Risk Factors for Coronary Artery Disease in Patients Undergoing Coronary Angiogram at a Tertiary Level Hospital in Nepal

Background: Ischemic heart disease is the leading cause of CVD health loss globally, as well as in each world region, followed by stroke. In Nepal, CVD was found to be the second most common non-communicable disease among indoor patients of the non-specialist hospital. Age, gender, smoking, obesity, dyslipidemia, physical inactivity, hypertension, and diabetes mellitus (DM) are established risk factors for CVD. In Nepal, hypertension is found to be the most prevalent risk factor for CVD. Aims and Objectives: This study aimed to assess risk factors for coronary artery disease in patients undergoing coronary angiograms in Nepal. This study also investigated the socio-demographic characteristics of the participants and the nature of the involvement of coronary arteries. Materials and Methods: We examined in this cross-sectional study a total of 74 patients who underwent coronary angiography (CAG) at National Medical College between May 2020 and June 2021. Patients were grouped according to the number of major epicardial coronary arteries involved in SVD, DVD, and TVD. Patients were checked for risk factors like smoking, diabetes mellitus, hypertension, dyslipidemia, family history of coronary artery disease, and obesity. Microsoft Office Excel and SPSS version 21.0 were used for data analysis. The study was approved by the ethical committee. Results: Among 74 participants 53 were male. The mean age was 59.65±10.74 years. Premature coronary artery disease was present in six patients. SVD was the commonest CAD type. Hypertension was the commonest risk factor followed by Diabetes mellitus. Hypertension, Diabetes mellitus, Family history of premature CAD, and obesity were found to be statistically significant. Keywords: CAD, Risk factors for CAD, Premature CAD, Hypertension, Diabetes, obesity, family history of CAD, dyslipidemia, Smoking, SVD, DVD, TVD, Nepal

Estimated Prevalence of Familial Hypercholesterolemia Among Egyptian Patients with Acute Coronary Syndromes; Analysis from The Cardiorisk Project

Aims The prevalence of familial hypercholesterolemia (FH) in Egypt is largely un- known. We aimed to estimate the prevalence of FH among 3224 Egyptian patients with acute coronary syndromes enrolled from 2015 to 2018 in the nationwide cross- sectional cardioRisk project. Methods and Results We applied the Dutch Lipid Clinic criteria for the diagnosis of FH on the available data recorded for the patients enrolled in the CardioRisk project. Two main criteria were applied: the presence of premature CAD (given 2 points in the Dutch criteria), and the categorized low density lipoprotein cholesterol (LDL-C) lev- els (given 1, 3, 5, or 8 points in the Dutch criteria according to the level). From a total of 3224 patients, 2743 patients had available LDL-C levels. Among those patients, when applying the abovementioned 2 criteria, we estimated that 472 patients had at least ‘possible’ FH (17.2% of the total population). Specifically, 4 patients had ‘defi- nite’ FH (0.1%), 7 patients had ‘probable’ FH (0.25%), and 461 patients had ‘possi- ble’ FH (16.8%). Conclusion The estimated prevalence of at least ‘possible’ FH among Egyptian patients with ACS is 17%.

Fibrinogen and a Triad of Thrombosis, Inflammation, and the Renin-Angiotensin System in Premature Coronary Artery Disease in Women: A New Insight into Sex-Related Differences in the Pathogenesis of the Disease

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in women worldwide. Its social impact in the case of premature CAD is particularly devastating. Many differences in the presentation of the disease in women as compared to men, including atypical symptoms, microvascular involvement, and differences in pathology of plaque formation or progression, make CAD diagnosis in women a challenge. The contribution of different risk factors, such as smoking, diabetes, hyperlipidemia, or obesity, may vary between women and men. Certain pathological pathways may have different sex-related magnitudes on CAD formation and progression. In spite of the already known differences, we lack sufficiently powered studies, both clinical and experimental, that assess the multipathogenic differences in CAD formation and progression related to sex in different age periods. A growing quantity of data that are presented in this article suggest that thrombosis with fibrinogen is of more concern in the case of premature CAD in women than are other coagulation factors, such as factors VII and VIII, tissue-type plasminogen activator, and plasminogen inhibitor-1. The rise in fibrinogen levels in inflammation is mainly affected by interleukin-6 (IL-6). The renin–angiotensin (RA) system affects the inflammatory process by increasing the IL-6 level. Unlike in men, in young women, the hypertensive arm of the RA system is naturally downregulated by estrogens. At the same time, estrogens promote the fibrinolytic path of the RA system. In young women, the promoted fibrinolytic process upregulates IL-6 release from leukocytes via fibrin degradation products. Moreover, fibrinogen, whose higher levels are observed in women, increases IL-6 synthesis and exacerbates inflammation, contributing to CAD. Therefore, the synergistic interplay between thrombosis, inflammation, and the RA system appears to have a more significant influence on the underlying CAD atherosclerotic plaque formation in young women than in men. This issue is further discussed in this review. Fibrinogen is the biomolecule that is central to these three pathways. In this review, fibrinogen is shown as the biomolecule that possesses a different impact on CAD formation, progression, and destabilization in women to that observed in men, being more pathogenic in women at the early stages of the disease than in men. Fibrinogen is a three-chain glycoprotein involved in thrombosis. Although the role of thrombosis is of great magnitude in acute coronary events, fibrinogen also induces atherosclerosis formation by accumulating in the arterial wall and enabling low-density lipoprotein cholesterol aggregation. Its level rises during inflammation and is associated with most cardiovascular risk factors, particularly smoking and diabetes. It was noted that fibrinogen levels were higher in women than in men as well as in the case of premature CAD in women. The causes of this phenomenon are not well understood. The higher fibrinogen levels were found to be associated with a greater extent of coronary atherosclerosis in women with CAD but not in men. Moreover, the lysability of a fibrin clot, which is dependent on fibrinogen properties, was reduced in women with subclinical CAD compared to men at the same stage of the disease, as well as in comparison to women without coronary artery atherosclerosis. These findings suggest that the magnitude of the pathological pathways contributing to premature CAD differs in women and men, and they are discussed in this review. While many gaps in both experimental and clinical studies on sex-related differences in premature CAD exist, further studies on pathological pathways are needed.

Family history of premature coronary artery disease is not associated with coronary artery calcification

Funding Acknowledgements Type of funding sources: None. Background Controversy exists regarding the association of family history(FH) of premature coronary artery disease (CAD) with coronary artery calcification (CAC). The purpose of this study was to assess the potential association between family history of premature CAD (<55 years in first-degree male relatives and <65 years in first-degree female relatives) and CAC. Methods A retrospective study of 3613 asymptomatic individuals who underwent assessment of CAC score (CACs) according with the Agatston method. Individuals were selected based on the presence or absence of FH of premature CAD. Individuals with history of hypercholesterolaemia, hypertension, diabetes mellitus or obesity (BMI> 30), smokers (current or previous) were excluded. Furthermore, we excluded subjects with late-onset family history of CAD (>55 years in first-degree male relatives and >65 years in first-degree female relatives). Results Mean age of the cohort was 50.4 ± 9.5 year (74.6% males) and 15.6% reported FH in a parent, sibling or both (prevalence was 12.8% in parents only, 1.9% in siblings only and 0.9% in both parents and siblings). The prevalence of CAC was similar in individuals with FH (35%) and those without (36%), p = 0.2; with no difference in the mean CACs between the two groups, p = 0.4 (Table 1). Individuals with FH in parents only or siblings only had a similar incidence of CAC compared to those without FH (p = 0.9 and 0.7, respectively), with no difference in the mean CACs, p= 0.9 in both. Additionally, the incidence of CAC was not different in individuals with FH in both parents and siblings compared to those without FH (p= 0.1) and again there was no difference in the mean CACs (p = 0.6). Conclusion In asymptomatic individuals with none of the conventional risk factors for atherosclerosis, there was no relationship between the incidence and extent of CAC and the presence of FH of premature CAD. CAC distribution based on FH of CAD No FH Yes FH FH in parents only FH in siblings FH in both Number 3047 566 464 68 34 Males 74.8% 73.3% 74.3% 69.1% 67.7% Age (mean ± SD) 52 ± 9.6 46.9 ± 8.2 46.6 ± 8.1 49.5 ± 8.4 47.3 ± 8.2 Prevalence of CAC 35% 36% 35.2% 36.7% 41% Log-transformed CACs (± SD) 0.5 ± 0.8 0.5 ± 0.8 0.5 ± 0.8 0.5 ± 0.8 0.7 ± 0.9

Risk Factors of Premature Coronary Artery Disease

Introduction: Coronary artery disease (CAD) is one of the commonest and leading causes of death throughout the world. It is becoming common in the younger age group as well. This study was carried out to analyze the risk factors present in young patients who presented with acute Myocardial Infarction (M.I). Materials and Methods: In this descriptive cross-sectional study, we included 120 patients of age 20-35 years of age who presented with the first episode of acute M.I. Study was conducted at Pakistan Institute Of Medical Sciences, Islamabad, department of cardiology for all patients with first MI from 1st February 2016 to 31st January 2018. Twelve risk factors were studied including Gender, Hypertension, Diabetes mellitus, dyslipidemia, sedentary lifestyle, family history of premature CAD, obesity, smoking, dietary habits, profession, socioeconomic stress, drug addictions. The frequency of risk factors was calculated. Results: Results showed that some of the risk factors were present in higher proportion e.g. smoking, sedentary lifestyle, poor dietary habits, and stressful socioeconomic conditions. Most of the patients in the younger age group were drivers. The results of our study showed that male patients were higher(93.3%) in proportion to female patients (6.7%). 33% of patients were drivers, 13% plumbers, 13% shopkeepers, 10% businessmen, 8% laborers, 5% policemen, 5% students, 5% bank officers, 3% engineers, 2% teachers, 1% doctors. 68.3% of patients were smokers. 58.3% of patients were having high-stress scores. 23.3% of patients were having moderate stress score.18.3% were having a low-stress score. 56% of patients were having dyslipidemia.48% of patients were obese. Family history was present in 26.7% of patients. Conclusion: For patients presenting with premature CAD, Some of the modifiable risk factors include hypertension, sedentary lifestyle, fatty dietary habits, obesity, smoking, diabetes, dyslipidemia. The profession also affects the development of IHD as is evident from our study. So primary preventive strategies need to be implied to prevent the development of IHD, especially in individuals who are at risk.

Mutational Spectrum of LDLR and PCSK9 Genes Identified in Iranian Patients With Premature Coronary Artery Disease and Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a common, yet underdiagnosed, genetic disorder characterized by lifelong elevated low-density lipoprotein cholesterol levels, which can increase the risk of early-onset coronary artery disease (CAD). In the present study, we screened the nucleotide variations of the LDLR and PCSK9 genes, as well as a part of the APOB gene, in Iranian patients with FH and premature CAD to find the genetic cause of the disorder. Fifteen unrelated individuals with a clinical diagnosis of FH and premature CAD were recruited. Direct DNA sequencing was applied to screen the whole coding exons and exon–intron boundaries of the LDLR and PCSK9 genes and the main parts of their introns, together with exon 26 of the APOB gene. The pathogenicity of the identified mutations was investigated via either segregation analyses in the family or in silico predictive software. Six different point mutations (p.Cys148Tyr, p.Cys216Tyr, p.Cys302Trp, p.Cys338Trp, p.Leu479Gln, and p.G593Afs∗72) in LDLR and a double mutation (p.Asp172His and p.Ala53Val) in both LDLR and PCSK9 genes were identified in seven families with clinically diagnosed FH (43%), whereas no pathogenic mutations were found in eight families with clinically diagnosed FH. This study is the first to identify 1 pathogenic mutation in the LDLR gene (c.1014C > G [p.Cys338Trp]) and to cosegregate it from the affected individual in the family. No mutations were found in the APOB gene, whereas several silent mutations/polymorphisms were identified in the LDLR and PCSK9 genes. Genetic testing and reports on nucleotide alterations in the Iranian population are still limited. Our findings not only further confirm the significant role of FH in the incidence of premature CAD but also enlarge the spectrum of LDLR and PCSK9 variations and exhibit the heterogeneity of FH in Iranians. In patients with no mutation in the examined genes, the disease could be begotten either by a polygenic cause or by gene defects occurring in other related genes and regions not targeted in this study.

Risk Factor Burden and Long‐Term Prognosis of Patients With Premature Coronary Artery Disease

Background Coronary artery disease (CAD) is increasing among young adults. We aimed to describe the cardiovascular risk factors and long‐term prognosis of premature CAD. Methods and Results Using the Duke Databank for Cardiovascular Disease, we evaluated 3655 patients admitted between 1995 and 2013 with a first diagnosis of obstructive CAD before the age of 50 years. Major adverse cardiovascular events (MACEs), defined as the composite of death, myocardial infarction, stroke, or revascularization, were ascertained for up to 10 years. Cox proportional hazard regression models were used to assess associations with the rate of first recurrent event, and negative binomial log‐linear regression was used for rate of multiple event recurrences. Past or current smoking was the most frequent cardiovascular factor (60.8%), followed by hypertension (52.8%) and family history of CAD (39.8%). Within a 10‐year follow‐up, 52.9% of patients had at least 1 MACE, 18.6% had at least 2 recurrent MACEs, and 7.9% had at least 3 recurrent MACEs, with death occurring in 20.9% of patients. Across follow‐up, 31.7% to 37.2% of patients continued smoking, 81.7% to 89.3% had low‐density lipoprotein cholesterol levels beyond the goal of 70 mg/dL, and 16% had new‐onset diabetes mellitus. Female sex, diabetes mellitus, chronic kidney disease, multivessel disease, and chronic inflammatory disease were factors associated with recurrent MACEs. Conclusions Premature CAD is an aggressive disease with frequent ischemic recurrences and premature death. Individuals with premature CAD have a high proportion of modifiable cardiovascular risk factors, but failure to control them is frequently observed.

Abstract 17423: Impact of Hypertriglyceridemia on ST-Elevation Myocardial Infarction Outcomes

Introduction: There has been conflicting data regarding the impact of hypertriglyceridemia (HTG) on STEMI outcomes, including reports of a “lipid paradox” defined as lower event rates in patients with HTG. Therefore, the association between HTG and outcomes in STEMI deserves further investigation especially given the results of REDUCE-IT trial. Methods: A prospective, multicenter database of the Midwest STEMI Consortium was examined. The Midwest STEMI Consortium is a unique association of 4 large STEMI systems of care: Iowa Heart Center, Minneapolis Heart Institute Foundation, Prairie Cardiovascular, and The Christ Hospital. We included all consecutive STEMI patients between age of 40 and 75. Those with missing TG levels were excluded (23%). We compared 3 groups of TG levels: normal (<150 mg/dl), moderate (150 to 499 mg/dl), and severe (>500 mg/dl) for MACE (death, MI, or stroke) and all-cause mortality. Results: Of 6492 consecutive STEMI patients from 03/2003 to 01/2020, 3760 (58%) met inclusion criteria. The mean (SD) age was 59.1 ± 9.2 and male gender was predominant (76%). A little over one-third of the study participants had moderate HTG (35%). Patients with higher TG levels had lower HDL levels and increased rates of history of premature CAD, DM, and HTN (Table). Moderate HTG was not a risk factor for MACE or all-cause mortality. Severe HTG was significantly associated with increased in-hospital (p=0.016) but not 1-year all-cause mortality (p=0.21) (Figure). Conclusions: In STEMI patients, higher TG levels were associated with increased in-hospital but not 1-year all-cause mortality.

Abstract 12689: Targeted Exon Sequencing of Lipid-related Genes in Patients With Clinically Diagnosed Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is at high risk of premature coronary artery disease (CAD). Japan Atherosclerosis Society (JAS) has published original criteria for FH. Patients are diagnosed clinical FH if at least 2 of the following criteria are satisfied: i) LDL-C ≥ 180 mg/dL, ii) Tendon/ skin xanthomas, iii) History of FH or premature CAD within 2nd degree blood relatives. Although it is easy to apply these criteria for FH-suspected patients, in fact, we are not sure whether other lipid-related genes may be overlapped in addition to those of conventional FH genes such as LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9). Methods and Results: Ninety-one heterozygous FH (HeFH) patients in Osaka University Hospital, who met the clinical FH criteria of JAS were enrolled after obtaining informed consent. Genomic DNA for each patient was extracted from peripheral blood cells. Targeted exon sequencing was performed to investigate 36 lipid-related genes including conventional FH genes. We have defined pathogenic variants if they fulfilled i) rare protein truncating variants, ii) rare damaging missense variants, and iii) ClinVar-registered pathogenic or likely pathogenic variants. Among 91 HeFH patients (52.9 ± 14.7 years), 41 patients (45.1%) were males. We have identified LDLR pathogenic variants in 61 patients (67.0%) and PCSK9 variants in 1 patient (1.1%). Among these 62 patients, 22 patients (35.5%) additionally have pathogenic variants of other lipid-related genes, which include apolipoprotein E2 (APOE2) in 1 patient, apolipoprotein E4 (APOE4) in 10 patients, ATP-binding cassette subfamily G member 5 (ABCG5) in 2 patients, apolipoprotein C3 (APOC3) in 1 patient, and CD36 in 10 patients. As for remaining 29 patients without conventional FH gene variants, 13 patients (44.8%) have pathogenic variants of other lipid-related genes, which include APOE4 in 11 patients, apolipoprotein E5 (APOE5) in 1 patient, and variants of ABCG5 in 1 patient. Conclusion: We have identified several variants of lipid-related genes in addition to conventional FH genes in HeFH patients diagnosed according to JAS criteria. These variants may affect the atherogenicity of patients and selection of medication.