Keywords

From Early to Recent Ideas on RV Function

Ideas about right ventricular (RV) function have changed tremendously since the second century when Galen described the RV as merely a conduit, through which part of the blood moves to the lungs for nourishment. The remainder of the blood was thought to go through invisible pores of the septum to the left ventricle for the formation of the vital spirit [1]. It took about ten centuries before Galen’s view was opposed. In the thirteenth century, Ibn Nafis disputed the existence of septum pores and stated for the first time in known history that all the blood had to go through the lungs to get from the right to the left ventricle [1, 2]. Ibn Nafis’ idea about RV function was also different from Galen’s view as he believed that it was responsible for thinning of the blood, making it fit for mixing with air in the lungs [2]. The origin of the idea that the right ventricle is responsible for transmission of blood through the lungs and not for their nourishment has been accredited mostly to William Harvey who described this idea in 1628 in his de Motu Cordis, about three centuries later than Ibn Nafis [3, 4]. Even though Ibn Nafis and Harvey both emphasized the role the right ventricle plays in the pulmonary circulation, centuries passed before the true importance of RV function for both the pulmonary and systemic circulation would be established. The road to this understanding started in the 1940s during which more detailed studies on RV function were performed. Several open-pericardial, open-thorax dog experiments showed that cauterization of the right ventricle did not lead to changes in systemic venous or pulmonary artery pressures [5,6,7]. Based on these studies it was, still then, concluded that an actively functioning RV was not essential for the maintenance of a normal pressure gradient in the pulmonary and systemic arterial tree. However, several studies conducted between 1950 and 1980 that used experimental models excluding the RV from the circulation concluded that the RV was unquestionably necessary for the maintenance of blood flow and life [8,9,10]. But because the models used in these studies were far from physiological, the idea of the necessity of the right ventricle for the maintenance of circulation did not gain much support. It took until 1982 to recognize the role of the RV, when it was shown that RV myocardial infarction, this time using an animal model with an intact pericardium, did lead to a reduction in cardiac output [11]. Since then, multiple studies have shown RV function to be of functional and/or prognostic significance in exercising healthy subjects and in disease states [12,13,14,15]. Thus at present, we know that the right ventricle is not just a passive conduit for systemic venous return: the RV plays an important role in maintaining cardiac output in both health and disease.

Physiology of RV Contraction and Relaxation

Myocyte Contraction

In both the left and right ventricles, the structural unit of a cardiomyocyte that is responsible for diastolic muscle properties and cardiac contraction is the sarcomere [16]. The sarcomeric thick (myosin) and thin (actin) filamentous proteins (see Fig. 1.1) determine the contractile properties. The third filament, titin, is responsible for the passive properties of the sarcomere. The myosin filament is composed of a body and cross-bridges. The cross-bridges consist of an “arm and head” and extend outward from the body [17]. The actin filament is made of actin and tropomyosin which form the backbone of the filament. Attached to tropomyosin is the troponin complex (troponin I, T, and C). In a relaxed state, the troponin complex is attached to tropomyosin in a manner that prevents the binding of myosin heads with actin. Cardiomyocyte contraction is initiated by the arrival of the action potential. During the action potential, calcium channels in the cell membrane open, allowing calcium to enter the cell [18]. This event triggers the release of calcium from the sarcoplasmic reticulum, which causes the main increase in the cytosolic calcium concentration (calcium-induced calcium release). The increase in free calcium concentration allows binding of calcium to the myofilamental protein troponin C, thereby changing the confirmation of the troponin complex. The result is exposure of the myosin-binding sites of the actin filament, creating the opportunity for a reaction between actin and myosin heads resulting in sliding of actin along myosin and consequently shortening of the muscle [17, 19].

Fig. 1.1
figure 1

The structural unit of a cardiomyocyte that is responsible for contraction, the sarcomere, is presented at two different muscle lengths. Each sarcomere is bounded at the end by Z-discs. Two types of filaments are shown: (1) the thick filament (blue), with the myosin heads extending from the backbone and connected to the Z-disc by a titin molecule (drawn here is one molecule instead of six), and (2) the thin filament (green), directly attached to the Z-disc. Note that both filaments overlap each other, the extension of which is dependent on muscle length. (Reprinted from Westerhof et al. [17]. With permission from Springer Science)

Full size image

Myocyte Relaxation

After muscle shortening, calcium ions are pumped out of the cytosol back into the sarcoplasmic reticulum and to the extracellular fluid allowing the sarcomere to relax and lengthen up to its initial diastolic state [17, 18]. The sarcomeric protein that is responsible for the stiffness of the relaxed, diastolic muscle is titin (see Fig. 1.1) [20]. It is the largest protein in the human body and it extends from the Z-disc to the center of the myosin filament. It has several “springlike” regions which determine the stiffness of the protein. Alteration of phosphorylation of these regions or alternative splicing can increase or decrease titin compliance [21]. Myocardial passive tension is also influenced by extracellular collagen, especially at longer sarcomere length. However, titin remains an important contributor to total passive tension, even at large sarcomere lengths [20].

RV Contraction, Ejection, and RV Pressure Curve

That contraction of one single cardiomyocyte leads to shortening of the muscle cell is clear. A more complicated story is how the combined shortening of all the individual RV cardiomyocytes results in the ejection of blood into the pulmonary artery (PA). This is due to the complex geometry and contraction sequence of the RV. The RV is composed of two different anatomical parts, that is, the body (sinus) and the outflow tract (conus or infundibulum). The sinus contains more than 80% of total RV volume [22] and has a different fiber orientation compared to the conus. Also, the timing of contraction during the cardiac cycle is different between these two compartments [22,23,24,25,26,27]. RV contraction occurs sequentially starting at the apex of the ventricle moving in a peristalsis-like pattern towards the conus [25]. In early systole, the conus even expands before it starts to contract about 20–50 ms later than the body of the ventricle [22, 24, 26]. During early diastole, the conus’ tonus partially continues and relaxation may not be seen until atrial contraction [22, 24, 26].

The net result of RV contraction is a chamber volume reduction with propulsion of blood into the pulmonary artery. This is mediated by several mechanisms. The largest contribution to RV volume decrease is shortening of the ventricle in the longitudinal direction, that is, from base to apex [28]. Another mechanism of volume reduction is movement of the RV free wall to the septum (transverse shortening) [4, 29, 30]. Several investigators have mentioned another mechanism of ejection, that is, ejection of blood due to blood momentum [31,32,33]. Blood momentum refers to the event of continued movement of blood mass under the late-systolic negative pressure gradient (PA > RV pressure) [8, 33]. This mechanism was originally suggested based on LV ejection hemodynamics [33], but similar observations were made on RV ejection hemodynamics. RV ejection, starting when the RV pressure exceeds PA pressure leading to pulmonary valve opening (see Fig. 1.2), continues even when myocardial muscle relaxes and ventricular pressure decreases to values lower than PA pressure. Indeed, RV ejection continues in the presence of declining RV pressure and a negative pressure gradient between the RV and PA [30, 31, 34, 35]. Both observations support the theory of blood momentum. The fact that continued ejection can occur in the course of a declining RV pressure is likely the effect of mass: moving mass continues moving even when a counteracting force exists. Importantly, the disparity between end systole (end of active myocardial shortening) and end ejection makes it necessary to assume equal use of terminology concerning the two events to avoid confusion. However, in pressure-volume analysis end systole is defined as end ejection (see description on pressure-volume analysis below).

Fig. 1.2
figure 2

Simultaneously recorded electrocardiogram (ECG), right ventricular (RV) dP/dt, pulmonary artery (PA) flow, PA and RV pressure. Note the short duration of the pre-ejection time (PEP) and the negative pressure gradient visible during late ejection. HOI hangout interval, RVET RV ejection time, PAP pulmonary artery pressure, RVP right ventricular pressure. (Reprinted from Dell’Italia and Walsh [35]. With permission from Elsevier)

Full size image

Influence of LV Contraction on RV Ejection

The RV is connected in series with the LV; this is called series ventricular interaction [36]. As a result, RV stroke volume will greatly determine LV filling and subsequently LV stroke volume. Consequently, factors that influence RV output will also affect LV output. Diseases that affect RV function are described in detail in subsequent chapters in this book.

On top of the indirect series interaction, a direct ventricular interaction occurs as both ventricles share the interventricular septum, have intertwined muscle bundles, and are enclosed by one single pericardium [8, 36]. Because the pericardium encloses the septum-sharing ventricles and is highly resistant to acute distention, the compliance of one ventricle is influenced by the volume and pressure of the other ventricle [37,38,39]. Also during systole, ventricular interaction can be observed as LV contraction influences pressure development in the RV [36, 40]. Approximately 20–40% of the RV systolic pressure development may result from LV contraction [41].

Although ventricular interactions are present in healthy subjects, negative consequences of ventricular interaction manifest only in disease states. For example, in pulmonary arterial hypertension, LV diastolic filling is impaired by both a reduced RV stroke volume resulting from an increased pulmonary vascular resistance (series ventricular interaction) and leftward ventricular septum bowing resulting from RV pressure and volume overload (direct ventricular interaction) [42].

Description of RV Function

The cardiovascular system has the essential task to provide the tissues in our body with sufficient nutrients and oxygen. Therefore, it is important to maintain cardiac output at an adequate level. Since the left and right ventricles are connected in series, cardiac output is more or less similar for both. Often used methods to determine RV cardiac output are thermodilution or the direct Fick method during a right-heart catheterization [43]. Cardiac output is determined by stroke volume and heart rate. Cardiac magnetic resonance imaging (MRI) is a noninvasive method to assess RV stroke volume. With MRI, aortic and pulmonary flows can be measured. Stroke volume can also be determined by taking the difference between end-systolic and end-diastolic volume. It holds for all methods that both LV and RV measurements can be used to determine stroke volume, since it should be the same for both ventricles. Please note that when valvular insufficiency or a shunt is present, the use of ventricular volumes is not accurate [44]. Despite the fact that stroke volume is the net result of RV contraction, it only gives a limited amount of information about RV function per se. Stroke volume is first of all determined by RV filling (preload). Stroke volume is further determined by RV myocardial function (ventricular contractility) and by the load that opposes RV ejection (arterial system, afterload). Therefore, to understand RV myocardial function, load-independent measures are needed as provided by ventricular pressure-volume analysis.

The Ventricular Pressure-Volume Loop

The first person to describe the cardiac cycle by means of a pressure-volume graph was Otto Frank in 1898 [17, 45]. He described pressure changes during isovolumic (non-ejecting) contractions at various filling volumes and showed maximal pressure increases with increasing diastolic volume. Later, in 1914, Starling described ejection against a constant ejection pressure and found increased stroke volumes with increased filling. The combination of the two findings is what we nowadays call the Frank-Starling mechanism, which will be explained in detail in the section “Regulation of RV Function” below.

A pressure-volume loop describes the changes in ventricular pressure and volume observed during the cardiac cycle (see Fig. 1.3a for a schematic presentation). The cardiac cycle can be divided into four different phases: (1) the filling phase, (2) isovolumic contraction phase, (3) ejection phase, and (4) isovolumic relaxation phase. During the filling phase, RV volume increases considerably while RV pressure only slightly changes [46]. After the onset of contraction, RV pressure increases rapidly. The pulmonary valve opens when RV pressure exceeds PA pressure, thereby ending the isovolumic contraction phase. Normally, this RV isovolumic contraction phase is of short duration due to the low PA pressures (see also Fig. 1.2) [47]. In the ejection phase RV pressure peaks early to subsequently rapid decline during late ejection [48]. During late ejection, a negative pressure gradient between the RV and PA can be observed; this is referred to as the hangout interval (see Fig. 1.2) [35]. The isovolumic relaxation phase starts at pulmonary valve closure and pressure declines back to its initial value.

Fig. 1.3
figure 3

(a) Schematic presentation of a pressure-volume (P-V) loop of a single beat. Diastole (or the filling phase) starts after tricuspid valve opening (lower left corner P-V loop). At this moment, the volume in the ventricle is at its minimum, corresponding to end-systolic volume (ESV). During the filling phase, volume increases up to maximum filling, that is, end-diastolic volume (EDV). Contraction leads to an increase in pressure (isovolumic contraction) until the pulmonary valve opens. This is the start of ejection. After valve closure, isovolumic relaxation occurs with a rapid decrease in pressure until the intracardiac valve opens again and the ventricle reenters its filling phase. Right ventricular ejection fraction (RVEF) can be calculated from a single pressure-volume loop by dividing stroke volume and end-diastolic volume, and then multiplying by 100%. Effective arterial elastance (Ea) is a measure of RV afterload and calculated as the slope of the dotted line from the end-systolic P-V point to the x-intercept at EDV. (b) Schematic representation of multiple pressure-volume loops obtained during gradual preload reduction. Note that the end-diastolic pressure-volume points can be connected by a nonlinear line, the end-diastolic pressure volume relation (EDPVR). Also shown is the linear end-systolic pressure volume relation (ESPVR) and its slope Ees (end-systolic elastance)

Full size image

The information that can be derived from a single pressure-volume loop includes stroke volume, end-diastolic volume, end-systolic volume, and ejection fraction (calculated from end-diastolic volume and stroke volume, see Fig. 1.3a). The information that these parameters give about RV myocardial properties is limited. However, if multiple loops under alteration of loading conditions (preferable preload reduction by vena cava occlusion [17]) are collected, information on both systolic and diastolic properties of the ventricle can be obtained.

Systolic Properties: The End-Systolic Pressure-Volume Relation

Figure 1.3b gives a graphical representation of multiple pressure-volume loops obtained during preload reduction [49]. Although multiple pressure-volume loops can also be acquired by changing afterload, the preferable method is preload reduction, since changes in afterload are more likely to affect the systolic and/or diastolic properties one wishes to measure [50]. When multiple pressure-volume loops are obtained during preload reduction, for example by partial vena cava occlusion using a balloon catheter, both the end-systolic and end-diastolic pressure-volume points can be connected by a line (see Fig. 1.3b). The line connecting the end-systolic pressure-volume points is referred to as the end-systolic pressure-volume relation (ESPVR). This relation is reasonably linear over a physiological range in both the LV and the RV [34, 51, 52]. Therefore, in practice, linearity is assumed for the ESPVR. The slope of the ESPVR is called end-systolic elastance (Ees) and due to the assumption of linearity it can be described by the following formula: Ees = Pes/(Ves − V0), where Pes is end-systolic pressure, Ves is end-systolic volume, and V0 is the so called intercept volume of the ESPVR. Ees is used as a measure of myocardial contractility for several reasons. First of all, positive and negative inotropic agents such as catecholamines and acute B-blockade, respectively, increase or decrease Ees [46, 51,52,53,54,55,56]. In addition, Ees is assumed independent of pre- or afterload, and therefore considered load independent [34, 56].

In theory, elastance is a measure of stiffness in terms of pressure and volume and the idea that ventricular properties could be described by elastance came from Suga’s work on the isolated heart, where the time-varying elastance concept was proposed in the late 1960s [57]. The time-varying ventricular elastance implies that the heart changes its stiffness during the cardiac cycle, with maximal elastance occurring near or at end systole. More extensive information on the theory of time-varying elastance can be found elsewhere [17, 45].

Considerations for the Application of RV ESPVR and Ees

For the assessment of changes in contractile state one should consider that the measured ventricular properties, both systolic and diastolic (see below), are influenced by the amount of muscle mass, myocardial properties, and ventricular configuration [45, 50]. Therefore, a shift of the ESPVR in an acute setting (where muscle mass and ventricular configuration are constant) reflects a change in myocardial contractility. However, in a clinical setting muscle mass or ventricular configuration may change over time and an observed shift in the ESPVR can therefore not only be attributed to a change in myocardial contractility [50].

The Cardiopulmonary System

The systolic properties of the right ventricle have to be seen in light of its load [58]. The pulmonary circulation is a low-pressure, high-compliance system in contrast with the systemic circulation. Because the afterload for the right ventricle is low, there is no need for a high Ees. However, during exercise, or in disease states in which the afterload increases, the Ees has to increase as well [59, 60]. An appropriate measure to describe the afterload is called effective arterial elastance (Ea) , which is a measure of total resistance [61]. It can be determined by the ratio of end-systolic pressure to stroke volume (see Fig. 1.3b). In healthy individuals, the transfer of energy from the right ventricle to the pulmonary artery is optimal. In other words, RV contractility is adequately matched to the afterload. This concept is called coupling and is represented by the ratio of Ees/Ea. Both Ees and Ea describe the function of a subsystem (right ventricle and pulmonary circulation, respectively), independently of each other. The function of the cardiopulmonary system as a whole results from the interaction of these subsystems. Stroke volume, for example, is determined not only by RV function, but also by afterload. Other often used parameters that result from functional interaction include cardiac output, RV ejection fraction, and pulmonary artery pressure [60].

Diastolic Properties: The End-Diastolic Pressure-Volume Relation

In contrast with the rather linear end-systolic pressure-volume relation, the diastolic pressure-volume relation is nonlinear (see Fig. 1.3b) [45, 50]. The end-diastolic pressure-volume relation (EDPVR) shows that at low volumes pressure increases only minimally for a given increase in volume. At higher volumes the pressure rise for an increase in volume is progressively larger, which gives the EDPVR its characteristic nonlinear curve [50]. The sarcomeric structures responsible for the steeper rise in pressure at larger filling volumes are the titin molecules, while outside the sarcomere the extracellular matrix (collagen) resists the further stretching of the myocyte [50, 62]. Diastolic elastance can be measured like systolic elastance with multiple pressure-volume loops under quick alteration of preload and reflects the passive properties of the ventricle (see Fig. 1.3b) [50]. However, because of the nonlinearity of the EDPVR, nonlinear regression analysis is mandatory to obtain a curve fit and a diastolic stiffness constant [50, 63]. RV diastolic stiffness can be described by the slope of the EDPVR at end-diastolic volume. This measure is called end-diastolic elastance (Eed) [64].

Single-Beat Analysis of Ees and Eed

Because the measurement of systolic and diastolic elastances as described above requires simultaneous measurement of RV pressure and volume including an intervention on ventricular loading, this measurement is not easy to apply in a clinical setting and may even be contraindicated in some patients. To overcome these problems, more applicable methods have been developed that do not require multiple pressure-volume loops. These so-called single-beat analyses are available for both the left and right ventricles and for both the systolic [53, 65, 66] and diastolic elastance [63]. Results of the single-beat method to calculate the coupling of Ees/Ea are comparable to the multiple-beat method [67].

Regulation of RV Function

The regulation of RV function can best be illustrated by its response to changes in volume and afterload. The RV ventricular response to filling (diastolic) volume is described by the Frank-Starling mechanism and is based on the alteration of the sensitivity of the myofilaments to calcium, as will be described below [18]. The response of the right ventricle to changes in afterload is mediated by neurohormonal mechanisms. Cardiac output can further be altered by changes in heart rate. For mechanisms of subacute and chronic alterations in contractility and diastolic function we refer to the chapters on disease states with altered ventricular loading by volume and/or afterload.

Volume Response: The Frank-Starling Mechanism

The Frank-Starling mechanism refers to the observation that with increasing ventricular end-diastolic volume, stroke volume simultaneously increases. Changes in end-diastolic volume are usually mediated by changes in venous return. Consequently, stroke volume is regulated by venous return in most conditions [19]. At a molecular level the Frank-Starling mechanism refers to the observation that with greater sarcomere length at the start of contraction, a greater force is generated. This is caused by an altered myofilamental sensitivity to calcium by stretching. The proposed mechanism for this altered myofilamental sensitivity has long been the theory of “lattice spacing” [68]. This theory is based on a decrease in spacing between the filaments upon stretching. Consequently, the binding of myosin heads to actin is more likely to occur, thereby increasing force per amount of calcium available. Recently, another explanation has been put forward [68]. It was observed that the stretching of sarcomeres favorably alters the orientation of the myosin heads, making it easier to bind with the actin filament. According to these new findings, the Frank-Starling mechanism may be largely explained by favorable alteration in myosin head orientation, and to a lesser extent by lattice spacing.

Afterload Response: Sympathetic Activation

When the afterload of the right ventricle is acutely increased, stroke volume will decrease if no compensatory mechanisms existed. However, compensatory mechanisms do exist and stroke volume can be maintained to a certain extent under altered loading conditions. One mechanism to maintain stroke volume is by the Frank-Starling mechanism as described above. This occurs when the RV’s end-diastolic volume increases as a result of the increased afterload. Another mechanism to maintain stroke volume in an acute setting is through an increase in contractility, facilitated by sympathetic nervous system activation. Sympathetic activation of the heart occurs through B-adrenergic receptors that are localized on cardiomyocytes. Stimulation of B-adrenergic receptors leads to an increase in contractility (inotropy) through increased availability of free intracellular calcium. Sympathetic activation also slightly reduces myofilamental calcium sensitivity. However, the increase in intracellular calcium availability outweighs this reduction [18]. Secondly, sympathetic activation leads to faster relaxation (lusitropy) as a result of a faster reuptake of calcium ions by the sarcoplasmic reticulum and consequently a faster release of calcium from the myofilaments.

A secondary, slower mechanism that increases contractile force has been described by Gleb von Anrep [69]. The so-called Anrep effect refers to the observation that after the initial response, cardiomyocytes further increase their contractile force slowly over the following minutes [69]. The Anrep effect results from autocrine/paracrine mechanisms involving stretch-induced release of angiotensin II and endothelin. More detailed information on the Anrep phenomenon can be found elsewhere [69, 70].

Conclusions

RV function is important in both healthy individuals and disease states. The right ventricle has a complex geometry consisting of two different anatomical parts and RV contraction occurs in a peristaltic-like pattern. In the healthy right ventricle, ejection continues after maximal shortening and in the presence of a negative pressure gradient. Despite the complex hemodynamics, RV systolic and diastolic function can be described by a time-varying elastance. RV output is highly sensitive to changes in filling, which is mediated through the Frank-Starling mechanism, and increases in afterload. An accurate description of RV function incorporates so-called load-independent measurements.