Importance of the new score
This large, observational study first derived a long-term prognosis model for NICM HF 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 clinical characteristics and biomarkers; it showed a good predictive ability for both all-cause mortality and HF hospitalization within the derivation and validation datasets. The Alpha score, as a simple and easy-to-use score, could be used for clinical risk stratification before CRT implantation and long-term follow-up.
The published scores
Over the past decades, prior risk models [9, 10, 14-16] were derived 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 [11]and sex category, renal function, ECG/QRS width, ejection fraction, and NYHA class (ScREEN) [8] scores were derived and validated in European multicenter studies, and ejection fraction, atrial fibrillation, age, renal function, and NYHA class (EARRN) [10] does not have a validation population.
The prevalence of ischemic HF in CRT candidates was greater than 50% in most studies [1, 7, 9, 10, 18] conducted in North America and Europe. However, the situation in Asia is significantly different with regards to the subtype of CRT candidates[19-21]. Based on the Japan Cardiac Device Treatment Registry (JCDTR) database [21], the proportion of HF patients with NICM is as great as 70%. Based on our previous studies, patients with NICM were also common (>60%)in China [6, 22].
Studies have shown that patients with a non-ischemic etiology have a better prognosis than patients with an ischemic etiology. With a lower myocardial fibrosis scar fibrosis scar burden, NICM has the favorable reverse remodeling rather than ICM, which may be a possible mechanism.[23, 24]. Thus, various physiological mechanisms may lead to different pathophysiology, clinical status, and response to device therapy. The distinct physiological mechanisms between NICM and ICM could lead to different pathophysiology, clinical status and responses to device therapy. This was a negligible but significant reason for poor discrimination in many of the predictive models among CRT patients. The performance of risk models based on the Western population might be modest in NICM patients with CRT; These scores are readily available to clinicians as they are 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 HF outcomes. It is known that inflammation plays an important role in the pathogenesis and progression of heart failure [9, 25]. HsCRP, one of the circulating biomarkers of inflammation related to the severity of heart failure, is a sensitive predictor and is widely used to evaluate clinical outcomes [9, 26, 27]. Chi Cai, et al [19] indicated that an elevated baseline level of HsCRP level was an independent predictor of adverse survival and increased HF hospitalization. In contrast, other studies [28], with relatively small sample sizes, have shown that baseline levels of HsCRP were not associated with long-term outcomes, and the sample size of those studies is relatively small.
As a marker of ventricle dysfunction, the plasma NT pro-BNP level is a comprehensive index of cardiac function with high sensitivity and specificity. Similarly, in our study, elevated NT pro-BNP levels were an independent predictor of HF progression and mortality, which is consistent with several earlier studies [16, 29, 30].
The LBBB was traditionally a strong predictor of electrical LV discordance in numerous large trials [7, 31-34]. Our results are consistent with the findings of the MADIT-CRT[7], RAFT[35], and REVERSERS[36] trials, which have been shown that non-LBBB patients have an increased rate of mortality due to CRT compared to that in those with LBBBs. A meta-analysis of the major CRT trials also confirmed that a greater benefit from the devices was found when a LBBB morphology was present in patients who underwent CRT, which is strongly recommended for symptomatic HF patients in current guidelines.
The LA, as a reservoir for blood and a contractile chamber, important in LV filling, plays small but significant role in circulation. The size of the LA has been suggested as an independent factor for adverse cardiovascular events in multiple previous studies, especially among HF patients[37-39]. When atrial fibrillation occurs, patients who have undergone CRT not only lose approximately 25% of diastolic blood filling but also suffer from decreased biventricular pacing due to the rapid atrial rate and variability of atrioventricular conduction time. Some studies believe that the duration of atrial fibrillation, rather than atrial fibrillation itself, is associated with prognosis[31, 40]. In our study, atrial fibrillation included paroxysmal atrial fibrillation and persistent atrial fibrillation. In this study, considering these factors, atrial size is a more reliable indicator of LA function. Although the mechanism remains uncertain, the larger LA size is associated with pulmonary hemodynamic alterations and LA dilatation dysfunction [7, 34, 39, 41, 42].
Some studies suggest that patient characteristics, such as severity of mitral insufficiency, renal failure, baseline LVEF and age, are risk factors for poor prognosis in patients receiving CRT[9, 16, 42]. However, there is not enough data to prove that these variables are independent predictors in NICM patients.
Limitations of our study
This study has some limitations. First, as it is an observational, retrospective study. The baseline characteristics were retrieved from Fuwai Hospital’s medical records, and we had no data on serial measurements of biomarkers and ECG parameters. Therefore, our results 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 in all CRT recipients. Third, data on the final LV 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.