Hypertrophic cardiomyopathy (HCM) is characterized by increased thickness of the left ventricular wall that cannot be explained by abnormal loading conditions (such as hypertension or valvular disease) [1]. Most patients remain asymptomatic or mildly symptomatic throughout their lives, while others have dyspnea, exercise intolerance, chest pain, palpitations, presyncope, and syncope [2, 3]. Clinically, HCM can be classified into 3 types-obstructive, nonobstructive and liable obstructive based on echocardiographic measurement of the difference in peak pressure step between the left ventricular outflow tract (LVOT) gradient [1, 4]. Hypertrophic obstructive cardiomyopathy (HOCM), defined as a maximal LVOT gradient greater than or equal to 30 mmHg at rest or with provocation, is present in approximately two-thirds of patients with HCM [2].

Previous studies have shown that HOCM is an independent predictor of poor prognosis in patients with HCM [5, 6]. However, LVOT obstruction has some unique limitations as a potential risk indicator for sudden cardiac death (SCD), since HCM gradients are dynamic and can be influenced by a variety of environmental factors and routine activities; furthermore, data on the effect of LVOT gradient on the incidence of SCD in HCM patients are rather conflicting [7, 8]. It has also been reported that hypertrophic nonobstructive cardiomyopathy (HNCM) is not always considered to be at low risk [2]. The purpose of this study was to explore the clinical prognosis of HOCM patients through a multicenter cohort study with data-driven propensity score matching (PSM) analysis.

In the present study, we found that the LVOT gradient had no effect on HCM prognosis either before or after matching by data-driven PSM analysis in a multicenter cohort study. Additionally, subgroup analyses showed that HOCM was not significant in all subgroups of all-cause mortality, cardiovascular mortality/cardiac transplantation and SCD.

HOCM occurs in up to 70% of HCM patients and is associated with pernicious events and has been considered a marker of poor prognosis [6, 12]. LVOT obstruction is reported to be associated with symptom progression and increased mortality in HCM patients and is an independent predictor of adverse outcomes, arrhythmias, and SCD [1, 5, 13]. However, the incidence of cardiovascular mortality/cardiac transplantation and SCD in patients with HOCM varies between studies [2, 14]. The long-term prognosis of HOCM has been shown to be similar to that of the general population [4]. Furthermore, Pozios et al. [2] found that HNCM patients had 4 times more ventricular tachycardia/ventricular fibrillation episodes than labile-obstructive patients and 3 times more ventricular tachycardia/ventricular fibrillation episodes than HOCM patients. Moreover, ICD discharges were also more frequent in the HNCM subgroups [2]. Similarly, in the present study, ICD implantation was more common in HNCM patients. In addition, another study revealed that only 30% of HCM-related deaths were associated with LVOT obstruction [15]. In patients with HCM with a benign presentation and without risk factors, only 29% with SCD had LVOT obstruction [16]. Therefore, LVOT obstruction alone may not always confer high risk and thus is not considered to be one of the traditional risk factors for SCD [3].

In the present study, to better study the effect of LVOT gradient on the prognosis of HCM, we excluded those patients who were undergoing ASA and SM surgery. Furthermore, a data-driven PSM analysis was performed to adjust for potential confounders from other baseline variables between HOCM and HNCM. And subgroup analysis was performed to study whether HOCM was significant in different clinical factors subsets. The result showed that there were no significant differences in the prognosis of HOCM and HNCM in the logit-matched cohorts, and LVOT obstruction had no impact on the prognosis of HCM. Also, HOCM was not significant in different subsets for all-cause mortality, cardiovascular mortality/cardiac transplantation and SCD. In the Cox-matched cohorts, there was a significant difference in all-cause mortality between HOCM and HNCM, which was in contrast to the pre-matched and logit-matched results. We consider it possible that Cox matching did not match all indicators, so the results may not be reliable. We recommend using the logit-matched method, for which the logit-matched method outperforms the conventional Cox-matched method in terms of successfully matching proportions.

Moreover, LVOT obstruction had no effect on HCM prognosis in the present study. Considering that this study is a retrospective, another reason may be that people with HOCM are more cautious and keep in mind the advice of their physicians to avoid sudden heavy work, which is often a precursor to SCD [17, 18]. On the other hand, HCM gradients are dynamic, spontaneous changes that can be influenced by a variety of environmental factors and daily activities [18]. Additionally, the contribution of LVOT obstruction to risk stratification is considered to be limited due to the low annual rate of SCD and the particularly low positive predictive value of obstruction [19]. Finally, studies have shown that the prognosis of patients with HOCM after clinical treatment was not different from that of age- and sex-matched populations [4, 20].

Historically, cardiomyopathy was the main cause of SCD in young people under 35 years of age [21]. And HCM has been reported to be one of the most common causes of SCD in young children and adults, the annual incidence of SCD in children, adolescents or young adults was 2% and in adults it was 0.5–1.5% [1, 22]. And HOCM was associated with an increased risk of SCD and heart failure [1]. However, most studies have failed to show an association between LVOT gradient and poor prognosis, and only two large studies have shown a slightly increased risk of SCD in patients with a resting gradient $\ge$30 mmHg [23]. Therefore, the effect of LVOT obstruction on the risk of SCD has been debatable [24, 25, 26], as some HNCM patients produce significant changes in the LVOT gradient even when regular daily activity is performed [7, 27]. The unique ability of patients with HCM to transition briefly from an obstructive to a nonobstructive state alters the full significance of this risk factor in some patients [25]. While the prognostic role of exercise-induced LVOT obstruction is uncertain, it is currently not included in the calculator of SCD risk scores [24]. Therefore, the 2011 American College of Cardiology Foundation/American Heart Association (ACCF/AHA) HCM guidelines only identify LVOT obstruction as a potential moderator of SCD risk and include it in borderline cases [28]. It was not until the 2014 European Society of Cardiology (ESC) HCM guidelines identified LVOT obstruction as the most important clinical feature for increased risk of SCD [11].

There are some limitations in the present study. First, this is a multicenter retrospective study, and the patients included in the study were from 13 tertiary centers, so there may be some heterogeneity among the different hospitals. Second, in the present study we were focusing on the impact of LVOT on HCM mortality, and considering that surgery would change the primary LVOT obstruction of patients, so we excluded patients who underwent ASA and SM. Third, not all patients had a Valsalva maneuver, so there may be liable-obstruction diagnosed as non-obstruction. Fourth, as shown in the ESC HCM risk-SCD calculator, not only the presence or absence of LVOT gradient but also its degree is associated with prognosis. Unfortunately, there were too many missing data of LVOT gradient in the present study, so we did not make further analysis. Finally, the medications were only recorded during the in-hospital treatment of the patients, and no follow-up data were recorded, which we did not further analyzed in the present study.

In the present multicenter cohort study, there were no significant differences in all-cause mortality, cardiovascular mortality/cardiac transplantation or SCD between HOCM and HNCM before and after matching analysis, and according to the Cox proportional hazard regression model, LVOT obstruction was not an independent risk predictor of HCM.

All data generated or analyzed during this study are included in this published article.

YH, HM, NS, SZ were responsible for patient follow-up and compiled the data. NS, SZ, YZ, YS, WH and TZ conceived and designed the study, revised manuscript critically for important intellectual content. YH, HM, LZ and XL designed the manuscript content and wrote the manuscript. YH and HM contributed equally to this work, LZ and XL took full responsibility for its content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Ethic number: 2022 No 424. Informed consent was obtained from all individual participants included in the study.

The authors would like to thank the following hospitals for the multicenter data:

The First Affiliated Hospital of Chengdu Medical; The Second Affiliated Hospital of Chengdu Medical College & Nuclear Industry 416 Hospital; The Third Affiliated Hospital of Chengdu Medical & Pidu District People’s Hospital; Mianyang Central Hospital; Sichuan Mianyang 404 Hospital; The Third People’s Hospital of Chengdu; Hospital of Chengdu University of TCM & TCM Hospital of Sichuan Province; Xichang People’s Hospital; The First Affiliated Hospital of Chongqing Medical University; The Second Affiliated Hospital of Chongqing Medical University; The Affiliated Hospital of Southwest Medical University and so on.

This work was supported by National Natural Science Foundation of China (No. 32171182), Zhong Nanshan Medical Foundation of Guangdong Province (No. ZNSA-2020017).

The authors declare no conflict of interest. Prof. Xiaoping Li has received one research grant from Zhong Nanshan Medical Foundation of Guangdong Province (No. ZNSA-2020017). Prof. Rong Luo has received one research grant from the National Natural Science Foundation of China (No. 32171182).