The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

Nagai, Masashi; Awano, Hiroyuki; Yamamoto, Tetsushi; Bo, Ryosuke; Matsuo, Masafumi; Iijima, Kazumoto

doi:10.1016/j.cardfail.2020.08.002

Cited by 14 publications

(21 citation statements)

References 41 publications

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“…Of the 259 studies identified, 8 met the inclusion criteria and were included in the systematic review [19][20][21][22][23][24][25][26], and 4 were included in the meta-analysis (Table 1 and Figure 1) [20][21][22]24]. Four studies were excluded for various reasons (Supplementary Table S1) [34][35][36][37]. The main characteristics of the included studies are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

“…Of the 259 studies identified, 8 met the inclusion criteria and were included in the systematic review [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ], and 4 were included in the meta-analysis ( Table 1 and Figure 1 ) [ 20 , 21 , 22 , 24 ]. Four studies were excluded for various reasons ( Supplementary Table S1 ) [ 34 , 35 , 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

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Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

et al. 2021

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The transforming growth factor beta (TGFβ) pathway could modulate the Duchenne muscular dystrophy (DMD) phenotype. This meta-analysis aims to estimate the association of genetic variants involved in the TGFβ pathway, including the latent transforming growth factor beta binding protein 4 (LTBP4) and secreted phosphoprotein 1 (SPP1) genes, among others, with age of loss of ambulation (LoA) and cardiac function in patients with DMD. Meta-analyses were conducted for the hazard ratio (HR) of LoA for each genetic variant. A subgroup analysis was performed in patients treated exclusively with glucocorticoids. Eight studies were included in the systematic review and four in the meta-analyses. The systematic review suggests a protective effect of LTBP4 haplotype IAAM (recessive model) for LoA. It is also suggested that the SPP1 rs28357094 genotype G (dominant model) is associated with early LoA in glucocorticoids-treated patients. The meta-analysis of the LTBP4 haplotype IAAM showed a protective association with LoA, with an HR = 0.78 (95% CI: 0.67–0.90). No association with LoA was observed for the SPP1 rs28357094. The LTBP4 haplotype IAAM is associated with a later LoA, especially in the Caucasian population, while the SPP1 rs28357094 genotype G could be associated with a poor response to glucocorticoids. Future research is suggested for SPP1 rs11730582, LTBP4 rs710160, and THBS1 rs2725797.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

et al. 2021

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“…Also, modifier genes are likely to play an important role in phenotype variability. Recently, one modifier gene, ACTN3, was shown to contribute to the phenotype variability of LV function, and other modifier genes are likely to be identified 36 …”

Section: Discussionmentioning

confidence: 99%

A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy

Kipke

Birnkrant

Jin

et al. 2021

Pediatric Pulmonology

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Objective To perform a systematic review of studies evaluating pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy (DMD). Methods: PubMed, Google Scholar, and Embase were searched through October 8, 2020. Articles were selected using pre‐determined criteria; 26 underwent detailed review by two co‐authors. Study quality was assessed with the Newcastle–Ottawa scoring system (NOS); GRADE assessment evaluated their overall clinical importance. Results There were few randomized controlled trials. Two of four trials of angiotensin converting enzyme inhibitors (ACEI) or ACEI plus beta‐blockers (BB) found improved LV function. Two of two randomized trials of aldosterone antagonists (AA), when added to ACEI and BB therapy, demonstrated less decline of LV circumferential strain over 1 year of treatment. Observational studies of ACEI and BB had differing patient ages, symptomatology, cohort size, study duration and baseline heart function. LV function, assessed via unblinded imaging, was the most frequent outcome measure. LV dysfunction improved in some trials but was unconfirmed in others. Class IV heart failure patients had transient improvement of symptoms and LVEF. Most NOS scores reflected a low level of study quality. The Grade certainty rating, used for the summation of studies, was between “low” and “moderate.” Conclusion Randomized trial evidence was inconsistent that either ACEI or BB or their combination improve LV function and/or alter progressive LV dysfunction. When ACEI and BB therapy are initiated for symptomatic Class IV heart failure, symptoms and LVEF improve transiently. AAs retard the rate of decline of LV function when initiated in younger DMD patients.

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“…We have previously reported that the ACTN3 XX null genotype is related to the early onset of dilated cardiomyopathy in DMD patients [26]. To evaluate the contribution of the ACTN3 genotype to cTnI level, patients with DMD were grouped into three genotypes: the RR, RX, and XX genotypes.…”

Section: Actn3 Genotype and Serum Ctni Levels In Patients With Dmdmentioning

confidence: 99%

“…Genomic DNA was isolated using standard phenol-chloroform extraction methods. ACTN3 exon 15 was ampli ed by polymerase chain reaction (PCR) as previously described [26]. The puri ed PCR-ampli ed products were sequenced using the Premix sequencing system (Fasmac Co., Ltd., Kanagawa, Japan).…”

Section: Actn3genotypingmentioning

confidence: 99%

Comparison of the Levels of Cardiac Troponin I in Patients with Duchenne and Becker Muscular Dystrophies to Assess Cardiac Dysfunction

Yamaguchi

Awano

Yamamoto

et al. 2021

Preprint

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Background: Cardiac troponin I (cTnI), uniquely expressed in the myocardium, is a marker for acute myocardial injury. Its clinical significance in Duchenne and Becker muscular dystrophy (DMD and BMD) and its relation to alpha-actinin-3 (ACTN3) genotype as a genetic modifier of cardiomyopathy are still unknown.Methods and Results: Overall, 529 and 131 serum cTnI values of 127 DMD and 47 BMD patients, respectively, were reviewed. cTnI elevation was generally observed in the second decade of life. Both cTnI levels and the proportion of abnormal cTnI levels were significantly higher in DMD patients than in BMD patients (age range: 1< years ≤10 and 10< years ≤18 and 10< years ≤18, respectively). Decreased left ventricular ejection fraction was observed after cTnI elevation in both populations. cTnI levels by age in DMD patients with ACTN3 null genotype tended to increase highly and early.Conclusions: Myocardial injury indicated by cTnI was more common and severe in DMD patients than in BMD patients. cTnI elevation preceding cardiac dysfunction may represent an early phase of cardiomyopathy progression and may be a biomarker for early detection of cardiomyopathy in DMD and BMD patients. The ACTN3 null genotype may be a risk factor for early myocardial injury.

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The ACTN3 577XX Null Genotype Is Associated with Low Left Ventricular Dilation-Free Survival Rate in Patients with Duchenne Muscular Dystrophy

Cited by 14 publications

References 41 publications

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

Genetic Modifiers and Phenotype of Duchenne Muscular Dystrophy: A Systematic Review and Meta-Analysis

A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy

Comparison of the Levels of Cardiac Troponin I in Patients with Duchenne and Becker Muscular Dystrophies to Assess Cardiac Dysfunction

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