atrial electromechanical delays ( aemds ) are defined as the time intervals between the atrial electrical depolarization and the initiation or peak of atrial mechanical contraction .
it has been shown that prolonged aemds can be used as markers to discriminate patients with paroxysmal atrial fibrillation ( paf ) from controls without paf or to predict the occurrence of paf in case - control or observational studies.1)2)3)4)5)6)7)8)9)10 ) the clinical evidence supports the notion that prolonged aemds reflect left atrial electrical remodeling , which is essential for the maintenance of atrial fibrillation ( af).7 ) however , studies on this aspect have evaluated the single aemd using specific , yet independent definitions .
the discriminative and predictive values of the aemds with such different definitions have not previously been compared with each other , and the potential influences of major clinical variables on aemds have not been sufficiently excluded in previous studies . in this study , we conducted a retrospective analysis to more accurately evaluate the discriminative values of aemds while excluding the influences of major clinical variables , and compared the discriminative values of predefined aemds when differentiating between the paf patients and the controls .
patients were screened who were first diagnosed with paf between 2010 and 2013 with available electrocardiographic and echocardiographic records ; furthermore , those patients selected had clear p waves on surface electrocardiogram ( ecg ) channel , pulsed wave doppler images ( pwdi ) of trans - mitral inflow , and tissue doppler images ( tdi ) of mitral annular motion .
those patients excluded from this study had ambiguous ecg or doppler study images , or abnormal rhythms other than normal sinus rhythm at the time of echocardiographic measurements . in addition , those patients were also excluded who reported current medication with drugs influencing intracardiac conduction ( beta - blocker , nondihydropyridine calcium channel blocker , class ic or iii antiarrhythmic drugs ) in the prior week ( 3 months for amiodarone ) before echocardiographic measurements .
however , the patients with the following were permitted to participate in the study : use of dihydropyridine calcium channel blockers , alpha - blockers , or diuretics .
other exclusion criteria were : a history of previous cardiac surgery , reduced ejection fraction ( < 50% ) , enlarged left ventricle size ( end diastolic dimension > 55 mm ) , valvular heart disease ( american college of cardiology / american heart association grade 2 ) , any cardiomyopathy , coronary artery disease requiring interventional treatment , uncontrolled thyroid disease , advanced chronic kidney disease ( estimated glomerular filtration rate < 30 ml / min/1.73 m ) or liver disease ( bilirubin>2.0 mg / dl ) , malignancy , chronic inflammatory or systemic connective tissue diseases , and the presence of moderate electrolyte imbalances .
data for the healthy control group was extracted from the echocardiography registry of dong - a university medical center , busan , korea , and there was a screening of subjects who underwent echocardiography during health care examinations from 2010 to 2013 .
the excluded subjects from this study had documented atrial tachycardia , flutter , or fibrillation .
the matched healthy controls were selected in a 1:2 ratio for those patients with available medical records , age , sex , a history of hypertension , and diabetes mellitus .
age discrepancies of less than 5 years were allowed for patient - control age matching .
the identical inclusion and exclusion criteria for the paf patient selection were used for the selection of the control subjects .
the present study protocol was reviewed and approved by the internal review board of dong - a university hospital , busan , korea .
echocardiography was performed using an ie33 ultrasound system and 2.5 mhz transducers ( philips ultrasound , andover , ma , usa ) .
the standard m - mode , 2d , and doppler echocardiography were routinely performed , in accordance with the recommendations of the american society of echocardiography.11)12 ) the ecg was recorded continuously during echocardiographic studies at a sweep speed of 100 mm / sec and the amplitude gain was set to 70% .
the pwdi sample volume for late diastolic trans - mitral inflow velocity measurement was placed on the center of the mitral valve at the level of the mitral annulus , in the apical 4-chamber view .
the sampling window was positioned as parallel as possible to the longitudinal axis of the left ventricle .
the tdi echocardiography was performed using a transducer frequency of 3.5 to 4.0 mhz , adjusting the spectral pulsed doppler signal filters to obtain the nyquist limit of 15 cm / s to 20 cm / s with the optimal gain settings .
the tdi sample volume for late diastolic mitral annular motion was placed at the lateral mitral annulus .
all measurements were repeated 3 times and their average values were used for the analysis .
the aemds were defined as the time interval ( milliseconds , ms ) from the atrial electrical depolarization to the initiation or peak of atrial mechanical contraction seen in the echocardiographic studies .
the time intervals , from the initiation of p wave on surface ecg to the initiation and peak of late diastolic transmitral inflow on pwdi , were defined as aemdi and aemdp , respectively ( fig .
the time intervals , from the initiation of p wave on surface ecg to the initiation and peak of late diastolic lateral mitral annular motion on tdi , were defined as aemdim and aemdpm , respectively ( fig .
there was also a measurement of other conventional echocardiographic parameters : left ventricular ejection fraction , left ventricular end diastolic dimension , left ventricular mass index , left atrial volume index ( lavi ) , peak trans - mitral inflow ( mitral e and a ) velocities on pwdi during diastole , as well as early diastolic lateral mitral annular motion velocity ( mitral e ' ) on tdi .
all echocardiographic measurements were performed by a well - trained and experienced sonographer who was blinded to each patient 's clinical information , furthermore , the data acquired were further confirmed by an echocardiologist .
electrocardiographic parameters , including p wave duration , p wave amplitude , qrs duration , pr interval , and rr interval , were calculated in limb lead ii using a digital caliper of tracemaster viewer ( philips electronics , andover , ma , usa ) . the presence of bundle branch block , pathologic q waves , abnormal st - segment elevation or depression , and t - wave inversion suggesting structural heart disease were evaluated using a standard 12-lead ecg acquired before the echocardiographic measurements .
all electrocardiographic measurements were performed by a general cardiologist who was blinded to each patient 's clinical information , and the data acquired were further confirmed by an electrophysiologist .
the data are presented as the mean valuesstandard deviation for continuous variables and as numbers with percentages for categorical variables .
the differences between normally distributed continuous values were assessed by independent sample t - tests , whereas the proportional differences between categorical values were assessed by a chi - square test .
the relationships between aemd values and electrocardiographic or echocardiographic parameters were assessed by pearson 's correlation and linear regression analysis .
the discriminative values of the aemds for paf were identified using their receiver operating characteristic ( roc ) curves .
all statistical comparisons were two - sided and p - values < 0.05 were regarded as statistically significant .
case - control matching and all statistical analyses were conducted using statistical package for the social sciences version 20.0 ( spss inc . ,
a comparison between roc curves was performed using medcalc ( medcalc software company , brunswick , me , usa ) .
patients were screened who were first diagnosed with paf between 2010 and 2013 with available electrocardiographic and echocardiographic records ; furthermore , those patients selected had clear p waves on surface electrocardiogram ( ecg ) channel , pulsed wave doppler images ( pwdi ) of trans - mitral inflow , and tissue doppler images ( tdi ) of mitral annular motion .
those patients excluded from this study had ambiguous ecg or doppler study images , or abnormal rhythms other than normal sinus rhythm at the time of echocardiographic measurements . in addition , those patients were also excluded who reported current medication with drugs influencing intracardiac conduction ( beta - blocker , nondihydropyridine calcium channel blocker , class ic or iii antiarrhythmic drugs ) in the prior week ( 3 months for amiodarone ) before echocardiographic measurements .
however , the patients with the following were permitted to participate in the study : use of dihydropyridine calcium channel blockers , alpha - blockers , or diuretics .
other exclusion criteria were : a history of previous cardiac surgery , reduced ejection fraction ( < 50% ) , enlarged left ventricle size ( end diastolic dimension > 55 mm ) , valvular heart disease ( american college of cardiology / american heart association grade 2 ) , any cardiomyopathy , coronary artery disease requiring interventional treatment , uncontrolled thyroid disease , advanced chronic kidney disease ( estimated glomerular filtration rate < 30 ml / min/1.73 m ) or liver disease ( bilirubin>2.0 mg / dl ) , malignancy , chronic inflammatory or systemic connective tissue diseases , and the presence of moderate electrolyte imbalances .
data for the healthy control group was extracted from the echocardiography registry of dong - a university medical center , busan , korea , and there was a screening of subjects who underwent echocardiography during health care examinations from 2010 to 2013 .
the excluded subjects from this study had documented atrial tachycardia , flutter , or fibrillation .
the matched healthy controls were selected in a 1:2 ratio for those patients with available medical records , age , sex , a history of hypertension , and diabetes mellitus .
age discrepancies of less than 5 years were allowed for patient - control age matching .
the identical inclusion and exclusion criteria for the paf patient selection were used for the selection of the control subjects .
the present study protocol was reviewed and approved by the internal review board of dong - a university hospital , busan , korea .
echocardiography was performed using an ie33 ultrasound system and 2.5 mhz transducers ( philips ultrasound , andover , ma , usa ) . the standard m - mode , 2d , and doppler echocardiography were routinely performed , in accordance with the recommendations of the american society of echocardiography.11)12 ) the ecg was recorded continuously during echocardiographic studies at a sweep speed of 100 mm / sec and the amplitude gain was set to 70% . the pwdi sample volume for late diastolic trans - mitral inflow velocity measurement
was placed on the center of the mitral valve at the level of the mitral annulus , in the apical 4-chamber view .
the sampling window was positioned as parallel as possible to the longitudinal axis of the left ventricle .
the tdi echocardiography was performed using a transducer frequency of 3.5 to 4.0 mhz , adjusting the spectral pulsed doppler signal filters to obtain the nyquist limit of 15 cm / s to 20 cm / s with the optimal gain settings .
the tdi sample volume for late diastolic mitral annular motion was placed at the lateral mitral annulus .
all measurements were repeated 3 times and their average values were used for the analysis .
the aemds were defined as the time interval ( milliseconds , ms ) from the atrial electrical depolarization to the initiation or peak of atrial mechanical contraction seen in the echocardiographic studies .
the time intervals , from the initiation of p wave on surface ecg to the initiation and peak of late diastolic transmitral inflow on pwdi , were defined as aemdi and aemdp , respectively ( fig .
the time intervals , from the initiation of p wave on surface ecg to the initiation and peak of late diastolic lateral mitral annular motion on tdi , were defined as aemdim and aemdpm , respectively ( fig .
there was also a measurement of other conventional echocardiographic parameters : left ventricular ejection fraction , left ventricular end diastolic dimension , left ventricular mass index , left atrial volume index ( lavi ) , peak trans - mitral inflow ( mitral e and a ) velocities on pwdi during diastole , as well as early diastolic lateral mitral annular motion velocity ( mitral e ' ) on tdi .
all echocardiographic measurements were performed by a well - trained and experienced sonographer who was blinded to each patient 's clinical information , furthermore , the data acquired were further confirmed by an echocardiologist .
electrocardiographic parameters , including p wave duration , p wave amplitude , qrs duration , pr interval , and rr interval , were calculated in limb lead ii using a digital caliper of tracemaster viewer ( philips electronics , andover , ma , usa ) . the presence of bundle branch block , pathologic q waves , abnormal st - segment elevation or depression , and t - wave inversion suggesting structural heart disease were evaluated using a standard 12-lead ecg acquired before the echocardiographic measurements .
all electrocardiographic measurements were performed by a general cardiologist who was blinded to each patient 's clinical information , and the data acquired were further confirmed by an electrophysiologist .
the data are presented as the mean valuesstandard deviation for continuous variables and as numbers with percentages for categorical variables .
the differences between normally distributed continuous values were assessed by independent sample t - tests , whereas the proportional differences between categorical values were assessed by a chi - square test .
the relationships between aemd values and electrocardiographic or echocardiographic parameters were assessed by pearson 's correlation and linear regression analysis .
the discriminative values of the aemds for paf were identified using their receiver operating characteristic ( roc ) curves .
all statistical comparisons were two - sided and p - values < 0.05 were regarded as statistically significant .
case - control matching and all statistical analyses were conducted using statistical package for the social sciences version 20.0 ( spss inc . ,
was performed using medcalc ( medcalc software company , brunswick , me , usa ) .
among the 304 documented paf patients screened for the study , the following categories were excluded : 73 for underlying structural heart diseases or other significant medical conditions , 51 for e / a summation or ambiguous initiation of a wave , and 11 for ambiguous initiation of p waves ; and 42 patients had af , and 62 were taking drugs that could potentially influence intracardiac conduction at the time of echocardiographic measurements .
furthermore , 130 matched healthy controls were then chosen , matched for age , sex , history of hypertension , and diabetes mellitus .
the mean age of the study population was 5716 years and 117 subjects ( 60% ) were male .
there was no significant difference in the baseline clinical characteristics between the paf and control groups ( table 1 ) .
the aemdi , aemdp , aemdim , and aemdpm measurements were consistently longer in the paf group ( table 2 ) , and the lavi and p wave amplitude values were higher .
all 4 aemds were proven to be effective to discriminate the paf patients from controls ( table 3 ) . among the aemds , in discriminating the paf patients from the controls , a prolonged aemdi had a larger auc than the other aemds , lavi , and p wave amplitude .
however , the aemdp , aemdim , and aemdpm measurements had aucs similar to those of lavi and p wave amplitude .
the aemdi value of 64 ms had a sensitivity of 75% and specificity of 86% for the discrimination of patients with paf from the controls .
there were weak correlations between the aemdi and lavi ( r=0.311 , p<0.001 ) , and the p wave amplitude ( r=0.088 , p=0.227 ) .
the prolonged aemdi was not explained by lavi ( r=0.011 , p=0.140 ) or p wave amplitude ( r=0.08 , p=0.227 ) in linear regression analyses .
among the 304 documented paf patients screened for the study , the following categories were excluded : 73 for underlying structural heart diseases or other significant medical conditions , 51 for e / a summation or ambiguous initiation of a wave , and 11 for ambiguous initiation of p waves ; and 42 patients had af , and 62 were taking drugs that could potentially influence intracardiac conduction at the time of echocardiographic measurements .
furthermore , 130 matched healthy controls were then chosen , matched for age , sex , history of hypertension , and diabetes mellitus .
the mean age of the study population was 5716 years and 117 subjects ( 60% ) were male .
there was no significant difference in the baseline clinical characteristics between the paf and control groups ( table 1 ) .
the aemdi , aemdp , aemdim , and aemdpm measurements were consistently longer in the paf group ( table 2 ) , and the lavi and p wave amplitude values were higher .
all 4 aemds were proven to be effective to discriminate the paf patients from controls ( table 3 ) . among the aemds , in discriminating the paf patients from the controls , a prolonged aemdi had a larger auc than the other aemds , lavi , and p wave amplitude . however , the aemdp , aemdim , and aemdpm measurements had aucs similar to those of lavi and p wave amplitude .
the aemdi value of 64 ms had a sensitivity of 75% and specificity of 86% for the discrimination of patients with paf from the controls .
there were weak correlations between the aemdi and lavi ( r=0.311 , p<0.001 ) , and the p wave amplitude ( r=0.088 , p=0.227 ) .
the prolonged aemdi was not explained by lavi ( r=0.011 , p=0.140 ) or p wave amplitude ( r=0.08 , p=0.227 ) in linear regression analyses .
previous studies have attempted to predict the occurrence of paf using various electrocardiographic or echocardiographic parameters , including p wave morphology on surface ecg , p wave - triggered signal - averaged ecg , and left atrial size and function.5)13)14)15)16 ) several aemds using a number of different definitions have also been tested to discriminate paf patients from healthy controls , or predict the occurrence of paf using m - mode tdi,1 ) aemdp,5)7 ) aemdim2)4)8 ) , and aemdpm.3)6)9)10 ) the aemdp has been shown to be effective for discriminating patients with paf from controls with sensitivity of 78%-81% and specificity of 71%-78%.5)7 ) the aemdim and aemdpm have also been shown to be effective in predicting the occurrence of new onset af or the recurrence of af after coronary artery bypass surgery , radiofrequency catheter ablation , and electrical cardioversion.6)7)8)9)10 ) in this study , we measured the 4 aemds , each of which has been tested in other studies , except for aemdi , with different definitions to determine which aemd is the best discriminator for paf . for measurements of the aemds using tdi , the tdi sample volume was placed at the lateral mitral annulus , because previous studies have shown good discriminative or predictive values for paf when late diastolic atrial motion velocity is measured at this location.2)3)4)6)8)9)10 ) the aemds are known to be influenced by cardiac and non - cardiac factors .
previous studies have revealed a significant prolongation of aemds in various cardiac and non - cardiac conditions including hypertension,17 ) valvular heart disease,17 ) cardiomyopathy,18 ) atrial septal defect,19 ) type i diabetes mellitus,20 ) obstructive sleep apnea,21 ) connective tissue diseases affecting the atrial myocardium,22)23 ) acute alcohol consumption,24 ) hypothyroidism,25 ) and other conditions . in this study
, we attempted to evaluate the true discriminative value of prolonged aemd for paf by excluding patients and controls with potential confounding factors , including structural heart disease , cardioactive drugs , electrolyte imbalances , and other significant medical conditions .
strict patient - control matching , for age , sex , history of hypertension and diabetes mellitus , was also incorporated to minimize potential influences .
similar to previous study results , all the 4 aemds of different definitions were proven to be effective to discriminate the paf patients from the controls ( table 3 ) . among the 4 aemds ,
the aemdi value of 64 ms had a sensitivity of 75% and a specificity of 86% , which were comparable to previous study results .
the aemdi was not evaluated in previous studies , possibly because of technical issues . in clinical practice , it is often impossible to measure the aemdi because of technical issues . however , if the aemdi is technically measurable , the prolonged aemdi may be a better discriminator than the other aemds for paf .
although aemdp , aemdim , and aemdpm have been shown to be discriminators or predictors for paf in previous studies , most of the studies did not postulate whether aemds were superior to conventional risk factors for paf , such as left atrial chamber size .
the results , of this study , show that the aemdp , aemdim , and aemdpm measurements were no better than the lavi and p wave amplitude approaches .
it is not certain why the aemdi is superior to the lavi and p wave amplitude .
the prolonged aemdi may actually reflect left atrial remodeling , which is a complex process consisting of anatomic and electrophysiologic changes .
previous electrophysiologic studies already reported that prolonged aemds can reflect mechanical and electrophysiologic remodeling of the left atrium.7)10 ) intra - atrial conduction delay , resulting from left atrial remodeling , may prolong the coupling interval between atrial electrical depolarization and mechanical contraction .
the difference in aucs between aemdi and lavi or p wave amplitude may reflect , at least in part , the proportion of left atrial anatomic and electrophysiologic remodeling that can not be measured by left atrial chamber size or p wave morphology alone .
that hypothesis may be supported by results of this study , which showed a weak relationship between the aemdi and lavi or p wave amplitude .
first , this is a relatively small case - controlled study involving a limited number of paf patients . because subjects with unsuitable echocardiographic images or potential confounding factors were excluded with strict patient - control matching performed for major clinical variables , the study results should be interpreted cautiously , bearing in mind the risk of patient selection bias .
second , the burden of paf itself was not considered . the frequency and duration of paf episodes could not be quantified using a predefined electrocardiographic evaluation schedule and patients with at least a single episode of documented paf were included for analysis according to the initial study plan .
the probable burden of paf could vary among the patients , and hence the degree of left atrial remodeling could be heterogeneous . the cut - off values for aemdi should be adjusted accordingly in further studies .
third , the recovery time from atrial stunning after spontaneous cardioversion was not taken into consideration .
the echocardiographic measurements were performed during normal sinus rhythm after spontaneous cardioversion , however , the time interval could not be evaluated from the electrocardiographic diagnosis to the echocardiographic measurement .
thus , this study can not exclude the possibility of incorrect measurements of aemds because of early echocardiographic measurements before complete recovery from atrial stunning .
fourth , although medical records were meticulously reviewed , this study can not exclude the possibility that subjects in the healthy control group could have had asymptomatic atrial arrhythmias or other medical confounders .
fifth , although the aemdi was better discriminator , it is not always possible to measure the aemdi in clinical practice , possibly because of technical issues .
in addition , many patients with suspected paf will already be receiving cardioactive drugs or have coexistent medical conditions , which potentially influence the aemdi at the time of echocardiographic measurements .
although modern diagnostic technology is developing rapidly , paf diagnosis still relies on electrocardiographic studies .
hence , the measurements of aemds during normal sinus rhythm may give more exact information for the presence of left atrial remodeling , in addition to conventional electrocardiographic and echocardiographic parameters such as the lavi and p wave amplitude .
prolonged aemd analysis , in combination with typical history and suspicious electrocardiographic abnormalities , may help clinicians in making presumptive diagnoses and give guidance to perform regular electrocardiographic follow - up in order to confirm the diagnosis . in conclusion ,
all the 4 aemds were proven to be effective to discriminate paf patients from controls who were matched for age , sex , history of hypertension , and diabetes mellitus . among the 4 aemds ,
the prolonged aemdi was better discriminator than the other aemds , lavi , and p wave amplitude .
however , the aemdp , aemdim , and aemdpm measurements were no better than the lavi and p wave amplitude in discrimination of the paf patients from the controls .
in conclusion , all the 4 aemds were proven to be effective to discriminate paf patients from controls who were matched for age , sex , history of hypertension , and diabetes mellitus . among the 4 aemds ,
the prolonged aemdi was better discriminator than the other aemds , lavi , and p wave amplitude .
however , the aemdp , aemdim , and aemdpm measurements were no better than the lavi and p wave amplitude in discrimination of the paf patients from the controls .
 background and objectivesprevious studies have evaluated atrial electromechanical delays ( aemds ) with a number of different definitions to discriminate patients with paroxysmal atrial fibrillation ( paf ) from controls without paf . however , their discriminative values for paf have not previously been directly compared.subjects and methodsa total of 65 paf patients and 130 control subjects matched for age , sex , history of hypertension , and diabetes mellitus were selected . 
 the aemdi and aemdp were defined as the time intervals from the initiation of the p wave on the surface electrocardiogram to the initiation and peak of the late diastolic transmitral inflow on pulsed wave doppler images , respectively . 
 the aemdim and aemdpm were defined as the time intervals from the initiation of the p wave on the surface electrocardiogram to the initiation and peak of the late diastolic lateral mitral annular motion on tissue doppler images , respectively.resultsthere were no significant differences in the clinical characteristics between the two groups . 
 all 4 aemds were consistently longer in the paf group , and proven effective to differentiate the paf patients from the controls . 
 the aemdi measurement had a larger area under the curve ( auc ) than the other aemds , left atrial volume index , and p wave amplitude . 
 however , the aemdp , aemdim , and aemdpm measurements had aucs similar to those of the left atrial volume index and p wave amplitude.conclusionthe findings suggest that the aemdi is better than the other aemds for the discrimination of paf patients from the controls . 
Introduction
Subjects and Methods
Study population
Measurements of echocardiographic parameters
Measurements of electrocardiographic parameters
Statistical analysis
Results
Baseline characteristics
Comparison of differently defined atrial electromechanical delays
Discussion
Conclusion