Abstract Body (Do not enter title and authors here): Introduction:
Hypertrophic cardiomyopathy (HCM) often causes major adverse cardiovascular events (MACE) and worsening heart failure (WHF). Endothelial cell (EC) dysfunction is known to occur in patients with HCM. However, the prognostic value of proteins related to EC function in HCM is unknown. The present study aimed to test the hypothesis that the levels of plasma proteins related to EC function predict future MACE and WHF in patients with HCM.

Methods:
In this multicenter prospective cohort study of patients with HCM, we measured plasma levels of 90 proteins related to EC function upon enrollment. The primary outcome measure was MACE, defined as the composite of sudden cardiac death, death due to HF, heart transplant, HF hospitalization, any increase of New York Heart Association (NYHA) class, new-onset atrial fibrillation, and stroke. The secondary outcome measure was WHF, defined as increase in NYHA class or HF hospitalization. We developed EC protein-based LASSO classification models to predict MACE or WHF using data from one institution (training set). We tested the predictive ability in independent samples from the other institution (test set) and performed time-to-event analyses.

Results:
The study included 722 patients (n=458 in the training set and n=264 in the test set). During the median follow-up period of 3.3 years, the outcome event of MACE occurred in 192 (27%) patients and WHF in 139 (19%) patients. The area under the receiver-operating-characteristics curve to predict MACE was 0.71 (95% confidence interval [CI] 0.64-0.77. Figure 1a) and that for WHF was 0.69 (95% CI 0.61-0.77. Figure 1b). When we divided the test set into high- and low-risk groups according to the predicted probabilities derived from the training set, log-rank tests and Cox proportional hazards models revealed that the high-risk groups had significantly higher risks of developing MACE and WHF (log-rank P<0.001, HR 2.45 [95% CI 1.47-4.10], P=0.0006. Figure 2) and WHF (log-rank P<0.001, HR 2.62 [95% CI 1.52-4.54], P=0.0006. Figure 3) compared with the low-risk groups.

Conclusions:
The present multicenter prospective study demonstrated that plasma proteins related to EC function predict MACE and WHF in patients with HCM. These EC-related proteins have a potential to become novel biomarkers for risk stratification in HCM to improve current prediction models.