with the rapid increase in the applications of coronary angiography , a growing number of coronary artery ectasia ( cae ) cases have been detected .
cae is an independent predictor of mortality , and aneurysmal patients with nonobstructive diseases have mortality rates similar to those of patients with 3-vessel diseases .
the largest cohort study of cae to date found that aneurysmal patients had a 5-year mortality rate of 26% mortality in 1983 .
two decades later , the 5-year mortality rate of patients with coronary aneurysms remained as high as 29% despite the progressive advances and improvements in medical therapy for coronary artery diseases , and there was no statistically significant difference between the survival rate of aneurysmal patients with and without obstructive coronary artery disease ( o - cad ) .
several inflammatory biomarkers have been found to be associated with cae . in particular , the high - sensitivity c - reactive protein ( hs - crp )
the hs - crp was found to be significantly higher in patients with cae than in those with o - cad or with normal coronary angiography .
inflammation contributes to the initiation and progression of atherosclerosis , but its role in the progression of cae remains unclear .
the prognostic value of hs - crp in cardiovascular diseases has been well evaluated , such as in stable coronary artery disease and acute coronary syndrome .
in addition , the hs - crp could improve risk prediction accuracy for adverse cardiovascular events ( cvs ) .
however , the prognostic value of hs - crp in established cae has not been assessed so far . since death and myocardial infarction are the prominent features of cae , the present investigation was designed to evaluate whether the baseline hs - crp could predict the composite cvs ( cardiac death and nonfetal myocardial infarction ) associated with cae .
if so , it might be used to guide the risk stratification and clinical decisions of cae patients .
the study population consisted of consecutively enrolled cae patients who had been admitted to our hospital and had undergone a coronary angiography during january 2009 and july 2013 .
the indication for coronary angiography was either the presence of typical angina or positive or equivocal results of noninvasive screening tests for myocardial ischemia .
cae was defined as a localized or diffused luminal dilation exceeding 1.5-fold of the normal adjacent arterial segment .
the cae patients were included consecutively , regardless of whether they had an o - cad or not .
those who presented the following characteristics were excluded from the study : acute coronary syndrome , acute or chronic infection , renal failure , hepatic dysfunction , malignant disease , hematological disorder , pregnancy , severe valvular disease , cardiomyopathy , congenital heart disease , and drugs or alcohol abuse .
the patients medical history and physician - administered physical examination information were obtained from the hospital 's medical records .
all patients provided their informed consent , and the study was approved by local ethics committee .
the baseline hs - crp values and other blood biomarkers were also collected from our medical records system , and all these biomarkers were measured from the samples collected in the morning after an overnight fast . the hs - crp was determined with an aus5400 ( olympus , japan ) molecular analyzer at our clinical laboratory department .
the follow - up was performed through telephone interviews and consultation of the hospital 's medical records in july 2014 .
the researchers who conducted the follow - up were blind to the baseline status of the cae patients .
the observational outcome was the composite of two cvs : cardiac death and nonfatal myocardial infarction .
cardiac deaths were defined as death diagnosed by medical practitioners as definitely cardiogenic or unexplained sudden death . where a patient had reached more than one end point , only the first event was taken into count .
all the data were analyzed with sas software , version 9.3 ( sas institute , cary , nc , usa ) , and a two - tailed p < 0.05 was considered statistically significant .
the continuous variables were expressed as mean  standard deviation while the categorical data were given as counts and percentages .
the student 's t - test or wilcoxon 's rank - sum test ( as appropriate ) were used to compare the continuous variables , and we used the chi - square test to analyze the categorical variables . to determine the independent prognostic value of baseline hs - crp for predicting cvs , we employed multivariable cox proportional hazards regression models .
three parts of variables were adjusted : ( 1 ) the prognostic factors of cae identified in a previous study ( such as age , diabetes mellitus , and hyperlipidemia ) , ( 2 ) the baseline demographics and routine laboratory examination results having statistical significance ( p < 0.05 ) in comparison between groups with cvs and without cvs , and ( 3 ) the baseline characteristics variables with p < 0.05 according to the centers for disease control ( cdc ) and the american heart association ( aha ) recommended cutoff point of hs - crp ( 3 mg / l ) for high - risk category .
next , the event - free survival rate of categorized hs - crp ( > 3 mg / l vs. 3 mg
/ l ) was illustrated with a kaplan - meier curve , and the values were compared with a log - rank test .
the adjusted kaplan  meier curve and hazard ratios ( hrs ) were also obtained .
subsequently , we examined the net reclassification improvement ( nri ) and of the risk categories ( > 3 mg / l , 3 mg / l ) for the prediction of the 3-year event - free survival and the integrated discrimination improvement ( idi ) by adapting recent approaches to convert the numbers into suitable survival data .
the nri measures the correctness of reclassification of patients based on their predicted probabilities of events using the new model with the option of imposing meaningful risk categories ( > 3
mg / l ) . the idi measures the new model 's improvement in average sensitivity without sacrificing average specificity .
the multivariate logistic regression model was used for this analysis . a combination of the classical cardiovascular risk factors ( age , sex , body mass index ( bmi ) , low - density lipoprotein ( ldl)/high - density lipoprotein ratio , smoking , diabetes , hypertension , and number of diseased vessels ) was included in the basic model to derive the basic categories .
mg / l ) was added into the new model based on the basic model .
the study population consisted of consecutively enrolled cae patients who had been admitted to our hospital and had undergone a coronary angiography during january 2009 and july 2013 .
the indication for coronary angiography was either the presence of typical angina or positive or equivocal results of noninvasive screening tests for myocardial ischemia .
cae was defined as a localized or diffused luminal dilation exceeding 1.5-fold of the normal adjacent arterial segment .
the cae patients were included consecutively , regardless of whether they had an o - cad or not .
those who presented the following characteristics were excluded from the study : acute coronary syndrome , acute or chronic infection , renal failure , hepatic dysfunction , malignant disease , hematological disorder , pregnancy , severe valvular disease , cardiomyopathy , congenital heart disease , and drugs or alcohol abuse .
the patients medical history and physician - administered physical examination information were obtained from the hospital 's medical records .
all patients provided their informed consent , and the study was approved by local ethics committee .
the baseline hs - crp values and other blood biomarkers were also collected from our medical records system , and all these biomarkers were measured from the samples collected in the morning after an overnight fast . the hs - crp was determined with an aus5400 ( olympus , japan ) molecular analyzer at our clinical laboratory department .
the follow - up was performed through telephone interviews and consultation of the hospital 's medical records in july 2014 .
the researchers who conducted the follow - up were blind to the baseline status of the cae patients .
the observational outcome was the composite of two cvs : cardiac death and nonfatal myocardial infarction .
cardiac deaths were defined as death diagnosed by medical practitioners as definitely cardiogenic or unexplained sudden death . where a patient had reached more than one end point , only the first event was taken into count .
all the data were analyzed with sas software , version 9.3 ( sas institute , cary , nc , usa ) , and a two - tailed p < 0.05 was considered statistically significant .
the continuous variables were expressed as mean  standard deviation while the categorical data were given as counts and percentages .
the student 's t - test or wilcoxon 's rank - sum test ( as appropriate ) were used to compare the continuous variables , and we used the chi - square test to analyze the categorical variables . to determine the independent prognostic value of baseline hs - crp for predicting cvs , we employed multivariable cox proportional hazards regression models .
three parts of variables were adjusted : ( 1 ) the prognostic factors of cae identified in a previous study ( such as age , diabetes mellitus , and hyperlipidemia ) , ( 2 ) the baseline demographics and routine laboratory examination results having statistical significance ( p < 0.05 ) in comparison between groups with cvs and without cvs , and ( 3 ) the baseline characteristics variables with p < 0.05 according to the centers for disease control ( cdc ) and the american heart association ( aha ) recommended cutoff point of hs - crp ( 3 mg / l ) for high - risk category .
next , the event - free survival rate of categorized hs - crp ( > 3 mg /
/ l ) was illustrated with a kaplan - meier curve , and the values were compared with a log - rank test .
the adjusted kaplan  meier curve and hazard ratios ( hrs ) were also obtained .
subsequently , we examined the net reclassification improvement ( nri ) and of the risk categories ( > 3 mg / l , 3 mg / l ) for the prediction of the 3-year event - free survival and the integrated discrimination improvement ( idi ) by adapting recent approaches to convert the numbers into suitable survival data .
the nri measures the correctness of reclassification of patients based on their predicted probabilities of events using the new model with the option of imposing meaningful risk categories ( > 3
the idi measures the new model 's improvement in average sensitivity without sacrificing average specificity .
the multivariate logistic regression model was used for this analysis . a combination of the classical cardiovascular risk factors ( age , sex , body mass index ( bmi ) , low - density lipoprotein ( ldl)/high - density lipoprotein ratio , smoking , diabetes , hypertension , and number of diseased vessels ) was included in the basic model to derive the basic categories
mg / l ) was added into the new model based on the basic model .
based on the inclusion and exclusion criteria , 577 cae patients were included in our study cohort , and we eventually obtained follow - up results for 540 ( 93.6% ) of them .
the longest follow - up duration was about 66 months , while the shortest was 12 months . during this follow - up period , 30 cvs12 cardiac deaths and 18 nonfatal myocardial infarctions 
comparisons of the baseline characteristics between the groups of patients with cvs and without cvs were shown in table 1 .
the patients with cvs were much older ( 62.87  10.01 vs. 56.68  10.95 months , p = 0.0026 ) and had a relatively lower left ventricular ejection fraction ( 55.38%  12.36% vs. 60.49%  9.93% , p = 0.0081 ) than those without cvs . however , there was no statistically significant difference between the groups in terms of sex , hypertension , hyperlipidemia , diabetes mellitus , smoking , family history of coronary heart diseases , prior myocardial infarctions , prior cerebral vascular diseases , gensini score , and medications . baseline characteristics of cae patients who had composite cardiovascular events and those who were events - free * t - test value ; chi - square test value .
aceis : angiotensin - converting enzyme inhibitors ; arbs : angiotensin receptor blockers ; bmi : body mass index ; chd : coronary heart disease ; cv : cardiovascular ; cvd : cerebral vascular disease ; lvef : left ventricular ejection fraction ; mi : myocardial infarction .
comparisons of the routine laboratory examination results between groups with cvs and without cvs according to the binary classification ( by the median level ) and quartered ( by quartiles ) classification are shown in the supplementary materials [ supplementary tables 1a and 1b ] . in the binary classification ,
the group with cvs had a larger proportion of parameters  including left ventricular ejection fraction ( 79.3% vs. 49.7% , p = 0.0013)below the median level than the group without cvs .
conversely , there was a smaller proportion of direct bilirubin ( 30.8% vs. 52.9% , p = 0.0263 ) below the median level in the group with cvs than the group without cvs . in the quartered classification , the following variables had statistical significance : the left ventricular ejection fraction , neutrophils , brain natriuretic peptide , and direct bilirubin .
comparisons for composite cardiovascular events by the median of various routine laboratory examination results bnp : brain natriuretic peptide ; cv : cardiovascular events ; dbil : direct bilirubin ; hs - crp : high - sensitivity c - reactive protein ; ldl - c : low density lipiproten - cholesteral ; lvef : left ventricular ejection fraction . comparison for composite cardiovascular events by the quartile of various routine laboratory examination results bnp : brain natriuretic peptide ; cv : cardiovascular ; dbil : direct bilirubin ; hs - crp : high - sensitivity c - reactive protein ; ldl - c : low density lipiproten - cholesteral ; lvef : left ventricular ejection fraction . table 2 shows comparisons of the baseline characteristics between cae patients with hs - crp
3 mg / l and those with hs - crp > 3 mg / l .
the patients with hs - crp > 3 mg / l showed a greater incidence of hypertension ( 35.6% vs. 26.9% , p = 0.0270 ) and a larger bmi ( 27.09  3.71 vs. 26.20  3.14 kg / m , p = 0.0036 ) . in terms of medications
, there was more aspirin usage in the group with hs - crp > 3 mg / l .
there were no significantly statistical differences between the two groups in the other baseline characteristics .
comparison of the baseline characteristics of the cae patients with hs - crp 3 mg / l and hs - crp > 3 mg / l * t - test value ; chi - square test value .
acei : angiotensin - converting enzyme inhibitor ; arbs : angiotensin receptor blockers ; bmi : body mass index ; cabg : coronary artery bypass graft ; chd : coronary heart disease ; cvd : cerebral vascular disease ; mi : myocardial infarction .
the multivariable analysis of the association between an hs - crp > 3 mg / l vs. an hs - crp 3 mg / l and cvs was obtained with cox proportional hazard models [ table 3 ] . after adjustment for the prognostic factors of cae identified by a previous study ( i.e. , age , diabetes mellitus and hyperlipidemia ) , a higher hs - crp level ( > 3 mg / l ) remained an independently significant predictor of cvs ( hr : 2.33 , 95% confidence interval [ ci ] : 1.134.81 , p = 0.0215 ) . after further adjustment for brain natriuretic peptide and lymphocyte , an hs - crp level > 3
mg / l was still associated with a higher risk of cvs ( hr : 2.11 , 95% ci : 1.024.38 , p = 0.0445 ) .
adjustment for bmi , neutrophils , left ventricle ejection fraction , direct bilirubin , and sex seemed to increase the strength of this association ( hr : 2.99 , 95% ci : 1.316.81 , p = 0.0091 ) .
hrs ( 95% ci ) of cardiovascular events in relation to baseline hs - crp ( > 3 mg / l vs. 3 mg
/ l ) among cae patients bmi : body mass index ; cae : coronary artery ectasia ; hs - crp : high - sensitivity c - reactive protein ; hrs : hazard ratios ; ci : confidence interval .
model 1 diabetes mellitus and hyperlipidemia ; model 2 adjusted for the above variables plus age ; model 3 adjusted for the above variables plus brain natriuretic peptide ; model 4 adjusted for the above variables plus lymphocyte ; model 5 adjusted the above variables plus bmi , neutrophils and left ventricle ejection fraction ; model 6 adjusted for the above variables direct bilirubin ; model 7 adjusted for the above variables and plus gender .
meier analysis of cv - free survival according to the hs - crp level ( 3 mg / l ) is curved in [ figure 1 ] . from the curve in figure 1a , it is apparent that the event - free survival rate of the patients with hs - crp > 3 mg / l differed from that with hs - crp 3 mg / l ( log - rank test for trend , p = 0.0235 ) . after adjusting for the age , gender , diabetes mellitus , hyperlipidemia , bmi , lymphocyte , neutrophils , natriuretic peptide , left ventricle ejection fraction , and direct bilirubin ,
the cumulative 66-month event - free survival rate of cae patients with hs - crp 3 mg / l remained considerably better than that of patients with hs - crp > 3 mg / l [ hr = 2.66 , 95% ci : 1.225.77 , p = 0.014 ; figure 1b ] .
kaplan  meier curve for composite cardiovascular events by hs - crp ( > 3 mg / l vs. 3 mg
( a ) the survival rate of the patients with hs - crp > 3 mg / l notably distinguished from those counterpart ( log - rank test , p = 0.0235 ) .
( b ) the cardiovascular events risk of patients with hs - crp > 3 mg / l was still much higher than those with hs - crp 3 mg /
l ( hr = 2.66 , 95% ci : 1.225.77 , p = 0.014 ) .
the adjusting variables include age , gender , diabetes mellitus , hyperlipidemia , body mass index , lymphocyte , neutrophils , natriuretic peptide , left ventricle ejection fraction , and direct bilirubin .
hs - crp : high - sensitivity c - reactive protein ; hr : hazard ratio ; ci : confidence interval ; cae : coronary artery ectasia .
the reclassification was assessed to further explore whether the hs - crp added to the predictive value of traditional risk factors for the outcomes of cae [ table 4 ] .
unexpectedly , the nri for hs - crp was merely 0.01 ( p = 0.8798 ) .
however , the hs - crp yielded an idi of 0.02 ( p = 0.033 ) .
the p value improved from 0.344 to 0.897 in the hosmer  lemeshow test , which quantifies the extent to which the predicted probabilities match the actual experience . however , there was no improvement in the reclassification of hs - crp for the prediction of cardiovascular death or of nonfatal myocardial infarction .
net reclassification improvement and integrated discrimination improvement for hs - crp mi : myocardial infarction ; bmi : body mass index ; ldl : low - density lipoprotein ; hdl : high - density lipoprotein ; nri : net reclassification improvement ; idi : integrated discrimination improvement ; the basic model comprised age , sex , bmi , ldl / hdl ratio , smoking , diabetes , hypertension , and number of diseased vessels .
the present study assessed the prognostic value of hs - crp for patients with cae .
the major finding of this study is that the hs - crp on admission is an independent predictor of the cardiovascular outcomes in cae patients .
there has been relatively limited research on the outcome of cae and the prognosis for patients with the condition remained .
three decades ago , the largest cohort study of cae to date found that the aneurysmal patients had a 5-year mortality rate of 26% . in 2004 , baman et al . reported a 5-year mortality rate of 29.1% in a cohort of 276 cae patients
however , in another study of 258 cae patients , the cardiovascular deaths over the follow - up period of 49  21 months only represented 2% . in the present study , we obtained follow - up data for 540 cae patients over a median follow - up period of 36 ( 37.41  15.88 ) months , and observed 12 ( 2.22% ) cardiac deaths and 18 ( 3.33% ) nonfatal myocardial infarctions . in light of these numbers
a phenomenon that might be partially explained by the advances in medical therapy . in the present analysis , hs - crp
> 3 mg / l was identified as an independent predictor of poor prognosis in patients with cae .
however , there has been conflicting information about the ideal and incremental level of hs - crp for the prediction of cvs . in several studies ,
a median hs - crp value of 2 mg / l was regarded as the appropriate cutoff point for the identification of increased risks of cvs . however , more than 50% of adults and
41% of 20-year - olds in the united states have an hs - crp level > 2 mg / l .
therefore , an hs - crp of 2 mg / l might not be an ideal cutoff point for risk stratification .
the clinically applied threshold of hs - crp > 3 mg / l might be more suitable for the identification of high risks of future cardiovascular complications . in a study , patients with coronary artery disease were followed for a median of 5.0 years ( 5.1  0.3 years ) , and those with an hs - crp > 3 mg / l had a significantly higher coronary events risk than those with an hs - crp level 3
patients with stable angina whose hs - crp exceeded 3 mg / l were subjected to more frequent subsequent cardiovascular death , myocardial infarctions , and strokes . in the present study , we applied the cdc / aha hs - crp cutoff point ( > 3
mg / l ) for the identification of the higher risk group and demonstrated that an elevated level of hs - crp was associated with an increased risk of cardiovascular death and nonfetal myocardial infarction in cae patients .
but the survival rate of cae patients is similar during 5-year 's follow - up , no matter with o - cad or not .
consistent with this result , there was no significant difference of gensini score between the group with cvs and without cvs [ table 1 ] , indicating that the poor prognosis of cae was not associated with the severity of the concomitant o - cad .
the present study demonstrated that an elevated level of hs - crp was associated with a higher risk of cvs , indicating that crp might be involved in the progression of cae .
previous investigators have shown an increase in plasma crp in cae patients , and several reports have suggested that crp might contribute to the adverse cvs . at first , systematic inflammation  as reflected in the concentration of crp  preceded the onset of cvs rather than being a result of ischemia .
second , crp could increase monocyte adhesion to endothelial cells and the secretion of matrix metalloproteinases , leading to endothelial dysfunction and medial destruction .
third , the pro - thrombotic effects of crp were demonstrated in human as well as transgenic mouse .
finally , the therapeutic inhibition of crp could counteract the increase in infarct size and cardiac dysfunction produced by the injection of human crp in rats .
besides demonstrating the prognostic role of crp in cae patients , this study also had its clinical implications .
consideration of hs - crp level could be used in the risk stratification of cae patients .
irrespective of ldl cholesterol concentration , a higher hs - crp concentration has previously been associated with a higher coronary event rates .
similarly , in this study , a higher hs - crp level indicated a poor prognosis in cae patients .
therefore , consideration of hs - crp level might be helpful in tailoring the therapy to individual cae patients .
this might have influenced the accuracy of the multivariable cox models and might limit the generalizability of the results .
nevertheless , the present results suggested that crp might contribute to the progression of cae .
second , the small value of the hs - crp nri for the outcomes might have resulted from the relatively small sample size and limited follow - up time .
however , we found an idi of 0.02 ( p = 0.033 ) and p value improvement in the hosmer  lemeshow test ; these results were similar to those observed in cases of stable o - cad .
finally , as we only used the hs - crp level on admission in the analyses , there was a lack of the longitudinal detection and continuous observation . however , considering the decade - to - decade consistency in crp values , the crp has been sufficiently suitable for the long - term prediction of cae patients prognosis . in conclusion ,
the hs - crp on admission was an independent predictor of cae patients adverse cvs in .
in addition , this study suggested that the crp may play a role in cae , as a relationship was found between elevated hs - crp levels and poor cae prognosis .
an hs - crp cutoff point of 3 mg / l might be considered for risk stratification in patients with cae .
supplementary information is linked to the online version of the paper on the chinese medical journal website .
this work was supported by a grant from the beijing municipal science and technology commission ( no .
this work was supported by a grant from the beijing municipal science and technology commission ( no .
 background : despite its severity , coronary artery ectasia ( cae ) is still poorly understood . 
 high - sensitivity c - reactive protein ( hs - crp ) has been recognized as a prognostic factor in some cardiovascular diseases but not assessed in cae . 
 the aim of this observational study was to investigate the prognostic value of hs - crp in cae.methods:our analysis evaluated the effect of the baseline hs - crp on cardiovascular events ( cvs ) ( cardiac death and nonfetal myocardial infarction ) in consecutively enrolled stable cae patients . 
 we used the cox proportional hazards regression models to examine the association between baseline hs - crp level and follow - up cvs in cae . 
 the net reclassification improvement and integrated discrimination improvement ( idi ) of hs - crp were also assessed.results:we obtained the follow - up results of 540 patients over a median follow - up period of 36 ( 37.41  15.88 ) months . 
 the multivariable cox analysis showed that the hs - crp was a significant predictor of adverse outcomes in cae ( hazard ratio [ hr ] : 2.99 , 95% confidence interval [ ci ] : 1.316.81 , p = 0.0091 ) . in kaplan  
 meier analysis , the group with hs - crp > 3 mg / l had a lower cumulative 66-month event - free survival rate ( log - rank test for trend , p = 0.0235 ) and a higher risk of cvs ( hr = 2.66 , 95% ci : 1.225.77 , p = 0.0140 ) than the group with hs - crp 3 
 mg / l . 
 hs - crp added predictive information beyond that given by the baseline model comprising the classical risk factors ( p value for idi = 0.0330).conclusions : a higher level of hs - crp was independently associated with cardiac death and nonfatal myocardial infarction in cae patients 
 . the hs - crp level may therefore provide prognostic information for the risk stratification of cae patients . 
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Study design and enrollment
Laboratory examinations
Follow-up
Statistical analysis
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Financial support and sponsorship
Conflicts of interest