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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 8  |  Issue : 1  |  Page : 35-41

Predictors of response to cardiac resynchronization therapy: A prospective observational study


1 Department of Cardiology, THS Wellness Private Limited, Kamala Nehru Hospital, Pune, Maharashtra, India
2 Department of Cardiology, Dr. D. Y. Patil Medical College, Pune, Maharashtra, India

Date of Submission17-Jan-2022
Date of Decision02-Apr-2022
Date of Acceptance06-Apr-2022
Date of Web Publication26-Apr-2022

Correspondence Address:
Rajendra Patil
Department of Cardiology, Dr. D.Y. Patil Medical College, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpcs.jpcs_2_22

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  Abstract 


Introduction: Cardiac resynchronization therapy (CRT) has revolutionized the treatment of cardiac dyssynchrony in chronic heart failure (HF), yet, complications and failures are reported in some patients. We aim to determine the predictors of response to CRT through clinical, electrocardiographic ECG, and echocardiographic assessment of patients following CRT and recommend the best practices to achieve optimum results for patients. Methodology: We analyzed the history, clinical examination, brain natriuretic peptide (BNP) levels, ECG, and echocardiography findings of 35 patients before CRT and on day 7 and day 180 following CRT. Observations: 71.4% of patients responded to CRT and 28.6% were nonresponders. The responders had fewer hospitalizations for HF. They showed a significant improvement in the New York Heart Association (NYHA) class, mean 6 min walk distance (6MWD), BNP level, QRS duration, and echocardiographic parameters on day 7 and day 180. The duration of HF ≤3 years, NYHA class III–IV symptoms, baseline 6MWD ≥240 m, QRS duration ≥150 ms, LVEF ≥25%, septal to posterior wall motion delay ≥130 ms, and mean pulmonary arterial pressure <50 mmHg were identified as the strong predictors of response to CRT. Recommendations: Patients with symptomatic HF should undergo early CRT to reduce recurrent hospitalizations and those with NYHA Class III–IV symptoms should be offered CRT before the duration of HF exceeds 3 years. BNP levels and echocardiography are invaluable tools to assess outcomes following therapy. A multiparametric, echocardiographic approach is helpful in selecting patients likely to undergo reverse remodeling after CRT and predicting outcomes.

Keywords: Brain natriuretic peptide level, cardiac dyssynchrony, cardiac resynchronization therapy, chronic heart failure, echocardiography


How to cite this article:
Parikh J, Patil R, Jadhav AK. Predictors of response to cardiac resynchronization therapy: A prospective observational study. J Pract Cardiovasc Sci 2022;8:35-41

How to cite this URL:
Parikh J, Patil R, Jadhav AK. Predictors of response to cardiac resynchronization therapy: A prospective observational study. J Pract Cardiovasc Sci [serial online] 2022 [cited 2022 Aug 17];8:35-41. Available from: https://www.j-pcs.org/text.asp?2022/8/1/35/344127




  Introduction Top


Heart failure (HF) is a major global health issue, with a worldwide prevalence of >37.7 million.[1] Chronic HF is commonly associated with conduction abnormalities such as bundle branch blocks leading to suboptimal ventricular filling, reduced left ventricular contractility, prolonged duration of mitral regurgitation, reduced forward stroke volume, and paradoxical septal wall motion.[2],[3],[4],[5] These mechanical manifestations together are termed ventricular dyssynchrony, defined by a QRS duration >120 ms. It occurs in approximately one-third of systolic HFs and is associated with an increased mortality.[6],[7] Ventricular dyssynchrony is treated by the implantation of a cardiac resynchronization therapy (CRT) device that coordinates the contraction of the dyssynchronous dilated heart and improves the left ventricular systolic function over a period of time.[8]

Several studies have demonstrated that CRT not only improves the clinical symptoms, the New York Heart Association (NYHA) class, exercise capacity, quality of life, ventricular function, and reverse remodeling but also increases survival and lowers the incidence of HF-related hospital admissions when compared with patients receiving optimal medical treatment alone.[9],[10],[11] However, CRT remains technically challenging, and implantable devices expose patients to device-related symptoms, device failure, and surgical complications. Nearly 30%–35% of patients show either no improvement or worsening symptoms after 6 months of CRT.[12],[13] This study aims to determine the predictors of CRT response through echocardiographic assessment in addition to well-established clinical and ECG parameters in patients following CRT and recommend the best practices to achieve optimum results for patients.


  Methodology Top


Study design

We conducted a prospective, observational study of 35 consecutive patients who underwent pacing only (CRT-P) or pacing plus defibrillation (CRT-D) at a tertiary referral institute in India after clearance from the Institutional Ethics Committee. Written and informed consent of all the study participants was obtained on enrollment in the study.

Sample size calculation

Approximately 20% of the admissions to the cardiology department had HF. Approximately a third of patients with systolic HF had ventricular dyssynchrony and were candidates for CRT. Considering a prevalence of 8%–10% of receiving CRT in HF as per the reference of previous studies, the following formula (Daniel, 1999) was used:

n = Z2 P (1 – P)/d2

Where, n = sample size, Z = level of confidence (for the level of confidence of 95%, Z value is 1.96), P = expected prevalence (in proportion of one; so for 10%, P = 0.1) and d = precision (in proportion of one; so 10%, d = 0.1). Thus, n = 34.2 = 35.

Method

CRT was offered to those patients who had a left ventricular ejection fraction (LVEF) of 35% or less, sinus rhythm, left bundle branch block (LBBB) with a QRS duration of 120 ms or longer, and NYHA class II, III, or ambulatory IV symptoms while receiving optimal medical treatment. Patients with recent acute coronary syndrome, non-LBBB type QRS morphology, atrial fibrillation, and complete heart block were excluded from the study. NYHA class, 6 min walk distance (6MWD), brain natriuretic peptide (BNP) levels, and ECG (heart rate and QRS duration) were documented in all patients prior to and on day 7 and day 180 following CRT device implantation. The number of hospitalizations for HF within 6 months following CRT was noted. Automated 3D echocardiography was performed before CRT and on day 7 and day 180 following CRT. The left ventricular dimensions (LVEDD, LVESD, LVEDV, LVESV), LV systolic function (LV dP/dT, LV EF%), TAPSE, LVOT, and RVOT pre-ejection time with pre-ejection delay, septal to posterior wall motion delay (SPWMD), septal to lateral wall motion delay (SLWMD) in peak systolic velocity, LV global longitudinal strain (LVGLS), systolic dyssynchrony index (SDI), mitral regurgitation (MR) jet area, and pulmonary arterial (PA) pressure were studied on echocardiography. All the parameters on day 7 and day 180 were compared with the data recorded before CRT to ascertain short and intermediate term changes in clinical and echocardiographic profile and to identify predictors of CRT response.

Statistical analysis

Descriptive statistics were reported as mean ± standard deviation or mean and range for the continuous variables. The categorical data were summarized as frequencies and percentages. The data were compared by paired t-test (continuous variables), Chi-square test, Mann–Whitney U test, or Fisher's exact tests (dichotomous variables) as appropriate, using the SPSS version 20.0 (SPSS Inc., Chicago, Illinois, USA) and Interactive Chi-square software (http://www.quantpsy.org/chisq/chisq.htm). P < 0.05 was considered statistically significant.

Observations

Twenty-four men and 11 women with a mean age of 61.51 ± 11.0 years were studied. Twenty-five (71.4%) had a previous history of ischemic heart disease, 24 (68.6%) had diabetes, 15 (48.9%) had hypertension, and 23 (65.7%) patients had estimated glomerular filtration rate (eGFR) <90 ml/min/m2. Twenty (57.1%) patients had NYHA Class III symptoms of HF, nine (25.7%) had Class II, and six (17.2%) had Class IV symptoms. The most common cause of HF was ischemic cardiomyopathy seen in 25 patients, followed by LV noncompaction in three patients, alcoholic cardiomyopathy, myocarditis, and idiopathic dilated cardiomyopathy in two patients each and postpartum cardiomyopathy in one patient. All patients were on guideline-directed medical therapy for HF. Twenty-seven (77.1%) patients underwent CRT-D and eight (22.9%) patients underwent CRT-P implantation. None died during the entire study [Table 1].
Table 1: Baseline characteristics of subjects studied

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Following the PROSPECT[14] study design based on the extent of LV reverse remodeling at 6 months' follow-up, patients were classified as negative responders (increased LVESV), nonresponders (decreased LVESV 0%–14%), responders (decreased LVESV 15%–29%), or super-responders (decreased LVESV ≥30%). In our study, 25 patients (71.4%) were responders, of which four (11.4%) were super responders. Ten (28.6%) were nonresponders, and there were no negative responders. CRT reduced the number of hospitalizations for HF (P < 0.001). While the majority of patients (42.9%) did not require hospitalization for HF within 6 months of CRT, nine (25.7%) needed a single hospitalization. Eleven patients needed ≥ 2 hospitalizations, of which ten were nonresponders. The NYHA class, mean 6MWD, BNP level, QRS duration, LVEDV, LVESV, LV dP/dT, LVEF, TDI, TAPSE, LVOT pre-ejection period, pre-ejection delay, SPWMD, SLWMD, LVGLS, SDI, MR jet area, and PA pressure showed significant improvement at day 7 and day 180 (P < 0.05). In addition, on day 180, LVESD and LVEDD were also improved (P < 0.05) [Table 2] and [Table 3].
Table 2: Comparison of clinical and ECG parameters and outcome

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Table 3: Comparison of ECHO parameters and outcome

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The duration of HF for ≤ 3 years, NYHA Class III–IV symptoms, baseline 6MWD ≥240 m, QRS duration ≥150 ms, LVEF ≥25%, SPWMD ≥130 ms, and mean PA pressure <50 mmHg correlated well with CRT response (P < 0.05) and was identified as predictors of CRT response. Age >60 years, gender, etiology of HF, presence or absence of diabetes or hypertension, eGFR <90 ml/min/m2, type of CRT (CRT-D or CRT-P), baseline heart rate, baseline BNP level <360 pg/ml, baseline LV dimensions (LVEDV, LVESV, LVEDD, and LVESD), LV dP/dT ≥650 mmHg/s, TDI ≥65 ms, TAPSE ≥15 mm, LVOT preejection delay ≥160 ms, RVOT preejection period ≥ 90 ms, preejection delay ≥65 ms, SLWMD ≥60 ms, LVGLS ≥-13%, SDI ≥9.8% and MR jet area ≥6 cm2 did not correlate well with CRT response (P > 0.05) [Table 4] and [Table 5].
Table 4: Correlation of demographic, clinical and electrocardiographic predictors with outcome

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Table 5: Correlation of echocardiographic predictors with outcome

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  Discussion Top


We studied 35 patients with a mean age of 61.51 ± 11.0 years, of which 24 (68.6%) were male and 11 (31.4%) were female. Similar mean age and male predominance were seen in other studies. In our study, CRT response was achieved in 25 patients (71.4%). This result is comparable to previous studies.[15],[16],[17],[18] The response to CRT, however, varies significantly among individuals, and different predictors of response to CRT have been proposed. Age, gender, and etiology of HF were not predictors of CRT response in our study, but previous studies have shown female gender and etiology to be predictors of CRT response.[16],[18] A significant correlation was demonstrated between the duration of HF for ≤3 years and CRT response. António et al.[19] showed HF symptoms for <12 months as an independent predictor of super-response to CRT suggesting that resynchronization could be more efficient in early HF. Consistent with the study by Shanks et al.,[18] our study showed patients with worse NYHA class and a higher baseline 6MWD had a better response to CRT and the presence of diabetes and hypertension were not predictors of response to CRT. Mohamed et al.[16] concluded that eGFR ≥90 ml/min/m2 was an independent predictor of CRT response, but this was not demonstrated in our study. Similar to the COMPANION trial,[20] our study also did not show any correlation of response with the type of CRT. Nawar et al.[21] found that a cut-off BNP value of 360 pg/ml predicted CRT response; we failed to find a similar correlation. In line with previous data,[22],[23],[24] the present study showed that the QRS duration has a major impact on the efficacy of CRT. Therefore, patients with QRS duration <130ms should not be considered for CRT implantation.

CRT responders showed a significant improvement in the indices of LV and RV dimensions. Mean LVEDV and mean LVESV improved on day 7 and day 180. Mean LVEDD and LVESD did not improve on day 7 but improved on day 180 among responders. However, the correlation was statistically insignificant; Shanks et al.[18] had similar results. Echocardiographic indices for LV function (mean LV dP/dT and LVEF) improved on day 7 and day 180 in responders but not in nonresponders. While LV dP/dT ≥650mmHg/s was not correlated with CRT response, patients with baseline LVEF ≥25% showed significantly better response. Marsan et al.[25] also demonstrated LVEF ≥25% as a predictor of CRT response. TDI ≥65ms, TAPSE ≥15mm, LVOT pre-ejection period ≥ 160ms, RVOT pre-ejection period ≥90ms, pre-ejection delay ≥65ms, SLWMD ≥60ms, and LVGLS ≥-13% were not significantly related to CRT response in our study. SPWMD ≥130 ms, an indicator of reverse remodeling after CRT, was found to be a predictor of CRT response implying its usefulness in identifying patients likely to benefit from biventricular pacing.[16],[26] SDI has a good accuracy to predict treatment response with a mean cut-off value of 9.8%.[27] In our study, the mean SDI reduced progressively on day 7 and day 180. However, SDI of 9.8% could not be correlated with response. Functional MR is reduced by CRT in patients with HF and LBBB. We assessed MR vena contracta and MR jet area in all patients at baseline and on follow-up. Mean MR jet area reduced on day 7 and day 180 but this could not be significantly correlated with response. Comparable results are found in other studies too.[16],[18] Pulmonary artery hypertension is correlated with poor clinical prognosis in patients with chronic HF, and patients with elevated PA pressure derive less benefit from CRT.[28] In our study, mean PA pressure reduced from baseline on day 7 and day 180. Patients with baseline mean PA pressure <50 mmHg showed a better response to CRT; this serves as an independent predictor for long-term prognosis.

One major limitation of our study was the relatively high level of interobserver and intraobserver variability in echocardiographic evaluation along with suboptimal imaging in patients with poor acoustic windows. This variability in image acquisition and time-consuming offline analysis currently acts as a major hurdle in translating this expert single-center experience to widespread use. In addition, logistical issues prevented us from performing a cardiac magnetic resonance imaging (MRI) in our patients prior to CRT device implantation. This would have enabled better placement of the LV lead by assessing the size, shape, and function of the left ventricle as well as the extent of LV dyssynchrony.


  Conclusions Top


CRT reduces the number of hospitalizations for HF and improves the NYHA Class in patients with a reduced LVEF and a wide QRS complex. We found that those with NYHA Class III–IV symptoms, duration of HF for ≤3 years and baseline 6MWD ≥240m had a better response to CRT. Hence, we strongly recommend that symptomatic HF patients should undergo CRT implantation to reduce the hospitalizations and symptoms related to HF, and those with NYHA Class III–IV symptoms should be offered CRT before the duration of HF exceeds 3 years.

Our study revealed that electrocardiographic and echocardiographic indices, such as QRS duration ≥150 ms, LV EF ≥25%, SPWMD ≥130 ms, and baseline mean PA pressure <50 mmHg are independent predictors of response to CRT at long-term follow-up. The current patient selection criteria in the existing studies, based on ECG, are insufficient to properly identify CRT responders and our study underscores the importance of the use of echocardiography along with BNP level monitoring to assess outcomes following therapy. The use of cardiac MRI, computed tomography, and nuclear imaging techniques to detect pathophysiological issues, including the extent and location of scar tissue, optimal LV lead position, and availability of coronary veins may also be important to consider before CRT.

Through this study, we hope to contribute toward the definition of a gold standard for the assessment of left ventricular dyssynchrony in patients undergoing CRT. Additional multicenter studies in larger cohorts are needed to explore the relative merits of the different techniques for the prediction of response to CRT. Since different parameters provide complementary information on ventricular dyssynchrony, we recommend a multiparametric echocardiographic approach for selecting patients likely to undergo reverse remodeling after CRT and predicting clinical outcome.

Ethics clearance

The study was carried out after obtaining clearance from the Institutional Ethics Committee.

Acknowledgments

Editorial assistance provided by Dr. Gauri Kadam.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Park MY, Altman RK, Orencole M, Kumar P, Parks KA, Heist KE, et al. Characteristics of responders to cardiac resynchronization therapy: The impact of echocardiographic left ventricular volume. Clin Cardiol 2012;35:777-80.  Back to cited text no. 13
    
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van Bommel RJ, Bax JJ, Abraham WT, Chung ES, Pires LA, Tavazzi L, et al. Characteristics of heart failure patients associated with good and poor response to cardiac resynchronization therapy: A PROSPECT (Predictors of Response to CRT) sub-analysis. Eur Heart J 2009;30:2470-7.  Back to cited text no. 14
    
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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