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European Journal of Heart Failure 2008 10(12):1192-1200; doi:10.1016/j.ejheart.2008.09.003
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© 2008 European Society of Cardiology

Usefulness of systolic time intervals in the identification of abnormal ventriculo-arterial coupling in stable heart failure patients

Hao-Min Chenga, Wen-Chung Yub, Shih-Hsien Sungb, Kang-Ling Wangb, Shao-Yuan Chuangc and Chen-Huan Chena,d,e,f,*

a Department of Research and Education Taiwan
b Department of Medicine, Taipei Veterans General Hospital Taiwan
c Institute of Biomedical Sciences, Academia Sinica Taipei, Taiwan
d Cardiovascular Research Center Taiwan
e Department of Public Health Taiwan
f I-Lan University Hospital, National Yang-Ming University Taipei, Taiwan

* Corresponding author. No. 201, Sec. 2, Shih-Pai Road, Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan. Tel.: +866 2 28712121x2073; fax: +886 2 28717431. E-mail address: chench{at}vghtpe.gov.tw (C.-H. Chen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: The ratio of effective arterial elastance (Ea) to ventricular end-systolic elastance (Ees) indicates the status of ventriculo-arterial coupling.

Aims: We investigated if systolic time intervals (pre-ejection period, PEP; ejection time, ET; and their ratio, PEP/ET) can be used to identify heart failure patients with abnormal ventriculo-arterial coupling.

Methods: Age and sex-matched study subjects included 54 apparently healthy subjects with normal left ventricular (LV) function, and stable patients with LV diastolic (n=54) and systolic dysfunction (n=54). Ees and Ea were estimated non-invasively by echocardiography, and abnormal ventriculo-arterial coupling was defined as Ea/Ees>1.2. PEP, ET, and PEP/ET were measured automatically using electrocardiography, phonocardiography, and brachial pulse volume recording.

Results: Ea/Ees>1.2 was present in 48.1% of subjects with systolic dysfunction. The PEP/ET was significantly associated with most parameters of LV structure and function, and Ea/Ees (r=0.67, p<0.001). Using PEP/ET≥0.423 as cut point, the sensitivity and specificity to identify patients with Ea/Ees>1.2 were 85.7% and 84.3%, respectively for the whole population, and 84.6% and 78.6%, for patients with systolic dysfunction.

Conclusion: Abnormal ventriculo-arterial coupling was present in almost half of stable patients with systolic dysfunction. PEP/ET was useful in identifying such patients.

Key Words: Systolic time intervals • Ventricular-arterial coupling • Systolic heart failure

Received November 13, 2007; Revised June 1, 2008; Accepted September 8, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Heart failure is a major health problem worldwide [1,2]. Optimal treatment of this disabling and fatal condition may require functional characterization of the failed left ventricle (LV) and its interaction with the arterial system [3]. Most LV performance indices, including ejection fraction, stroke volume, and cardiac output, are load-dependent and are influenced by the functional coupling of the LV with the arteries [4]. Ventriculo-arterial coupling is related to the efficiency of mechanical energetic transfer from the heart to the arteries [5]. The physiological significance has been studied experimentally using the framework of the ratio of effective arterial elastance (Ea) to end-systolic elastance (Ees), which is relatively independent of the loading conditions [6]. Although it has been shown that nitroprusside significantly improved ventriculo-arterial coupling assessed by the ratio of Ea to Ees (Ea/Ees) in patients with heart failure,[3] it remains unclear how often the ventriculo-arterial coupling is suboptimal in stable heart failure patients who may benefit from vasodilator therapy on top of the standard neurohormonal blockade [7].

The systolic time intervals, including pre-ejection period (PEP), ejection time (ET), and their ratio (PEP/ET), is one of the established non-invasive techniques for the quantitative assessment of cardiac performance [8]. PEP is prolonged and ET is shortened in patients with congestive heart failure, and PEP/ET correlates with ejection fraction [9]. Clinical values of the systolic time intervals in the assessment of LV systolic function have been validated in patients with severe heart failure and ischaemic heart disease, [10-12] and in patients receiving cardiac resynchronization therapy [13]. Recently, Sunagawa et al. proposed a framework linking Ees/Ea (the inverse of Ea/Ees) with systolic time intervals and ventricular and aortic pressure [14]. To our knowledge, the potential of systolic time intervals in the assessment of ventriculo-arterial coupling in patients with heart failure has not been reported. Therefore, the purposes of the present study were to investigate the prevalence of abnormal ventriculo-arterial coupling in stable heart failure patients and the usefulness of systolic time intervals in the identification of such patients.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
There were three groups of subjects in the present study. The main patient group included 54 stable heart failure patients with echocardiographic evidence of LV systolic dysfunction. The second patient group consisted of 54 age- and sex-matched stable patients with isolated LV diastolic dysfunction. The third group comprised 54 age- and sex-matched apparently healthy subjects with normal LV function. Patients with LV systolic dysfunction were enrolled consecutively for the study. Data for the age- and sex-matched patients with LV diastolic dysfunction and the normal controls were selected from previous studies [15]. None of the subjects had atrial fibrillation or bundle branch block on their electrocardiograms or significant aortic valve disease shown by echocardiography. All study subjects were invited to undergo a two-hour comprehensive non-invasive cardiovascular evaluation, including echocardiography and systolic time intervals, along with assessment of symptoms and signs of heart failure according to the Framingham criteria [16].

The study protocols were approved by our hospital institutional review board and all subjects gave informed consent before entry into this study.

Heart rate was determined from the surface electrocardiogram, and the systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured with an electronic oscillometric sphygmomanometer.

2.2. Echocardiographic evaluation
Echocardiographic examination was performed using a multi-frequency transducer incorporated in a SONOS 5500 echocardiograph (Hewlett Packard, Inc., Agilent Technologies, Andover, MA) according to the recommendations of the American Society of Echocardiography [17]. All of the following dimensions were measured online from the 2D-guided M-mode echocardiography: aortic root diameter, left atrial dimension, LV internal dimension at end-systole and end-diastole, and thickness of the interventricular septum and LV posterior wall. LV mass, LV end-systolic and end-diastolic volumes, and LV ejection fraction were calculated from the M-mode measurements. LV end-diastolic volume index (LVEDVI) was LV end-diastolic volume divided by body surface area.

Septal-to-posterior wall motion delay (SPWMD) is the delay between the motion of the interventricular septum and LV posterior wall, calculated as the shortest interval between the maximal posterior displacement of the septum and the maximal displacement of the LV posterior wall using a mono-dimensional short-axis view at the papillary muscle level [18].

Stroke volume (SV) was measured by pulsed-wave Doppler echocardiography [19]. Mitral inflow profiles, including the ratio of early to late diastolic transmitral velocity (E/A) and the deceleration time (DT) of the early velocity wave, were sampled between the tips of the anterior and posterior mitral leaflets. Isovolumic relaxation time (IVRT) was the interval between the aortic valve closing artifact and the mitral valve opening artifact. Interventricular delay (IVD) was measured as the time difference between the simultaneously recorded onset of the QRS interval to aortic and pulmonary flow. Motion of the mitral annulus was recorded in the apical four-chamber view by tissue Doppler technique [20]. The major negative myocardial velocity with the movement of the annulus towards the base of the heart during the early phase of diastole velocity was recorded (E'). The average of the velocities from the septal and lateral site of the mitral annulus was used for calculation of the ratio of the early diastolic transmitral velocity to early mitral annular diastolic velocity ratio (E/E').

Patients with an LV ejection fraction<50% were considered to have systolic dysfunction [21]. Patients with isolated diastolic dysfunction should have an LV ejection fraction>50%, and the following echocardiographic characteristics: 1) LVEDVI<97 ml/m2 and E/E'>15; or 2) LVEDVI<97 ml/m2, 15>E/E'>8, and abnormal LV filling (E/A>50year<0.5, DT>50year>280 ms) [22].

2.3. Non-invasive estimation of Ees and Ea
Ees was estimated with a previously proposed single-beat method employing SBP, DBP, SV, LV ejection fraction, and an estimated normalized ventricular elastance at arterial end-diastole [E(Nd)]: Ees=[DBP–(E(Nd)*SBP*0.9)]/[E(Nd)*SV], where E(Nd) was estimated from a group-averaged value adjusted for individual contractile/loading effects [19]. Ea was the ratio of LV end-systolic blood pressure (Pes), which is approximated to value of SBPx2/3+DBPx1/3, to the value of SV [23]. Heart failure patients with a value of Ea/Ees>1.2 were considered as having abnormal ventriculo-arterial coupling [24].

2.4. Systolic time intervals
A newly developed device (VP-1000, Colin Corporation, Komaki, Japan) was used for fast evaluation of the cardiac and arterial functions [25]. The device performed electrocardiography, phonocardiography, and pulse volume recording on four extremities (ankles and arms). After completion of preparation, the fully automatic data acquisition and processing procedure started with the simultaneous measurement of blood pressure over the four extremities by oscillometric principle. This was followed by pulse volume recording over the arms and ankles for 10 s, when the cuff pressures were maintained at 60 mmHg.

The beat-by-beat total electromechanical systolic interval (QS2) and LV ejection time (ET) were measured and the pre-ejection period (PEP) was derived by subtracting ET from QS2 automatically [26]. QS2 was measured from the onset of the QRS complex to the first high frequency vibrations of the aortic component of the second heart sound. ET was measured from the beginning upstroke to the dicrotic notch of the pulse volume trace of the right brachial artery. ET and PEP were the averages of around 10 beats.

2.5. Estimation of Ea/Ees by systolic time intervals
A framework to estimate Ees/Ea using systolic time intervals without measuring ventricular volume or altering the loading condition has been proposed by Sunagawa et al. [14] Using the concept of the pressure-volume relationship, Ees/Ea is algebraically expressed as Ees/Ea=Pad/Pes (1+k*ET/PEP)–1 [Eq. (1)], where Pad is aortic diastolic pressure and can be approximated with DBP, and k is the slope ratio of two straight lines that approximate the isovolumic phase and the ejection phase of the time-varying elastance curve, respectively [14]. Because k is empirically related to Ees/Ea by the equation: k=0.53*(Ees/Ea)0.51[Eq. (2)], Ees/Ea can be solved from Eqs. (1) and (2) with known Pad, Pes, ET, and PEP. Ea/Ees was simply a reciprocal of Ees/Ea.

2.6. Reproducibility of PEP and ET
Measurements of PEP and ET were repeated after 5 min in 20 randomly selected patients. The variability of the paired measurements was calculated.

2.7. Statistical analysis
Between-group comparisons were performed by one way ANOVA and Scheffe's method. Pearson's correlation coefficients of systolic time intervals and Ea/Ees with other parameters were provided with Bonferroni's correction. Determinants of Ea/Ees and PEP/ET were identified by stepwise multiple linear regression analysis. Agreement between Ea/Ees estimates was examined by Bland-Altman analysis. The Receiver operating characteristics (ROC) analysis was performed to determine the optimal cut-off value for PEP/ET in the prediction of abnormal ventriculo-arterial coupling defined by Ea/Ees>1.2. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for either Ea/Ees estimated from PEP/ET and blood pressure, or PEP/ET alone in identifying abnormal ventriculo-arterial coupling were calculated. All statistical significances were set at p<0.05 and all statistical analyses were carried out using SAS 8.02.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
The characteristics of our study population are summarized in Table 1. Of the patients with isolated diastolic dysfunction, 70.4% were in New York Heart Association Functional Classification (Fc) I and 29.6% in Fc II; 18.5% had rales on chest auscultation, and 24.1% had peripheral oedema. Of the patients with systolic dysfunction, 27.8% were in Fc I, 59.3% in Fc II, and 13.0% in Fc III; 59.3% had rales on chest auscultation, and 27.8% had peripheral oedema. The percentages of smokers, and a history of hypertension, diabetes, coronary artery disease, and chronic renal failure were 9.1%, 67.3%, 22.9%, 9.8%, and 31.9% in the diastolic dysfunction group, and 42.9%, 79.6%, 32.7%, 33.3%, and 31.3% in the systolic dysfunction group, respectively. The percentages of patients receiving treatment with β-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors, diuretics, and angiotensin receptor blockers were 34.5%, 27.6%, 26.7%, 30.0%, and 20.0% in the diastolic dysfunction group, and 49.0%, 8.3%, 22.9%, 47.9%, and 23.5% in the systolic dysfunction group, respectively.


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  		Table 1 Clinical characteristics of the study population

 
Patients with LV systolic dysfunction had increased LV mass, LV end-diastolic volume, left atrial size, IVRT, SPWMD, IVD, E/E', Ea, Ea/Ees, PEP, and PEP/ET, and decreased LV ejection fraction, Ees, and ET; and patients with LV diastolic dysfunction had increased LV mass, left atrial size, IVRT, E/E', PEP, and PEP/ET, and decreased E/A, respectively, in comparison with the normal controls. In particular, patients with diastolic dysfunction had Ea, Ees, and Ea/Ees values similar to those in the normal controls. On the other hand, patients with systolic dysfunction had a higher percentage of smokers and coronary artery disease, greater LV mass, LV end-diastolic volume, left atrial size, Ea/Ees, PEP, and PEP/ET, and a lower use of calcium channel blockers, and lower LV ejection fraction, Ees, and ET, than patients with diastolic dysfunction. PEP, ET, and PEP/ET were not significantly different in patients with systolic or diastolic dysfunction who were or were not receiving β-blockers (data not shown).

The prevalence of abnormal ventriculo-arterial coupling defined by echocardiographic Ea/Ees>1.2 was 0% in normal controls, 3.7% in patients with diastolic dysfunction, 48.1% in patients with systolic dysfunction, and 17.3% in patients with either diastolic or systolic dysfunction. Characteristics of patients with systolic dysfunction and abnormal ventriculo-arterial coupling are shown in Table 2. Although they were 10 years younger, the patients with systolic dysfunction and abnormal ventriculo-arterial coupling had even greater heart size (increased LV mass and LV end-diastolic volume), more depressed systolic function (increased E/E' and decreased Ees and LV ejection fraction), and more prominent changes in systolic time intervals (prolonged PEP, shortened ET, and increased PEP/ET), compared with patients with systolic dysfunction and normal ventriculo-arterial coupling.


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  		Table 2 Clinical characteristics of patients with LV systolic dysfunction stratified by status of ventriculo-arterial coupling

 
3.1. Correlates of Ea/Ees and systolic time intervals
With Bonferroni's correction for the multiple variables examined, the threshold of P values for the correlation coefficients was set at 0.003. Ea/Ees was significantly associated with LV mass (r=0.56), LV end-diastolic volume (r=0.75), left atrial size (r=0.41), LV ejection fraction (r=–0.72), Ees (r=–0.62), E/E' (r=0.37), SPWMD (r=0.40), IVD (r=0.56), Ea (r=0.30), and PEP/ET(r=0.68). By stepwise multiple linear regression analysis (model r2=0.77, p<0.001), the independent determinants of Ea/Ees were LV ejection fraction (partial r2=0.15), PEP/ET (partial r2=0.58), and IVD (partial r2=0.04).

By stepwise multiple linear regression analysis (model r2=0.62, P<0.001), the independent determinants of PEP/ET were Ea/Ees (partial r2=0.56) and IVRT (partial r2=0.03). None of the medications were significant determinants for PEP/ET in the multivariate model.

3.2. Estimation of Ea/Ees by PEP/ET and blood pressure
Ea/Ees values estimated from PEP/ET and blood pressure according to the framework proposed by Sunagawa et al. for normal controls, patients with diastolic dysfunction, and patients with systolic dysfunction were 0.7±0.2, 0.9±0.3, and 1.3±0.7, respectively. As compared with the reference Ea/Ees values estimated by the echocardiographic single-beat method (Table 1), Sunagawa's framework significantly overestimated the Ea/Ees values with a mean difference of 0.08±0.37 (p=0.009) in the whole study population. The mean differences were 0.09±0.16 (p<0.001) in normal controls, 0.27±0.26 (p<0.001) in patients with diastolic dysfunction, and 0.11±0.54 (p=0.165) in patients with systolic dysfunction, respectively. The agreement between Ea/Ees values estimated by the singe-beat method and those estimated from the systolic time intervals and blood pressure in the whole study population are shown in Fig. 1 and in patients with systolic dysfunction in Fig. 2.


Figure 01
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  		Fig. 1 Bland-Altman analysis of estimated Ea/Ees by PEP/ET and blood pressure (Sunagawa's framework) versus reference Ea/Ees by echocardiographic single-beat method in the whole study population. Dashed line indicates line of identity. Ea=effective arterial elastance; Ees=end-systolic elastance; Ea/Ees=ratio of Ea to Ees; ET=ejection time; PEP=pre-ejection period; PEP/ET=ratio of PEP to ET.

 


Figure 02
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  		Fig. 2 Bland-Altman analysis of estimated Ea/Ees by PEP/ET and blood pressure (Sunagawa's framework) versus reference Ea/Ees by echocardiographic single-beat method in patients with systolic dysfunction. Dashed line indicates line of identity. Ea=effective arterial elastance; Ees=end-systolic elastance; Ea/Ees=ratio of Ea to Ees; ET=ejection time; PEP=pre-ejection period; PEP/ET=ratio of PEP to ET.

 
3.3. Identification of patients with abnormal ventriculo-arterial coupling
The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of Ea/Ees estimated by systolic time intervals and blood pressure in identifying patients with abnormal ventriculo-arterial coupling in the whole study population and in patients with LV systolic dysfunction, respectively, are shown in Table 3.


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  		Table 3 Sensitivity, specificity, positive and negative predictive values, and accuracy in predicting echocardiographic Ea/Ees>1.2

 
The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of PEP/ET>0.423 in identifying patients with abnormal ventriculo-arterial coupling in the whole study population and in patients with LV systolic dysfunction, respectively, are shown in Table 3 and Fig. 3.


Figure 03
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  		Fig. 3 Receiver operating characteristic curve (ROC) analysis of PEP/ET discriminating between study subjects with and without ventriculo-arterial mismatch. AUC=area under curve. PEP=Pre-ejection period; PEP/ET=ratio of PEP to ET.

 
3.4. Reproducibility of PEP and ET
There was no significant difference between the means of the two measurements for PEP and ET in the 20 randomly selected subjects. The mean and standard deviation of the difference between the two measurements repeated in 5 min were 0.3±4.9 ms for PEP and 0.8±5.8 ms for ET (95% confidence intervals were –2.0 to 2.6 ms, p=0.787, for PEP, and –2.0 to 3.5 ms, p=0.569, for ET). The variability of the paired measurements (the difference divided by the mean value of the repeated two measurements) accounted for 0.1±4.3% and 0.2±2.0% of the mean values of the paired measurements of PEP and ET, respectively. The correlation coefficient between the two measurements were 0.946 and 0.982 for PEP and ET, respectively (p<0.001).


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study demonstrated that abnormal ventriculo-arterial coupling defined by Ea/Ees>1.2 was rare in patients with diastolic dysfunction and was present in almost half of the patients with systolic dysfunction. Systolic time intervals, PEP/ET in particular, correlated well with Ea/Ees and PEP/ET was the major independent determinant of Ea/Ees. Based on the framework proposed by Sunagawa et al, Ea/Ees could also be estimated from PEP/ET and oscillometric brachial blood pressure. Using PEP/ET (>0.423) alone, heart failure patients with ventriculo-arterial mismatch could be identified with reasonable accuracy.

4.1. Ventriculo-arterial mismatch in heart failure
The normal LV operates efficiently with an Ea/Ees ratio around 0.6 [27]. The ratio increases as the pump function deteriorates with concomitant peripheral vasoconstriction resulting partly from enhanced sympathetic stimulation and altered baroreceptor gain. The increased Ea/Ees can be significantly reduced by vasodilator therapy which may optimize mechanoenergetic performance of the LV in heart failure subjects through lowering peripheral vessel resistance [28,21].

To our knowledge, the prevalence of ventriculo-arterial mismatch in heart failure patients has not been well defined, probably because of the difficulty in estimating Ees non-invasively. In the present study, abnormal ventriculo-arterial coupling was present in 48.1% of stable patients with systolic dysfunction, in contrast to only 3.7% of those with LV diastolic dysfunction. It is thus apparent that ventriculo-arterial mismatch is mainly a problem in patients with systolic dysfunction.

In 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles, a fixed dose of isosorbide dinitrate plus hydralazine in addition to standard therapy for heart failure significantly improved the rate of death from any cause, the rate of first hospitalisation for heart failure, and the quality of life [7]. The clinical benefits of vasodilator therapy may partly result from its favourable effect on LV function and ventriculo-arterial coupling [3,28]. If confirmed, the identification of patients with systolic dysfunction and abnormal ventriculo-arterial coupling may be clinically important since they represent a substantial proportion of heart failure patients and may benefit from additional vasodilator therapy.

With the development of the single-beat method, Ea/Ees can be estimated non-invasively using echocardiographic measurements, oscillometric blood pressures, and a universal transfer function [19]. The non-invasive single-beat method for the estimation of Ea/Ees may still be too cumbersome for daily practice. The present study proposed a much simpler method for the assessment of ventriculo-arterial coupling in stable heart failure patients. Using PEP/ET and oscillometric brachial blood pressures, both can be automatically and rapidly obtained in one device, Ea/Ees can be estimated at the point of care. In addition, using PEP/ET alone, patients with abnormal ventriculo-arterial coupling could be identified with a negative predictive value of 96.5% for the whole study population including normal controls and patients with diastolic and systolic dysfunction, and a positive predictive value of 77.8% for patients with known systolic dysfunction. The reasonably good predictive values may suggest that the automated measurement of PEP/ET could be used as a screening tool to identify patients with abnormal ventriculo-arterial coupling in an unselected population and patients with known systolic dysfunction. Further studies are warranted to confirm the usefulness of PEP/ET in the identification and optimization of abnormal ventriculo-arterial coupling in patients with known systolic dysfunction.

4.2. The link between Ea/Ees and PEP/ET
Sunagawa ea al. proposed the single-beat estimate of ventricular-arterial coupling [14] using the equation: Ees/Ea=Pad/Pes (1+k*ET/PEP)–1. The rationale is that the approximation of time-varying elastance curve could be made with two straight lines, one for the isovolumic phase (PEP) and the other for the ejection phase (ET). The slope ratio k of these two lines quantitatively depended on the ventriculo-arterial coupling state. Using this approximation, Ees/Ea can be estimated from Pes, Pad, and PEP/ET over wide ranges of contractility and loading conditions. Other approaches have been proposed for estimating Ees without loading interventions, and these are generally referred to as single-beat methods based primarily on the similarities between the amplitude and time-normalized human LV time-varying elastance curves during early isovolumic contraction [29]. The fact that E(Nd), the normalized ventricular elastance at arterial end-diastole, can be estimated by identification of the timing of normalized ventricular ejection (PEP divided by PEP+ET) on the universal normalized time-varying elastance curve [19,29] supports that systolic time intervals are major determinants of Ees and Ea/Ees.

The framework proposed by Sunagawa et al. was based on a study in 11 anesthetized dogs and has never been validated in humans. It has been shown that the slope ratio k and Ees/Ea are mutually dependent on each other and k may be affected by ET/PEP and Pad/Pes [14]. It is not known if the empirical k value is the same between dogs and humans. The use of the dog empirical k value may partly explain the small but significant discrepancies between the reference values of echocardiographic Ea/Ees and those derived from ET/PEP, Pad/Pes, and k. However, remarkable similarity of the normalized time-varying elastance curves among animals, and in patients with various cardiac diseases has been demonstrated previously [30]. Although in the present study we did not collect invasive haemodynamic data in order to produce a human empirical k value, our results suggest that the framework may also be valid in humans and patients with various degrees of LV dysfunction, by showing the high correlation between Ea/Ees and PEP/ET (r=0.68), and the improvement of the correlation by adding blood pressure variables into the framework (r=0.77, Fig. 1).

4.3. Subjects with LV diastolic dysfunction
Patients with diastolic heart failure are characterized by older age, female gender, diabetes and obesity, arterial hypertension, and LV hypertrophy [22]. In the present study, patients with LV diastolic dysfunction defined by the echocardiographic criteria proposed by the Heart Failure and Echocardiography Associations of the European Society of Cardiology [22] had normal blood pressure and Ea. Because 67.3% of the patients had history of hypertension, it was likely that their blood pressure and Ea had been normalized by effective antihypertensive treatment. In hypertensive patients, optimal antihypertensive treatment may favourably shift ventriculo-arterial coupling from cardiac output maximization to ventricular mechanical efficiency optimization [31]. The low prevalence of abnormal ventriculo-arterial coupling in patients with diastolic dysfunction found in this study may partly result from successful antihypertensive treatment.

4.4. Limitations of the present study
Our study used a case-control design that precludes the investigation of causal effects. Our results may further be confounded by the use of multiple cardiovascular medications in heart failure patients, since the systolic time intervals and echocardiographic measurements are subject to pharmacological manipulation. However, the significant correlations between systolic time intervals and echocardiographic measurements of cardiovascular structure and function, indicated the existence of a tight mechanistic link between time intervals and cardiovascular structure and function and ventriculo-arterial coupling. Lastly, the accuracy of several proposed single-beat methods for non-invasive estimation of Ees has been questioned [32-34]. In general, some of the inaccuracy is from the inherent limitations of Ees, such as curvilinearity of the end-systolic pressure volume relationship, relative afterload dependence, and inconstant V0 [34]. Specifically, the single-beat method used in the current study was based on the assumptions of linear end-systolic pressure volume relationship, constant V0, and the similarity of the normalized elastance function curves among normal subjects and patients with various heart diseases [30]. Although later studies have confirmed that the individual normalized elastance function curves were similar but not identical, [34] we have modified and validated the methodology for human use by accounting for the potential variation of the generalized normalized elastance function curve with individual contractile and loading effects [19].

In conclusion, abnormal ventriculo-arterial coupling was present in almost half of our stable patients with systolic dysfunction. PEP/ET was useful in identifying such patients.


   Acknowledgement
 
We thank the Colin Corporation Japan for free loan of the VP-1000 apparatus.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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