Correlations between cardiac troponin I and nonsustained ventricular tachycardia in hypertrophic obstructive cardiomyopathy

Abstract Background Nonsustained ventricular tachycardia (NSVT) is an independent risk factor for sudden cardiac death (SCD) in patients with hypertrophic obstructive cardiomyopathy (HOCM). However, data concerning the correlations of cardiac biomarkers and NSVT in HOCM are rather limited. Hypothesis Our study aimed to investigate the associations between the occurrence of NSVT and circulating biomarkers representing myocardial injury (cardiac troponin I, cTnI), cardiac function (N‐terminal pro‐brain natriuretic peptide, NT‐pro BNP), and inflammation (high‐sensitivity C‐reactive protein) in a large Chinese HOCM cohort. Methods A total of 755 consecutive HOCM patients were recruited. Systematic cardiac evaluations and circulating biomarkers were examined routinely in all subjects under the clinically stable status. According to the results of 24‐hour Holter monitoring, patients were divided into the NSVT group (n = 138) and the nonventricular tachycardia (non‐VT) group (n = 617). Results Compared with the non‐VT group, circulating levels of both cTnI and NT‐pro BNP elevated significantly in patients with positive NSVT episodes (P < .001). Multivariable analyses demonstrated that cTnI was independently associated with the presence of NSVT (OR = 1.675, 95% CI: 1.406‐1.994, P < .001). Concentrations of cTnI increased progressively not only with the aggravation of ventricular arrhythmic events (P < .001), but also with the growing risk of SCD in HOCM patients (P < .001). Serum cTnI ≥ 0.0265 ng/mL indicated predictive value for the occurrence of NSVT in the HOCM cohort (area under the curve = 0.707, 95% CI: 0.660‐0.754, P < .001). Conclusions Elevated cTnI was an independent determinant of NSVT, and it seemed to be valuable for assessing the clinical status of ventricular arrhythmias and the risk of SCD in patients with HOCM.


| INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is the most common inheritable cardiovascular disorder, with an estimated prevalence of 0.2% in the general population. 1 It is mainly caused by mutations in genes encoding for sarcomeres, and confers a nearly 1% annual mortality rate 2 linked to the complications of progressive heart failure, embolic stroke, and sudden death. Asymmetric septal hypertrophy constitutes the majority of HCM phenotypes, and approximately 70% of patients suffer from the associated obstruction of the left ventricular outflow tract (LVOT), 3 referred to as hypertrophic obstructive cardiomyopathy (HOCM).
HCM is an important cause of sudden cardiac death (SCD), especially in young individuals. [4][5][6] The European Society of Cardiology (ESC) 2014 guideline on HCM has suggested an easily applicable risk prediction model for estimating the 5-year risk of SCD in HCM patients. 7 Nonsustained ventricular tachycardia (NSVT) is demonstrated as an independent risk factor for SCD and has been included in the current HCM risk-SCD scoring model. As a common arrhythmia in HCM, the detection rate of NSVT is approximately 20% to 35% using 24-to 48-hour Holter monitoring. 8,9 The presence of NSVT episode, independent of its frequency, duration, or rate, carries a 2.8 relative risk of SCD compared to subjects without NSVT. 8 It has been reported that the prevalence of NSVT in HCM patients increases with age 8,10 and correlates with left atrial size and left ventricular (LV) wall thickness on transthoracic echocardiography (TTE), 8,10 global longitudinal peak strain, LV twist deformation and mechanical dispersion on speckle tracking echocardiography, 11,12 both the presence and extent of late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR), 13,14 as well as high heterogeneity of myocardial blood flow detected by positron emission tomography. 15 However, there is a paucity of data on clinically accessible biomarkers and their potential prognostic values for NSVT in the setting of HOCM.
LVOT obstruction is a hallmark of more severe symptoms and worse prognosis in patients with HCM. 16,17 Previous studies indicated that circulating biomarkers representing myocardial injury (cardiac troponin I, cTnI), cardiac function (N-terminal pro-brain natriuretic peptide, NT-pro BNP), and inflammation (high sensitivity C-reactive protein, hs-CRP) played important roles in predicting adverse outcomes in HCM patients. [18][19][20] Whether these cardiac biomarkers are relevant to ventricular arrhythmias (particularly to the occurrence of NSVT) in patients with LVOT obstruction remains unresolved. Therefore, in this study, we attempt to explore and clarify the correlations between the presence of NSVT and circulating biomarkers of cTnI, NT-pro BNP, and hs-CRP in a relatively large Chinese HOCM cohort.

| Study population
We thoroughly reviewed the medical records of consecutive HOCM patients in our hospital from January 2014 to June 2019. Circulating levels of cTnI, NT-pro BNP, and hs-CRP, as well as cardiac evaluations of 12-lead electrocardiogram, 24-hour Holter monitoring, TTE, and CMR, were examined routinely in all individuals. Participants met the following diagnostic criteria of HOCM: (a) a maximum LV wall thickness ≥ 15 mm in adults (or 13-14 mm with a definite family history of HCM) by TTE or CMR, in the absence of other accountable cardiac or systemic diseases; and (b) an instantaneous peak Doppler LVOT gradient (LVOTG) ≥30 mm Hg at rest or during physiological provocation such as Valsalva maneuver, standing, or exercise. 10 Patients who had myocardial infarctions, myocarditis, congenital heart diseases, primary valvular heart diseases, pulmonary heart diseases, severe renal impairments, connective tissue diseases, infections, neoplasms, or with a medical history of coronary revascularization, percutaneous alcohol septal ablation, or surgical septal myectomy in the past were excluded from the study. Finally, a total of 755 HOCM patients were enrolled. The current study was in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee of our hospital.

| Laboratory examinations
Circulating levels of cTnI, NT-pro BNP, and hs-CRP were measured prior to all invasive procedures or treatment, when heart failure symptoms of patients could be controlled by regular oral medications. The time intervals between the blood tests of biomarkers and the completion of cardiac evaluations (Holter monitoring, TTE, and CMR) were usually within 7 days. Serum cTnI was determined using the immunochemiluminometric assay (Access AccuTnI, Beckman Coulter, California) on a Beckman Coulter Access 2 analyzer. The upper limit of its normal range (the 99th percentile of normal population) was 0.04 ng/mL, and the lower limit of detection was 0.01 ng/mL. Plasma NT-pro BNP was examined by the electrochemiluminescent immunoassay (Elecsys pro-BNP II assay, Roche Diagnostics, Mannheim, Germany) on a Cobas 6000 analyzer (Roche Diagnostics), with the lower detection limit of 0.6 PMol/L. A particle-enhanced immunoturbidimetric assay (Ultrasensitive CRP kit, Orion Diagnostica, Espoo, Finland) was applied for the measurement of serum hs-CRP on an Olympus AU-5400 analyzer (Olympus Diagnostics). The lower detection limit of hs-CRP was 0.25 mg/L.

| 24-hour Holter monitoring
Twenty four-hour Holter monitoring was tested within 3 days after the detection of circulating biomarkers. The occurrence and hourly frequency of ventricular arrhythmic events were recorded. NSVT was defined as an episode of ≥3 consecutive ventricular beats with a rate of ≥120 beats per minute, lasting <30 seconds. 10

| CMR image acquisition
CMR studies were performed using a 1.5-Tesla scanner. Cine images consisting of LV two-chamber and four-chamber long-axis views, LV short-axis views, and LVOT views were acquired through true fast imaging with a steady-state precession sequence. The maximal LV wall thickness was traced and measured from LV short-axis views at end-diastole. Approximately 10 to 15 minutes after a bolus injection of 0.2 mmol/kg gadolinium-diethylenetriamine pentaacetic acid, LGE images were obtained using a segmented phase-sensitive inversion recovery (PSIR) turbo fast low angle shot (FLASH) sequence.

| TTE evaluation
The parasternal acoustic window was applied to record two-

| SCD risk estimation
The risk of SCD in HOCM patients was predicted using the ESC online HCM risk-SCD calculator. According to this risk model, patients with an HCM Risk-SCD higher than 6% were considered as high risk. 7

| Demographics, clinical features, and medications of the HOCM cohort
Our study cohort consisted of 755 consecutive HOCM patients, with 57.4% males and a mean age of 51.0 ± 12.9 years. A total of 138 patients (18.3%) with positive NSVT episodes on Holter monitoring were classified into the NSVT group, and the rest 617 patients with negative VT detection were categorized as the nonventricular tachycardia (non-VT) group. Although patients diagnosed with NSVT seemed to have comparatively more complaints of chest pain, dyspnea, palpitation, and unexplained syncope, the statistical differences between the two groups were unremarkable. Hypertension accounted for a greater proportion in individuals of the non-VT group (P = .029).

| Comparisons of circulating biomarkers and cardiac evaluations between the NSVT and the non-VT group
Patients in the NSVT group had significantly elevated levels of cTnI (P < .001) and NT-pro BNP (P < .001), whereas the concentrations of serum hs-CRP were similar between the two groups (Table 2, Figure 1A,B). Holter monitoring revealed that patients with NSVT suffered from increased burden of ventricular arrhythmic events, with greater numbers of premature ventricular contractions (PVCs) (P = .001), more various PVC morphologies (P < .001), as well as higher prevalence of ventricular bigeminy (P < .001), and paired ventricular beats (P < .001). CMR indicated that NSVT patients possessed much thicker ventricular walls (P < .001), slightly decreased LV ejection fractions (P = .018), and enhanced positive rate of LGE (P = .003).
TTE showed not significant differences either in peak LVOTGs or in severity degrees of mitral regurgitation between the two groups ( Table 2). In our study, 86.2% of the entire population presented with positive LGE on CMR, and we further analyzed the involved locations of LGE in our HOCM cohort (Table S1). Compared to patients with LGE located only in the interventricular septal area, the proportion of NSVT in patients with LGE in both septum and other ventricular walls was significantly higher (22.8% vs 13.7%, P = .007).

| Logistic regression analyses to identify independent determinants of NSVT
Univariable logistic regression analyses suggested that Ln cTnI, Ln NT-pro BNP, maximal LV wall thickness, LV ejection fraction, LV enddiastolic volume, and LGE(+) were significantly associated with the occurrence of NSVT in HOCM patients (

| ROC curve analysis of cTnI to predict NSVT in HOCM
The efficiency of cTnI in predicting the occurrence of NSVT was evaluated by ROC curve analysis ( Figure 1C). The AUC of cTnI was 0.707 (95% CI: 0.660-0.754, P < .001). The optimal cutoff value of cTnI was 0.0265 ng/ mL, with the sensitivity of 68.8% and the specificity of 61.3%.  3.6 | Correlations between cTnI and the risk of SCD in the HOCM cohort    In this context, exploring more easily applicable predictive factors for SCD is of great clinical significance. In our study, we found a positive correlation between Ln cTnI and the 5-year risk of SCD in HOCM.

| Levels of cTnI according to the classification of ventricular arrhythmias
Individuals with a HCM risk-SCD over 6% had significantly elevated serum cTnI levels compared with their counterparts in the low or intermediate risk groups. Our results indicated, to some extent, that higher concentrations of cTnI might be helpful in the pre-evaluation for the risk of SCD in HOCM. Since the measurement of cTnI is simple and widely accessible, it should be used as part of a routine assessment to provide more screening and prognostic information for the clinical status of ventricular arrhythmias and the risk of SCD in patients with HOCM. However, to further demonstrate whether cTnI is additive to the risk prediction of HOCM patients, more long-term prospective follow-up studies are needed in the future.

| Study limitations
First, this was a single-center, cross-sectional retrospective study.
Although we suggested an independent association between elevated levels of cTnI and the presence of NSVT in HOCM patients, the retrospective nature of the current study limited our ability to determine a causal relationship. Second, the positive detection rate of NSVT episodes was based on the results of 24-hour Holter monitoring. The relatively short duration of the examination might have somehow underestimated the incidence of NSVT in the HOCM cohort. Finally, the risk of SCD in the study population was estimated by the HCM risk-SCD score due to the absence of long-term clinical follow-up data. There was no doubt that prospective studies were desirable; F I G U R E 2 A, Levels of serum cTnI according to classifications of ventricular arrhythmic events in patients with HOCM. B,C, Correlations between cTnI and the risk of SCD at 5 years in patients with HOCM. cTnI, cardiac troponin I; HOCM, hypertrophic obstructive cardiomyopathy; NSVT, nonsustained ventricular tachycardia; PVC, premature ventricular contraction; SCD, sudden cardiac death however, since a considerable number of subjects underwent alcohol septal ablation or septal myectomy in their later course of the disease, those invasive procedures could inevitably affect the natural prevalence of NSVT and the outcomes of HOCM patients. Therefore, we chose to utilize the scoring model to estimate the risk of SCD in our HOCM cohort.

| CONCLUSIONS
To the best of our knowledge, this was the first study that systematically investigated correlations of different circulating biomarkers (cTnI, NT-pro BNP, and hs-CRP) and the presence of NSVT in a large Chinese HOCM cohort. Elevated serum cTnI was an independent determinant of NSVT episodes, and it seemed to be a valuable index to assess the clinical status of ventricular arrhythmias and the risk of SCD in patients with HOCM.