High Prevalence of Left Ventricular Non-Compaction and Its Effect on Chemotherapy-Related Cardiac Dysfunction in Patients With Hematological Diseases

Mitsuhito Hirano; Koichi Kimura; Tomohiro Ishigaki; Masanori Nojima; Masao Daimon; Hiroyuki Morita; Katsu Takenaka; Boqing Xu; Naoko Sawada; Megumi Hirokawa; Issei Komuro; Takayuki Morisaki; Hiroshi Yotsuyanagi; Toyotaka Kawamata; Kazuaki Yokoyama; Takaaki Konuma; Seiko Kato; Hiroshi Yasui; Tokiko Nagamura-Inoue; Kaoru Uchimaru; Satoshi Takahashi; Yoichi Imai; Arinobu Tojo

doi:10.1253/circj.CJ-20-0344

Abstract

Background: Recent progress in chemotherapy has prolonged the survival of patients with hematological diseases, but has also increased the number of patients with chemotherapy-related cardiac dysfunction (CTRCD). However, the causes of individual variations and risk factors for CTRCD have yet to be fully elucidated.

Methods and Results: Consecutive echocardiograms of 371 patients were retrospectively evaluated for the presence of left ventricular (LV) non-compaction (LVNC). Individual LV ejection fraction (LVEF) outcome estimates were made using bivariate linear regression with log-transformed duration Akaike information criterion (AIC) model fitting. The prevalence of LVNC was 6-fold higher in patients with hematological diseases than in those with non-hematological diseases (12% vs. 2%; risk ratio 6.1; 95% confidence interval [CI] 2.0, 18.2). Among patients with hematological diseases, the ratio of myeloid diseases was significantly higher in the group with LVNC (P=0.031). Deterioration of LVEF was more severe in patients with than without LVNC (–14.4 percentage points/year [95% CI –21.0, –7.9] vs. –4.6 percentage points/year [95% CI –6.8, –2.4], respectively), even after multivariate adjustment for baseline LVEF, background disease distributions, cumulative anthracycline dose, and other baseline factors.

Conclusions: LVNC is relatively prevalent in patients with hematological diseases (particularly myeloid diseases) and can be one of the major risk factors for CTRCD. Detailed cardiac evaluations including LVNC are recommended for patients undergoing chemotherapy.

Recent advances in chemotherapy treatment have significantly improved the survival of patients with hematological diseases. As survival rates increase, concerns about chemotherapy-related cardiac dysfunction (CTRCD) have become a major problem. Currently, CTRCD is one of the most serious complications, with increased morbidity and mortality.¹^,² Various chemotherapy options, including anthracyclines, alkylating agents, antimetabolites, microtubule inhibitors, monoclonal antibodies, tyrosine kinase inhibitors, and proteasome inhibitors, are associated with CTRCD.³ In particular, anthracyclines and related compounds, such as doxorubicin, daunorubicin, idarubicin, epirubicin, and the anthraquinone mitoxantrone, are known to exhibit dose-dependent cardiotoxicity. The risk of CTRCD increases when the cumulative doxorubicin dose exceeds 400–550 mg/m².¹^,⁴ However, there is considerable variability among patients in terms of their susceptibility, and a severe cardiac complication can occur even with a lower dose than the cut-off values. The timing of the clinical manifestation of CTRCD also varies widely. In most cases, early complications occur within the first year of treatment, whereas late complications can emerge as late-onset cardiotoxicity after several years.⁵^,⁶ These significant individual variations and the inability to predict CTRCD may lead to a negative effect on prognosis and inappropriate interruption of lifesaving chemotherapy.

Left ventricular (LV) non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculations, intertrabecular recesses, and LV meshwork with compacted and non-compacted myocardial layers.⁷^–¹⁰ Previous studies have reported that LVNC is a genetic disorder with a sporadic and familial form, and several gene mutations linked to LVNC have been found.¹¹^–¹³ The reported prevalence of LVNC varies widely, from 0.26–1.3% in the general population⁷^,⁸ to 3.0–3.7% in patients with heart failure,⁷^,¹⁴ 7.9–13.3% in patients with β-thalassemia,¹⁵^,¹⁶ and 19% in patients with dystrophin-associated muscular dystrophy.¹⁷ In recent years, the rate of LVNC detection has increased due to improvements in echocardiographic imaging and magnetic resonance imaging (MRI). Although most patients with LVNC are asymptomatic, the presence of LVNC in some cases can be associated with deterioration of secondary cardiac complications, lethal arrhythmias, thromboembolic events, and poor survival outcomes.⁷^–¹⁰^,¹⁸

The aim of the present study was to examine the hypothesis that the presence of LVNC can be a leading cause of CTRCD in patients with hematological diseases.

Methods

Patient Analysis

Retrospective analysis was performed in 371 consecutive patients who underwent echocardiography in our hospital (IMSUT Hospital; The Institute of Medical Science, The University of Tokyo) from January to December 2017. Fifty-six patients with significant (more than mild) valvular disease, congenital heart disease, neuromuscular disease, and/or echocardiographic images that were insufficient for evaluation of the presence of LVNC were excluded from the analysis. Of the remaining 315 patients, 110 had hematological diseases and 205 had non-hematological diseases. Because our institute is a specialized research hospital, the ratio of patients with to those without hematological diseases is relatively high compared with general hospitals.

In patients with hematological diseases, differences in characteristics were compared between those with and without LVNC. CTRCD was defined as a decline of more than 10 percentage points in LV ejection fraction (LVEF) to less than 53% in subsequent echocardiography.¹ Sequential analysis of available past echocardiographic results was used to estimate the sequential changes in LVEF after the first chemotherapy treatment.

Diagnostic Criteria for LVNC

Echocardiography was performed by an experienced cardiologist using a well-maintained Aplio400 digital ultrasound system (Toshiba Medical Systems, Tochigi, Japan) according to standardized methods described in the American Society of Echocardiography and Japanese Society of Echocardiography guidelines.¹⁹^–²¹ The Teichholz or Simpson method was used to calculate LVEF in patients without or with regional wall motion dysfunction, respectively. The presence of LVNC was diagnosed on the basis of retrospective review by a reviewer who was blinded to all patient background information. Diagnostic criteria for LVNC were proposed by Chin et al, Jenni et al, and Stollberger et al.²²^–²⁵ In the present study, the presence of LVNC was diagnosed if the echocardiogram fulfilled all the following criteria: (1) the presence of a bilayered myocardium, consisting of a thin (<8.1 mm) compacted (C) layer and a significantly thicker non-compacted (NC) layer with multiple (>3) trabeculations and C/(NC+C) being <0.5 at end-diastole; (2) NC/C >2 at end-systole; and (3) predominant localization of trabeculations and deep intertrabecular recesses in apical posterolateral regions (Figure 1).

Figure 1.

Representative echocardiograms of left ventricular non-compaction (LVNC). Representative echocardiograms of (A) a 39-year-old patient with acute myeloid leukemia and (B) a 55-year-old patient with acute lymphoblastic leukemia. LVNC is characterized by multiple trabeculations and a deep intertrabecular recess meshwork consisting of compacted and non-compacted myocardial layers (arrows) with predominant localization in apical posterolateral regions.

Statistical Analysis

All diagnoses, imaging reviews, and data collection were performed by independent researchers. All statistical analyses were performed by another independent expert statistician (M.N.) who had full access to the data and took responsibility for the integrity of the data analysis. Statistical analyses were performed using SPSS Version 25 (IBM Corp., Armonk, NY, USA). Graphs were created using GraphPad Prism Version 8.2.1 (GraphPad Software, La Jolla, CA, USA).

Univariate analyses were performed using Fisher’s exact test for categorical values and Welch’s t-test for continuous values. Linear mixed models (including individual as a random effect) were used to estimate the group-level mean LVEF change with duration after chemotherapy to obtain results that took into consideration measurement repetition, intraindividual correlation, and baseline values. To select the optimum variable transformation for the duration after chemotherapy, the Akaike information criterion (AIC) was used to evaluate model fit, which resulted in the selection of the log-transformed model, which had the smallest AIC compared with linear, squared, and cubed models. In cases where a log-transformed time scale was selected, it was assumed that the effect of the passage of time on the outcome is weakened, whereas the effect was assumed to be constant with a normal time scale. Individual estimates of changes in LVEF 12 months after chemotherapy were made using bivariate linear regression with natural log-transformed duration (i.e., ln[months+1]) with a baseline value of +1 to avoid having to calculate the logarithm of 0. After specifying a regression formula for each individual, ln(12 months+1) was assigned to the log-transformed duration term to obtain the estimate, which was used only to draw polyline graphs. In addition, potential confounding factors were adjusted for by including them in the linear mixed model, constructed as described above. Confounding factors selected in the model were age, sex (as basic demographic status), and variables with P<0.05 in the baseline comparison of with vs. without LVNC. Interaction terms were included if statistical interaction should be considered between selected variables and the duration after chemotherapy to the outcome.

Results are presented as the mean±SD, number and percentages, or 95% confidence intervals (CIs). All P values were 2-sided, and P≤0.05 were considered statistically significant.

Results

The prevalence of LVNC was 12% (13/110 patients) in patients with hematological diseases, which was 6-fold higher (risk ratio 6.1; 95% CI 2.0, 18.2; P<0.01) than that in patients with non-hematological diseases, in whom LVNC prevalence was 2% (4/205 patients; Figure 2). Of the 205 patients with non-hematological diseases, 17% (n=34) had solid tumors.

Figure 2.

Flow chart of the retrospective analysis. LVNC, left ventricular non-compaction.

Among patients with hematological diseases, there were no significant differences in baseline characteristics between those with and without LVNC, with the exception of the distribution of hematological diseases (Table 1). The proportion of patients with myeloid diseases was significantly higher in the group with LVNC (P=0.031), whereas the proportion of patients with lymphoid diseases was significantly higher in the group without LVNC (P=0.003). There was no significant difference in baseline LVEF between patients with lymphoid diseases (65.4±6.8%) and those with myeloid diseases (63.5±7.7%; P=0.450). Most of the 13 patients with hematological diseases and LVNC had myeloid diseases with detectable chromosomal aberrations (Table 2).

Table 1. Baseline Characteristics of Patients With Hematological Diseases

	LVNC absent (n=97)	LVNC present (n=13)	P value
Male sex	61 (62.9)	8 (61.5)	1.000
Age (years)	59±14	52±17	0.086
Height (cm)	163.6±9.5	166.2±9.0	0.358
Body weight (kg)	58.4±11.2	58.5±13.0	0.979
SBP (mmHg)	118±16	123±24	0.424
DBP (mmHg)	68±10	70±15	0.652
Diabetes	12 (12.4)	3 (23.1)	0.382
Hypertension	28 (28.9)	4 (30.8)	1.000
Dyslipidemia	10 (10.3)	3 (23.1)	0.182
Obesity	10 (10.3)	1 (7.7)	1.000
Smoking	18 (18.6)	1 (7.7)	0.460
Myeloid disease	34 (35.1)	9 (69.2)	0.031
Lymphoid disease	59 (60.8)	2 (15.4)	0.003
Other hematological disease	4 (4.1)	2 (15.4)	0.148

Unless indicated otherwise, data are given as the mean±SD or as n (%). DBP, diastolic blood pressure; LVNC, left ventricular non-compaction; SBP, systolic blood pressure.

Table 2. Hematological Disease Distribution in Patients With LVNC

Patient no.	Age (years)	Sex	Disease	Chromosomal aberrations in hematological cells
Myeloid diseases
1	73	Male	Myelodysplastic syndrome	Negative
2	73	Male	Myelodysplastic syndrome	Positive
3	52	Male	Myelodysplastic syndrome	Positive
4	35	Female	Acute myeloid leukemia	Positive
5	39	Male	Acute myeloid leukemia	Positive
6	71	Female	Acute myeloid leukemia	Positive
7	29	Male	Acute myeloid leukemia	N/A
8	50	Male	Chronic myeloid leukemia	Positive
9	57	Male	Myelofibrosis	Positive
Lymphoid diseases
10	55	Female	Acute lymphoblastic leukemia	N/A
11	68	Female	Angioimmunoblastic T cell lymphoma	Negative
Other diseases
12	23	Female	Idiopathic thrombocytopenic purpura	Negative
13	47	Male	Hereditary non-spherocytic hemolytic anemia	N/A

LVNC, left ventricular non-compaction; N/A, not applicable.

In the present retrospective study, sequential echocardiographic results before and after chemotherapy were available for 39 patients with hematological diseases (31 with LVNC, 8 without LVNC). There were significant differences in baseline hemoglobin between patients with and without LVNC (8.2±0.7 vs. 9.8±2.7 g/dL, respectively; P=0.004; Supplementary Table 1), but there were no differences in baseline LVEF between these 2 groups (65.1±10.3% vs. 64.6±6.3%, respectively; P=0.872; Supplementary Table 2). At 12 months after chemotherapy, the estimated CTRCD rates in patients with and without LVNC were 50% and 19%, respectively. The deterioration in LVEF was relatively mild in patients without LVNC (estimated deterioration rate −4.6 percentage points 12 months after chemotherapy; 95% CI −6.8, −2.4; Figure 3A), whereas significant deterioration was observed in those with LVNC (estimated deterioration rate −14.4 percentage points 12 months after chemotherapy; 95% CI −21.0, −7.9; Figure 3B). A comparison of long-term outcomes between the 2 groups using a visualization of a pooled linear regression analysis in sequential echocardiographic data demonstrated that the rate of LVEF deterioration was more severe in those with LVNC (Figure 3C). Even after adjusting for baseline age, sex, hemoglobin, background diseases (myeloid vs. lymphoid), LV diameter at diastole, and LVEF values in the linear mixed model, the difference in the rate of change in LVEF (from before to after chemotherapy) was significantly different between the groups with and without LVNC (estimated difference in the rate of change in LVEF −10.9 percentage points 12 months after chemotherapy; 95% CI −16.2, −5.5). During the follow-up period, there were no significant differences in chemotherapy response rates (i.e., complete response or partial response) between patients without or with LVNC (74% vs. 75%, respectively; P=1.000).

Figure 3.

Effect of left ventricular non-compaction (LVNC) on chemotherapy-related cardiac dysfunction. The presence of LVNC is associated with significant deterioration in left ventricular ejection fraction (LVEF) after chemotherapy. (A) In the group without LVNC (n=31), the mean (±SD) LVEF, estimated by individual-specific linear regression, changed from 64.6±6.3% at baseline to 59.0±7.5% 12 months after the chemotherapy (change in LVEF estimated using a group-specific linear mixed model: –4.6 percentage points; 95% confidence interval [CI] –6.8, −2.4). (B) In the group with LVNC (n=8), the mean (±SD) LVEF changed from 65.1±10.3% at baseline to 50.7±17.9% 12 months after chemotherapy (–14.4 percentage points; 95% CI –21.0, –7.9). (C) Visualization of pooled regression analysis of sequential echocardiogram data for long-term observations comparing differences in the rate of change in LVEF between patients with and without LVNC. In the group with LVNC (n=8 patients with 20 echocardiogram results) the deterioration in LVEF was significantly more severe than in the group without LVNC (n=31 patients with 62 echocardiogram results). Even after baseline adjustment using the linear mixed model, the rate of change in LVEF was significantly different between groups with and without LVNC (estimated difference in rate of change in LVEF –10.9 percentage points 12 months after chemotherapy; 95% CI –16.2, –5.5).

Furthermore, multivariate linear mixed regression analysis unexpectedly revealed that patients with lymphoid diseases (dominant among patients without LVNC) exhibited more severe LVEF deterioration (estimated difference in LVEF change rate −7.1 percentage points 12 months after chemotherapy; 95% CI −12.5, −1.6) than patients with myeloid diseases (dominant among patients with LVNC). However, because this has a negative confounding effect on the association between LVNC and LVEF caused by differences in background disease (or therapeutic differences), its adjustment could rather emphasize the difference in changes in LVEF in the presence of LVNC. In addition, despite the significant difference in baseline hemoglobin, the effect of hemoglobin on LVEF after chemotherapy was not relevant in the multivariate analysis (Supplementary Table 3).

The combinations of chemotherapeutic agents used during the observation period were too different among patients to enable separate drug analyses. However, there were no significant differences between the groups with and without LVNC with regard to the use of anthracyclines, alkylating agents, antimetabolites, microtubule inhibitors, monoclonal antibodies, tyrosine kinase inhibitors, proteasome inhibitors, and hematopoietic stem cell transplantation (Table 3). The cumulative anthracycline dose was significantly higher in group without LVNC than in the group with LVNC (124 vs. 23 mg/m², respectively; P=0.001). Although the interaction between the dose and LVNC was not significant, LVEF deterioration was more severe in the group with than without LVNC, even after adjustment for differences in cumulative anthracycline dose.

Table 3. Treatments in Patients With and Without LVNC During the Observation Period

	LVNC absent (n=31)	LVNC present (n=8)	P value
Treatment
Anthracyclines	18 (58.1)	3 (37.5)	0.432
Alkylating agents	27 (87.1)	7 (87.5)	1.000
Antimetabolites	24 (77.4)	8 (100)	0.308
Microtubule inhibitors	19 (61.3)	2 (25.0)	0.112
Monoclonal antibodies	11 (35.5)	1 (12.5)	0.394
Tyrosine kinase inhibitors	1 (3.2)	1 (12.5)	0.373
Proteasome inhibitors	1 (3.2)	0 (0)	1.000
Hematopoietic stem cell transplantation	14 (45.2)	6 (75.0)	0.235
Cumulative anthracycline dose (mg/m²)	124±139	23±39	0.001

Unless indicated otherwise, data are given as the mean±SD or as n (%). LVNC, left ventricular non-compaction.

Discussion

There are 3 major findings of the present study: (1) patients with hematological diseases had a high prevalence of LVNC; (2) most patients with LVNC and hematological diseases had myeloid diseases; and (3) the presence of LVNC was associated with a significant deterioration in cardiac function after chemotherapy.

Little is known about the relationship between LVNC and hematological diseases. To the best of our knowledge, LVNC prevalence is known to be high in one hematological disease, β-thalassemia. Using cardiac MRI, Piga et al¹⁵ and Bonamini et al¹⁶ reported a prevalence of LVNC of 8–13% in patients with β-thalassemia. Although the present study included patients with various hematological malignancies, almost the same prevalence of LVNC (12%) was found using another imaging modality (echocardiography). β-thalassemia is an inherited blood disorder characterized by abnormal hemoglobin production and severe anemia. Conversely, most of the hematological diseases in the present study were adult-onset diseases. In such acquired hematological diseases, particularly in myeloid diseases, normal hematopoiesis is often decreased or disrupted. Furthermore, chemotherapy induces severe anemia due to myelosuppression, which requires frequent transfusion. The persistence of anemia and repeated transfusions during the treatment process can induce hypoxic stress and frequent changes in LV loading conditions. This stress and these conditions may have induced, to some extent, the acquired phenotypic prominence of LVNC.

LVNC is a genetic disorder and several gene mutations linked to LVNC have already been identified.¹¹^–¹³ Although most of the hematologic tumors of adult onset are believed to result from somatic mutations, recent reports show that the development of hematologic diseases is driven not only by somatic mutations, but also by germline mutations.²⁶ Some mutual genetic and chromosomal aberrations have been reported in both LVNC and hematological diseases (Table 4). For example, deletion of chromosome 5q,²⁷^–²⁹ trisomy 13,³⁰^–³² mutations in NOTCH,³³^,³⁴ PR/SET domain 16 (PRDM16),³⁵^,³⁶ tropomyosin 1 (TPM1),³⁷^,³⁸ and tafazzin (TAZ) variants,³⁹^,⁴⁰ which are associated with LVNC, have also been reported to be related to myeloid diseases. There could be some common vulnerabilities to LVNC and hematological diseases, although further studies are necessary to clarify the association.

Table 4. Possible Relationships Between Previously Reported Gene Chromosomal Aberrations in LVNC and Hematological Diseases

Genetic and chromosomal aberrations reported in LVNC	Related hematological disease
Deletion of chromosome 5q²⁷	Myelodysplastic syndrome²⁸^,²⁹
Trisomy 13³⁰^,³¹	Acute myeloid leukemia³²
Notch or MIB1 mutation³³	Acute myeloid leukemia³⁴
PRDM16 mutation³⁵	Acute myeloid leukemia³⁶
TPM1 mutation³⁷	Acute myeloid leukemia³⁸
TAZ variants³⁹	Chronic myeloid leukemia⁴⁰

LVNC, left ventricular non-compaction; MIB1, mindbomb E3 ubiquitin protein ligase 1; PRDM16, PR/SET domain 16; TAZ, tafazzin; TPM1, tropomyosin 1.

To diagnose the presence of LVNC, we used a combination of multiple major criteria because there is no single gold-standard criterion for the diagnosis of LVNC. Using these criteria, the prevalence of LVNC in non-hematological patients was in the previously reported ranges. Moreover, in a previous study we reported a high prevalence (19%) of LVNC in patients with muscular dystrophy using the same criteria and echocardiography.¹⁷ Soon after, our findings were validated by Statile et al, who reported a higher prevalence (28%) of LVNC in patients with muscular dystrophy using cardiac MRI.⁴¹ These results suggest that our echocardiographic criteria may be relatively conservative, but at least the criteria we used avoid overdiagnosing LVNC.

The present study revealed not only the high prevalence of LVNC in hematological diseases, but also that LVNC was more frequently associated with myeloid diseases than lymphoid diseases. In patients with LVNC, myeloid diseases such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) account for a high proportion of background diseases. Because differences in the background disease will result in therapeutic differences, these differences may have affected the results in the present study. However, the results of this study showed a paradoxical effect of LVNC on LVEF deterioration in that more severe LVEF deterioration was observed in patients with lymphoid diseases (dominant in those without LVNC) than in patients with myeloid diseases (dominant in those with LVNC).

In recent years, pharmaceutical researchers have identified many drugs that can induce cardiotoxicity. CTRCD is an important issue in clinical practice and is a recent hot topic termed “cardio-oncology”. Except for a past history of cardiovascular diseases, little is known about risk factors that can be used to predict the emergence of cardiotoxicity in a patient. The present study has revealed that patients with LVNC are at high risk of significant deterioration of cardiac function after chemotherapy compared with patients without LVNC. Because the structural feature of an abnormal non-compacted LV layer is a sponge-like form with prominent trabeculations, the leading cause of the greater deterioration in LVEF may be the greater vulnerability of this abnormal myocardial layer to anemia, hypoxia, and cardiotoxicity following chemotherapy. As a result, patients with LVNC exhibited significant deterioration in LV function, even though their cumulative anthracycline dose was significantly lower than that in the group without LVNC. Our novel finding suggests that the presence of LVNC has a marked effect on patients’ long-term outcomes and is one of the major risk factors for CTRCD.

Study Limitations

This study has several limitations. Although the baseline LVEF between the groups with and without LVNC did not differ significantly, subsequent LVEF data showed high variability particularly in the group with LVNC. This high variability may have affected the results of the statistical analyses. However, we think LVEF is an established variable for CTRCD and speculate that our data are somewhat more suitable for revealing differences in subtle changes in LVEF compared with data from other institutions: in the present study, the results of echocardiography were evaluated by a single cardiologist who has expertise in echocardiography and decades of experience, whereas other larger institutions usually have more than 1 cardiologist and 1 sonographer in their echocardiography unit, which may result in interobserver fluctuations in measurement results.

The number of patients in the present study was limited, and the combination and duration of administration of chemotherapeutic agents varied widely. Although the effects of various chemotherapeutic agents on the outcome should be considered, we could only perform a multivariate analysis stratified for the use of anthracycline, and found no notable change in the interaction term between LVNC and time (without anthracycline −10.9 [95% CI −17.2, −4.6; P<0.001]; with anthracycline −8.3 [95% CI −19.0, 2.35; P=0.122]). A similar analysis for the other agents could not be performed because the distribution of the other agents was statistically skewed. Nevertheless, further prospective studies including more patients are warranted in order to clarify genetic relationships, the underlying mechanism causing cardiotoxicity, and suitable therapeutic strategies for preventing and treating CTRCD.

Conclusions

This study found that LVNC is prevalent in patients with hematological diseases, and is significantly associated with more severe deterioration of cardiac function after chemotherapy. Detailed cardiac evaluations that include LVNC are recommended for all patients undergoing chemotherapy.

Acknowledgments

The authors express their gratitude to Hisako Ishii (Department of Laboratory Medicine) and Tomoe Senkoji (Department of General Medicine, The Institute of Medical Science, The University of Tokyo) for their crucial support.

Sources of Funding

This work was supported, in part, by a Japan Society for the Promotion of Science KAKENHI grant (JP17K07092 to K.K.).

Disclosures

I.K. is a member of Circulation Journal ’ Editorial Team. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by Institutional Review Board of The Institute of Medical Science, The University of Tokyo (Reference no. 29-38-B0728). The study was performed in accordance with the Declaration of Helsinki and the ethical standards of the responsible committee on human experimentation.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0344

References

1. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 2768–2801.
2. Okwuosa TM, Prabhu N, Patel H, Kuzel T, Venugopal P, Williams KA, et al. The cardiologist and the cancer patient challenges to cardio-oncology (or onco-cardiology) and call to action. J Am Coll Cardiol 2018; 72: 228–232.
3. Jain D, Russell RR, Schwartz RG, Panjrath GS, Aronow W. Cardiac complications of cancer therapy: Pathophysiology, identification, prevention, treatment, and future directions. Curr Cardiol Rep 2017; 19: 36.
4. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: A retrospective analysis of three trials. Cancer 2003; 97: 2869–2879.
5. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266: 1672–1677.
6. Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, et al. Anthracycline-induced cardiomyopathy: Clinical relevance and response to pharmacologic therapy. Am J Coll Cardiol 2010; 55: 213–220.
7. Oechslin E, Jenni R. Left ventricular non-compaction revisited: A distinct phenotype with genetic heterogeneity? Eur Heart J 2011; 32: 1446–1456.
8. Ikeda U, Minamisawa M, Koyama J. Isolated left ventricular non-compaction cardiomyopathy in adults. J Cardiol 2015; 65: 91–97.
9. Carrilho-Ferreira P, Almeida AG, Pinto FJ. Non-compaction cardiomyopathy: Prevalence, prognosis, pathoetiology, genetics, and risk of cardioembolism. Curr Heart Fail Rep 2014; 11: 393–403.
10. Paterick TE, Tajik AJ. Left ventricular noncompaction: A diagnostically challenging cardiomyopathy. Circ J 2012; 76: 1556–1562.
11. Finsterer J, Stollberger C, Towbin JA. Left ventricular noncompaction cardiomyopathy: Cardiac, neuromuscular, and genetic factors. Nat Rev Cardiol 2017; 14: 224–237.
12. Arbustini E, Favalli V, Narula N, Serio A, Grasso M. Left ventricular noncompaction: A distinct genetic cardiomyopathy? Am J Coll Cardiol 2016; 68: 949–966.
13. Arbustini E, Weidemann F, Hall JL. Left ventricular noncompaction: A distinct cardiomyopathy or a trait shared by different cardiac diseases? Am J Coll Cardiol 2014; 64: 1840–1850.
14. Sandhu R, Finkelhor RS, Gunawardena DR, Bahler RC. Prevalence and characteristics of left ventricular noncompaction in a community hospital cohort of patients with systolic dysfunction. Echocardiography 2008; 1: 8–12.
15. Piga A, Longo F, Musallam KM, Veltri A, Ferroni F, Chiribiri A, et al. Left ventricular noncompaction in patients with beta-thalassemia: Uncovering a previously unrecognized abnormality. Am J Hematol 2012; 87: 1079–1083.
16. Bonamini R, Imazio M, Faletti R, Gatti M, Xhyheri B, Limone M, et al. Prevalence and prognostic impact of left ventricular non-compaction in patients with thalassemia. Intern Emerg Med 2019; 14: 1299–1306.
17. Kimura K, Takenaka K, Ebihara A, Uno K, Morita H, Nakajima T, et al. Prognostic impact of left ventricular noncompaction in patients with Duchenne/Becker muscular dystrophy: Prospective multicenter cohort study. Int J Cardiol 2013; 168: 1900–1904.
18. Towbin JA, Lorts A, Jefferies JL. Left ventricular non-compaction cardiomyopathy. Lancet 2015; 386: 813–825.
19. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015; 28: 1–39.e14.
20. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016; 29: 277–314.
21. Daimon M, Akaishi M, Asanuma T, Hashimoto S, Izumi C, Iwanaga S, et al. Guideline from Japanese Society of Echocardiography: 2018 focused update incorporated into Guidance for the Management and Maintenance of Echocardiography Equipment. J Echocardiogr 2018; 16: 1–5.
22. Garcia-Pavia P, de la Pompa JL. Left ventricular noncompaction: A genetic cardiomyopathy looking for diagnostic criteria. Am J Coll Cardiol 2014; 64: 1981–1983.
23. Chin TK, Perloff JK, Williams RG, Jue K, Mohrmann R. Isolated noncompaction of left ventricular myocardium: A study of eight cases. Circulation 1990; 82: 507–513.
24. Jenni R, Oechslin E, Schneider J, Attenhofer Jost C, Kaufmann PA. Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: A step towards classification as a distinct cardiomyopathy. Heart 2001; 86: 666–671.
25. Stollberger C, Gerecke B, Finsterer J, Engberding R. Refinement of echocardiographic criteria for left ventricular noncompaction. Int J Cardiol 2013; 165: 463–467.
26. Furutani E, Shimamura A. Germline genetic predisposition to hematologic malignancy. J Clin Oncol 2017; 35: 1018–1028.
27. Pauli RM, Scheib-Wixted S, Cripe L, Izumo S, Sekhon GS. Ventricular noncompaction and distal chromosome 5q deletion. Am J Med Genet 1999; 85: 419–423.
28. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355: 1456–1465.
29. Boultwood J, Fidler C, Strickson AJ, Watkins F, Gama S, Kearney L, et al. Narrowing and genomic annotation of the commonly deleted region of the 5q-syndrome. Blood 2002; 99: 4638–4641.
30. Monden Y, Shiraishi H, Ichida F, Momoi M. Trisomy 13 in a 9-year-old girl with left ventricular noncompaction. Pediatr Cardiol 2011; 32: 206–207.
31. Hayashi A, Kumada T, Nozaki F, Hiejima I, Shibata M, Kusunoki T, et al. Left ventricular noncompaction cardiomyopathy in a patient with trisomy 13: A report and review of the literature. Am J Med Genet A 2017; 173: 1947–1950.
32. Dicker F, Haferlach C, Kern W, Haferlach T, Schnittger S. Trisomy 13 is strongly associated with AML1/RUNX1 mutations and increased FLT3 expression in acute myeloid leukemia. Blood 2007; 110: 1308–1316.
33. Luxan G, Casanova JC, Martinez-Poveda B, Prados B, D’Amato G, MacGrogan D, et al. Mutations in the NOTCH pathway regulator MIB1 cause left ventricular noncompaction cardiomyopathy. Nat Med 2013; 19: 193–201.
34. Kannan S, Sutphin RM, Hall MG, Golfman LS, Fang W, Nolo RM, et al. Notch activation inhibits AML growth and survival: A potential therapeutic approach. J Exp Med 2013; 210: 321–337.
35. Arndt AK, Schafer S, Drenckhahn JD, Sabeh MK, Plovie ER, Caliebe A, et al. Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. Am J Hum Genet 2013; 93: 67–77.
36. Corrigan D, Luchsinger L, Snoeck H. The role of PRDM16 and its isoforms in acute myeloid leukemia. Exp Hematol 2016; 44(Suppl): S65 (abstract).
37. Chang B, Nishizawa T, Furutani M, Fujiki A, Tani M, Kawaguchi M, et al. Identification of a novel TPM1 mutation in a family with left ventricular noncompaction and sudden death. Mol Genet Metab 2011; 102: 200–206.
38. Handschuh L, Kazmierczak M, Milewski MC, Goralski M, Luczak M, Wojtaszewska M, et al. Gene expression profiling of acute myeloid leukemia samples from adult patients with AML-M1 and -M2 through boutique microarrays, real-time PCR and droplet digital PCR. Int J Oncol 2018; 52: 656–678.
39. Hirono K, Hata Y, Nakazawa M, Momoi N, Tsuji T, Matsuoka T, et al. Clinical and echocardiographic impact of tafazzin variants on dilated cardiomyopathy phenotype in left ventricular non-compaction patients in early infancy. Circ J 2018; 82: 2609–2618.
40. Marsola A, Simoes BP, Palma LC, Berzoti-Coelho MG, Burin SM, de Castro FA. Expression of Hippo signaling pathway and Aurora kinase genes in chronic myeloid leukemia. Med Oncol 2018; 35: 26.
41. Statile CJ, Taylor MD, Mazur W, Cripe LH, King E, Pratt J, et al. Left ventricular noncompaction in Duchenne muscular dystrophy. J Cardiovasc Magn Reson 2013; 15: 67.

Corresponding author

Register with J-STAGE for free!