slow coronary flow ( scf ) phenomenon is a coronary microvascular disease diagnosed by detection of delayed dyeopacification in coronary arteries during an angiography in the lack of obstructive coronary artery disease .
the incidence of scf has been reported to be approximately 1 - 7% in patients who undergo a diagnostic coronary angiography due to suspected coronary artery disease.1 ) despite being a well - known phenomenon , the pathophysiologic mechanisms of scf remain unknown .
potential mechanisms involved in scf are : small vessel and endothelial dysfunctions,2)3 ) inflammation,4)5 ) diffuse atherosclerosis,6 ) and increased platelet aggregability.7 ) platelets have been shown to have an important role in the pathogenesis of acute coronary syndrome .
some mediators involved in inflammatory processes and coagulatory pathways might have contributed to the development of atherosclerotic and atherothrombotic diseases.8)9 ) mean platelet volume ( mpv ) , an index of platelet activation , has been shown to be associated with adverse cardiovascular outcomes.10 ) mpv was found to be elevated in scf cases compared to normal ones.11 ) platelet distribution width ( pdw ) is found to be increased during platelet activation.12 ) platelet larger cell ratio ( p - lcr ) , an idicator of larger platelet circulating ( > 12 fl ) , has also been used to monitor platelet activity.13 ) given the probabale pathophysiologic roles of inflammation and platelet dysfunction in the development of scf , we sought to determine the relationship between scf and platelet activation using platelet volume indices mpv , pdw , and p - lcr .
in a case - control study , a total of 1650 consecutive patients who underwent diagnostic coronary angiography due to unstable angina and/or chest discomfort without positive non - invasive tests were evaluated in our two university centers , including seyyed - al - shohada heart center and taleghani hospital from april 2013 to november 2013 .
the local ethics committee in the urmia university of medical sciences , west - azerbaijan province , iran , approved this investigation . of evaluated participants , 50 diagnosed with scf based on thrombolysis in myocardial infarction frame counting ( tfc ) method
30 participants had normal coronary flow ( ncf ) were considered as control group after fulfilling inclusion and exclusion criteria .
exclusion criteria were : 1 ) diagnosed as coronary artery disease ; 2 ) coronary artery stenosis > 50% of the coronary artery diameter in angiographic evaluation ; 3 ) peripheral arterial disease ; 4 ) valvular heart disease ; 5 ) thrombocytopenia ; 6 ) hematologic diseases ; 7 ) hepatic diseases ; 8) chronic inflammatory disease ; 9 ) malignancies ; 10 ) infectious disease ; 11 ) autoimmune disease ; 12 ) anemia ; 13 ) renal failure ; and 14 ) thyroid diseases .
all patients underwent coronary angiographic examination through femoral artery using judkins ' method ( siemens , forcheim , germany ) .
the contrast media of iodixanol ( ge healthcare , cork , ireland ) was used in all cases .
two cardiologists who were blinded to the patients ' condition and clinical features evaluated all angiograms to identify scf using tfc method.14 ) the numbers of angiographic frames were recorded at 30 frames per second .
the coronary flow was calculated as reaching contrast media to the defined distal part of coronary arteries .
the end distal parts in the left anterior descending ( lad ) and left circumflex ( lcx ) arteries were distal bifurcation points .
the calculated frame counting for lad artery was divided by 1.7 based on the predefined criteria.14 ) according to gibson et al.14 ) the cut - off values for detecting scf were 36.22.6 , 20.43 , and 22.24.1 frames for lad , rca , and lcx arteries , respectively .
automated cell count analyzer ( sysmex , kobe , japan ) was used to measure complete blood count .
continuous variables were analyzed using t - test , one - way analysis of variance or mann whitney u test as appropriate based on the variables ' distribution normality .
receiver operating characteristic curve was constructed to detect the accuracy of platelet volume indices to differentiate scf from ncf .
multivariate logistic regression analysis and backward stepwise were conducted to determine the predictors of scf among our studied cohort . in this analysis ,
demographics and laboratories were entered into the model as covariates , and the status of scf was considered as a dependent variable .
all analyses were performed using statistical package for the social sciences ( spss ) version of 18.0 ( spss inc . ,
in a case - control study , a total of 1650 consecutive patients who underwent diagnostic coronary angiography due to unstable angina and/or chest discomfort without positive non - invasive tests were evaluated in our two university centers , including seyyed - al - shohada heart center and taleghani hospital from april 2013 to november 2013 .
the local ethics committee in the urmia university of medical sciences , west - azerbaijan province , iran , approved this investigation . of evaluated participants , 50 diagnosed with scf based on thrombolysis in myocardial infarction frame counting ( tfc ) method
30 participants had normal coronary flow ( ncf ) were considered as control group after fulfilling inclusion and exclusion criteria .
exclusion criteria were : 1 ) diagnosed as coronary artery disease ; 2 ) coronary artery stenosis > 50% of the coronary artery diameter in angiographic evaluation ; 3 ) peripheral arterial disease ; 4 ) valvular heart disease ; 5 ) thrombocytopenia ; 6 ) hematologic diseases ; 7 ) hepatic diseases ; 8) chronic inflammatory disease ; 9 ) malignancies ; 10 ) infectious disease ; 11 ) autoimmune disease ; 12 ) anemia ; 13 ) renal failure ; and 14 ) thyroid diseases .
all patients underwent coronary angiographic examination through femoral artery using judkins ' method ( siemens , forcheim , germany ) .
the contrast media of iodixanol ( ge healthcare , cork , ireland ) was used in all cases .
two cardiologists who were blinded to the patients ' condition and clinical features evaluated all angiograms to identify scf using tfc method.14 ) the numbers of angiographic frames were recorded at 30 frames per second .
the coronary flow was calculated as reaching contrast media to the defined distal part of coronary arteries .
the end distal parts in the left anterior descending ( lad ) and left circumflex ( lcx ) arteries were distal bifurcation points .
the calculated frame counting for lad artery was divided by 1.7 based on the predefined criteria.14 ) according to gibson et al.14 ) the cut - off values for detecting scf were 36.22.6 , 20.43 , and 22.24.1 frames for lad , rca , and lcx arteries , respectively .
automated cell count analyzer ( sysmex , kobe , japan ) was used to measure complete blood count .
continuous variables were analyzed using t - test , one - way analysis of variance or mann whitney u test as appropriate based on the variables ' distribution normality .
receiver operating characteristic curve was constructed to detect the accuracy of platelet volume indices to differentiate scf from ncf .
multivariate logistic regression analysis and backward stepwise were conducted to determine the predictors of scf among our studied cohort . in this analysis ,
demographics and laboratories were entered into the model as covariates , and the status of scf was considered as a dependent variable .
all analyses were performed using statistical package for the social sciences ( spss ) version of 18.0 ( spss inc . ,
baseline clinical characteristics of patients were summarized in table 1 . a total of 50 patients with scf and 30 patients with ncf were studied .
based on the baseline characteristics , patients with scf were more likely to have diabetes and hypertension than ncf ( 24% vs. 6.7% , p=0.048 and 50% vs. 23.3% , p=0.018 , respectively ) . the platelet volume indices mpv ( p=0.005 ) , pdw ( p=0.007 ) , and p - lcr ( p=0.039 )
were significantly higher in the scf group compared to those in the ncf group ( table 1 ) . based on correlation analysis , positive and significant correlations existed between the platelet volume indices and the tfc values in three coronary arteries except between p - lcr and lad and lcx arteries ( table 2 ) .
when comparing the differences of platelet volume indices and the extent of scf , the amounts of mpv , pdw , and p - lcr were significantly higher in patients with three scf arteries compared to those of patients without scf ( p=0.004 , p=0.005 , and p=0.014 , respectively ) .
in addition , pdw was significantly ( p=0.026 ) higher in patients with two scf arteries compared with patients without scf ( fig .
receiver operating characteristic curve analysis showed that the best cut - off values of mpv , pdw , and p - lcr to distinguish scf from ncf were 10.4 fl , 13.9 fl , and 28% , respectively ( fig .
, mpv had significantly higher amount of area under the curve ( auc ) ( auc=0.669 , p=0.012 ) . all variables whose p were significant ( p<0.05 ) based on bivariate analysis
were entered into the linear regression analysis . according to this model , mpv { =32.393 , 95% confidence interval ( ci ) 0.678 - 11.048 ,
p=0.027 } , pdw ( =0.428 , 95% ci 0.060 - 3.924 , p=0.043 ) , and p - lcr ( =-0.771 , 95% ci -1.917 - -0.117 , p=0.027 ) were independent predictors of mean tfc ( table 3 ) .
results of multivariate analysis were summarized in the table 4 . according to this model , mpv { odds ratio ( or)=32.393 , 95% ci=1.189 - 882.606 , p=0.039 } and p - lcr ( or=0.566 , 95% ci=0.330 - 0.937 , p=0.028 ) were independent predictors of scf among all variables measured in this study .
in this study , for the first time , we showed that the platelet volume indices mpv , pdw , and p - lcr were significantly higher in the patients with scf compared to those in the ncf group .
there were positive correlations between platelet volume indices and the tfc measured for three coronary arteries .
furthermore , mpv , pdw , and p - lcr were found to be the independent predictors of mean tfc .
platelets are important blood cells that participate in the processes of atherothrombotic events , coagulation , and inflammation.8 ) mpv , pdw , and p - lcr are indicators of platelet size , volume , and activation .
elevated mpv value has been shown to be involved in the pathogenesis of atherosclerosis and thrombogenesis.15 ) gke et al.7 ) have deomonastrated that platelet aggregability induced by ristocetin , collagen , and adenosine diphosphate was significantly higher in patients with scf compared to that of ncf , indicating the potential of platelet in scf pathogenesis . in a case - control study , celik et al.11 )
have demonstrated that increased mpv and plasma sp - selectin values are higher in scf patients compared to those of ncf ones , with positive correlations between mpv values and the tfc of coronary artery .
they concluded that the increased platelet activity existed in scf might be a pathogenesis for scf development .
elsherbiny et al.16 ) have shown that mpv is higher in scf compared to ncf .
nurkelam et al.17 ) have reported that scf cases with unstable angina has higher mpv compared to scf ones with stable coronary artery disease and ncf cases .
other studies have also confirmed that elevated mpv is associated with the presence of scf.18)19 ) furthermore , it has been shown that mpv correlated with the extent of scf.19 ) in consistent with those research findings , our results also reveald that mpv was significantly higher in scf compared to ncf cases .
our results also revealed that mpv was associated with mean tfc of three coronary arteries . in addition , for the first time , we found that pdw and p - lcr were also higher in scf .
li et al.4 ) found that c - reactive protein ( crp ) and interlukin-6 were higher in scf patients and that scf was was correlated with mean tfc . in additon , some adhesion molecules , including intercellular adhesion molecule-1 , vascular cell adhesion molecule-1 , and e - selectin as markers of endothelial activation or inflammation were reported to be significantly higher in patients diagnosed with scf.5 ) given the probable role of inflammation in the scf pathogenesis , some clinical trials have been conducted .
albayrak et al.20 ) have demonstrated that nebivolol reduced crp level and controlled the chest pain of patients with scf .
the impact of simvastatin on improving myocardial perfusion in scf is another evidence to support the role of inflammatory processes in the scf development.6 ) in addition , platelets involve in inflammatory pathways through releasing mediators , and larger ones contain more mediators and activity . considering the results of this study and those other studies demonstrating increased platelet indices in scf patients , further clinical trials are needed to illustrate the effects of anti - platelet and anti - inflammatory agents on scf and to prove the relationship between platelet - related disorders and scf pathogenesis . in order for recurrent chest pain to be controlled ,
some drugs such as beta - blockers , nitrates , and statins have been used . however , no proper impact of these agents have been demonstrated . in this study
. however , due to the above mentioned pathophysiologic mechanisms of scf , including inflammation , thrombogeneity , and atherosclerosis , and due to the relationship between increased platelet volume indices and scf , it may be of great benefit to prescribe anti - platelet and anti - inflammatory agents to reduce platelet volume indices . beside the therapeutic use of these markers , they could be used for risk staritification of scf cases .
based on our findings , it can be proposed that increased platelet volume indices mpv , pdw , and p - lcr are inexpensive and widely available tests associated with scf and that they might be involved in the pathophisiology of scf .
considering the fact that platelet volume indices were indicators of platelet activation and consequent inflammatory processes , we suggest that increased mpv , pdw , and p - lcr could be indicators of platelet dysfunction and inflammation in patients diagnosed with scf .
therefore , platelet volume indices mpv , pdw , and p - lcr could be considered for monitoring drug efficacy and risk stratification of such cases .
firstly , the small sample size and the lack of some variables , including lipid profile tests and familial history of cardiovascular disease , were the main limitation of this study .
secondly , we did not measure other inflammation and platelet function markers such as crp , which could provide more information regrding the pathophysilogic mechanisms involved in scf .
finally , because we chose the participants consecutively based on the inclusion and exclusion criteria , selection bias may have occurred during patients enrollment .
platelet volume indices mpv , pdw , and p - lcr were significantly higher in scf patients compared to those in ncf .
the increases of platelet volume indices mpv , pdw , and p - lcr were associated with the extent of scf . moreover ,
mpv , pdw , and p - lcr were found to be indipendent predictors of mean tfc .
firstly , the small sample size and the lack of some variables , including lipid profile tests and familial history of cardiovascular disease , were the main limitation of this study .
secondly , we did not measure other inflammation and platelet function markers such as crp , which could provide more information regrding the pathophysilogic mechanisms involved in scf .
finally , because we chose the participants consecutively based on the inclusion and exclusion criteria , selection bias may have occurred during patients enrollment .
platelet volume indices mpv , pdw , and p - lcr were significantly higher in scf patients compared to those in ncf .
the increases of platelet volume indices mpv , pdw , and p - lcr were associated with the extent of scf . moreover ,
mpv , pdw , and p - lcr were found to be indipendent predictors of mean tfc .
 background and objectiveswe sought to determine the relationship between mean platelet volume ( mpv ) , platelet distribution width ( pdw ) , and platelet larger cell ratio ( p - lcr ) with slow coronary flow ( scf).subjects and methodseighty participants who underwent coronary angiography were divided into two groups , 50 participants with scf as case group , and 30 with normal coronary flow ( ncf ) as control group . 
 baseline characteristics and laboratory data were collected before angiography.resultsplatelet volume indices mpv ( 10.81.2 fl ) , pdw ( 14.52.2 fl ) , and p - lcr ( 30.58.1% ) in the scf group were significantly ( p<0.05 ) higher than those ( 10.10.9 fl , 13.21.8 fl , and 26.86.8% , respectively ) in the ncf group . 
 the patients with three scf arteries had significantly higher platelet volume indices compared to those with ncf arteries ; however , the patients with one scf artery did not . based on linear regression model , mpv , pdw , and p - lcr were independent predictors of mean infarction frame counting ( tfc ) . 
 in multivariate analysis , mpv { odds ratio ( or)=32.393 , 95% confidence interval ( ci)=1.189 - 882.606 , p=0.039 } and p - lcr ( or=0.566 , 95% ci=0.330 - 0.937 , p=0.028 ) were independent predictors of scf.conclusionplatelet volume indices mpv , pdw , and p - lcr were associated with both the presence and extent of scf . 
Introduction
Subjects and Methods
Study patients
Angiographic examination
Laboratory examination
Statistical analysis
Results
Discussion
Study limitaions
Conclusions