Fragmented QRS is associated with intraventricular dyssynchrony and independently predicts nonresponse to cardiac resynchronization therapy—Systematic review and meta‐analysis

Abstract Background Fragmented QRS (fQRS) is postulated to be associated with ventricular dyssynchrony and might be able to predict a nonresponse to cardiac resynchronization therapy (CRT) implantation. In this systematic review and meta‐analysis, we aim to assess whether fQRS can be a marker of intraventricular dyssynchronies in patients with ischemic and nonischemic cardiomyopathy and whether it is an independent predictor of nonresponse in patients receiving CRT. Methods We performed a comprehensive search on topics that assesses fQRS and its association with intraventricular dyssynchrony and nonresponse to CRT up until September 2019. Results Fragmented QRS is associated with intraventricular dyssynchrony (OR 10.34 [3.39, 31.54], p < .001; I 2: 80% with sensitivity 76.8%, specificity 77%, LR+ 3.3, and LR− 0.3). Subgroup analysis showed that fQRS is associated with intraventricular dyssynchrony in patients with narrow QRS complex (OR 20.92 [12.24, 35.73], p < .001; I 2: 0%) and nonischemic cardiomyopathy (OR of 19.97 [12.12, 32.92], p < .001; I 2: 0%). Fragmented QRS was also associated with a higher time‐to‐peak myocardial sustained systolic (Ts‐SD) (OR 15.19 [12.58, 17.80], p < .001; I 2: 0% and positive Yu index (OR 15.61 [9.07, 26.86], p < .001; I 2: 0%). Fragmented QRS has a pooled adjusted OR of OR of 1.70 [1.35, 2.14], p < .001; I 2: 62% for association with a nonresponse to CRT. QRS duration is found to be higher in nonresponders group mean difference −8.54 [−13.38, −3.70], p < .001; I 2: 70%. Conclusion Fragmented QRS is associated with intraventricular dyssynchrony and is independently associated with nonresponse to cardiac resynchronization therapy.


| INTRODUC TI ON
Fragmented QRS (fQRS) is often caused by myocardial scarring with consequent heterogeneous ventricular activation and dyssynchronous contraction of the ventricles. (Basaran et al., 2011) Several studies have shown that fQRS is commonly generated after myocardial infarction and reflects the varying conduction abnormalities and the delay of peri-infarct area conductions due to myocardial necrosis or scarring. Fragmented QRS has been shown to appear 24-48 hr after onset of ACS symptoms. (Das, Khan, Jacob, Kumar, & Mahenthiran, 2006) It has been previously shown that increased fragmentation of QRS wave was associated with previous myocardial infarction, ventricular enlargement, and decreased LVEF. (Sha et al., 2011).
Cardiac resynchronization therapy (CRT) is an integral mode of intervention in patients with heart failure (HF) with reduced ejection fraction and was associated with reduced morbidity and mortality in appropriate patients. (Ponikowski et al., 2016;Yancy et al., 2017) Usually these patients have wide QRS, and the guidelines also adhere to the QRS duration. However, studies have shown that up to 50% of patients with HF and normal QRS duration has mechanical ventricular dyssynchrony, and these patients may benefit from CRT (Dohi, Suffoletto, Murali, Bazaz, & Gorcsan, 2005;Yu et al., 2006). There is the need for other methods of assessment other than QRS duration, although whether the benefit of CRT in normal QRS duration with dyssynchrony is not the scope of our study. Nonresponsiveness to CRT is also problematic; approximately 30% of those implanted with CRT did not respond well to the treatment (Bax et al., 2004;Yu et al., 2005). This leads to a costly procedure without apparent benefit and increased risk of other complications related to CRT.
Fragmented QRS is postulated to be one of the markers to fill these gaps in selective patients; it was thought to be associated with ventricular dyssynchrony and might be able to predict a nonresponse to CRT implantation. In this systematic review and meta-analysis, we aim to assess (a) fQRS as a marker of intraventricular dyssynchronies in patients with ischemic and nonischemic cardiomyopathy and (b) whether fQRS is an independent predictor of nonresponse in patients receiving CRT.

| Search strategy
We performed a comprehensive search on topics that assesses fQRS and its association with intraventricular dyssynchrony and nonresponse to CRT with keywords ("fragmented QRS" and "dyssynchrony" OR "cardiac resynchronization therapy") and its synonym from inception up until September 2019 through PubMed, Europe PMC, Cochrane Central Database, and hand sampling from potential articles cited by other studies. The records were then F I G U R E 1 Study flow diagram systematically evaluated using inclusion and exclusion criteria. We also perform hand sampling from references of the included studies.

| Selection criteria
The inclusion criteria for this study are all studies that assess fQRS, intraventricular dyssynchrony, and nonresponse to CRT. We include all related clinical researches/original articles and exclude case reports, review articles, and non-English language articles.

| Data extraction
Data extraction and quality assessment were done by two independent authors (E.Y and R.P) using standardized extraction form which includes authors, year of publication, study design, subject characteristics, study definition of dyssynchrony and nonresponse to CRT, sample size, QRS duration, prevalence of fQRS, and followup duration.

| Statistical analysis
To perform the meta-analysis, we used RevMan version 5.3 software (Cochrane Collaboration) and STATA/MP 14 (StataCorp LLC).
We used the odds ratio (OR) and a 95% CI as a pooled measure for dichotomous data. We used mean difference and its standard deviation (SD) as a pooled measure for the continuous data.
Inconsistency index (I 2 ) test, which ranges from 0% to 100%, was used to assess heterogeneity across studies. A value above 50% or p < .05 indicates statistically significant heterogeneity. We used the Mantel-Haenzsel or inverse variance (for adjusted OR) method for OR and inverse variance for mean difference with a fixed-effect model for meta-analysis, and a random-effect model was used in case of heterogeneity if appropriate. All p values were two-tailed with a statistical significance set at .05 or below. We also perform sensitivity analysis and subgroup analysis whenever possible/appropriate.

| RE SULTS
We found a total of 3,049 results on the initial search. There were 3,021 records after removal of duplicates. A total of 3,011 records were excluded after screening the title/abstracts. After assessing ten full texts for eligibility, we excluded two because of no control group. We included eight studies in qualitative synthesis and seven studies meta-analysis (Celikyurt et al., 2013(Celikyurt et al., , 2012Hu et al., 2019;Rad et al., 2015;Sinha et al., 2016;Tigen et al., 2009;Yusuf et al., 2013;Zhao et al., 2015) (Figure 1). One study was excluded from meta-analysis because it has different definition of nonresponder outcome that being "Cardiac death, heart transplantation, or HF hospitalization." Four studies were prospective cohorts, three were cross-sectional, and one was retrospective cohort. There were a total of 864 subjects from eight studies. (Table 1).  Fragmented QRS was also associated with a higher time-to-peak myocardial sustained systolic and its standard deviation (Ts-SD) (OR 15.19 [12.58,17.80], p < .001; I 2 : 0%, p = 1) and positive Yu index (OR 15.61 [9.07,26.86], p < .001; I 2 : 0%, p = .46).

TA B L E 1 Studies included in the systematic review
We found this finding to be in accordance with the findings in this meta-analysis, in the terms that patients with fragmented QRS were over 20 times more likely to suffer from intraventricular asynchrony.
The findings of our analysis on the relation of fragmented QRS with CRT responders were supported by Varma (2009. It is shown in this study that the significance of fragmented QRS as a predictor of CRT responders stems from the findings that LV conduction delays and LV conductivity in patients with heart failure varied significantly with QRS configuration. It is found that LV conduction delays exceeding 100 ms were only found in 23% patients with narrow QRS configuration. The authors stated that these variations might affect CRT efficacy in patients with widened QRS configuration (Varma, 2009). Fragmented QRS causes heterogeneous ventricular activation along with dyssynchrony in patients with ischemic and non-ischemic cardiomyopathy, possibly impeding the efficacy of pacemaker (Basaran et al., 2011;Das et al., 2008). A higher number of leads with fQRS predict a nonresponse to CRT (Celikyurt et al., 2013). There are several factors such as left ventricular end-diastolic diameter that may also affect nonresponsiveness to CRT; however, our meta-analysis showed that the fragmented QRS is independent to other factors considered/found in the respective studies. In a study by Takenaka et al. (2019, QRS widening

TA B L E 1 (Continued)
The clinical implication of this study is that fQRS can be used as a marker for intraventricular dyssynchrony for both narrow and wide QRS complex. This may potentially identify patients that will benefit from CRT, although more study is needed. Fragmented QRS was also a predictor of nonresponse in patients receiving CRT; this interpretation is limited to those with wide QRS complex. Combined with other predictors, a scoring system can be developed to better identify patients that at risk of failing to receive benefits from CRT implantation. Hence, unnecessary CRT implantation can be avoided. The interpretation of fQRS, however, was known to have a poor inter-and intra-observer variability in patients with cardiomyopathy according to a study (Vandenberk et al., 2018).
Limitation of this systematic review and meta-analysis includes publication bias in which studies with positive results were more likely to be published and included in this systematic review. The pooled sample size is relatively small, and the definition of intraventricular dyssynchrony and nonresponse to CRT varied between studies. Future studies can address the issues of CRT implantation in those with fQRS and narrow QRS complex; the studies in this meta-analysis only address that fQRS is associated with intraventricular dyssynchrony but not whether they will benefit from CRT F I G U R E 2 Fragmented QRS and intraventricular dyssynchrony. Fragmented QRS was associated with intraventricular dyssynchrony (a) and has sensitivity 76.8% and specificity 77% (b). Fragmented QRS was associated with intraventricular dyssynchrony upon subgroup analysis on patients with narrow QRS complex (c) and nonischemic cardiomyopathy (d