Right Ventricle and Cardiac Resynchronization Therapy. Spectator or Actor?

Cardiac resynchronization therapy (CRT) is an efficient therapeutic option for patients with HF and reduced ejection fraction (HFrEF). CRT improves clinical status, leads to reverse remodeling of left ventricle (LV), and decreases morbidity and mortality in patients with HFrEF^1,2. CRT is indicated in patients with symptomatic HFrEF with a QRS duration ≥130ms with LVEF ≤35% despite optimal medical treatment³. Restoring LV synchronism and contractility is the rationale behind CRT. The effect of CRT upon RV is less clear and the complex relationship between RV function and CRT has become a subject of intensive research lately.

Furthermore, RV function plays an essential role in end-stage HF patients as a strong prognostic factor⁴. For instance, before left ventricle assist device implantation, RV function evaluation is mandatory.

Cardiac magnetic resonance (CMR) is considered the gold standard technique for evaluation of RV volumes and ejection fraction quantification⁵. Several of the echocardiographic parameters can offer an alternative to CMR in clinical follow up, especially the newer techniques like 3D, speckle tracking echocardiography.

This review’s purpose is to summarize the role of RV function using echocardiographic parameters, in the evolution of HF patients undergoing CRT, providing an outlook of recent studies.

The position of RV in the thorax, its complex crescent shape and pattern of contraction lead to a challenging evaluation by 2D echocardiography. The RV is the most anteriorly positioned cardiac chamber, located behind the sternum. Due to its shape it requires multiple acoustic windows for evaluation⁶.

RV size should be routinely measured using multiple acoustic windows. In general, a diameter above 41 mm at the base and above 35 mm at the midlevel in the RV-focused view indicates RV dilatation⁶. In laboratories with experience in 3D echocardiography RV volumes measurement is recommended⁶.

Conventional echocardiographic parameters of the RV systolic function evaluation are: tricuspid annular plane systolic excursion (TAPSE), and RV fractional area change (RV FAC). RV myocardial performance index, or TEI index is a measurement of both systolic and diastolic RV function.

More recent echocardiographic parameters gather: tricuspid S-wave velocity using tissue Doppler imaging (TDI), RV longitudinal strain (RVLS) by speckle tracking echocardiography and three dimensional (3D) echocardiography RV volume evaluation, 3D RV strain.

Figure 1

The gold standard for evaluation of RV to pulmonary circulation coupling is obtained by invasive measures using pressure-volume loop-derived RV systolic elastance/arterial elastance (Ees/Ea). Lately there are several studies indicating that RV to pulmonary circulation coupling can be also evaluated by echocardiography¹⁴. Combining parameters of RV systolic function with pulmonary arterial systolic pressure (PASP) seems to be and accurate estimation of RV to pulmonary circulation coupling¹⁵. A study by Guazzi et al. proposed TAPSE/PASP ratio which was taken as a noninvasive index of RV to pulmonary circulation coupling based on the correlation with invasively evaluated RV systolic elastance/arterial elastance¹⁵. Another study by Tello at al confirmed that among different parameters of RV function only TAPSE/PASP emerged as an independent predictor of Ees/Ea¹⁴. In several trials TAPSE/PASP ratio proved to be a predictor of worse prognosis in heart failure patients^15,16 and also in patients undergoing CRT¹⁷. A group by Iacoviello et al proposed a combination of RV longitudinal strain (free wall and global) and PASP that can provide a reliable index of RV pulmonary circulation coupling¹⁸. This parameter also proved to be independently associated with higher risk of events¹⁸.

Figure 2

RV and LV are connected by sharing myocardial fibers within the interventricular septum¹⁹. The ventricles interact in systole whereas LV contraction increases RV contraction¹⁹ a phenomenon called systolic ventricular interaction²⁰. When LV becomes dysfunctional this leads to increased filling pressures and consequently to the elevation of pulmonary artery pressure and the afterload of RV²¹. Along with the deterioration of LVEF, systolic ventricular interaction is also leading to a reduction of RV contractile performance even when the RV is not directly involved in the disease²⁰. Next, as the LV becomes more dysfunctional the septal fibres become less oblique, dramatically reducing their mechanical advantage and further impairing RV contractile function²⁰. Along with RV failure appears functional tricuspid regurgitation which alters furthermore the RV systolic function.

In patients with LV systolic dysfunction and left bundle branch block (LBBB) there are some others particularities. LBBB leads to an abnormal contraction of the interventricular septum (IVS) with marked early systolic shortening and leftward motion²². Because IVS also contributes to RV contraction, this abnormal movement may also affect RV²³.

A very recent study of Storsten et al. investigated how LBBB and CRT modify RV free wall motion. The work gathers animal experimental data with human measurements in patients with non-ischemic cardiomyopathy, LBBB and a normal RV function²³. The study revealed an abnormal early systolic premature shortening of the RV free wall visible with echocardiographic longitudinal strain analysis. Interestingly, in this study, CRT reduced or abolished this abnormal RV shortening, therefore increasing the RV workload²³.

Figure 3

Next, Lumens et al. tried to prove this hypothesis using computer simulations with models of artificial heart²⁴ with the purpose of analyzing the mechanics of a failing heart with LBBB and treatment with CRT²⁴. They confirmed the early systolic RV shortening in patients with LBBB and the fact that it amenable by CRT. However, CRT did not lead to this mechanical change in the heart with additional RV failure. Both studies support the idea that the presence of the early systolic RV shortening associated with LBBB may have prognostic value and it is modifiable by CRT, and also that a dysfunctional RV leads to less response to CRT.

The presence of RV systolic dysfunction is associated with a higher risk of adverse cardiovascular events²⁵ but also less response in CRT patients^26,27. There is a consensus in literature that RV systolic dysfunction implies a higher risk of cardiovascular events in HFrEF patients, but if it predicts also response to CRT is less clear.

The main parameter used in these trials to assess RV function is TAPSE. A study by Leong et al which included 848 CRT patients show that RV dysfunction (TAPSE <14mm) was associated with a greater incidence of all-cause mortality²⁵. Patients with lower TAPSE had a higher mortality, regardless of assigned treatment, in a the study CARE HF (Cardiac Resynchronization in Heart Failure) performed over 813 patients²⁸. Another analysis of CARE HF study performed by Ghio et al indicate that 18 months after CRT, the decrease in end systolic volume and the increase in EF were less in patients with a TAPSE <14 mm when compared with patients with TAPSE>14 mm²⁶.

Scuteri et al., use several markers of RV systolic function (TAPSE, PASP, RV end systolic and end diastolic area and RV FAC) and show a negative correlation between baseline RV systolic dysfunction and left ventricular remodeling response to CRT²⁷.

Interestingly, a very recent work by Patel et al use visual evaluation of RV systolic function done by cardiologists with board certification in echocardiography. This study shows that CRT response was significantly higher in patients with normal RV compared with patients with dysfunctional RV. Normal RV function was associated with better survival compared with patients with RV dysfunction²⁹.

Other studies use the composite parameters to evaluate RV to pulmonary circulation coupling and its significance in HF patients with or without CRT. For example, Bracanca et al. evaluated the role of RV-PA coupling estimated by TAPSE/PASP ratio in CRT patients. TAPSE/PASP outperformed PASP and TAPSE in predicting the response to CRT¹⁷.

A low TAPSE/PASP ratio correlated with high risk of cardiovascular events in HF patients with reduced and also with preserved EF¹⁵. The novel parameter used to estimate RA to pulmonary artery coupling: RV strain/PASP ratio also proved to be associated with an increased mortality risk and worse outcome in HF patients¹⁶.

In contradiction with the data above, Sharma et al conducted systematic search in literature including of 16 studies published between 1966 to 2015 (N =1764), and concluded that baseline RV function as assessed by TAPSE, FAC, RV strain and RVEF does not determine response to CRT as assessed by change in LVEF³⁰.

Another study by Bernard et al. used systolic peak velocity at the tricuspid annulus (S’) to evaluate RV function. Interestingly, RV dysfunction defined by S’ velocity <11.5cm/sec was associated with significantly more severe LV longitudinal dyssynchrony. Moreover S’ velocity was correlated with LV longitudinal dyssynchrony. However, LV radial contractility and dyssynchrony were not affected by RV function³¹.

Very recent work published by Strosten and Lumens with a combination of patient and animal experimental data and computer simulation show that LBBB reduces work upon RV free wall. Conversely CRT induces an increase of work load upon RV that may be supported by only by a functional RV^23,24. This may explain why a dysfunctional RV may be associated with worse outcome after CRT²⁴.

RV failure implies a worse prognosis in patients undergoing CRT but the direct effect of CRT upon RV function is still under debate. Table 1 summarizes the main studies that analyzed the effect of CRT upon RV function and structure. Contradictory results may be noticed among the trials.

Leong et al. prove that improvement in RV function after CRT was independent of the improvement in LV systolic function but significantly associated with the improvement in LV diastolic function²⁵. More so, in a study performed using pressure volume loop catheter approach Schmeisser et al. show that the improvement of RV to pulmonary circulation coupling is associated with a greater RV remodeling after CRT³².

Another study by Abdelhamid et al show that CRT promotes RV reverse remodeling and improves RV systolic function in volumetric CRT responders³³. The group discusses that this may be a consequence of reducing mitral regurgitation, and the decrease of pulmonary hypertension.

Another study of Burri et al. using radionuclide angiography show that CRT has no acute effect on RVEF, and only slightly improves RVEF at follow-up. Patients with reduced RVEF at baseline were less likely to respond to CRT, indicating that right ventricular systolic dysfunction may play a role in patient selection³⁶. Nevertheless, baseline RVEF alone cannot be used to exclude patients from CRT, as 47% of patients with reduced RVEF still showed improvement in NYHA classification³⁶.

However, in CARE HF trial (Cardiac Resynchronization in Heart Failure) CRT improved LV but not RV structure and function with little evidence of an interaction with TAPSE²⁸. The recent study of Storsten show an acute increase of the RV free wall workload in hearts with LBBB treated with CRT²³. This may explain the lack of an obvious improvement of RV function after CRT. Further studies are needed to clearfy how RV function and structure change after CRT and if this change may be related to CRT response.

A complete evaluation of RV systolic function and structure needs multiple echocardiographic parameters, by using the conventional and the newest techniques. Echocardiographic evaluation of RV systolic function, in the setting of CRT, may contribute to identify the patients with a higher risk of cardiovascular events. However, currently there are no data indicating that CRT patient selection should be influenced by RV systolic function. Recent data support the idea that there is a specific pattern of RV contraction in LBBB patients which is corrected by CRT with the exception of those with RV failure.