Aortic stenosis (AS) is one of the most common valvular heart diseases, and its prevalence is rapidly increasing [1]. AS is a progressive disease, and the rapid progression of AS is associated with poor prognosis [2]. Currently, there is no available pharmacological therapy and aortic valve replacement (AVR) represents the only therapeutic strategy. AS progresses more rapidly in patients who require valve replacement in the future [3, 4, 5]. Studies showed the rapid progression of AS was one of the independent predictors for AVR, and those with rapid progression should undergo early AVR rather than when symptoms occur [2, 6]. An early AVR on asymptomatic severe patients was associated with a more significant reduction in mortality [7]. Echocardiogram plays a key role in AS, where the different echocardiographic parameters were used for AS diagnosis and prognostic stratification [8]. Many studies graded rapid progression according to the cutoff value of an annual increase of aortic jet velocity (Vmax) $\ge$0.3 m/s/year [2, 9]. Clinically, both the American College of Cardiology (ACC) and European Society of Cardiology (ESC) guidelines consider an annual Vmax increase $\ge$0.3 m/s/year as one of the indications for AVR (classes of recommendations: IIa, level of evidence: B–C) [4, 10, 11]. Identification of clinical predictors for rapid progression may allow for the secondary prevention.

Ventricular cardiomyocytes predominantly secrete B-type natriuretic peptide (BNP) in response to increased wall stress before the symptoms appear. Previous studies found that increased BNP level was related to poor prognosis in AS patients. Patients with higher BNP had more adverse events and more severe status [12, 13, 14]. However, little is known about the relationship between BNP and the progression rate of AS. Thus, the objective of our study was to assess the relationship between the baseline BNP and the AS progression rate.

The baseline clinical, laboratory, and echocardiographic characteristics of the population (n = 200) are presented in Table 1. The mean age was 66 $\pm$ 11 years, 52% were female, and the baseline Vmax was 3.47 $\pm$ 0.73 m/s. Patients with rapid progression were older, more likely to be male, had higher log BNP, and a higher percentage of diabetes. As shown in Table 2, as the log BNP tertiles increased from T1 to T3, patients became older, had a higher percentage of heart failure, lower LVEF, higher baseline Vmax, baseline MPG, more rapid progression of Vmax, and a lower percentage of BAV, dyslipidemia and statins intake.

During the median follow-up of 595 days, the overall median (interquartile) progression of Vmax was 0.26 (0.09–0.58) m/s/year and of MPG was 4.68 (1.22–9.36) mmHg/year. Patients in higher tertiles of log BNP had more rapid Vmax progression (p = 0.018) (Fig. 1). Similarly, considering the tertiles of the BNP ratio, patients in high tertiles progressed more rapidly (p = 0.033) (Fig. 1).

Fig. 1.

Comparison of annual Vmax progression across different tertiles BNP. (A) Log BNP. (B) BNP ratio. Vmax progression is expressed as median $\pm$ interquartile range.

In univariate linear regression analysis, log BNP was positively associated with Vmax progression ($\beta$ = 0.157, p = 0.009). However, this correlation was not significant in multivariate linear regression analysis (p = 0.062) (Table 3). BNP ratio was positively correlated with Vmax progression in univariate ($\beta$ = 0.014, p 0.001) and multivariate ($\beta$ = 0.012, p = 0.001) linear regression analyses (Table 4). In univariate binary logistic analysis, log BNP was associated with rapid progression of Vmax (OR = 1.839; 95% CI: 1.028–3.292, p = 0.040). After adjusting the covariates, this association was still significant (OR = 2.424; 95% CI: 1.108–5.307, p = 0.027) (Table 5). We further used BNP ratio to detect the association between BNP and rapid progression. We found higher BNP ratio was associated with rapid progression (OR = 1.112; 95% CI: 1.022–1.209, p = 0.013). In multivariate analysis, BNP ratio was the independent predictor for rapid progression (OR = 1.134; 95% CI: 1.020–1.261, p = 0.020) (Table 6). Further subgroup analysis was performed according to BAV. BNP ratio was significantly associated with rapid progression of AS in BAV patients (OR = 1.329, 95% CI: 1.021–1.731, p = 0.034). However, after excluding BAV, this association was not significant (OR = 1.074, 95% CI: 0.989–1.166, p = 0.092). There was no significant interaction between the presence and absence of BAV (p for interaction = 0.130).

The present study showed the quantitative association between BNP at first echocardiogram and AS progression, emphasizing the significance of BNP in predicting AS progression. Higher BNP was the independent predictor for the rapid progression of AS.

BNP is a hormone released from the myocardium under increased wall stress in the setting of volume expansion and pressure overload. BNP is a globally acceptable biomarker for heart failure and is elevated in patients with AS. Using BNP could be viewed as a surrogate marker of disease progression as it correlates with functional status, symptom onset, and disease severity in AS patients. BNP was associated with left ventricular (LV) diastolic function [16], LV end-systolic wall stress [17], and LV hypertrophy [18], suggesting that the higher BNP could cause symptoms and poor prognosis. AS was associated with cardiac remodeling in response to pressure overload, which was reflected by different geometric ventricular patterns. AS patients were more likely to have concentric hypertrophy. Symptomatic AS patients had significantly more percentage of mixed hypertrophy than asymptomatic patients, underlying the potential association between cardiac remodeling and prognosis [19]. A cross-sectional study showed symptomatic patients had significantly higher BNP [14]. Asymptomatic patients who developed symptoms during follow-up had higher BNP levels compared with those who remained asymptomatic [20]. Higher annualized BNP progression could be a sign of the progressive exhaustion of LV adaption to the increased afterload, which precedes the occurrence of symptoms [21]. Previous study has shown that BNP level is positively correlated with Vmax and MPG, and negatively correlated with aortic valve area [14]. The progression of AS could affect the cardiac remodeling (e.g., hypertrophy), which could secondarily enhance the secretion of BNP. Therefore, higher BNP may be an indication of AS progression.

BNP could predict the prognosis of AS patients [20]. A higher BNP was associated with an increased risk of adverse outcomes in asymptomatic severe AS patients with normal LVEF who were not referred for AVR [13]. Moreover, a higher annualized BNP increase in asymptomatic patients without AVR was related to a higher rate of adverse cardiac events [21]. The relationship between pre-procedural high BNP levels and worse outcomes after AVR has been demonstrated in several studies [12, 20]. Higher BNP before TAVR was associated with an increased risk for adverse events [12, 22]. Preoperative BNP could predict death after surgical aortic valve replacement, which is even more accurate than logistic EuroSCORE [20]. An elevated BNP level on arrival in intensive care unit is an independent predictor of postoperative heart failure after AVR [23]. Sato showed TAVR could gradually decrease the BNP in AS patients during follow-up, coinciding with cardiac structure and function recovery. A subsequent increase of BNP after TAVR was associated with higher mortality [24]. Aortic balloon valvuloplasty in severe AS patients could decrease the BNP level [25]. Additionally, BNP 24h post-procedure could predict the 1-year mortality after TAVR [26].

Besides the rapid progression of Vmax, higher BNP is one of the indications for AVR. Patients with higher BNP were more likely to undergo intervention during follow-up [20]. According to the ESC guideline for valvular disease, marked BNP elevation in asymptomatic severe AS patients with normal LVEF was an indication for AVR [11]. In ACC guideline, AVR is reasonable when BNP $>$3 times normal in asymptomatic severe AS patients [10]. Our investigation supported the importance of BNP and rapid Vmax progression in AVR indications since both were linked with the poor outcome.

BNP level is higher in older people and women than in younger people and men [27]. In fact, using age- and sex- specific BNP levels can improve the diagnostic accuracy [28]. BNP ratio, the ratio of measured BNP to BNP reference values for a specific age and sex, can reflect the state of BNP activation and cardiac function. A higher BNP ratio was shown to be associated with higher mortality in AS [29]. Consistent with the log BNP, we showed BNP ratio was also associated with rapid progression of AS, strengthening its role in AS prediction.

The data set was confined to the Chinese population, implying that ethnic distinctions cannot be eliminated. Second, we used baseline BNP levels and could not assess the effect of temporal variations on the link with AS progression. Third, the aortic valve area was not included in this study since it was not frequently assessed in our center. Fourth, chronic kidney disease (CKD) could affect the level of BNP [30], but in this study we adjusted creatinine (as indicator of CKD) in the multivariate analyses. Fifth, because of retrospective nature of our study which mainly included outpatients, we failed to obtain all patients’ weight and height, and therefore body mass index could not be calculated. Sixth, we did not use cardiac remodeling parameters to further detect the association between BNP and AS.

In this study, we showed a significant and independent association between BNP and the rapid advancement of AS. Patients with higher BNP were more likely to have a rapid progression, which may have a prognostic role in clinical decision. Additional prospective studies are required to corroborate our findings.

Conceptualization—KH, XM and YZ; methodology—KH, MX and XM; software—KH and XM; validation—DS and LY; formal analysis—KH; investigation—KH; resources—XM and YZ; data curation—XM and YZ; writing—original draft preparation—KH; writing—review and editing—ZW, FG, XM and YZ; visualization—KH; supervision—YZ; project administration—YZ; funding acquisition—XM and YZ. All authors have read and agreed to the published version of the manuscript.

Not applicable.

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This work was supported by National Key Research and Development Program of China (2017YFC0908800), China Postdoctoral Science Foundation (2021M692253), Beijing Postdoctoral Research Foundation (2021-ZZ-023), and Beijing Municipal Administration of Hospitals Mission Plan (SML20180601).

The authors declare no conflict of interest.