Mid‐ventricular obstruction is associated with non‐sustained ventricular tachycardia in patients with hypertrophic obstructive cardiomyopathy

Abstract Background Mid‐ventricular obstruction (MVO) is a rare subtype of hypertrophic cardiomyopathy (HCM) but it is associated with ventricular arrhythmia. The relationship between MVO and non‐sustained ventricular tachycardia (NSVT) in HCM patients is unknown. Hypothesis The severity of MVO increases the incidence of NSVT in patients with hypertrophic obstructive cardiomyopathy (HOCM). Methods Five hundred and seventy‐two consecutive patients diagnosed with HOCM in Fuwai Hospital between January 2015 and December 2017 were enrolled in this study. Holter electrocardiographic and clinical parameters were compared between HOCM patients with and without MVO. Results Seventy‐six (13.3%) of 572 patients were diagnosed with MVO. Compared to patients without MVO, those with MVO were much younger, and had a higher incidence of syncope, greater left ventricular (LV) posterior wall thickness, a higher percentage of LV late gadolinium enhancement, and higher prevalence of NSVT. Furthermore, the prevalence of NSVT increased with the severity of MVO (without, mild, moderate or severe: 11.1%, 18.2%, 25.6%, respectively, p for trend < .01). Similarly, the prevalence of NSVT differed among patients with isolated LV outflow tract (LVOTO), both MVO and LVOTO, and isolated MVO (11.1%, 21.3%, 26.6%, respectively, p for trend = .018). In addition to age, diabetes, left atrial diameter, and maximal wall thickness, multivariate analysis revealed the presence of MVO as an independent risk factor for NSVT (Odds ratio 2.69; 95% confidence interval 1.41 to 5.13, p = .003). Conclusions The presence and severity of MVO was associated with higher incidence of NSVT in HOCM patients.


| INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease with a prevalence of approximately 0.2%-0.5% in the general population. 1 The majority of HCM patients have a left ventricular outflow tract obstruction (LVOTO) at rest or with provocation. 2 HCM patients with mid-ventricular obstruction (MVO), impedance to flow at the middle of the left ventricle, is a less common subtype of HCM but it is associated with ventricular arrhythmia and a worse prognosis. [3][4][5] However, most studies concerning the relationship between HCM with MVO and ventricular arrhythmia were case reports or small series. [6][7][8][9][10][11] Moreover, no studies have focused on the relationship between HCM with MVO and non-sustained ventricular tachycardia (NSVT), which was a strong predictor of sudden cardiac death in patients with HCM. The hypothesis of this study was that MVO severity affects NSVT incisence in patients with hypertrophic obstructive cardiomyopathy (HOCM).

| Population
We retrospectively reviewed 857 consecutive patients who diag- and moderate or severe, >50 mmHg (N = 43). In addition, the prevalence rate among patients with isolated LVOTO, both LVOTO and MVO, and isolated MVO was also analyzed.
The diagnosis of HOCM was based on the 2020 American Heart Association/American College of Cardiology guideline and the 2014 European Society of Cardiology guideline, which mainly included unexplained septal hypertrophy with a thickness > 15 mm or a thickness of septal cardium >13 mm with a family history of HCM. 12,13 The indication for LVOT obstruction was an LVOT gradient ≥30 mmHg at rest or with provocation. MVO was defined as peak mid-ventricular gradient ≥30 mmHg, with a simultaneous appearance of midventricular muscular apposition, causing an hourglass shape of the left ventricle on echocardiography ( Figure 1). 4,14 All study participants signed informed consent forms before enrollment, and this study was approved by the Ethics Committee of Fuwai Hospital. All procedures of this study were conducted in accordance with the ethical principles stated in the Declaration of Helsinki.

| Twenty-four-hour Holter electrocardiography
Twenty-four-hour Holter electrocardiogram was performed for all study subjects. These data were technically of good quality, and rhythm and arrhythmia were analyzed conventionally. NSVT was defined as an episode of ≥3 consecutive ventricular beats with a rate of at least 100 beats/min, lasting for <30 s. Each NSVT episode was recorded for frequency, duration, and maximal rate. Couplets were two consecutive premature ventricular complexes (PVCs). More details can be found in our previous publication. 15 F I G U R E 1 (A) A dagger-shaped waveform is obtained, showing a high mid-ventricular gradient, and the estimated peak velocity of 3.74 m/s.

| Statistical analysis
The results are presented as mean ± standard deviation or number were used for calculation and illustration, respectively.

| Baseline patient characteristics
In the present study, 76 (13.3%) patients were diagnosed with MVO, and 61 of 76 patients had both MVO and LVOTO. The mean age of patients with MVO at diagnosis was 44.6 ± 12.2 years, and the mean mid-ventricular gradient was 52.7 ± 17.1 mmHg. The clinical characteristics of patients with and without MVO are summarized in Table 1. Patients with MVO were significantly younger and had a lower LVOT gradient, higher prevalence rate of aneurysms, and greater LV posterior wall thickness than those without MVO. The history of syncope in patients with MVO was significantly higher than in patients without MVO. Furthermore, 296 patients underwent cardiac magnetic resonance, the percentage of LV late gadolinium enhancement (LGE) was also significantly higher in patients with MVO than those in without MVO.

| Clinical data associated with NSVT
The variables with a p < .1 in univariate analysis or previously demonstrated to be associated with NSVT are presented in

| NSVT characteristics in patients with and without MVO
Seventy-four patients (12.9%) had NSVT during their initial Holter electrocardiogram recordings. The mean number of runs of NSVT during the 24-h Holter electrocardiogram was 4.4 ± 11.7 (range, 1-97).
The mean number of beats in the longest run was 7.0 ± 6.0 beats (range, 3-35 beats) and the mean maximum rate of the NSVT runs was 132.0 ± 23.1 beats/min. NSVT characteristics of patients with and without MVO are presented in Supplemental Table 1.The mean runs, duration, and maximal heart rate of NSVT episodes did not differ between patients with and without MVO.

| DISCUSSION
The main findings of this study are as follows: first, the prevalence rate of MVO in this study was approximately 13.3%. Second, the presence and severity of MVO significantly associated with a higher incidence of NSVT. Third, in addition to age, diabetes, left atrial diameter, and maximal wall thickness, the presence of MVO was found to be an independent risk factor for NSVT.
Overall, 13.3% of HOCM patients in the present single-center cohort study had MVO. The frequency of MVO was similar to that noted in previous studies, which had reported the incidence of MVO to be between 8% and 12.9% among HCM patients. 3,4,16,17 Due to the low-prevalence rate of MVO in HCM patients, there is a paucity of information on the link between NSVT and MVO. Some case reports have shown that mid-ventricular obstructive HCM with apical aneurysm usually presented with ventricular arrhythmia. 6,7 Moreover, some small series indicated that there was a potential relationship between MVO and ventricular arrhythmia in HCM patients. 9,18 These studies showed a high prevalence rate of NSVT in HCM patients with MVO.
Clinical studies of HCM with MVO are limited. Cai and colleagues analyzed 60 HCM patients with MVO, and their results demonstrated that patients with MVO had a higher incidence of NSVT and were more likely to have myocardial fibrosis on cardiac magnetic resonance imaging than patients with apical HCM. 19 In addition, two other large single-center studies showed that patients with MVO had a higher incidence of sudden cardiac death and potential lethal arrhythmia events than those with isolated LVOT obstruction. 3,4 These studies suggested that patients with MVO were potentially associated with a higher incidence of NSVT than those without MVO (patients with apical HCM or HCM patients with isolated LVOTO). In our present study, F I G U R E 2 Prevalence of ventricular arrhythmias on 24-h Holter electrocardiogram recording in patients with and without MVO. MVO, mid-ventricular obstruction; NSVT, non-sustained ventricular tachycardia; PVCs, premature of ventricular complexes myocardium will increase its oxygen consumption and impair coronary flow through extravascular compression of the coronary artery, which leads to chronic myocardial ischemia. 22 One study suggested that patients with severe cavity obliteration had lower myocardial flow perfusion than those with no or mild cavity obliteration during an exercise stress test. 22 Long-term myocardial ischemia is the main cause of myocardial fibrosis. In the presents study, 296 patients underwent cardiac magnetic resonance, and patients with MVO had a higher percentage of LV LGE than those without MVO. Cai also found a higher positive rate of myocardial fibrosis in HCM patients with MVO than those with apical HCM. 19 In addition, the presence of MVO is associated with a higher possibility of the development of apical aneurysm, which has been demonstrated as a strong predictor of NSVT in HCM patients. 3,4,9,18 Studies have shown a prevalence of apical aneurysm of about 20% in patients with MVO during a long-term follow-up period. 3,19 Although the mechanisms of the devel- MVO is a rare type of HCM, accounting for approximately 10% of cases. 23 Patients with MVO had a higher incidence of NSVT, which was a significant risk factor of lethal cardiovascular events and sudden cardiac death (SCD), independent of its frequency, duration, and number of episodes than in those with isolated LVOT obstruction. 24 Moreover, patients with MVO are also more prone to apical aneurysms, with a prevalence rate of up to >20% during a long-term follow up. In a single-center study, a peak MVO gradient >70 mmHg was the only independent risk factor for the formation of apical aneurysms. 9 Moreover, patients with MVO had a higher incidence of syncope than those without MVO in the present study. According to recent guide- which was much higher than that reported in a recent meta-analysis of HCM patients overall (3.3%/year). 25,26 Therefore, septal myectomy is an effective treatment for patients with MVO to relieve midventricular cavity obstruction and improve symptoms and heart function. However, further investigation is needed to determine whether patients with MVO need ICD implantation. We expect that early diagnosis and appropriately timed treatments will reduce the occurrence of NSVT and the formation of aneurysms in patients with MVO and will eventually improve patients' symptoms and long-term prognosis.

| LIMITATION
The limitations of the present study are as follows. First, our study had a single-center design with a small sample size of MVO patients.
Hence, our study findings should be prudently extrapolated to other centers, and further studies with a larger population should be conducted to confirm our results. Second, due to the retrospective nature of data collection, some factors such as myocardial flow perfusion and myocardial fibrosis extension could not be evaluated in this study.