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You J, Kim MJ, Cha S, Baek JS, Yum MS, Lee BH, Yu JJ. Cardiac Involvement in Becker Muscular Dystrophy: Insights from Echocardiographic Analysis. J Child Neurol 2025:8830738251327248. [PMID: 40123366 DOI: 10.1177/08830738251327248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2025]
Abstract
Becker muscular dystrophy is an infrequent genetic disorder that results from dystrophin gene mutations. Cardiac involvement is a primary manifestation. The time of onset of underlying cardiac functional abnormalities remains largely undefined. This study involved 17 pediatric patients with Becker muscular dystrophy who visited our hospital between January 1, 2002, and December 31, 2018, and underwent echocardiographic imaging analysis. Another set of 17 controls matched for age and sex to the patient cohort was chosen for comparison. Patients with Becker muscular dystrophy demonstrated a decline in echocardiographic measures, especially deformation parameters, compared with the control group. This alteration is influenced by age. Our findings suggest that early echocardiographic monitoring may help identify subclinical cardiac dysfunction, particularly in younger patients (<10 years of age).
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Affiliation(s)
- Jihye You
- Department of Pediatrics, Jeonbuk National University Children's Hospital, Jeonju, Korea
| | - Mi Jin Kim
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Seulgi Cha
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jae Suk Baek
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Mi-Sun Yum
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Beom Hee Lee
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jeong Jin Yu
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Landfeldt E, Alemán A, Abner S, Zhang R, Werner C, Tomazos I, Lochmüller H, Quinlivan RM, Wahbi K. Predictors of cardiac disease in duchenne muscular dystrophy: a systematic review and evidence grading. Orphanet J Rare Dis 2024; 19:359. [PMID: 39342355 PMCID: PMC11439250 DOI: 10.1186/s13023-024-03372-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Accepted: 09/18/2024] [Indexed: 10/01/2024] Open
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is a rare disease that causes progressive muscle degeneration resulting in life-threatening cardiac complications. The objective of this systematic literature review was to describe and grade the published evidence of predictors of cardiac disease in DMD. METHODS The review encompassed searches of Embase, MEDLINE ALL, and the Cochrane Database of Systematic Reviews from January 1, 2000, to December 31, 2022, for predictors of cardiac disease in DMD. The certainty of evidence (i.e., very low to high) was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework. RESULTS We included 33 publications encompassing 9,232 patients with DMD. We found moderate- to high-quality evidence that cardiac medication (i.e., ACE inhibitors [enalapril and perindopril], β-blockers [carvedilol], and mineralocorticoid receptor antagonists [eplerenone]) are significantly associated with preserved left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV), and left ventricular circumferential strain (LVCS). DMD mutations in exons 51 and 52 were found to be significantly associated with lower risk of cardiomyopathy; deletions treatable by exon 53 skipping and mutations in the Dp116 coding region with improved LVEF and prolonged cardiac dysfunction-free survival; and exons 45-50 and 52 with early left ventricular systolic dysfunction (low/very low-quality evidence). We found high-quality evidence that glucocorticoids (deflazacort) are significantly associated with preserved LVEF and improved fractional shortening (FS), and low-quality evidence that glucocorticoids (deflazacort, prednisone, and/or prednisolone) are associated with improved ejection fraction (EF) and lower risk of cardiomyopathy, ventricular dysfunction, and heart failure-related mortality. Full-time mechanical ventilation was found to be significantly correlated with LVEF (low-quality evidence), muscle strength with FS (low-quality evidence), and genetic modifiers (i.e., LTBP4 rs10880 and ACTN3) with LVEF, lower risk of cardiomyopathy and left ventricular dilation (low-quality evidence). CONCLUSION Several sources of cardiac disease heterogeneity are well-studied in patients with DMD. Yet, the certainty of evidence is generally low, and little is known of the contribution of non-pharmacological interventions, as well as the impact of different criteria for initiation of specific treatments. Our findings help raise awareness of prevailing unmet needs, shape expectations of treatment outcomes, and inform the design of future research.
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Affiliation(s)
- Erik Landfeldt
- IQVIA, Pyramidvägen 7, 169 56, Solna, Stockholm, Sweden.
| | - Alberto Alemán
- Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Research Institute, University of Ottawa, Ottawa, ON, Canada
- Division of Neurology, Department of Medicine, The Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
| | | | | | | | | | - Hanns Lochmüller
- Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Research Institute, University of Ottawa, Ottawa, ON, Canada
- Division of Neurology, Department of Medicine, The Ottawa Hospital, Brain and Mind Research Institute, University of Ottawa, Ottawa, Canada
- Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Ros M Quinlivan
- Centre for Neuromuscular Diseases, UCL Institute of Neurology, National Hospital, London, UK
| | - Karim Wahbi
- Cardiology Department, AP-HP, Cochin Hospital, Paris, France
- Université de Paris, Paris, France
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Łoboda A, Dulak J. Cardioprotective Effects of Hydrogen Sulfide and Its Potential Therapeutic Implications in the Amelioration of Duchenne Muscular Dystrophy Cardiomyopathy. Cells 2024; 13:158. [PMID: 38247849 PMCID: PMC10814317 DOI: 10.3390/cells13020158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/10/2024] [Accepted: 01/12/2024] [Indexed: 01/23/2024] Open
Abstract
Hydrogen sulfide (H2S) belongs to the family of gasotransmitters and can modulate a myriad of biological signaling pathways. Among others, its cardioprotective effects, through antioxidant, anti-inflammatory, anti-fibrotic, and proangiogenic activities, are well-documented in experimental studies. Cardiorespiratory failure, predominantly cardiomyopathy, is a life-threatening complication that is the number one cause of death in patients with Duchenne muscular dystrophy (DMD). Although recent data suggest the role of H2S in ameliorating muscle wasting in murine and Caenorhabditis elegans models of DMD, possible cardioprotective effects have not yet been addressed. In this review, we summarize the current understanding of the role of H2S in animal models of cardiac dysfunctions and cardiac cells. We highlight that DMD may be amenable to H2S supplementation, and we suggest H2S as a possible factor regulating DMD-associated cardiomyopathy.
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Affiliation(s)
- Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7 Street, 30-387 Kraków, Poland;
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Del Rio-Pertuz G, Morataya C, Parmar K, Dubay S, Argueta-Sosa E. Dilated cardiomyopathy as the initial presentation of Becker muscular dystrophy: a systematic review of published cases. Orphanet J Rare Dis 2022; 17:194. [PMID: 35549971 PMCID: PMC9097097 DOI: 10.1186/s13023-022-02346-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Accepted: 04/26/2022] [Indexed: 11/10/2022] Open
Abstract
There are scarce publications regarding the presentation and outcome of Becker muscular dystrophy in adulthood when idiopathic dilated cardiomyopathy is the initial disease manifestation. We performed a systematic review using Medline, Embase, Cochrane, and Scopus to identify cases of adults with idiopathic dilated cardiomyopathy who were subsequently diagnosed with Becker muscular dystrophy from inception through August 2020. Six cases were found. We identified young males (Median age: 26 years) with Becker muscular dystrophy who first presented with dilated cardiomyopathy. Most patients initially presented with congestive heart failure symptoms (5/6, 83%), and had a median left ventricular ejection fraction of 23%. One case did have calf pseudohypertrophy. Musculoskeletal symptoms later appeared one to six years after the initial dilated cardiomyopathy presentation. Heart transplantation was the most common management strategy (4/6, 67%). A left ventricular assist device was used in one case as a bridge to heart transplant. Dilated cardiomyopathy can be the initial presentation of Becker muscular dystrophy in the third to fourth decades of life in adult patients, and musculoskeletal symptoms can be subclinical.
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Affiliation(s)
- Gaspar Del Rio-Pertuz
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX, 79430, USA.
| | - Cristina Morataya
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX, 79430, USA
| | - Kanak Parmar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, 3601 4th St, Lubbock, TX, 79430, USA
| | - Sarah Dubay
- Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - Erwin Argueta-Sosa
- Division of Cardiology, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
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Ferizovic N, Summers J, de Zárate IBO, Werner C, Jiang J, Landfeldt E, Buesch K. Prognostic indicators of disease progression in Duchenne muscular dystrophy: A literature review and evidence synthesis. PLoS One 2022; 17:e0265879. [PMID: 35333888 PMCID: PMC8956179 DOI: 10.1371/journal.pone.0265879] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Accepted: 03/09/2022] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is a rare, severely debilitating, and fatal neuromuscular disease characterized by progressive muscle degeneration. Like in many orphan diseases, randomized controlled trials are uncommon in DMD, resulting in the need to indirectly compare treatment effects, for example by pooling individual patient-level data from multiple sources. However, to derive reliable estimates, it is necessary to ensure that the samples considered are comparable with respect to factors significantly affecting the clinical progression of the disease. To help inform such analyses, the objective of this study was to review and synthesise published evidence of prognostic indicators of disease progression in DMD. We searched MEDLINE (via Ovid), Embase (via Ovid) and the Cochrane Library (via Wiley) for records published from inception up until April 23 2021, reporting evidence of prognostic indicators of disease progression in DMD. Risk of bias was established with the grading system of the Centre for Evidence-Based Medicine (CEBM). RESULTS Our search included 135 studies involving 25,610 patients from 18 countries across six continents (Africa, Asia, Australia, Europe, North America and South America). We identified a total of 23 prognostic indicators of disease progression in DMD, namely age at diagnosis, age at onset of symptoms, ataluren treatment, ATL1102, BMI, cardiac medication, DMD genetic modifiers, DMD mutation type, drisapersen, edasalonexent, eteplirsen, glucocorticoid exposure, height, idebenone, lower limb surgery, orthoses, oxandrolone, spinal surgery, TAS-205, vamorolone, vitlolarsen, ventilation support, and weight. Of these, cardiac medication, DMD genetic modifiers, DMD mutation type, and glucocorticoid exposure were designated core prognostic indicators, each supported by a high level of evidence and significantly affecting a wide range of clinical outcomes. CONCLUSION This study provides a current summary of prognostic indicators of disease progression in DMD, which will help inform the design of comparative analyses and future data collection initiatives in this patient population.
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Affiliation(s)
- Nermina Ferizovic
- MAP BioPharma Ltd, Cambridge, England, United Kingdom
- BresMed Health Solutions, Sheffield, England, United Kingdom
| | | | | | | | - Joel Jiang
- PTC Therapeutics, South Plainfield, New Jersey, United States of America
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Raccah BH, Biton B, Amir O, Gotsman I, Nahman D, Matok I. Anti-Remodeling Cardiac Therapy in Patients With Duchenne Muscular Dystrophy, Meta-Analysis Study. Front Pharmacol 2022; 12:769896. [PMID: 35126112 PMCID: PMC8811374 DOI: 10.3389/fphar.2021.769896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2021] [Accepted: 12/21/2021] [Indexed: 12/04/2022] Open
Abstract
Background: Almost all Duchenne muscular dystrophy (DMD) patients that reach their 30s present cardiomyopathy. As a result, this population remains under-treated. There is no sufficient proof of the efficacy of anti-remodeling cardiac therapy for DMD cardiomyopathy (DMDCM). We aim to assess the efficacy of anti-remodeling cardiac therapy for DMDCM by using meta-analysis. Methods: PubMed (MEDLINE), Embase, and Cochrane library were searched through January 2021. Randomized control trials, case-control studies, and observational studies that reported assessments of cardiovascular outcomes and death of participants using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid-receptor antagonists and Ivabradine, were included. The primary outcome was total mortality. Secondary outcomes included changes in left ventricular ejection fraction (LVEF), serum natriuretic peptide levels (BNP), and heart rate (HR). Data were extracted for eligibility by two independent reviewers. Random-effects meta-analysis was used to pool results. Results: Twelve studies with 439 patients were included in our meta-analysis. Treated patients have lower HR, mean difference of −17 beats per minute (CI [−25]–[−9], p < 0.01). The LVEF was improved in treated patients, with a mean difference of LVEF of 3.77% (CI 0.44–7.12, p < 0.03). Although mortality rates did not reach statistical significance there was a trend for total mortality reduction (hazard ratio 0.36, CI (0.1–1.25), p = 0.107) and for BNP reduction (SSMD: 0.141, CI ([−0.19]–[0.47]), p = 0.3). Conclusion: Pharmacologic treatment for DMDCM patients is associated with decreased HR and improved LVEF. Therefore, DMDCM patients may benefit from implementing guideline therapy for HF.
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Affiliation(s)
- Bruria Hirsh Raccah
- Division of Clinical Pharmacy, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, the Hebrew University of Jerusalem, Jerusalem, Israel
- Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
| | - Bar Biton
- Division of Clinical Pharmacy, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, the Hebrew University of Jerusalem, Jerusalem, Israel
| | - Offer Amir
- Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
- The Azrieli Faculty of Medicine in the Galilee, Bar-Ilan University, Safed, Israel
| | - Israel Gotsman
- Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
| | - Dean Nahman
- Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University, Jerusalem, Israel
| | - Ilan Matok
- Division of Clinical Pharmacy, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, the Hebrew University of Jerusalem, Jerusalem, Israel
- *Correspondence: Ilan Matok,
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7
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Cardiac Complications of Neuromuscular Disorders. Neuromuscul Disord 2022. [DOI: 10.1016/b978-0-323-71317-7.00003-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Florczyk-Soluch U, Polak K, Dulak J. The multifaceted view of heart problem in Duchenne muscular dystrophy. Cell Mol Life Sci 2021; 78:5447-5468. [PMID: 34091693 PMCID: PMC8257522 DOI: 10.1007/s00018-021-03862-2] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 04/29/2021] [Accepted: 05/20/2021] [Indexed: 12/14/2022]
Abstract
Dystrophin is a large protein serving as local scaffolding repetitively bridging cytoskeleton and the outside of striated muscle cell. As such dystrophin is a critical brick primarily in dystrophin-associated protein complex (DAGC) and in a larger submembranous unit, costamere. Accordingly, the lack of functional dystrophin laying at the root of Duchenne muscular dystrophy (DMD) drives sarcolemma instability. From this point on, the cascade inevitably leading to the death of myocyte begins. In cardiomyocytes, intracellular calcium overload and related mitochondrial-mediated cell death mainly contribute to myocardial dysfunction and dilation while other protein dysregulation and/or mislocalization may affect electrical conduction system and favor arrhythmogenesis. Although clinically DMD manifests as progressive muscle weakness and skeletal muscle symptoms define characteristic of DMD, it is the heart problem the biggest challenge that most often develop in the form of dilated cardiomyopathy (DCM). Current standards of treatment and recent progress in respiratory care, introduced in most settings in the 1990s, have improved quality of life and median life expectancy to 4th decade of patient's age. At the same time, cardiac causes of death related to DMD increases. Despite preventive and palliative cardiac treatments available, the prognoses remain poor. Direct therapeutic targeting of dystrophin deficiency is critical, however, hindered by the large size of the dystrophin cDNA and/or stochastic, often extensive genetic changes in DMD gene. The correlation between cardiac involvement and mutations affecting specific dystrophin isoforms, may provide a mutation-specific cardiac management and novel therapeutic approaches for patients with CM. Nonetheless, the successful cardiac treatment poses a big challenge and may require combined therapy to combat dystrophin deficiency and its after-effects (critical in DMD pathogenesis). This review locates the multifaceted heart problem in the course of DMD, balancing the insights into basic science, translational efforts and clinical manifestation of dystrophic heart disease.
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Affiliation(s)
- Urszula Florczyk-Soluch
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Katarzyna Polak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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Matsumura T, Hashimoto H, Sekimizu M, Saito AM, Iwata Y, Asakura M, Kimura K, Tamura T, Funato M, Segawa K, Ogata K, Nakajima T. Study Protocol for a Multicenter, Open-Label, Single-Arm Study of Tranilast for Cardiomyopathy of Muscular Dystrophy. Kurume Med J 2021; 66:121-126. [PMID: 34135201 DOI: 10.2739/kurumemedj.ms662006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Duchenne (DMD) and other forms of muscular dystrophy (MD) are collectively rare and affect approx imately 20 per 100,000 people. The on-going development of exon skipping and other novel therapies for DMD is expected to lead to improvements in motor function prognosis. However, improvements in motor dysfunction with these novel therapies are associated with the risk of increase in cardiac burden. Development of therapies to improve cardiac function, therefore, is an urgent issue. This single-arm, open-label, multicenter study will include 20 patients with MD aged 13 years or older. Tranilast, a transient receptor potential cation channel subfamily V member 2 (TRPV2) inhibitor, will be administered orally for a period of 28 weeks at a dose of 300 mg/day divided into three daily doses. If consent to continue administration is obtained at 28 weeks, the drug will be administered for an additional 116 weeks. The primary outcome will be the change in brain natriuretic peptide (BNP) at 6 months after the start of administration compared to baseline. Tranilast is an anti-allergy agent that was developed in Japan. It has been used in a large number of clinical cases, including pediatric cases, and has been shown to be safe. We expect this study to provide basic data for developing new treatment method in cardiomyopathy/skeletal myopathy using TRPV2 inhibitors. Moreover, such therapies may also be effective in treating general heart failure without MD. Therefore, if the effectiveness of TRPV2 inhibitors could be confirmed in this study, great social and economic benefits could be achieved.
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Affiliation(s)
- Tsuyoshi Matsumura
- Department of Neurology, National Hospital Organization Osaka Toneyama Medical Center
| | | | - Masahiro Sekimizu
- Clinical Research Center.,Department of Pediatrics, National Hospital Organization Nagoya Medical Center
| | | | - Yuko Iwata
- Department of Clinical Research and Development, National Cerebral and Cardiovascular Center
| | - Masanori Asakura
- Department of Internal Medicine, Cardiovascular Division, Hyogo College of Medicine
| | - Koichi Kimura
- Department of General Medicine, The Institute of Medical Science, The University of Tokyo
| | - Takuhisa Tamura
- Department of Neurology, National Hospital Organization Higashisaitama National Hospital
| | | | - Kazuhiko Segawa
- Department of Cardiology, National Center Hospital, National Center of Neurology and Psychiatry
| | - Katsuhisa Ogata
- Department of Neurology, National Hospital Organization Higashisaitama National Hospital
| | - Takashi Nakajima
- Department of Clinical research, Department of Neurology, Niigata National Hospital
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Kipke J, Birnkrant DJ, Jin JB, Aneja A, Bahler RC. A systematic review of pharmacologic therapies for the cardiomyopathy of Duchenne muscular dystrophy. Pediatr Pulmonol 2021; 56:782-795. [PMID: 33621446 DOI: 10.1002/ppul.25261] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 12/09/2020] [Accepted: 12/29/2020] [Indexed: 12/30/2022]
Abstract
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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Affiliation(s)
- Jasmine Kipke
- Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - David J Birnkrant
- Department of Pediatrics, Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Justin B Jin
- Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio, USA.,Department of Pediatric Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio, USA
| | - Ashish Aneja
- Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio, USA
| | - Robert C Bahler
- Case Western Reserve University School of Medicine at MetroHealth Medical Center, Cleveland, Ohio, USA
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Abstract
PURPOSE OF REVIEW Duchenne muscular dystrophy is one of many neuromuscular disorders, but it frequently causes severe disability early in life and early death. Cardiac involvement is an important cause of morbidity and mortality. RECENT FINDINGS Heart disease in Duchenne muscular dystrophy can include a cardiomyopathy leading to end-stage heart failure along with associated supraventricular and ventricular arrhythmias. This article reviews the diagnosis and treatment of heart disease in Duchenne muscular dystrophy as well as emerging therapies.
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Affiliation(s)
- Jeffrey A Shih
- University of Massachusetts, 55 Lake Avenue North, Worcester, MA, 01532, USA.
| | - Alejandro Folch
- University of Massachusetts, 55 Lake Avenue North, Worcester, MA, 01532, USA
| | - Brenda L Wong
- University of Massachusetts, 55 Lake Avenue North, Worcester, MA, 01532, USA
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Rodriguez-Gonzalez M, Lubian-Gutierrez M, Cascales-Poyatos HM, Perez-Reviriego AA, Castellano-Martinez A. Role of the Renin-Angiotensin-Aldosterone System in Dystrophin-Deficient Cardiomyopathy. Int J Mol Sci 2020; 22:356. [PMID: 33396334 PMCID: PMC7796305 DOI: 10.3390/ijms22010356] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 12/27/2020] [Accepted: 12/28/2020] [Indexed: 12/16/2022] Open
Abstract
Dystrophin-deficient cardiomyopathy (DDC) is currently the leading cause of death in patients with dystrophinopathies. Targeting myocardial fibrosis (MF) has become a major therapeutic goal in order to prevent the occurrence of DDC. We aimed to review and summarize the current evidence about the role of the renin-angiotensin-aldosterone system (RAAS) in the development and perpetuation of MF in DCC. We conducted a comprehensive search of peer-reviewed English literature on PubMed about this subject. We found increasing preclinical evidence from studies in animal models during the last 20 years pointing out a central role of RAAS in the development of MF in DDC. Local tissue RAAS acts directly mainly through its main fibrotic component angiotensin II (ANG2) and its transducer receptor (AT1R) and downstream TGF-b pathway. Additionally, it modulates the actions of most of the remaining pro-fibrotic factors involved in DDC. Despite limited clinical evidence, RAAS blockade constitutes the most studied, available and promising therapeutic strategy against MF and DDC. Conclusion: Based on the evidence reviewed, it would be recommendable to start RAAS blockade therapy through angiotensin converter enzyme inhibitors (ACEI) or AT1R blockers (ARBs) alone or in combination with mineralocorticoid receptor antagonists (MRa) at the youngest age after the diagnosis of dystrophinopathies, in order to delay the occurrence or slow the progression of MF, even before the detection of any cardiovascular alteration.
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Affiliation(s)
- Moises Rodriguez-Gonzalez
- Pediatric Cardiology Division of Puerta del Mar University Hospital, University of Cadiz, 11009 Cadiz, Spain
- Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, University of Cadiz, 11009 Cadiz, Spain;
| | - Manuel Lubian-Gutierrez
- Pediatric Neurology Division of Puerta del Mar University Hospital, University of Cadiz, 11009 Cadiz, Spain;
- Pediatric Division of Doctor Cayetano Roldan Primary Care Center, 11100 San Fernando, Spain
| | | | | | - Ana Castellano-Martinez
- Biomedical Research and Innovation Institute of Cadiz (INiBICA), Research Unit, Puerta del Mar University Hospital, University of Cadiz, 11009 Cadiz, Spain;
- Pediatric Nephrology Division of Puerta del Mar University Hospital, University of Cadiz, 11009 Cadiz, Spain
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Łoboda A, Dulak J. Muscle and cardiac therapeutic strategies for Duchenne muscular dystrophy: past, present, and future. Pharmacol Rep 2020; 72:1227-1263. [PMID: 32691346 PMCID: PMC7550322 DOI: 10.1007/s43440-020-00134-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 07/08/2020] [Accepted: 07/09/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration and results in functional decline, loss of ambulation and early death of young men due to cardiac or respiratory failure. Although the major cause of the disease has been known for many years-namely mutation in the DMD gene encoding dystrophin, one of the largest human genes-DMD is still incurable, and its treatment is challenging. METHODS A comprehensive and systematic review of literature on the gene, cell, and pharmacological experimental therapies aimed at restoring functional dystrophin or to counteract the associated processes contributing to disease progression like inflammation, fibrosis, calcium signaling or angiogenesis was carried out. RESULTS Although some therapies lead to satisfying effects in skeletal muscle, they are highly ineffective in the heart; therefore, targeting defective cardiac and respiratory systems is vital in DMD patients. Unfortunately, most of the pharmacological compounds treat only the symptoms of the disease. Some drugs addressing the underlying cause, like eteplirsen, golodirsen, and ataluren, have recently been conditionally approved; however, they can correct only specific mutations in the DMD gene and are therefore suitable for small sub-populations of affected individuals. CONCLUSION In this review, we summarize the possible therapeutic options and describe the current status of various, still imperfect, strategies used for attenuating the disease progression.
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Affiliation(s)
- Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
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14
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Adorisio R, Mencarelli E, Cantarutti N, Calvieri C, Amato L, Cicenia M, Silvetti M, D’Amico A, Grandinetti M, Drago F, Amodeo A. Duchenne Dilated Cardiomyopathy: Cardiac Management from Prevention to Advanced Cardiovascular Therapies. J Clin Med 2020; 9:jcm9103186. [PMID: 33019553 PMCID: PMC7600130 DOI: 10.3390/jcm9103186] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 09/23/2020] [Accepted: 09/29/2020] [Indexed: 02/07/2023] Open
Abstract
Duchenne muscular dystrophy (DMD) cardiomyopathy (DCM) is characterized by a hypokinetic, dilated phenotype progressively increasing with age. Regular cardiac care is crucial in DMD care. Early recognition and prophylactic use of angiotensin converting enzyme inhibitors (ACEi) are the main stay therapeutic strategy to delay incidence of DMD-DCM. Pharmacological treatment to improve symptoms and left ventricle (LV) systolic function, have been widely implemented in the past years. Because of lack of DMD specific drugs, actual indications for established DCM include current treatment for heart failure (HF). This review focuses on current HF strategies to identify, characterize, and treat DMD-DCM.
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Affiliation(s)
- Rachele Adorisio
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (E.M.); (L.A.); (M.G.); (A.A.)
- Correspondence: ; Tel.: +39-06-6859-2217; Fax: +39-06-6859-2607
| | - Erica Mencarelli
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (E.M.); (L.A.); (M.G.); (A.A.)
| | - Nicoletta Cantarutti
- Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.C.); (C.C.); (M.C.); (M.S.); (F.D.)
| | - Camilla Calvieri
- Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.C.); (C.C.); (M.C.); (M.S.); (F.D.)
| | - Liliana Amato
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (E.M.); (L.A.); (M.G.); (A.A.)
| | - Marianna Cicenia
- Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.C.); (C.C.); (M.C.); (M.S.); (F.D.)
| | - Massimo Silvetti
- Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.C.); (C.C.); (M.C.); (M.S.); (F.D.)
| | - Adele D’Amico
- Neuromuscolar Disease, Genetic and Rare Disease Research Area, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Maria Grandinetti
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (E.M.); (L.A.); (M.G.); (A.A.)
- Department of Cardiovascular and Thoracic Sciences, Fondazione Policlinico Universitario A, Gemelli IRCCS, 20097 Rome, Italy
| | - Fabrizio Drago
- Pediatric Cardiology and Cardiac Arrhythmias/Syncope Unit, Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (N.C.); (C.C.); (M.C.); (M.S.); (F.D.)
| | - Antonio Amodeo
- Heart Failure Clinic-Heart Failure, Heart Transplant, Mechanical Circulatory Support Unit, Department of Pediatric Cardiology and Cardiac Surgery, Heart and Lung Transplant, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (E.M.); (L.A.); (M.G.); (A.A.)
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Abstract
BACKGROUND Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in 2009. OBJECTIVES To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied. SELECTION CRITERIA Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure. DATA COLLECTION AND ANALYSIS Two review authors independently extracted and assessed data from the included trials. MAIN RESULTS We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers. However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses. AUTHORS' CONCLUSIONS There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.
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Affiliation(s)
- Samer Alabed
- Academic Unit of Radiology, University of Sheffield, Sheffield, UK
| | - Ammar Sabouni
- KasrAlAiny School of Medicine, Cairo University, Cairo, Egypt
| | - Suleiman Al Dakhoul
- Department of Medicine, The Wirral University Teaching Hospitals, Upton, Wirral, UK
| | - Yamama Bdaiwi
- Faculty of Medicine, Damascus University, Damascus, Syrian Arab Republic
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16
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Jelinkova S, Vilotic A, Pribyl J, Aimond F, Salykin A, Acimovic I, Pesl M, Caluori G, Klimovic S, Urban T, Dobrovolna H, Soska V, Skladal P, Lacampagne A, Dvorak P, Meli AC, Rotrekl V. DMD Pluripotent Stem Cell Derived Cardiac Cells Recapitulate in vitro Human Cardiac Pathophysiology. Front Bioeng Biotechnol 2020; 8:535. [PMID: 32656189 PMCID: PMC7325914 DOI: 10.3389/fbioe.2020.00535] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Accepted: 05/04/2020] [Indexed: 12/17/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by the lack of functional dystrophin. DMD is associated with progressive dilated cardiomyopathy, eventually leading to heart failure as the main cause of death in DMD patients. Although several molecular mechanisms leading to the DMD cardiomyocyte (DMD-CM) death were described, mostly in mouse model, no suitable human CM model was until recently available together with proper clarification of the DMD-CM phenotype and delay in cardiac symptoms manifestation. We obtained several independent dystrophin-deficient human pluripotent stem cell (hPSC) lines from DMD patients and CRISPR/Cas9-generated DMD gene mutation. We differentiated DMD-hPSC into cardiac cells (CC) creating a human DMD-CC disease model. We observed that mutation-carrying cells were less prone to differentiate into CCs. DMD-CCs demonstrated an enhanced cell death rate in time. Furthermore, ion channel expression was altered in terms of potassium (Kir2.1 overexpression) and calcium handling (dihydropyridine receptor overexpression). DMD-CCs exhibited increased time of calcium transient rising compared to aged-matched control, suggesting mishandling of calcium release. We observed mechanical impairment (hypocontractility), bradycardia, increased heart rate variability, and blunted β-adrenergic response connected with remodeling of β-adrenergic receptors expression in DMD-CCs. Overall, these results indicated that our DMD-CC models are functionally affected by dystrophin-deficiency associated and recapitulate functional defects and cardiac wasting observed in the disease. It offers an accurate tool to study human cardiomyopathy progression and test therapies in vitro.
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Affiliation(s)
- Sarka Jelinkova
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia
| | - Aleksandra Vilotic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Jan Pribyl
- CEITEC, Masaryk University, Brno, Czechia
| | - Franck Aimond
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Anton Salykin
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Ivana Acimovic
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Martin Pesl
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia.,First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Guido Caluori
- International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia.,First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Simon Klimovic
- Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czechia
| | - Tomas Urban
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Hana Dobrovolna
- Department of Clinical Biochemistry, St. Anne's University Hospital of Brno, Brno, Czechia
| | - Vladimir Soska
- Department of Clinical Biochemistry, St. Anne's University Hospital of Brno, Brno, Czechia.,Second Clinic of Internal Medicine, Masaryk University of Brno, Brno, Czechia
| | - Petr Skladal
- First Department of Internal Medicine-Cardioangiology, Faculty of Medicine, Masaryk University, Brno, Czechia.,Department of Biochemistry, Faculty of Science, Masaryk University, Brno, Czechia
| | - Alain Lacampagne
- PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Petr Dvorak
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia
| | - Albano C Meli
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,PhyMedExp, University of Montpellier, INSERM, CNRS, Montpellier, France
| | - Vladimir Rotrekl
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czechia.,International Clinical Research Center ICRC, St. Anne's University Hospital Brno, Brno, Czechia
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17
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Law ML, Cohen H, Martin AA, Angulski ABB, Metzger JM. Dysregulation of Calcium Handling in Duchenne Muscular Dystrophy-Associated Dilated Cardiomyopathy: Mechanisms and Experimental Therapeutic Strategies. J Clin Med 2020; 9:jcm9020520. [PMID: 32075145 PMCID: PMC7074327 DOI: 10.3390/jcm9020520] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 02/06/2020] [Indexed: 02/07/2023] Open
Abstract
: Duchenne muscular dystrophy (DMD) is an X-linked recessive disease resulting in the loss of dystrophin, a key cytoskeletal protein in the dystrophin-glycoprotein complex. Dystrophin connects the extracellular matrix with the cytoskeleton and stabilizes the sarcolemma. Cardiomyopathy is prominent in adolescents and young adults with DMD, manifesting as dilated cardiomyopathy (DCM) in the later stages of disease. Sarcolemmal instability, leading to calcium mishandling and overload in the cardiac myocyte, is a key mechanistic contributor to muscle cell death, fibrosis, and diminished cardiac contractile function in DMD patients. Current therapies for DMD cardiomyopathy can slow disease progression, but they do not directly target aberrant calcium handling and calcium overload. Experimental therapeutic targets that address calcium mishandling and overload include membrane stabilization, inhibition of stretch-activated channels, ryanodine receptor stabilization, and augmentation of calcium cycling via modulation of the Serca2a/phospholamban (PLN) complex or cytosolic calcium buffering. This paper addresses what is known about the mechanistic basis of calcium mishandling in DCM, with a focus on DMD cardiomyopathy. Additionally, we discuss currently utilized therapies for DMD cardiomyopathy, and review experimental therapeutic strategies targeting the calcium handling defects in DCM and DMD cardiomyopathy.
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Affiliation(s)
- Michelle L. Law
- Department of Family and Consumer Sciences, Robbins College of Health and Human Sciences, Baylor University, Waco, TX 76706, USA;
| | - Houda Cohen
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (H.C.); (A.A.M.); (A.B.B.A.)
| | - Ashley A. Martin
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (H.C.); (A.A.M.); (A.B.B.A.)
| | - Addeli Bez Batti Angulski
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (H.C.); (A.A.M.); (A.B.B.A.)
| | - Joseph M. Metzger
- Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA; (H.C.); (A.A.M.); (A.B.B.A.)
- Correspondence: ; Tel.: +1-612-625-5902; Fax: +1-612-625-5149
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18
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Nikhanj A, Yogasundaram H, Miskew Nichols B, Richman-Eisenstat J, Phan C, Bakal JA, Siddiqi ZA, Oudit GY. Cardiac Intervention Improves Heart Disease and Clinical Outcomes in Patients With Muscular Dystrophy in a Multidisciplinary Care Setting. J Am Heart Assoc 2020; 9:e014004. [PMID: 31931688 PMCID: PMC7033817 DOI: 10.1161/jaha.119.014004] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Background Patients with muscular dystrophy (MD) represent a vulnerable patient population with no clearly defined care model in modern‐day clinical practice to manage a high burden of heart disease and comorbidities. We demonstrate the effectiveness of cardiac interventions, namely the initiation and optimization of medical and device therapies, as part of a multidisciplinary care approach to improve clinical outcomes in patients with MD. Methods and Results We conducted a prospective cohort study at the Neuromuscular Multidisciplinary clinic following patients with dystrophinopathies, limb‐girdle MD, type 1 myotonic dystrophy, and facioscapulohumeral MD. A negative control group classified as non‐MD myopathies without heart disease, was also tracked. Our cohort of 185 patients (median age: 42 years; 79 [42.7%] women), included 145 patients with MD. Cardiomyopathy was present in 65.6% of the patients with dystrophinopathies (21 of 32) and 27.3% of the patients with limb‐girdle MD (9 of 33). Conduction abnormalities were common in type 1 myotonic dystrophy (33.3% [20/60] patients). Cardiac intervention reversed systolic dysfunction, with left ventricular ejection fraction improving from 43% to 50.0% over a 3‐year period. A sustained reduction in healthcare utilization was also observed. The number of outpatient clinic visits decreased from 3.0 to 1.5 visits per year, the duration of hospitalizations was reduced from 14.2 to 0.9 days per year, and the number of cardiac‐related hospitalizations decreased from 0.4 to 0.1 hospitalizations per year associated with low mortality. Conclusions Our study demonstrates that cardiac intervention as part of a comprehensive multidisciplinary care approach to treating patients with MD leads to a sustained improvement in clinical outcomes.
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Affiliation(s)
- Anish Nikhanj
- Division of Cardiology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada.,Mazankowski Alberta Heart Institute Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Haran Yogasundaram
- Division of Cardiology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada.,Mazankowski Alberta Heart Institute Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Bailey Miskew Nichols
- Division of Cardiology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada.,Mazankowski Alberta Heart Institute Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Janice Richman-Eisenstat
- Division of Pulmonary Medicine Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Cecile Phan
- Division of Neurology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Jeffrey A Bakal
- Department of Medicine Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Zaeem A Siddiqi
- Division of Neurology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
| | - Gavin Y Oudit
- Division of Cardiology Faculty of Medicine and Dentistry University of Alberta Edmonton Canada.,Mazankowski Alberta Heart Institute Faculty of Medicine and Dentistry University of Alberta Edmonton Canada
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19
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Segawa K, Sugawara N, Maruo K, Kimura K, Komaki H, Takahashi Y, Sasaki M. Left Ventricular End-Diastolic Diameter and Cardiac Mortality in Duchenne Muscular Dystrophy. Neuropsychiatr Dis Treat 2020; 16:171-178. [PMID: 32021209 PMCID: PMC6972578 DOI: 10.2147/ndt.s235166] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/07/2019] [Indexed: 01/16/2023] Open
Abstract
PURPOSE This study aimed to examine weather left ventricular end-diastolic diameter (LVDd) could predict mortality from heart failure in patients with Duchenne muscular dystrophy (DMD) receiving standard cardio-protective therapies. PATIENTS AND METHODS One hundred thirty-three patients with DMD aged ≥10 years who underwent echocardiography from 2011 to 2015 were included in this study and retrospectively followed until August 2018. Patients were divided into two groups according to LVDd at initial echocardiography: ≤ 54 mm (Group 1: n=119) and ≥ 55 mm (Group 2: n=14). To identify factors other than LVDd that may affect heart failure-related mortality, Group 2 patients who developed no left atrial (LA) enlargement, moderate mitral regurgitation (MR), or pulmonary hypertension (PH) during the observation period (Group 2A: n=5) were compared with those who newly developed one or more of those complications (Group 2B: n=7). Clinical outcomes were all-cause mortality and mortality from heart failure. RESULTS Mean observation period was 5.5±1.5 years in Group 1 and 4.4±1.9 years in Group 2. A total of 14 patients (10.5%) died, including 6 of 119 (5.0%) patients in Group 1 and 8 of 14 (57.1%) patients in Group 2 (p<0.001). Among these, 1 (0.8%) patient in Group 1 and 8 (57.1%) patients in Group 2 died from heart failure (p<0.001). Group 2B patients had shorter survival compared to Group 2A patients (p=0.006). CONCLUSION LVDd ≥ 55 mm is a predictive factor for mortality from heart failure in patients with DMD. Complications including LA enlargement, moderate MR, and PH were found to be predictive factors for mortality from heart failure in a short period.
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Affiliation(s)
- Kazuhiko Segawa
- Department of Cardiology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Norio Sugawara
- Department of Psychiatry, Dokkyo Medical University School of Medicine, Tochigi, Japan
| | - Kazushi Maruo
- Department of Biostatistics, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan
| | - Koichi Kimura
- Department of General Medicine, The Institute of Medical Science, the University of Tokyo, Tokyo, Japan
| | - Hirofumi Komaki
- Translational Medical Center, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Yuji Takahashi
- Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
| | - Masayuki Sasaki
- Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan
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20
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Sato M, Shiba N, Miyazaki D, Shiba Y, Echigoya Y, Yokota T, Takizawa H, Aoki Y, Takeda S, Nakamura A. Amelioration of intracellular Ca 2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun 2019; 520:179-185. [PMID: 31585729 DOI: 10.1016/j.bbrc.2019.09.095] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Accepted: 09/22/2019] [Indexed: 01/02/2023]
Abstract
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by frameshift mutations in the DMD gene. DMD involves cardiac muscle, and the presence of ventricular arrhythmias or congestive failure is critical for prognosis. Several novel therapeutic approaches are being evaluated in ongoing clinical trials. Among them, exon-skipping therapy to correct frameshift mutations with antisense oligonucleotides is promising; however, their therapeutic efficacies on cardiac muscle in vivo remain unknown. In this study, we established induced-pluripotent stem cells (iPSCs) from T cells from a DMD patient carrying a DMD-exon 46-55 deletion, differentiated the iPSCs into cardiomyocytes, and treated them with phosphorodiamidate morpholino oligomers. The efficiency of exon-45 skipping increased in a dose-dependent manner and enabled restoration of the DMD gene product, dystrophin. Further, Ca2+-imaging analysis showed a decreased number of arrhythmic cells and improved transient Ca2+ signaling after exon skipping. Thus, exon-45 skipping may be effective for cardiac involvement in DMD patients harboring the DMD-exon 46-55 deletion.
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Affiliation(s)
- Mitsuto Sato
- Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan
| | - Naoko Shiba
- Department of Regenerative Science and Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan
| | - Daigo Miyazaki
- Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; Intractable Disease Care Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan
| | - Yuji Shiba
- Department of Regenerative Science and Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan
| | - Yusuke Echigoya
- Laboratory of Biomedical Science, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan
| | - Toshifumi Yokota
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada
| | - Hotake Takizawa
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan
| | - Yoshitsugu Aoki
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan
| | - Shin'ichi Takeda
- Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan
| | - Akinori Nakamura
- Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; Department of Clinical Research, National Hospital Organization Matsumoto Medical Center, Murai-Machi Minami, Matsumoto, 399-8701, Japan.
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21
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Meyers TA, Townsend D. Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy. Int J Mol Sci 2019; 20:E4098. [PMID: 31443395 PMCID: PMC6747383 DOI: 10.3390/ijms20174098] [Citation(s) in RCA: 79] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 08/12/2019] [Accepted: 08/19/2019] [Indexed: 12/25/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.
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Affiliation(s)
- Tatyana A Meyers
- Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA
| | - DeWayne Townsend
- Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, MN 55455, USA.
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van der Bijl P, Delgado V, Bootsma M, Bax JJ. Risk Stratification of Genetic, Dilated Cardiomyopathies Associated With Neuromuscular Disorders: Role of Cardiac Imaging. Circulation 2019; 137:2514-2527. [PMID: 29866775 DOI: 10.1161/circulationaha.117.031110] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The etiology of dilated cardiomyopathy (DCM) can be grouped as either genetic or nongenetic. More than 50 pathogenic genes have been described, with sarcomeric and lamin A/C mutations being the most common. Mutation carriers for genetic DCM are often asymptomatic until cardiac disease manifests with heart failure, arrhythmias, or sudden cardiac death. Preventive strategies are promising but can only be applied and tested adequately if genetic DCM can be diagnosed at an early stage. Early diagnosis of mutation carriers that may develop overt DCM requires advanced imaging techniques that can detect subtle structural and functional abnormalities. Advanced echocardiographic techniques such as tissue Doppler imaging and speckle tracking strain analysis permit early detection of functional abnormalities, whereas cardiovascular magnetic resonance techniques provide information on tissue characterization and myocardial energetics that may be altered at an early stage. Furthermore, nuclear imaging techniques provide information on cellular function (metabolism, perfusion). Once the diagnosis of overt DCM has been established, various imaging parameters such as echocardiography-based myocardial mechanics and cardiovascular magnetic resonance-based tissue characterization have shown incremental benefit to left ventricular ejection fraction in risk stratification. Further research is required to understand how imaging techniques may help to choose management strategies that could delay progression when instituted early in the course of the disease. The present article reviews the role of imaging in the risk stratification of genetic DCM in general, with specific emphasis on DCM associated with neuromuscular disorders.
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Affiliation(s)
| | - Victoria Delgado
- Department of Cardiology, Leiden University Medical Center, The Netherlands
| | - Marianne Bootsma
- Department of Cardiology, Leiden University Medical Center, The Netherlands
| | - Jeroen J Bax
- Department of Cardiology, Leiden University Medical Center, The Netherlands.
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Adorisio R, Calvieri C, Cantarutti N, D'Amico A, Catteruccia M, Bertini E, Baban A, Filippelli S, Perri G, Amodeo A, Drago F. Heart rate reduction strategy using ivabradine in end-stage Duchenne cardiomyopathy. Int J Cardiol 2019; 280:99-103. [DOI: 10.1016/j.ijcard.2019.01.052] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 01/07/2019] [Accepted: 01/14/2019] [Indexed: 12/15/2022]
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Soslow JH, Xu M, Slaughter JC, Crum K, Chew JD, Burnette WB, Su YR, Tomasek K, Parra DA, Markham LW. The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Duchenne Muscular Dystrophy Cardiomyopathy. J Card Fail 2019; 25:259-267. [PMID: 30763738 DOI: 10.1016/j.cardfail.2019.02.006] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 01/30/2019] [Accepted: 02/05/2019] [Indexed: 01/16/2023]
Abstract
BACKGROUND Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Standard cardiac biomarkers are poor indicators of DMD cardiovascular disease. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover. Given the cardiac fibrosis seen in DMD, we hypothesized that MMPs and TIMPs correlate with severity of DMD cardiomyopathy. METHODS AND RESULTS Prospectively enrolled DMD subjects (n = 42) underwent cardiac magnetic resonance imaging for function and late gadolinium enhancement (LGE), including LGE severity from 0 (no LGE) to 4 (severe). Serum from DMD and healthy male control subjects (n = 15) analyzed for MMPs 1, 2, 3, 7, 9, and 10 and TIMPs 1-4. MMP1, MMP7, and MMP10 were higher in DMD than in control (respectively, median 5080 pg/mL vs 2120 pg/mL [P = .007], 2170 pg/mL vs 1420 pg/mL [P < .001], and 216 pg/mL vs 140pg/mL [P = .040]); TIMP4 was lower in DMD (124 pg/mL vs 263 pg/mL; P = .046). Within DMD, MMP7 correlated inversely with left ventricular ejection fraction (r = -0.40; P = .012) and directly with strain (r = 0.54; P = .001) and LGE severity (r = 0.47; P = .003). MMP7 was higher in DMD patients with LGE compared with those without LGE and control subjects (P < .001). CONCLUSIONS Multiple MMPs are elevated in DMD compared with control subjects. MMP7 is related to DMD cardiac dysfunction and myocardial fibrosis, possibly through remodeling of the extracellular matrix.
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Affiliation(s)
- Jonathan H Soslow
- Thomas P Graham Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
| | - Meng Xu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - James C Slaughter
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kimberly Crum
- Thomas P Graham Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Joshua D Chew
- Thomas P Graham Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - W Bryan Burnette
- Division of Neurology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Yan Ru Su
- Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Kelsey Tomasek
- Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David A Parra
- Thomas P Graham Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Larry W Markham
- Thomas P Graham Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee; Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Bourke JP, Bueser T, Quinlivan R, Cochrane Neuromuscular Group. Interventions for preventing and treating cardiac complications in Duchenne and Becker muscular dystrophy and X-linked dilated cardiomyopathy. Cochrane Database Syst Rev 2018; 10:CD009068. [PMID: 30326162 PMCID: PMC6517009 DOI: 10.1002/14651858.cd009068.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and X-linked dilated cardiomyopathy (XLDCM). In recent years, co-ordinated multidisciplinary management for these diseases has improved the quality of care, with early corticosteroid use prolonging independent ambulation, and the routine use of non-invasive ventilation signficantly increasing survival. The next target to improve outcomes is optimising treatments to delay the onset or slow the progression of cardiac involvement and so prolong survival further. OBJECTIVES To assess the effects of interventions for preventing or treating cardiac involvement in DMD, BMD, and XLDCM, using measures of change in cardiac function over six months. SEARCH METHODS On 16 October 2017 we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE and Embase, and on 12 December 2017, we searched two clinical trials registries. We also searched conference proceedings and bibliographies. SELECTION CRITERIA We considered only randomised controlled trials (RCTs), quasi-RCTs and randomised cross-over trials for inclusion. In the Discussion, we reviewed open studies, longitudinal observational studies and individual case reports but only discussed studies that adequately described the diagnosis, intervention, pretreatment, and post-treatment states and in which follow-up lasted for at least six months. DATA COLLECTION AND ANALYSIS Two authors independently reviewed the titles and abstracts identified from the search and performed data extraction. All three authors assessed risk of bias independently, compared results, and decided which trials met the inclusion criteria. They assessed the certainty of evidence using GRADE criteria. MAIN RESULTS We included five studies (N = 205) in the review; four studies included participants with DMD only, and one study included participants with DMD or BMD. All studied different interventions, and meta-analysis was not possible. We found no studies for XLDCM. None of the trials reported cardiac function as improved or stable cardiac versus deteriorated.The randomised first part of a two-part study of perindopril (N = 28) versus placebo (N = 27) in boys with DMD with normal heart function at baseline showed no difference in the number of participants with a left ventricular ejection fraction (LVEF%) of less than 45% after three years of therapy (n = 1 in each group; risk ratio (RR) 1.04, 95% confidence interval (CI) 0.07 to 15.77). This result is uncertain because of study limitations, indirectness and imprecision. In a non-randomised follow-up study, after 10 years, more participants who had received placebo from the beginning had reduced LVEF% (less than 45%). Adverse event rates were similar between the placebo and treatment groups (low-certainty evidence).A study comparing treatment with lisinopril versus losartan in 23 boys newly diagnosed with Duchenne cardiomyopathy showed that after 12 months, both were equally effective in preserving or improving LVEF% (lisinopril 54.6% (standard deviation (SD) 5.19), losartan 55.2% (SD 7.19); mean difference (MD) -0.60% CI -6.67 to 5.47: N = 16). The certainty of evidence was very low because of very serious imprecision and study limitations (risk of bias). Two participants in the losartan group were withdrawn due to adverse events: one participant developed an allergic reaction, and a second exceeded the safety standard with a fall in ejection fraction greater than 10%. Authors reported no other adverse events related to the medication (N = 22; very low-certainty evidence).A study comparing idebenone versus placebo in 21 boys with DMD showed little or no difference in mean change in cardiac function between the two groups from baseline to 12 months; for fractional shortening the mean change was 1.4% (SD 4.1) in the idebenone group and 1.6% (SD 2.6) in the placebo group (MD -0.20%, 95% CI -3.07 to 2.67, N = 21), and for ejection fraction the mean change was -1.9% (SD 9.8) in the idebenone group and 0.4% (SD 5.5) in the placebo group (MD -2.30%, 95% CI -9.18 to 4.58, N = 21). The certainty of evidence was very low because of study limitations and very serious imprecision. Reported adverse events were similar between the treatment and placebo groups (low-certainty evidence).A multicentre controlled study added eplerenone or placebo to 42 patients with DMD with early cardiomyopathy but preserved left ventricular function already established on ACEI or ARB therapy. Results showed that eplerenone slowed the rate of decline of magnetic resonance (MR)-assessed left ventricular circumferential strain at 12 months (eplerenone group median 1.0%, interquartile range (IQR) 0.3 to -2.2; placebo group median 2.2%, IQR 1.3 to -3.1%; P = 0.020). The median decline in LVEF over the same period was also less in the eplerenone group (-1.8%, IQR -2.9 to 6.0) than in the placebo group (-3.7%, IQR -10.8 to 1.0; P = 0.032). We downgraded the certainty of evidence to very low for study limitations and serious imprecision. Serious adverse events were reported in two patients given placebo but none in the treatment group (very low-certainty evidence).A randomised placebo-controlled study of subcutaneous growth hormone in 16 participants with DMD or BMD showed an increase in left ventricular mass after three months' treatment but no significant improvement in cardiac function. The evidence was of very low certainty due to imprecision, indirectness, and study limitations. There were no clinically significant adverse events (very low-certainty evidence).Some studies were at risk of bias, and all were small. Therefore, although there is some evidence from non-randomised data to support the prophylactic use of perindopril for cardioprotection ahead of detectable cardiomyopathy, and for lisinopril or losartan plus eplerenone once cardiomyopathy is detectable, this must be considered of very low certainty. Findings from non-randomised studies, some of which have been long term, have led to the use of these drugs in daily clinical practice. AUTHORS' CONCLUSIONS Based on the available evidence from RCTs, early treatment with ACE inhibitors or ARBs may be comparably beneficial for people with a dystrophinopathy; however, the certainty of evidence is very low. Very low-certainty evidence indicates that adding eplerenone might give additional benefit when early cardiomyopathy is detected. No clinically meaningful effect was seen for growth hormone or idebenone, although the certainty of the evidence is also very low.
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Affiliation(s)
- John P Bourke
- Freeman HospitalDepartment of CardiologyFreeman RoadNewcastle Upon TyneUKNE7 DN
| | - Teofila Bueser
- King's College LondonFlorence Nightingale Faculty of Nursing & MidwiferyLondonUKSE1 8WA
| | - Rosaline Quinlivan
- UCL Institute of Neurology and National Hospital for Neurology and Neurosurgery and Great Ormond StreetMRC Centre for Neuromuscular Diseases and Dubowitz Neuromuscular CentrePO Box 114LondonUKWC1B 3BN
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Hor KN, Mah ML, Johnston P, Cripe TP, Cripe LH. Advances in the diagnosis and management of cardiomyopathy in Duchenne muscular dystrophy. Neuromuscul Disord 2018; 28:711-716. [PMID: 30064893 DOI: 10.1016/j.nmd.2018.06.014] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2018] [Revised: 06/28/2018] [Accepted: 06/28/2018] [Indexed: 02/07/2023]
Abstract
Patients with Duchenne muscular dystrophy suffer debilitating muscle destruction, resulting in loss of ambulation, diminished respiratory function, gastrointestinal disturbances and cardiomyopathy. Although it is the most common cause of death in these patients, cardiomyopathy is poorly understood in terms of distinct pathogenesis, natural history, and specific, effective therapeutic interventions. We review the state-of-the-art knowledge of Duchenne muscular dystrophy-associated cardiomyopathy including clinical evaluation, imaging, medical and perioperative management, and prospects for gene therapy. We also review cardiomyopathy in heterozygote carriers. By describing our current understanding and best practices, we hope to improve harmonization of care across institutions and identify collective knowledge gaps to guide future research efforts.
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Affiliation(s)
- Kan N Hor
- The Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - May Ling Mah
- The Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - Pace Johnston
- The Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - Timothy P Cripe
- The Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA
| | - Linda H Cripe
- The Department of Pediatrics, Ohio State University College of Medicine, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
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27
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Russo V, Papa AA, Williams EA, Rago A, Palladino A, Politano L, Nigro G. ACE inhibition to slow progression of myocardial fibrosis in muscular dystrophies. Trends Cardiovasc Med 2018; 28:330-337. [PMID: 29292032 DOI: 10.1016/j.tcm.2017.12.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2017] [Revised: 12/09/2017] [Accepted: 12/09/2017] [Indexed: 12/26/2022]
Abstract
Muscular dystrophy (MD) connotes a heterogeneous group of inherited disordersaffecting skeletal and cardiac muscle. Inseveral forms of MD, the cardiac disease may be the predominant manifestationof the underlying genetic myopathy. The cardiacinvolvement is due to progressive interstitial fibrosis and fatty replacement inboth the atria and ventricles, which may lead to cardiomyopathy, conductiondefects and tachyarrhythmias. Angiotensin-convertingenzyme inhibitors (ACE-Is) modulate the production of angiotensin II and limitthe amount of fibrosis in the myocardium, reducing mortality andhospitalization in cardiac patients. The aim of present review is to describethe antifibrotic proprieties of ACE inhibitor therapy and to summarize thecurrent body of scientific literature relating to the use of ACE-Is for theprevention and treatment of cardiomyopathy in patients with musculardystrophies.
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Affiliation(s)
- Vincenzo Russo
- Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy.
| | - Andrea Antonio Papa
- Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy; Cardiomyology and Genetic Section, Department of Internal and Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Emmanuel Ato Williams
- Department of Cardiology, Liverpool Heart and Chest Hospital, Liverpool, United Kingdom
| | - Anna Rago
- Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy
| | - Alberto Palladino
- Cardiomyology and Genetic Section, Department of Internal and Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Luisa Politano
- Cardiomyology and Genetic Section, Department of Internal and Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Gerardo Nigro
- Chair of Cardiology, University of Campania "Luigi Vanvitelli", Monaldi Hospital, Naples, Italy
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28
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Power LC, O'Grady GL, Hornung TS, Jefferies C, Gusso S, Hofman PL. Imaging the heart to detect cardiomyopathy in Duchenne muscular dystrophy: A review. Neuromuscul Disord 2018; 28:717-730. [PMID: 30119965 DOI: 10.1016/j.nmd.2018.05.011] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 05/24/2018] [Accepted: 05/29/2018] [Indexed: 01/16/2023]
Abstract
Duchenne Muscular Dystrophy is the most common paediatric neuromuscular disorder. Mutations in the DMD gene on the X-chromosome result in progressive skeletal muscle weakness as the main clinical manifestation. However, cardiac muscle is also affected, with cardiomyopathy becoming an increasingly recognised cause of morbidity, and now the leading cause of mortality in this group. The diagnosis of cardiomyopathy has often been made late due to technical limitations in transthoracic echocardiograms and delayed symptomatology in less mobile patients. Increasingly, evidence supports earlier pharmacological intervention in cardiomyopathy to improve outcomes. However, the optimal timing of initiation remains uncertain, and the benefits of prophylactic therapy are unproven. Current treatment guidelines suggest initiation of therapy once cardiac dysfunction is detected. This review focuses on new and evolving techniques for earlier detection of Duchenne muscular dystrophy-associated cardiomyopathy. Transthoracic echocardiography or cardiac magnetic resonance imaging performed under physiological stress (dobutamine or exercise), can unmask early cardiac dysfunction. Cardiac magnetic resonance imaging can define cardiac function with greater accuracy and reliability than an echocardiogram, and is not limited by body habitus. Improved imaging techniques, used in a timely fashion, offer the potential for early detection of cardiomyopathy and improved long-term outcomes.
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Affiliation(s)
- Lisa C Power
- Paediatric Neurology Department, Starship Children's Hospital, Auckland, New Zealand; Paediatric Endocrinology Department, Starship Children's Hospital, Auckland, New Zealand; Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Gina L O'Grady
- Paediatric Neurology Department, Starship Children's Hospital, Auckland, New Zealand.
| | - Tim S Hornung
- Paediatric Cardiology Department, Starship Children's Hospital, Auckland, New Zealand
| | - Craig Jefferies
- Paediatric Endocrinology Department, Starship Children's Hospital, Auckland, New Zealand
| | - Silmara Gusso
- Liggins Institute, University of Auckland, Auckland, New Zealand
| | - Paul L Hofman
- Paediatric Endocrinology Department, Starship Children's Hospital, Auckland, New Zealand; Liggins Institute, University of Auckland, Auckland, New Zealand
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29
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Fayssoil A, Abasse S, Silverston K. Cardiac Involvement Classification and Therapeutic Management in Patients with Duchenne Muscular Dystrophy. J Neuromuscul Dis 2018; 4:17-23. [PMID: 28269790 PMCID: PMC5345647 DOI: 10.3233/jnd-160194] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Duchenne muscular dystrophy (DMD) is an inherited myogenic disorder due to mutations in the dystrophin gene on chromosome Xp21.1. The clinical picture included peripheral muscle weakness, cardiomyopathy and chronic respiratory insufficiency. In this paper, the authors review cardiac involvement in patients with DMD, propose a cardiac impairment classification and discuss therapeutic management options.
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Affiliation(s)
- Abdallah Fayssoil
- APHP, Raymond Poincare Hospital, University of Versailles, Garches, France.,Myology Institute, Pitié Salpetrière Hospital, Paris, France
| | - Soumeth Abasse
- Pediatric Center, Mayotte Hospital Center, Mayotte, Island
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30
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Mavrogeni SI, Markousis-Mavrogenis G, Papavasiliou A, Papadopoulos G, Kolovou G. Cardiac Involvement in Duchenne Muscular Dystrophy and Related Dystrophinopathies. Methods Mol Biol 2018; 1687:31-42. [PMID: 29067654 DOI: 10.1007/978-1-4939-7374-3_3] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Dystrophinopathies include Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy (XLCM), and facioscapulohumeral muscular dystrophy (FSHD). DMD/BMD are X-linked recessive disorders, related to the synthesis of dystrophin. Most of DMD after the third decade of their age develop cardiomyopathy that remains silent, due to relative physical inactivity. Cardiac disease in female carriers presents with hypertrophy, arrhythmias or dilated cardiomyopathy, clinically overt by increasing age.In ECG, DMD presents increased R/S ratio in the right precordial leads, deep Q waves in the lateral leads, conduction abnormalities, and arrhythmias. Echocardiography, although widely available and inexpensive, is highly depended on the acoustic window and operator's experience. Tissue Doppler can be used to identify early changes of cardiomyopathy and detect progressive cardiac damage. CMR, a noninvasive, nonradiating technique, by evaluation of cardiac volumes, mass, ejection fraction, inflammation, and fibrosis, is ideal for early diagnosis. Subepicardial fibrosis in the inferolateral wall is the typical CMR lesion in DMD/BMD.Early initiation of angiotensin converting enzyme inhibitors (ACEI) treatment, such as perindopril, was associated with lower mortality in DMD with normal LV ejection fraction at study entry. Other studies documented that a beta-blocker (BB), in addition to ACEI, improves LV systolic function in MD. These encouraging results recommend initiation of ACEI and/or BB early after diagnosis of the muscular dystrophy, especially in DMD.
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MESH Headings
- Adolescent
- Adrenergic beta-Antagonists/therapeutic use
- Angiotensin-Converting Enzyme Inhibitors/therapeutic use
- Arrhythmias, Cardiac/diagnosis
- Arrhythmias, Cardiac/drug therapy
- Arrhythmias, Cardiac/physiopathology
- Cardiomyopathies/diagnosis
- Cardiomyopathies/drug therapy
- Cardiomyopathies/genetics
- Cardiomyopathies/physiopathology
- Cardiomyopathy, Dilated/diagnosis
- Cardiomyopathy, Dilated/drug therapy
- Cardiomyopathy, Dilated/genetics
- Cardiomyopathy, Dilated/physiopathology
- Dystrophin/genetics
- Echocardiography
- Electrocardiography
- Female
- Heart/physiopathology
- Humans
- Male
- Muscular Dystrophy, Duchenne/diagnosis
- Muscular Dystrophy, Duchenne/drug therapy
- Muscular Dystrophy, Duchenne/genetics
- Muscular Dystrophy, Duchenne/physiopathology
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Affiliation(s)
- Sophie I Mavrogeni
- Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61 P.Faliro, Athens, Greece.
| | | | | | | | - Genovefa Kolovou
- Onassis Cardiac Surgery Center, 50 Esperou Street, 175-61 P.Faliro, Athens, Greece
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31
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Singh RK, Canter CE, Shi L, Colan SD, Dodd DA, Everitt MD, Hsu DT, Jefferies JL, Kantor PF, Pahl E, Rossano JW, Towbin JA, Wilkinson JD, Lipshultz SE. Survival Without Cardiac Transplantation Among Children With Dilated Cardiomyopathy. J Am Coll Cardiol 2017; 70:2663-2673. [PMID: 29169474 DOI: 10.1016/j.jacc.2017.09.1089] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 08/30/2017] [Accepted: 09/18/2017] [Indexed: 12/31/2022]
Abstract
BACKGROUND Studies of children with dilated cardiomyopathy (DCM) have suggested that improved survival has been primarily due to utilization of heart transplantation. OBJECTIVES This study sought to determine transplant-free survival for these children over 20 years and identify the clinical characteristics at diagnosis that predicted death. METHODS Children <18 years of age with some type of DCM enrolled in the Pediatric Cardiomyopathy Registry were divided by year of diagnosis into an early cohort (1990 to 1999) and a late cohort (2000 to 2009). Competing risks and multivariable modeling were used to estimate the cumulative incidence of death, transplant, and echocardiographic normalization by cohort and to identify the factors associated with death. RESULTS Of 1,953 children, 1,199 were in the early cohort and 754 were in the late cohort. Most children in both cohorts had idiopathic DCM (64% vs. 63%, respectively). Median age (1.6 vs. 1.7 years), left ventricular end-diastolic z-scores (+4.2 vs. +4.2), and left ventricular fractional shortening (16% vs. 17%) at diagnosis were similar between cohorts. Although the rates of echocardiographic normalization (30% and 27%) and heart transplantation (24% and 24%) were similar, the death rate was higher in the early cohort than in the late cohort (18% vs. 9%; p = 0.04). Being in the early cohort (hazard ratio: 1.4; 95% confidence interval: 1.04 to 1.9; p = 0.03) independently predicted death. CONCLUSIONS Children with DCM have improved survival in the more recent era. This appears to be associated with factors other than heart transplantation, which was equally prevalent in both eras. (Pediatric Cardiomyopathy Registry [PCMR]; NCT00005391).
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Affiliation(s)
- Rakesh K Singh
- Department of Pediatrics, University of California-San Diego and Rady Children's Hospital, San Diego, California.
| | - Charles E Canter
- Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri
| | - Ling Shi
- New England Research Institutes, Watertown, Massachusetts
| | - Steven D Colan
- Department of Pediatrics, Boston's Children's Hospital, Boston, Massachusetts
| | - Debra A Dodd
- Department of Pediatrics, Vanderbilt University and Monroe Carell Jr. Children's Hospital, Nashville, Tennessee
| | - Melanie D Everitt
- Department of Pediatrics, Children's Hospital Colorado and University of Colorado, Aurora, Colorado
| | - Daphne T Hsu
- Department of Pediatrics, Children's Hospital at Montefiore, Bronx, New York
| | - John L Jefferies
- Department of Pediatrics, The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Paul F Kantor
- Department of Pediatrics, Stollery Children's Hospital, Edmonton, Alberta, Canada
| | - Elfriede Pahl
- Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
| | - Joseph W Rossano
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jeffrey A Towbin
- Department of Pediatrics, Le Bonheur Children's Hospital, Memphis, Tennessee
| | - James D Wilkinson
- Department of Pediatrics, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, Michigan
| | - Steven E Lipshultz
- Department of Pediatrics, Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, Michigan
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32
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Mavrogeni S, Papavasiliou A, Giannakopoulou K, Markousis-Mavrogenis G, Pons MR, Karanasios E, Nikas I, Papadopoulos G, Kolovou G, Chrousos GP. Oedema-fibrosis in Duchenne Muscular Dystrophy: Role of cardiovascular magnetic resonance imaging. Eur J Clin Invest 2017; 47. [PMID: 29027210 DOI: 10.1111/eci.12843] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2017] [Accepted: 10/09/2017] [Indexed: 12/13/2022]
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder characterized by progressive, irreversible loss of cardiac and skeletal muscular function. Muscular enlargement in DMD is attributed to oedema, due to the increased cytoplasmic Na+ concentration. The aim of this review was to present the current experience and emphasize the role of cardiovascular magnetic resonance (CMR) in the diagnosis of this condition. DMD patients' survival depends on ventilatory assistance, as respiratory muscle dysfunction was the most common cause of death in the past. Currently, due to improved ventilatory assistance, cardiomyopathy has become the main cause of death, even though clinically overt heart failure may be absent. CMR is the technique of choice to assess the pathophysiologic phenomena taking place in DMD, such as myocardial oedema and subepicardial fibrosis. The classic index to assess oedema is the T2-weighted short-tau inversion recovery (T2w-STIR), as it suppresses the signal from flowing blood and resident fat and enhances sensitivity to tissue fluid. Furthermore, CMR is the most reliable technique to detect and quantify fibrosis in DMD. Recently, the new indices T2, T1 mapping (native and postcontrast) and the extracellular volume (ECV) allow a more accurate approach of myocardial oedema and fibrosis. To conclude, the assessment of cardiac oedema and subepicardial fibrosis in the inferolateral wall of the left heart ventricle are the most important early finding in DMD with preserved ventricular function, and CMR, using both the classic and the new indices, is the best technique to detect and monitor these lesions.
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Affiliation(s)
| | | | - Katerina Giannakopoulou
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | | | - Maria Roser Pons
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Evangelos Karanasios
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Ioannis Nikas
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - George Papadopoulos
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | | | - George P Chrousos
- First Dept of Paediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
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Mavrogeni S, Pons R, Nikas I, Papadopoulos G, Verganelakis DA, Kolovou G, Chrousos GP. Brain and heart magnetic resonance imaging/spectroscopy in duchenne muscular dystrophy. Eur J Clin Invest 2017; 47. [PMID: 28981141 DOI: 10.1111/eci.12842] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 10/02/2017] [Indexed: 01/04/2023]
Abstract
Duchenne muscular dystrophy (DMD) is an X-linked muscle disorder characterized by progressive and irreversible loss of muscular function. As muscular disease progresses, the repair mechanisms cannot compensate for cellular damage, leading inevitably to necrosis and progressive replacement by fibrous and fatty tissue. Cardiomyopathy and respiratory failure are the main causes of death in DMD. In addition to the well-described muscle and heart disease, cognitive dysfunction affects around 30% of DMD boys. Myocardial fibrosis, assessed by late gadolinium enhancement (LGE), using cardiovascular magnetic resonance imaging (CMR), is an early marker of heart involvement in both DMD patients and female carriers. In parallel, brain MRI identifies smaller total brain volume, smaller grey matter volume, lower white matter fractional anisotropy and higher white matter radial diffusivity in DMD patients. The in vivo brain evaluation of mdx mice, a surrogate animal model of DMD, showed an increased inorganic phosphate (P(i))/phosphocreatine (PCr) and pH. In this paper, we propose a holistic approach using techniques of magnetic resonance imaging, spectroscopy and diffusion tensor imaging as a tool to create a "heart and brain imaging map" in DMD patients that could potentially facilitate the patients' risk stratification and also future research studies in the field.
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Affiliation(s)
| | - Roser Pons
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Ioannis Nikas
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - George Papadopoulos
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | - Dimitrios A Verganelakis
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
| | | | - George P Chrousos
- 1st Department of Pediatrics, National and Kapodistrian University of Athens, Aghia Sophia Children's Hospital, Athens, Greece
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Sadek AA, Mahmoud SM, El-Aal MA, Allam AA, El-Halim WIA. Evaluation of cardiac functions in children with Duchenne Muscular Dystrophy: A prospective case-control study. Electron Physician 2017; 9:5732-5739. [PMID: 29403612 PMCID: PMC5783121 DOI: 10.19082/5732] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2017] [Accepted: 08/26/2017] [Indexed: 12/21/2022] Open
Abstract
Background Duchenne muscular dystrophy (DMD) is the most common childhood form of muscular dystrophy. The incidence of cardiomyopathy in DMD increases with age, so its early detection is important because institution of cardioprotective medical therapies may slow adverse remodeling and attenuate heart failure symptoms in these patients. Objective To assess the cardiac functions in children clinically suspected to have DMD. Methods Over a one-year period, 28 male children aged from 3 to 18 years old, who met the criteria for diagnosis of DMD compared to 47 healthy controls children, were approached to participate in the study. The included children were subjected to full clinical examination, and blood samples were collected to determine creatinine phosphokinase (CPK), troponin I enzyme, myoglobin and lactate dehydrogenase (LDH) enzyme level. Echocardiography and 12-leads electrocardiogram (ECG) were also done for children in both groups. Data were analyzed using Independent-samples t-test, Mann-Whitney U, Chi square, and Fisher’s exact test. Results The mean age of the cases group was 7.29±3.24 years versus 8.06±2.86 years for controls. In DMD group, 25% had positive family history of DMD while 35.7% of them had positive consanguinity. All cases had elevated CPK level while CPK level in controls was normal (p<0.0001). LDH level was elevated in 19 cases (67.86%) of DMD while all controls children had normal LDH level (p<0.0001). Furthermore, the mean serum myoglobin level of DMD patients was higher relative to that of healthy controls (39.39±7.25 versus 33.68 ±12.38 ng/ml respectively) (p=0.01). Echocardiography of our patients revealed that seven cases (25%) had low ejection fraction (EF) and fraction shortening (FS). In addition, all controls children had normal EF (p<0.0001) and normal FS (p<0.0001). Interestingly, ECG showed that 28.57% of cases had sinus tachycardia vs. 6.88% for controls (p=0.0001). Prolonged QTc interval was present in 39.29% of cases (mean 431.39±43.60) while all controls had normal QTc duration for age (mean of 415.17±25.2) (p<0.0001). Conclusion ECG manifestations in children with DMD in the form of sinus tachycardia and prolonged QTc interval are an early alarm for developing cardiomyopathy before overt echocardiographic findings appear.
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Affiliation(s)
- Abdelrahim Abdrabou Sadek
- Assistant Professor, Head of Pediatric Neurology and Psychiatry Unit, Pediatric Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | | | - Mohammed Abd El-Aal
- Professor and Chairman of Pediatric Cardiology Unit and Pediatric Department, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Ahmed Ahmed Allam
- Lecturer, Clinical Pathology Department, Faculty of Medicine, Sohag University, Sohag, Egypt
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Cheeran D, Khan S, Khera R, Bhatt A, Garg S, Grodin JL, Morlend R, Araj FG, Amin AA, Thibodeau JT, Das S, Drazner MH, Mammen PPA. Predictors of Death in Adults With Duchenne Muscular Dystrophy-Associated Cardiomyopathy. J Am Heart Assoc 2017; 6:JAHA.117.006340. [PMID: 29042427 PMCID: PMC5721845 DOI: 10.1161/jaha.117.006340] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Duchenne muscular dystrophy (DMD) is frequently complicated by development of a cardiomyopathy. Despite significant medical advances provided to DMD patients over the past 2 decades, there remains a group of DMD patients who die prematurely. The current study sought to identify a set of prognostic factors that portend a worse outcome among adult DMD patients. Methods and Results A retrospective cohort of 43 consecutive patients was followed in the adult UT Southwestern Neuromuscular Cardiomyopathy Clinic. Clinical data were abstracted from the electronic medical record to generate baseline characteristics. The population was stratified by survival to time of analysis and compared with characteristics associated with death. The DMD population was in the early 20s, with median follow‐up times over 2 years. All the patients had developed a cardiomyopathy, with the majority of the patients on angiotensin‐converting enzyme inhibitors (86%) and steroids (56%), but few other guideline‐directed heart failure medications. Comparison between the nonsurviving and surviving cohorts found several poor prognostic factors, including lower body mass index (17.3 [14.8–19.3] versus 25.8 [20.8–29.1] kg/m2, P<0.01), alanine aminotransferase levels (26 [18–42] versus 53 [37–81] units/L, P=0.001), maximum inspiratory pressures (13 [0–30] versus 33 [25–40] cmH2O, P=0.03), and elevated cardiac biomarkers (N‐terminal pro‐brain natriuretic peptide: 288 [72–1632] versus 35 [21–135] pg/mL, P=0.03]. Conclusions The findings demonstrate a DMD population with a high burden of cardiomyopathy. The nonsurviving cohort was comparatively underweight, and had worse respiratory profiles and elevated cardiac biomarkers. Collectively, these factors highlight a high‐risk cardiovascular population with a worse prognosis.
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Affiliation(s)
- Daniel Cheeran
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Shaida Khan
- Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Rohan Khera
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Anish Bhatt
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Sonia Garg
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Justin L Grodin
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Robert Morlend
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Faris G Araj
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Alpesh A Amin
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Jennifer T Thibodeau
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Sandeep Das
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX
| | - Mark H Drazner
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX
| | - Pradeep P A Mammen
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX .,Heart Failure, Ventricular Assist Device & Heart Transplant Program, University of Texas Southwestern Medical Center, Dallas, TX.,Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX.,UT Southwestern Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX
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Feingold B, Mahle WT, Auerbach S, Clemens P, Domenighetti AA, Jefferies JL, Judge DP, Lal AK, Markham LW, Parks WJ, Tsuda T, Wang PJ, Yoo SJ. Management of Cardiac Involvement Associated With Neuromuscular Diseases: A Scientific Statement From the American Heart Association. Circulation 2017; 136:e200-e231. [DOI: 10.1161/cir.0000000000000526] [Citation(s) in RCA: 145] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Aimo A, Giannoni A, Castiglione V, Mancuso M, Siciliano G, Piepoli MF, Passino C, Emdin M. Neurohormonal modulation for treatment of cardiac involvement in dystrophinopathies and mitochondrial disease. Eur J Prev Cardiol 2017; 24:1718-1724. [DOI: 10.1177/2047487317725018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Affiliation(s)
- Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alberto Giannoni
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | | | | | | | | | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
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Kamdar F, Garry DJ. Dystrophin-Deficient Cardiomyopathy. J Am Coll Cardiol 2017; 67:2533-46. [PMID: 27230049 DOI: 10.1016/j.jacc.2016.02.081] [Citation(s) in RCA: 249] [Impact Index Per Article: 31.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 02/16/2016] [Accepted: 02/23/2016] [Indexed: 12/25/2022]
Abstract
Dystrophinopathies are a group of distinct neuromuscular diseases that result from mutations in the structural cytoskeletal Dystrophin gene. Dystrophinopathies include Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), X-linked dilated cardiomyopathy, as well as DMD and BMD female carriers. The primary presenting symptom in most dystrophinopathies is skeletal muscle weakness. However, cardiac muscle is also a subtype of striated muscle and is similarly affected in many of the muscular dystrophies. Cardiomyopathies associated with dystrophinopathies are an increasingly recognized manifestation of these neuromuscular disorders and contribute significantly to their morbidity and mortality. Recent studies suggest that these patient populations would benefit from cardiovascular therapies, annual cardiovascular imaging studies, and close follow-up with cardiovascular specialists. Moreover, patients with DMD and BMD who develop end-stage heart failure may benefit from the use of advanced therapies. This review focuses on the pathophysiology, cardiac involvement, and treatment of cardiomyopathy in the dystrophic patient.
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Affiliation(s)
- Forum Kamdar
- Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota
| | - Daniel J Garry
- Cardiovascular Division, Lillehei Heart Institute, University of Minnesota, Minneapolis, Minnesota.
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Perspective on precision medicine in paediatric heart failure. Clin Sci (Lond) 2017; 131:439-448. [DOI: 10.1042/cs20160414] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/25/2016] [Accepted: 01/03/2017] [Indexed: 01/02/2023]
Abstract
In 2015, President Obama launched the Precision Medicine Initiative (PMI), which introduced new funding to a method of research with the potential to study rare and complex diseases. Paediatric heart failure, a heterogeneous syndrome affecting approximately 1 in 100000 children, is one such condition in which precision medicine techniques may be applied with great benefit. Current heart failure therapies target downstream effects of heart failure rather than the underlying cause of heart failure. As such, they are often ineffective in paediatric heart failure, which is typically of primary (e.g. genetic) rather than secondary (e.g. acquired) aetiology. It is, therefore, important to develop therapies that can target the causes of heart failure in children with greater specificity thereby decreasing morbidity, mortality and burden of illness on both patients and their families. The benefits of co-ordinated research in genomics, proteomics, metabolomics, transcriptomics and phenomics along with dietary, lifestyle and social factors have led to novel therapeutic and prognostic applications in other fields such as oncology. Applying such co-ordinated research efforts to heart failure constitutes an important step in advancing care and improving the lives of those affected.
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El-Aloul B, Altamirano-Diaz L, Zapata-Aldana E, Rodrigues R, Malvankar-Mehta MS, Nguyen CT, Campbell C. Pharmacological therapy for the prevention and management of cardiomyopathy in Duchenne muscular dystrophy: A systematic review. Neuromuscul Disord 2016; 27:4-14. [PMID: 27815032 DOI: 10.1016/j.nmd.2016.09.019] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2016] [Revised: 09/16/2016] [Accepted: 09/26/2016] [Indexed: 01/03/2023]
Abstract
Cardiomyopathy is a major source of morbidity and mortality in Duchenne muscular dystrophy (DMD) patients now that respiratory care has improved. There is currently no definitive evidence guiding the management of DMD-associated cardiomyopathy (DMD-CM). The objective of this systematic review was to evaluate the effectiveness of pharmacotherapies for the prevention and/or management of DMD-CM and to determine the optimal timing to commence these interventions. A systematic search was conducted in January 2016 using MEDLINE, EMBASE and CINAHL databases and grey literature sources for studies evaluating the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, beta-blockers or aldosterone antagonists. Study quality assessment was conducted using the Downs and Black quality assessment checklist. PRISMA reporting guidelines were used. Of the 15 studies included in this review, most were of low methodological quality. Meta-analysis was not possible due to heterogeneity of studies. ACE inhibitors, angiotensin receptor blockers, beta-blockers and/or aldosterone antagonists tended to improve or preserve left ventricular systolic function and delay the progression of DMD-CM. While there is evidence supporting the use of heart failure medication in patients with DMD, data regarding these interventions for delaying the onset of DMD-CM and when to initiate therapy are lacking. PROSPERO registration: CRD42015029555.
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Affiliation(s)
- Basmah El-Aloul
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Luis Altamirano-Diaz
- Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Eugenio Zapata-Aldana
- Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Clinical Neurological Sciences, Children's Hospital, London Health Sciences Center, London, ON, Canada
| | - Rebecca Rodrigues
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Monali S Malvankar-Mehta
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Department of Ophthalmology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada
| | - Cam-Tu Nguyen
- Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Clinical Neurological Sciences, Children's Hospital, London Health Sciences Center, London, ON, Canada
| | - Craig Campbell
- Department of Epidemiology and Biostatistics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Department of Paediatrics, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada; Clinical Neurological Sciences, Children's Hospital, London Health Sciences Center, London, ON, Canada.
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Archer JE, Gardner AC, Roper HP, Chikermane AA, Tatman AJ. Duchenne muscular dystrophy: the management of scoliosis. JOURNAL OF SPINE SURGERY 2016; 2:185-194. [PMID: 27757431 DOI: 10.21037/jss.2016.08.05] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
This study summaries the current management of scoliosis in patients with Duchenne Muscular Dystrophy. A literature review of Medline was performed and the collected articles critically appraised. This literature is discussed to give an overview of the current management of scoliosis within Duchenne Muscular Dystrophy. Importantly, improvements in respiratory care, the use of steroids and improving surgical techniques have allowed patients to maintain quality of life and improved life expectancy in this patient group.
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Affiliation(s)
- James E Archer
- The Royal Orthopaedic Hospital, Northfield, Birmingham, West Midlands, UK; ; Heartlands Hospital, Bordesley Green East, Birmingham, West Midlands, UK
| | - Adrian C Gardner
- The Royal Orthopaedic Hospital, Northfield, Birmingham, West Midlands, UK
| | - Helen P Roper
- Heartlands Hospital, Bordesley Green East, Birmingham, West Midlands, UK
| | | | - Andrew J Tatman
- Birmingham Children's Hospital, Steelhouse Lane, Birmingham, UK
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43
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Ho R, Nguyen ML, Mather P. Cardiomyopathy in becker muscular dystrophy: Overview. World J Cardiol 2016; 8:356-361. [PMID: 27354892 PMCID: PMC4919702 DOI: 10.4330/wjc.v8.i6.356] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2015] [Revised: 04/07/2016] [Accepted: 04/22/2016] [Indexed: 02/06/2023] Open
Abstract
Becker muscular dystrophy (BMD) is an X-linked recessive disorder involving mutations of the dystrophin gene. Cardiac involvement in BMD has been described and cardiomyopathy represents the number one cause of death in these patients. In this paper, the pathophysiology, clinical evaluations and management of cardiomyopathy in patients with BMD will be discussed.
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Alabed S, Sabouni A, Al Dakhoul S, Bdaiwi Y, Frobel-Mercier AK. Beta-blockers for congestive heart failure in children. Cochrane Database Syst Rev 2016:CD007037. [PMID: 26820557 DOI: 10.1002/14651858.cd007037.pub3] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
BACKGROUND Beta-blockers are an essential part of standard therapy in adult congestive heart failure and therefore, are expected to be beneficial in children. However, congestive heart failure in children differs from that in adults in terms of characteristics, aetiology, and drug clearance. Therefore, paediatric needs must be specifically investigated. This is an update of a Cochrane review previously published in 2009. OBJECTIVES To assess the effect of beta-adrenoceptor-blockers (beta-blockers) in children with congestive heart failure. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and LILACS up to November 2015. Bibliographies of identified studies were checked. No language restrictions were applied. SELECTION CRITERIA Randomised, controlled, clinical trials investigating the effect of beta-blocker therapy on paediatric congestive heart failure. DATA COLLECTION AND ANALYSIS Two review authors independently extracted and assessed data from the included trials. MAIN RESULTS We identified four new studies for the review update; the review now includes seven studies with 420 participants. Four small studies with 20 to 30 children each, and two larger studies of 80 children each, showed an improvement of congestive heart failure with beta-blocker therapy. A larger study with 161 participants showed no evidence of benefit over placebo in a composite measure of heart failure outcomes. The included studies showed no significant difference in mortality or heart transplantation rates between the beta-blocker and control groups. No significant adverse events were reported with beta-blockers, apart from one episode of complete heart block. A meta-analysis of left ventricular ejection fraction (LVEF) and fractional shortening (LVFS) data showed a very small improvement with beta-blockers.However, there were vast differences in the age, age range, and health of the participants (aetiology and severity of heart failure; heterogeneity of diagnoses and co-morbidities); there was a range of treatments across studies (choice of beta-blocker, dosing, duration of treatment); and a lack of standardised methods and outcome measures. Therefore, the primary outcomes could not be pooled in meta-analyses. AUTHORS' CONCLUSIONS There is not enough evidence to support or discourage the use of beta-blockers in children with congestive heart failure, or to propose a paediatric dosing scheme. However, the sparse data available suggested that children with congestive heart failure might benefit from beta-blocker treatment. Further investigations in clearly defined populations with standardised methodology are required to establish guidelines for therapy. Pharmacokinetic investigations of beta-blockers in children are also required to provide effective dosing in future trials.
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Affiliation(s)
- Samer Alabed
- Department of Cardiovascular Science, The University of Sheffield, Sheffield, UK
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McNally EM, Kaltman JR, Benson DW, Canter CE, Cripe LH, Duan D, Finder JD, Groh WJ, Hoffman EP, Judge DP, Kertesz N, Kinnett K, Kirsch R, Metzger JM, Pearson GD, Rafael-Fortney JA, Raman SV, Spurney CF, Targum SL, Wagner KR, Markham LW. Contemporary cardiac issues in Duchenne muscular dystrophy. Working Group of the National Heart, Lung, and Blood Institute in collaboration with Parent Project Muscular Dystrophy. Circulation 2015; 131:1590-8. [PMID: 25940966 DOI: 10.1161/circulationaha.114.015151] [Citation(s) in RCA: 230] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Elizabeth M McNally
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.).
| | - Jonathan R Kaltman
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.).
| | - D Woodrow Benson
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Charles E Canter
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Linda H Cripe
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Dongsheng Duan
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Jonathan D Finder
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | | | - Eric P Hoffman
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Daniel P Judge
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Naomi Kertesz
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Kathi Kinnett
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Roxanne Kirsch
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Joseph M Metzger
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Gail D Pearson
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Jill A Rafael-Fortney
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Subha V Raman
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Christopher F Spurney
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Shari L Targum
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Kathryn R Wagner
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.)
| | - Larry W Markham
- From Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL (E.M.M.); Division of Cardiovascular Sciences, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (J.R.K., G.D.P.); Division of Cardiology, Children's Hospital of Wisconsin, Milwaukee (D.W.B.); Department of Pediatrics, Washington University, St. Louis, MO (C.E.C.); The Heart Center, Nationwide Children's Hospital, Columbus, OH (L.H.C., N.K.); Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia (D.D.); Division of Pulmonary Medicine, Children's Hospital of Pittsburgh, PA (J.D.F.); Center for Genetic Medicine Research (E.P.H.) and Division of Cardiology, Children's National Heart Institute, Center for Genetic Medicine Research (C.F.S.), Children's National Health System, Washington, DC; Division of Cardiology, Johns Hopkins School of Medicine, Baltimore, MD (D.P.J.); Parent Project Muscular Dystrophy, Middletown, OH (K.K.); Division of Cardiac Critical Care, Children's Hospital of Philadelphia, PA (R.K.); Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis (J.M.M.); Department of Molecular and Cellular Biochemistry (J.A.R.-F.) and Division of Cardiovascular Medicine (S.V.R.), Ohio State University, Columbus; Division of Cardiovascular and Renal Products, US Food and Drug Administration, Silver Spring, MD (S.L.T.); Hugo W. Moser Research Institute, Kennedy Krieger Institute, Baltimore, MD (K.R.W.); and Division of Pediatric Cardiology, Department of Pediatrics, Vanderbilt University, Nashville, TN (L.W.M.).
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X-Linked Dilated Cardiomyopathy: A Cardiospecific Phenotype of Dystrophinopathy. Pharmaceuticals (Basel) 2015; 8:303-20. [PMID: 26066469 PMCID: PMC4491663 DOI: 10.3390/ph8020303] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2015] [Accepted: 06/04/2015] [Indexed: 12/12/2022] Open
Abstract
X-linked dilated cardiomyopathy (XLDCM) is a distinct phenotype of dystrophinopathy characterized by preferential cardiac involvement without any overt skeletal myopathy. XLDCM is caused by mutations of the Duchenne muscular dystrophy (DMD) gene and results in lethal heart failure in individuals between 10 and 20 years. Patients with Becker muscular dystrophy, an allelic disorder, have a milder phenotype of skeletal muscle involvement compared to Duchenne muscular dystrophy (DMD) and sometimes present with dilated cardiomyopathy. The precise relationship between mutations in the DMD gene and cardiomyopathy remain unclear. However, some hypothetical mechanisms are being considered to be associated with the presence of some several dystrophin isoforms, certain reported mutations, and an unknown dystrophin-related pathophysiological mechanism. Recent therapy for Duchenne muscular dystrophy, the severe dystrophinopathy phenotype, appears promising, but the presence of XLDCM highlights the importance of focusing on cardiomyopathy while elucidating the pathomechanism and developing treatment.
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Spurney CF, McCaffrey FM, Cnaan A, Morgenroth LP, Ghelani SJ, Gordish-Dressman H, Arrieta A, Connolly AM, Lotze TE, McDonald CM, Leshner RT, Clemens PR. Feasibility and Reproducibility of Echocardiographic Measures in Children with Muscular Dystrophies. J Am Soc Echocardiogr 2015; 28:999-1008. [PMID: 25906753 DOI: 10.1016/j.echo.2015.03.003] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2014] [Indexed: 01/16/2023]
Abstract
BACKGROUND Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field of therapeutics for dystrophic cardiomyopathy. METHODS Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function. RESULTS Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient [ICC] = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects. CONCLUSIONS In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD.
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Affiliation(s)
| | | | - Avital Cnaan
- Children's National Health System, Washington, District of Columbia
| | | | - Sunil J Ghelani
- Children's National Health System, Washington, District of Columbia
| | | | - Adrienne Arrieta
- Children's National Health System, Washington, District of Columbia
| | | | | | | | - Robert T Leshner
- Children's National Health System, Washington, District of Columbia; University of California, San Diego, San Diego, California
| | - Paula R Clemens
- University of Pittsburgh, Pittsburgh, Pennsylvania; Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania
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Ashwath ML, Jacobs IB, Crowe CA, Ashwath RC, Super DM, Bahler RC. Left ventricular dysfunction in duchenne muscular dystrophy and genotype. Am J Cardiol 2014; 114:284-9. [PMID: 24878125 DOI: 10.1016/j.amjcard.2014.04.038] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Revised: 04/17/2014] [Accepted: 04/17/2014] [Indexed: 12/26/2022]
Abstract
Prognosis in patients with Duchenne muscular dystrophy (DMD) is guarded, and most deaths are due to cardiac or respiratory causes. It is unclear if some DMD gene mutations might be predictive of either mild or severe cardiac dysfunction. We studied 75 patients with DMD followed at our institution. Cardiac function, as assessed by yearly echocardiography, showed marked variability in left ventricular (LV) function. Some patients in their 3rd decade had no or minimal dysfunction, whereas others in their 2nd decade had very severe dysfunction. Therefore, 4 severity groups were defined ranging from no or mild LV dysfunction to severe LV dysfunction using patient age at first abnormal echocardiographic finding and degree of LV dysfunction. Genetic data were collected for all patients. Most patients had mutations from exon 1 to 20 to exon 41 to 55. The distribution of the 4 severity groups of LV dysfunction did not significantly differ between these 2 mutation groups. An analysis based on the number of exons involved (<5 vs ≥5 exons) also found no significant difference in cardiac severity. When patients having identical mutations were compared with their cardiac course, concordance was often not evident. Steroid therapy had no apparent protection for the development of cardiomyopathy. In conclusion, 75 patients with DMD showed marked variability in the severity of LV dysfunction. Neither the age of onset nor the severity of cardiomyopathy correlated with any of the mutation groups.
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Affiliation(s)
- Mahi L Ashwath
- MetroHealth Medical Center, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Irwin B Jacobs
- MetroHealth Medical Center, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Carol A Crowe
- MetroHealth Medical Center, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ravi C Ashwath
- Rainbow Babies and Childrens Hospital, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Dennis M Super
- MetroHealth Medical Center, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Robert C Bahler
- MetroHealth Medical Center, Departments of Medicine and Pediatrics, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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Florian A, Ludwig A, Rösch S, Yildiz H, Sechtem U, Yilmaz A. Myocardial fibrosis imaging based on T1-mapping and extracellular volume fraction (ECV) measurement in muscular dystrophy patients: diagnostic value compared with conventional late gadolinium enhancement (LGE) imaging. Eur Heart J Cardiovasc Imaging 2014; 15:1004-12. [PMID: 24686257 DOI: 10.1093/ehjci/jeu050] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
AIM Cardiac involvement with progressive myocardial fibrosis leading to dilated cardiomyopathy is a major cause of death in muscular dystrophy patients. Extracellular volume fraction (ECV) measurement based on T1-mapping pre- and post-contrast promises the detection of early 'diffuse' myocardial fibrosis that cannot be depicted by conventional contrast-imaging based on late gadolinium enhancement (LGE). With this study, we evaluated the presence of diffuse myocardial fibrosis in regions of 'normal' (LGE-negative) and 'diseased' (LGE-positive) appearing myocardium as well as its relation to the extent of left ventricular (LV) dysfunction and the occurrence of arrhythmias in Becker muscular dystrophy (BMD) patients. METHODS AND RESULTS Twenty-seven BMD patients (35 ± 12 years) and 17 matched male healthy controls (33 ± 8 years) underwent cardiovascular magnetic resonance (CMR) studies including ECV measurement and LGE-imaging. Ambulatory monitoring of arrhythmic events was performed by means of an external event loop recorder. Twenty BMD patients (74%) demonstrated cardiac involvement as detected by typical inferolateral presence of LGE. Twelve patients (44%) had an impaired LV ejection fraction-all being LGE-positive. Global myocardial ECV was significantly higher in the BMD group (29 ± 6%) compared with the control group (24 ± 2%, P = 0.001). Patients with cardiac involvement demonstrated higher global ECV (31 ± 6%) as well as significantly increased regional ECV not only in LGE-positive segments (34 ± 6%), but also in LGE-negative segments (28 ± 6%) compared with BMD patients without cardiac involvement and to controls, respectively (24 ± 3 and 24 ± 2%, P = 0.005). Global ECV in patients with cardiac involvement substantially correlated to LV ejection fraction (r = -0.629, P = 0.003) and to the number of LGE-positive segments (r = 0.783, P < 0.001). On univariable analysis, global ECV-but not the categorical presence of LGE per se--was significantly associated with arrhythmic events (OR: 1.97, CI: 32.22-1.21, P = 0.032). CONCLUSION ECV measurement by CMR is a useful tool in assessing the total extent of myocardial fibrosis as well as in depicting subtle diffuse fibrosis in areas of normal appearing myocardium on LGE-images. Thus, myocardial ECV is a potential additional quantitative tool for accurate detection of cardiac involvement and risk stratification in muscular dystrophy patients.
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Affiliation(s)
- Anca Florian
- Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Campus 1, building A1, 48149 Münster, Germany
| | - Anna Ludwig
- Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Sabine Rösch
- Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Handan Yildiz
- Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Udo Sechtem
- Division of Cardiology, Robert-Bosch-Krankenhaus, Stuttgart, Germany
| | - Ali Yilmaz
- Department of Cardiology and Angiology, University Hospital Münster, Albert-Schweitzer-Campus 1, building A1, 48149 Münster, Germany
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