A Novel Risk Model of Mortality and Hospitalization of Cardiac Resynchronization Therapy in Patients with Non-ischemic Cardiomyopathy: the Alpha-score

Non-ischemic cardiomyopathy (NICM) has been associated with a better LV reverse remodeling response and better clinical outcomes after cardiac resynchronization therapy (CRT). The aims of our study were to identify the predictors of mortality and heart failure hospitalization in patients treated with CRT and design a risk score for prognosis. A cohort of 422 consecutive NICM patients with CRT was retrospectively enrolled between January 2010 and December 2017. The primary endpoint was all-cause mortality and the secondary endpoint was heart failure hospitalization.

2 Abstract Background Non-ischemic cardiomyopathy (NICM) has been associated with a better LV reverse remodeling response and better clinical outcomes after cardiac resynchronization therapy (CRT). The aims of our study were to identify the predictors of mortality and heart failure hospitalization in patients treated with CRT and design a risk score for prognosis.

Methods
A cohort of 422 consecutive NICM patients with CRT was retrospectively enrolled between January 2010 and December 2017. The primary endpoint was all-cause mortality and the secondary endpoint was heart failure hospitalization.

Results
In a multivariate analysis the predictors of all-cause death were left atrial diameter

Conclusion
The Alpha-score may enable better discrimination and accurate prediction of long-term outcomes among NICM patients with CRT. 3 Background Cardiac resynchronization therapy (CRT) improves cardiac function and decreases hospital admissions and mortality among patients with advanced heart failure and left ventricular dyssynchrony [1][2][3]. However, based on criteria derived from numerous large-sample randomized trials, approximately one-third of CRT recipients fail to achieve expected benefits from the device[4]. Since implantation of CRT is an invasive approach with a relative higher the economic burden, the application of a risk model for candidate stratification could be useful for optimal selection of patients and to identify eligible patients who are most likely to get the most benefic. Non-ischemic cardiomyopathy (NICM) is one of the major reasons of heart failure, especially in Asia[5, 6] Given that NICM patients had distinctive pathophysiology compared to ischemic patients, the predictors in NICM patients should be different from the published models, and weight of the values for similar predictors might be distinct [7]. Multiple studies have tried to combine various clinical and biomarker metrics into a risk score to predict the prognosis [8][9][10][11]. However, to our knowledge, there have not been a predictive risk model for long-term outcomes focused on NICM patients with CRT. Therefore, our study focused on (i) investigating the independent predictors of all-cause mortality and heart transplantation or heart failure in NICM patients treated with CRT; (ii) developing a new risk model for stratifying NICM CRT candidates; and (iii) assessing the performance of the new scores for all-cause mortality, heart transplantation and heart failure hospitalization.

Study population
We enrolled 459 consecutive patients with CRT in the Arrhythmia Center of Fuwai Hospital during January 2010 and December 2017.
Diagnosis of NICM patients was conducted according to classification by the cardiomyopathies criteria [12], defined as the presence of systolic dysfunction without a history of myocardial infarction and/or the absence of significant coronary artery disease documented on a coronary angiogram. Inclusion criteria were in accordance with guidelines for cardiac resynchronization and defibrillation [13]. All patients had already been on optimal medical therapy for at least 3 months before CRT implantation. Patients were excluded if they (1) were age <18 years, (2) were pregnant, (3) had prior pacemakers or implantable cardioverter defibrillator implantation, or (4) were lost to follow-up.
Ten candidates failed LV lead implantation; ten declined CRT implantation because of financial problems; three patients were excluded based on the exclusion criteria, and 14 patients were lost during follow-up. Finally, a total of 422 eligible NICM patients with CRT were enrolled. (Fig. 1) The Institutional Review Board of Fuwai Hospital approved the study, and all participants provided signed informed consent.

Device implantation
All patients were implanted with CRT-P or CRT-D according to contemporary clinical practice guidelines [13]. The leads of the left ventricle (LV) were inserted into a lateral or posterolateral coronary sinus branch through the subclavian route. The atrioventricular interval was optimized by programming the day after implantation. All participants 5 followed up with optimal programming and standard medications for heart failure after implantation.

Follow-up and study endpoints
All patients underwent regular follow-up via outpatient' clinical visits or telephone interviews. The primary endpoint of the study was all-cause mortality or heart transplantation. The second endpoint was HF hospitalization. In addition, if patients were hospitalized for HF more than once, only the first hospitalization counted. Two independent physicians who were blinded to the patients' clinical data evaluated the endpoints.

Statistical analysis
Statistical analyses were performed using SPSS version 23 (IBM Corp, Chicago, IL).
Continuous data are presented as the mean and standard deviation (SD), and categorical variables are presented as numbers and percentages. The Kolmogorov-Smirnov test was used to test the normality of the distribution of continuous variables. Student's t test, nonparametric equivalent tests and chi-square tests were used as appropriate. The Kaplan-Meier method was used to construct survival curve with log-rank test according different scores and risk groups. Adjusted hazard ratios were calculated by Cox regression analysis after correcting for differences in baseline characteristics. Variables with a bootstrapped P<0.05 were assigned a weighted point score based on their associated hazard ratio and a simple score was calculated by summing all the points. The optimal cutoff point was searched by identifying the Youden index point (sensitivity 1 specificity -1). Discrimination was assessed by the area under the receiver-operating characteristic curve (AUC) or c statistic to assess discrimination in receiver operating characteristic (ROC) curves. Calibration of the score was assessed by the Hosmer-Lemeshow test. The AUC can range from 0.5 (no discrimination) to 1.0 (perfect discrimination). Two-sided p 6 values <0.05 were considered statistically significant. Table 1  however, there were no significant statistical differences in age, gender, CRT type, or prevalence of atrial fibrillation at baseline between the two groups.

Independent predictors of the primary endpoint from the derivation dataset
In multivariable analysis ( Each predictor was assigned 1 point based on the categories and regression coefficients from the multiple Cox regression model.

Performance of the Alpha-score
As shown in Fig.2 and Fig.3, the risk of poor outcomes increased with the accumulation of risk factors. Kaplan-Meier survival estimates according to Alpha-score and different risk groups for primary endpoint and heart failure hospitalization. Notably, based on the Alphascore system, the rate of heart failure hospitalization among patients with higher scores was significantly higher than that among patients with lower scores.

What we found for our new score
This large observational study first derived a long-term prognosis model for NICM heart failure patients implanted with CRT. The Alpha-score was based on the largest retrospective cohort of Chinese NICM patients with CRT. The risk score performed well in predicting the long-term prognosis of NICM patients based on the clinical characteristics and biomarkers; it showed good predictive ability for both all-cause mortality and heart failure hospitalization within the derivation and validation datasets. In addition, a simple easy-to-use application was developed for clinical risk stratification before CRT implantation and long-term follow-up, which can calculate the score any time and any place.

The published scores
Over the past decades, prior risk models [9, 10, 14-16]performed with good calibration and accuracy in derivation cohorts or western validation cohorts; however, Asian populations, especially Chinese participants, are rarely used for validation [17]. VALID-CRT The prevalence of ischemic heart failure in CRT candidates was over 50% in most studies [1,7,9,10,18] conducted in North America and Europe. However, the situation in Asia is significantly different regarding the subtype of CRT candidates [19][20][21]. Based on the Japan Cardiac Device Treatment Registry (JCDTR) database [21], the proportion of non-ischemic cardiomyopathy was up to 70%. Based on our previous studies, patients with NICM were also common at a rate of above 60% in China. [6,22] Previous studies showed that patients with a non-ischemic etiology had a better prognosis than patients with an ischemic etiology. A possible mechanism might be the favorable reverse remodeling and replacement of the myocardial fibrosis scar burden in the LV lead tip area [23,24]. The different physiological mechanisms could lead to varied pathophysiology, differing clinical status and distinctive responses to device therapy between ischemic and non-ischemic cardiomyopathy. This was a negligible but significant reason for poor discrimination in many predictive models among CRT patients. The performance of risk models based on Western population might be modest in NICM patients with CRT; these scores are readily acceptable to clinicians based on common clinical risk factors, although it is suggested that recalibration based on different etiologies might improve the applicability of the scores for the NICM population.

Variables associated with the risk of all-cause mortality and heart failure exacerbation
The five identified baseline covariates in the Alpha-score are aligned with those identified in previous studies. Several earlier studies reported that inflammation and heart functional biomarkers were associated with heart failure outcomes. It is known that inflammation plays an important role in the pathogenesis and progression of heart failure[9, 25]. High sensitivity CRP (HsCRP), one of the circulating biomarkers of inflammation related to the severity of heart failure, is a sensitive predictor and is widely 9 used to evaluate clinical outcomes[9, 26, 27]. Chi Cai, et al [19] indicated that the elevated baseline HsCRP level was an independent predictor of adverse survival and increased HF hospitalization. In contrast, some studies [28] showed that baseline level of HsCRP was not associated with long-term outcomes, and the sample size of those studies is relatively small. Similarly, in our study, elevated NT-proBNP levels have been shown to be an independent predictor of HF progression and mortality, which is in line with several earlier studies [16,29,30] LBBB was traditionally a strong predictor of electrical LV discordance in numerous large trials[7, [31][32][33][34]. We have shown that non-LBBB patients who are CRT recipients tend to have poorer outcomes. Although the mechanism remains uncertain, the larger LA is associated with pulmonary hemodynamic alterations and LA dilatation dysfunction[7, [34][35][36][37]].

Limitations of our study
This study has some limitations. First, as it is an observational, retrospective study, the baseline characteristics were based on medical records from Fuwai Hospital, and we had no data on serial measurements of biomarkers and echocardiography parameters. Therefore, our findings may not provide model prediction values for the CRT response.
Second, the proportion of CRT-D patients in the validation dataset was relatively small, and the patient composition might limit the applicability of the Alpha-score to all CRT recipients. Third, data on final left ventricular lead location, cardiac magnetic resonance imaging for scar tissue and QRS duration after implantation were not collected prospectively. Finally, although the validation dataset was selected randomly in our cohort and determination was good, the potential clinical utility of the Alpha model for risk stratification requires a larger population and further investigation. Despite these limitations, this is the first and largest risk model for NICM patients with CRT in Asia. We believe that the Alpha-score could provide useful prognostic information on NICM among CRT recipients.    Abbreviations as Table 1 19 Figures Figure 1 A diagram to describe the flow of participants through the study.

Conclusions
20 Figure 2 Plot of Kaplan Meier estimates of survival free of primary endpoint according to Alpha-score and score-tertile. Comparison of area under the curve for Alpha-score of all-cause death and heart transplantation among overall 422 NICM patients with CRT.