Endothelin-converting Enzyme-1b Genetic Variants Increase the Risk of Coronary Artery Ectasia.

Coronary artery ectasia (CAE), defined as a 1.5-fold or greater enlargement of a coronary artery segment compared to the adjacent normal coronary artery, is frequently associated with atherosclerotic coronary artery disease (CAD). Membrane-bound endothelin converting enzyme-1 (ECE-1) is involved in the maturation process of the most potent vasoconstrictor ET-1. Polymorphisms in the endothelin (ET) gene family have been shown associated with the development of atherosclerosis. This study aims to investigate the effects of rs213045 and rs2038089 polymorphisms in the ECE-1 gene which have been previously shown to be associated with atherosclerosis and hypertension (HT), in CAE patients. Ninety-six CAE and 175 patients with normal coronary arteries were included in the study. ECE-1b gene variations rs213045 and rs2038089 were determined by real-time PCR. The frequencies of rs213045 C > A (C338A) CC genotype (60.4% vs. 35.4%, p < 0.001) and rs2038089 T > C T allele (64.58% vs. 35.42%, p = 0.017) were higher in the CAE group compared to the control group. The multivariate regression analysis showed that the ECE-1b rs213045 CC genotype (p = 0.001), rs2038089 T allele (p = 0.017), and hypercholesterolemia (HC) (p = 0.001) are risk factors for CAE. Moreover, in nondiabetic individuals of the CAE and control groups, it was observed that the rs213045 CC genotype (p < 0.001), and rs2038089 T allele (p = 0.003) were a risk factor for CAE, but this relationship was not found in the diabetic subgroups of the study groups (p > 0.05). These results show that ECE-1b polymorphisms may be associated with the risk of CAE and this relationship may change according to the presence of type II diabetes.

Receptor for advanced glycation end products polymorphisms in coronary artery ectasia.

BACKGROUND: Although the implication of receptor of advanced glycation endproducts (RAGE) has been reported in coronary artery disease, its roles in coronary artery ectasia (CAE) have remained undetermined. Furthermore, the effect of RAGE polymorfisms were not well-defined in scope of soluble RAGE (sRAGE) levels. Thus, we aimed to investigate the influence of the functional polymorphisms of RAGE -374T > A (rs1800624) and G82S (rs2070600) in CAE development. METHODS: This prospective observational study was conducted in 2 groups selected of 2452 patients who underwent elective coronary angiography (CAG) for evaluation after positive noninvasive heart tests. Group-I included 98 patients with non-obstructive coronary artery disease and CAE, and Group-II (control) included 100 patients with normal coronary arteries. SNPs were genotyped by real-time PCR using Taqman® genotyping assay. Serum sRAGE and soluble lectin-like oxidized receptor-1 (sOLR1) were assayed by ELISA and serum lipids were measured enzymatically. RESULTS: The frequencies of the RAGE -374A allele and -374AA genotype were significantly higher in CAE patients compared to controls (p < 0.001). sRAGE levels were not different between study groups, while sOLR1 levels were elevated in CAE (p = 0.004). In controls without systemic disease, -374A allele was associated with low sRAGE levels (p < 0.05), but this association was not significant in controls with HT. Similarly, sRAGE levels of CAE patients with both HT and T2DM were higher than those no systemic disease (p = 0.02). The -374A allele was also associated with younger patient age and higher platelet count in the CAE group in both total and subgroup analyses. In the correlation analyses, the -374A allele was also negatively correlated with age and positively correlated with Plt in all of these CAE groups. In the total CAE group, sRAGE levels also showed a positive correlation with age and a negative correlation with HDL-cholesterol levels. On the other hand, a negative correlation was observed between sRAGE and Plt in the total, hypertensive and no systemic disease control subgroups. Multivariate logistic regression analysis confirmed that the -374A allele (p < 0.001), hyperlipidemia (p < 0.05), and high sOLR1 level (p < 0.05) are risk factors for CAE. ROC curve analysis shows that RAGE -374A allele has AUC of 0.713 (sensitivity: 83.7 %, specificity: 59.0 %), which is higher than HLD (sensitivity: 59.2 %, specificity: 69.0 %), HT (sensitivity: 62.4 %, specificity: 61.1 %) and high sOLR1 level (≥0.67 ng/ml)) (sensitivity: 59.8 %, specificity: 58.5 %). CONCLUSION: Beside the demonstration of the relationship between -374A allele and increased risk of CAE for the first time, our results indicate that antihypertensive and antidiabetic treatment in CAE patients causes an increase in sRAGE levels. The lack of an association between the expected -374A allele and low sRAGE levels in total CAE group was attributed to the high proportion of hypertensive patients and hence to antihypertensive treatment. Moreover, the RAGE -374A allele is associated with younger age at CAE and higher Plt, suggesting that -374A may also be associated with platelet activation, which plays a role in the pathogenesis of CAE. However, our data need to be confirmed in a large study for definitive conclusions.

Unusual effects of PCSK9 E670G (rs505151) variation in patients with in-stent restenosis: Variable effects on restenosis risk according to concomitant chronic conditions.

Recent reports showing that neo-atherosclerosis formation in stented coronary artery is characterized by the accumulation of lipid-laden macrophages within the neointima has strengthened the possibility that elevated low-density lipoprotein (LDL)-cholesterol may be a risk factor for in-stent restenosis (ISR). Protein Convertase Subtilisin/Kexin-9 (PCSK9) protein plays an important role in cholesterol metabolism by degrading of LDL receptors. The gain-of-function E670G (rs505151) mutation of the PCSK9 gene is a well-known genetic risk factor for hypercholesterolemia. This study evaluated for the first time the association of the E670G variation with the serum lipids, PCSK9 levels and concomitant diseases on the ISR risk. The study included 109 ISR, and 82 Non-ISR patients, based on the results of coronary angiography. Genotypes were determined using the real-time PCR and serum PCSK9 levels were measured by ELISA technique. The rare G allele of PCSK9 E670G (p < 0.05), hyperlipidemia (HL) (p < 0.001), and type 2 diabetes (T2DM) (p < 0.01) were associated with increased risk for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR (p < 0.001), while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. In addition, diabetic ISRs had higher serum PCSK9 levels (p < 0.05) and the E670G-AA genotype was associated with increased levels of diabetes markers. Our results indicated that the unusual effects of both G allele and AA genotype of the PCSK9 E670G variation may be involved in the risk of ISR in association with concomitant metabolic diseases.

This study evaluated the association of the Protein Convertase Subtilisin/Kexin-9 (PCSK9) E670G mutation with the serum lipids, PCSK9 levels and concomitant diseases on the in-stent restenosis (ISR) risk. The E670G-G allele, hyperlipidemia, and type 2 diabetes (T2DM) were found risk factors for ISR. In hyperlipidemic conditions, the E670G-G allele was associated with hypercholesterolemia and a higher risk of ISR, while the E670G-AA genotype has been associated with a high prevalence of T2DM and hypertension. Our results indicated that the unusual effects of both genotypes of the E670G that may be involved in the ISR risk in association with concomitant diseases.

Next-generation sequencing of prolidase gene identifies novel and common variants associated with low prolidase in coronary artery ectasia.

BACKGROUND: Decreased collagen biosynthesis and increased collagenolysis can cause ectasia progression in the arterial walls. Prolidase is a key enzyme in collagen synthesis; a decrease in prolidase activity or level may decrease collagen biosynthesis, which may contribute to ectasia formation. Considering that, the variations in PEPD gene encoding prolidase enzyme were evaluated by analyzing next-generation sequencing (NGS) for the first time together with known risk factors in coronary artery ectasia (CAE) patients. METHODS: Molecular analysis of the PEPD gene was performed on genomic DNA by NGS in 76 CAE patients and 76 controls. The serum levels of prolidase were measured by the sandwich-ELISA technique. RESULTS: Serum prolidase levels were significantly lower in CAE group compared to control group, and it was significantly lower in males than females in both groups (p < 0.001). On the other hand, elevated prolidase levels were observed in CAE patients in the presence of diabetes (p < 0.001), hypertension (p < 0.05) and hyperlipidemia (p < 0.05). Logistic regression analysis demonstrated that the low prolidase level (p < 0.001), hypertension (p < 0.02) and hyperlipidemia (p < 0.012) were significantly associated with increased CAE risk. We identified four missense mutations in the PEPD gene, namely G296S, T266A, P365L and S134C (novel) that could be associated with CAE. The pathogenicity of these mutations was predicted to be "damaging" for G296S, S134C and P365L, but "benign" for T266A. We also identified a novel 5'UTR variation (Chr19:34012748 G>A) in one patient who had a low prolidase level. In addition, rs17570 and rs1061338 common variations of the PEPD gene were associated with low prolidase levels in CAE patients, while rs17569 variation was associated with high prolidase levels in both CAE and controls (p < 0.05). CONCLUSIONS: Our findings indicate that the low serum prolidase levels observed in CAE patients is significantly associated with PEPD gene variations. It was concluded that low serum prolidase level and associated PEPD mutations may be potential biomarkers for the diagnosis of CAE.

Long-Term Follow-Up of Patients With Isolated Side Branch Coronary Artery Disease.

The data with respect to stable coronary artery disease (SCAD) are mainly confined to main vessel disease. However, there is a lack of information and long-term outcomes regarding isolated side branch disease. This study aimed to evaluate long-term major adverse cardiac and cerebrovascular events (MACCEs) in patients with isolated side branch coronary artery disease (CAD). A total of 437 patients with isolated side branch SCAD were included. After a median follow-up of 38 months, the overall MACCE and all-cause mortality rates were 14.6% and 5.9%, respectively. Among angiographic features, 68.2% of patients had diagonal artery and 82.2% had ostial lesions. In 28.8% of patients, the vessel diameter was ≥2.75 mm. According to the American College of Cardiology lesion classification, 84.2% of patients had either class B or C lesions. Age, ostial lesions, glycated hemoglobin A1c, and neutrophil levels were independent predictors of MACCE. On the other hand, side branch location, vessel diameter, and lesion complexity did not affect outcomes. Clinical risk factors seem to have a greater impact on MACCE rather than lesion morphology. Therefore, the treatment of clinical risk factors is of paramount importance in these patients.

Incidence of atrial fibrillation and its effects on long-term follow-up outcomes in patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction.

OBJECTIVE: The incidence of atrial fibrillation (AF) in patients with ST segment elevation myocardial infarction (STEMI) varies between 7% and 21%, and most of these studies were in the thrombolytic era. However, the frequency of new-onset AF during the primary percutaneous coronary intervention (PCI) period is still unclear. We aimed to investigate the frequency of new-onset AF and its effects on long-term clinical events in patients undergoing primary PCI. METHODS: A total of 1,603 patients who were diagnosed with STEMI and underwent primary PCI were included in the study. All the patients were monitored for at least 48 hours after the procedure. The primary endpoint of the study was defined as new-onset AF during hospitalization. RESULTS: The median follow-up period of our study was 44 months. New-onset AF developed in 85 (6.1%) patients. CHADs-VASc > 2, KILLIP > 2, and left atrial diameter were found to be independent predictors for the development of new-onset AF. In the AF (+) group, the all-cause and in-hospital mortality rates were found to be significantly higher. New-onset AF development in patients with STEMI was detected as an independent predictor of in-hospital mortality. CONCLUSION: In the era of primary percutaneous transluminal coronary angioplasty, new-onset AF rates were found to be lower than the literature data. In addition, new-onset AF was found to be a predictor of in-hospital mortality, and deaths occurred mostly in the early period. Therefore, close follow-up of these patients in the early period and re-evaluation in terms of AF burden when the patient becomes stable are important.

The comparison of serum TGF-beta levels and associated polymorphisms in patients with coronary artery ectasia and normal coronary artery.

BACKGROUND: Coronary artery ectasia (CAE) is described as the enlargement of a coronary artery segment by 1.5 times or more, which is generally associated with the atherosclerotic process. Atherosclerotic changes lead to arterial remodeling result in CAE. In our study, we measured serum transforming growth factor (TGF)-ß1 levels, which have a protective role against atherosclerosis. Further, we aimed to assess the TGF-ß1 gene variants rs1800469 (-509C>T, c.-1347C>T) and rs1800470 (c.+29T>C, p.Pro10Leu, rs1982073), which might have an effect on TGF production. Overall, 2877 patients were screened including 56 patients with CAE and 44 patients with normal coronary arteries who were included in the study. Serum TGF-ß1 levels were measured using ELISA and compared between two groups. Additionally, TGF-ß1 rs1800469 and rs1800470 gene variations were determined using TaqMan® SNP Genotyping Assays. RESULTS: Serum TGF-ß1 levels were significantly lower in patients with CAE than in controls (p=0.012). However, there was no difference in terms of the genotype and allele distributions of TGF-ß1 rs1800469 and rs1800470 polymorphisms. Serum TGF-ß1 levels were higher in individuals carrying the TGF-ß1 rs1800470 G allele (GG+AG) than in individuals with normal homozygous AA genotype in the CAE group (p=0.012). CONCLUSION: Our findings suggest that lower serum TGF-ß1 levels are associated with an increased risk for CAE development and that TGF-ß1 polymorphisms exert a protective effect. Furthermore, TGF-ß1 rs1800470 G allele carriers were shown to have higher TGF-ß1 levels in the CAE group. This suggests that having the G allele in the TGF-ß1 rs1800470 polymorphism could prevent CAE development.

Avoiding the emergence of contrast-induced acute kidney injury in acute coronary syndrome: routine hydration treatment.

BACKGROUND: Patients with acute coronary syndrome (ACS) have about a three-fold risk for developing contrast-induced acute kidney injury(CI-AKI). Investigating studies on routine hydration therapy have frequently included patients with stable coronary artery disease and high risk of CI-AKI [estimated glomerular filtration rate (eGFR) < 60 ml/min]. However, data on routine hydration treatment in non-ST segment elevation myocardial infarction (NSTEMI) patients with eGFR ≥60 ml/min are insufficient. We aimed to investigate the association between routine hydration therapy and CI-AKI development in NSTEMI patients at low risk for nephropathy. METHODS AND RESULTS: We randomly assigned a total of 401 NSTEMI patients to two groups: the routine hydration group (198 patients) and the nonhydration group (control group) (203 patients). Intravenous hydration with isotonic saline (1 ml/kg/h, 0.9% sodium chloride) was given for 3-12 h before and 24 h after contrast exposure to the hydration group. CI-AKI was defined as the increase in serum creatinine values 0.5 mg/dl or 25% between 48 and 72 h after the invasive procedures. In our study, the incidence of CI-AKI development in the routine hydration group (7.1%) was significantly lower than in the nonhydration group (14.1%) (P: 0.02). This study revealed that older age, amount of contrast media, and routine hydration were independent risk factors for developing CI-AKI (P < 0.01, P: 0.04, P < 0.01, respectively). CONCLUSION: We found that preprocedural and postprocedural intravenous hydration therapy reduces the development of CI-AKI in patients with NSTEMI at low risk for CI-AKI. We suggest administering routine hydration therapy in all ACS patients regardless of eGFR values.