Keywords

Introduction

Although the left (LV) and right (RV) ventricles have different embryological origins, they are bound together through epicardial myofibers that encircle them, through myofibers that form a common apex, through the interventricular septum, their attachment to each other at the septal hinge points, the common pericardial space, the in-series configuration of the pulmonary and systemic circulation, and the coronary circulation [1, 2]. As a result, the RV and LV are anatomically and functionally connected. This tight coupling between the ventricles affects RV and LV function in health and disease. In normal physiology, RV and LV cardiac cycle events such as the onset of contraction, aortic and pulmonary flow, and RV and LV filling are closely aligned. In various conditions, such as adverse loading, electromechanical dyssynchrony, and ventricular failure, the alignment of these events is disrupted, further contributing to dysfunction and adverse ventricular-ventricular interactions. The impact of events and function in one ventricle on the contralateral ventricle is clinically important as in various diseases, RV and LV systolic functions are linearly related [3, 4]. Moreover, coexisting LV dysfunction is a key risk factor for functional decline and mortality in diseases characterized by RV dysfunction [5], and concomitant RV failure is a risk factor for death in diseases primarily characterized by LV failure [6, 7].

Physiology of RV-LV Interactions

Over the past decades, fundamental experimental work has been instrumental in delineating the importance of ventricular-ventricular interactions to cardiac function and its mechanisms (Fig. 4.1). These experiments first delineated the contribution of the LV to normal RV function. In open-chest experiments, the RV was completely electrically separated from the LV by a full-thickness RV ventriculotomy, but then sewed together to restore mechanical continuity [8]. Thus, electrical stimulation of each ventricle individually, without activation of the entire heart, could delineate the hemodynamic effects of one ventricle on developed pressure in the ipsilateral and contralateral ventricle [8]. In this experiment, stimulating the LV led to almost normal RV pressure development and pulmonary blood flow. In fact, two waveforms for RV pressure and pulmonary arterial blood flow delineated the direct contribution of RV free-wall contraction, versus LV and septal contraction, to RV developed pressure. For RV pressure and pulmonary arterial blood flow, the LV and septal contribution were larger than the RV free-wall component. In contrast, stimulating the RV to contract led to normal RV developed pressure, but minimal developed pressure in the LV [8]. Taking these experiments further by surgically disrupting the LV free wall, to prevent it from generating any force, further confirmed these observations, with a dramatic decrease of around 45% in the systolic pressure generated by the RV [9]. The differential influence of RV and LV contraction to RV developed pressure and output has also been shown in human subjects using preexcitation of the RV by pacing or measuring hemodynamics during extrasystolic beats [10]. As in the experimental models, measurement of LV pressures during these events revealed the significant contribution of LV contraction to pressure development in the human RV [10].

Fig. 4.1
figure 1

Schematic representation of key mechanisms underlying adverse right ventricular (RV)-left ventricular (LV) interactions. Schematically depicted is a dilated RV with leftward septal shift, typical of severe pulmonary hypertension. These mechanisms manifest in other conditions as well as are detailed in the text. Within the constraints of the relatively fixed pericardial space, the hypertensive dilated RV compresses the LV and impedes its filling. Prolonged RV systolic duration and incoordinate timing of events contribute to this interaction and may impact RV and LV coronary filling and ischemia, thereby worsening dysfunction. RV dilatation predisposes to tricuspid regurgitation, which may further impede effective RV output. Decreased RV output further reduces LV filling and LV output, with a resultant decrease in cardiac output. The distorted RV and LV geometry and septal shift increase wall stress in the septum and septal hinge-point regions which triggers molecular fibrosis signaling and fibrosis. These further worsen the function of the ischemic, metabolically challenged RV. Distorted septal and ventricular geometry further impairs the function of common myofibers in the septum and superficial epicardial layers contributing to RV and LV dysfunction. Several of these mechanisms can be targeted or leveraged therapeutically to improve contralateral ventricular function

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Consequently, modulating LV contractile force, for example by changing LV volume, or by occlusion of the left coronary artery, impedes RV developed pressure [9]. Indeed, these studies showed that over 50% of the mechanical work of the normal RV may be generated by LV contraction and that the LV free wall plays a pivotal role in RV function [9]. Moreover, even when the RV free wall is entirely replaced with a noncontractile prosthesis, so that there is a total lack of RV free-wall contraction, there is still near-normal RV pressure generation, as a consequence of normal LV shortening [11]. In some experiments, the change in RV developed force in response to modulation of LV contraction, or loading, correlated with the degree of septal bulging into the RV cavity during systole, suggesting that the septum plays an important role in mediating these physiologic ventricular-ventricular interactions. Interestingly, however, surgically disrupting the septum did not affect RV developed pressure, but was associated with a dramatic decrease in LV developed pressure [12]. In contrast, injecting glutaraldehyde to the septum affected developed pressure in both ventricles [12]. The timing of contraction of the RV and LV further contributes to these interactions with LV contribution to RV developed pressure and pulmonary artery blood flow starting in the LV isovolumic contraction period [13].

These experiments show that under normal physiological conditions, the LV has enormous impact on RV pressure development and pulmonary arterial blood flow. This raises the question of what is the impact of the RV on normal LV function. The experiments above show that, under normal circumstances, RV contraction has little impact on developed pressure in the LV or on aortic blood flow. Even experimental ischemia of the RV free wall has minimal impact on LV developed pressure [12], and replacing the RV free wall with a noncontractile prosthesis had little effect on LV developed pressure and flow [11]. This may lead one to think that the RV has little effect on LV function, but this assumption would not be true. Firstly, the in-series configuration of the RV and LV determines that the flow generated by the RV through the pulmonary bed forms the LV preload. Additionally, changes in RV volume can profoundly affect LV contractile function. Indeed, in the aforementioned experiments that replaced the RV free wall with a noncontractile prosthesis, progressive enlargement of the noncontractile RV, by progressively repositioning a clamp along the prosthesis to increase RV cavity volume, led to progressive reduction in LV pressure development and stroke work [11]. In fact, changes in RV volume are associated with changes in the LV pressure-volume relation, which is a fundamental property and descriptor of ventricular function [10]. For example, experimental coronary artery ligation to induce acute RV ischemia causes acute RV dilatation and reduced LV end-systolic elastance, a pressure-volume measure of contractility [14]. The change in LV function and output cannot be attributed solely to reduced LV volume secondary to RV dilatation as end-systolic elastance is a load-independent measure of LV contractility [14]. Interestingly, decreased LV end-systolic elastance secondary to RV ischemia could be reversed by creation of a superior vena cava to pulmonary artery shunt which “bypasses” the RV and reduces RV volume loading to restore more normal LV geometry [14]. This experimental observation has clinical implications in the treatment of complex congenital heart disease where placement of a superior vena cava to pulmonary artery shunt is commonly performed. The clinically important impact of RV volumes on LV stroke volume is also clinically evident during mechanical ventilation [15].

Compression of the LV during RV dilatation is dependent on the confined pericardial space that the ventricles share. In this situation, dilation of one ventricle in a confined space causes compression of the contralateral ventricle. Consequently, releasing the pericardium can normalize LV contractility even when the ischemic RV remains dilated [16]. In essence, this overlaps with the pathophysiology of cardiac tamponade where respiratory-dependent changes in RV and LV filling cause enlargement of one chamber, at the expense of the other, when the pericardial restraint or pressures are high.

RV-LV Interactions When the RV Is Hypertensive

The impact of a dilated RV on LV function becomes critical when the RV is additionally hypertensive. In patients with severe pulmonary arterial hypertension (PAH), RV dilatation compresses the LV within the confines of the relatively fixed, noncompliant, pericardial space, while high RV pressures displace the interventricular septum leftward [17]. The compressed LV and small LV volumes are further exacerbated by reduced preload due to RV dysfunction and the resulting decreased stroke volume is ejected into the pulmonary bed [17]. The combination of these factors leads to reduced LV filling while the distorted LV geometry may impede its normal contractility [18,19,20,21,22,23]. The importance of these LV geometrical changes is demonstrated by the finding that in PAH, LV, more than RV, end-diastolic volume is linearly related to cardiac output [19]. The importance of the interaction between the dilated hypertensive RV and compressed LV is further confirmed by the LV eccentricity index being linked to catheter-measured hemodynamics as well as death or lung transplantation in children with PAH [24,25,26,27]. Although perhaps most emphasized in PAH, this pathophysiological mechanism is relevant to any condition with severe RV hypertension. For example, in patients with repaired tetralogy of Fallot with severe RV hypertension from RV-pulmonary artery conduit stenosis, prolonged septal shift and prolonged RV contraction produce reduced LV filling as the septum bulges into the LV during LV diastole [28]. Consequently, alleviating stenosis of the RV-PA conduit reduces RV hypertension and normalizes septal curvature and RV contraction time, which synchronizes LV and RV contraction and relaxation [28]. The restoration of normal RV-LV interactions increases LV diastolic filling and improves exercise capacity, which is an important clinical outcome in this population [28]. Impaired LV systolic function during RV hypertension induced by pulmonary artery constriction can partly be attributed to changed LV geometry and alterations at the septal insertion points where the RV and LV connect [23]. These alterations at the septal hinge points will be further detailed later in the chapter.

As these observations suggest, the temporal disparity between RV and LV cardiac cycle events compounds the geometrical interactions induced by left septal shift. In the hypertensive RV, be it from severe conduit stenosis or PAH, RV contraction and systolic time prolong because of prolonged isovolumic contraction and relaxation [29]. Prolongation of RV systole in the dysfunctional hypertensive RV causes peak RV myocardial shortening and persistence of elevated RV pressures into early LV diastole, at the same time that LV pressures are rapidly falling during isovolumic relaxation and rapid filling [20, 30]. This causes an abrupt leftward shift of the interventricular septum exactly as the LV is rapidly relaxing and the mitral valve is opening, impeding the dominant phase of LV filling in early LV diastole [30]. Consequently children with PAH exhibit impaired LV diastolic filling and function [26]. These adverse geometrical-temporal RV-LV interactions worsen with increasing heart rate, as diastole, and the time available for ventricular filling, is disproportionately shortened versus systole by heart rate [29]. The systolic to diastolic duration ratio, as measured from the duration of tricuspid regurgitation spectral Doppler [29], or strain imaging [20, 31], is a marker of RV systolic prolongation and decreased RV and LV filling, associated with death or lung transplantation [29]. The result of shortened RV diastolic duration and impaired LV filling is clinically important reduced stroke volume and cardiac output [19, 32,33,34]. The compromised hemodynamics are further worsened by inefficient RV pump function, as even though RV contraction (systolic duration) is prolonged, the short RV ejection time due to the high pulmonary vascular resistance compromises RV output, LV preload, and consequently LV filling and cardiac output [34]. These adverse interactions translate into clinical outcomes as left septal shift, LV filling, and RV systolic to diastolic duration ratio are linked to clinical outcome [29, 35].

As mentioned above, RV hypertension, dilation, and septal displacement further compromise efficient RV pump function and RV-LV interactions as they lead to incoordinate RV contraction between the septum and lateral wall and between the RV and LV lateral walls [34, 36,37,38,39]. An interventricular mechanical delay, that can occur in both RV and LV dysfunction, may further worsen LV function as well as increase the risk of arrhythmia and decrease exercise tolerance [40, 41]. The pathophysiological effect of incoordinate RV and LV cardiac cycle events also becomes evident during support of the LV by an assist device. LV assist devices are associated with shortening of LV systolic duration, disparity between LV and RV filling, and reduction in LV stroke volume secondary to reduced preload [42]. These experimental findings translate into clinical decision-making, as the speed setting in the LV assist device impacts LV sphericity, rightward septal bulge, LV-RV interactions, and RV filling, all of which ultimately affect cardiac output [43]. While the above observations emphasize RV systolic interactions, diastolic RV-LV interactions are also important. During lower body suction in patients with heart failure, decreased RV end-diastolic volume results in increased LV end-diastolic volume despite reduced pulmonary capillary wedge pressure [44, 45]. Experimentally, RV free-wall stiffening, which occurs when the RV is hypertensive [46], leads to increased septal diastolic length and increased LV stiffness, even when LV volume is constant [47]. This interaction may be mediated by the common myocardial tracts encircling the two ventricles.

Mediation of ventricular-ventricular interactions through the common myocardial tracts is also invoked as LV geometrical-temporal interactions do not account for all the adverse RV-LV interactions described above. When the RV acutely dilates secondary to right coronary obstruction and ischemia within the pericardium, there is a compression of the LV, but also impaired LV contractility that is independent of loading conditions [16]. Although leftward septal displacement within the constraints of the noncompliant pericardium is crucial in mediating ventricular interactions [48], release of the pericardium leads to restoration of LV contractility that is not solely attributable to reduced LV volume or distorted LV geometry [16]. These load-independent changes in LV contractility may stem from changed contractility in the shared superficial myofiber tracts running between the ventricles [18, 49, 50].

These shared myocardial tracts can be leveraged for therapeutic benefit. It had previously been established that acutely constricting the aorta during acute increases in RV afterload leads to increased stroke volume [51]. Although changed coronary flow patterns may explain beneficial effects of supra-aortic banding in RV pressure loading, these experiments kept coronary flow constant, so that the effects occurred independent of right coronary artery perfusion [51]. This demonstrates that, under these circumstances, there are additional factors that contribute to RV-LV interactions, most likely the shared epicardial and septal fibers [52, 53].

Increasing of the contralateral ventricle’s afterload to improve ipsilateral ventricular function is also used in patients who have congenitally corrected transposition of the great arteries and tricuspid regurgitation. In this congenital heart disease, the RV is the systemic ventricle and the tricuspid valve is often malformed (“Ebstein-like”) and regurgitant [54]. Often, the dilated, systemic RV and interventricular septum bulge towards the LV, further distorting the tricuspid annulus with progressively worsening tricuspid regurgitation and RV dilation [55]. Pulmonary artery banding can be used in these patients to increase LV afterload and pressure, so that the septum shifts towards the RV, into a more neutral position, thereby improving TV annular configuration and reducing TR [55]. In this condition, pulmonary artery banding may also increase contractility of the sub-pulmonary LV, leading to increased contractility of the systemic RV through the shared myocardial fibers. However, in practice, placing an adequately tight band to induce LV pressure load on the one hand, while avoiding LV failure from excessive pressure loading on the other, is a delicate balance and one not easily assessed. Increasing the contralateral ventricle’s afterload has also been harnessed in children with severe dilated LV cardiomyopathy and left-heart failure, where pulmonary artery banding in carefully selected patients can lead to reduced LV dilatation, decreased mitral regurgitation, and increased LVEF [56].

The systolic interactions between the RV and LV are mediated not only by changes in septal position, and the common superficial myocardial tracts, but also by the oblique orientation of the myofibers in the interventricular septum [57]. In left-heart failure, as the LV remodels and progressively becomes more spherical, the septal fibers lose their oblique angle, thereby reducing their mechanical efficiency to reduce not only LV, but also RV contractile function. The decrease in RV function can lead to increasing tricuspid regurgitation and further RV dilatation, and a viscous cycle of additional reduction in the oblique angle of the septal myofibers [57].

Mechanical-Molecular RV-LV Interactions in RV Hypertension

Our group’s experiments in a more chronic rabbit model of RV hypertension from pulmonary artery banding further extended the potential therapeutic effects of harnessing common myocardial fibers discussed above in regard to the benefits of acute aortic constriction on RV function during acute RV hypertension [52]. We found that RV hypertension leads to RV and LV dysfunction and impaired contractile function in association with myocyte hypertrophy and development of interstitial fibrosis [52]. By adding a mildly constricting aortic band, we obtained an increase in RV contractility without compromising LV contractility (indeed there was even a small increase in LV contractility) [52]. This functional benefit was associated with improved histological findings including decreased extracellular matrix remodeling, decreased biventricular fibrosis, and decreased profibrotic molecular signaling through the transforming growth factor beta (TGFβ1) and endothelin (ET)-1 pathways [52, 58, 59]. Similarly, in juvenile rabbits with RV hypertension and pulmonary artery banding, septal apoptosis, fibrosis, and reduced capillary density develop and extend to the LV free wall [60]. The improved RV and LV function with addition of a mild aortic band in the pulmonary artery band rabbit model may also stem from partial reversal of leftward septal displacement, improved RV and LV geometry, and increased LV contractility secondary to the increased LV load. The development of RV and LV fibrosis secondary to RV hypertension can also be ameliorated by pharmacological therapy including angiotensin receptor and ET-1 receptor blockade which reduce TGFβ1 signaling [58, 59, 61].

RV-LV Interactions at the Septal Hinge-Point Regions

The geometrical-temporal RV-LV cross talk in RV hypertension occurs, at least in part, at the septal hinge-point regions where increased shear stress and regional injury occur [21, 62, 63]. Indeed, LV circumferential and RV longitudinal shortening at the RV septal insertion regions contribute to increased stress, shear forces, and fibrosis [21, 64, 65]. These increased mechanical stresses trigger mechanotransduction and molecular signaling through integrins to upregulate transforming growth factor beta (TGFβ) signaling that ultimately is associated with extracellular matrix remodeling and fibrosis [66]. This mechanotransduction signaling is most prominent in the hypertensive RV and septal hinge-point regions [63, 66]. However, effects may not all be detrimental, as concomitantly with increased fibrosis, we also found increased elastin deposition at the septal hinge points [66]. Elastin, a more compliant material than stiff fibrillar collagen, may serve to increase compliance in these septal connecting regions, thereby partially buffering the LV from adverse myocardial RV-LV interactions [66].

The high-stress septal hinge-point areas also manifest clinically in human PAH patients, where MRI delayed gadolinium enhancement fibrosis imaging is increased at the RV septal insertion points in relation to the severity of RV afterload [64, 67, 68]. Thus, septal hinge-point fibrosis may be clinically important as it is associated with reduced RV function and increased mortality [64, 67]. In children with PAH, we found that decreased LV myocardial shortening was most prominent at the septum, consistent with the experimental and clinical findings at the septal hinge-point regions [69].

Similar to findings in rat and rabbit PAB models, mice with PAB demonstrate impaired RV and LV systolic function along with decreased LV stroke work, torsion and torsion rate, and mildly increased LV fibrosis, attributed to increased myocardial stress [70]. The LV histological and functional changes and fibrosis were accompanied by increased β-MHC expression and decreased expression of Ca2+-handling proteins [70]. The changes in α- and β-MHC expression were in turn associated with the changes in LV mechanics. Interestingly, the association between increased RV pressure loading and decreased LV torsion mechanics is in contrast to findings from acute experiments where the LV responded to an acute increase in RV pressure loading and decreased RV stroke volume by an acute increase in torsion and untwist rate [71]. The differences between these results may possibly be explained by the development of myocardial hypertrophy and fibrosis in the chronic models and by differences in volume loading, coronary perfusion, and different myocardial mechanics in acute versus chronic conditions. Indeed, acute RV pressure loading can lead to acute decreases in LV contractility, developed pressure, diastolic volume, and cardiac output that correlate with decreased LV and septal circumferential strain, LV untwisting, and apical rotation [72]. The septal circumferential strain, which likely correlates with septal oblique myofibers described above, was the most important factor associated with reduced LV performance [72].

Therapeutic Targeting of Molecular-Tissue RV-LV Interactions in RV Hypertension

Increasing the pressure load of the contralateral ventricle through aortic or pulmonary artery banding may be effective in changing ventricular geometry, septal position, and contralateral ventricular contractility. However, this invasive approach may be difficult to apply clinically in fragile patients. Consequently, pharmacologically inhibiting the adverse molecular signaling in the RV and the septal hinge-point regions leading to tissue injury and increased fibrosis may be a therapeutic option to address the molecular-tissue effects of adverse RV-LV interactions. As detailed above, in PAB rabbit models, we showed that angiotensin and endothelin-receptor blockades, both of which decrease TGFβ signaling, lead to decreased biventricular fibrosis and improved biventricular function [58, 59, 61].

Pharmacological therapy to reduce heart rate may also be beneficial in certain circumstances to address the temporal aspects of adverse RV-LV interactions in RV pressure loading and PAH. In rat models of PAH and pulmonary artery banding, we showed that slowing heart rate using the beta-adrenergic receptor antagonist carvedilol, or the non-adrenergic agent ivabradine, improves RV and LV function through alignment of RV and LV events [73,74,75]. We attributed this realignment in RV-LV events to improved RV diastolic relaxation, possibly due to improved Ca2+ cycling [73,74,75]. Importantly, the improved biventricular function was associated with reduced fibrosis and cardiomyocyte hypertrophy, even though RV systolic pressures and RV-LV geometry and compression were unchanged, showing that heart rate-reducing agents were not acting through alleviation of pulmonary arterial or RV pressures [73,74,75].

RV-LV Interactions in Congenital Heart Disease

Because of pressure and/or volume loading and distorted ventricular structure and geometry, various congenital heart diseases can demonstrate the physiological and clinical importance of ventricular-ventricular interactions. An intriguing example is when one of the ventricles is severely hypoplastic. Functionally single ventricles have markedly altered myocardial mechanics including myocardial shortening, twist, and radial motion. While these may be impacted by multiple factors, the lack of a contralateral ventricle may constitute one of these factors. An example of such adverse interactions can be seen in hypoplastic left-heart syndrome, where the direct and indirect impacts of an underdeveloped LV may alter RV and TV annular configuration and worsen TR, which increases the risk for death or need for heart transplant [76]. The presence of a small LV can also distort RV geometry and cause RV apical bulging, which we found to be associated with impaired RV mechanics and increased risk for heart transplant or death [77]. We further found diminished septal strain in HLHS patients with a moderately hypoplastic LV (and hence relatively larger LV) versus a diminutive (and hence almost absent) LV, in association with asymmetric RV mechanics and worse clinical outcome [78]. Thus, the presence of a hypoplastic LV may be worse than having no discernable LV, as RV geometry appears to be adversely affected.

A maldeveloped RV can also impact LV function, as occurs in Ebstein’s anomaly of the tricuspid valve. In this condition, the tricuspid septal and inferior leaflets are displaced and rotated apically and towards the RV outflow tract. This yields a variable length of the interventricular septum as part of functional right atrium, a small “functional” RV distal to the displaced tricuspid leaflets, that has impaired myocardial function, and variable but often severe TR. In these children, we found that an early diastolic leftward interventricular shift is found in most patients and associated with decreased LV filling and with more TR [79]. Moreover, reduced pulmonary artery antegrade flow was associated with lower LV filling, LV volumes, LVEF, and output. Importantly, from a clinical perspective, impaired LV systolic and diastolic volumes and performance were associated with reduced exercise capacity [79]. We hypothesized that prolonged RV systole and increased TR may impede LV filling, whereas decreased LVEF, SV, systolic strain, and delayed aortic and atrioventricular valve opening and closure suggest impaired contractile force development, possibly related to enlargement and dysfunction of the “functional” RV (the portion of the RV that remains distal to the displaced tricuspid valve). We also hypothesized that early rightward IVS motion may impede LV systolic function, and an ineffective leftward systolic septal shift may impede pressure development [79]. Thus, although the pathophysiology is completely different from PAH, some of the adverse RV-LV interactions have similar features stemming from impaired RV contractile function and disparate RV and LV events and geometry. Indeed, severe Ebstein’s anomaly that manifests clinically in the early neonatal period can be very difficult to manage, even if the LV functions well. Thus, the RV is clearly central to cardiac function and clinical outcomes in these situations.

The effects of an abnormal RV on the LV are also apparent in repaired tetralogy of Fallot. Tetralogy of Fallot is a cyanotic congenital heart disease characterized by RV outflow tract obstruction and a large ventricular septal defect. After surgical “repair” in infancy, which patch-closes the ventricular septal defect and relieves RV outflow tract obstruction, there is often pulmonary regurgitation due to disruption of the pulmonary valve [80]. Consequently, chronic RV volume loading and dilatation impact both RV and LV filling, function, and mechanics [81]. RV dilatation is associated with impaired LV intracavitary flow patterns, specifically, LV diastolic flow and flow of the residual blood volume that is retained in the ventricle after ejection [82]. These impaired LV flow patterns correlate with reduced LV circumferential shortening and ejection fraction [82]. These abnormal flow patterns are likely associated with impaired LV kinetic energy [83]. Reduced LV twist and strain have also been found in this population, in relation to RV dilatation [4, 84,85,86,87,88]. The common apical myofibers, which determine to a large extent LV twist-untwist, may be responsible for the decrease in LV torsion, and consequently decreases in LV intraventricular pressure gradients and diastolic suction [89, 90]. Indeed, even though tetralogy of Fallot is thought to be a “right-heart” disease, both RV and LV diastolic functions are impaired after tetralogy of Fallot surgical repair, in part due to the effects of adverse ventricular-ventricular interactions [91,92,93]. The association between RV and LV function in repaired tetralogy of Fallot is also found at the myocardial level [94]. Our group showed that reduced LV early diastolic deformation is associated with RV dilatation and pulmonary regurgitation [91]. However, LV dysfunction in repaired tetralogy of Fallot may not only stem from RV abnormalities. Aortic dilatation is very common after tetralogy of Fallot repair and may be associated with increased aortic shear stress, stiffness, and abnormal flow that may directly impact LV function [95, 96].

Summary

In summary, the RV and LV are tightly linked. Consequently, function and events in one ventricle can profoundly impact the contralateral ventricle. These adverse interactions are found in diverse acquired and congenital heart diseases and seem to be critical in severe RV hypertension, most importantly PAH. The challenge is often to determine which outcomes are due to adverse RV-LV interactions versus ipsilateral effects. Answering this question will assist in designing therapies that can leverage beneficial ventricular-ventricular interactions while reducing the effects of adverse RV-LV interactions.