CT coronary angiography in asymptomatic male patients with high atherosclerosis risk: Is it justified?

PURPOSE: To study the necessity of coronary artery screening with computerized tomography coronary angiography (CTCA) in asymptomatic male patients. MATERIAL AND METHODS: A total of 226 asymptomatic male patients aged over 50 years were included in this prospective study, according to a clinical protocol approved by the Heraklion University Hospital's Ethics Committee. All participants had at least 3 or more known atherosclerosis risk factors. All patients had none or normal noninvasive cardiological tests in the past and had no contraindications for CTCA. All patients gave their informed consent after being notified regarding contrast medium and radiation dose risks. RESULTS: Significant stenoses were found in 52 asymptomatic males (23%). Out of them, 38 male patients underwent invasive coronography and 14 patients were lost in follow-up. In 18 patients, no lesions were found (47.4%). In the other 20 (52.6%) patients, 28 lesions were found. Stent placement was performed in 11 patients, bypass surgery was proposed in 3 patients, and in another 6 patients conservative treatment was suggested. Patients with findings in CTCA were more likely to have a family history of coronary artery disease, compared to patients with normal CTCA (P < 0.05 by using Fischer's Exact Test). Sensitivity of CTCA for significant stenosis was 74.3% with a specificity of 62%. CONCLUSION: CTCA may be used to screen for clinically significant coronary artery disease (CAD) in asymptomatic male patients, particularly those with positive family history or potentially high-risk patients with >3 risk factors for CAD.

Left dominant arrhythmogenic cardiomyopathy: a morbid association of ventricular arrhythmias and unexplained infero-lateral T-wave inversion.

Left-dominant arrhythmogenic cardiomyopathy is a subtype of arrhythmogenic right ventricular cardiomyopathy characterized by early predominant left ventricular involvement. Α 34-year-old man presented with palpitations and a history of frequent ventricular extrasystoles of both LBBB and RBBB configuration. Cardiac workup revealed repolarization abnormalities at infero-lateral leads in the absence of diagnostic structural/functional alterations or obstructive coronary artery disease. Six months later he died suddenly. Histopathology was diagnostic for arrhythmogenic right ventricular cardiomyopathy affecting predominantly the left ventricle at subepicardial/midwall myocardial layers. Thus, ventricular arrhythmias accompanied by unexplained infero-lateral T-wave inversion should warn of a possible morbid association underlying left-dominant arrhythmogenic cardiomyopathy.

Genetic variability of the distal promoter of the ST2 gene is associated with angiographic severity of coronary artery disease.

Genetic polymorphy of the distal promoter region of the ST2 gene influences transcriptional activity and susceptibility to atopic dermatitis and asthma. Based on the inflammatory background of atherosclerosis we hypothesized that ST2 distal promoter genetic polymorphy could also affect susceptibility to coronary artery disease (CAD). To test our hypothesis we performed direct sequencing of a 825 bp locus of the distal promoter -with previously reported significant polymorphy in 63 angiographically diagnosed CAD patients and 63 age and sex matched controls with negative coronary angiography. We identified 13 polymorphisms spanning this region two of which (-27307 T/A and -27614 C/A) had allele frequencies greater than 0.05. We further genotyped 111 subjects by applying allele-specific real-time PCR for the -27307 T/A and 27614 C/A polymorphisms, thereby increasing our sample to 129 CAD patients and 108 age- and sex-matched controls. We identified no phenotype-genotype interactions between cases and controls. However, among case subjects the severity of CAD expressed as a mean number of diseased vessels was greater in -27307 A allele carriers and either allele carriers (-27614 A or -27307 A) than in non-carriers (2.56 ± 0.73 vs. 1.83 ± 0.84, adjusted P = 0.027; 2.47 ± 0.74 vs. 1.8 ± 0.83, adjusted P = 0.023). Additionally, either allele carriers (-27614 A or -27307 A) were significantly more common in the multi-vessel disease group (n = 54) than in the single-vessel disease group (n = 75). In conclusion, we reported two new polymorphisms in the distal promoter region of the ST2 gene that possibly influence susceptibility to severe CAD. The functional impact of these polymorphisms remains to be determined.

Interleukin 8 gene polymorphisms and susceptibility to restenosis after percutaneous coronary intervention.

Interleukin-8 is a strong mediator of inflammation and has been implicated in the biochemical pathways involved in a wide range of inflammatory diseases including atherosclerosis. We investigated the potential influence of two common functional polymorphisms of the interleukin (IL)-8 gene: -251A/T and 781C/T on susceptibility to in stent restenosis (ISR) following percutaneous coronary intervention (PCI). The hypothesis was tested by screening for the prevalence of the above polymorphisms in 201 coronary artery disease (CAD) patients subjected to PCI and presenting with symptoms or signs of recurrent ischemia. Patients were angiographically re-evaluated and formed the ISR group (n = 73) and the non-ISR group (n = 128) based on the presence or absence of ISR. One hundred and forty-seven subjects without angiographic evidence of CAD formed a reference control group (non-CAD group). A borderline statistically significant higher frequency of the TT(251)TT(781) combined genotype was observed in patients with ISR on re-evaluation compared with patients with normal follow-up angiography. The predominance of TT(251)TT(781) was independent of conventional risk factors for cardiovascular disease. Consequently, T(251)T(781) haplotype was significantly more common in the ISR group. The above observations indicate that the genetic diversity of the IL-8 gene influences patient susceptibility to ISR and suggests the implication of IL-8-mediated pathways in the process of ISR. However, the rarity of T(251)T(781) haplotype makes any clinical application of the above observations unfeasible.

Genetic diversity of RANTES gene promoter and susceptibility to coronary artery disease and restenosis after percutaneous coronary intervention.

Regulated on activation, normal T cell expressed and secreted (RANTES) gene promoter is a regulatory region and a site of notable genetic diversity. In order to explore a possible interaction between RANTES promoter genetic diversity and susceptibility to coronary artery disease (CAD) and in stent restenosis (ISR), we initially sequenced a locus extending from -516 to 40 covering the entire region of the RANTES promoter in 100 subjects randomly selected from our cohort. Four single nucleotide polymorphisms (SNPs) were identified: -403G/A, -256G/A, -109C/T and -28C/G. The frequency of the -109C/T and -256G/A variations was <0.01, and was considered to be of limited significance. The frequency of the -403G/A and -28C/G polymorphisms was evaluated in the entire sample, which consisted of 118 patients subjected to percutaneous coronary intervention (PCI) without ISR on angiographic re-evaluation (no IRS group), 74 CAD patients with ISR on angiographic re-evaluation (IRS group) and 146 controls without angiographic evidence of CAD (no CAD group). No association was established between the RANTES promoter genotype and ISR. A genotype-phenotype interaction was observed between the -403G/A polymorphism and CAD. The -403A homozygotes were significantly more common in the CAD group than in the controls. The severity of CAD among case subjects, expressed as the mean number of diseased vessels, was significantly higher among -403A homozygotes as compared to wild-type homozygotes and heterozygotes. In conclusion, the RANTES -403A allele was associated with the presence and severity of CAD independently of conventional cardiovascular risk factors. The RANTES promoter genotype did not influence susceptibility to ISR in patients subjected to PCI.

Interleukin 8 and susceptibility to coronary artery disease: a population genetics perspective.

INTRODUCTION: Interleukin 8 is a strong chemoattractant factor for neutrophils and T lymphocytes. We investigated the potential influence of two common polymorphisms of the interleukin-8 gene, -251A/T, and 781C/T on susceptibility to coronary artery disease. MATERIALS AND METHODS: The hypothesis was tested by screening for the prevalence of the above polymorphisms in 241 angiographically diagnosed coronary artery disease patients compared to 157 selected controls with negative coronary angiography. RESULTS AND DISCUSSION: We found no significant differences between cases and controls concerning the allelic and genotypic frequencies of both the studied polymorphisms. Nevertheless, a statistically significant lower frequency of the AA containing genotypes was observed in cases presenting with acute coronary syndromes compared to asymptomatic subjects or patients with stable coronary artery disease (OR = 0.44, 95%CI: 0.2-0.98, p = 0.04). The strongest statistical significance was observed in the AA(251)TT(781) combined genotype (OR = 0.34, 95%CI: 0.14-0.85, p = 0.02). CONCLUSION: Our results suggest that the genetic diversity of the interleukin-8 gene influences the clinical manifestation of CAD.

CX3CR1 receptor is up-regulated in monocytes of coronary artery diseased patients: impact of pre-inflammatory stimuli and renin-angiotensin system modulators.

Fractalkine/CX3CR1 pathway is considered a major modulator of atherosclerosis. In the present study, expression of CX3CR1 on PBMCs/monocytes of healthy individuals and coronary artery diseased patients was initially assessed by flow cytometry. Effects of pre-inflammatory cytokines interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha on expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) were further assessed in three cell models: THP-1 monocytes, Jurkat T lymphocytes and primary monocytes isolated from healthy donors. Finally, effects of angiotensin-converting enzyme (ACE) inhibitors captopril, lisinopril and angiotensin receptor blocker (ARB) losartan on chemokine receptor expression were evaluated in the same cell models either in a naive or stimulated state. INF-gamma significantly affected the chemokine receptor phenotype of THP-1 cells by increasing the rate of CX3CR1-positive cells. Pre-treatment with the ACE inhibitors, captopril and lisinopril, and the ARB, losartan, did not influence these effects. Captopril and lisinopril similarly had no effect on either stimulated or naive primary monocytes. Yet, a small but repeatable increase in CX3CR1 expression after treatment with losartan was noted. Nevertheless, the latter observation did not retain statistical significance after applying the Bonferroni correction. In conclusion, our data did not indicate any significant effect of the ACE inhibitors on the chemokine receptor phenotype of monocytes.

Effects of polymorphisms in chemokine ligands and receptors on susceptibility to coronary artery disease.

INTRODUCTION: Atherosclerosis, the underlying disorder of coronary artery disease (CAD), is an inflammatory process involving multiple molecular pathways. Chemokine-mediated mechanisms are potent regulators of atherosclerosis. Genetic variations that alter such signaling pathways could affect susceptibility to CAD. We investigated the effect of 5 common variations of chemokine and chemokine receptor genes (SDF1-3'A, CCR5-delta32, CCR2-64I, CX3CR1-V249I and CX3CR1-T280M) on predisposition to CAD. MATERIALS AND METHODS: The hypothesis was tested by screening the prevalence of the above polymorphisms in 210 angiographically diagnosed CAD patients (152 with history of acute coronary syndromes, 58 with stable disease) in comparison to 165 selected controls with negative coronary angiography. Genotyping was performed by PCR/RFLP analysis. RESULTS: There were no significant differences among cases and controls concerning allelic and genotypic frequencies of SDF1-3'A, CCR5-delta32, CCR2-64I and CX3CR1-V249I variations. A borderline higher allelic frequency of the M280 variant was observed in controls compared to CAD group (adjusted OR=0.65, 95% CI: 0.35-0.99, p=0.05). Subjects carrying at least one copy of the M280 allele were significantly more common in the control group, suggesting an atheroprotective effect of this variant (adjusted OR=0.58, 95% CI: 0.35-0.97, p=0.04). CONCLUSIONS: The study confers additional data in the field of genetic predisposition to CAD: it confirms the atheroprotective effect of the M280 variant in a completely different population and supports the role of the fractalkine-CX3CR1 pathway in atherosclerosis.