The Ventricular-Arterial Coupling: From Basic Pathophysiology to Clinical Application in the Echocardiography Laboratory.

The interplay between cardiac function and arterial system, which in turn affects ventricular performance, is defined commonly ventricular-arterial coupling and is an expression of global cardiovascular efficiency. This relation can be expressed in mathematical terms as the ratio between arterial elastance (EA) and end-systolic elastance (EES) of the left ventricle (LV). The noninvasive calculation requires complicated formulae, which can be, however, easily implemented in computerized algorithms, allowing the adoption of this index in the clinical evaluation of patients. This review summarizes the up-to-date literature on the topic, with particular focus on the main clinical studies, which range over different clinical scenarios, namely hypertension, heart failure, coronary artery disease, and valvular heart disease.

THEORETICAL BASIS

The interaction between left ventricle (LV) and arterial system, termed usually ventricular-arterial coupling, is recognized nowadays as a key determinant of global cardiovascular performance.[12] The cardiovascular system is structured to provide adequate pressure and flow to the tissues both at rest and during exercise. Studying LV efficiency requires not only investigating the properties of LV itself, but also of the modulating role of the arterial system on LV performance and cardiac energetics.

The analysis of this interaction requires LV and arterial system to be described in similar mathematical terms.[3] Actually the best way to assess arterial afterload would be aortic input impedance derived from the Fourier analysis of aortic pressure and flow.[4] However, aortic input impedance is described in the frequency domain, whereas measures of LV contractility are best described in the time domain; consequently direct comparisons between arterial and LV function is difficult. To overcome this limitation, the ventricular-arterial coupling is commonly calculated by the ratio of effective arterial elastance (EA), a measure of afterload, to LV end-systolic elastance (EES), a relatively load independent measure of LV chamber performance. Both these measures are expressed in mmHg/ml and therefore comparable mathematically. Normal invasively determined EEA and EES values in resting subjects are 2.2 ± 0.8 mmHg/ml and 2.3 ± 1.0 mmHg/ml, respectively. As a consequence, when EA/EES ratio is approximately equal to 1.0, LV and arterial system are optimally coupled to produce stroke work, a measure of the efficiency of LV work, corresponding to the product of systolic arterial pressure and stroke volume, and related to O2 consumption.[5] When EA/EES ratio is <1.0, the stroke work remains close to optimal values, but when EA/EES ratio is >1.0, the stroke work significantly falls and the LV becomes progressively less efficient.

In practice, EES indicates how much the LV end-systolic volume increases and stroke volume decreases in response to an elevation of end-systolic pressure. In a patient with a failing heart, EES is reduced and EA is increased. In this situation, LV and arterial system are coupled in a suboptimal way resulting in a EA/EES ratio >1.0.[6] An increase in heart rate will further increase EA, worsening the coupling.[7] On the contrary, vasodilator therapy, lowering EA, brings the EA/EES ratio back down toward 1.0, improving the coupling. Similarly, inotropic therapy, increasing EES, improves the coupling.[8]

HOW TO MEASURE EA AND EES IN THE ECHO LAB?

The arterial system is functionally described by the relation between the stroke volume and the end-systolic arterial pressure.[910] The higher the stroke volume, the greater the arterial end-systolic pressure. The slope of this relation represents the EA. Assuming that zero stroke volume is associated with zero pressure, then EA can be simply calculated as the ratio of end-systolic pressure to stroke volume [Figure 1]. Arterial pressure can be conveniently estimated using a cuff sphygmomanometer; end-systolic pressure can be estimated as 0.9 times the peak brachial systolic pressure. Thus, EA can be easily calculated as 0.9 times the brachial systolic pressure divided by stroke volume, determined at LV outflow tract level by Doppler techniques.

Figure 1

Relation between stroke volume and end-systolic arterial pressure. The slope of the relation is the arterial elastance (EA), which can be easily calculated by the ratio between end-systolic pressure and stroke volume, since the relation intercepts the point zero

Analogous assessment of EES is unfortunately much more complicated. Traditionally, LV has been evaluated by the analysis of pressure-volume loops, plotting LV pressure versus volume through the cardiac cycle. Varying the load and connecting the end-systolic points of several beats, LV end-systolic pressure-volume relation can be derived. The slope of this relation approximately corresponds to EES. An increase in contractility tends to shift the relation to the left, increasing EES. The above described approach, however, requires usually invasive measurements and is time-consuming; so it is not commonly employed in the clinical practice.

Because LV end-systolic pressure-volume relation does not intercept the point zero, EES cannot be accurately calculated simply as end-systolic pressure divided by the end-systolic volume [Figure 2]. Actually a rough estimate of ventricular-arterial coupling could be obtained using such a simplified approach:

Figure 2

Relation between end-systolic left ventricular pressure and end-systolic left ventricular volume. The slope of the relation in end-systolic elastance of the left ventricle (EES). Since this linear relation does not intercept the point zero, EES cannot be simply calculated by the ratio between end-systolic pressure and end-systolic volume

EA = ESP/SV, EES = ESP/ESV

where ESP is the end systolic pressure, SV is the stroke volume, and ESV is the end systolic volume. So:

EA/EES = (ESP/SV)/(ESP/ESV) and then simplifying, eliminating ESP:

EA/EES = ESV/SV

The problem with this simplified approach is that the ESV/SV ratio is related in mathematical terms to the ejection fraction (1/EF - 1) and therefore it does not add substantial information to the traditional ejection fraction measurement.

The significant advantage of a correctly measured EA/EES ratio over ejection fraction is that examining the different components of EA/EES allows to evaluate whether alterations are due to changes in arterial properties, LV properties or both, allowing a better clinical assessment of the patient and a tailored therapy.

To date, the echocardiographic/Doppler gold standard for the determination of EA/EES ratio is the so-called single-beat method developed by Chen and coworkers.[11] According to this method, EES can be calculated noninvasively by the formula:

EES = (DBP − (End(est)× SBP × 0.9))/End(est)× SV

where DBP and SBP are diastolic and systolic arm-cuff blood pressures, End(est) is the estimated normalized ventricular elastance at the onset of ejection, and SV is Doppler-derived stroke volume. End(est) is described by an apparently very complicated formula:

End(est)= 0.0275 − 0.165 × EF + 0.3656 × (DBP/SBP × 0.9) + 0.515 × End(avg),

where EF is the basal ejection fraction and End(avg) is derived by the following formula:

End(avg)= 0.35695 − 7.2266 × tNd + 74.249 × tNd2−307.39 × tNd3 + 684.54 × tNd4 – 856.92 × tNd5 + 571.95 × tNd6 − 159.1 × tNd7

where tNd is the ratio of preejection period to total systolic period.

Similarly, the elastance of the arterial system can be numerically expressed as EA, using the following formula[12];

EA = (SBP × 0.9)/SV

In this way, being EES and EA expressed in the same units, the calculation of EA/EES ratio is correctly feasible.

Obviously, to allow clinical application, all these formulas have to be implemented in computerized algorithms; the operator is just requested to insert simple noninvasive parameters which can be collected easily: systolic and diastolic blood pressures, stroke volume, ejection fraction, preejection and total systolic periods [Figure 3].

Figure 3

The echo figures display the evaluation of ejection fraction (panel A), time-velocity integral (VTI), preejection and ejection time (panel B) using aortic pulsed-Doppler waveform on the left ventricular outflow tract (LVOT). These parameters, along with systolic and diastolic and systolic blood pressure and LVOT diameter, allow the correct determination of EA/EES ratio

CLINICAL APPLICATIONS

The clinical role of ventricular-arterial coupling is currently being investigated in several clinical scenarios. One of the main applications is the pathophysiology of hypertension as a determinant of heart failure. The rationale is supported by preclinical findings such as the work of Prabhu,[13] which described that, in an animal model of tachycardia induced heart failure, ventricular-arterial coupling impairment precedes pump dysfunction. Lam et al.,[14] considered 527 hypertensive patients from the Valsartan in Diastolic Dysfunction (VALIDD) and the Exforge Intensive Control of Hypertension to Evaluate Efficacy in Diastolic Dysfunction (EXCEED) trials, without clinical signs of heart failure, with normal LV ejection fraction and with ventricular diastolic dysfunction. After antihypertensive therapy a reduction of EA/EES ratio was found to be in direct relation to the degree of blood pressure lowering, in parallel with modest reductions in LV mass, concentric remodeling, and brain natriuretic peptide (BNP) hematic levels. These results were blunted in women and in obese individuals: The smaller impact of antihypertensive therapy on ventricular-arterial coupling in this subset of patients may lead to greater mechanical inefficiency and compensatory LV remodeling, which may explain the predisposition to the development of heart failure with preserved ejection fraction. Osranek et al.,[15] examined 18 hypertensive patients without other forms of cardiopathy, before and after obtaining good blood pressure control. The peculiarity of this work consists in the experimental determination of EES for each patient plotting ESP versus LV volume at rest and during isometric exercise. EA/EES ratio decreased in all patients, especially in those with a shorter history of hypertension. The reduction of EA/EES ratio determines a net increase in mechanical efficiency at the cost of a minor decrease in stroke volume and permits a smaller loss of mechanical efficiency in case of afterload increase. In the context of risk factor interaction with cardiac function, Miyoshi et al.,[16] devised a more complex model, postulating an interplay between left atrium, LV, and arterial system; a detailed analysis of this model, however, lies outside the aims of this article.

The studies presented above did not consider the clinical outcome of the patients. In the last years, however, some papers addressed the prognostic role of the ventricular-arterial coupling in several clinical conditions. In the context of coronary artery disease EA/EES ratio emerged as an independent echocardiographic correlate of BNP levels in patients with previous myocardial infarction and as a predictor of long-term cardiovascular mortality equivalent to BNP itself.[17] The best cutoff to discriminate patients with good prognosis from those with a worse outcome, according to receiver operating characteristic (ROC) curves analysis, was identified as a EA/EES ratio of 1.47, which had approximately the same discrimination capacity of a BNP cutoff of 250 pg/ml. An analogous correlation between Ea/Ees ratio and BNP level has been previously highlighted by Mehra et al.,[18] in the setting of heart transplantation: the transplanted organ is unable to interact with the vasculature, and therefore, operates with low efficiency which is paralleled by a tandem increase in BNP independently from alterations in blood pressure.

Young Her et al.,[19] studied ventricular stiffness and ventricular-arterial interaction parameters in patients with nonischemic dilated cardiomyopathy (NIDM). They enrolled 25 patients with NIDM and advanced systolic dysfunction which were matched with uncomplicated hypertensive patients and marathon runners. EA/EES ratio and diastolic elastance emerged as reliable predictors of exercise capacity. In the wake of these results the authors suggested the clinical validation of a new index of “total ventricular stiffness” which incorporates an index of diastolic efficiency. However, this concept still lacks adequate clinical validation.

Another possible field of application of ventricular-arterial coupling is the clinical management of candidates for cardiac resynchronization therapy. Zanon et al.,[20] found in a population of 78 patient with dilated cardiomyopathy with ischemic and non-ischemic etiology, that a high basal EA/EES ratio was a good predictor of responsiveness to cardiac resynchronization therapy both in term of quality of life and end systolic volume, especially in nonischemic patients, where the responsiveness to resynchronization is not influenced by the localization of necrotic tissue.

Still pertaining to heart failure, Reil et al.,[21] found recently in a subpopulation of the Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT), that further reduction of heart rate with ivabradine in heart failure patients already treated with optimized medical therapy, determined a reduction of EA/EES. This result was mainly ascribable to the reduction of EA as a result of decreased vascular pulsatile load with unaltered systemic vascular resistance and left ventricular contractility, the last notoriously unaffected by ivabradine.

EA/EES ratio seems to be a reliable tool in valvular heart disease as well. Guarracino et al.,[22] evaluated the hemodynamic effects of the MitraClip procedure in terms of improvement of ventricular-arterial coupling. The main concern with the correction of severe mitral regurgitation, especially in severely compromised patients, is the possible further impairment of LV systolic function, which, on the other hand, is hardly comparable in term of ejection fraction before and after the procedure. Interestingly, the authors observed, though in a numerically limited cohort, that the MitraClip procedure does not deteriorate significantly EA/EES ratio, despite a reduction in ejection fraction. Table 1 summarizes the main findings of the published studies using the single beat EA/EES ratio method.

Table 1

Clinical application of single beat EA/EES ratio method: Published studies

Author (year)	Population	N	Main findings
Mehra et al., (2004)	Heart transplant recipients	40	Elevation in BNP is explained by ventricular-arterial uncoupling
Osranek et al., (2008)	Hypertensive patients	18	Treatment of hypertension determines a net increase in mechanical efficiency
Antonini-Canterin et al., (2009)	Patients with a history of myocardial infarction	41	EA/EES ratio is an independent correlate of BNP levels and predicts long-term cardiovascular mortality
Young Her et al., (2009)	Dilated cardiomyopathy, hypertensive patients, and marathon runners	25	EA/EES ratio and diastolic elastance seem reliable predictors of exercise capacity
Zanon et al., (2009)	Patients eligible to cardiac resynchronization therapy	78	High EA/EES ratio is a predictor of responsiveness to cardiac resynchronization therapy, especially in nonischemic patients
Miyoshi et al., (2011)	Subjects with cardiovascular risk factors	64	Impaired left atrial and left ventricular relaxation in the longitudinal direction, evaluated by speckle tracking analysis, are early signs of abnormal left atrial-left ventricular-arterial coupling
Lam et al., (2013)	Hypertensive patients with diastolic dysfunction and normal systolic function	527	Reduction of EA/EES is related to the degree of blood pressure lowering, in parallel with reductions in LV mass, concentric remodeling and BNP levels
Reil et al., (2013)	Patients with systolic heart failure (EF ≥ 35%) from the SHIFT trial	275	Reduction of heart rate with ivabradine causes a reduction of EA/EES, mainly due to the reduction of EA as a consequence of decreased vascular pulsatile load
Guarracino et al., (2013)	Patients selected for MitraClip procedure	18	MitraClip procedure does not deteriorate EA/EES ratio, despite a reduction in ejection fraction

SHIFT = Systolic heart failure treatment with the if inhibitor ivabradine trial, BNP = B-type natriuretic peptide, EA = arterial elastance, EES = end-systolic elastance, LV = left ventricle

Finally, in the last years, the concept of ventricular-arterial interaction has been extensively studied in the field of aortic valve stenosis. Lancellotti et al.,[23] enrolled 163 asymptomatic patients with severe aortic stenosis and normal systolic function and identified four parameters associated with development of symptoms during a mean follow-up of 20 months. Among peak aortic jet velocity, LV systolic longitudinal deformation and left atrial area index, valvular-arterial impedance emerged as a relevant determinant of disease progression. This parameter, calculated as the sum of systolic arterial pressure and mean transvalvular pressure gradient divided by the stroke volume index, though mathematically different from the EA/EES ratio, can be considered another expression of ventricular-arterial interaction. Similar results were obtained by Hachicha et al.,[24] in a retrospective study of 544 asymptomatic patients with moderate-to-severe aortic stenosis: The level of valvular-arterial impedance was indirectly related to their survival at a median follow-up of 2.1 years.

CONCLUSIONS

Ventricular-arterial coupling represents a comprehensive expression of cardiac function and efficiency which can be numerically described by the ratio between arterial and ventricular elastance. In the echocardiography laboratory these parameters can be estimated with good accuracy noninvasively using mathematical formulae, apparently complicated, but which can be easily implemented in a computerized algorithm. The potentials of the application of ventricular-arterial coupling in clinical practice are large, emerging from the promising results of the first studies, in different settings, in particular in the field of hypertension, heart failure, coronary artery disease, and valvular heart disease.