Increased Left Ventricular Trabeculation Is Associated With Increased B-Type Natriuretic Peptide Levels and Impaired Outcomes in Nonischemic Cardiomyopathy

Journal Pre-proof Increased left ventricular trabeculation is associated with increased BNP level and impaired outcomes in non-ischemic cardiomyopathy Takayuki Kawamura, MD, Masakazu Yasuda, MD, Mana Okune, MD, Kazuyoshi Kakehi, MD, Yoshinori Kagioka, MD, Takashi Nakamura, MD, Shunichi Miyazaki, MD, Yoshitaka Iwanaga, MD PII:

S0828-282X(19)31268-1

DOI:

https://doi.org/10.1016/j.cjca.2019.09.012

Reference:

CJCA 3451

To appear in:

Canadian Journal of Cardiology

Received Date: 27 June 2019 Revised Date:

19 September 2019

Accepted Date: 22 September 2019

Please cite this article as: Kawamura T, Yasuda M, Okune M, Kakehi K, Kagioka Y, Nakamura T, Miyazaki S, Iwanaga Y, Increased left ventricular trabeculation is associated with increased BNP level and impaired outcomes in non-ischemic cardiomyopathy, Canadian Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.cjca.2019.09.012. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society.

Increased left ventricular trabeculation is associated with increased BNP level and impaired outcomes in non-ischemic cardiomyopathy

Takayuki Kawamura MD, Masakazu Yasuda MD, Mana Okune MD, Kazuyoshi Kakehi MD, Yoshinori Kagioka MD, Takashi Nakamura MD, Shunichi Miyazaki MD, and Yoshitaka Iwanaga MD

Division of Cardiology, Department of Internal Medicine, Kindai University Faculty of Medicine

Brief title: Hypertrabeculation in non-ischemic cardiomyopathy

Correspondence to: Yoshitaka Iwanaga MD, Division of Cardiology, Department of Internal Medicine, Kindai University Faculty of Medicine. 377-2 Ohno-Higashi, Osakasayama 589-8511, Japan Phone: +81-72-366-0221, Fax: +81-72-368-2378 E-mail: [email protected]

Word count: 4944 Number of tables and figures: 8

1

Abstract Background: The clinical significance of left ventricular (LV) trabeculation remains unknown in cardiomyopathies. B-type natriuretic peptide (BNP) strongly reflects LV end-diastolic wall stress and is a useful prognostic marker of cardiovascular diseases. The enhanced identification of LV trabeculae (T) using cardiac magnetic resonance and the evaluation of its relationship with BNP may elucidate the biological significance and clinical impact of trabeculation in patients with non-ischemic cardiomyopathy (NICM). Methods: LV volume and mass of 515 patients with NICM and 36 controls were analyzed using a steady-state free precession sequence and individual T mass was planimetered. Major adverse cardiac events (MACEs) were assessed. Results: T mass index correlated with LV end-diastolic volume index (EDVI), LV mass index, and papillary muscle mass index (all P < 0.001). Also, T mass index was positively correlated with BNP level (R = 0.381, P < 0.001) and was an independent determinant of BNP after adjusting for age, sex, body mass index (BMI), etiology, LV ejection fraction, and LVEDVI (P < 0.001). Kaplan−Meier analysis during a median follow-up of 17.3 months showed that higher T mass index/increased BNP level correlated with MACE. Upon multivariate analysis, T mass index (P = 0.031)/BNP (P < 0.001) remained associated with poor outcomes when combined with age, gender, BMI, and etiology. Conclusion:

Increased

LV

trabeculation

was

associated

with

LV

dysfunction/remodeling and impaired outcomes in NICM of various etiologies. This may support the biological significance of LV trabeculation and be attributed to its association with BNP through LV wall stress.

2

Keywords: Cardiac magnetic resonance imaging, Clinical outcomes, Non-ischemic cardiomyopathy, Trabeculae

3

Brief Summary The clinical significance of LV trabeculation remains unknown in non-ischemic cardiomyopathy (NICM). In the analysis of 515 patients with NICM using cardiac magnetic resonance, hypertrabeculation was independently correlated with increased BNP levels. LV measures, age, and etiology were also the independent determinants. Hypertrabeculation as well as increased BNP were significantly associated with poorer clinical outcomes. The present findings may shed light on the biological aspects and clinical outcomes of trabeculae formation in NICM.

4

Introduction Non-ischemic cardiomyopathy (NICM) has been increasingly recognized as a cause of cardiovascular morbidity and mortality (1,2). Historically, NICM has been characterized by changes in the morphology or function of the heart. The condition in which the heart is enlarged and thickened is termed as “hypertrophic” cardiomyopathy (HCM) whereas that in which the heart is characterized by thin wall and is enlarged is termed as “dilated” cardiomyopathy (DCM). The heart can also be stiff, disturbing normal relaxation due to infiltration; such a condition is termed as “restrictive” cardiomyopathy as in amyloidosis (i.e., cardiac amyloidosis [CA] with infiltration by amyloid protein) or sarcoidosis (i.e., cardiac sarcoidosis [CS] with granulomatous involvement of the heart). Among these, left ventricular non-compaction (LVNC) has recently received considerable attention because of its enigmatic nature, where increased trabeculation in left ventricle (LV) has reportedly been associated with adverse cardiovascular outcomes (3). To date, it remains uncertain whether LVNC is distinct from other types of NICM with different pathophysiology and outcomes (4,5). In addition, increased trabeculation has been frequently observed in other types of cardiomyopathies with variations reported even in healthy subjects (6,7). Kawel et al. reported that LV functional/morphological indices were associated with LV hypertrabeculation in 1000 participants

of the Multi-Ethnic Study of Atherosclerosis

cohort

(8).

LV

hypertrabeculation may be caused by pressure/volume overload as it results in myocardial hypertrophy. The clinical significance and relationship with the outcomes, however, remain unclear. LV hypertrabeculation may be a part of the cardiomyopathic process or just a concomitant phenomenon in patients with NICM. Cardiac magnetic resonance (CMR) using the cine steady-state free precession

5

sequence (SSFP) provides high-resolution imaging of LV with excellent visual contrast between the myocardium and LV blood pool (9). It also enables improved identification of the trabeculae (T) and papillary muscles (PMs) (10). Accordingly, we quantified T and PM using CMR imaging and analyzed the data to clarify the clinical significance of hypertrabeculation and PM hypertrophy in patients with NICM of various etiologies. The relationship between hypertrabeculation and the possible determinants, including LV geometry, function, and clinical factors, were evaluated in this study. Particularly, the association of trabeculation with plasma B-type natriuretic peptide (BNP) level, which is a useful prognostic marker reflecting myocardial wall stress, was assessed. In addition, we clarified their precise contributions to the clinical outcomes, including cardiovascular mortality and heart failure (HF) in this study.

6

Methods Study protocol This

retrospective,

single-centered

study

enrolled

consecutive

patients

with

cardiomyopathy who were referred for CMR imaging between February 2010 and December 2017 to the Kindai University Hospital. In the present cohort of NICM, patients with coronary artery diseases (significant stenosis of ≥50% of a major coronary artery determined using coronary angiography or computed tomography), significant primary valve diseases, congenital heart diseases, acute myocarditis, stress cardiomyopathy, and post-chemotherapeutic LV dysfunction were excluded (11). Those with arrhythmogenic right ventricular cardiomyopathy, Anderson-Fabry disease, and conditions associated with connective tissue disorders were also excluded because of the small number. A total of 515 patients met the eligibility criteria. This study was approved by the Institutional Review Board at our facility. Further diagnosis was made based on the following conventional criteria: LVNC, ratio of >2.3 of non-compacted to compacted myocardium in end-diastole as determined using CMR imaging (12); DCM, LV dysfunction and dilatation in the absence of coronary artery diseases and specific heart muscle diseases (13); HCM, LV hypertrophy ≥15 mm and asymmetric/focal hypertrophy in the absence of other diseases that may account for the hypertrophy (14); CS, fulfilling the guidelines published in 2017 by the Japanese Circulation Society or the characteristic manifestations and positive findings of echocardiography, 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), or CMR imaging with or without extra-cardiac sarcoidosis after excluding other known cardiac diseases (15); CA, the histological confirmation of amyloidosis

by

tissue

biopsies.

Initial

7

diagnosis

was

established

using

electrocardiography (ECG), echocardiography, and 24-h Holter ECG. Left atrial dimension and degree of mitral regurgitation (MR) were also assessed by echocardiography. MR was graded as none to mild, moderate, moderately severe or severe after analyzing jet area and width, spectral Doppler intensity, as well as regurgitation quantitation with the continuity equation and/or PISA method as appropriate (16). Plasma BNP and serum creatinine levels were also determined within a few weeks before and after CMR imaging. Estimated glomerular filtration rate (eGFR) was calculated using the equation specific to the Japanese population: eGFR = 194 × (serum creatinine) − 1.094 × (age) − 0.287 (× 0.739 for females) (17). Thirty-six subjects without any functional or morphological abnormalities using CMR imaging and without any family history of cardiovascular diseases were included in the study as controls. CMR image acquisition and analysis CMR imaging was performed using a 1.5T scanner (Intera 1.5T, Philips Medical Systems, the Netherlands) according to a standardized protocol (18). Cine images were acquired using a SSFP breath-hold sequence in three long-axis planes and contiguous short-axis slices (10 mm, no gap) from the atrioventricular ring to the apex. The LV volume, LV mass, and wall thickness were calculated using commercially available workstations (Aze Virtual Place, Aze Ltd., Japan), as previously described (19). To calculate LV mass, the endocardial and epicardial contours were outlined in a semi-automatic fashion on successive short-axis cine images at the end-diastole, and the endocardial contour was carefully drawn to exclude T and PMs (TPMs) (Figure 1A). LV mass was derived by the summation of volume obtained using the disk method and the myocardial muscle weight was obtained by multiplying it by 1.05 g/cm3 (18). To assess

8

TPM mass, the endocardial border was drawn to include T and PMs using a semi-automatic threshold tool based on the difference between bright blood and darker myocardial intensities, and LV plus TPM mass was calculated (Figure 1B). LV trabeculation was defined at the end-diastolic phase as myocardium protruding from the LV wall into the LV cavity. Then, the contours of PMs were manually drawn separately on each end-diastole in every slice (Figure 1C). If PMs could not be clearly distinguished from T on long- and short-axis images, they were treated as T (7,12). T mass, which was defined as the mass including all LV trabeculations and excluding the PMs and LV blood between the T, was calculated by subtracting PM mass from TPM mass (Figure 1D). These measurements were performed by the researchers (T.K. and M.Y.) blinded to the patients’ clinical data and outcomes. Clinical follow-up Long-term clinical follow-up through 83 months from CMR testing was accomplished using a questionnaire that was completed by the patient, telephone interview, or chart review. Combined major adverse cardiac event (MACE) measures were cardiovascular mortality, admission for worsening HF, and sustained ventricular tachycardia/fibrillation, including appropriate implantable cardioverter-defibrillator discharge. Although all events were based on clinical diagnosis, patient medical records were reviewed by the authors or the physician-in-charge who were blinded to the CMR and baseline clinical data to validate these events. Statistical analysis The groups were compared using the χ2 test for proportions and an unpaired t-test or analysis of variance for continuous variables, as appropriate. Linear regression analysis determined the linearity of the relationship between two variables, and Pearson’s

9

correlation coefficient was calculated. Furthermore, multiple logistic regression analysis was used to determine the predictors of T mass index or BNP among significant factors obtained by univariate analysis using the JMP V.13.0 (SAS Institute, USA). Event-free survival curves were analyzed using the Kaplan–Meier method, and the curves were compared using the log-rank test. Multivariate analysis of the clinical outcomes was evaluated using the Cox’s proportional hazard model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Reproducibility was assessed using intraclass correlation coefficient (ICC) using a randomly selected sub-sample of 50 subjects. A value of P < 0.05 was considered to be statistically significant. Results are presented as the mean ± standard deviation (SD).

10

Results Baseline patient characteristics A total of 515 consecutive patients with NICM who underwent CMR imaging were enrolled and analyzed in the present study. Baseline clinical characteristics of patients with NICM are shown in Table 1. The mean age of patients was 64.2 ± 13.9 years, and 59.4% of the patients were male. According to the New York Heart Association (NYHA) functional classification, 38.3% of patients were symptomatic (i.e., NYHA classification ≥ II) and mean plasma BNP level was 242.7 ± 356.2 pg/mL. The most frequent etiology was DCM (36.9%) followed by HCM (33.4%). In contrast, there were only 13 patients with CA (2.5%). In normal controls (n = 36), the mean age was 66.0 ± 14.6 years and 50.0% of the subjects were male, which were not different from those in patients with NICM. CMR imaging findings CMR imaging of T mass in 6 representative cases, a control and patients with LVNC, DCM, HCM, CS, and CA are depicted in Figure 1E. Baseline CMR measurements showed that in patients with NICM, LV ejection fraction (EF) was significantly lower and LV mass index, PM mass index, and T mass indices were higher than in controls (all P < 0.001). Conversely, EDV/LV mass, PM mass/LV mass, T mass/LV mass, and PM mass/T mass ratios were similar between the two groups. Compared with controls, significantly higher T mass index was observed in patients with NICMs other than CS (P < 0.01, Figure 2A). T mass index was also greater in those with LVNC than in those with DCM, HCM, or CS (all P < 0.001). A significantly higher T mass/LV mass ratio was noted only in patients with LVNC compared to other groups of NICM or normal subjects (all P < 0.001). Regarding reproducibility of CMR imaging findings,

11

interobserver ICCs were 0.93, 0.94, 0.96, 0.87, and 0.85 for EDV, end-systolic volume (ESV), LV mass, PM mass, and T mass, respectively. Univariate and multivariate analysis for assessing determinants of T mass index or BNP T mass index was positively associated with log BNP levels in all patients with NICM and controls (n = 551) (Figure 2B). Positive correlations were also observed between the T mass index and LV EDV, LV mass, and PM mass indices, whereas LV EF was negatively correlated (Figure 3). Similar correlations were observed in a subset analysis involving only patients with LVNC (n = 39) (Supplemental Figure S1). Table 3 shows the predictors of T mass index and log BNP level determined using multivariable regression analysis. The independent predictors of T mass index were log BNP level, LV EDV index, LV mass index, PM mass index, etiology, and age; the independent predictors of log BNP level were T mass index, LV EDV index, LV EF, etiology, age, gender, and body mass index (BMI) (Table 3). Clinical outcomes During a median follow-up of 17.7 months, 83 (16.1%) patients had MACEs. Moreover, 17 patients died due to sudden cardiac arrest, 15 patients had severe ventricular arrhythmias, and 51 patients were hospitalized with HF. The Kaplan–Meier analysis showed significant associations between clinical outcomes and the T mass index grouping by the median value (low < 12.1 g/m2, high ≥ 12.1 g/m2) (P = 0.002, Figure 4A) and T mass/LV mass grouping by the median value (low < 0.171 g/m2, high ≥ 0.171 g/m2) (P = 0.021, Figure 4B). In addition, high BNP levels (median value, ≥131.1) were associated with poor clinical outcomes (P < 0.001, Figure 4C). Age, BMI, and etiology were also associated with MACE (Supplemental Figure S2). In multivariable Cox

12

proportional analysis, T mass index (model 1), T mass/LV mass (model 2), and log BNP level (model 3) were independently associated with MACE (all models P < 0.001) when they were combined with age, gender, BMI, and etiology (Table 4). Furthermore, the combined analysis for T mass index and BNP level showed that the group with higher T mass index/higher BNP level was associated with the highest risk of MACE (P < 0.001, Figure 4D). In multivariable Cox proportional analysis after adjusting for age, gender, BMI groups, and etiology, T mass index group (HR, 2.000; 95% CI, 1.180-3.476; P = 0.010) and BNP level group (HR,1.895; 95% CI, 1.136-3.260; P = 0.014) were independently associated with MACE. Sub-analysis in patients with each form of NICM (DCM, HCM, CS, or CA) showed that CA showed the worst prognosis (P < 0.001, Supplemental Figure S2). CS showed worse prognosis than DCM or HCM (P < 0.05) and there was no difference between DCM and HCM. The Kaplan–Meier analysis in DCM, CS, and CA showed significant associations between clinical outcomes and the T mass index grouping by each median value (Supplemental Figure S3). In HCM, the association was not significant (P = 0.139), however, there was a significant association between MACE and T mass/LV mass (P = 0.044). The lower value of T mass index was associated with poor outcomes only in CA.

13

Discussion Trabeculae in controls and patients with NICM This study was undertaken to elucidate the biological significance and clinical impact of trabeculation in patients with NICM. We found that compared with controls, patients with NICM exhibited significantly increased T mass in addition to increased PM mass. However, there was no difference in T mass/LV mass ratio between the groups. This was concordant with a previous report, which showed that for patients with DCM, HCM, LVNC and controls, only LVNC was associated with the increased T mass/LV mass ratio (12). Dawson et al. studied normal LV trabeculation as the basis of differentiation from pathological noncompaction in 120 volunteers using CMR imaging (20). They measured the thickness of trabecular and compacted layers in LV segments and observed age- and sex-related morphometric differences. A negative association of LV EF and a positive association of LV EDV and LV ESV with the maximum ratio of non-compacted (trabeculated) versus compacted myocardium were found in both the entire cohort and subjects without cardiac diseases or hypertension in 1000 participants of the Multi-Ethnic Study of atherosclerosis cohort (8). Both LV EDV and LV ESV were also positively associated with the maximum thickness of trabeculation. However, although an increased T mass was observed in patients with NICM (12), a detailed analysis was not performed and the pathophysiological and clinical significances are still unclear. The current study therefore attempted to clarify this and demonstrated that T mass index independently reflected many parameters including LV EDV index, LV mass index, PM mass index, and LV EF (Table 3). Furthermore, poor clinical outcomes were significantly associated with increased T mass index and T mass/LV mass ratio.

14

Thus, LV hypertrabeculation may be a significant prognostic marker as it reflects hemodynamic and geometric alterations in NICM. Relationship of trabeculation with BNP Recently, we reported that plasma BNP may be a more sensitive integrated marker for assessing clinical outcomes than LV mass or LV fibrosis mass in patients with HCM (21). In the present study, the BNP level independently reflected T mass index and was also an excellent prognostic marker. We previously demonstrated an excellent correlation between BNP level and LV end-diastolic wall stress (EDWS) (R2 = 0.89, P < 0.001) in patients with HF of various etiologies (22). Increased LV EDWS is associated with LV remodeling, which eventually leads the disease progression, by increasing myocardial oxygen consumption and inducing ventricular hypertrophy, a feedback response for normalizing wall stress; cardiac decompensation is assumed to be a dysfunction of this feedback loop (23). In this process, hormones and molecules such as catecholamine, angiotensin, endothelin, inflammatory cytokines, reactive oxygen species, and matrix metalloproteinase may cause various molecular and cellular remodeling in myocytes and fibroblasts in a direct or indirect manner (24,25). Halaney et al. reported that the presence of trabeculae reduces wall stress in the apex, where free-running trabeculae are frequently observed and where wall stress may be the highest (26). Although EDWS was not estimated in the present study, a robust association between BNP levels and T mass index suggests that increased LV EDWS may enforce the generation of trabeculation as a compensatory mechanism (27). This phenomenon may establish an association with the hypothesis that multiple diverse pathophysiologies can produce such a common phenotype as hypertrabeculation. Comparison between LVNC and other NICMs

15

LVNC has recently received considerable attention because of its enigmatic nature; moreover, there has been considerable discussion on whether LVNC is a physiological or pathological phenotype of the myocardium. Oechslin et al. proposed three groups of the myocardial phenotype of LVNC; noncompaction cardiomyopathy, pathologic remodeling, and physiologic, reversible remodeling (28). In pathologic remodeling, increase in volume or pressure results in myocardial hypertrophy; similarly, it could also result in the morphological appearance of LVNC. In the sub-group analysis of patients with LVNC in the present study, similar associations between T mass index and BNP level or LV measures (LV EDV index, LV mass index, PM mass index, and LV EF) were observed despite high T mass values. At least in part, the pathologic remodeling pathway may be working in patients of LVNC etiology investigated in this study, and also common to other etiologies of NICM. Although the genetic basis of LVNC is heterogeneous and often overlapping with those of other NICM, specific mutations associated with LVNC like bone morphogenetic protein 10 may suggest that LVNC is a genetically determined specific cardiomyopathy with the unique pathogenesis (4,5,29). LVNC is complex and heterogeneous, and may be a syndrome partially associated with other etiologies of NICM. Study limitations Several limitations should be considered when interpreting the results of this study. First, in addition to the relatively small population size of each etiology, the study population comprised older patients (64.2 ± 13.9 years) compared with those enrolled in most studies of NICM (10). Thus, potential confounders that arise with aging that may affect the implementation of the findings (19). Second, as consecutive patients with NICM who were referred for CMR imaging to a single center were enrolled, a significant

16

selection bias as well as a biased distribution of the disease etiology may be expected. A multi-center approach to increase patient’s numbers for various etiologies of NICM will be necessary. Third, genetic tests were not conducted for the studied patients. Genetic difference between Japanese and Caucasian patients is a possible confounder that may affect the results of our study (30). Lastly, we could not perform serial CMR examination and BNP testing in the present study. Associations of functional/geometric changes including EF and T mass over time with clinical outcomes or BNP changes, may reveal additional insights about trabecular formation. Conclusions T mass assessed using CMR imaging and comprehensively analyzed in 515 consecutive patients with NICM and 36 controls revealed that hypertrabeculation was independently associated with increased BNP levels. LV EDV index, LV mass index, PM mass index, age, and etiology were also the independent determinants of T mass index. Hypertrabeculation, as well as increased BNP, were significantly associated with poor clinical outcomes. These findings suggest that increased T mass reflects LV functional/morphological alterations in association with increased BNP levels and may have a potential value in making prognostic predictions and guiding therapy in patients with NICM of various etiologies. Hypertrabeculation is perhaps a trait shared among different cardiac diseases, and a close relationship between LV trabeculation and BNP levels may explain hypertrabeculation generated by increased LV wall stress.

17

Acknowledgements None

Sources of funding None

Competing Interests The authors declare that they have no competing interests.

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Japan. Ann Nucl Cardiol 2017;31:42–45. 16. Zoghbi WA, Enriquez-Sarano M, Foster E, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777–802. 17. Matsuo S, Imai E, Horio M, et al; Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis. 2009;53:982–92. 18. Kramer CM, Barkhausen J, Flamm SD, Kim RJ, Nagel E. Standardized cardiovascular magnetic resonance imaging (CMR) protocols, society for cardiovascular magnetic resonance: board of trustees task force on standardized protocols. J Cardiovasc Magn Reson 2008;10:35. 19. Nakamura T, Iwanaga Y, Yasuda M, et al. Relationship of basal-septal fibrosis with LV outflow tract obstruction in hypertrophic cardiomyopathy: insights from cardiac magnetic resonance analysis. Int J Cardiovasc Imaging 2016;32:613–20. 20. Dawson DK, Maceira AM, Raj VJ, Graham C, Pennell DJ, Kilner PJ. Regional thicknesses and thickening of compacted and trabeculated myocardial layers of the normal left ventricle studied by cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2011;4:139–46. 21. Miyaji Y, Iwanaga Y, Nakamura T, Yasuda M, Kawamura T, Miyazaki S. Interrelationship between the Myocardial Mass, Fibrosis, BNP, and Clinical Outcomes in Hypertrophic Cardiomyopathy. Intern Med. 2016;55:1261–8. 22. Iwanaga Y, Nishi I, Furuichi S, et al. B-type natriuretic peptide strongly reflects diastolic wall stress in patients with chronic heart failure: comparison between systolic and diastolic heart failure. J Am Coll Cardiol 47:742–48, 2006.

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23. Yin FC. Ventricular wall stress. Circ Res 1981;49:829–42. 24. Colucci WS. Molecular and cellular mechanisms of myocardial failure. Am J Cardiol 1997;80:15L–25L. 25. Di Napoli P, Taccardi AA, Grilli A, et al. Left ventricular wall stress as a direct correlate of cardiomyocyte apoptosis in patients with severe dilated cardiomyopathy. Am Heart J 2003;146:1105–11. 26. Halaney DL, Sanyal A, Nafissi NA, et al. The Effect of Trabeculae Carneae on Left Ventricular Diastolic Compliance: Improvement in Compliance With Trabecular Cutting. J Biomech Eng. 2017;139. 27. Lee J, Vedula V, Baek KI, et al. Spatial and temporal variations in hemodynamic forces initiate cardiac trabeculation. JCI Insight. 2018;3:e96672. 28. Oechslin E, Jenni R. Left Ventricular Noncompaction: From Physiologic Remodeling to Noncompaction Cardiomyopathy. J Am Coll Cardiol. 2018;71:723– 26. 29. Hirono K, Saito K, Munkhsaikhan U, et al. Familial Left Ventricular Non-Compaction Is Associated With a Rare p.V407I Variant in Bone Morphogenetic Protein 10. Circ J. 2019;83:1737–1746. 30. Otsuka H, Arimura T, Abe T, et al. Prevalence and distribution of sarcomeric gene mutations in Japanese patients with familial hypertrophic cardiomyopathy. Circ J. 2012;76:453–61.

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Table 1. Baseline clinical characteristics of patients

All patients (n = 515) Age (years)

64.2 ± 13.9

Males

306 (59.4)

BMI (kg/m2)

23.0 ± 4.3

NYHA functional class ≥II

197 (38.3)

Atrial fibrillation

112 (21.7)

VT/VF

107 (20.8)

Hospitalization for HF

200 (38.8)

BNP (pg/mL)

242.7 ± 356.2

eGFR (mL/min/1.73 m2)

78.6 ± 25.1

LAD (mm)

41.9 ± 7.3

Moderate or greater MR

129 (25.1)

Medication Ca-blocker

139 (27.0)

β-blocker

299 (58.1)

ACEI/ARB

314 (61.0)

Diuretic

213 (41.4)

MRA

102 (19.8)

Inotropic agents

20 (3.9)

Antiarrhythmic agents

38 (7.4)

Diagnosis LVNC DCM

39 (7.6) 23

190 (36.9)

HCM

172 (33.4)

CS

101 (19.6)

CA

13 (2.5)

Values are presented as mean ± SD or number (%) ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; BNP, B-type natriuretic peptide; CA, cardiac amyloidosis; CS, cardiac sarcoidosis; DCM, dilated cardiomyopathy; eGFR, estimated glomerular filtration rate; HCM, hypertrophic cardiomyopathy; HF, heart failure; LAD, left atrial dimension; LVNC, left ventricular noncompaction; MR, mitral regurgitation; MRA, mineralocorticoid receptor antagonist; NYHA, New York Heart Association; VT/VF, ventricular tachycardia/fibrillation

24

Table 2. Cardiac magnetic resonance imaging findings of patients

All patients

Controls

(n = 515)

(n = 36)

LV EF (%)

37.3 ± 15.3

55.2 ± 5.5

<0.001

LV EDV index (mL/m2)

111.2 ± 40.7

77.8 ± 11.6

<0.001

LV ESV index (mL/m2)

74.3 ± 43.5

35.0 ± 7.6

<0.001

LV mass index (g/m2)

73.6 ± 23.7

50.1 ± 6.6

<0.001

LV EDV/mass ratio (mL/g)

1.57 ± 0.51

1.57 ± 0.24

0.957

PM mass index (g/m2)

4.26 ± 1.81

2.80 ± 0.82

<0.001

PM mass/LV mass ratio

0.059 ± 0.021

0.056 ± 0.015

0.388

T mass index (g/m2)

13.6 ± 6.7

8.6 ± 2.3

<0.001

T mass/LV mass ratio

0.186 ± 0.076

0.170 ± 0.038

0.221

PM mass/T mass ratio

0.362 ± 0.182

0.351 ± 0.150

0.742

P value

Values are the mean ± SD. EDV, end-diastolic volume; EF, ejection fraction; ESV, end-systolic volume; LV, left ventricular; PM, papillary muscle; T, trabeculae

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Table 3. Predictors determined using multivariable regression analysis

Variables

β coefficient

P value

Log BNP

0.094

0.009

LV EDV index

0.339

<0.001

LV mass index

0.301

<0.001

PM mass index

0.092

0.012

-

<0.001

0.068

0.030

T mass index

0.166

<0.001

LV EDV index

0.182

0.003

LV EF

−0.345

<0.001

-

<0.001

Age

0.142

<0.001

Gender (male)

0.090

0.016

BMI

−0.213

<0.001

Predictors of T mass index

Etiology Age

Predictors of log BNP

Etiology

BMI, body mass index; BNP, B-type natriuretic peptide; EDV, end-diastolic volume; EF, ejection fraction; LV, left ventricular; PM, papillary muscle; T, trabeculae; β coefficient, the standardized partial regression coefficient

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Table 4. Multivariate Cox proportional hazard analysis for MACE

Variables

Hazard ratio

95% CI

Model 1

P value <0.001

T mass index

1.036

1.003–1.070

0.031

Age

1.018

0.998–1.039

0.073

Gender (male)

1.311

0.821–2.117

0.261

BMI

0.884

0.829–0.943

<0.001

-

-

<0.001

Etiology

Model 2

<0.001

T mass/LV mass

57.82

4.222–791.9

0.002

Age

1.018

0.998–1.038

0.079

Gender (male)

1.338

0.835–2.166

0.230

BMI

0.879

0.824–0.938

<0.001

-

-

<0.001

Etiology

Model 3

<0.001

Log BNP

1.425

1.178–1.724

<0.001

Age

1.018

0.998–1.038

0.078

Gender (male)

1.384

0.873–2.219

0.171

BMI

0.911

0.854–0.973

0.005

-

-

<0.001

Etiology

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Three models were examined to clarify the association of MACE with each variable; T mass index (model 1), T mass/LV mass (model 2), and log BNP (model 3), after adjustment of baseline clinical factors. BMI, body mass index; BNP, B-type natriuretic peptide; CI, confidence interval; MACE, major adverse cardiac events; T, trabeculae

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Figure legends Figure 1. Quantification of LV mass, TPM mass, PM mass, and T mass in a representative case. The endocardial (blue line) and epicardial contours (red line) were outlined on successive short-axis cine images at the end-diastole, and the endocardial contour was carefully drawn to exclude TPMs for LV mass calculation (A). The endocardial border (green line) was drawn to include T and PMs for TPM/LV mass calculation (B). The contours of PMs (yellow line) were manually drawn separately for PM mass calculation (C). T mass shown in pink was calculated by subtracting PMs mass from TPM mass (D). Representative T mass images (pink) in a control, LVNC, DCM, HCM, CS, and CA cases were shown (E). DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LV, left ventricular; LVNC, LV noncompaction; PM, papillary muscle; T, trabeculae; TPM, trabeculae and papillary muscle

Figure 2. T mass index and T mass/LV mass ratio in controls and patients with NICM (A) and its relationship with BNP levels (B) BNP, B-type natriuretic peptide; Con, control; CA, cardiac amyloidosis; CS, cardiac sarcoidosis; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LVNC, left ventricular noncompaction; T, trabeculae

Figure 3. Associations between T mass index and LV EDV index (A), LV mass index (B), PM mass index (C), and LV EF (D) EDV, end-diastolic volume; EF, ejection fraction; LV, left ventricular; PM, papillary muscle; T, trabeculae

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Figure 4. Kaplan–Meier analysis for MACE-free survival in patients stratified according to baseline T mass index (A), T mass /LV mass ratio (B), BNP level (C), and T mass index/BNP levels (D). High group: red dotted line and low group: blue solid line BNP, B-type natriuretic peptide; LV, left ventricular; MACE, major adverse cardiac events; T, trabeculae

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