
==== Front
J Cardiovasc Magn Reson
J Cardiovasc Magn Reson
Journal of Cardiovascular Magnetic Resonance
1097-6647
1532-429X
Elsevier

S1097-6647(24)01099-8
10.1016/j.jocmr.2024.101072
101072
Short Communication
Accelerated myocardial fibrosis in young to middle-aged patients with hypertrophic cardiomyopathy
Nakamori Shiro ae
Rowin Ethan J. bc
Rodriguez Jennifer a
Ngo Long H. a
Manning Warren J. ad
Maron Martin bc
Nezafat Reza rnezafat@bidmc.harvard.edu
a⁎
a Departments of Medicine (Cardiovascular Division) Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
b Hypertrophic Cardiomyopathy Center, Lahey Medical Center, Burlington, Massachusetts, USA
c Tufts University School of Medicine, Boston, Massachusetts, USA
d Departments of Radiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
e Department of Cardiology and Nephrology, Mie University Graduate School of Medicine, Tsu, Japan
⁎ Corresponding author. Department of Medicine, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. rnezafat@bidmc.harvard.edu
02 8 2024
2024
02 8 2024
26 2 10107227 3 2024
15 7 2024
26 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Background

The extent of late gadolinium enhancement (LGE) on cardiovascular magnetic resonance (CMR) in patients with hypertrophic cardiomyopathy (HCM) is associated with an increased risk of sudden cardiac death events. However, the clinical significance of age-specific longitudinal changes in LGE is not well characterized in HCM. We sought to assess whether the risk of LGE progression diverges between young to middle-aged (ages 20-59 years) and older (≥ 60) adults with HCM.

Methods

A total of 102 HCM patients (age <60 years; n=75, age ≥60 years; n=27) undergoing serial CMR studies from two tertiary medical centers were evaluated. The median time interval between initial and follow-up CMR scans was 3.7 years. LGE was semiautomatically quantified by measuring regions with signal intensity >6 SD above the nulled remote myocardium and manually adjusting a grayscale threshold.

Results

LGE was identified at baseline in 61 of the 102 HCM patients (60%), occupying 4.8 ± 3.9% of the left ventricular (LV) mass. At the end of the follow-up period, 53 of the 61 patients (87%) demonstrated an increase in the extent of LGE to 7.7 ± 5.4%, and 8 patients had no change. In 5 patients (5%), LGE increased to extensive with >15% of the LV mass. The rate of LGE progression was 0.7 ± 1.0%/year, including 21 patients (21%) with particularly accelerated progression of ≥1%/year. The risk of LGE progression ≥1%/year was significantly higher in patients <60 years than those ≥ 60 years (25% vs. 7%, p=0.03). The odds of LGE progression ≥1%/year was almost 4 times greater for patients <60 years compared with those ≥ 60 years (odds ratio, 4.2; 95%CI, 1.1-27.9). Age <60 years and LGE extent ≥ 10% were significant baseline predictors for future LGE progression ≥1%/year, even after adjustment for other potential risk factors.

Conclusion

In HCM, progressive fibrosis occurs more frequently in young to middle-aged patients, underscoring the importance of repeating CMR to re-evaluate for potential LGE progression in this age group.

Graphical abstract

ga1

Keywords

Age
Cardiovascular magnetic resonance
Hypertrophic cardiomyopathy
Late gadolinium enhancement
Progressive fibrosis
Abbreviations

CMR cardiovascular magnetic resonance

HCM hypertrophic cardiomyopathy

ICD implantable cardioverter-defibrillator

LGE late gadolinium enhancement

LV left ventricular

LVEF left ventricular ejection fraction

SCD sudden cardiac death

SD standard deviation

VT ventricular tachycardia

CI confidence interval

99mTc-PYP 99m Technetium-pyrophosphate
==== Body
pmc1 Introduction

Sudden cardiac death (SCD) is the most devastating complication in hypertrophic cardiomyopathy (HCM) [1]. Effective prevention of SCD can be achieved using implantable cardioverter-defibrillators (ICD) in high-risk patients [1]. The most recent 2020 American College of Cardiology/American Heart Association HCM guidelines [2] have recognized extensive cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) scar burden (≥15% of left ventricular [LV] mass) as a major SCD risk factor because LGE represents regions of an abnormal myocardial substrate with replacement fibrosis and the nidus for the generation of ventricular tachyarrhythmias [3].

However, there is limited data on how LGE changes over time in HCM [4], [5], [6], [7], and more specifically the impact of age on the risk for LGE progression remains unclear. This is particularly relevant, given its important weight in the guidelines as a variable that can impact decisions regarding prophylactic ICD and recommendations for the timing of follow-up scans. Therefore, we examined the LGE progression of HCM patients as stratified by age and evaluated the feasibility of repeating CMR to reevaluate for potential LGE progression.

2 Methods

2.1 Study population

The study cohorts consist of 102 HCM patients identified from reviews of the CMR referral records from 2 academic medical centers: Beth Israel Deaconess Medical Center (BIDMC), Boston, Massachusetts (n = 48) and Tufts Medical Center, Boston, Massachusetts (n = 54). A subset of patients previously evaluated for LGE in HCM [7] were included in this study. The patients were referred for a clinical CMR exam for evaluation of HCM between March 2008 and August 2019, and clinical diagnosis of HCM was based on CMR documentation of a hypertrophied (wall thickness ≥15 mm) and nondilated LV in the absence of another cardiac or systemic disease capable of producing similar magnitude of hypertrophy [3]. The date of the first evaluation was the time of the initial CMR examination. The median time interval between initial and follow-up CMR scans was 3.7 years. At study entry, each patient was assessed for the conventional primary prevention SCD risk factors described in HCM; 1) history of HCM-related SCD in ≥1 first-degree or other close relative ≤50 years of age, 2) massive LV hypertrophy (maximum wall thickness ≥30 mm in any segment detected on echocardiography and confirmed by CMR), 3) unexplained syncope, inconsistent with neurocardiogenic origin, occurring within 5 years of CMR, 4) non-sustained ventricular tachycardia (VT) on ambulatory monitoring (considered as an independent risk marker when runs are frequent [≥3], longer [≥10 beats], and faster [≥200 beats/min]), as well as markers that have emerged more recently with the introduction of CMR to HCM practice, i.e., LGE ≥15%, LV ejection fraction (EF) <50%, and LV apical aneurysm. This study was approved by the participating institutions' Institutional Review Board.

2.2 Image acquisition and analysis

CMR images were acquired with 1.5T (Achieva 1.5T, Philips Healthcare, Best, Netherlands) or 3T (Magnetom Vida; Siemens Healthineers, Erlangen, Germany). The CMR protocol included balanced steady-state free-precession cine and LGE. LGE imaging was performed by a breath-hold or respiratory-gated, two-dimensional or three-dimensional acquisitions, 10–20 min after intravenous administration of gadolinium-based contrast agent (0.1–0.2 mmol/kg). The LGE images were acquired using a conventional inversion recovery-based gradient echo imaging sequence. Inversion time of the LGE was optimized to null normal myocardial signal, and the field of view ranged from 320–360 mm. The following imaging parameters were used for site 1 (BIDMC): repetition time = 4.2–5.0 ms, echo time = 1.8–2.5 ms, flip angle = 15–20°, slice thickness = 8 mm, and phase encoding lines = 95–125. Imaging parameters for site 2 (Tufts) were: repetition time = 4.4–5.0 ms, echo time = 2.3–3.0 ms, flip angle = 20°, slice thickness = 8 mm, and phase encoding lines = 100–154.

Standard CMR analyses were used to evaluate biventricular volumes, systolic function, and LGE scar quantification. LV apical aneurysm was identified by cine CMR, independent of size, with discrete thin-walled dyskinetic or akinetic apical segments. LGE images were analyzed by two experienced readers (S.N. for the BIDMC dataset and E.J.R. for the Tufts dataset) blinded to patients’ clinical outcomes. For quantitative LGE analysis, the reader first manually delineated the myocardial borders in all short-axis images and semiautomatically quantified by measuring regions with signal intensity >6 standard deviation (SD) above nulled remote myocardium. To evaluate inter- and intra-observer reproducibility, one reader (S.N.) measured all LGE images twice on 2 separate days with a washout period of at least 2 weeks.

2.3 Statistical analysis

Continuous variables are reported as mean ± SD. Normally distributed continuous variables were compared using an unpaired Student's t-test or paired t-test when applicable. Mann-Whitney nonparametric test was used if not normally distributed. Categorical variables were reported as counts and percentages and compared using a chi-square or McNemar test. C-statistic using a logistic regression model was calculated to find an appropriate age cutoff for the accelerated LGE progression ≥1%/year. All tests were 2-sided, and a p-value <0.05 was considered significant. Statistical analyses were performed using MedCalc version 20.211 (MedCalc Software Ltd, Ostend, Belgium).

3 Results

The age of 60 years yielded the largest C-statistic of 0.61 (95% confidence interval [CI]: 0.51–0.70) for the accelerated LGE progression ≥1%/year after using cutoffs at every 5 years of age from 40–65 years. The mean (SD) age of participants was 45 (16) years: 75 (74%) young to middle-aged (ages 20–59 years) and 27 (26%) older (≥60) adults. The population was 68% male; 86% identified as being asymptomatic or mildly symptomatic (i.e., New York Heart Association functional class 1 or 2) and 23% reported as having ≥1 risk factor (Table 1).Table 1 Baseline and follow-up clinical characteristics and CMR findings stratified by age.

Table 1	All HCM patients	Age <60 years	Age ≥60 years	
	(n-102)	(n = 75)	(n = 27)	
	Baseline CMR	Follow-up CMR	p-Value	Baseline CMR	Follow-up CMR	p-Value	Baseline CMR	Follow-up CMR	p-Value	
Clinical parameters										
Age, years	45 ± 16	50 ± 16	<0.001	39 ± 13*	43 ± 14	<0.001	63 ± 3	68 ± 4	<0.001	
Male, %	69 (68)			52 (72)			17 (63)			
Body surface area, m2	1.97 ± 0.25	1.99 ± 0.24	0.08	1.99 ± 0.25	2.02 ± 0.24	0.02	1.92 ± 0.23	1.90 ± 0.24	0.25	
NYHA functional class, %			<0.001			0.32			<0.001	
 I	61 (60)	51 (50)		46 (61)	45 (60)		15 (56)	6 (22)		
 II	27 (26)	35 (34)		24 (32)*	25 (33)		3 (11)	10 (37)		
 III/IV	14 (14)	16 (16)		5 (7)*	5 (7)		9 (33)	11 (41)		
Atrial fibrillation, %	20 (20)	22 (22)	0.50	12 (16)	14 (19)	0.50	8 (30)	8 (30)	-	
Hypertension, %	19 (19)	20 (20)	0.99	9 (12)*	9 (12)	-	10 (37)	11 (41)	0.99	


	

	

	

	

	

	

	

	

	

	
Medications										
Beta-blockers, %	46 (45)	59 (58)	0.007	32 (43)	42 (56)	0.02	14 (52)	17 (63)	0.38	
Calcium channel blockers, %	12 (12)	33 (32)	<0.001	10 (13)	25 (33)	<0.001	2 (7)	8 (30)	0.06	
Disopyramide, %	2 (2)	4 (4)	0.50	2 (3)	3 (4)	0.99	0	1 (4)	0.99	
ACEi/ARB, %	12 (12)	25 (25)	0.003	7 (9)	16 (21)	0.04	5 (19)	9 (33)	0.13	
Amiodarone, %	0	4 (4)	0.13	0	3 (4)	0.25	0	1 (4)	0.99	
Diuretics, %	7 (7)	18 (18)	0.02	5 (7)	12 (13)	0.06	2 (7)	6 (22)	0.38	


	

	

	

	

	

	

	

	

	

	
Risk factors of sudden cardiac death									
Patients with no risk factors, %	79 (77)	75 (74)	0.48	56 (75)	51 (68)	0.30	23 (85)	24 (89)	0.99	
Patients with ≥1 risk factors, %	23 (23)	27 (26)	0.48	19 (25)	24 (32)	0.30	4 (15)	3 (11)	0.99	
Family history of SCD, %	6 (6)	6 (6)	-	6 (8)*	6 (8)	-	0	0	-	
Maximal wall thickness ≥30 mm, %	1 (1)	3 (3)	0.50	0	2 (3)	0.50	1 (4)	1 (4)	-	
Unexplained syncope, %	5 (5)	5 (5)	-	4 (5)	4 (5)	-	1 (4)	1 (4)	-	
Non-sustained VT, %	8 (8)	6 (6)	0.77	6 (8)	5 (7)	0.99	2 (8)	1 (4)	0.99	
LGE ≥15%, %	0	5 (5)	0.06	0	4 (6)	0.13	0	1 (4)	0.99	
LV ejection fraction <50%, %	1 (1)	4 (4)	0.38	1 (1)	4 (5)	0.38	0	0	-	
LV apical aneurysm, %	4 (4)	9 (9)	0.06	4 (5)	9 (12)	0.06	0	0	-	


	

	

	

	

	

	

	

	

	

	
CMR findings										
LV mass, g	156.2 ± 47.5	171.1 ± 57.5	<0.001	161.2 ± 49.3	174.8 ± 61.5	0.002	142.1 ± 39.8	160.8 ± 43.9	<0.001	
LV mass index, g/m2	78.9 ± 21.1	85.7 ± 26.9	<0.001	80.2 ± 22.0	86.4 ± 29.7	0.003	75.0 ± 18.1	83.9 ± 16.9	0.001	
Maximal wall thickness, mm	18.5 ± 3.8	19.9 ± 4.3	<0.001	18.8 ± 3.9	20.2 ± 4.6	<0.001	17.8 ± 3.6	19.2 ± 3.3	0.006	
LV ejection fraction, %	64.4 ± 7.0	62.9 ± 6.9	0.049	64.1 ± 7.6	62.0 ± 6.9	0.03	65.4 ± 4.8	65.3 ± 6.4	0.94	
LV end-diastolic volume, mL	161.5 ± 37.8	174.0 ± 41.7	<0.001	167.9 ± 36.7*	180.5 ± 41.3	0.001	143.9 ± 35.8	156.7 ± 38.2	0.004	
LV end-diastolic volume index, mL/m2	81.8 ± 15.7	87.4 ± 16.4	0.001	84.4 ± 15.8*	89.3 ± 16.7	0.03	74.6 ± 13.3	82.1 ± 14.5	0.002	
LV end-systolic volume, mL	58.1 ± 18.9	65.4 ± 23.3	<0.001	60.8 ± 19.2*	69.1 ± 23.4	<0.001	50.4 ± 16.0	55.3 ± 20.4	0.07	
LV end-systolic volume index, mL/m2	29.3 ± 8.3	32.7 ± 10.2	0.001	30.5 ± 8.6*	34.2 ± 10.3	0.007	26.0 ± 6.5	28.8 ± 8.7	0.06	
LA diameter, mm	43.2 ± 14.9	47.1 ± 17.4	0.004	43.7 ± 16.3	47.2 ± 17.6	0.02	42.0 ± 10.2	46.8 ± 17.3	0.09	
RV ejection fraction, %	61.8 ± 6.7	61.1 ± 6.9	0.22	61.4 ± 6.8	61.0 ± 7.0	0.37	62.6 ± 6.5	61.5 ± 6.8	0.38	
RV end-diastolic volume, mL	146.0 ± 39.6	151.7 ± 38.0	0.06	151.9 ± 39.2*	156.3 ± 37.4	0.34	129.8 ± 36.7	139.2 ± 37.5	0.04	
RV end-diastolic volume index, mL/m2	73.9 ± 17.5	76.3 ± 16.3	0.23	76.3 ± 17.4*	77.5 ± 15.7	0.95	67.3 ± 16.4	73.1 ± 17.8	0.03	
RV end-systolic volume, mL	56.4 ± 20.8	61.5 ± 26.3	0.01	59.0 ± 20.9*	62.8 ± 24.7	0.12	49.5 ± 19.2	58.2 ± 30.7	0.04	
LGE presence, %	61 (60)	86 (84)	<0.001	40 (53)*	60 (80)	<0.001	21 (78)	26 (96)	0.06	
LGE volume (% of LV mass), %	4.8 ± 3.9	6.2 ± 4.9	<0.001	4.8 ± 4.1	6.3 ± 5.3	<0.001	4.7 ± 3.7	6.0 ± 3.9	<0.001	
Interval between 1st and 2nd CMRs, years	4.3 ± 3.3	4.3 ± 3.6	4.4 ± 2.2	
LGE volume changes, %	2.4 ± 2.8	2.5 ± 3.0	2.1 ± 2.1	
LGE volume changes/year, %	0.7 ± 1.0	0.8 ± 1.1*	0.4 ± 0.3	
LGE volume changes/year ≥1%, %	21 (21)	19 (25)*	2 (7)	
ACEi/ARB angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, CMR cardiovascular magnetic resonance, HCM hypertrophic cardiomyopathy, LA left atrial, LGE late gadolinium enhancement, LV left ventricular, NYHA New York Heart Association, RV right ventricular, SCD sudden cardiac death, VT ventricular tachycardia.

* p < 0.05, baseline data, age <60 years vs age ≥60 years.

LGE was observed in 61 patients (60%), occupying 4.8 ± 3.9% of the LV mass. At the end of the follow-up period, 53 of the 61 patients (87%) demonstrated an increase in the extent of LGE to 7.7 ± 5.4%, and LGE increased to extensive with >15% of the LV mass in 5 patients (8%). Additionally, 25 patients without LGE at baseline developed a new LGE; thus, 86 (84%) patients had LGE, occupying 6.2 ± 4.9%, by the follow-up CMR. Overall, the rate of LGE progression was 0.7 ± 1.0%/year, including 21 patients (21%) with particularly accelerated progression of ≥1%/year. Between the baseline and follow-up CMR scans, 4 patients underwent myectomy (n = 3) or alcohol septal ablation (n = 1). There was no difference in LGE progression between the groups with and without intervention (0.7 ± 0.8% vs 0.7 ± 1.0%, p = 0.92). The risk of LGE progression ≥1%/year was significantly higher in patients <60 years than those ≥60 years (25% vs 7%, p = 0.03) and similar between young (age <40 years) and middle-aged patients (40 ≤ age <60 years) (26% vs 25%, p = 0.94). The odds of LGE progression ≥1%/year was almost 4 times greater for patients <60 years compared with those ≥60 years (odds ratio, 4.2; 95% CI, 1.1–27.9) (Fig. 1). Resting LV outflow obstruction (gradient ≥30 mmHg) was present in 28 (27%), and there was no difference in LGE progression between the groups with and without LV outflow obstruction (0.7 ± 0.9% vs 0.7 ± 1.0%, p = 0.82). Additionally, accelerated myocardial fibrosis was observed in young to middle-aged patients irrespective of the presence of LV outflow obstruction. In 74 nonobstructive patients, myocardial fibrosis progression was higher in those <60 years compared to those ≥60 years (0.9 ± 1.1 vs 0.4 ± 0.4%/year, p = 0.02). Similarly, 28 obstructive patients showed a similar trend, but the difference was not statistically significant (0.8 ± 1.1 vs 0.5 ± 0.3%/year, p = 0.26). At the follow-up, 3 patients (3%) had progression to LVEF <50% and 5 (5%) developed a new LV apical aneurysm (Fig. 2). This observation was predominantly observed in adult HCM <60 years patients. LGE progression moderately correlated with changes in LV mass, indexed LV mass index, and maximal LV end-diastolic wall thickness (r = 0.39, 0.41, 0.42, respectively, p < 0.001 for all). The intraclass correlation coefficients for inter-observer and intra-observer measurements of LGE volume were 0.89 (95% CI, 0.65–0.97) and 0.93 (95% CI, 0.76–0.98), respectively.Fig. 1 A 30-year-old male with non-sustained VT and accelerated LGE progression ≥1%/year. (A) At baseline, subtle LGE (LGE extent; 0.5%) is observed in the septal wall. (B) Follow-up CMR 8.1 years later depicts a substantial increase in the wall thickness and LGE progression at the corresponding locations, and LGE extent increases to 9.8%. CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement, VT ventricular tachycardia.

Fig. 1

Fig. 2 A 50-year-old male with accelerated LGE progression ≥1%/year and apical aneurysm formation. (A) At baseline, transmural LGE is observed at the apex, with no apical aneurysm. (B) Follow-up CMR 2.9 years later demonstrates apical aneurysm and a substantial increase in the LGE extent at the apex and new LGE in the anterior and inferior wall at the mid-ventricular level. LGE extent increases from 5.2%–14.0%. CMR cardiovascular magnetic resonance, LGE late gadolinium enhancement.

Fig. 2

4 Discussion

Our data from HCM patients with serial CMR imaging add to the considerable evidence of HCM as a progressive disease, predominantly in young to middle-aged populations. It has previously been shown that LGE increases over time but [4], [5], [6], [7]; to the best of our knowledge, this is the first study demonstrating that LGE is more progressive in patients <60 years. This finding may partially explain the impact of age at HCM diagnosis on overall mortality risk. Scar progression can alter the electrophysiologic properties through increased dispersion of action potential duration and membrane recovery and contribute to lethal ventricular arrhythmias. Thus, the fibrotic progression and tissue heterogeneity, not simply fibrotic mass, may promote reentry and result in sustained VT by creating regions of conduction block with nonuniform anisotropy and slow conduction through diffuse and heterogeneous alterations in myocardial structure [8]. This finding supports the results of previous studies showing that catheter ablation of VT in HCM is less successful, although LGE scar in HCM suggests likely similarity with macroreentrant post-infarction VT mechanisms [9]. Indeed, it is unclear whether LGE develops continuously or in a nonlinear manner. However, it may be that the rate of LGE progression is a more accurate predictor of arrhythmic events such as SCD than its presence and extent, which are also proposed by the previous study showing SCD events increased with time after initial evaluation in young to middle-aged patients [10]. Of note, these findings emphasize that it is reasonable to consider repeating CMR every 5 years, especially in young to middle-aged patients, to reevaluate for progression in LGE because a 5% LGE increase over 5 years can potentially result in a patient being reclassiﬁed in a higher severity category (e.g., from 10%–15% LGE). Given moderate correlations between LGE progression, LV mass, and maximal LV wall thickness increase, repeating cine CMR may be appropriate for assessing LGE progression for HCM patients with renal dysfunction.

4.1 Study limitations

This was a retrospective observational study, with a small sample size despite having a cohort from two tertiary medical centers, and thus some degree of survivorship bias may be present to explain why the extent of LGE may be less in older HCM patients. The decision for referral for their first or second CMR could have impacted our findings. There was a variable time interval between CMR scans. CMR images were acquired with 1.5T or 3T, which might affect LGE quantification. However, a study reported very close agreement for myocardial enhancement at both 1.5T and 3T. It is challenging to determine how changes in imaging protocols over the years have affected the LGE measurements. However, it is likely that the impact will be similar in both study groups as they were both imaged and scanned over the same period.

Although very unlikely, there might be an unrecognized subset of patients with presumed HCM who in actuality have transthyretin amyloid cardiomyopathy or Anderson-Fabry disease because this study did not incorporate native T1 mapping and 99mTc-PYP and measure alpha-galactosidase enzyme activity into the evaluation of every patient diagnosed with HCM.

5 Conclusion

One-quarter of HCM patients <60 years exhibit LGE progression ≥1%/year, underscoring the importance of repeating CMR to reevaluate for potential LGE progression in this age group. Prospective, longitudinal, large multicenter studies at fixed time intervals are warranted to examine the utility of combined assessment with LGE extent and progression and optimal scan intervals in predicting SCD in young to middle-aged adult HCM patients.

Funding

This study was supported by 10.13039/100000050 National Heart, Lung, and Blood Institute R01HL158098 . Reza Nezafat receives grant funding from the 10.13039/100000002 NIH 1R01HL129185 , 1R01HL129157 , 1R01HL127015 , and R01HL154744 (Bethesda, Maryland, USA). The remaining authors have nothing to disclose.

Author contributions

Warren J. Manning: Writing – review and editing, Supervision. Martin Maron: Writing – review and editing, Supervision. Reza Nezafat: Writing – review and editing, Writing – original draft, Supervision, Methodology, Investigation, Funding acquisition, Conceptualization. Shiro Nakamori: Writing – review and editing, Writing – original draft, Methodology, Investigation, Formal analysis, Conceptualization. Ethan J. Rowin: Writing – review and editing, Investigation, Formal analysis, Conceptualization. Jennifer Rodriguez: Writing – review and editing, Project administration. Long H. Ngo: Writing – review and editing, Supervision.

Ethics approval and consent

This study was conducted in accordance with the principles of the Declaration of Helsinki. The participating institutions' Institutional Review Board approved the protocols for this retrospective study and waived the need to obtain individual consent. No studies involving animals were performed.

Consent for publication

Not applicable.

Declaration of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledegments

Not applicable.
==== Refs
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