Analysis of Traditional Risk Factors of Atherosclerosis and Novel Risk Markers of Inammation in Coronary Ectasia Can We Solve The Enigma ??

Background: Coronary artery ectasia(CAE) is speculated as a variant of atherosclerosis. The pathogenesis of CAE remains an enigma. Here in our study, we aimed to elucidate the role of traditional risk factors of atherosclerosis and inammation in coronary ectasia. Methods and Results: This comparative study was carried in a tertiary hospital in South India.Patients with coronary artery ectasia and obstructive coronary artery disease were included as cases and controls . Traditional risk factors of atherosclerosis and risk markers of inammation (neutrophil-lymphocyte ratio(NLR), red cell distribution width (RDW), mean platelet volume (MPV) )were evaluated and comparative analysis was done. Coronary ectasia was observed in 5.6%(n=136)of the study population. Among those with ectasia,112(82.4%) patients were having signicant obstructive CAD (mixed group), isolated ectasia observed in24 (17.6%)patients. Isolated ectasia had an inverse association with diabetes mellitus and male:female ratio of (7:1). DM was seen only in 25% of isolated ectasia groups compared to 42.9%, 47.4% among mixed and obstructive CAD groups respectively (p < 0.05). Traditional risk factors were not signicantly different between the mixed group and obstructive CAD group. Inammatory markers were signicantly higher among the both ectasia group compared to obstructive CAD group NLR: 3.98±0.89, 3.58±0.56, 2.82±0.60 p <0.001. RDW:12.59±0.60, 12.29±0.85,12.02±0.70, p<0.005. MPV was elevated in all three groups but not much different among groups. Conclusion: Coronary ectasia commonly seen in association with CAD, the of traditional factors of atherosclerosis is similar between CAE+CAD, obstructive CAD group suggest and similar risk prole even DM in both mixed CAE+ CAD and pure CAD group, supports the hypothesis that underlying pathogenesis in CAE ,CAD are same which is atherosclerosis. Even in isolated ectasia group about 40% had minimal stenosis < 40% (Unpublished Data) further strengthen the relation with atherosclerosis. Histopathologically also ectasia resembles atherosclerosis except for medial degeneration.


Abstract
Background: Coronary artery ectasia(CAE) is speculated as a variant of atherosclerosis. The pathogenesis of CAE remains an enigma. Here in our study, we aimed to elucidate the role of traditional risk factors of atherosclerosis and in ammation in coronary ectasia.
Methods and Results: This comparative study was carried in a tertiary hospital in South India.Patients with coronary artery ectasia and obstructive coronary artery disease were included as cases and controls . Traditional risk factors of atherosclerosis and risk markers of in ammation (neutrophil-lymphocyte ratio(NLR), red cell distribution width (RDW), mean platelet volume (MPV) )were evaluated and comparative analysis was done. Coronary ectasia was observed in 5.6%(n=136)of the study population. Among those with ectasia,112(82.4%) patients were having signi cant obstructive CAD (mixed group), isolated ectasia observed in24 (17.6%)patients. Isolated ectasia had an inverse association with diabetes mellitus and male:female ratio of (7:1). DM was seen only in 25% of isolated ectasia groups compared to 42.9%, 47.4% among mixed and obstructive CAD groups respectively (p < 0.05). Traditional risk factors were not signi cantly different between the mixed group and obstructive CAD group. In ammatory markers were signi cantly higher among the both ectasia group compared to obstructive CAD group NLR: 3.98±0.89, 3.58±0.56, 2.82±0.60 p <0.001. RDW:12.59±0.60, 12.29±0.85,12.02±0.70, p<0.005. MPV was elevated in all three groups but not much different among groups.
Conclusion: Coronary ectasia commonly seen in association with obstructive CAD, the prevalence of traditional risk factors of atherosclerosis is similar between CAE+CAD, obstructive CAD group suggest atherosclerosis as the underlying pathophysiology. Elevated markers of in ammation suggest overlying in ammation on atherosclerosis to be the contributor of ectasia.

Highlights
Among the patients with ectasia 82.4% had associated signi cant coronary artery diseases.
Even in the isolated ectasia group signi cant number of patients had minimal CAD could have been well demonstrated with IVUS not done in our study Hence the association between obstructive CAD and CAE , and sharing of risk factors of atherosclerosis suggest underlying mechanism is atherosclerosis Signi cantly elevated in ammatory markers in ectasia group suggest in ammation initiate the medial destruction and Coronary ectasia Background Coronary artery Ectasia (CAE) has been de ned as an abnormal dilatation of coronary artery, with luminal diameter exceeding 1.5 times the adjacent normal reference segment. The term "Ectasia" was coined by Lars Bjork in his report of 3 patients with Tetralogy of Fallot . The prevalence of Coronary Artery Ectasia varies form 0.3-12.5% among patients undergoing diagnostic angiography for varies ischemic syndromes. Highest prevalence reported from India 10% -12% and Pakistan 12.5% . CAE may occur as an isolated form but most commonly seen in association with obstructive CoronaryArteryDisease. Ectasia is often viewed as a variant form of obstructive Coronary Artery Disease (CAD) and atherosclerosis is considered as a contributing factor in more than half of the cases. Although the association with atherosclerotic CAD is well evident, the relationship between traditional atherosclerotic risk factors and Ectasia remains controversial. Especially its poor correlation with Diabetes mellitus suggested Ectasia is a distinctive form of atherosclerosis characterized by positive remodeling-(Glagovian phenomenon) in contrast to obstructive disease (Negative Remodeling) . .Hemodynamic factors like ow, stretch, shear stress along with in ammatory signals were proposed as the triggers for this abnormal vascular remodeling and postulated as the link between atherosclerosis and CAE in susceptible individual. Multiple studies in this area were showing con icting evidence, hence the exact pathogenic mechanism still not conclusively de ned and in hypothetical stage .
The etiopathogenisis of this entity puzzled the clinician since its discovery, but still there are some unclear unde ned areas. Clinical signi cance remains uncertain and there is no consensus opinion regarding management. Hence further research is essential to solve these enigmas. Being in the region with highest prevalence of CAE, we have planned to analyze the traditional risk factors of atherosclerosis and risk markers of in ammation in patients with Coronary ectasia . Coronary Angiography : After obtaining an informed written Coronary angiography was done through either right femoral artery or right radial artery approach after sterile aseptic precaution under local anaesthesia using Judkins right and left (JR ,JL ) coronary catheter . 4 or 5 views for LAD( RAO caudal , AP caudal ,AP cranial ,LAO caudal ,LAO cranial) and 2 or 3views for RCA LAO ,AP cranial LAO cranial were recorded .The lms were reviewed by junior resident and ndings were con rmed by experienced interventional cardiologist De nition of Ectasia : In our study we followed the de nition used in CASS registry abnormal dilatation of coronary artery, with luminal diameter exceeding 1.5 times the adjacent normal reference segment. If no adjacent normal segment could be identi ed, the mean diameters of the coronary segments in a control group without heart disease served as normal values." De nition of obstructive CAD in angiogram : Obstructive CAD was diagnosed if a patient had > 50% loss of luminal diameter compared to the reference normal segment.

De nition of Groups:
According to the angiography patients were categorized into three groups Group A = Isolated Ectasia patients having Ectasia without any evidence of signi cant obstruction in coronary artery (>50%), Group B Mixed CAE + CAD group Patients with Ectasia and also having signi cant obstruction in any of the coronaries .Group C= Pure CAD group patients having only CAD without evidence of CAE Patients were treated according to the guideline given by American College of Cardiology /American Heart Association . Left ventricular systolic function was recoded with Philips IE 33 echocardiography machine . Clinical events LVF ,in hospital mortality were recorded . Outcome data during follow up were collected speci cally regarding the Unstable angina ,MI mortality and recoded for analysis Stastical Analysis ; Continuous variables were analyzed with Mean ± SD (BMI, Lipid parameters ,age) . Categorical variables sex ,DM hypertension ,vessel involved outcome ) were described with number & percentage .Chi Square test used to assess the signi cance P value < 0.05 were considered as stastically signi cant.

Results
Prevalence : Totally 2434 patients undergone coronary angiogram during the study period with the suspicion of Coronary Artery Disease (Chronic Stable Angina ,ACS) Of those 1966 patients was eligible for our study . Coronary ectasia was found in 136 (5.6%) patients of whom 24 (1.0%) patients were diagnosed to have isolated ectasia (isolated ectasia group) without evidence of signi cant obstructive coronary disease and 112 (4.6%) (CAE+CAD group) patients with ectasia were having associated with obstructive CAD . Remaining1830 patients were having pure obstructive CAD (CAD group)(75.2%).Baseline characters have been tabulated in Table 1. Isolated ectasia (dilated coronaropathy) contributes to 17.6%(n=24 )of coronary ectasia ,remaining 82.4% had associated obstructive CAD (n=112) .

Age & Sex :
Mean age of the population in isolated ectasia is signi cantly lower (44±8.6 Vs 54.32±8.72 Vs 56±7.8 P<0.001) compared to mixed CAE +CAD group and isolated CAD. Sex distribution showed male predominance in all the groups .the proportion among total ectactic population is M: F 3.1:1.Signi cant male dominance was noted in Isolated ectasia group (7:1 p value <0.001). But when comparing total ectasia group (n=136) to isolated CAD the male dominance nulli ed indicated that male sex is a signi cant risk factor for Dilated coronaropathy(Isolated ectasia). But male sex is not a signi cant risk factor mixed ectasia group (CAE+CAD) when comparing with isolated CAD group the male(2.7:1 Vs 2.5:1 P value NS) dominance is due to high incidence of CAD among males .

Other Conventional Risk Factors :
Diabetes Mellitus was observed in 25% ( n=6/24)of patients with isolated ectasia In mixed group DM was seen in 48/112 patients and in pure CAD 47.4% of patients were having DM . Prevalence DM is similar in mixed group and pure CAD But in isolated ectasia prevalence of signi cantly lower when compared to other groups indicating the inverse association between Diabetes mellitus & isolated ectasia, not in mixed group Systemic Hypertension was found in 33.3% (n=8/24)of isolated ectasia group whereas in mixed and pure CAD group it was 47.3 % (n=53/112) and 49.4% respectively . Five among 24 isolated ectasia patients (20.8%)were obese with the BMI of >30, in mixed group 23.2% were obese in pure CAD 22.6% were obese .Mean LDL was 105± 22.68 mg% in isolated ectasia patients with LDL > 100 mg % was observed in 29.2% of the patients . In mixed and pure CAD group mean LDL cholesterol was 104.9±19.8, 108±16.7 mg% respectively with high LDL was noted among 36.6% ,and 37.1% of the patients in these group the difference was not signi cant .Similarly HDL cholesterol was low in half the isolated ectasia group 54.1% but the difference between the groups were not statistically signi cant , the mean among different group was 37.9±-8 in isolated ectasia patients 36.19±7.13 & 37.52±6.9 in mixed group and pure CAD population. Signi cantly less number of people in isolated ectasia were having hypertriglyceridemia but the mean level was not statistically signi cant across the 3 groups .

Novel Risk Markers :
Mean Neutrophil count was signi cantly higher among isolated ectasia group and in CAE+CAD group compared to pure CAD group 5.986±1.497 Patients in the isolated ectasia group were younger than other groups (44±8.6 Vs 54.32±8.72 Vs 56±7.8 P<0.001) .This nding is consistent with the nding of some previous studies .Gender distribution showed male predominance in all the groups .the proportion among total ectactic population is M:F 3.1:1.Signi cant male dominance was noted in Isolated ectasia group (7:1 p value <0.001). But when comparing total ectasia group (n=136) to pure CAD the male dominance nulli ed indicated that male sex is a signi cant risk factor for Dilated coronaropathy(Isolated ectasia). But male sex is not a signi cant risk factor mixed ectasia group (CAE+CAD) when comparing with isolated CAD group the male(2.7:1 Vs 2.5:1 P value NS) dominance is due to high incidence of CAD among males . Male dominance(M:F 2-3:1) was noted in some previous studies also especially in isolated ectasia group but no statistical signi cance was found between CAD and CAE group .Some authors attributed that the difference is due to lower incidence of CAD among women but G G Hartnell [viii] reported signi cant male dominance despite the allowance given for lower incidence of CAD in females .
Among the traditional risk factors, Diabetes mellitus has unique position with ectasia, Giannoglou GD et al [ix] Williams SB[x] et al reported negative association between ectasia and diabetes mellitus . After a metaanalysis Huang et al concluded that DM has inverse association with CAE and act as a protective factor too[xi]. . In our study we found a similar inverse relation between isolated ectasia and DM 6 (25%) vs 48(42.9%) vs 868(47.4%) <0.05 with signi cantly lower incidence of DM in isolated ectasia group compared mixed and pure CAD group. But there was no difference between mixed and pure CAD group which is contradictory to the meta-analysis QJ Haung .,et al. Negative association between DM and ectasia observed only in patients with isolated Ectasia vs others . Other traditional risk factors like LDL ,HDL does not different among all the three groups .But people with isolated ectasia had signi cantly lower BMI compared to others .Which we suspected probably due to less incidence of Diabetes and younger hard working manual labourers in ectasia group .
Isolated ectasia is unique observed in smoking, younger population having signi cantly low prevalence of DM. But the ectasia coexisting with obstructive CAD (Mixed)does not differ much from pure obstructive CAD.

Novel Risk markers :
Evidence for the link between in ammation and CAE becoming strong day by day . To evaluate the in ammatory hypothesis with underlying atherosclerosis as possible pathogenic mechanism of coronary artery ectasia we assessed the inexpensive markers of in ammation. In line with previous observation our study also showed high neutrophil count and NLR in CAE group compared to pure CAD group. Atherosclerosis primarily intimal disease , CAE differs histologically from obstructive disease by signi cant tunica media destruction. This high neutrophil mediated in ammatory activity have been proposed as the explanation for CAE in obstructive CAD (mixed group). MPV platelet volume a marker of hyperactive platelet found to be higher among CAE compared to healthy control but similar between CAE and CAD group .Here in our study MPV was not signi cantly different between groups. MPV an indicator of platelet activity is not different among the groups, suggest that platelet appears to be equally active in CAD and Ectasia group. But here we did not compare with the normal control group , so we cannot underestimate the role of MPV. Another indirect marker of in ammation is RDW which was signi cantly elevated among isolated CAE compared to CAD similar to report by Xiao-Lin Li et al [xiii] . Among the novel easily available markers of in ammation, RDW, NLR, signi cantly elevated in isolated ectasia, mixed group(NLR ) supporting the in ammatory hypothesis.
Summary & Conclusion 1. Association of CAE with obstructive CAD (82.4%) and similar risk pro le even DM in both mixed CAE+ CAD and pure CAD group, supports the hypothesis that underlying pathogenesis in CAE ,CAD are same which is atherosclerosis. Even in isolated ectasia group about 40% had minimal stenosis < 40% (Unpublished Data) further strengthen the relation with atherosclerosis. Histopathologically also ectasia resembles atherosclerosis except for medial degeneration.     Figure 1 a: Summary of the study population