Cardiac resynchronization therapy (CRT) was developed as a treatment for heart failure (HF), and is effective in improving left ventricular (LV) function, with significant impact on the prognosis of symptomatic patients with advanced LV dysfunction and wide QRS.1

Since 2001, the benefits of CRT in terms of reverse remodeling and improvements in symptom severity, quality of life, hospitalization and survival have been clearly demonstrated in randomized controlled clinical trials, as shown in reviews.2 However, despite well-defined selection criteria, the CRT non-response rate, which reaches 30-40% in major trials, still represents a major concern.

Different variables have been studied to determine markers that might predict CRT response.3–12 Echocardiographic measures of ventricular dyssynchrony, for example, cannot identify responders.12

Identifying genuine predictors of CRT non-response remains a challenge.

The study's main purpose was to assess the baseline variables that might significantly influence an echocardiographic response to CRT in HF.

We performed a prospective, single-center, cohort study in a central hospital with a multidisciplinary program for HF and CRT, between 2012 and 2014.

Blood collection and analysis

Blood samples were collected in a fasting state for assessment of complete blood count, creatinine, C-reactive protein and brain natriuretic peptide, measured by standard techniques. Creatinine clearance was calculated by the Cockcroft-Gault formula14:

Of the 116 consecutive patients referred for CRT, 79 (68.4% male, 24% with ischemic etiology) were included in the study. Four patients were lost to follow-up and 33 were excluded because they were referred for exercise training after CRT or refused to participate in the study.

Patients’ baseline characteristics are summarized in Table 1.

At six months, 54 patients (68.3%) were clinical responders and 51 (64.6%) were echocardiographic responders.

Of the 54 clinical responders, 10 (18.5%) did not respond by echocardiographic criteria and of the 51 echocardiographic responders, six (11.7%) did not improve clinically.

Seventy-seven patients (97.5%) had complete left bundle branch block (LBBB), 50 of them echocardiographic responders (64%). Two patients had complete right bundle branch block (RBBB), one responding to CRT.

Univariate analysis results for baseline variables are summarized in Table 2.

Serum creatinine and TAPSE values were associated with echocardiographic response (p=0.031 and p=0.045, respectively) (Figures 1 and 2).

Figure 1.

Creatinine distribution according to echocardiographic response to cardiac resynchronization therapy.

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Figure 2.

Distribution of tricuspid annular plane systolic excursion TAPSE values according to echocardiographic response to cardiac resynchronization therapy.

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On multivariate analysis only TAPSE was independently associated with echocardiographic response (odds ratio 1.13; 95% CI: 1.02-1.26; p=0.020). TAPSE <15 was associated with non-response (p=0.0052). Eight patients (10%) had TAPSE <14 mm, seven of whom (87.5%) were non-responders. There were no responders (and two non-responders) with TAPSE <10 mm.

There is considerable disagreement in the literature regarding the definition of a CRT responder, as shown by Fornwalt et al.17 in a 26 CRT trials analysis, in which the level of agreement between primary endpoints was poor, with the proportion of patients defined as having a positive CRT response ranging from 32% to 91%.

Clinical response by itself is non-specific, largely subjective and too dependent on different variables. On the other hand, LVEF, although influenced by preload, afterload, HR, and mitral regurgitation, is the most widely used echocardiographic parameter and an important index of LV function, due to its clinical prognostic value.18

In our study, echocardiographic response was defined as ≥5% absolute improvement in LVEF, in order to include the majority of responders. Using a larger LVEF increase would restrict the range of responders, improving response specificity, but decreasing sensitivity. There is still discussion concerning the best LVEF change to identify those who are really responding.17

We observed clinical response in 68.3% of patients and echocardiographic response in 64.6% (non-response in 35.4%).

Demographic and clinical variables did not differ between responders and non-responders. Other investigators also did not find gender or etiology, adjusted to LV volumes, to be independent predictors.8 On the other hand, sub-analyses of randomized clinical trials have suggested that CRT has greater beneficial effects on LV function and/or prognosis in females6,9,10,19 and in nonischemic etiology.7,11

Of our patients, 34% were in atrial fibrillation, the most common arrhythmia in HF and associated with worse prognosis.20 It is unclear if, correcting for age and comorbidity, the prognosis for patients in AF is in fact worse21 or whether it is only a marker of more severe disease.13

We did not find a significant relation between QRS duration and response. Previous randomized controlled trials did not clearly show QRS duration as a predictive factor.22–24 However, in a recent meta-analysis including five randomized trials, QRS duration was a powerful predictor of CRT effectiveness.25 Moreover, a sub-analysis of the MADIT-CRT trial associated longer QRS (>150 ms) with benefits of CRT in LV function, morbidity and mortality.7 The REVERSE study confirmed the importance of QRS duration and LBBB pattern in CRT outcomes.26 With regard to our study, the sample size, the higher percentage of patients with nonischemic etiology and mean QRS >150 ms influenced our results.

In our population, only two patients (2.5%) had RBBB and, although these are generally not expected to benefit from CRT,13 one was a responder.

The only laboratory parameter with statistical significance in univariate analysis was serum creatinine (Figure 1), although creatinine clearance14 showed no association with CRT response. Although lower creatinine levels were seen in patients who responded to CRT (p=0.045), multivariate analysis did not demonstrate an independent association with response.

In contrast to our results, Fung et al.,27 in a population with renal insufficiency, showed that responders had worse baseline renal function. In our study, most patients had normal renal function or mild dysfunction (34.2% and 36.6%, respectively), with only two patients (0.25%) having severe renal dysfunction as defined by the guidelines.28 Different populations in the two studies may have contributed to the difference in results. The relation of serum creatinine and creatinine clearance to response and outcome remains controversial.29

CPET, Holter and peripheral arterial tonometry variables could not identify echocardiographic responders.

Non-responders had greater baseline LV volume, LV mass and left atrial volume and lower LVEF and GLS, although the differences did not reach statistical significance.

In the literature, there have sometimes been conflicting data on the impact of baseline LV dimensions on CRT response, depending on study populations.3,9,10 Park et al. demonstrated that baseline LV volume was a predictor of echocardiographic CRT response.8 Rickard et al.3 showed that the smaller the LV size, the greater the improvement in LVEF and all-cause mortality after CRT. In contrast, the MADIT-CRT trial10 showed that a larger LV was associated with echocardiographic response, and a sub-analysis of PROSPECT9 found no difference in responders.

Regarding the predictive value of baseline LVEF, we found no relation with less severe patients, unlike in the MADIT sub-analysis,30 in which patients with better LVEF had a greater response. However, because different inclusion criteria and definitions of CRT response were used, direct comparisons of results are difficult or impossible.

The right ventricle has always been considered the ‘poor relative’ of the left ventricle, although its importance in exercise tolerance and prognosis has been demonstrated.31 Because CRT was developed to improve LV synchronicity and function, its effects on right ventricular (RV) function have not been fully examined, although some studies have shown benefit.9,32

An important issue concerns the potential role of baseline RV dysfunction in LV reverse remodeling after CRT. In our study, TAPSE (Figure 3), a marker of overall RV function33 and an independent predictor of mortality in HF patients,34,35 showed an association with echocardiographic response to CRT by multivariate analysis (Figure 2), with responders having higher baseline TAPSE values. RV dysfunction was present in 7% of responders compared to 36% of non-responders, and TAPSE <15 mm was statistically associated with non-response, although TAPSE <17 mm (the cut-point for RV dysfunction in clinical practice) showed no association. There were no responders with TAPSE <10 mm. This means that only moderate or severe RV dysfunction was related to CRT non-response.

Figure 3.

Measurement of tricuspid annular plane systolic excursion by M-mode echocardiography.

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Our results are in agreement with Capelli et al.,36 who demonstrated that CRT induces both RV and LV reverse remodeling, and is more effective in patients with higher TAPSE. In addition, Scuteri et al.32 concluded that low baseline TAPSE was associated with poor response and adverse prognosis, while Sade et al.37 showed that preserved RV function is an independent predictor of long-term event-free survival after CRT.

On the other hand, a sub-analysis of the REVERSE study38 demonstrated that while LV reverse remodeling was greater in patients with TAPSE >14 mm, the difference was not statistically significant. Also, in CARE-HF,39 patients with severely reduced TAPSE (<14 mm) had a significantly lower response rate, though this association was not strong enough to consider TAPSE an independent predictor.

Some of the uncertainty regarding whether TAPSE is an independent predictor of CRT response may result from differences in study populations and particularly in the criteria used to define CRT response.

In conclusion, in this advanced HF population, TAPSE was the only independent predictor of CRT response regarding all the analyzed variables. RV function clearly has a role in the selection of candidates for CRT.

The study was performed in a single center, and the sample size was moderate, mostly of patients with non-ischemic etiology referred for CRT. Follow-up duration was only six months, even though a small percentage of patients can be late responders. These results need to be reproduced in a larger study, separating patients with ischemic and non-ischemic etiology, with a longer follow-up period.

This work was supported by research grant PTDC/DES/120249/2010 from the Foundation for Science and Technology (FCT).

The authors declare no conflicts of interest.