Efficacy of a fine fiber film applied with a water-based lotion to improve dry skin.

BACKGROUND: Dry skin can trigger eczema that affects >10% of the US population. Dressing films have been developed to improve diseased skin, but there is limited knowledge about their effects, especially for dry skin-related symptoms. We developed an electrospinning method that creates a coating film, called a fine fiber (FF) film, characterized by the production of a transparent, thin, flexible, and adherent membrane on the skin surface. OBJECTIVE: The aim of this pilot study was to examine the effects of the FF film on dry skin. METHODS: Three treatments (lotion only, lotion with the FF film, and lotion with an alternative film) were designed to treat subjects with rough skin on their lower legs. Twenty-four females were enrolled and used either a water-based lotion U or a petrolatum-based lotion P and the FF film for 2 weeks followed by a regression phase for 1 week. Skin hydration and roughness scores were assessed as were the subjects' perceptions of the effects. RESULTS: When the FF film was applied with lotion U, skin hydration was significantly improved even after 1 week, accompanied by a significant improvement of skin roughness and an increase in skin hydration by the end of the regression phase. An evaluation of moisture permeability suggested that the FF film, especially with lotion U, performed as a semipermeable membrane with optimal moisture healing effects on dry skin. CONCLUSION: The FF film together with a water-based lotion is a promising treatment to quickly improve dry skin conditions.

Non-invasive human skin transcriptome analysis using mRNA in skin surface lipids.

Non-invasive acquisition of mRNA data from the skin can be extremely useful for understanding skin physiology and diseases. Inspired by the holocrine process, in which the sebaceous glands secrete cell contents into the sebum, we focused on the possible presence of mRNAs in skin surface lipids (SSLs). We found that measurable levels of human mRNAs exist in SSLs, where the sebum protects them from degradation by RNases. The AmpliSeq transcriptome analysis was modified to measure SSL-RNA levels, and our results revealed that the SSL-RNAs predominantly comprised mRNAs derived from sebaceous glands, the epidermis, and hair follicles. Analysis of SSL-RNAs non-invasively collected from patients with atopic dermatitis revealed increased expression of inflammation-related genes and decreased expression of terminal differentiation-related genes, consistent with the results of previous reports. Further, we found that lipid synthesis-related genes were downregulated in the sebaceous glands of patients with atopic dermatitis. These results indicate that the analysis of SSL-RNAs is a promising strategy to understand the pathophysiology of skin diseases.

Exploitation of long-lasting ultraweak photon emission to estimate skin photodamage after ultraviolet exposure.

BACKGROUND: Establishing a noninvasive method to estimate skin damage immediately after ultraviolet (UV) exposure is required to minimize the anticipated severe symptoms triggered by early phase UV-induced reactions in the skin. To develop a suitable method, we focused on ultraweak photon emission (UPE) immediately after UV exposure to characterize the relationship of UPE to skin photodamage caused by the UV exposure. MATERIALS AND METHODS: Analysis of the correlation between UV-induced UPE and erythema formation characterized by skin redness was conducted in a clinical study. To clarify the source of UPE, time-dependent lipid oxidation was analyzed in human epidermal keratinocytes in vitro using a fluorescence indicator as well as the lipid hydroperoxide (LPO) assay. RESULTS: The average amount of UV-induced long-lasting UPE per second, especially from 1 to 3 minutes compared to other time periods after the UV radiation, increased in a dose-dependent manner and was highly correlated with the intensity of cutaneous redness 24 hours after UV exposure. In addition, cellular examinations elucidated that both the long-lasting UPE signals and the increased amounts of LPO 2 minutes after UV radiation were significantly suppressed by Trolox (a vitamin E derivative), which has been shown to inhibit UV-induced erythema formation in human skin. CONCLUSION: Long-lasting UPE generated between 1 and 3 minutes immediately after UV exposure, which is associated with LPO production, is a valuable indicator to estimate and/or avoid severe cutaneous photodamage.

Autophagy Declines with Premature Skin Aging resulting in Dynamic Alterations in Skin Pigmentation and Epidermal Differentiation.

Autophagy is a membrane traffic system that provides sustainable degradation of cellular components for homeostasis, and is thus considered to promote health and longevity, though its activity declines with aging. The present findings show deterioration of autophagy in association with premature skin aging. Autophagy flux was successfully determined in skin tissues, which demonstrated significantly decreased autophagy in hyperpigmented skin such as that seen in senile lentigo. Furthermore, an exacerbated decline in autophagy was confirmed in xerotic hyperpigmentation areas, accompanied by severe dehydration and a barrier defect, which showed correlations with skin physiological conditions. The enhancement of autophagy in skin ex vivo ameliorated skin integrity, including pigmentation and epidermal differentiation. The present results indicate that the restoration of autophagy can contribute to improving premature skin aging by various intrinsic and extrinsic factors via the normalization of protein homeostasis.

Impact of infliximab administration before plasma exchange therapy on patients with Kawasaki disease.

Plasma exchange is a therapeutic option in refractory Kawasaki disease (KD). However, the effects of other immunosuppressive treatments on plasma exchange therapy have not been studied. We investigated the effect of infliximab on plasma exchange in KD as well as on the outcome in patients with KD. We studied 16 patients with intravenous immunoglobulin-resistant KD who finally underwent plasma exchange. The patients were divided into two groups: patients who received infliximab before plasma exchange (infliximab group) and patients who did not (non-infliximab group). The infliximab group showed a lesser median number of required total plasma exchange sessions (P = .002) and higher change and reduction rates in C-reactive protein before and after the first plasma exchange (both P = .027) than that of the non-infliximab group. Infliximab administered before plasma exchange reduced the number of total plasma exchange sessions and improved the plasma exchange efficacy.

The Surprising Effect of Phenformin on Cutaneous Darkening and Characterization of Its Underlying Mechanism by a Forward Chemical Genetics Approach.

Melanin in the epidermis is known to ultimately regulate human skin pigmentation. Recently, we exploited a phenotypic-based screening system composed of ex vivo human skin cultures to search for effective materials to regulate skin pigmentation. Since a previous study reported the potent inhibitory effect of metformin on melanogenesis, we evaluated several biguanide compounds. The unexpected effect of phenformin, once used as an oral anti-diabetic drug, on cutaneous darkening motivated us to investigate its underlying mechanism utilizing a chemical genetics approach, and especially to identify alternatives to phenformin because of its risk of severe lactic acidosis. Chemical pull-down assays with phenformin-immobilized beads were performed on lysates of human epidermal keratinocytes, and subsequent mass spectrometry identified 7-dehydrocholesterol reductase (DHCR7). Consistent with this, AY9944, an inhibitor of DHCR7, was found to decrease autophagic melanosome degradation in keratinocytes and to intensely darken skin in ex vivo cultures, suggesting the involvement of cholesterol biosynthesis in the metabolism of melanosomes. Thus, our results validated the combined utilization of the phenotypic screening system and chemical genetics as a new approach to develop promising materials for brightening/lightening and/or tanning technologies.

Quantitative changes in the secretion of exosomes from keratinocytes homeostatically regulate skin pigmentation in a paracrine manner.

The content and distribution of melanin in the epidermis determines the wide variety of skin colors associated with ethnic/racial diversity. Although it was previously reported that qualitative changes in keratinocyte-derived exosomes regulate melanocyte pigmentation in vitro, their practical involvement, especially in skin color development in vivo, has remained unclear. To address this unexplained scientific concern, the correlation of epidermal exosomes isolated from human skin tissues with melanosomal protein expression levels was demonstrated in this study for the first time. After confirming the quantitative effect of human keratinocyte-derived exosomes on human melanocyte activation, even in the absence of ultraviolet B (UV-B) exposure, the impact of exosomes secreted from UV-B-irradiated keratinocytes on melanogenesis was consistently detected, which suggests their constitutive role in regulating cutaneous pigmentation. Additionally, both a specific exosome secretion inducer and a suppressor were consistently found to significantly control melanin synthesis in a co-culture system composed of keratinocytes and melanocytes as well as in an ex vivo skin culture system. These results suggest that quantitative changes, in addition to already known qualitative changes, in exosomes secreted from human epidermal keratinocytes homeostatically regulate melanogenic activity in a paracrine manner, which leads to skin color determination.

A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected. METHODS: To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes. RESULTS: The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD. CONCLUSION: These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.

Transient Q-waves in an infant with asymptomatic myocardial infarction due to Kawasaki disease.

Giant coronary artery aneurysms are a complication of Kawasaki disease and can be fatal if associated with thrombosis. We describe the clinical outcome of a boy with Kawasaki disease who exhibited "supergiant" coronary artery aneurysms at the age of 14 months and, despite treatment with anticoagulant and antiplatelet medication, developed a left coronary artery thrombosis and presented following a myocardial infarction at 2 years old. Although his symptoms were minimal, the myocardial infarction was identified by abnormal Q-waves and giant negative T-waves in precordial leads of routine electrocardiography. Intensive anticoagulant therapy combining heparin injections and high-dose warfarin was successful. The abnormal Q-waves and negative T-waves had completely disappeared 2 weeks later, likely in association with confirmed reperfusion. On the basis of prompt identification of abnormal Q-waves by electrocardiography, the patient could avoid thrombolytic therapy and catheter or surgical intervention.

Substantial evidence for the rhododendrol-induced generation of hydroxyl radicals that causes melanocyte cytotoxicity and induces chemical leukoderma.

BACKGROUND: Rhododendrol (4-(4-hydroxyphenyl)-2-butanol) has been used as a lightening/whitening cosmetic but was recently reported to induce leukoderma. Although rhododendrol has been shown to be transformed by tyrosinase to hydroxyl-rhododendrol, which is cytotoxic to melanocytes, its detailed mechanism of action including the involvement of reactive oxygen species is not clearly understood. OBJECTIVE: To confirm the relationship of hydroxyl radical generation to melanocyte cytotoxicity induced by rhododendrol, this study was performed. METHODS: An electron spin resonance method with a highly sensitive detection system was utilized to monitor hydroxyl radicals generated from two distinct normal human epidermal melanocyte lines with different levels of tyrosinase activity after the addition of various amounts of rhododendrol. Cytotoxicity of rhododendrol was analyzed by AlamarBlue assay under the same condition. RESULTS: Hydroxyl radicals were generated depending on the amounts of rhododendrol and/or tyrosinase. After the correlation between hydroxyl radical generation with melanocyte viability was confirmed, an inhibitor of oxidative stress, N-acetyl cysteine, was shown to dramatically diminish rhododendrol-induced generation of hydroxyl radicals and melanocyte cytotoxicity by increasing glutathione levels. In contrast, buthionine sulfoximine, which depletes glutathione, augmented both of those parameters. CONCLUSION: Suppressing oxidative stress would prevent and/or mitigate some phenol derivative-induced leukoderma by avoiding hydroxyl radical-initiated melanocyte cytotoxicity.

Decreased Circulating Insulin-Like Growth Factor 1 Levels Are Associated with Cardiac Diastolic Dysfunction in Small for Gestational Age Infants.

OBJECTIVE: To evaluate the impact of serum insulin-like growth factor-1 (IGF-1) levels on cardiac function in small for gestational age (SGA) infants. STUDY DESIGN: This is a prospective, observational study. Serum IGF-1 levels at birth and echocardiography measurements at 1 week of age were compared between SGA and appropriate for gestational age (AGA) infants. RESULTS: Thirty-one SGA infants and 27 AGA infants were enrolled. Serum IGF-1 levels were lower in the SGA infants than in the AGA infants. SGA infants had lower mitral lateral annular systolic (S') and early diastolic (E') tissue Doppler imaging velocities compared with AGA infants (S', 5.1 ± 0.9 vs 5.7 ± 1.2 cm/s; E', 6.1 ± 1.5 cm/s vs 7.1 ± 1.3 cm/s; p < 0.05). Serum IGF-1 levels positively correlated with E' velocity in the entire population (r = 0.44, p < 0.001) and in SGA infants (r = 0.39, p < 0.05). In multivariate linear regression analysis, serum IGF-1 and S' velocity were independently associated with E' velocity in the entire population and in SGA infants. CONCLUSION: Decreased serum IGF-I levels could account for cardiac diastolic dysfunction in SGA infants.

Analysis of biomarker serum levels in IVIG and infliximab refractory Kawasaki disease patients.

Infliximab (IFX) is effective for treatment of refractory Kawasaki disease (KD). However, the precise mechanisms and biomarkers for IFX efficacy are unknown. We tried to evaluate the effect and response to IFX therapy by measuring serum cytokine levels. Twenty-nine children with KD who had been resistant to two courses of high-dose intravenous immunoglobulin were enrolled and treated with IFX. Plasma samples were analyzed for cytokines before and after IFX administration. Serum levels of interleukin-6, granulocyte colony-stimulating factor (G-CSF), interferon-gamma-induced monokine, interferon-gamma inducible protein 10 (IP-10), monocyte chemotactic protein 1, and soluble tumor necrosis factor-alpha receptor (sTNFR) 1 and 2 were significantly elevated before IFX treatment, but promptly decreased after the administration. The pre-treatment G-CSF and sTNFR1 levels in non-responders to IFX were significantly higher than in responders, who were defined as patients who defervesce (< 37.5 °C). After IFX administration, elevated cytokines declined to normal ranges in responders, but in non-responsive group, G-CSF and sTNFR1 remained elevated without failing to normal levels. IFX treatment significantly reduced the levels of serum cytokines, chemokines, and sTNFRs in refractory KD. G-CSF and sTNFR1 may be indicators predictive of poor response to IFX.

Infliximab for the Treatment of Refractory Kawasaki Disease: A Nationwide Survey in Japan.

OBJECTIVE: To assess the safety and efficacy of infliximab (IFX) for the treatment of patients with Kawasaki disease (KD). STUDY DESIGN: This was a nationwide survey of 274 Japanese institutions exploring how IFX was used to treat patients with KD. The patients' sex, age, treatment course, pre- and post-IFX therapy blood test results, coronary artery lesions (CALs), and adverse events (AEs) were evaluated. RESULTS: We analyzed 434 patients with KD who received IFX between March 2005 and November 2014. The median age at onset was 33 months (range 1-138), and 66 patients (15.2%) were under 1 year old. In all cases, IFX was administered as additional treatment. The median days of illness at the initiation of IFX was 9 days. In 275 patients (63.4%), IFX was administered as third-line treatment, and in 106 patients (24.4%), IFX was administered as fourth-line treatment. Single dose IFX 5 mg/kg was administered to 412 patients (94.9%). After IFX, 363 patients (83.6%) became afebrile within 2 days, and the white blood cell count, percentage of neutrophils, and serum C-reactive protein levels significantly decreased (P < .001), although 119 patients (27.4%) received additional treatment. Before IFX, 132 patients (30.4%) had already developed CALs. In patients without CALs before IFX, 31 patients (10.3%) newly developed CAL after IFX, whereas 32 patients (24.2%) with CAL before IFX showed increased CAL severity. Eighty AEs were observed in 69 patients (15.9%); however, serious AEs were few and reversible. CONCLUSIONS: IFX might be an effective and tolerable treatment for refractory KD.

Sudden improvement in ventricular repolarization abnormality after a short detraining period in an athlete.

We describe the case of a 17-year-old male soccer player with T-wave inversion in precordial leads in resting electrocardiography, which also disclosed sinus bradycardia, early repolarization, and increased QRS voltage. These findings strongly suggested cardiomyopathy. The patient's T-wave inversion disappeared during only 2 weeks of detraining, and it re-appeared 2 weeks after resumption of intensive training. This sudden change in electrocardiographic parameters over a short period helped in identifying the adolescent as having athlete's heart.

Prognostic Significance of QT Interval Dispersion in the Response to Intravenous Immunoglobulin Therapy in Kawasaki Disease.

BACKGROUND: Kawasaki disease (KD) is classified as a systemic vasculitis syndrome and QT interval dispersion (QTD) has been associated with cardiac involvement and disease activity in patients with cardiovasculitis. We examined whether baseline QTD could predict a response to intravenous immunoglobulin (IVIG) in KD.Methods and Results:QTD was recorded in 86 patients with KD before IVIG, who were separated into IVIG responders (R group; n=62) and nonresponders (N group; n=24). The association between baseline QTD and response to IVIG was investigated, and the predictive response value was compared with conventional risk scores from Gunma and Kurume universities. Baseline-corrected QTDs with Bazett's (QTbcD) and Fridericia's (QTfcD) formulae were significantly increased in the N group (R group vs. N group: 31.6 [28.3, 44.0] ms vs. 66.6 [50.5, 76.3] ms and 27.4 [25.2, 39.1] ms vs. 55.2 [42.4, 66.3] ms, respectively, both P<0.001). Multiple logistic regression analysis revealed QTfcD as an independent predictor of a response to IVIG after adjustment for conventional scores (odds ratio: 1.133, 95% confidence interval: 1.061-1.210, P<0.001). Moreover, QTfcD provided incremental predictive value for IVIG nonresponders over Gunma score (increment in global χ2=25.46, P<0.001). CONCLUSIONS: QTD was significantly associated with a response to IVIG in KD patients and may represent a useful identifier of IVIG nonresponders with high risk of coronary aneurysm.

Impact of Decreased Serum Insulin-Like Growth Factor-1 Levels on Central Aortic Compliance in Small-for-Gestational-Age Infants.

BACKGROUND: Intrauterine growth restriction is associated with arterial hypertension in adulthood; however, the underlying mechanism is unclear. OBJECTIVES: We hypothesized that serum insulin-like growth factor-1 (IGF-1) levels affect central aortic elastic properties and structure in small-for-gestational-age (SGA) infants. METHODS: Eighteen SGA infants and 22 appropriate-for-gestational-age (AGA) infants were enrolled in this study. The serum IGF-1 level within 1 h of birth and abdominal aortic echo parameters at 1 week of age were retrospectively compared. RESULTS: In the SGA infants, IGF-1 levels (27.6 ± 17.7 vs. 42.6 ± 15 ng/ml, p = 0.006), aortic strain (10.2 ± 3.1 vs. 12.8 ± 3.1%, p = 0.01), and aortic distensibility (0.73 ± 0.19 vs. 0.92 ± 0.34 cm2/dyn × 10-4, p = 0.05) were significantly lower compared with AGA infants. By contrast, blood pressure, aortic intima-media thickness (aIMT) in relation to body weight (383 ± 163 vs. 256 ± 43 µm/kg, p < 0.001), aortic stiffness index in relation to body weight (2.0 ± 1.7 vs. 1.1 ± 0.4, p = 0.005), and arterial pressure-strain elastic modulus (293 ± 72 vs. 242 ± 78 mm Hg, p = 0.04) were higher compared with AGA infants. In the SGA infants, IGF-1 levels were significantly correlated with aortic strain (r = 0.49, p = 0.04), aIMT in relation to body weight (r = -0.61, p = 0.007), and aortic stiffness index in relation to body weight (r = -0.63, p = 0.005). CONCLUSIONS: Decreased serum IGF-1 levels in SGA infants may affect the vascular compliance and structure of the central aorta.

Decreased Aortic Elasticity in Children With Marfan Syndrome or Loeys-Dietz Syndrome.

BACKGROUND: The characteristics of aortic elasticity are unclear in children with connective tissue disorders (CTDs) such as Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS), especially in those with a non-dilated aortic root (AoR). This study evaluated the aortic elasticity properties of pediatric MFS and LDS patients with either dilated or non-dilated AoR.Methods and Results:The 31 children with MFS or LDS were classified into dilated (Z score of AoR diameter ≥2.5; n=17) or non-dilated (Z score of AoR diameter <2.5; n=14) AoR groups and compared with controls. Using transthoracic echocardiography, we analyzed the aortic elasticity parameters of distensibility, strain, and stiffness index at the levels of the AoR, sinotubular junction, ascending aorta, and descending aorta. Aortic distensibility and strain were significantly lower in both test groups than in controls at the AoR level. The Z score of AoR diameter significantly correlated with aortic distensibility (R=-0.63, P<0.001), strain (R=-0.54, P=0.002), and stiffness index (R=0.52, P=0.002) in the patients' groups. Multivariate analysis revealed that aortic distensibility and the type of CTD were independently associated with AoR dilatation. CONCLUSIONS: Aortic elasticity at the level of the AoR may be decreased in children with MFS or LDS even before AoR dilatation progresses. Less aortic distensibility and CTD type are considered important parameters in estimating AoR dilatation in these patients. (Circ J 2016; 80: 2369-2375).

Cardiovascular Remodeling and Dysfunction Across a Range of Growth Restriction Severity in Small for Gestational Age Infants　- Implications for Fetal Programming.

BACKGROUND: The purpose of this study was to clarify cardiovascular structure and function in small for gestational age (SGA) infants across a range of intrauterine growth restriction (IUGR) severity. METHODS AND RESULTS: This prospective study included 38 SGA infants and 30 appropriate for gestational age (AGA) infants. SGA infants were subclassified into severe and mild SGA according to the degree of IUGR. Cardiovascular structure and function were evaluated using echocardiography at 1 week of age. Compared with the AGA infants, both the severe and mild SGA infants showed increased left ventricular diastolic dimensions (severe SGA 10.2±2.4, mild SGA 8.2±1.3, and AGA 7.3±0.7 mm/kg, P<0.05 for all) and decreased global longitudinal strain (severe -21.1±1.6, mild -22.5±1.8, and AGA -23.8±1.8%, P<0.05 for all). Severe SGA infants showed a decreased mitral annular early diastolic velocity (severe 5.6±1.4 vs. AGA 7.0±1.3 cm/s, P<0.01) and increased isovolumic relaxation time (severe 51.3±9.2 vs. AGA 42.7±8.2 ms, P<0.01). Weight-adjusted aortic intima-media thickness and arterial wall stiffness were significantly greater in both SGA infant groups. These cardiovascular parameters tended to deteriorate with increasing IUGR severity. CONCLUSIONS: SGA infants, including those with mild SGA, showed cardiovascular remodeling and dysfunction, which increased with IUGR severity. (Circ J 2016; 80: 2212-2220).

Left ventricular non-compaction revealed by aortic regurgitation due to Kawasaki disease in a boy with LDB3 mutation.

Kawasaki disease (KD) is an acute febrile illness of childhood characterized by systemic vasculitis, especially coronary arteritis. Aortic valve regurgitation (AVR) is a relatively common complication. There have been no reports to date of heart failure and left ventricular non-compaction (LVNC) after acute KD, although the precise etiology of this condition remains unclear. A 6-month-old boy with KD was admitted to hospital. Despite high-dose i.v. gammaglobulin for dilation of the coronary artery, moderate AVR appeared, and thereafter he developed heart failure. A rough, dense LV myocardium indicated LVNC. On genetic testing a heterogenous 163G > A substitution changing a valine to isoleucine in LIM domain binding protein 3 (LDB3) was identified. Additional cardiac stress, such as that caused by AVR and/or KD might have triggered cardiac failure in the form of LVNC due to LDB3 mutation.