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Alcohol septal ablation markedly reduces energy loss in hypertrophic cardiomyopathy with left ventricular outflow tract obstruction: A four-dimensional flow cardiac magnetic resonance study

Background Functional follow-up modalities of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) outflow tract obstruction (LVOTO) subjected to alcohol septal ablation (ASA) are limited. Methods This retrospective cohort study included patients of HCM with LVOTO who underwent ASA and four-dimensional (4D) flow cardiac magnetic resonance imaging (MRI) both before and after ASA. We analyzed energy loss in one cardiac cycle within the three-chamber plane of the LV and aortic root, and compared between pre- and post-ASA measurements. Results Of the 26 included patients, 10 (39%) were male, and median age was 71 (interquartile range 58–78) years. ASA significantly reduced not only LVOT pressure gradient (70 [19–50] to 9 [3–16], P < 0.001), but also energy loss during one cardiac cycle within the three-chamber plane of the LV and aortic root (80 [65–99] to 56 [45–70], P < 0.001). A linear association was observed between the reductions of energy loss and pressure gradient (R2 = 0.58, P < 0.001). Conclusions ASA significantly reduced energy loss within the LV and aortic root as quantified by 4D flow MRI, reflecting the decreased cardiac workload. This approach is a promising candidate for serial functional follow-up in patients undergoing ASA.


Introduction
Septal myectomy is indicated for relieving symptoms and improving exercise capacity in hypertrophic cardiomyopathy (HCM) patients who have left ventricular outflow tract (LVOT) obstruction (LVOTO), a resting or provoked LVOT pressure gradient ≥50 mmHg, and moderate to severe symptoms (usually New York Heart Association [NYHA] functional class III-IV) that are drug-refractory [1,2]. Alcohol septal ablation (ASA), a transcatheter procedure, is an alternative to septal myectomy, that is indicated in patients with high surgery risk due to serious comorbidities or advanced age [2].
Functional follow-up modalities for HCM with LVOTO subjected to ASA are mainly limited to echocardiography, which visualizes the morphology and measures the peak velocity at LVOT, and catheterization, which directly assesses the LVOT pressure gradient. Recently, fourdimensional (4D) flow magnetic resonance imaging (MRI) has been increasingly applied in the cardiovascular field, given its advantages of providing information from the perspective of fluid dynamics by noninvasively visualizing blood flow and calculating quantitative parameters such as wall shear stress and energy loss within the cardiac chambers or blood vessels [3][4][5]. Several reports have demonstrated elevated intra-cardiac energy loss in various cardiac diseases, as well as its reduction along with the improvement of cardiac function achieved by optimal treatment [6,7]. This study aimed to investigate the influence of ASA on energy loss in the left ventricle (LV) and aortic root as measured by 4D flow MRI in HCM patients with LVOTO.

Study design and study population
This single-center retrospective cohort study was approved by the institutional research board of Sakakibara Heart Institute (NO. 19-120). All patients provided informed consent under an opt-out policy.
We screened consecutive patients who underwent ASA for drugrefractory symptomatic HCM with LVOTO at Sakakibara Heart Institute, a referral center in Tokyo, Japan, from April 2019 to December 2020. The study included patients who underwent 4D flow cardiac MRI before and after ASA (within 6 months from the procedure). The diagnosis of HCM with LVOTO was made based on current guidelines [1,2].

Indication and procedure for ASA
For each symptomatic HCM patient with LVOTO, both a beta-blocker and a class Ia antiarrhythmic agent (cibenzoline or disopyramide) were started and up-titrated according to residual symptoms unless intolerable. Patients presenting with NYHA functional class II-IV symptoms despite maximum tolerated medications were evaluated by catheterization including right heart catheterization, left ventriculography, coronary angiography, and recording of the LVOT pressure gradient. An LVOT peak-to-peak pressure gradient ≥50 mmHg at rest or upon provocation by the Valsalva maneuver, premature ventricular beat, or intravenous nitroglycerin (up to 100 μg) warrants septal reduction therapy, based on current guidelines [1,2]. The decision to perform ASA was made based on high surgery risk, suitable coronary anatomy, absence of the need for concomitant cardiac surgery, and informed patient consent, via a focus group discussion consisting of multidisciplinary HCM experts (including but not limited to ASA operators, septal myectomy operators, and cardiac imaging experts).
The ASA procedure was performed as previously described [8,9]. Briefly, after confirmatory coronary angiography and identifying the perfusion bed of the target septal branch with echocardiographic contrast injected through the over-the-wire balloon catheter, desiccated ethanol was infused through the balloon catheter, with continuous transthoracic echocardiography (TTE) monitoring to help determine the infusion endpoint. Pressure gradient recording and right heart  catheterization were performed immediately before and after the ASA procedure.

Acquisition of MRI
All patients included in the present study underwent standard-ofcare cardiac MRI within 6 months before and after ASA, along with 4D flow MRI, on a 1.5 T MRI system (MAGNETOM Sola, Siemens, Germany), with a maximum gradient strength of 45 mT/m and a maximum slew rate of 200 T/m/s, using a commercially available 18channel phased array body coil. Standard-of-care cardiac MRI included electrocardiogram-gated steady-state free procession cine cardiac MRI and late gadolinium enhancement if renal function was preserved. The imaging protocol for HCM with LVOTO in our institute specifies that three-chamber plane images should be included in each imaging series [10]. For the assessment of fluid dynamics, all 4D flow MRI acquisitions were performed during the waiting period after gadolinium injection. Time-resolved two-dimensional phase-contrast MRI of the three-chamber plane with three-directional velocity encoding (i.e. 4D flow) was implemented during breath-holding with prospective electrocardiogram-gating. The pulse sequence parameters were as follows: spatial resolution 1.8 × 1.8 × 6 mm 3 ; field of view 340 × 340 mm 2 ; velocity sensitivity 150 cm/s; echo time 2.4 ms; repetition time 33.2-49.8 ms; flip angle 12 • ; and view per cardiac phase 15-17. All 4D flow MRI scans were acquired with parallel imaging (GRAPPA) with an acceleration factor of R = 2 and 34 reference lines.

Post-processing and quantitative analysis of 4D flow MRI
Quantitative analysis of the 4D flow MRI was performed by a commercially available post-processing software (iTFlow version 1.9; Cardio Flow Design, Japan) [11]. We described the region of interest (ROI) as the area surrounded by the LV endocardium, sinotubular junction, and mitral annulus within the three-chamber plane. The ROI was traced manually by an experienced observer (ZD) in each single phase of the cine MRI, allowing the software to automatically calculate the in-plane energy loss (mW/m) within the region in each phase based on a previously established formula as follows [11,12]: where μ is the viscosity of the blood (μ = 0.004 Pa⋅s), i and j correspond to the principal velocity directions, u is the velocity field measured by 4D flow MRI, and S corresponds to pixels in the ROI. Energy loss generated within the ROI in each single phase was then integrated upon one cardiac cycle, yielding in-plane energy loss per cardiac cycle (EL cycle [mJ/m]).

Statistical analysis
Continuous variables are presented as the median (interquartile range). Categorical variables are presented as number (percentage). Both continuous and categorical variables were compared between preand post-ASA using paired tests (Wilcoxon signed rank and McNemar tests). All statistical analyses were performed using R 4.0.3 (R Foundation for Statistical Computing, Vienna, Austria). P < 0.05 was considered statistically significant.

Results
We screened 69 patients who underwent ASA for HCM with LVOTO during the study period, among whom 26 had standard-of-care as well as 4D flow cardiac MRI within 6 months before and after ASA, thus were included in this study. The included patients had a median age of 71 (58-78) years, and 10 (39%) were male (Table 1). A median of 1 (1-2) septal branch was treated, with a total ethanol volume of 3.5 (2.3-4.4) mL. The postprocedural peak creatine kinase was 1201 (953-1557) IU/ L. ASA significantly improved the LVOT pressure gradient and cardiac index measured by catheterization and LVOT peak velocity measured by  A). B and C demonstrates representative images of energy loss within the left ventricle and aortic root, before (B) and after (C) ASA in a same patient. Energy loss per cardiac cycle (EL cycle ) decreased significantly after ASA (D), which was linearly associated with the reduction of pressure gradient directly measured by catheterization (E). TTE, and resulted in a better NYHA functional class (Table 1, Fig. 1A).
Pre-and post-ASA MRI was taken with comparable heart rates ( Table 1). A typical presentation of pre-and post-ASA energy loss within the ROI in a single phase is illustrated in Fig. 1B-C. EL cycle decreased significantly with ASA, from 80 (65-99) to 56 (45-70) mJ/m (P < 0.001; Table 1, Fig. 1D). The reduction of EL cycle was significantly associated with a decrease in pressure gradient (R 2 = 0.58, P < 0.001; Fig. 1E).

Discussion
This study demonstrated that ASA reduced energy loss within the LV and aortic root, which was detected by serial 4D flow cardiac MRI. To our knowledge, this study is the first attempt to evaluate changes in fluid dynamics driven by ASA, with the exception of several single-case reports.
It has been shown that elevated energy loss arises from the altered blood flow due to the obstruction in aortic stenosis and HCM with LVOTO, which increases cardiac workload [13,14]. Case reports have also demonstrated that in HCM with LVOTO, ASA successfully optimized blood flow in the LVOT, and reduced turbulent kinetic energy. Although it is still debatable whether estimating energy deprivation via turbulent kinetic energy based on turbulent flow or via energy loss based on laminar flow, as in this study, is the best parameter, such quantifications are thought to be a promising approach to evaluate cardiac workload, and to follow-up patients serially [13,15]. Energy loss is an indirect calculation from velocity in every in-plane pixel in 4D flow MRI, reflecting the deprivation in energy corresponding to the alteration of total pressure, including both static and kinetic pressure. Conversely, pressure gradient in catheterization only measures that of static pressure. This might theoretically explain the discrepancy between the improvement of EL cycle and that of pressure gradient which was observed in few patients in this study.
Besides invasive procedures, mavacamten, a recently developed selective allosteric inhibitor of cardiac myosin ATPase, has also been proven to significantly relieve LVOT obstruction, and to improve exercise capacity and NYHA functional class in HCM with LVOTO [16]. Given the mechanism of mavacamten, which reduces cardiac workload during contraction, improves relaxation and promotes efficient energy use [17], the hemodynamic improvement is also expected to be reflected by 4D flow MRI parameters.
Taken together, 4D flow cardiac MRI is an appropriate candidate modality for serial assessment in HCM with LVOTO. It is more objective and reproducible when compared with TTE, and less invasive when compared with catheterization, though is not currently available in all institutions, nor valid in patients with arrhythmia such as atrial fibrillation.

Limitations
This was a single-center retrospective study with a small sample size. In this study, we evaluated EL cycle within the three-chamber plane, but not within the three-dimensional whole heart. The latter approach requires a longer time for MRI acquisition, precluding the use of breathholding. Thus, it would be less feasible in clinical practice, especially in symptomatic patients. Our approach is less time-consuming and could be performed within the waiting period after gadolinium injection, adding no excessive burden to the patients.

Conclusions
ASA in HCM patients with LVOTO significantly reduced energy loss within the LV and aortic root as quantified by 4D flow MRI, indicating a substantial decrease in the cardiac workload. This approach is a promising candidate for serial functional follow-up in patients who undergo ASA.

Funding
This study is supported by Japan Research Promotion Society for Cardiovascular Diseases (to ZD).