augmented contractility of postextrasystolic heartbeats has been described almost 130 years ago and later termed postextrasystolic potentiation ( pesp ) . for almost 1 century , pesp was thought to reflect normal cardiac function . however , during the second half of the previous century , an increasing number of reports showed that , measured at the blood pressure ( bp ) level , pesp is a typical finding in heart failure ( hf ) patients . there have been attempts to use pesp as a diagnostic test to identify ischemic , but viable , myocardium and elicit pesp by paired pacing to augment cardiac contractility in hf , but these approaches have not led to broad clinical application . the magnitude of systolic calcium transient is primarily determined by the amount of calcium stored in the sarcoplasmic reticulum and by the availability of sarcoplasmic reticulum calcium release channels ( ryanodine receptors ) . pesp and its augmentation in hf can be understood on the basis of the interplay of calciumhandling processes in cardiomyocytes : a premature beat leads to a cellular depolarization and influx of trigger calcium through ltype channels at a time point when a relevant fraction of ryanodine receptor channels is still refractory . resequestration of cytoplasmic calcium into the sarcoplasmic reticulum takes place during the postectopic pause , resulting in a higherthannormal sarcoplasmic reticulum calcium content to be released during the first postectopic beat . thus , the contractility of the first postectopic beat is augmented . in the failing myocardium , the sarcoplasmic reticulum contains less calcium , mostly because of leaky ryanodine receptors and a reduced capacity of the calcium uptake mechanism and partly compensated by upregulation of the plasma membrane sodium calcium exchanger . starting from this lower steady state , the relative increase in sarcoplasmic reticulum calcium content during the postectopic pause is even more pronounced , resulting in a greater amount of pesp than in a normal heart . this association between abnormal intracellular calcium cycling and increased pesp in hf is supported by both animal experiments and modeling studies . we hypothesized that pesp is a surrogate marker for hf at the cellular level that bears prognostic information in cardiac patients . the present study was designed to test pesp as a mortality predictor in myocardial infarction ( mi ) survivors . the study was a prospectively defined substudy of the autonomic regulation trial ( art ) . between may 2000 and march 2005 , consecutive patients were enrolled in the art study ( nct00196274 registration at clinicaltrials.gov ) at the german heart center and the klinikum rechts der isar ( both in munich , germany ) . eligible patients survived the acute phase of mi , were aged 80 years , in sinus rhythm , and not eligible for implantable cardioverterdefibrillator ( icd ) for secondary prevention before hospital discharge . mi diagnosis required 2 or more of the following findings : typical chest pain for 20 minutes , creatine kinase above twice the upper normal limit of the respective laboratory , and admission stsegment elevation 0.1 mv in at least 2 limb leads or 0.2 mv in at least 2 contiguous precordial leads . patients were followed for a median of 6.3 years ( interquartile range [ iqr ] , 5.5 to 7.0 ) with final followup in august 2010 . allcause mortality at 5 years after the index mi was prospectively defined as the primary study endpoint . the study protocol was approved by the local ethics committee and all participants gave informed written consent . an independent validation cohort comprised 146 patients suffering from hf and presenting in sinus rhythm at the glasgow royal infirmary ( glasgow , uk ) between 1995 and 1998 . these patients had an average age of 59 years , and 61 presented with new york heart association ( nyha ) class iii or iv . patients of the art cohort underwent simultaneous 30minute recordings of highresolution ecg ( 1.6khz sampling of orthogonal xyz leads ; tms international , enschede , the netherlands ) , and noninvasive arterial bp monitoring using a finger photoplethysmographic device ( fms , amsterdam , the netherlands ) . recordings were obtained in supine resting position after routine morning medications and performed after patients were transferred from the intensive care unit to the ward ( median day 7 ; iqr , 5 to 9 days after the index mi ) . raw signals were reviewed to eliminate artifacts and classify premature beats as sinus or ventricular premature complexes ( vpcs ) . a vpc qualified for pesp assessment if 20% premature , compared to the mean of preceding 5 sinus rhythm intervals , and if followed by 10 consecutive sinus rhythm beats . postvpc bp changes were quantified as the relationship of the first postvpc pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes . pesp was defined as present if the first postvpc pulse pressure wave exceeded the mean of the subsequent pulse pressure amplitudes ( figure 1 ) . in order to eliminate the influence of fluctuations in bp recordings , a technical threshold was introduced : taking into account that the mean standard deviation of systolic bp ( sbp ) in 10heartbeat sequences was 2.8% in our data , we defined pesp as present if the postvpc pulse pressure wave exceeded the mean of the subsequent pulse pressure amplitudes by more than 3% . if more vpcs in the same 30minute recording qualified for pesp evaluation , the ratios between the postvpc pulse pressure wave and the mean of the subsequent pulse pressure amplitudes were averaged . we also calculated the numerical ratio of pesp , that is , the relationship between postvpc pulse pressure and the mean pulse pressure of the subsequent sinus beats . determination of pesp based on ecg and bp signals . left panel shows ecg and blood pressure signals of a patient surviving the followup period ( upper tracing ) and a patient who died 16 months after the index mi ( lower tracing ) . the systolic pressure of the first postectopic beat in the upper tracing is clearly lower than that of the following 9 beats , indicating that pesp is not present . conversely , the systolic pressure of the corresponding beat in the lower tracing is noticeably higher than that of the subsequent beats ( pesp is present ) . right panels show peak systolic pressure of consecutive heart beats before , during , and after ectopic beats in these patients . vpc count was calculated from standard holter recordings as the number of vpcs per hour . the elements of the grace score included age , history of hf , history of mi , serum creatinine at admission , cardiac biomarker status at admission , sbp at admission , pulse frequency at admission , st deviation at admission , and inhospital percutaneous coronary intervention . left ventricular ( lv ) ejection fraction ( lvef ) was assessed by lv angiography ( n=445 ; 47.3% ) or biplane echocardiography according to simpson 's method ( n=496 ; 52.7% ; sonos 5500 ; hewlett packard , palo alto , ca ) , on median day 7 ( iqr , 5 to 9 days ) after the index mi . grace score and lvef were dichotomized at predefined cutoff values of 120% and 35% , respectively . incomplete revascularization at the time of pesp measurement was defined as remaining stenosis 75% in any of the main coronary vessels after percutaneous coronary intervention ( pci ) . all patients who had less than 4 years of followup were contacted by mail , telephone , or through the attending general practitioner . if none of these channels were successful , the local population registry was contacted to either provide a new address of the patient or confirm that the patient had deceased . patients who could not be reached by any of these channels were considered lost to followup and censored at the time of last contact . the prospectively defined study endpoint was death from any cause within 5 years of the index mi . we first calculated cox 's proportional hazards models with single predictors to evaluate their association with mortality . subsequently , a multivariable cox proportional hazards model was used with all 4 variables to simultaneously assess the independent prognostic value of each mortality predictor . the improvement of goodness of fit , measured by the cox model 's likelihood , upon the addition of pesp to the cox model fixed to lvef , grace score , and vpc counts was assessed in a permutation test framework . linear effect estimates were used in the cox model as a comparison to nonlinear effects by application of fractional polynomials showed no significant improvement in model fit ( ie , likelihood ) . the improvement of risk prediction by inclusion of pesp in the cox model is presented by the integrated discrimination improvement index ( idi ) . threefold crossvalidation was repeated 25 times for an averaged assessment and internal validation of idi values to be expected for external data . in a retrospective analysis , optimal cutoff values for the proportion between the first postvpc pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes ( termed further the numerical ratio of pesp ) were determined from the receiveroperator characteristic ( roc ) curve at the maximum of the youden index j = sensitivity+specificity1 . the corresponding 95% confidence intervals ( cis ) were determined by standard bootstrap with 5000 repetitions . roc analysis at 5 years was performed to assess corresponding areas under the receiveroperating characteristics curves ( aurocs ) . all statistical analyses were done using ibm spss statistics 20.0 and r 3.0.1 ( r foundation for statistical computing , vienna , austria ) . between may 2000 and march 2005 , consecutive patients were enrolled in the art study ( nct00196274 registration at clinicaltrials.gov ) at the german heart center and the klinikum rechts der isar ( both in munich , germany ) . eligible patients survived the acute phase of mi , were aged 80 years , in sinus rhythm , and not eligible for implantable cardioverterdefibrillator ( icd ) for secondary prevention before hospital discharge . mi diagnosis required 2 or more of the following findings : typical chest pain for 20 minutes , creatine kinase above twice the upper normal limit of the respective laboratory , and admission stsegment elevation 0.1 mv in at least 2 limb leads or 0.2 mv in at least 2 contiguous precordial leads . patients were followed for a median of 6.3 years ( interquartile range [ iqr ] , 5.5 to 7.0 ) with final followup in august 2010 . allcause mortality at 5 years after the index mi was prospectively defined as the primary study endpoint . the study protocol was approved by the local ethics committee and all participants gave informed written consent . an independent validation cohort comprised 146 patients suffering from hf and presenting in sinus rhythm at the glasgow royal infirmary ( glasgow , uk ) between 1995 and 1998 . these patients had an average age of 59 years , and 61 presented with new york heart association ( nyha ) class iii or iv . patients of the art cohort underwent simultaneous 30minute recordings of highresolution ecg ( 1.6khz sampling of orthogonal xyz leads ; tms international , enschede , the netherlands ) , and noninvasive arterial bp monitoring using a finger photoplethysmographic device ( fms , amsterdam , the netherlands ) . recordings were obtained in supine resting position after routine morning medications and performed after patients were transferred from the intensive care unit to the ward ( median day 7 ; iqr , 5 to 9 days after the index mi ) . raw signals were reviewed to eliminate artifacts and classify premature beats as sinus or ventricular premature complexes ( vpcs ) . a vpc qualified for pesp assessment if 20% premature , compared to the mean of preceding 5 sinus rhythm intervals , and if followed by 10 consecutive sinus rhythm beats . postvpc bp changes were quantified as the relationship of the first postvpc pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes . pesp was defined as present if the first postvpc pulse pressure wave exceeded the mean of the subsequent pulse pressure amplitudes ( figure 1 ) . in order to eliminate the influence of fluctuations in bp recordings , a technical threshold was introduced : taking into account that the mean standard deviation of systolic bp ( sbp ) in 10heartbeat sequences was 2.8% in our data , we defined pesp as present if the postvpc pulse pressure wave exceeded the mean of the subsequent pulse pressure amplitudes by more than 3% . if more vpcs in the same 30minute recording qualified for pesp evaluation , the ratios between the postvpc pulse pressure wave and the mean of the subsequent pulse pressure amplitudes were averaged . we also calculated the numerical ratio of pesp , that is , the relationship between postvpc pulse pressure and the mean pulse pressure of the subsequent sinus beats . determination of pesp based on ecg and bp signals . left panel shows ecg and blood pressure signals of a patient surviving the followup period ( upper tracing ) and a patient who died 16 months after the index mi ( lower tracing ) . the systolic pressure of the first postectopic beat in the upper tracing is clearly lower than that of the following 9 beats , indicating that pesp is not present . conversely , the systolic pressure of the corresponding beat in the lower tracing is noticeably higher than that of the subsequent beats ( pesp is present ) . right panels show peak systolic pressure of consecutive heart beats before , during , and after ectopic beats in these patients . vpc count was calculated from standard holter recordings as the number of vpcs per hour . the elements of the grace score included age , history of hf , history of mi , serum creatinine at admission , cardiac biomarker status at admission , sbp at admission , pulse frequency at admission , st deviation at admission , and inhospital percutaneous coronary intervention . left ventricular ( lv ) ejection fraction ( lvef ) was assessed by lv angiography ( n=445 ; 47.3% ) or biplane echocardiography according to simpson 's method ( n=496 ; 52.7% ; sonos 5500 ; hewlett packard , palo alto , ca ) , on median day 7 ( iqr , 5 to 9 days ) after the index mi . grace score and lvef were dichotomized at predefined cutoff values of 120% and 35% , respectively . incomplete revascularization at the time of pesp measurement was defined as remaining stenosis 75% in any of the main coronary vessels after percutaneous coronary intervention ( pci ) . all patients who had less than 4 years of followup were contacted by mail , telephone , or through the attending general practitioner . if none of these channels were successful , the local population registry was contacted to either provide a new address of the patient or confirm that the patient had deceased . patients who could not be reached by any of these channels were considered lost to followup and censored at the time of last contact . the prospectively defined study endpoint was death from any cause within 5 years of the index mi . we first calculated cox 's proportional hazards models with single predictors to evaluate their association with mortality . subsequently , a multivariable cox proportional hazards model was used with all 4 variables to simultaneously assess the independent prognostic value of each mortality predictor . the improvement of goodness of fit , measured by the cox model 's likelihood , upon the addition of pesp to the cox model fixed to lvef , grace score , and vpc counts was assessed in a permutation test framework . linear effect estimates were used in the cox model as a comparison to nonlinear effects by application of fractional polynomials showed no significant improvement in model fit ( ie , likelihood ) . the improvement of risk prediction by inclusion of pesp in the cox model is presented by the integrated discrimination improvement index ( idi ) . threefold crossvalidation was repeated 25 times for an averaged assessment and internal validation of idi values to be expected for external data . in a retrospective analysis , optimal cutoff values for the proportion between the first postvpc pulse wave amplitude and the mean of the subsequent 9 pulse wave amplitudes ( termed further the numerical ratio of pesp ) were determined from the receiveroperator characteristic ( roc ) curve at the maximum of the youden index j = sensitivity+specificity1 . the corresponding 95% confidence intervals ( cis ) roc analysis at 5 years was performed to assess corresponding areas under the receiveroperating characteristics curves ( aurocs ) . all statistical analyses were done using ibm spss statistics 20.0 and r 3.0.1 ( r foundation for statistical computing , vienna , austria ) . thirteen patients ( 1.4% ) were lost to followup , and 45 additional patients were censored between 4 and 5 years of followup . at 5 years , 72 patients ( 7.7% ) had died . clinical characteristics and therapy data ace indicates angiotensinconverting enzyme ; art , autonomic regulation trial ; cabg , coronary artery bypass grafting ; grace score , composite of age of the patient , serum creatinine , past myocardial infarction , past heart failure , inhospital percutaneous coronary intervention , heart rate , systolic blood pressure , st segment deviation , and positive enzymes ; iqr , interquartile range ; lvef , left ventricular ejection fraction ; mi , myocardial infarction ; nyha , new york heart association functional class ; pci , percutaneous coronary intervention ; stemi , stelevation myocardial infarction . a total of 220 ( 23.4% ) patients exhibited 1 or more vpcs during the 30minute recording suitable for pesp assessment . art indicates autonomic regulation trial ; pesp , postextrasystolic potentiation ; vpc , ventricular premature complex . figure 3a shows cumulative mortality curves for patients classified as pesp present , pesp absent , and pesp not measurable . the probability of death at 5 years was 29.4% in patients with pesp present and 5.8% in patients with pesp absent . the probability of death of patients in whom pesp could not be measured was similar to that of patients with pesp absent ( 6.3% ) . for the following analyses , we consequently merged the categories of pesp absent and pesp not measurable . merging these patient categories parallels the classification of heart rate turbulence , the assessment of which also considers patients without suitable vpcs to present with a negative result . a , mortality probability over 5 years in patients stratified according to the presence ( red curve ) and absence of pesp ( green curve ) . the mortality probability of patients whose recordings lacked vpcs suitable for the quantification of pesp is also shown ( gray curve ) . because there was no significant difference in patients with pesp absent and without suitable vpcs , both subgroups were merged for additional analyses . b , probability of death in patients stratified by the combination of pesp ( absent and present ) and lvef ( 35% and > 35% ) . the numbers of patients at risk in the individual groups at 0 , 1 , 2 , 3 , 4 , and 5 years are shown below the graphs in the same color coding . lvef indicates left ventricular ejection fraction ; pesp , postextrasystolic potentiation ; vpc , ventricular premature complex . in univariable cox regression analysis , all 4 considered risk factors ( ie , pesp , lvef , vpc count , and grace score ) were significantly associated with outcome . the presence of pesp was associated with a hazard ratio ( hr ) of 5.5 ( 95% ci , 3.2 to 9.4 ; p<0.001 ; left column of table 2 ) . in multivariable cox regression analysis , pesp , lvef , and grace score were significant risk predictors with hrs of 3.2 ( 95% ci , 1.8 to 5.7 ; p<0.001 ) , 2.6 ( 95% ci , 1.5 to 4.6 ; p=0.001 ) , and 4.7 ( 95% ci , 2.7 to 8.0 ; p<0.001 ) , respectively ( right column of table 2 ) . uni and multivariable cox regression analysis grace score indicates composite of age of the patient , serum creatinine , past myocardial infarction , past heart failure , inhospital percutaneous coronary intervention , heart rate , systolic blood pressure , st segment deviation and positive enzymes ; hr , hazard ratio with 95% confidence intervals in parentheses ; lvef , left ventricular ejection fraction ; pesp , postextrasystolic potentiation ; vpc , ventricular premature complex . the goodness of fit improved significantly when pesp was added to the cox model fixed to lvef , grace score , and vpc counts ( p<0.001 ) . the vif for pesp was 1.098 , which is way below the critical value 4 , which indicates collinearity . patients with both lvef > 35% and pesp absent had a 5year mortality risk of 5.1% . patients in whom only 1 variable was abnormal had mortality risks of 18.2% ( lvef 35% and pesp absent ) or 23.8% ( lvef > 35% and pesp present ) . when pesp was added to lvef , the idi index was 0.003 in survivors and 0.034 in nonsurvivors ( p=0.05 and 0.009 , respectively ) . an internal validation by 3fold crossvalidation , repeated 25 times , resulted in average idi values of 0.003 and 0.034 , stressing the robustness of the results . when a highrisk group was defined by use of lvef alone , positive predictive value was 23.0% at a sensitivity level of 27.8% ( table 3 ) . the definition of a highrisk group was more precise if lvef and pesp were used in combination : positive predictive value ( ppv ) remained stable at 23.1% , whereas sensitivity significantly increased to 43.1% ( p<0.001 ) . group sizes and numbers of primary endpoints , sensitivities , specificities , and positive and negative predictive values for selected subroups defined by lvef and pesp e indicates number of primary endpoints ; lvef , left ventricular ejetion fraction ; n , size of subgroup ; npv , negative predictive value ; pesp , postextrasystolic potentiation ; ppv , positive predictive value . because the baseline variables presented in table 1 might represent confounders , especially if associated both with pesp and mortality , we tested whether inclusion of these factors in the multivariable cox regression model consisting of pesp , lvef , vpc count , and grace score would reduce the prognostic power of pesp . none of the tested parameters led to a loss of significant association of pesp with mortality when included in the analysis . we conclude that the association of pesp and mortality is not a result of confounding by any of these parameters . hazard ratios for pesp , together with 95% confidence intervals , are shown for multivariable models in which singular additional baseline variables ( as indicated ) were included in the cox analysis in addition to the baseline model consisting of pesp , lvef , vpc count , and grace score . ass indicates acetylsalicylic acid ; ami , acute myocardial infarction ; cabg , coronary artery bypass grafting ; lvef , left ventricular ejection fraction ; nyha , new york heart association functional class ; pci , percutaneous coronary intervention ; pesp , postextrasystolic potentiation ; stemi , stelevation myocardial infarction ; vpc , ventricular premature complex . the novelty of the concept of pesp as a postmi risk predictor requires independent validation . to our best knowledge , there is only 1 other data set of simultaneous ecgs and continuous bp measurements suitable for both pesp quantification and risk assessment : a scottish cohort of 146 hf patients . during a followup period of 2.71.1 years pesp could be measured in 105 of these patients ; data in 41 were not suitable for assessment because of the lack of ventricular ectopy during the 10minute recording . figure 5 shows survival analysis of patients with pesp present and absent , including patients in whom pesp was not measurable . the same principal result as in the main study cohort is seen this was confirmed by uni and multivariable cox regression analysis , indicating that presence of pesp was a strong predictor of mortality independent of other established risk predictors ( data not shown ) . figure 6 depicts the mortality probability of patients from both cohorts as a function of numerical ratio of pesp . the optimum cutoff values for numerical ratio of pesp were 1.037 ( 95% ci , 0.994 to 1.045 ) and 1.093 ( 0.985 to 1.124 ) in the art and scottish cohorts , respectively . thus , the prospective definition of pesp present and absent was well within the 95% ci of both art and scottish cohorts . mortality probability over the followup period in patients stratified according to pesp presence ( red curve ) and absence ( green curve ) . mortality probability of patients in whom pesp was not evaluable is also shown ( gray curve ) . the numbers of patients of the 2 groups involved in the analysis at 0 , 1 , 2 , and 3 years are shown below the graph in the same color coding . mortality probabilities and their 95% confidence intervals on a continuous scale of a pesp numerical ratio . data from the postinfarction patients included in the art study are depicted in pink , and data from the heart failure patients from the validation study are shown in cyan . the horizontal axis shows the proportion of the first postvpc pulse wave amplitude to the mean of the subsequent 9 pulse wave amplitudes . art indicates autonomic regulation trial ; pesp indicates postextrasystolic potentiation ; vpc , ventricular premature complex . patients with both lvef > 35% and pesp absent had a 5year mortality risk of 5.1% . patients in whom only 1 variable was abnormal had mortality risks of 18.2% ( lvef 35% and pesp absent ) or 23.8% ( lvef > 35% and pesp present ) . when pesp was added to lvef , the idi index was 0.003 in survivors and 0.034 in nonsurvivors ( p=0.05 and 0.009 , respectively ) . an internal validation by 3fold crossvalidation , repeated 25 times , resulted in average idi values of 0.003 and 0.034 , stressing the robustness of the results . when a highrisk group was defined by use of lvef alone , positive predictive value was 23.0% at a sensitivity level of 27.8% ( table 3 ) . the definition of a highrisk group was more precise if lvef and pesp were used in combination : positive predictive value ( ppv ) remained stable at 23.1% , whereas sensitivity significantly increased to 43.1% ( p<0.001 ) . group sizes and numbers of primary endpoints , sensitivities , specificities , and positive and negative predictive values for selected subroups defined by lvef and pesp e indicates number of primary endpoints ; lvef , left ventricular ejetion fraction ; n , size of subgroup ; npv , negative predictive value ; pesp , postextrasystolic potentiation ; ppv , positive predictive value . because the baseline variables presented in table 1 might represent confounders , especially if associated both with pesp and mortality , we tested whether inclusion of these factors in the multivariable cox regression model consisting of pesp , lvef , vpc count , and grace score would reduce the prognostic power of pesp . none of the tested parameters led to a loss of significant association of pesp with mortality when included in the analysis . we conclude that the association of pesp and mortality is not a result of confounding by any of these parameters . hazard ratios for pesp , together with 95% confidence intervals , are shown for multivariable models in which singular additional baseline variables ( as indicated ) were included in the cox analysis in addition to the baseline model consisting of pesp , lvef , vpc count , and grace score . ass indicates acetylsalicylic acid ; ami , acute myocardial infarction ; cabg , coronary artery bypass grafting ; lvef , left ventricular ejection fraction ; nyha , new york heart association functional class ; pci , percutaneous coronary intervention ; pesp , postextrasystolic potentiation ; stemi , stelevation myocardial infarction ; vpc , ventricular premature complex . the novelty of the concept of pesp as a postmi risk predictor requires independent validation . to our best knowledge , there is only 1 other data set of simultaneous ecgs and continuous bp measurements suitable for both pesp quantification and risk assessment : a scottish cohort of 146 hf patients . during a followup period of 2.71.1 years , pesp could be measured in 105 of these patients ; data in 41 were not suitable for assessment because of the lack of ventricular ectopy during the 10minute recording . figure 5 shows survival analysis of patients with pesp present and absent , including patients in whom pesp was not measurable . the same principal result as in the main study cohort is seen this was confirmed by uni and multivariable cox regression analysis , indicating that presence of pesp was a strong predictor of mortality independent of other established risk predictors ( data not shown ) . figure 6 depicts the mortality probability of patients from both cohorts as a function of numerical ratio of pesp . the optimum cutoff values for numerical ratio of pesp were 1.037 ( 95% ci , 0.994 to 1.045 ) and 1.093 ( 0.985 to 1.124 ) in the art and scottish cohorts , respectively . thus , the prospective definition of pesp present and absent was well within the 95% ci of both art and scottish cohorts . mortality probability over the followup period in patients stratified according to pesp presence ( red curve ) and absence ( green curve ) . mortality probability of patients in whom pesp was not evaluable is also shown ( gray curve ) . the numbers of patients of the 2 groups involved in the analysis at 0 , 1 , 2 , and 3 years are shown below the graph in the same color coding . mortality probabilities and their 95% confidence intervals on a continuous scale of a pesp numerical ratio . data from the postinfarction patients included in the art study are depicted in pink , and data from the heart failure patients from the validation study are shown in cyan . the horizontal axis shows the proportion of the first postvpc pulse wave amplitude to the mean of the subsequent 9 pulse wave amplitudes . art indicates autonomic regulation trial ; pesp indicates postextrasystolic potentiation ; vpc , ventricular premature complex . this is the first study that prospectively investigated postextrasystolic bp potentiation as a risk predictor in cardiac patients . the main finding in our data is that pesp was a strong predictor of mortality in postmi and hf patients : in patients with pesp present in the art cohort , mortality was 5fold higher than in the remaining patients . in the multivariable model , which included the grace score , arrhythmia count , and lvef , the highrisk subgroup identified by pesp was small ( only 6.6% of the enrolled patients ) . naturally , our study does not provide data on whether any intervention can reduce this risk . however , because of the small size of the highrisk group identified by pesp , such an intervention would have to be targeted only at a small subgroup of postinfarction patients . the contribution to risk stratification provided by pesp and lvef was complementary : whereas the large subgroup of patients with both pesp and lvef normal was at very low risk of subsequent death ( 5year mortality risk , 5.1% ) , this risk was substantial for patients with 1 abnormal parameter , regardless of whether this was lvef ( 18.2% ) or pesp ( 23.8% ) . the highest mortality risk was observed in the subgroup of patients with both pesp and lvef abnormal ( 46.7% ) . the association of pesp with mortality was consistently observed also in the independent scottish cohort of hf patients . in both cohorts the concept that pesp represents a surrogate for clinical or subclinical hf might be counterintuitive at first sight . it is , however , supported not only by clinical observations , but also by experimental studies as well as by mathematical modeling of calcium cycling processes . for example , a mouse model of depressed lv function induced by overexpression of phospholamban ( the major negative regulator of sarcoplasmic reticulum calcium uptake ) showed a greater magnitude of pesp , compared to isogenic control mice . if pesp is invasively measured as lv dp / dtmax of the first postectopic beat , a potentiation is observed in both healthy subjects and hf patients , but augmented in the latter . the beattobeat bp changes are determined not only by the contractility of the heart , but also by a vascular component . if pesp is measured as sbp of the first postectopic beat , a potentiation is typically not observed in healthy subjects , but in hf patients . in both of our patient cohorts , the calcium cycling abnormalities underlying pesp may facilitate the generation of both early and delayed afterdepolarizations . consequently , pesp does not only indicate hfrelated abnormalities at the cellular level , but also a propensity to potentially lethal arrhythmias . pesp can be observed either after spontaneous vpcs  as it was done in this study  or after instrumentally induced vpcs . we foresee a scale of potential clinical applications , including risk assessment in various cardiac conditions , improved patient selection for icd and cardiac resynchronization therapy , and a contribution to the optimization of hf therapy . because the pharmacological modulation of the pathways involved in myocardial calcium homeostasis is a promising approach for the treatment of both systolic and diastolic hf , pesp might become helpful either in selecting patients who will most likely benefit from such treatment or in providing a measurable surrogate of treatment effects . because of the limited number of deaths ( especially in the group of patients with vpcs suitable for pesp assessment ) , the power to assess the association with morespecific endpoints is limited . when we repeated the analyses for the association with cardiac mortality ( as adjudicated by an event committee ) , we obtained practically the same results ( not shown here ) . because of even smaller numbers of sudden cardiac deaths because no independent cohort of mi patients was available to validate our results from the art trial , we used the scottish cohort of advanced hf patients for the validation study . mi was not an inclusion criterion for this cohort , even though 86% had ischemic heart disease . the disparities between the 2 cohorts might be interpreted as a weakness , because the 2 cohorts are not necessarily comparable both in terms of clinical variables and pathophysiology . however , the disparities may be also considered a strong point , because they permit to extend the results of our study to patients with hf of different origin . because we did not systematically assess subsequent icd implantations , we can not provide reliable data on how many of the patients received this therapy during followup . this might have lead to underestimation of the predictive power of pesp in case patients predicted to be at high risk had adequate icd shocks that prevented sudden cardiac death . to make the calculation less noise sensitive , we prospectively decided to relate the first postvpc pulse wave amplitude to the mean of the subsequent 9 pulse wave amplitudes , rather than to the prevpc pulse wave amplitude . when retrospectively using the ratio between the post and prevpc pulse wave amplitudes , the results were practically the same , although reaching slightly lesser statistical significances ( likely the result of noise influence ) . pesp can be observed either after spontaneous vpcs  as it was done in this study  or after instrumentally induced vpcs . we foresee a scale of potential clinical applications , including risk assessment in various cardiac conditions , improved patient selection for icd and cardiac resynchronization therapy , and a contribution to the optimization of hf therapy . because the pharmacological modulation of the pathways involved in myocardial calcium homeostasis is a promising approach for the treatment of both systolic and diastolic hf , pesp might become helpful either in selecting patients who will most likely benefit from such treatment or in providing a measurable surrogate of treatment effects . because of the limited number of deaths ( especially in the group of patients with vpcs suitable for pesp assessment ) , the power to assess the association with morespecific endpoints is limited . when we repeated the analyses for the association with cardiac mortality ( as adjudicated by an event committee ) , we obtained practically the same results ( not shown here ) . because of even smaller numbers of sudden cardiac deaths because no independent cohort of mi patients was available to validate our results from the art trial , we used the scottish cohort of advanced hf patients for the validation study . mi was not an inclusion criterion for this cohort , even though 86% had ischemic heart disease . the disparities between the 2 cohorts might be interpreted as a weakness , because the 2 cohorts are not necessarily comparable both in terms of clinical variables and pathophysiology . however , the disparities may be also considered a strong point , because they permit to extend the results of our study to patients with hf of different origin . because we did not systematically assess subsequent icd implantations , we can not provide reliable data on how many of the patients received this therapy during followup . this might have lead to underestimation of the predictive power of pesp in case patients predicted to be at high risk had adequate icd shocks that prevented sudden cardiac death . to make the calculation less noise sensitive , we prospectively decided to relate the first postvpc pulse wave amplitude to the mean of the subsequent 9 pulse wave amplitudes , rather than to the prevpc pulse wave amplitude . when retrospectively using the ratio between the post and prevpc pulse wave amplitudes , the results were practically the same , although reaching slightly lesser statistical significances ( likely the result of noise influence ) . a pesp bp pattern is characteristic of a disturbed contractile state of the heart . in this study ,