myocardial performance index reported to be unchanged. Other parameters including right ventricular Em/Am ratio and TAPSE were depressed in FMF group but missed significance. This is probably due to the lower number of subjects in the patients group and may explain the difference between our findings and those of Tavil et al. (43). In the second study, Caliskan et al. showed impaired coronary microvascular function in FMF patients by using echocardiography. In the same study left ventricular E/A ratio and isovolumic relaxation time of FMF patients were significantly different from healthy controls by using standard Doppler echocardiography. Interestingly, TDI examination of these subjects revealed no difference regarding LVDD between FMF patients and controls (42). However, both studies did not mention the number of subjects who had diastolic dysfunction according to the established criteria and made their conclusions only using the comparisons of E/A or Em/Am ratios between groups.

Aortic stiffness was reported to be a predictor of cardiovascular morbidity and mortality and can be assessed by noninvasive methods (44). Inflammation and disease related factors may cause aortic damage in autoimmune rheumatic diseases. In this context, impaired aortic mechanical properties have been reported in patients with SLE (45), Behcet's disease (30), and ankylosing spondylitis (46). A recent study including 31 FMF patients has also reported abnormal aortic stiffness parameters (47). In contrast to that study our results failed to demonstrate impaired elastic properties of the aorta (calculated from the AOST, index and aortic distensibility) in FMF patients compared to healthy controls. It is well known that aging is associated with impaired aortic elasticity (44) and one possible explanation for this discrepancy between our study and previous study may be related to the younger age of our patients (median 30 years compared to 37 years) (47).

In the present study, we excluded subjects with hypertension, diabetes mellitus, dyslipidemia, cardiac and pulmonary problems to avoid the negative effects of these variables on myocardium. In addition, the number of smoking subjects was similar between groups. We also analyzed subjects under fifty years of age and the subgroup analysis revealed the same findings. Thus, the abnormal findings of left ventricular diastolic and right ventricular systolic and diastolic functions are due to disease-related factors. Furthermore, correlation of right ventricular Em/Am ratio and TAPSE with CRP may support the role of inflammation in the myocardial dysfunction.

Limitations of the study

One limitation of this study is that we did not perform invasive methods to assess aortic elasticity and pulse pressure. Although invasive methods are still the gold standards, several reports demonstrated that M-mode echocar-diography is a reliable alternative to invasive techniques. Indeed, non-invasively calculated aortic elasticity showed excellent correlation with the indices derived from the invasive methods (44, 48). The other limitations of this study are as follows; the absence of patients not receiving colchicine and the absence of patients with acute attacks of FMF. Therefore, further studies include such patients are needed to confirm our results.

Conclusions

Our results suggest that subclinical myocardial involvement is present in patients with FMF, whereas pericardium and aorta seem to be spared during attack free periods.

References

(1.) Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med 1967; 43: 227-53.

(2.) Onen F. Familial Mediterranean Fever. Rheumatol Int 2006; 26: 489-96.

(3.) Lachmann HJ, sengul B, Yavuzsen TU, Booth DR, Booth SE, Bybee A, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEN mutations. Rheumatology (Oxford) 2006; 45: 746-50.

(4.) Tunca M, Kirkali G, Soyturk M, Akar S, Pepys MB, Hawkins PN. Acute phase response and evolution of familial Mediterranean fever. Lancet 1999; 24: 353: 1415.

(5.) Voskuyl AE. The heart and cardiovascular manifestations in rheumatoid arthritis. Rheumatology (Oxford) 2006; 45 Suppl 4: iv4-7.

(6.) Lautermann D, Braun J. Ankylosing spondylitis-cardiac manifestations. Clin Exp Rheumatol. 2002; 20 (6 Suppl 28): S11-5.

(7.) Doria A, laccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M. Cardiac involvement in systemic lupus erythematosus. Lupus 2005; 14: 683-6.

(8.) Gurgun C, Ercan E, Ceyhan C, Yavuzgil O, Zoghi M, Aksu K, et al. Cardiovascular involvement in Behcet's disease. Jpn Heart J 2002; 43: 389-98.

(9.) Livneh A, Langevitz P, Zemer D, Zaks N, Kees S, Lidar T, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879-85.

(10.) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183-97.

(11.) Quinones MA, Otto CM, Stoddard M, Waggoner A, Zoghbi WA. Recommendations for quantification of Doppler echocardiography: a report from the Doppler Quantification Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 2002; 15: 167-84.

(12.) Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003; 16: 777-802.

(13.) Schiller NB. Two-dimensional echocardiographic determination of left ventricular volume, systolic function, and mass. Summary and discussion of the 1989 recommendations of the American Society of Echocardiography. Circulation 1991; 84: 1280-7.

(14.) Drazner MH, Rame JE, Marino EK, Gottdiener JS, Kitzman DW, Gardin JM, et al. Increased left ventricular mass is a risk factor for the development of a depressed left ventricular ejection fraction within five years: the Cardiovascular Health Study. J Am Coll Cardiol 2004; 43: 2207-15.

(15.) How to diagnose diastolic heart failure. European Study Group on Diastolic Heart Failure. Eur Heart J 1998; 19: 990-1003.

(16.) De Boeck BW, Cramer MJ, Oh JK, van der Aa RP, Jaarsma W. Spectral pulsed tissue Doppler imaging in diastole: a tool to increase our insight in and assessment of diastolic relaxation of the left ventricle. Am Heart J 2003; 146: 411-9.

(17.) Bess RL, Khan S, Rosman HS, Cohen GI, Allebban Z, Gardin JM. Technical aspects of diastology: why mitral inflow and tissue Doppler imaging are the preferred parameters? Echocardiography (Mount Kisco, NY) 2006; 23: 332-9.

(18.) Redfield MM, Jacobsen SJ, Burnett JC, Jr., Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA 2003; 289: 194-202.

(19.) Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: A comparative simultaneous Doppler-catheterization study. Circulation 2000; 102: 1788-94.

(20.) Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine 2005; 84: 1-11.

(21.) Tutar E, Yalcinkaya F, Ozkaya N, Ekim M, Atalay S. Incidence of pericardial effusion during attacks of familial Mediterranean fever. Heart (British Cardiac Society) 2003; 89: 1257-8.

(22.) Okan T, Sari I, Akar S, Cece H, Gbldeli O, Guneri S, et al. Ventricular diastolic function of ankylosing spondylitis patients by using conventional pulsed wave Doppler, myocardial performance index and tissue Doppler imaging. Echocardiography 2008; 25: 47-56.

(23.) Gonzalez-Juanatey C, Testa A, Garcia-Castelo A, Garcia-Porrua C, Llorca J, Ollier WE, et al. Echocardiographic and Doppler findings in long-term treated rheumatoid arthritis patients without clinically evident cardiovascular disease. Semin Arthritis Rheum 2004; 33: 231-8.

(24.) Baris N, Okan T, Gurler O, Akdeniz B, Turker S, Ilknur T, et al. Evaluation of left ventricular diastolic dysfunction with conventional and current Doppler techniques in Behcet's disease. Clin Rheumatol 2006; 25: 873-6.

(25.) Sasson Z, Rasooly Y, Chow CW, Marshall S, Urowitz MB. Impairment of leftventricular diastolic function in systemic lupus erythematosus. Am J Cardiol 1992; 69: 1629-34.

(26.) Sun JP, Khan MA, Farhat AZ, Bahler RC. Alterations in cardiac diastolic function in patients with ankylosing spondylitis. Int J Cardiol 1992; 37: 65-72.

(27.) Rexhepaj N, Bajraktari G, Berisha I, Beqiri A, Shatri F, Hima F, et al. Left and right ventricular diastolic functions in patients with rheumatoid arthritis without clinically evident cardiovascular disease. Int J Clin Pract 2006; 60: 683-8.

(28.) Topal E, Ozdemir R, Aksoy Y, Acikgbz N, Ermis N, Sincer I, et al. Tissue Doppler velocities of the right and left ventricles and their association with C-reactive protein and homocysteine levels in Behcet's disease. Am J Cardiol 2005; 96: 1739-42.

(29.) Tektonidou MG, loannidis JP, Moyssakis I, Boki KA, Vassiliou V, Vlachoyiannopoulos PG, et al. Right ventricular diastolic dysfunction in patients with anticardiolipin antibodies and antiphospholipid syndrome. Ann Rheum Dis 2001; 60: 43-8.

(30.) Ikonomidis I, Lekakis J, Stamatelopoulos K, Markomihelakis N, Kaklamanis PG, Mavrikakis M. Aortic elastic properties and left ventricular diastolic function in patients with Adamantiades-Behcet's disease. J Am Coll Cardiol 2004; 43: 1075-81.

(31.) Maione S, Cuomo G, Giunta A, Tanturri de Horatio L, La Montagna G, Manguso F, et al. Echocardiographic alterations in systemic sclerosis: a longitudinal study. Semin Arthritis Rheum 2005; 34: 721-7.

(32.) Choong CY, Herrmann HC, Weyman AE, Fifer MA. Preload dependence of Doppler-derived indexes of left ventricular diastolic function in humans. J Am Coll Cardiol 1987; 10: 800-8.

(33.) Bruch C, Schmermund A, Bartel T, Schaar J, Erbel R. Tissue Doppler imaging: a newtechnique for assessment of pseudonormalization of the mitral inflow pattern. Echocardiography (Mount Kisco, NY) 2000; 17: 539-46.

(34.) Garcia MJ, Palac RT, Malenka DJ, Terrell P, Plehn JF. Color M-mode Doppler flow propagation velocity is a relatively preload-independent index of left ventricular filling. J Am Soc Echocardiogr 1999; 12: 129-37.

(35.) Dell'Italia LJ. The right ventricle: anatomy, physiology, and clinical importance. Curr Probl Cardiol 1991; 16: 653-720.

(36.) Yu CM, Lin H, Ho PC, Yang H. Assessment of left and right ventricular systolic and diastolic synchronicity in normal subjects by tissue Doppler echocardiography and the effects of age and heart rate. Echocardiography (Mount Kisco, NY) 2003; 20: 19-27.

(37.) Hammarstrom E, Wranne B, Pinto FJ, Puryear J, Popp RL. Tricuspid annular motion. J Am Soc Echocardiogr 1991; 4: 131-9.

(38.) Lopez-Candales A, Rajagopalan N, Saxena N, Gulyasy B, Edelman K, Bazaz R. Right ventricular systolic function is not the sole determinant of tricuspid annular motion. Am J Cardiol 2006; 98: 973-7.

(39.) Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993; 362: 801-9.

(40.) Akdogan A, Calguneri M, Yavuz B, Arslan EB, Kalyoncu U, Sahiner L, et al. Are familial Mediterranean fever (FMF) patients at increased risk for atherosclerosis? Impaired endothelial function and increased intima media thickness are found in FMF. J Am Coll Cardiol 2006; 48: 2351-3.

(41.) Sari I, Karaoglu O, Can G, Akar S, Gulcu A, Birlik M, et al. Early ultrasonographic markers of atherosclerosis in patients with familial Mediterranean fever. Clin Rheumatol 2007; 26: 1467-73.

(42.) Caliskan M, Gullu H, Yilmaz S, Erdogan D, Unler GK, Ciftci O, et al. Impaired coronary microvascular function in familial Mediterranean fever. Atherosclerosis 2007; 195: e161-7.

(43.) Tavil Y, Ureten K, Ozturk MA, Sen N, Kaya MG, Cemri M, et al. The detailed assessment of left and right ventricular functions by tissue Doppler imaging in patients with familial Mediterranean fever. Clin Rheumatol 2008; 27: 189-94

(44.) Stefanadis C, Dernellis J, Tsiamis E, Stratos C, Diamantopoulos L, Michaelides A, et al. Aortic stiffness as a risk factor for recurrent acute coronary events in patients with ischaemic heart disease. Eur Heart J 2000; 21: 390-6.

(45.) Brodszki J, Bengtsson C, Lanne T, Nived O, Sturfelt G, Marsal K. Abnormal mechanical properties of larger arteries in postmenopausal women with systemic lupus erythematosus. Lupus 2004; 13: 917-23.

(46.) Demiralp E, Kardesoglu E, Kiralp MZ, Cebeci BS, Keskin I, Ozmen N, et al. Aortic elasticity in patients with ankylosing spondylitis. Acta Cardiol 2004; 59: 630-4.

(47.) Tavil Y, Ozturk MA, Ureten K, Sen N, Kaya MG, Cemri M, et al. Assessment of aortic wall stiffness in patients with Familial Mediterranean Fever. Joint Bone Spine 2008; 75: 280-5.

(48.) Stefanadis C, Stratos C, Boudoulas H, Kourouklis C, Toutouzas P. Distensibility of the ascending aorta: comparison of invasive and non-invasive techniques in healthy men and in men with coronary artery disease. Eur Heart J 1990; 11: 990-6.

Ismail Sari, Ozlem Arican *, Gercek Can, Bahri Akdeniz *, Servet Akar, Merih Birlik, Mehmet Tunca **, Nurullah Akkoc, Sema Guneri *, Fatos Onen

From Departments of Rheumatology, * Cardiology and ** Internal Medicine, School of Medicine, Dokuz Eylul University, Izmir, Turkey

Address for Correspondence/Yazisma Adresi: Dr. Fatos Onen, Dokuz Eylul Universitesi Tip Fakultesi Ic Hastaliklan Anabilim Dali Immunoloji-Romatoloji Bilim Dali, 35340 Inciralti, Izmir, Turkiye Phone: +90 232 412 37 81 Fax: +90 232 279 27 39 E-mail: fatos.onen@deu.edu.tr
Table 1. Clinical and laboratory characteristics of the subjects

 FMF
Parameters patients (n=44) Controls (n=27) p

Age, years 30(19-47) 29.5 (22-38) 0.31
Sex, M/F 21/23 12/15 0.81
Smoking, % 30 30 1
BMI, kg/[m.sup.2] 23.4(18.8-30.8) 22.2(19.1-27.9) 0.81
BSA, [m.sup.2] 1.7(1.45-2.22) 1.78(1.5-2.4) 0.28
Pulse pressure, mm/Hg 40(20-62) 42(33-64) 0.21
Fasting glucose, mg/dL 87(72-104) 82(67-105) 0.21
Second hour glucose, 88(45-170) 82(44-154) 0.15
 mg/dL
Total Cholesterol, mg/dL 160 (101-226) 178 (123-219) 0.37
LDL Cholesterol, mg/dL 87(47-147) 98(55-145) 0.67
HDL Cholesterol, mg/dL 49(34-78) 55(36-98) 0.06
Triglyceride, mg/dL 97(43-184) 84(39-188) 0.06
ESR, mm/h 10(3-90) 8(2-18) 0.04
CRP, mg/L 2.5 (0.3-65.8) 0.93 (0.2-8.6) 0.002

Continuous data are presented as median with minimum-maximal values
For the comparison of continuous variables, Mann-Whitney U test was
used For comparison of proportions, the Fisher's Exact Test was used
BMI- body mass index, BSA- body surface area, CRP- C-reactive protein,
ESR- erythrocyte sedimentation rate, F- female, FMF-familial
Mediterranean fever, HDL-high-density lipoprotein, LDL- low-density
lipoprotein, M- male

Table 2. M- mode, two-dimensional and standard Doppler
echocardio-graphic data

Variables FMF patients (n=44) Controls (n=27)

Left atrial dimension, cm 3.4 (2.2-4.3) 3.2 (2.7-4.1)
LVDs, cm 3.1 (2.5-3.7) 2.9 (2.5-4)
LVDd, cm 4.6 (3.8-5.4) 4.7 (3.9-5.9)
IVS, cm 0.8 (0.5-1.2) 0.8 (0.6-1.2)
LVMI, g/[m.sup.2] 82.8 (29.9-125) 74.3 (33-121.7)
FS, % 34 (15.9-44.4) 35.6 (19.6-44)
EF, % 66 (57-72) 65 (60-74)
VP, cm/s 63 (39-100) 74 (40-94)
Vp <50 cm/s 7 1
TAPSE, cm 2 (l.3-2.5) 2.5 (1.7-3.2)
<0.001 *
TAPSE <2.0 cm 8 1

Mitral inflow
E peak velocity, cm/s 80 (50-110) 76.5 (60-110)
A peak velocity, cm/s 57 (30-80) 50 (40-70)
E/A ratio 1.4 (0.9-3) 1.47 (1-2.2)
IVRT, ms 75 (45-130) 77 (45-101)
E wave DT, ms 133 (65-210) 145 (110-196)

Tricuspid inflow
E peak velocity, cm/s 60 (30-90) 60 (40-87)
A peak velocity, cm/s 40 (23-86) 43 (30-80)
E/A ratio 1.4 (0.5-2.2) 1.4 (0.6-2.7)

Aortic elastance
AOS, cm 3.1 (2.4-4.6) 3 (2.3-3.5)
AOD, cm 2.9 (1.9-4.5) 2.7 (2-3.4)
AOST, % 7.5 (1.3-41.3) 6.4 (1.2-28)
[beta] index 5.4 (1.5-35.4) 7.9 (1.6-35.2)
Distensibility, 10-3/kPa 30.8 (4.2-126.3) 19.7 (4.3-102.4)

Variables p

Left atrial dimension, cm 0.7
LVDs, cm 0.83
LVDd, cm 0.38
IVS, cm 0.73
LVMI, g/[m.sup.2] 0.45
FS, % 0.18
EF, % 0.84
VP, cm/s 0.008 *
Vp <50 cm/s 0.12
TAPSE, cm
<0.001 *
TAPSE <2.0 cm 0.025 *

Mitral inflow
E peak velocity, cm/s 0.27
A peak velocity, cm/s 0.69
E/A ratio 0.52
IVRT, ms 0.94
E wave DT, ms 0.04 *

Tricuspid inflow
E peak velocity, cm/s 0.02
A peak velocity, cm/s 0.21
E/A ratio 0.47

Aortic elastance
AOS, cm 0.08
AOD, cm 0.09
AOST, % 0.67
[beta] index 0.53
Distensibility, 10-3/kPa 0.32

Continuous data are presented as median with minimum-maximal values
For the comparison of continuous variables, Mann-Whitney U test was
used. For comparison of proportions, the Fisher's exact test was used

* All the significant p values remained significant when only those
patients and controls under the age of 50 were analyzed

A- atrial contraction diastolic flow velocity, AOD- aortic diameter
in diastole, AOS- aortic diameter in systole, AOST- aortic strain,
index- aortic stiffness index, DT- deceleration time,

E- early diastolic flow velocity, EF- ejection fraction,
FS- fractional shortening, IVRT- isovolumic relaxation time,
IVS- wall thickness of interventricular septum, LVDd- left
ventricular end-diastolic dimension, LVDs- left ventricular
end-systolic dimension, LVMI- left ventricular mass index,
TAPSE- tricuspid annular plane systolic excursion, Vp- the
colour-M-mode slope of the early diastolic left ventricular
filling phase (mitral flow propagation velocity)

Table 3. TDI analysis of left ventricular lateral mitral
annulus and right ventricular tricuspid annulus

 FMF
Variables patients (n=44) Controls (n=27) p

Mitral lateral annulus
Em peak velocity, cm/s 18 (13-23) 17.4 (10-25) 0.99
Am peak velocity, cm/s 10 (6-17) 8 (4-21) 0.05
Sm peak velocity, cm/s 11 (9-17) 11.7 (3-16) 0.27
Em/Am ratio 1.77 (0.6-3.4) 1.79 (0.9-4.8) 0.02 *
E/Em ratio 4.5 (2.2-6.7) 4.7 (3.2-9) 0.5
Em/Awl, n 5 1 0.4

Tricuspid annulus
Em peak velocity, cm/s 16 (10-23) 17.3 (13-25) 0.02 *
Am peak velocity, cm/s 14 (9-21) 12 (6-19) 0.01 *
Sm peak velocity, cm/s 15 (7-22) 14 (11-21) 0.2
Em/Am ratio 1.1 (0.7-1.9) 1.4 (1-2.5) <0.001 *
Em/Awl, n 19 0 <0.001 *

Continuous data are presented as median with minimum-maximal values

For the comparison of continuous variables, Mann-Whitney U test was
used

For comparison of proportions, the Fisher's exact test was used

* All the significant p values remained significant when only those
patients and controls under the age of 50 were analyzed

A- myocardial atrial contraction diastolic flow velocity,
E- myocardial early diastolic flow velocity, TDI- tissue Doppler
imaging
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Title Annotation:Original Investigation/Orijinal Arastirma
Author:Sari, Ismail; Arican, Ozlem; Can, Gercek; Akdeniz, Bahri; Akar, Servet; Birlik, Merih; Tunca, Mehmet
Publication:The Anatolian Journal of Cardiology (Anadolu Kardiyoloji Dergisi)
Article Type:Clinical report
Date:Aug 1, 2008
Words:7028
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