Ventriculo-arterial decoupling in acutely altered hemodynamic states

The dynamic interaction between the heart and the systemic circulation allows the cardiovascular system to be efficient in providing adequate cardiac output and arterial pressures necessary for sufficient organ perfusion [1]. The cardiovascular system provides adequate pressure and flow to the peripheral organs in different physiological (rest and exercise) and pathological conditions because of the continuous modulation of the arterial system compliance, stiffness and resistance with respect to left ventricular (LV) systolic performance [2]. Cardiac output is the final result of this dynamic modulation. Because LV stroke volume depends on myocardial contractility and loading conditions (preload and afterload), both cardiac and arterial dysfunction can lead to acute hemodynamic decompensation and shock.


I ntroduction
Th e dynamic interaction between the heart and the systemic circulation allows the cardiovascular system to be effi cient in providing adequate cardiac output and arterial pressures necessary for suffi cient organ perfusion [1]. Th e cardiovascular system provides adequate pressure and fl ow to the peripheral organs in diff erent physiological (rest and exercise) and pathological conditions because of the continuous modulation of the arterial system compliance, stiff ness and resistance with respect to left ventricular (LV) systolic performance [2]. Card iac output is the fi nal result of this dynamic modulation. Because LV stroke volume depends on myocardial contractility and loading conditions (preload and afterload), both cardiac and arterial dysfunction can lead to acute hemodynamic decompensation and shock. According to the underlying pathophysiological mechanisms, altered hemodynamic profi les can be classifi ed as primarily refl ecting cardiogenic, hypovolemic, obstructive or distributive shock.
Low cardiac output resulting in systemic hypoperfusion requires prompt and adequate treatment to restore cardio vascular function and prevent organ hypo perfusion. Current clinical guidelines recommend resuscitation with intravascular fl uid infusions supplemented with selective use of inotropes and vasopressors to reverse shock in critically ill patients [3,4]. Howe ver, the treatment of acute he modynamic impairment should be tailored based on the etiological mechanism of the cardiovascular dysfunction. Herein lies a major problem with present guidelines: Th ey cannot distinguish the underlying causes of impaired LV stroke volume leading to impaired cardiac output.

Ventriculo-arterial coupling
Th e concept that the cardiovascular system works better when the heart and the ar terial system are coupled has been well demonstrated [5,6]. When t he h eart pumps blood into the vascular tree at a rate and volume that matches the capability of the arterial system to receive it, both cardiovascular performance and its associated cardiac energetics are optimal [7,8]. A cont ract ility or arterial tone that is too high or too low decouples these processes and can lead to cardiac failure independent of myocardial ischemia or the toxic eff ects of sepsis and related systemic disease processes. Th is optimization means that the LV workload and the arterial system optimally match when the left ventricle ejects the blood into the arterial system and is quantifi ed by ventriculo-arterial (V-A) coupling analysis. Th is process is optimized without excessive changes in LV pressure, and the mechanical energy of LV ejection is completely transferred from the ventricle to the arterial system [9,10]. Th e ro le o f V-A coupling in the management of critically ill patients with severe hemodynamic instability and shock is becoming increasingly clear.
V-A coupling can be defi ned as the ratio of the arterial elastance (Ea) to the ventricular elastance (Ees). Th is ratio was fi rst proposed by Suga [11] as a method t o evaluate the mechanical effi ciency of the cardiovascular system and the interaction between cardiac performance and vascular function. Th e Ea/Ees ratio has been consistently demonstrated to be a reliable and eff ective measure of cardiovascular performance [9,11,12]. Bur khoff and Sagawa, and successively many other investigators, have demonstrated that when the Ea/Es is near unity, the effi ciency of the system is optimal. In this case, the left ventricle provides an adequate stroke volume with the lowest possible energetic consumption [13,14]. Th us, V -A co upling is an eff ective index of the mechanical performance of the left ventricle and of the dynamic modulation of the cardiovascular system. In addition, the Ea/Ees refl ects cardiac energetics. Th e balance between myocardial oxygen consumption and the mechanical energy required to perform this work appears to be optimal when the heart and the peripheral vascular system are coupled.
Th e area of the LV pressure-volume (P-V) loop (Fig. 1) during a single cardiac cycle represents the total mechanical energy of the heart during that beat and has a linear correlation with myocardial oxygen consumption [15]. Th e energetic effi ciency of the cardiovascular system is optimal when all the pulsating energy of the heart is transmitted to the arterial system [12]. Eff ective unde rstanding of V-A coupling requires an appropriate understanding of the concepts of the determinants, Ea and Ees. And the eff ective use of these concepts requires an understanding as to how they may be derived at the bedside in critically ill patients.

Left ventricular elastance (E es)
When the left ventricle ejects, arterial pressure increases and the LV stroke volume is transferred into the aorta. As LV volume decreases to its end-systolic minimum, the actual end-systolic volume (ESV) is a function of not only intrinsic cardiac contractility, but also arterial pressure. For the same LV end-diastolic volume (EDV) and intrinsic cardiac contractility, if arterial pressure at end-systole were less, then LVESV would also be lower and LV stroke volume greater. Similarly, increasing arterial pressure has the opposite eff ect to increasing LVESV and decreasing stroke volume. Importantly, the resultant potential endsystolic pressure-volume points possible as arterial pressure is independently varied describe a tight linear relationship called the end-systolic pressure-volume relationship (ESPVR). Th e slope of the ESPVR is the LV elastance (Ees) (Fig. 1) and is determined for the intrinsic contractility of the heart. Th e steeper the slope, the greater the contractility [16]. Ees (mm Hg/ml) is a usef ul, load independent index of myocardial contractility and LV inotropic effi ciency (end-systolic LV stiff ness) [17]. Although myocardial cont ractility is the main deter minant of LV systolic function, biochemical properties of the LV myocytes (stiff ness, compliance, fi brosis, etc.), cardiac myocyte contraction synchrony and geometric remodeling of the LV cham ber can also signifi cantly infl uence LV performance [18]. Th erefore, Ees should be considered as an integrated measure of LV systolic performance derived from the complex association between the inotropic effi ciency and the functional, structural and geometric characteristics of the left ventricle [19].

Arterial elastance (Ea)
Ea (mm Hg/ml) is the expression of the total afterload imposed on the left ventricle and represents the complex association of diff erent arterial properties including wall stiff ness, compliance and outfl ow resistance. Th us, the total arterial compliance, impedance and the systolic and diastolic time interval are signifi cant components of the arterial load [11]. Graphically, Ea can be describ ed as the slope of the line running from the LVEDV to the LV endsystolic pressure (ESP) on the P-V loop (Fig. 1). Operation ally, Ea can be defi ned as the capability of the arterial vessels to increase pressure when LV stroke volume increases.

A-V coupling measurement
According t o the seminal studies of Frank and Starling, Grossman and colleagues, and subsequently other investigators, LV contractile function can be evaluated by the relationship between the ESP and the ESV [20,21]. After the experimental inve stiga tions of Suga and Sugawa on isolated canine hearts, the assessment of V-A coupling in humans has been less successful because of the invasive techniques needed to acquire these measures. Because of the recognized importance of V-A coupling in the management of critically ill patients, much eff ort has been put into achieving non-invasive measurement approaches [22]. Despite several proposed non-invas ive approaches to evaluate Ea/Ees, only the modifi ed single beat method developed by Chen et al. has been validated against the invasive measurement of Ees [23]. Th e single beat method is based on the assumption that because the time-variation of LV elastance is not infl uenced by loading conditions or heart rate (HR), the evaluation of the P-V loop can be obtained by a single heart beat [24]. Th e non-invasive method developed b y Chen et al. Since end-systolic arterial pressure occurs slightly after peak systolic pressure is achieved, Ea can be calculated as 0.9 × systolic arterial pressure/stroke volume , where 0.9 × systolic arterial pressure equals LVESP [23,25].
Since all these measures can be read ily m ade at the bedside, it is possible to assess V-A coupling in critically ill patients.

Ventriculo-arterial decoupling in altered hemod ynamic states
Although the occurrence of V-A decoupling is generally associated with pathological states, in some physiological conditions, such as during exercise or with increased age, a mismatch between LV performance and arterial system function can occur.
According to the physiological changes occurring during exercise, the cardiovascular system modulates its performance to provide adequate pressure and fl ow to peripheral organs in the presence of increased metabolic demand. Because the Ea/Ees is normally coupled in healthy humans at rest, during exercise Ees increases more than Ea; consequently, the ratio of Ea to Ees decreases [26]. Because LV performance and, therefore, Ees normally increases during exercise, Ea can increase, decrease or be unchanged. Th e Ea modifi cations impact Ea/Ees in conditions of increased LV work. Ea generally increases in elderly people as a consequence of the structural changes in the arterial properties (compliance, stiff ness, pulse wave). Th e mismatch between Ea and Ees during exercise can be blunted in elderly people because of a reduction in the cardiovascular reserve. Furthermore, cardiovascular diseases (hypertension, coronary artery disease, diabetes mellitus), which have an impact on V-A coupling, frequently occur in elderly patients.
Cardiovascular impairment leading to acute systemic hypotension and shock can occur in many diff erent clinical scenarios. Cardiovascular dysfunction is generally characterized by an altered Ea/Ees due to either the decrease in Ees or to the signifi cant increase in Ea. Operationally, the system becomes uncoupled when the ratio of arterial to ventricular elastance is > 1 (Ea/Ees > 1), while an Ea increase is the consequence of an increase of the arterial load.

Ventriculo-arterial decoupling due to decreased Ees
According to the hemodynamic profi le of the underlying pathology, an Ees decrease indicates an impairment in myocardial contractility, resulting in reduction of LV performance. Although myocardial ischemia and acute myocardial infarction are the most common causes of LV contractile dysfunction, other pathologies, such as myocarditis and severe cardiomyopathy (dilative and hyper trophic), can be characterized by myocardial depres sion and diminished Ees [27,28]. Th e acute decompensation of LV function c an le ad to severe hemodynamic impairment and shock.

Acute heart failure
Acute failure of LV systolic fu nction is characterized by the inability of the heart to provide an adequate stroke volume to match the metabolic demands of the body. Acute systolic cardiac dysfunction results in both a low ejection fraction and increased fi lling pressures in the attempt to maintain a suffi cient stroke volume. For this reason, the LV ESPVR is shifted downward and rightward, and Ees decreases. At the same time, Ea significantly increases because of increased sympathetic tone as the normal response of the autonomic nervous system to compensate for the reduced LV stroke volume. Th us, one sees tachycardia and increased arterial tone [2]. Hence, the cardiovascular system is generally u ncoupled in acute heart failure, and Ea/Ees increases up to three or four fold [29]. Th erefore, the treatment of acute heart failur e is usually to decrease Ea by calcium channel blockers, betablockers and other vasodilating agents, whereas Ees is increased by inotrope infusions. Traditionally, the management of acute heart failure is based on inotropic agents aimed to improve myocardial contractility and to restore organ perfusion [30]. Th e inotropic agents commonly employed in the treatment of acute heart failure (catecholamines and phosphodiesterase III inhibitors) induce well-described adverse eff ects, such as increased myocardial oxygen consumption, ar rhythmias and increased mortality [12]. In recent years, the therapeutic use of the no vel calcium sensitizer, levosimendan, has been progressively emphasized because of its inotropic and vasodilator properties [31,32]. Because of its intrinsic performance, lev osime ndan impacts both Ea and Ees and improves V-A coupling [12]. Moderate systemic arterial hypotension can be i nduced by levosimendan, which then requires the administration of low doses of norepinephrine. Th e association between the inotropic and vasopressor action seems to improve cardiovascular performance by matching Ea and Ees.

Cardiac surgery
Cardiogenic shock is the most severe clinical manifestation of perioperative acute heart failure after cardiac surgery and leads to systemic hypoperfusion and organ dysfunction that generally requires either pharmaco logical or mechanical support. Th e acute reduction in Ees, from many diff erent causes that range from inadequate myocardial protection to myocardial stun ning, is usually the main reason for the uncoupled Ea/Ees ratio. Treatment with inodilator drugs in post-cardiotomy acute heart failure has been demonstrated to be eff ective in restoring V-A coupling and improving LV performance [33,34].

Tachycardia
Tachycardia induced by stress conditions and during exercise is generally well tolerated by healthy people. Indeed, the increase in HR is a compensatory mechanism that enhances myocardial contractility and LV performance [2]. Th is force-frequency relationship has benefi cial eff ects on cardiac performance, which contribute to maintain the effi ciency of the cardiovascular system and provide optimal V-A coupling. Th e intrinsic mechanism underlying the force-frequency relationship is most likely the dynamic balance of the intracellular Ca 2 + concentration [35]. In acute heart failure patients, baseline LV V-A un coupling can be signifi cantly worsened by tachycardia because the normal force-frequency relationship is impaired.

Acute systemic hypotension
Several diff erent etiological mechanis ms can cause hypotension, but systemic arterial hypotension is generally the fi rst and often life-threatening symptom of acute cardiovascular dysfunction. Either heart failure or circulatory impairment can lead to systemic arterial hypotension and hemodynamic decompensation. Because peripheral organ perfusion strictly depends on the MAP, systemic arterial hypotension should be promptly reversed. According to recommended treatments, fl uid resuscitation is generally the fi rst therapeutic approach [3,4]. Indeed, the hemodynamic response to fl uid administration depe nds on either the increase in stroke volume consequent to fl uid resuscitation or on other factors, including arterial tone [1,36]. MAP is the product of the interaction between LV stroke volu me and arterial system function expressed by the Ea. Recently, we proposed a bedside method to evaluate the dynamic arterial elastance (Eadyn) to determine which patients are responders to fl uid resuscitation [37]. In mechanically ventilated patients, Eadyn corresponds to th e ratio of pulse pressure variation (PPV) to stroke volume variation (SVV) during a single positive pressure breath. Th e bedside evaluation of the Eadyn should allow either functional assessment of arterial tone or of fl uid responsive ness in severely hypotensive patients. Further investigations are required because of both the limitations of the published studies and the small populations enrolled, but the predictive value of Eadyn suggests a useful application in clinical practice.
Although MAP is the main determinant of organ perfusion, it can also be in fl uenced by fl ow distribution and tissue oxygenation. Despite the restoration of a normal MAP, patients with cardiovascular dysfunction can suff er from decreased organ oxygenation and perfusion [38]. In this context, a suffi cient MAP should be maintained in he modynamically instable patients to prevent any further tissue in jury [3].

Ventriculo-arterial decoupling due to increased Ea Acute systemic hypertension
Increased arterial pressure represents the most common cause of pressure overload of the left ventricle and plays a key role in the evolution of ventricular hypertrophy, dysfunction and failure. Hypertensive crisis is charac terized by a sudden increase in blood pressure associated with or followed by signs of impairment in target organs, such as heart, kidney and brain. Most patients arriving at the emergency department with elevated blood pressure and acute pulmonary edema have a normal LVEF, suggesting that acute heart failure in these situations is due to diastolic dysfunction [39]. However, LV systolic dysfunction has also been reported in association with un controlled systemic hypertension, which may be responsible for the development of acute heart failure and pulmonary edema [40]. In these situations, the acute LV decompensation dramatically improves with rapid blood pressure normalization.
Th e mechanism by which a hypertensive crisis may cause acute and severe LV systolic dysfunction, even causing acute pulmonary edema, consists of acute V-A uncoupling because of an abrupt and exaggerated increase in Ea. Such afterload mismatch leads to an exhaustion of the preload reserve of the left ventricle [40]. Th e rapid reduction in elevated blood pressure by aggressive treatment usually induces a regression of myocardial dysfunction by restoring Ea and, therefore, a coupling of the Ea/Ees ratio. Th us, consideration of the pathophysiological role of V-A decoupling allows the true pathogenic mechanism of acute heart failure in a patient with normal LV systolic function to be determined.

Ventriculo-arterial decoupling in septic shock
Th e hemodynamic profi le of s eptic shock is primarily characterized by generalized vasodilatation resulting in severe hypotension with systemic hypoperfusion [41]. Th e occurrence of myocardial depression and eventual cardiac dysfuncti on has been largely recognized in patients with septic shock, although the pathogenetic mechanisms of the myocardial injury are not yet completely understood [42,43].
In most of the patients with septic shock, cardiovascular effi cie ncy i s impaired, and the Ea/Ees becomes uncoupled (Ea/Ees > 1). Th e hemodynamic profi le is characterized by both the signifi cant increase in Ea and the decrease in Ees. Because the increase in Ea is generally induced by pharmacological vasoconstriction (norepinephrine) and the consequent increase in arterial tone, a decrease in Ees generally depends on the reduction in myocardial contractility. Whatever the underlying mechanism, when A-V uncoupling occurs in septic shock, the cardiac energetics are unfavorable and are often sacrifi ced to maintain tissue perfusion. Despite the severe hemodynamic dysfunction, Ea/Ees can be normally coupled in patients with septic shock (Ea/Ees = 1). In these cases, the proper interaction between LV performance and arterial system function can depend on both a normal cardiac function and on a proper therapeutic approach with fl uid administration, inotropes and vasoconstrictors.
According to international guidelines, management of septic shock requires either fl uid resuscitation or the employment of vasopressors (norepinephrine) to maintain an adequate cardiac output and tissue perfusion [4]. Th e use of inotropes is recommended when cardiac dysfunction and an increase in fi lling pressures occur. Recently, the use of levosimendan has been suggested for the treatment of myocardial dysfunction associated with septic shock [44,45].

Right ventricular dysfunction and V-A coupling
Th e cardiovascular system can be acu tely decompensated by right ventricular (RV) failure with consequent severe hemodynamic instability and systemic hypoperfusion [46]. Th e RV dysfunction can be due to intrinsic mechanisms that occur in myocardial infarction or can be secondary to an increase in the RV afterload caused by pulmonary hypertension. Despite the underlying etiological mechanisms, RV uncoupling can occur [47].
Because the right ventricle contributes to the effi ciency of the cardiovascular system through right V-A coupling, the assessment of the Ea/Ees of the right side of the circulation can play a role in the management of critically ill patients [48]. RV V-A coupling expresses the optimal interaction between RV performance and fun ction of the pulmonary vascular system. When Ees decreases (RV acute myocardial infarction, septic shock) or Ea increases (pulmonary hypertension, acute respiratory distress syndrome [ARDS]), the right side of the cardiovascular apparatus becomes uncoupled.
Although evaluation of RV elastance requires invasive techniques with signifi cant limitations for clinical practice, non-invasive models to assess the RV Ea/Ees have recently been proposed. Pulmonary artery catheterization and cardiac magnetic resonance may be useful in determining RV V-A coupling [48,49].

Conclusion
Although the management of shock patients has traditionally been based on ad vanced hemodynamic monitoring, the role of echocardiography in the evalu a tion of patients with acute hemodynamic decompen sation has been progressively expanding in the last decades.
Th e management of critically ill patients with acutely altered hemodynamic states can benefi t from the assessment of V-A coupling. Since the introduction of echocardiographic methods to assess cardiovascular function, the bedside evaluation of the Ea/Ees has become available and reliable.
Th e diagnostic function of echocardiographic assessment is enhanced by its capability to contribute to an evaluation of the Ea/Ees ratio and, therefore, V-A coupling in patients with acute hemodynamic impairment. Th e assessment of cardiovascular function by evaluation of the Ea/Ees ratio can off er an adjunctive perspective for understanding the pathophysiology of altered hemodynamic profi les, and for guiding therapeutic strategies and testing the eff ectiveness of treatments. However, this concept still needs to be tested in large trials.