National Tunisian Study of Cardiac Implantable Electronic Devices: Design and Protocol for a Nationwide Multicenter Prospective Observational Study.

BACKGROUND: In Tunisia, the number of cardiac implantable electronic devices (CIEDs) is increasing, owing to the increase in patient life expectancy and expanding indications. Despite their life-saving potential and a significant reduction in population morbidity and mortality, their increased numbers have been associated with the development of multiple early and late complications related to vascular access, pockets, leads, or patient characteristics. OBJECTIVE: The study aims to identify the rate, type, and predictors of complications occurring within the first year after CIED implantation. It also aims to describe the demographic and epidemiological characteristics of a nationwide sample of patients with CIED in Tunisia. Additionally, the study will evaluate the extent to which Tunisian electrophysiologists follow international guidelines for cardiac pacing and sudden cardiac death prevention. METHODS: The Tunisian National Study of Cardiac Implantable Electronic Devices (NATURE-CIED) is a national, multicenter, prospectively monitored study that includes consecutive patients who underwent primary CIED implantation, generator replacement, and upgrade procedure. Patients were enrolled between January 18, 2021, and February 18, 2022, at all Tunisian public and private CIED implantation centers that agreed to participate in the study. All enrolled patients entered a 1-year follow-up period, with 4 consecutive visits at 1, 3, 6, and 12 months after CIED implantation. The collected data are recorded electronically on the clinical suite platform (DACIMA Clinical Suite). RESULTS: The study started on January 18, 2021, and concluded on February 18, 2023. In total, 27 cardiologists actively participated in data collection. Over this period, 1500 patients were enrolled in the study consecutively. The mean age of the patients was 70.1 (SD 15.2) years, with a sex ratio of 1:15. Nine hundred (60%) patients were from the public sector, while 600 (40%) patients were from the private sector. A total of 1298 (86.3%) patients received a conventional pacemaker and 75 (5%) patients received a biventricular pacemaker (CRT-P). Implantable cardioverter defibrillators were implanted in 127 (8.5%) patients. Of these patients, 45 (3%) underwent CRT-D implantation. CONCLUSIONS: This study will establish the most extensive contemporary longitudinal cohort of patients undergoing CIED implantation in Tunisia, presenting a significant opportunity for real-world clinical epidemiology. It will address a crucial gap in the management of patients during the perioperative phase and follow-up, enabling the identification of individuals at particularly high risk of complications for optimal care. TRIAL REGISTRATION: ClinicalTrials.gov NCT05361759; https://classic.clinicaltrials.gov/ct2/show/NCT05361759. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/47525.

Identification of two variants in AGRN and RPL3L genes in a patient with catecholaminergic polymorphic ventricular tachycardia suggesting new candidate disease genes and digenic inheritance.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an arrhythmogenic syndrome characterized by life-threatening arrhythmias, a normal resting electrocardiogram and the absence of overt structural heart abnormalities. Mutations in RyR2 gene account for the large part of CPVT cases. Less frequently, mutations in CASQ2 gene have been linked to the recessive form of the disease. Overall, approximately 35% of CPVT patients remain without a genetic etiology implying that other genes might be found causative of the disease. Here, we present a 6-year-old boy born to first-degree related parents, with a typical phenotype of CPVT and a family history of sudden cardiac death of his brother at 7 years. A trio-based whole exome sequencing was performed, and we identified a homozygous variant in AGRN gene and a heterozygous variant in RPL3L gene. We hypothesized that the presence of the homozygous variant in AGRN accounts for the CPVT phenotype in this family and the heterozygous variant in RPL3L gene may act as a modifier gene. Further studies are needed to determine the role of these genes in CPVT.

Epidemiological characteristics, management, and outcomes of atrial fibrillation in TUNISIA: Results from the National Tunisian Registry of Atrial Fibrillation (NATURE-AF).

BACKGROUND: Contemporary registries on atrial fibrillation (AF) are scare in North African countries. HYPOTHESIS: In the context of the epidemiological transition, prevalence of valvular AF in Tunisia has decreased and the quality of management is still suboptimal. METHODS: NATURE-AF is a prospective Tunisian registry, involving consecutive patients with AF from March 1, 2017 to May 31, 2017, with a one-year follow-up period. All the patients with an Electrocardiogram-documented AF, confirmed in the year prior to enrolment were eligible. The epidemiological characteristics and outcomes were described. RESULTS: A total of 915 patients were included in this study, with a mean age of 64.3 ± 22 years and a male/female sex ratio of 0.93. Valvular AF was identified in 22.4% of the patients. The mean CHA2 DS2 VASC score in nonvalvular AF was 2.4 ± 1.6. Monotherapy with antiplatelet agents was prescribed for 13.8% of the patients. However, 21.7% of the subjects did not receive any antithrombotic agent. Oral anticoagulants were prescribed for half of the patients with a low embolic risk score. In 341 patients, the mean time in therapeutic range was 48.87 ± 28.69%. Amiodarone was the most common antiarrhythmic agent used (52.6%). During a 12-month follow-up period, 15 patients (1.64%) had thromboembolism, 53 patients (5.8%) had major hemorrhage, and 52 patients (5.7%) died. CONCLUSIONS: NATURE-AF has provided systematic collection of contemporary data regarding the epidemiological and clinical characteristics as well as the management of AF by cardiologists in Tunisia. Valvular AF is still prevalent and the quality of anticoagulation was suboptimal.

Multiallelic rare variants support an oligogenic origin of sudden cardiac death in the young.

Unexplained sudden death in the young is cardiovascular in most cases. Structural and conduction defects in cardiac-related genes can conspire to underlie sudden cardiac death. Here we report a clinical investigation and an extensive genetic assessment of a Tunisian family with sudden cardiac death in young members. In order to identify the family-genetic basis of sudden cardiac death, we performed Whole Exome Sequencing (WES), read depth copy-number-variation (CNV) screening and segregation analysis. We identify 6 ultra-rare pathogenic heterozygous variants in OBSCN, RYR2, DSC2, AKAP9, CACNA1C and RBM20 genes, and one homozygous splicing variant in TECRL gene consistent with an oligogenic model of inheritance. CNV analysis did not reveal any causative CNV consistent with the family phenotype. Overall, our results are highly suggestive for a cumulative effect of heterozygous missense variants as disease causation and to account for a greater disease severity among offspring. Our study further confirms the complexity of the inheritance of sudden cardiac death and highlights the utility of family-based WES and segregation analysis in the identification of family specific mutations within different cardiac genes pathways.

Clinical and genetic investigation of catecholaminergic polymorphic ventricular tachycardia in a consanguineous Tunisian family.

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare disease presenting with syncopal events and sudden cardiac death at a young age in the absence of structural heart disease. Two major genes have been shown to be responsible for CPVT: RYR2 and CASQ2 genes involved in calcium homeostasis.Methods: We report here clinical and molecular investigation of a consanguineous Tunisian family including three affected members. Involvement of RYR2 and CASQ2 genes was investigated.Results: Mutation screening for RYR2 gene showed that no mutation were detected in the coding sequence. A novel variation c.572C/T was identified in CASQ2 gene leading to a p.Pro191Leu.Conclusion: To our knowledge, this is the first clinical and genetic investigation of CPVT in North Africa.

Design and Rationale of the National Tunisian Registry of Atrial Fibrillation: Protocol for a Prospective, Multicenter Trial.

BACKGROUND: Atrial fibrillation (AF) is an important health problem in Tunisia. A significant change in the epidemiological pattern of heart disease has been seen in the last 3 decades; however, no large prospective multicenter trial reflecting national data has been published so far. Robust data on the contemporary epidemiological profile and management of AF patients in Tunisia are limited. OBJECTIVE: The aim of this study is to analyze, follow, and evaluate patients with AF in a large multicenter nationwide trial. METHODS: A total of 1800 consecutive patients with AF by electrocardiogram, reflecting all populations of all geographical regions of Tunisia, will be included in the study, with the objective of describing the epidemiological pattern of AF. Patients will be officially enrolled in the National Tunisian Registry of Atrial Fibrillation (NATURE-AF) only if an electrocardiogram diagnosis (12-lead, 24-hour Holter, or other electrocardiographic documentation) confirming AF is made. The qualifying episode of AF should have occurred within the last year, and patients do not need to be in AF at the time of enrollment. Patients will be followed for 1 year. Incidence of stroke or transient ischemic attack, thromboembolic events, and cardiovascular death will be recorded as the primary end point, and hemorrhagic accidents, measurement of international normalized ratio, and time in therapeutic range will be recorded as secondary end points. RESULTS: Results will be available at the end of the study; the demographic profile and general risk profile of Tunisian AF patients, frequency of anticoagulation, frequency of effective treatment, and risks of thromboembolism and bleeding will be evaluated according to the current guidelines. Major adverse events will be determined. NATURE-AF will be the largest registry for North African AF patients. CONCLUSIONS: This study would add data and provide a valuable opportunity for real-world clinical epidemiology in North African AF patients with insights into the uptake of contemporary AF management in this developing region. TRIAL REGISTRATION: ClinicalTrials.gov NCT03085576; https://clinicaltrials.gov/ct2/show/NCT03085576 (Archived by WebCite at http://www.webcitation.org/6zN2DN2QX). REGISTERED REPORT IDENTIFIER: RR1-10.2196/8523.

[Protein S, C and antithrombin deficiency: association with myocardial infarction and thromboembolism in the young]. / Déficits en protéine S, C et antithrombine: Association à l'infarctus du myocarde et aux évènements thrombo-emboliques chez le sujet jeune.

BACKGROUND: The pathogenesis of myocardial infarction (MI) in young involves new factors including constitutional or acquired thrombophilia. AIM: To determine in patients ² 50 years, the association between coagulation factors deficiency, myocardial infarction and cardiovascular events during follow-up. METHODS: Protein C (PC), PS and antithrombin (AT) were screened in 50 patients admitted for acute MI and in a healthy control group. Univariate and multivariate analysis were performed using SPSS 11.5 version. RESULTS: PS and PC deficiency were associated to MI (respectively 24% vs 0%, p=0.001 and 14% vs 0%, p=0.016), independently for PC. No AT deficiency was detected in both groups. During followup, PS and C deficiency were predictive for venous thrombosis (p<0.05) and PS deficiency for pulmonary embolism. CONCLUSION: Protein C and S deficiency may play an important role in MI in young and also in thromboembolic complications during follow-up. Nevertheless, therapeutic implications remain controversial.

Association of the insertion/deletion gene polymorphism of the apolipoprotein B signal peptide with myocardial infarction in Tunisian patients.

BACKGROUND: Numerous polymorphisms of the apolipoprotein B (APOB) gene have been described. Particularly, the insertion/deletion (Ins/Del) polymorphism located in the coding part of the signal peptide of apoB, associated with modification of lipid concentrations and the risk of coronary artery disease and/or myocardial infarction (MI), has been reported in the general population. Moreover, conflicting results emerge from the literature and suggest that the effect is context-dependent. In the present study, the first investigation of the Ins/Del polymorphism of the APOB gene in Tunisian patients with MI, we examined a possible association between this polymorphism and MI in a subgroup of the Tunisian population. METHODS: A total of 318 Tunisian patients with MI and 368 healthy controls were included in the study. Genomic DNA was extracted from white blood cells, and the Ins/Del polymorphism was determined by electrophoresis in polyacrylamide gels after PCR amplification. A binary logistic regression analysis was performed to test how the association between MI and Ins/Del polymorphism is independent from confounding factors. RESULTS: A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with MI had a frequency of 7.2% for the Del/Del genotype, 39.6% for the Ins/Del genotype, and 53.1% for the Ins/Ins genotype. Controls had a frequency of 3.0% for the Del/Del, 32.1% for the Ins/Del and 64.9% for the Ins/Ins genotype (chi2=12.93, p=0.002). The MI patient group showed a significantly higher frequency of the Del allele compared to controls (27.1% vs. 19.1%; chi2=12.50, p=0.0004). In comparison to the Ins/Ins homozygotes, the odds ratio (95% confidence interval) for MI was 1.51 (1.09-2.07) for Ins/Del heterozygotes and 2.95 (1.40-6.22) for Del/Del homozygotes. In multivariate analysis, age (p=0.001), smoking (p<0.001), hypertension (p=0.001), diabetes mellitus (p<0.001), and dyslipidemia (p=0.01) were independent correlates of the presence of MI, whereas the Ins/Del polymorphism (p=0.330) was not an independent predictor of MI. CONCLUSIONS: The present study shows a significant but not independent association between the Ins/Del polymorphism of the APOB gene and MI in the Tunisian population.

Association between the -2518G/A polymorphism in the monocyte chemoattractant protein-1 (MCP-1) gene and myocardial infarction in Tunisian patients.

BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1; gene name CCL2) has been suggested to play an important role in the initiation of atherosclerosis by recruiting monocytes to sites of injured endothelium. Recently, single nucleotide polymorphisms (SNPs) in the MCP-1 regulatory region have been identified. Controversial results regarding the association of the -2518G/A polymorphism of the MCP-1 gene with coronary artery disease (CAD) have been reported. In the present study, we examined a possible association between the -2518G/A polymorphism of the MCP-1 gene and myocardial infarction (MI) in a sample of the Tunisian population. METHODS: A total of 319 Tunisian patients with MI and 467 healthy controls were included in the study. The SNP of the MCP-1 gene was determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. RESULTS: Patients with MI had significantly higher frequency of the AG+GG genotypes compared to controls [42.9% vs. 35.8%; OR (95%CI), 1.34 (1.00-1.79); p=0.04]. The MI patient group showed a significant higher frequency of the G allele compared to the controls [0.242 vs. 0.195; OR (95%CI), 1.31(1.02-1.68), p=0.03]. The association between the -2518G/A polymorphism of the MCP-1 gene and MI was no longer significant after adjustment for other well-established risk factors. CONCLUSION: The present study showed a significant but not independent association between the -2518G/A polymorphism of the MCP-1 gene (presence of G allele) and MI in the Tunisian population.

Association of a 27-bp repeat polymorphism in intron 4 of endothelial constitutive nitric oxide synthase gene with myocardial infarction in Tunisian patients.

BACKGROUND: Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) mediates endothelium-dependent vasodilatation and antithrombotic action. Controversial results regarding the association of eNOS gene (NOS3) polymorphisms with myocardial infarction (MI) have been reported. In the present study, we examined a possible association between a 27-base pair (bp) repeat polymorphism in intron 4 of the NOS3 gene and MI in a subgroup of the Tunisian population. METHODS: A total of 310 Tunisian patients with MI and 250 healthy controls were included in the study. The NOS3 gene intron 4a4b variable number of tandem repeats polymorphism was analyzed by PCR. RESULTS: A significant difference in genotype distribution and allele frequency was observed between patients and controls. Patients with MI had a frequency of 4.8% for the 4a4a genotype, 33.9% for the 4a4b genotype and 61.3% for the 4b4b genotype. Controls had a frequency of only 1.6% for the 4a4a genotype, 24.4% for the 4a4b genotype and 74.0% for the 4b4b genotype (chi2=11.81, p=0.003). The MI patient group showed a significant higher frequency of the 4a allele compared to controls (0.218 vs. 0.139; chi2=5.81, p=0.01). CONCLUSIONS: In the present study, a significant association between the NOS34a/4b gene polymorphism (presence of 4a allele) and MI in the Tunisian population was found.

[Radiofrequency ablation of accessory atrioventricular pathways. Predictive factors of immediate and long-term results]. / Ablation par radiofréquence des voies accessoires auriculo-ventriculaires. Facteurs prédictifs du résultat immédiat et à long-terme.

UNLABELLED: The purpose of this study was to evaluate safety and efficacy of catheter ablation of accessory pathways (APs) and to identify predictive factors of acute result and outcome. The patient population included 173 patients who had undergone ablation of an AP. The success rate was 91.6%, a major complication occurred in 4 patients (2.3%) and 8 patients (4.9%) developed a recurrence after a successful ablation procedure. Only one factor predicted success (sex), tow variables predicted development of a major complication (septal AP, age < 16 years), and three factors predicted arrhythmia recurrence (mid septal, right free wall, and multiple APs). CONCLUSION: The results of this study may serve to identify sub-groups of patients most likely to have a favourable result in whom it would be reasonable for clinicians to recommend catheter ablation as first-line therapy.