left ventricular ( lv ) heart failure ( hf ) is a prevalent cardiac syndrome , characterized by altered lv size and shape , elevated filling pressure , increased biomarkers , specific risk factors , plus a wide variety of symptoms and signs.1 in hf often a distinction is made between patients on the basis of their ejection fraction ( ef ) .
about half of all hf patients present with a reduced ef ( denoted as hfref ) , while the others show a preserved ef ( denoted as hfpef ) . in order to distinguish between both groups ,
the following criteria are commonly used2 : an ef larger than or equal to 50% and an end - diastolic ventricular volume index ( edvi ) smaller than 97 ml / m are required for hfpef , while an ef smaller than 50% is set for hfref . for both groups ,
the gold standard3 of an end - diastolic ventricular pressure ( edp ) larger than 16 mmhg ( millimeter mercury ) is an additional requirement .
thus , the combination of lv pressure and volume plays a prominent role in the analysis of hf phenotypes .
ef is the pivotal measure in the current classification scheme.1 however , the ef is both a quantitative measure that relates the ejected stroke volume ( sv ) to the edv , as a percentage , as well as a qualitative measure that summarizes the complex ventricular interplay with the venous system during the filling phase ( preload ) and the arterial system during the ejection phase ( afterload ) within that same single metric . as a result ,
the ef as a preferred measure of ventricular performance is often questioned.1,48 to quote robotham , for instance :  thus , ef , although a relatively simple measure that is intuitively easily comprehended , is an extremely complex parameter describing the entire cardiovascular system and requires additional study.5 concentrating more specifically on hf , it is noted that despite recent insights into the recognition of the importance of lv reverse remodeling in hf , many clinicians do not consider simple measurements of lv structure ( ie , lv volume ) in their routine clinical decision - making process.9 instead , they often rely on ef when making decisions about medical and surgical treatment options.9 rather than combining the end - diastolic volume ( edv ) and the end - systolic volume ( esv ) of the ventricle in the single percentage of the ef , some authors advocate to study ventricular performance on the basis of both lv volumes by using a graph with the edv on the abscissa and the esv on the ordinate.1,10 recently , a linear relationship 
 esv = q+sedv(1)with slope s and intercept q , was reported for a study concerning 34 hfpef patients and 29 hfref patients ( fig .
each group clustered around its own regression line with a quite small overlap in the esv versus edv graph and , moreover , the slopes of these two lines were reported to be significantly different.8 to be specific , kerkhof reports a slope of 0.35 in hfpef versus a slope of 0.80 in hfref ( p < 0.0004 ) and an intercept of 6.97 ml / m in hfpef versus 19.24 ml / m in hfref.8 clearly , the ef and the slope of the regression line in the edv  esv graph are related , namely 
 ef = edvesvedv = edv(q+sedv)edv=1(s+qedv)(2 ) for a vanishing intercept ( q = 0 ) , this relation shows that ef equals 1 minus the slope s in the esv  edv graph .
as expected , figure 1 shows a steeper regression line for the hfref group ( ef < 50% ) than for the hfpef group ( ef 50% ) .
however for a nonvanishing intercept ( q  0 ) , the relation between ef and s may be strongly influenced by edv .
indeed , from figure 1 significant nonvanishing intercepts for both groups can be inferred , and hence , the presumed simple relation between ef and s is seriously distorted by prevailing values of edv . and , therefore , the ef and the esv  edv graph must be considered as different and noncomparable metrics representing the volumes edv and esv . clearly , the ef and the esv  edv graph appear to reflect quite differently the relationship between edv and esv and , with that , the ( patho-)physiological mechanisms of ventricular performance in the hf spectrum . therefore , this study aims to identify the dependence of the ef and the edv  esv graph on the major determinants of ventricular performance , in particular , for the phenotypes hfpef and hfref , and preferable by using a simple mathematical model of the cardiovascular system . using a monoventricular model ,
first the major determinants are identified and second the dependence of the ef and the edv  esv graph on these determinants is calculated .
our model of the cardiovascular system consists of the systemic circulation only , with the atrium and ventricle being filled from a simple constant pressure source and the heart ejecting into a circulatory system .
the model is discussed in detail in appendix a. in each simulation run , the model provides results on edv , esv , sv , ef , and end - diastolic pressure edp . the outcomes are classified as follows ( 2 ) : 
  hfpef , if ef 50% , edv < 175 ml and edp > 16 mmhg; hfref , if ef < 50% and edp > 16 mmhg.and any result of a simulation run outside of these constraints was neglected .
 hfpef , if ef 50% , edv < 175 ml and edp > 16 mmhg ;  hfref , if ef < 50% and edp > 16 mmhg . in order to be able to guide the model simulations , one aspect of the model needs explanation here .
the single - sided cardiac unit consists of a left atrium and a lv together with the mitral and aortic valves .
volume characteristics.11 this model reads as : 
 p(t)=e(t){v(t)v0}(3)where p(t ) is the time - dependent ventricular pressure ( mmhg ) , v(t ) the time - dependent ventricular volume ( ml ) , v0 the ( extrapolated ) ventricular volume ( ml ) at zero ventricular pressure , and e(t ) the time - dependent ventricular elastance ( mmhg / ml ) .
note that this relation holds for every point in time during the cardiac cycle and , in particular , for the end - systolic moment , in which case the relation is referred to as the end - systolic pressure  volume relationship . for
the lv , senzaki et al provide a formulation enabling to express the elastance as a function of time , namely in terms of a fourier series.12 we will use the suga  sagawa elastance model to investigate the major determinants of edv and esv and , by the same token , those of the ef ( see below in this section ) . in order to identify the major determinates of ef and the edv  esv graph , we reason as follows : 
 ef = edvesvedv=1esvedv=1min{v(t)}max{v(t)}(4)where t represents time ( s ) and v(t ) is the time - dependent ventricular volume ( ml ) .
clearly , edv is the maximum of v(t ) during diastole ( denoted as max{v(t ) } ) and esv is the minimum of v(t ) during systole ( denoted as min{v(t ) } ) . in order to relate the edv and esv to ventricular elastance , suga 
sagawa s pressure  volume relation p(t ) = e(t ) { v(t )  v0 } is used.13 upon rewriting the suga 
sagawa s relation , the edv is 
 edv=(1)max{v(t)}=(2)max{p(t)e(t)+v0}=(3)max{p(t)e(t)}+v0(4)max{p(t)}min{e(t)}+v0=(5)pfillemin+v0=(6)pfillemin(1+eminv0pfill)(5)with the following rationales at the numbered equal signs : ( 1 ) edv is the maximum ventricular volume during diastole ; ( 2 ) a rewritten form of suga 
sagawa s pressure  volume relation ; ( 3 ) the maximum of the sum of a ratio and a constant equals the maximum of the ratio summed to the constant ; ( 4 ) by application of the general rule that the maximum of a ratio is smaller than or equal to the ratio of the maximum of the fraction s numerator divided by the minimum of the fraction s denominator ; ( 5 ) the maximum pressure of the ventricle during diastole is the filling pressure pfill ( mmhg ) ( neglecting the atrial kick ) and the minimum ventricular elastance is defined as emin ( mmhg / ml ) ; ( 6 ) rewriting in a more convenient form by factoring the term pfill / emin .
likewise , and mutatis mutandis , the esv is found 
 esv=(1)min{v(t)}=(2)min{p(t)e(t)+v0}=(3)min{p(t)e(t)}+v0(4)min{p(t)}max{e(t)}+v0=(5)pdiasemax+v0=(6)pdiasemax(1+emaxv0pdias)(6)with the following rationales at the numbered equal signs : ( 1 ) esv is the minimum ventricular volume during systole ; ( 2 ) a rewritten form of suga 
sagawa s pressure  volume relation ; ( 3 ) the minimum of the sum of a ratio and a constant equals the minimum of the ratio summed to the constant ; ( 4 ) by application of the general rule that the minimum of a ratio is larger than or equal to the ratio of the minimum of the fraction s numerator divided by the maximum of the fraction s denominator ; ( 5 ) the minimum pressure of the ventricle during ejection is equal to the end - diastolic pressure in the aorta , ie , pdias ( mmhg ) and emax ( mmhg / ml ) is the maximum ventricular elastance and referred to as the maximum systolic elastance ; ( 6 ) rewriting in a more convenient form by factoring the term pdias / max .
( 4 ) : 
 ef = edvesvedv=1esvedv1pdiasemax+v0pfillemin+v0=1(pdiasemax)(1+emaxpdiasv0)(pfillemin)(1+eminpfillv0)1(pdiasemax)(pfillemin)(8 ) in eqns . ( 7 ) and ( 8) the last approximation holds , only if v0 vanishes ( ie , v0 = 0 ) or if the numerical values of the ratios emax / pdias and emin / pfill are of equal size because , in either way , the terms ( 1 + v0emax / pdias ) and ( 1 + v0emin / pfill ) cancel .
typical values are calculated from table 1 . in hfpef : emax / pdias = 0.11 ml and emin / pfill = 0.01 ; in hfref : emax / pdias = 0.02 ml and emin / pfill = 0.005 ml .
notice that emax in table 1 is estimated assuming that v0 = 0 and that , therefore , these values are rough estimates only .
so , these numerical values indicate that the terms ( 1 + v0emax / pdias ) and ( 1 + v0emin / pfill ) only cancel in the unlikely case of a vanishing v0 . therefore , the final approximations in eqns .
( 7 ) and ( 8) are somewhat questionable . to summarize these mathematical results : 
 there is no reason to assume that v0 vanishes in this model simulation study.the major determinants of the edv ( see eq . ( 5 ) ) are the ratio of the filling pressure ( pfill ) over the elastance during diastole ( emin ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pfill / emin can be interpreted as the preload normalized to the diastolic ventricular elastance.the major determinants of the esv ( see eq .
( 6 ) ) are the ratio of the diastolic aortic pressure ( pdias ) over the elastance during systole ( emax ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pdias / emax can be interpreted as an indicator of the afterload normalized to the systolic ventricular elastance.because the ef and the esv  edv graphs are defined in terms of the edv and esv , both the ef and the esv edv graphs share common determinants .
note that this sharing of determinants does not imply the equivalence of the ef and the esv  edv graph .
( 7 ) ) predicts a linear relation in the esv  edv graph with a small or even vanishing intercept and slope smaller than 1 and , moreover , infers an elastance - normalized afterload pdias / emax smaller than the elastance - normalized preload pfill / emin .
the major determinants of the edv ( see eq . ( 5 ) ) are the ratio of the filling pressure ( pfill ) over the elastance during diastole ( emin ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pfill / emin can be interpreted as the preload normalized to the diastolic ventricular elastance .
( 6 ) ) are the ratio of the diastolic aortic pressure ( pdias ) over the elastance during systole ( emax ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pdias / emax can be interpreted as an indicator of the afterload normalized to the systolic ventricular elastance . because the ef and the esv  edv graphs are defined in terms of the edv and esv , both the ef and the esv edv graphs share common determinants . note that this sharing of determinants does not imply the equivalence of the ef and the esv  edv graph .
see the introduction for the relation between ef and the slope of the esv  edv graph .
( 7 ) ) predicts a linear relation in the esv  edv graph with a small or even vanishing intercept and slope smaller than 1 and , moreover , infers an elastance - normalized afterload pdias / emax smaller than the elastance - normalized preload pfill / emin . on the basis of these findings
edv plot by varying the abovementioned determinants ( pdias , emax , pfill , emin , and v0 ) in order to identify major factors contributing to the distinct lv volume patterns manifested in hfpef relative to hfref ( cf .
our model of the cardiovascular system consists of the systemic circulation only , with the atrium and ventricle being filled from a simple constant pressure source and the heart ejecting into a circulatory system .
the model is discussed in detail in appendix a. in each simulation run , the model provides results on edv , esv , sv , ef , and end - diastolic pressure edp . the outcomes are classified as follows ( 2 ) : 
  hfpef , if ef 50% , edv < 175 ml and edp > 16 mmhg; hfref , if ef < 50% and edp > 16 mmhg.and any result of a simulation run outside of these constraints was neglected .
 hfpef , if ef 50% , edv < 175 ml and edp > 16 mmhg ;  hfref , if ef < 50% and edp > 16 mmhg . in order to be able to guide the model simulations , one aspect of the model needs explanation here .
the single - sided cardiac unit consists of a left atrium and a lv together with the mitral and aortic valves .
volume characteristics.11 this model reads as : 
 p(t)=e(t){v(t)v0}(3)where p(t ) is the time - dependent ventricular pressure ( mmhg ) , v(t ) the time - dependent ventricular volume ( ml ) , v0 the ( extrapolated ) ventricular volume ( ml ) at zero ventricular pressure , and e(t ) the time - dependent ventricular elastance ( mmhg / ml ) .
note that this relation holds for every point in time during the cardiac cycle and , in particular , for the end - systolic moment , in which case the relation is referred to as the end - systolic pressure  volume relationship . for
the lv , senzaki et al provide a formulation enabling to express the elastance as a function of time , namely in terms of a fourier series.12 we will use the suga  sagawa elastance model to investigate the major determinants of edv and esv and , by the same token , those of the ef ( see below in this section ) .
in order to identify the major determinates of ef and the edv  esv graph , we reason as follows : 
 ef = edvesvedv=1esvedv=1min{v(t)}max{v(t)}(4)where t represents time ( s ) and v(t ) is the time - dependent ventricular volume ( ml ) .
clearly , edv is the maximum of v(t ) during diastole ( denoted as max{v(t ) } ) and esv is the minimum of v(t ) during systole ( denoted as min{v(t ) } ) . in order to relate the edv and esv to ventricular elastance , suga 
sagawa s pressure  volume relation p(t ) = e(t ) { v(t )  v0 } is used.13 upon rewriting the suga 
sagawa s relation , the edv is 
 edv=(1)max{v(t)}=(2)max{p(t)e(t)+v0}=(3)max{p(t)e(t)}+v0(4)max{p(t)}min{e(t)}+v0=(5)pfillemin+v0=(6)pfillemin(1+eminv0pfill)(5)with the following rationales at the numbered equal signs : ( 1 ) edv is the maximum ventricular volume during diastole ; ( 2 ) a rewritten form of suga 
sagawa s pressure  volume relation ; ( 3 ) the maximum of the sum of a ratio and a constant equals the maximum of the ratio summed to the constant ; ( 4 ) by application of the general rule that the maximum of a ratio is smaller than or equal to the ratio of the maximum of the fraction s numerator divided by the minimum of the fraction s denominator ; ( 5 ) the maximum pressure of the ventricle during diastole is the filling pressure pfill ( mmhg ) ( neglecting the atrial kick ) and the minimum ventricular elastance is defined as emin ( mmhg / ml ) ; ( 6 ) rewriting in a more convenient form by factoring the term pfill / emin . likewise , and mutatis mutandis , the esv is found 
 esv=(1)min{v(t)}=(2)min{p(t)e(t)+v0}=(3)min{p(t)e(t)}+v0(4)min{p(t)}max{e(t)}+v0=(5)pdiasemax+v0=(6)pdiasemax(1+emaxv0pdias)(6)with the following rationales at the numbered equal signs : ( 1 ) esv is the minimum ventricular volume during systole ; ( 2 ) a rewritten form of suga 
sagawa s pressure  volume relation ; ( 3 ) the minimum of the sum of a ratio and a constant equals the minimum of the ratio summed to the constant ; ( 4 ) by application of the general rule that the minimum of a ratio is larger than or equal to the ratio of the minimum of the fraction s numerator divided by the maximum of the fraction s denominator ; ( 5 ) the minimum pressure of the ventricle during ejection is equal to the end - diastolic pressure in the aorta , ie , pdias ( mmhg ) and emax ( mmhg / ml ) is the maximum ventricular elastance and referred to as the maximum systolic elastance ; ( 6 ) rewriting in a more convenient form by factoring the term pdias / max .
( 4 ) : 
 ef = edvesvedv=1esvedv1pdiasemax+v0pfillemin+v0=1(pdiasemax)(1+emaxpdiasv0)(pfillemin)(1+eminpfillv0)1(pdiasemax)(pfillemin)(8 ) in eqns . ( 7 ) and ( 8) the last approximation holds , only if v0 vanishes ( ie , v0 = 0 ) or if the numerical values of the ratios emax / pdias and emin / pfill are of equal size because , in either way , the terms ( 1 + v0emax / pdias ) and ( 1 + v0emin / pfill ) cancel .
: emax / pdias = 0.11 ml and emin / pfill = 0.01 ; in hfref : emax / pdias = 0.02 ml and emin / pfill = 0.005 ml .
notice that emax in table 1 is estimated assuming that v0 = 0 and that , therefore , these values are rough estimates only .
so , these numerical values indicate that the terms ( 1 + v0emax / pdias ) and ( 1 + v0emin / pfill ) only cancel in the unlikely case of a vanishing v0 . therefore , the final approximations in eqns .
( 7 ) and ( 8) are somewhat questionable . to summarize these mathematical results : 
 there is no reason to assume that v0 vanishes in this model simulation study.the major determinants of the edv ( see eq . ( 5 ) ) are the ratio of the filling pressure ( pfill ) over the elastance during diastole ( emin ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pfill / emin can be interpreted as the preload normalized to the diastolic ventricular elastance.the major determinants of the esv ( see eq .
( 6 ) ) are the ratio of the diastolic aortic pressure ( pdias ) over the elastance during systole ( emax ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pdias / emax can be interpreted as an indicator of the afterload normalized to the systolic ventricular elastance.because the ef and the esv  edv graphs are defined in terms of the edv and esv , both the ef and the esv edv graphs share common determinants .
note that this sharing of determinants does not imply the equivalence of the ef and the esv  edv graph .
( 7 ) ) predicts a linear relation in the esv  edv graph with a small or even vanishing intercept and slope smaller than 1 and , moreover , infers an elastance - normalized afterload pdias / emax smaller than the elastance - normalized preload pfill / emin .
( 5 ) ) are the ratio of the filling pressure ( pfill ) over the elastance during diastole ( emin ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pfill / emin can be interpreted as the preload normalized to the diastolic ventricular elastance .
the major determinants of the esv ( see eq . ( 6 ) ) are the ratio of the diastolic aortic pressure ( pdias ) over the elastance during systole ( emax ) and the zero - pressure volume of the ventricle ( v0 ) .
note that the ratio pdias / emax can be interpreted as an indicator of the afterload normalized to the systolic ventricular elastance . because the ef and the esv  edv graphs are defined in terms of the edv and esv , both the ef and the esv edv graphs share common determinants .
note that this sharing of determinants does not imply the equivalence of the ef and the esv  edv graph .
see the introduction for the relation between ef and the slope of the esv  edv graph .
( 7 ) ) predicts a linear relation in the esv  edv graph with a small or even vanishing intercept and slope smaller than 1 and , moreover , infers an elastance - normalized afterload pdias / emax smaller than the elastance - normalized preload pfill / emin . on the basis of these findings
edv plot by varying the abovementioned determinants ( pdias , emax , pfill , emin , and v0 ) in order to identify major factors contributing to the distinct lv volume patterns manifested in hfpef relative to hfref ( cf .
figure 2 shows the simulation results of pressures , volumes , and elastances as a function of time and , additionally , the lv pressure  volume and elastance  volume loops for a control and the hfpef and hfref groups .
note that the model parameters are chosen such that the latter two groups represent values as given in table 1 .
the control represents the values provided by katz,14 ie , filling pressure of 7 mmhg , maximum ventricular pressure of 120 mmhg , end - systolic pressure of 95 mmhg , end - diastolic pressure in the aorta of 80 mmhg , edv 120 ml including atrial kick of 20 ml , end - systolic volume 50 ml , and an ef of 60% . note in particular the large difference in the maximum ventricular elastance in the three simulations .
the simulations closely resemble the data in table 1 and those reported by katz , with the exception of the pressures in hfref .
note that , the elastance  pressure plot and the pressure volume plot for the ventricle in figure 2 clearly show the constant value of the elastance during diastole and , consequently , a linear dependence of the pressure on the volume .
figures 37 show the changes in the cardiovascular model when one of the model parameters is varied . to be specific , in figures 3 , 4 , 5 , 6 , and 7 , respectively , the variable varied is the diastolic elastance ( emin ) , the filling pressure , the systolic elastance , the capillary resistance ( rc ) , and finally , the zero - pressure ventricular volume ( v0 ) . in each of these figures ,
the following is shown : 
  first and second rows show the lv pressure  volume and elastance  volume loops , respectively. third row shows the arterial and ventricular pressures and the ventricular volumes , the sv , and the ef as functions of the running variable. fourth row shows the esv  edv plot ( with slope and intercept of regression line ) and the starling curve with sv as function of edv . 
first and second rows show the lv pressure  volume and elastance  volume loops , respectively .
 third row shows the arterial and ventricular pressures and the ventricular volumes , the sv , and the ef as functions of the running variable . 
fourth row shows the esv  edv plot ( with slope and intercept of regression line ) and the starling curve with sv as function of edv .
note that in figure 6 , the ventricular volume and ventricular ef ( third row , third and fourth graph ) are shown as a function of diastolic pressure in the aorta .
the rationale for this exception is that end - diastolic pressure in the aorta ( pdias ) was identified as one of the determinants of esv but pdias is a variable calculated in a simulation with the model while the other running variables are parameters set in the model . in order to vary pdias , the parameter capillary resistance ( rc ) was varied instead with the results plotted with pdias on the abscissa . in figures 37 , the graphs with ventricular volume versus
the varying parameter ( third row , third graph from left ) show that the edv and esv vary in correspondence with eqns .
( 5 ) and ( 6 ) ; ie , for edv a proportional relation with filling pressure ( pfill ) and an inverse proportional relation with diastolic elastance ( emin ) is found , and moreover , for esv a proportional relation with diastolic pressure in the aorta ( pdias ) and an inverse proportional relation with systolic elastance ( emax ) is found .
finally , for both edv and esv a proportional relation with the zero - pressure ventricular volume ( v0 ) is found .
clearly , the same line is found by varying the diastolic elastance ( emin ) and filling pressure ( pfill ) , the major determinants of edv ( eq .
( 5 ) ) , and also , another line is found by varying the systolic elastance ( emax ) and diastolic pressure in the aorta ( pdias ) , the major determinants of esv ( eq . ( 6 ) ) .
thus , because of the differences in slopes and intercepts of these lines in the esv  edv graph , it might be possible to infer the involvement of diastolic factors ( filling pressure or diastolic elastance ) or , in contrast , systolic factors ( the diastolic pressure in the aorta or the systolic elastance ) on the basis of the location of a patient s edv and in esv in the esv  edv graph .
the ef  esv graphs in figures 37 show that , although the graphs are rather different , the results ( ie , lines ) overlap in a common region of the graph .
so , from the position of the line in the ef  esv graphs , it can not be interpreted which of the factors was involved .
this is a disadvantage of the ef  esv graph in comparison with the esv  edv graph .
by using a simple mathematical model of a monoventricular cardiovascular system , this study identified the major determinants of edv and esv and , by the same token , the major determinants in the graph of esv versus edv and the ef , in particular , for the different phenotypes hfpef and hfref . by using suga 
( 3 ) and a simple mathematical reasoning ( eqns . ( 5 ) and ( 6 ) ) , the diastolic elastance and the filling pressure were identified as the major determinants of edv , while the systolic elastance and the end - diastolic aortic pressure were identified as the major determinants of the esv .
simulations with the cardiovascular model , indeed , clearly confirmed these findings on the major determinants of esv and edv ( see figs .
elsewhere , shoucri described theoretical aspects of the relationship between ef and emax in hfpef patients with emphasis on iso - volumic pressure ( ie , the active force of the myocardium).15 unfortunately , filling pressure and elastance during systole and diastole are difficult to measure in clinical practice .
but , in contrast , edv and esv are far more easily measured in standard clinical routine using modern imaging modalities
. thus , edv and esv can be regarded as measures that are closely related ( eqns .
( 5 ) and ( 6 ) ) to the major determinants of the filling and diastolic pressures and the diastolic and systolic elastances . in fact , by virtue of our findings in eqns . ( 5 ) and ( 6 ) , the edv is related to a normalized preload , ie , the filling pressure relative to the diastolic elastance ( neglecting the zero - pressure ventricular volume v0 ) , while the esv is related to as a normalized afterload , ie , the end - diastolic pressure in the aorta relative to the systolic elastance ( neglecting the v0 ) .
so , edv and esv represent , in a normalized form , the classical concepts , of preload and afterload , respectively . in using esv and edv in clinically diagnostic decision making , a graph with the esv on the ordinate and edv on the abscissa ( the so - called esv 
edv graph ) allows the representation of esv and edv independently , and , with that , the normalized preload and afterload .
this study showed that the hfpef and hfref are represented in this esv  edv graph with different regression lines and , moreover , that the slope of the regression lines is related to the ef ( see eq .
that is , the lower the ef , the steeper the regression line , although this relation is obscured considerably by the edv .
so , the esv  edv graph allows the differentiation between the phenotypes hfpef and hfref ( fig .
this differentiation of hfpef and hfref in the esv  edv graph , on the basis of the esv and edv , can be given a more ( patho-)physiological interpretation .
table 1 shows that the major difference between hfpef and hfref as regards the maximum elastance ( ie , the systolic elastance ) is 7.98 mmhg / ml in hfpef and 1.13 mmhg / ml in hfref , while in both groups the left ventricular end - diastolic pressure ( lv edp ) , as a measure of the filling pressure , is elevated to around 22.5 mmhg ( much higher than 7 mmhg typically found in healthy controls ) and , finally , the diastolic pressure in the aorta is 73 mmhg ( around 7080 mmhg typically found in healthy controls ) .
this finding shows that the normalized afterload ( end - diastolic pressure in the aorta relative to the systolic elastance ) is significantly increased from 9.2 ml in hfpef to 64 ml in hfref ( from table 1 by dividing diastolic pressure by emax ) , a finding that is reflected by the esv , ie , 27.66 ml in hfpef and 147.02 ml in hfref ( table 1 ) .
note that the ratios are almost equal , ie , 9.2/64 = 0.15 fairly well compares with 27.66/147.02 = 0.19 .
so , this confirms that the esv may be given a ( patho-)physiological interpretation as normalized afterload with end - diastolic aortic pressure and systolic elastance as major determinants .
likewise , the pathophysiological interpretation of the normalized preload ( filling pressure relative to the diastolic elastance ) could be confirmed by experimental findings .
but , from the reported filling pressure of around 22.5 mmhg in both groups , considerably higher than in healthy controls , and the significantly increased edv of 224.95 ml in hfref compared to 113.47 ml in hfpef ( table 1 ) , we calculate a diastolic elastance of 0.2 mmhg / ml in hrref and of 0.1 mmhg / ml in hfpef ( calculated from table 1 by dividing lvedp by edv ) . for an
equally increased filling pressure and a two - fold larger diastolic elastance , the normalized preload in hfref is expected to be twice as large as in hfpef , a finding reflected by edv in hfref and hfpef .
we infer that the edv may be given a ( patho-)physiological interpretation as normalized preload with filling pressure and diastolic elastance as major determinants .
so , the esv  edv graph differentiates between hfpef and hfref and , moreover , may be given a ( patho- ) physiological interpretation .
in contrast to the esv  edv graph that represents the esv and edv independently , the ef summarizes the esv and edv in one single metric and with that the ef summarized the complex interplay of cardiac filling and ejection in one metric . in terms of our model ,
the interplay of systolic and diastolic elastances as well as the filling and the end - diastolic aortic pressures , as the major determinants of esv and edv , are mapped into a single number with a size between 0 and 100% .
( 8) ) , it is highly implausible that each ( patho- ) physiological condition in one of the determinants is mapped into a unique numerical value of the ef and , consequently , it is equally implausible that a given value of the ef can be interpreted unambiguously in terms of the underlying ( patho- ) physiological mechanism .
loss of insight is the price paid for summarizing too briefly . from these model - based results
, one may infer that a plot of a patient s esv and edv in the esv  edv graph allows a clinical differentiation between diastolic or systolic involvement while the ef does not offer such a distinction .
so , the esv  edv graph allows a better tool for the understanding of hfref and hfpef .
however , this model - based result is a guidance for future clinical research that should establish the practical value of the esv  edv graph over the single metric of ef.1 the advantage of mathematical modeling is the experimenter s full control of all parameters and conditions in the model and , with that , the simplicity to carry out a simulation experiment that is not so easily clinically performed .
the validity of the modeling study needs , however , to be demonstrated by either the validity of model itself or by the validity of the obtained results . in this study ,
the validity of the model is based on the following considerations : ( 1 ) the model is built up of well - established components ( ie , suga 
sagawa s elastance model of the ventricle , senzaki et al s normalized elastance function , and the generally accepted three - element windkessel model of the arterial circulation).17 ( 2 ) by comparing the simulation results ( fig .
3 ) with the pressure and volumes in hfpef and hfref ( table 1 ) , we recognize the validity of the model .
sagawa s elastance model , major determinants of the esv and edv were identified and these major determinants correspond with the simulations as well as the pathophysiological knowledge , ie , ( a ) diastolic elastance and filling pressure together mainly determine edv , while ( b ) systolic elastance and end - diastolic pressure in the aorta together mainly determine esv . in this perspective of the model s validity
, we suggest to use our findings as a guidance in future clinical studies in order to provide supporting evidence .
although the model mimics the characteristics of control , hfpef , and hfref patients quite accurately , this study clearly has its limitations because of the assumptions made in our mathematical model . to be more specific , ( 1 )
ventricular heart connected to a simple model of the filling system of the heart and a three - element windkessel extended with a venous part , to model the systemic circulation .
( 2 ) the system is an open loop with the simple model of a filling system that is not connected to the venous part of systemic circulation .
( 3 ) the model represents a denervated heart and a circulation without many control mechanisms , eg , neuro - humoral control of heart rate , flow resistance , filling pressure , and cardiac contractility . for some of the limitations , we could compensate by choosing adequate parameters  eg , the different filling pressures , heart rate , maximum elastance in hfpef and hfref  while other features will be incorporated in a future more advanced model  eg , a model with a closed circulation of both the systemic and the pulmonary circulation including neuro - humoral mechanisms .
it is to be expected that a more advanced model will reveal more details in the determining factors of esvs and edvs ( and with that in the esv 
nevertheless , it is hoped that the present insight will provide an adequate guidance for both clinical and modeling studies in the future .
by using a simple mathematical model of the circulation , the filling pressure and diastolic elastance are identified as the major determinants of edv , while the end - diastolic aortic pressure in the aorta and the systolic elastance are identified as the major determinants of the esv . by mathematical analysis and with simulations ,
the dependence of the ef and the esv  edv graph on the determinants was studied .
it was found that the esv  edv graph allows the separation between diastolic and systolic dysfunction , while these two pathologies are intricately summarized in the single metric of ef .
 in left ventricular heart failure , often a distinction is made between patients with a reduced and a preserved ejection fraction ( ef ) . 
 as ef is a composite metric of both the end - diastolic volume ( edv ) and the end - systolic ventricular volume ( esv ) , the lucidity of the ef is sometimes questioned . as an alternative , the esv  edv graph is advocated . 
 this study identifies the dependence of the ef and the edv  esv graph on the major determinants of ventricular performance . 
 numerical simulations were made using a model of the systemic circulation , consisting of an atrium  ventricle valves combination ; a simple constant pressure as venous filling system ; and a three - element windkessel extended with a venous system . 
 esv  
 edv graphs and efs were calculated using this model while varying one by one the filling pressure , diastolic and systolic ventricular elastances , and diastolic pressure in the aorta . in conclusion , 
 the esv  edv graph separates between diastolic and systolic dysfunction while the ef encompasses these two pathologies . 
 therefore , the esv  edv graph can provide an advantage over ef in heart failure studies . 
Introduction
Methods
Cardiovascular model
Major determinants
Results
Discussion
Limitations
Conclusion