Relation Between Familial Mediterranean Fever and QT Markers (QTc, QTd, and QTcd): A Systematic Review and Meta-Analysis

The aim of this study is to perform a meta-analysis to evaluate the possible association betweenQT markers and familial Mediterranean fever (FMF). PUBMED, Web of Science, OVID, and SCOPUS databases were searched. Inclusion criteria were randomized control trials or observational studies that compared measurement of the QT markers in FMF patients and healthy controls in both males and females without any age restriction or other comorbidities. RevMan software (5.4) was used to perform the analysis. A total of 14 studies with 1,154 individuals were included in the study. The pooled effect estimate showed a statistically significant association between FMF group and prolonged corrected QT (QTc) and QT dispersion (QTd) (MD= 7.06, 95% CI = 2.68 to 11.43, p-value = 0.002) and (MD= 6.08, 95% CI = 0.84 to 11.32, p-value= 0.02), respectively. No statistically significant difference between FMF group and QT interval and corrected QT dispersion (QTcd) (MD= 2.34, 95% CI = -1.21 to 5.89, p-value = 0.20) and (MD= 4.82, 95% CI = -0.57 to 10.20, p-value = 0.08), respectively. Our findings revealed a statistically significant relationship between FMF and extended QTc and QTd. More randomized multicenter trials are required to confirm our findings.


Introduction And Background
Familial Mediterranean fever (FMF) is an autosomal recessive auto-inflammatory disease featuring recurrent bouts of fever, abdominal pain, and arthritis along with serous membrane inflammation, which varies in duration from hours to days and occurs at variable intervals [1]. FMF is diagnosed using Tel-Hashomer clinical criteria, which should compromise two or more major symptoms, including (febrile episodes with serositis or a favorable response to colchicine or amyloidosis), range and pattern of fever: recurrent (at least three episodes), febrile (rectal temperature ≥ 38 °C) and short in duration (12 hours to three days). Incomplete attacks (must be recurrent) are defined as differing from typical attacks in one or two features as follows: 1) temperature <38 °C, 2) attack duration longer or shorter than a typical attack (but no less than six hours and no more than seven days), or one major plus two minor symptoms, including (a first-degree relative with FMF, erysipelas like erythema and recurrent febrile episodes). FMF is more prevalent in Turks, Armenians, Italians, Mediterranean, and Middle Eastern descent than in Greeks, Iranians, and Jews. For instance, its prevalence in Turkey is estimated to be one in 1,000 children. Mediterranean fever (MEFV) gene [1][2][3] mutation is thought to be responsible for its occurrence.
The constant inflammatory process -even in between attacks -has a destructive effect on the heart and may disrupt the course of ventricular repolarization, leading to increased dispersion of recovery time throughout the ventricle (high QT dispersion [QTd]), which also happens in other inflammatory diseases such as SLE. Additionally, amyloidosis due to FMF can be considered a confounding factor for arrhythmia development.
Several studies have specifically investigated repolarization and markers changes in FMF patients. Available markers are the QT interval representing the time from the beginning of depolarization till the end of repolarization in the chosen lead axis. QTc is calculated using the Bazzett formula and developed to yield a corrected measure since the QT interval varies with heart rate. QTd is the difference between the longest (QT max) and the shortest QT, while corrected QT dispersion (QTcd) is its counterpart but corrected for heart rate. Repolarization abnormalities marked by a high QTd, or QT variability are arrhythmogenic, as they increase the risk of developing a tachyarrhythmia called Torsades de Pointes which may lead to ventricular fibrillation and sudden cardiac death [4][5][6]. 1 2 1 1 1 Contradictory results were reported regarding these markers in FMF. Studies have contrasting inferences on the value of QT markers in FMF; some studies claimed no difference between FMF patients and controls [7,8], while others found high QTd in these patients [9]. Moreover, some studies reported a higher QTc value in FMF patients than in controls [10]. The aim of this systematic review and meta-analysis is to pool the available data to find if there is an actual association between FMF and abnormal QT markers.
This article was previously presented as a meeting abstract at the 6th Heart in Diabetes Conference on June 24, 2022, in Philadelphia, PA, USA.

Search Strategy
We searched the following databases: PUBMED, Web of Science, OVID, and SCOPUS. The terms used during the search were ("Familial Mediterranean Fever" OR "Familial Paroxysmal Polyserositis" OR "Mediterranean Fever, Familial" OR "Periodic Disease" OR "Periodic Peritonitis" OR "Recurrent Polyserositis" OR "Benign Paroxysmal Peritonitis") AND ("Torsades de Pointes" OR "QT interval" OR "QT").

Definition of Variables
QTd is the difference between the maximum QT value and the minimum QT value measured with a 12derivation surface electrocardiogram (ECG). It has been proposed as a non-invasive ECG parameter for inspecting the homogeneity of ventricular recovery time. Since increased QTd shows heterogeneity in ventricular repolarization, it is conclusively associated with increased liability for developing ventricular arrhythmia and sudden cardiac death. Additionally, Corrected QT (QTc) represents ventricular repolarization and is measured as the difference between the longest and shortest QTc interval on surface electrocardiography (ECG). It refers to the QT interval adjusted for the heart rate. QTc can forecast the risk of developing malignant arrhythmias as its prolongation may lead to fatal ventricular arrhythmias. On the other hand, QTcd is calculated as the difference between the maximum and the minimum QTc distances in milliseconds by any ECG derivation.

Inclusion Criteria and Selection Process
Yielded results from databases were imported into the Covidence platform. We reviewed the title and abstract of each paper from the searches and retrieved potentially relevant references. Following this initial screening, we obtained the full text of potentially relevant studies. The full-text screening was done for the papers using predetermined inclusion criteria which are any randomized control trials or observational studies that compared measurement of the QT markers (QTc, QTd, and QTcd) in FMF patients and healthy controls in both males and females without any age restriction or any other comorbidities. Meanwhile, reviews, case reports, editorials, and animal studies were excluded. Any conflicts about study inclusions were resolved by consensus.

Data Extraction and Quality Assessment
Two authors (MA and NI) independently extracted data and consulted the first author (KRM) when needed. They extracted details of the study design, participant characteristics, intervention and comparator, and outcomes. Quality assessment was done by the New Castle Ottawa scale assessment tool. Studies quality was ranked as good, fair, or poor.

Statistical Analysis
A meta-analysis was performed to assess the relationship between FMF and QT anomalies. For statistical analysis, RevMan 5.4 was employed. To ensure our analysis's high quality, we used the PRISMA Statement checklist. The continuous outcomes were quantified with a 95% confidence interval as mean difference (MD) and standard deviation (SD). If the P-value was less than 0.05, the findings were deemed significant.

Clinical Criteria of FMF
FMF is diagnosed by Tel-Hashomer clinical criteria, which should compromise two or more major symptoms, including (febrile episodes with serositis or a favorable response to colchicine or amyloidosis) or one major plus two minor symptoms, including (a first-degree relative with FMF, erysipelas like erythema and recurrent febrile episodes).

Literature Search
After completing the literature search, 698 publications resulted, and then 647 were deemed eligible for the title and abstract screening after removing duplicates. Of the 647, 21 were eligible for full-text screening. After the full-text screening, 14 studies were included in the meta-analysis (7-10,14-18, 27-31), and seven were excluded (32-38) for different reasons, as shown in Figure 1.

FIGURE 1: PRISMA flow diagram
Characteristics QT, QTc, QTd, and QTcd outcomes were reported in 9, 13, 12, and 11 studies, respectively. Most of the studies were of good quality (11 studies), one study was of fair quality, and only two had poor quality. The quality assessment summary is shown in Table 1.  The total number of patients included in the meta-analysis is 1154,603 in the FMF group and 551 in the control group; other baseline characteristics are found in Table 2.

Study
Duration of the disease " mean, SD"

1)
Nussinovitch In electrocardiographic parameters, analysis of QT, QT dispersion, corrected QT (QTc), and QTc dispersion were similar between the groups. The Tp-Te and cTp-Te intervals and Tp-Te/QT and cTp-Te/QT ratios were significantly prolonged in FMF patients. Multivariate linear regression analyses indicated that erythrocyte sedimentation rate was an independent predictor of a prolonged cTp-Te interval.
The study revealed that when compared with control subjects, Tp-Te and cTp-Te intervals and cTp-Te/QT ratio were increased in FMF patients.
14) Ahbap, "years" The study included 69 patients with FMF and 71 healthy subjects as controls.
No statistically significant differences were found between the groups in QT dispersion, corrected QT dispersion, and systolic-diastolic function of the left ventricle parameters. During the 12 months of follow-up, no ventricular arrhythmias were documented in either group.
The study found that diastolic dysfunction was not associated with QT dispersion. No difference in QT markers was observed in cases and controls.  (Figure 2). No publication bias was observed. We did subgroup analysis based on age (children and adults). No statistically significant difference between the FMF and control groups was found in both children and adults (MD 2.18, 95% CI = -10.01-14.37, p = 0.73) and (MD 2.82, 95% CI = -1.22-6.85, p = 0.17), respectively.

FIGURE 3: Corrected QT (QTc) outcome
QTd: The pooled effect showed a statistically significant difference between the FMF and control groups (MD 6.08, 95% CI = 0.84-11.32, p = 0.02). We observed heterogeneity (P < 0.00001, I² = 92%) that was not solved by leaving one out of a test or subgroup analysis (Figure 4). There was no evidence of publication bias. Subgroup analysis was done based on age, a statistically significant difference between the FMF and control groups was found in both children and adults (MD 2.86, 95% CI = 0.19-5.54, p = 0.04) and (MD 7.23, 95% CI = 0.08-14.37, p = 0.05), respectively.

Discussion
FMF is a chronic disease that is characterized by recurrent attacks of inflammation that manifest with fever, abdominal pain, and arthritis [11]. Our analysis showed a statistically significant association between FMF and the prolongation of QTc and QTd intervals compared with the control group. Similarly, subgroup analysis for age showed a statistically significant association between FMF and prolongation of QTc and QTd intervals compared with the control group in both children and adults. Whereas QT interval and cQTd did not significantly differ between FMF and control groups.
These results were consistent with Akcay et al. regarding QTc prolongation and increased QTd [9]. This difference was attributed to the increased inflammatory activity and associated atherosclerosis that occurs with FMF. This was evidenced by the elevated levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) among FMF patients compared to healthy controls. In addition, several studies have indeed demonstrated an association between the chronic inflammatory state of FMF and atherosclerosis [12,13], further accusing atherosclerosis of QTc interval prolongation and increased QTd. Koca et al. also showed a prolonged QTc interval. However, they did not find a correlation between inflammatory markers and electrocardiographic (ECG) parameters in FMF patients [14]. They attributed this to the shorter disease duration of their participants and the ECG measurements being taken during an attack-free period.
Amyloidosis also appears to contribute to increased QTd in FMF patients. Ahbap et al. found that QTd significantly increased in FMF patients, particularly those with amyloidosis, compared to FMF without healthy controls [15]. On the other hand, Nussinovitch et al. found no correlation between amyloidosis in FMF and increased QTd [16]. Of note, both studies had a low sample size for FMF patients with amyloidosis of 12 and 18, respectively, warranting further research.
Contradictory to our results, Topal et al. found no significant difference between FMF patients and healthy controls in all ventricular repolarization parameters [17]. Their findings may be due to the significant discrepancy in age between the FMF patients and healthy controls in their study. Similarly, Giese et al. also found no association between FMF and ECG parameters [18]. These variations between the different studies included in our analysis may be explained by the differences in age, duration of disease, colchicine therapy, or amyloidosis between studies.
Many studies have shown that prolonged QTc is associated with increased mortality, particularly among patients with chronic inflammatory diseases, such as rheumatoid arthritis [6,19,20]. One mechanism that underlies this association is the one described by Zabel et al. that prolonged QTc interval is associated with depolarizations during phases 2 and 3 of the action potential in animal models, thus impeding the process of repolarization [21]. Such early and incomplete action potentials can result in lethal ventricular arrhythmias such as torsade de pointes, ultimately resulting in ventricular fibrillation and sudden cardiac death [22,23]. QTc interval prolongation is also associated with increased mortality among patients with acute myocardial infarction [24]. Indeed, Gendelman et al. have demonstrated that FMF patients are at increased risk of mortality due to ischemic heart diseases, echoing the importance of QTc interval as a prognostic factor for FMF patients [25].
Although QTc interval and QTd were found to be significantly different between FMF patients and controls in our study, the results among the studies involved were inconsistent. This can be attributed to the different timing of ECG measurements during disease activity for FMF patients. Results can be influenced depending on whether the measurements were recorded during an exacerbation or attack-free period. In addition, different approaches to ECG measurements used between studies, either manual or computerized, can be a contributing factor. Furthermore, patient compliance with colchicine treatment can have a role in the in QTc interval and QTd variation. Colchicine reduces inflammatory markers in FMF patients and has a beneficial effect on cardiac arrhythmias [26]. However, one study demonstrated that, for FMF patients, being colchicine-sensitive or resistant has no significant effect on QT interval variability, warranting further research in that regard [8].

Future Implications
Regular follow-up and electrocardiographic and echocardiographic monitoring of FMF patients regarding their ventricular repolarization parameters is needed to allow for early detection and management of ventricular arrhythmias.

Strengths
The overall quality was high in most of the studies included in our analysis. The analysis included multiple studies, allowing for a fairly high combined sample size.

Limitations
Regarding quality assessment, two of the 14 included studies in the meta-analysis were of poor quality. The effect of colchicine on the outcomes of the patients was not investigated in the included studies. Although most of the included studies are case-control studies that included FMF patients and matched controls for age, sex, and comorbidities, other included studies did not give attention to matched controls for age, sex, and comorbidities, so prospective multicenter randomized studies with larger sample sizes and longer follow-up periods giving attention to matched controls for age, sex, and comorbidities are needed to further evaluate the relationship between FMF and ventricular repolarization parameters and to assess the effect of colchicine on the QT markers in FMF patients.

Conclusions
Our analysis revealed a statistically significant link between FMF and prolonged QTc and QTd, but no statistically significant difference was observed in QT and QTcd. Therefore, FMF patients are at increased risk of developing arrhythmia. As a result, FMF patients should be scheduled for frequent follow-ups to avoid developing arrhythmias. More randomized multicenter trials are needed to confirm our findings and to establish the association between FMF and subsequent arrhythmia.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.