Open access peer-reviewed chapter
Abstract
Duchenne muscular dystrophy cardiomyopathy (DMD-DCM) is characterized by progressive ventricular dilation and dysfunction that can begin at any age and worsens over time. Thanks to the lengthening of life expectancy due to better management of respiratory involvement, end-stage heart failure (HF) is becoming the main cause of death for DMD patients. Therefore, from the time of DMD diagnosis, every effort should be focused to early detect the onset and the worsening of the DMD-DCM, with the aim of starting and modulating the therapy to slow the progression of cardiac dysfunction. In cardiac evaluation, biomarkers, electrocardiograms, and echocardiograms must be considered, but cardiac magnetic resonance (CMR) is now acquiring a leading role due to its sensitivity in the earlier identification of cardiac involvement. The management of DMD-DCM at end stage is a difficult challenge that requires a multidisciplinary team composed of clinical cardiologists, electrophysiologists, cardiac surgeons, neuromuscular specialists, and psychologists. Because of the lack of specific drugs for DMD, we will review the actual cardiovascular armamentarium including drugs used for HF.
Keywords
- duchenne muscular dystrophy
- DMD
- dilated cardiomyopathy
- neuromuscular disease
- dystrophin
- heart failure
1. Introduction
Duchenne muscular dystrophy (DMD) is an X-linked degenerative neuromuscular disease that affects the skeletal muscles and the heart and over time leads to loss of walking, severe respiratory complications and progressive cardiac dilation and dysfunction.
It is caused by a mutation of the DMD gene, the largest gene in the human genome, mapped on the X-chromosome that codes for dystrophin, an essential protein for the stability of the myocyte membranes. The type of mutation and the degree of reduced expression of this structural protein influences the degree of muscle and cardiac impairment and especially the speed of myopathy progression. The milder forms are generally identified with the term Becker’s muscular dystrophy (BMD) while the most severe and rapidly evolving forms, due to a severe reduction or total absence of dystrophin, are properly defined as DMD. Due to the X-linked recessive inheritance, the condition of female carriers must also be considered; they have a second normally functioning allele of dystrophin gene, thus they are generally characterized by a completely normal muscular and cardiac phenotype but may also present a mild/variable expression of the disease [1].
The incidence of DMD is approximately 1 in 5000 live male births, with 2/3 of the cases due to the transmission of the X-chromosome containing the mutated gene from a carrier female to male offspring and the remaining 1/3 of cases consequent to de novo mutations.
Generally the first manifestation of the DMD is muscle weakness that begins around the age of four and worsens quickly, leading to the loss of independent walking by the age of ten and to respiratory dysfunction around the second decade of life. The cardiac involvement begins around 6–10 years of age [2, 3] while cardiovascular symptoms are rare before the age of twenty and often appear when the degree of cardiac dysfunction is severe [4].
In last decades, the life expectancy of patients with DMD has grown considerably as a result of advances in the prevention and management of respiratory complications. As a result, there has been a significant increase in manifestations of advanced cardiomyopathy that is becoming the main cause of morbidity and mortality for these patients. This has led to a growing interest in the prevention and management of DMD-DCM [5, 6, 7].
While some aspects of DMD-DCM assessment and therapy are well defined by current guidelines [8], such as the need of routine cardiac evaluation and the indication to start prophylactic cardio-protective therapy from the age of ten in all patients, many other aspects remain under investigation, especially at end stage phase.
2. Genetic basis and pathophysiology of DMD-DCM
The DMD gene, encoded on the X chromosome, is the longest gene of our genome; it contains long introns with many “hotspots” susceptible to a high rate of mutations which can lead to the deletion (60–65% of all DMD mutations) or duplication (10%) of one or many exons. Shorter mutations such as point mutations are responsible for the remaining 25% of DMD cases. One third of DMD cases are due to de novo mutations while two third are inherited. The mutations resulting in the production of a truncated protein or of a dystrophin lacking in structural domains necessary for interaction with other proteins, are responsible for the most severe forms of the disease [9].
Dystrophin is a long intracellular protein of 3685 aminoacids and a molecular weight of 427 kDa. It is composed by four domains: an
Figure 1.
The dystrophin- associated protein complex (DAPC). Dystrophin and DAPC plays an essential structural role in linking the actin of cytoskeleton to the extracellular matrix. The subunits of the DAPC, such as the sarcoglycans, have a vital role in the maintenance of muscle integrity. Dystrophin, a flexible rod-like cytoplasmic protein, directly interacts with the actin polymers of the cytoskeleton and with a complex of transmembrane glico-proteins composed by sarcoglycans, beta- and alpha-dystroglycan that creates a connection with the extracellular matrix by its linking with laminin-2.
Fibrosis, abnormal Ca2+ homeostasis and elevated reactive oxygen species are also predisposing factor to the onset of ventricular arrhythmias in DMD-DCM. Recently, a predisposition to pacing induced ventricular arrhythmias was demonstrated in an animal model of DMD. In this model, the aberrant Ca2+ release through RyR2, which leads to delayed after depolarizations (DADs) and triggered ventricular arrhythmias, was related to the oxidated Ca2+/calmodulin-dependent protein kinase II, Ox-CaMKII. Genetic inhibition of Ox-CaMKII normalized intracellular Ca2+ and prevented ventricular arrhythmias in this model [12]. Another interesting study suggested that arrhythmias could also result from an alteration of the components of the cardiac gap junction; in particular it has been proposed that the dislocation and anomalous S-nitrosylation of connexin 43 (Cx43) lead to the early depolarization of the cytoplasmic membrane and the consequent generation of action potentials. Then, these channels can be therapeutic targets to prevent fatal arrhythmias in patients with DMD [13].
3. Clinical course
The diagnosis of DMD may occur around 4 yo for difficulty in gait, calf hypertrophy, delayed speech, inability to jump or stand without using the arms for assistance (Gower maneuver), toe walking and difficulty in climbing stairs. Over the time the progressive muscle waste leads to loss of ambulatory capacity and to decline of respiratory and cardiac functions [14].
Literature reports the beginning of ongoing cardiac disease processes as around 6–10 years of age. Echocardiographic abnormalities and clinical DCM can occur at any age but often appear around 14–15 yo and are common over 18 years of age [15]. Symptoms are mild or completely absent up to the most advanced stages of cardiomyopathy, and this is mainly due to the significant reduction in oxygen consumption and in energy expenditure consequent to muscle weakness. It is remarkable that often the severity of cardiomyopathy does not correlate with the degree of skeletal muscle weakness, thus regular cardiac evaluation is very important also in patients with mild motility impairment and it is required before any invasive diagnostic procedure or surgery.
In the last decade, the increase in life expectancy, deriving from the better management of the respiratory involvement and the improved supportive cares, have resulted in a sharp increase in the number of patients with severe cardiomyopathy, and to date, end-stage HF has becoming one of the leading causes of morbidity and mortality in DMD [6].
Data from a multicentre Pediatric Cardiomyopathy Registry (PCMR) show a high prevalence of DCM also in milder forms of dystrophinopathies as in BMD (up to 90% of cases). Interestingly, in these patients, detection of cardiomyopathy often occurs at a more advanced stage and the progression of the LV dysfunction and dilation may be more rapid than in patients with DMD. Despite this, mortality rate for DMD patients with DCM is significantly worse than that of BMD patients, who can undergo heart transplant [16].
4. Noninvasive assessing of DMD-DCM
From the time of DMD diagnosis, every effort should be focused to detect early the onset and the progression of DCM. Early recognition and periodic re-evaluation are essential to guide therapy and to identify patients at increased risk of progression of cardiomyopathy and major cardiac events. Clinical evaluation remains challenging because most of these patients have often low blood pressure values and cool extremities because of reduced skeletal muscular mass even in the presence of hemodynamic compensation. Therefore, multiparametric evaluation is crucial to correctly recognize the progression of cardiac impairment [8].
4.1 Cardiovascular biomarkers
Serum biomarkers are often very useful for the diagnosis and monitoring heart disease. In particular, serum levels of cardiac troponin I/T are known to be associated to the extension of myocardial damage, but there are conflicting results about their diagnostic and prognostic implications in the DMD-DCM. Actually, only troponin I showed to be reliable in patients with neuromuscular disorder [17]. Troponin I levels seem to be significantly elevated in patients with initial myocardial fibrosis expressed by mild late gadolinium enhancement (LGE) at the cardiac magnetic resonance (CMR) compared to those without LGE. Interestingly, this positive association between troponin levels and myocardial fibrosis is lost when LGE degree becomes moderate-to-severe, probably because at advanced stage of cardiomyopathy most of myocardium is already substituted by fibro-fatty tissue, therefore the release of myocardio-necrosis enzymes is reduced [18].
Natriuretic peptides are well established markers of HF and congestion in DCM. In DMD, pulmonary hypertension caused by impairment of the respiratory muscles and restrictive physiopathology are considered to be involved in the mechanism of increased values of plasma natriuretic peptide. In addition to the more commonly used brain natriuretic peptide (BNP), a significant elevation in plasma alpha-atrial natriuretic peptide (alphaANP) levels is found as a sign of a poor prognosis and may be a useful index for the management of patients with DMD-DCM [19].
In the management of HF is very important to assess renal function. In DMD serum creatinine values are generally very low as a consequence of their reduced muscle mass and therefore creatinine cannot be considered a good marker of renal function. In these patients, serum values of cystatin C, a protein produced by all cells, not only by muscle cells, are a good parameter for assessing renal function, because they better correlate with glomerular filtration rate (GFR) and cardiac dysfunction. Furthermore, it is reported a significant correlation between Cystatin C and cardiac dysfunction, providing for the first time a novel marker to identify cardio-renal syndrome in patients with DMD [20].
4.2 Electrocardiography and cardiac imaging
Electrocardiogram and transthoracic echocardiogram are the two fundamental exams advised to establish baseline cardiac involvement and they are recommended annually in all patients since the diagnosis of DMD. After the age of ten, cardiac assessment should have been
For earlier detection of LV impairment, speckle tracking echocardiography is also very useful, as it is a technique able to evaluate subclinical LV dysfunction before development of overt LVEF reduction. Global longitudinal strain (GLS), obtained by 2D speckle tracking echocardiography is abnormal in nearly 50% of DMD patients with a normal LVEF, and a decrease of 0,34% per year of GLS in DMD patients according to age has been recently reported [24]. The lowest values of strain is often observed in the inferolateral and anterolateral mid-basal segments. However, speckle tracking analysis is often limited in DMD because echocardiographic image quality is poor in these patients and declines by 2,5% for each 1 year increase in age because of chest deformities, lung hyperinflation, and limited mobility [25].
CMR can be useful also to evaluate more precisely the severity of myocardial dysfunction and fibrosis in further stages, to assess the efficacy of anti-remodeling therapy, to screen asymptomatic DMD female carriers. However, the high costs, patient’s claustrophobia and the technical difficulties to obtain the exam in patients with home ventilator may limit its use in this group of patients.
5. Management of DMD-DCM from prevention to end-stage HF
In the clinical course of DMD-DCM three stages of DCM can be distinguished: a
Figure 2.
Cardiac magnetic resonance (CMR), electrocardiographic (EKG) features and clinical status at different stages of the DMD-DCM progression. In the pre-clinical stage left ventricular (LV) function is still preserved, CMR may identify initial fibrosis, at the EKG some alterations such as QRS fragmentation, rsr’ complexes in V1 and alterations of ventricular repolarization may appear, and blood levels of troponin T (TnT) may be slightly or moderately high while NTproBNP is normal. The clinical stage is characterized by a certain degree of LV dysfunction and dilation, inflammation and fibrotic replacement of the heart muscle are extended, as shown by the wide distribution of late gadolinium enhancement (LGE) areas at CMR imagines, abnormal Q waves appear at the ECG, and the values of TnT and NTpro BNP are usually very high and moderately high respectively. In the end-stage, LV dilation and dysfunction are severe, much of the heart muscle is replaced by fibrous tissue, filling pressure increases, and episodes of acute heart failure and ventricular arrhythmias become frequent, NTproBNP values are very high while TnT values may not be particularly high due to reduced total cardiac muscle mass.
The
At this stage of the DMD-DCM, the aim will be to delay the onset of ventricular contractile dysfunction. Current recommendation advices to start angiotensin converting enzyme inhibitor (ACE- I) as preventive strategy. Perindopril 2–4 mg/die, [28] or an angiotensin receptor blocker (ARB) can be prescribed in all DMD patients from the age of ten. The indication to start therapy earlier, in patients with initial signs of cardiac involvement (such as the presence of mild LGE) but with preserved contractile function is still under debate and investigation [8].
At this early phase of DCM, when LV is mildly dilated, the use of mineralocorticoid receptor antagonist (MRA), such as eplerenone or spironolactone, may slow the rate of decline of LV function. Further studies are needed to determine the effect of combined cardioprotective therapy on event-free survival in these patients [29, 30].
The
The
In end-stage CMD signs and symptoms of systemic or pulmonary congestion may be clinically evident and loop diuretics are indicated. For chronic use furosemide 1 to 6 mg/kg/die is generally effective, but in some cases the addiction of Metolazone, a thiazide-like diuretic, is required. It is important to underline that there is no evidence of the effectiveness of loop diuretics in improving survival, so they are to be considered only for relieving symptoms [38].
In patients with severe LV dysfunction an antithrombotic therapy should be considered in the primary prevention of thromboembolic events, although not routinely recommended [39].
As mentioned above, DMD patients are at risk of arrhythmias such as atrial fibrillation, atrial flutter and ventricular tachycardia and this risk increases as cardiomyopathy progresses. To date, the management of arrhythmias, with drugs and devices, in DMD-DCM is based on general international guidelines, as there are no specific recommendations for DMD. Implantable cardioverter defibrillator (ICD) has gained acceptance in selected patients [40]. The effectiveness of cardiac resynchronization therapy (CRT) in these patients seems to be poor probably due to the presence of the extensive postero-lateral fibrosis and poorly explored.
Patients with DMD are generally not considered suitable for cardiac transplant candidacy due to early walking impairment, predisposition to respiratory complications, and their short life expectancy. Heart transplant (HTx) has been considered in few highly selected cases in which respiratory compromise was not relevant and reported [40]. In BMD, HTx is considered in end stage phase of CMP.
Few cases of patients with end-stage DMD-DCM and preserved or only mild reduced respiratory function, left ventricle assist device (LVAD) has been considered as a destination therapy [41, 42]. To date, the international literature about LVAD in DMD patients is poor and proper selection of patient and ethical aspect should be accurately evaluated case by case. Share decision making process is also crucial and exploratory dialog with patients and caregivers should be routinely carried out during follow up, not only in urgent situation [43].
Recently, a retrospective study on DMD patients evaluated the effects of advanced cardiac therapies (i.e. ICD, LVAD, HTx) on large DMD population. Out of 436 DMD patients, 9 had ICD placed, 4 had LVAD and 1 HTx. The authors concluded that advanced HF therapies may be used effectively in select subjects with DMD but further studies are needed to stratify the risk and select patients [40].
In the process of choosing about advanced cardiac therapies for end-stage DMD-DCM an in-depth personalized assessment is crucial, and involves the collaboration of the patient and his family with a team of experts composed of cardiologists, cardiac surgeons, neuromuscular specialists, anesthetists, pneumologists, bioethics experts and psychologists.
6. DMD-specific drugs: corticosteroids and new target therapies
Given their effectiveness in slowing the progression of muscle damage and in prolonging the ability to walk and the life-expectancy, corticosteroids such as prednisone and deflazacort have become the standard basic treatment of patients with DMD from the moment of diagnosis or, in any case, by the age of five [44]. While some preclinical studies have suggested that corticosteroids can accelerate cardiomyopathy, subsequent clinical studies have supported their beneficial role in preserving ventricular function and delaying the progression of heart disease, especially by slowing down the inflammation and the fibrotic process and by increasing myogenic repair and myoblast proliferation [45].
Schram et al. [46] showed that steroid therapy was associated with a significantly lower all-cause mortality rate, due to a substantial reduction in HF–related deaths. In this observational study, patients treated with combination of steroid and ACE-I, experienced a much lower incidence of new-onset cardiomyopathy than those treated without steroid.
In recent years a new MRA, called Vamorolone, has been discovered. This new MRA is able to mimic the anti-inflammatory effects of glucocorticoids and it could represent, in the near future, an alternative to the others. It has been reported it seems to have less side effects and greater antifibrotic effect thanks to the inhibition of the aldosterone pathway [47].
Moreover, several other new therapeutic strategies are under investigation, focused to mitigate inflammation and fibrosis or to restore the dystrophin expression. These last strategy includes:
the read-through therapies , such as Ataluren (Translarna™, PTC Therap), the first molecule approved in Europe for DMD, that enables the transcription of mRNA containing premature stop codons;the antisense oligonucleotides (AONs) that can bind pre-mRNA in specific splicing sites allowing to skip the exons containing mutations and restoring the reading frame of the dystrophin;the viral gene therapies, that exploit viral vectors to transfer truncated versions of dystrophin gene into myocytes;t
he upregulation of Utrophin , a protein similar to dystrophin, that can supply its structural function;the cell based therapies that consist on the administration of healthy myocytes precursors that can colonize skeletal and cardiac muscle of the recipient.
Most of these gene-targeted therapies are still under study and the evaluation of their efficacy is mainly based on the increased expression of dystrophin in skeletal myocytes and on the slowing of the myopathy progression. Whether these therapies are able to increase dystrophin expression equally in skeletal muscle cells and in cardiomyocytes is still unclear since the heart cannot be routinely biopsied. This is a crucial point as isolated improvement in muscle function would lead to increased demand on a weak heart, accelerating the progression of cardiomyopathy. In particular, Ataluren has shown a modest increase in dystrophin expression in mouse heart, while in a small cohort of humans neither measurable improvement nor deterioration in heart function were observed during 24 months of treatment. Instead, there are strong evidences regarding the benefit on heart function from gene therapies that use micro-dystrophin genes. In preclinical studies a robust expression of micro-dystrophin in cardiomyocytes has been proved, but the high dose required may be burdened significant side effects and the presence of micro-dystrophin instead of wild-type dystrophin can still lead to the development of a BMD-like cardiomyopathy. Further studies are needed to better understand the long-term effects of these therapies on the heart [48].
6.1 Cardiomyopathy in DMD female carriers
Most women carrying the DMD mutation in one of the two X chromosomes are asymptomatic for life due to the presence of sufficient normal dystrophin produced by the unchanged allele of the gene. Some of these women, called “manifesting carriers”, may have mild or moderate forms of myopathy and cardiomyopathy; this is probably due to a mosaic inactivation of the healthy allele in skeletal and heart muscles, or simply to the reduced total amount of normal dystrophin in the cells. In particular, cardiomyopathy can occur in up to 8% of cases and symptoms can appear from adolescence to late adulthood even without any correlation with musculoskeletal manifestations [49]. Therefore, current guidelines recommend to perform echocardiography every 5 years in all adult dystrophinopathy carriers [14]. The severity of disease can vary widely and can worsen during concomitant events such as pregnancy and childbirth. It is interesting to note that in 45% of DMD carriers, subepicardial LGE in the inferolateral free LV wall is detectable at CMR as well as in the initial forms of cardiomyopathy in DMD male patients and this is associated with myocardial enzyme release and with a greater probability of progression of the cardiomyopathy [50].
7. Conclusion
Given the primary role of cardiomyopathy in determining the prognosis of DMD patients, every effort should be focused on preventing or slowing the progression of their cardiac dysfunction. Many drugs commonly used for HF have proven to be quite effective, especially if used from the very early stages of the disease, before heart dysfunction becomes evident. So current recommendations underline the importance of routinely cardiac evaluation since the diagnosis of DMD to early recognize heart abnormalities and start ACE-I. In this preclinical stage of DMD-DCM, CMR plays a substantial role due to its sensitivity in identifying initial areas of fibrotic replacement of the heart muscle. Because of the lack of specific DMD-DCM therapies, current drugs used for HF might be used and further studies are required to address their efficacy, especially at end-stage DCM. To date some new target therapies are available and many others are under evaluation, so that in the near future we will be able to count on a much wider range of specific therapeutic possibilities than now. Moreover, in the end-of- life management, ethical issues are still a matter of intense debate in order to identify potential advanced cardiac therapies candidates. Surely, in this challenging course of treatment, sharing decisions with the patient and his caregivers and the support of a multidisciplinary team are crucial cornerstones for obtaining the best possible results.
References
- 1.
Lim KRQ , Sheri N, Nguyen Q , Yokota T. Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies. Genes (Basel). 2020 Jul 8;11(7):765. doi: 10.3390/genes11070765 - 2.
Tandon A, Villa CR, Hor KN, Jefferies JL, Gao Z, Towbin JA, Wong BL, Mazur W, Fleck RJ, Sticka JJ, Benson DW, Taylor MD. Myocardial fibrosis burden predicts left ventricular ejection fraction and is associated with age and steroid treatment duration in duchenne muscular dystrophy. J Am Heart Assoc. 2015 Mar 26;4(4):e001338. doi: 10.1161/JAHA.114.001338 - 3.
Hor KN, Taylor MD, Al-Khalidi HR, Cripe LH, Raman SV, Jefferies JL, O'Donnell R, Benson DW, Mazur W. Prevalence and distribution of late gadolinium enhancement in a large population of patients with Duchenne muscular dystrophy: effect of age and left ventricular systolic function. J Cardiovasc Magn Reson. 2013 Dec 21;15(1):107. doi: 10.1186/1532-429X-15-107 - 4.
D'Amario D, Amodeo A, Adorisio R, Tiziano FD, Leone AM, Perri G, Bruno P, Massetti M, Ferlini A, Pane M, Niccoli G, Porto I, D'Angelo GA, Borovac JA, Mercuri E, Crea F. A current approach to heart failure in Duchenne muscular dystrophy. Heart. 2017 Nov;103(22):1770-1779. doi: 10.1136/heartjnl-2017-311269. Epub 2017 Jul 1 - 5.
Fayssoil A, Yaou RB, Ogna A, Leturcq F, Nardi O, Clair B, Wahbi K, Lofaso F, Laforet P, Duboc D, Orlikowski D, Annane D. Clinical profiles and prognosis of acute heart failure in adult patients with dystrophinopathies on home mechanical ventilation. ESC Heart Fail. 2017 Nov;4(4):527-534. doi: 10.1002/ehf2.12165. Epub 2017 May 18 - 6.
Buddhe S, Cripe L, Friedland-Little J, Kertesz N, Eghtesady P, Finder J, Hor K, Judge DP, Kinnett K, McNally EM, Raman S, Thompson WR, Wagner KR, Olson AK. Cardiac Management of the Patient With Duchenne Muscular Dystrophy. Pediatrics. 2018 Oct;142(Suppl 2):S72-S81. doi: 10.1542/peds.2018-0333I - 7.
Eagle M, Baudouin SV, Chandler C, Giddings DR, Bullock R, Bushby K. Survival in Duchenne muscular dystrophy: improvements in life expectancy since 1967 and the impact of home nocturnal ventilation. Neuromuscul Disord. 2002 Dec;12(10):926-9. doi: 10.1016/s0960-8966(02)00140-2 - 8.
Birnkrant DJ, Bushby K, Bann CM, Alman BA, Apkon SD, Blackwell A, Case LE, Cripe L, Hadjiyannakis S, Olson AK, Sheehan DW, Bolen J, Weber DR, Ward LM; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management. Lancet Neurol. 2018 Apr;17(4):347-361. doi: 10.1016/S1474-4422(18)30025-5. Epub 2018 Feb 3 - 9.
D'Amario D, Gowran A, Canonico F, Castiglioni E, Rovina D, Santoro R, Spinelli P, Adorisio R, Amodeo A, Perrucci GL, Borovac JA, Pompilio G, Crea F. Dystrophin Cardiomyopathies: Clinical Management, Molecular Pathogenesis and Evolution towards Precision Medicine. J Clin Med. 2018 Sep 19;7(9):291. doi: 10.3390/jcm7090291 - 10.
Frankel KA, Rosser RJ. The pathology of the heart in progressive muscular dystrophy: epimyocardial fibrosis. Hum Pathol. 1976 Jul;7(4):375-86. doi: 10.1016/s0046-8177(76)80053-6 - 11.
van Westering TL, Betts CA, Wood MJ. Current understanding of molecular pathology and treatment of cardiomyopathy in duchenne muscular dystrophy. Molecules. 2015 May 15;20(5):8823-55. doi: 10.3390/molecules20058823 - 12.
Wang Q , Quick AP, Cao S, Reynolds J, Chiang DY, Beavers D, Li N, Wang G, Rodney GG, Anderson ME, Wehrens XHT. Oxidized CaMKII (Ca2+/Calmodulin-Dependent Protein Kinase II) Is Essential for Ventricular Arrhythmia in a Mouse Model of Duchenne Muscular Dystrophy. Circ Arrhythm Electrophysiol. 2018 Apr;11(4):e005682. doi: 10.1161/CIRCEP.117.005682 - 13.
Lillo MA, Himelman E, Shirokova N, Xie LH, Fraidenraich D, Contreras JE. S-nitrosylation of connexin43 hemichannels elicits cardiac stress-induced arrhythmias in Duchenne muscular dystrophy mice. JCI Insight. 2019 Dec 19;4(24). pii: 130091 - 14.
Bushby K, Finkel R, Birnkrant DJ, Case LE, Clemens PR, Cripe L, Kaul A, Kinnett K, McDonald C, Pandya S, Poysky J, Shapiro F, Tomezsko J, Constantin C; DMD Care Considerations Working Group. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010 Feb;9(2):177-89. doi: 10.1016/S1474-4422(09)70272-8 - 15.
Nigro G, Comi LI, Politano L, Bain RJ. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol. 1990 Mar;26(3):271-7. doi: 10.1016/0167-5273(90)90082-g - 16.
Connuck DM, Sleeper LA, Colan SD, Cox GF, Towbin JA, Lowe AM, Wilkinson JD, Orav EJ, Cuniberti L, Salbert BA, Lipshultz SE; Pediatric Cardiomyopathy Registry Study Group. Characteristics and outcomes of cardiomyopathy in children with Duchenne or Becker muscular dystrophy: a comparative study from the Pediatric Cardiomyopathy Registry. Am Heart J. 2008 Jun;155(6):998-1005. doi: 10.1016/j.ahj.2008.01.018. Epub 2008 Mar 19 - 17.
Schmid J, Birner Gruenberger R, Liesinger L, Stojakovic T, Scharnagl H, Dieplinger B, Asslaber M, Radl R, Polacin M, Beer M, Szolar D, Quasthoff S, Binder J.S., Rainer P. Elevated cardiac troponin T but not troponin I in patients with skeletal muscle disease. European Heart Journal ( 2017 ) 38 ( Supplement ), 553554 - 18.
Voleti S, Olivieri L, Hamann K, Gordish-Dressman H, Spurney C. Troponin I Levels Correlate with Cardiac MR LGE and Native T1 Values in Duchenne Muscular Dystrophy Cardiomyopathy and Identify Early Disease Progression. Pediatr Cardiol . 2020 May 31. doi: 10.1007/s00246-020-02372-5 - 19.
Yanagisawa A, Yokota N, Miyagawa M, Kawamura J, Ishihara T, Aoyagi T, Ishikawa K. Plasma levels of atrial natriuretic peptide in patients with Duchenne's progressive muscular dystrophy. Am Heart J. 1990 Nov;120(5):1154-8. doi: 10.1016/0002-8703(90)90130-p - 20.
Villa CR, Kaddourah A, Mathew J, Ryan TD, Wong BL, Goldstein SL, Jefferies JL. Identifying evidence of cardio-renal syndrome in patients with Duchenne muscular dystrophy using cystatin C. Neuromuscul Disord. 2016 Oct;26(10):637-642 - 21.
Fayssoil A, Abasse S, Silverston K. Cardiac Involvement Classification and Therapeutic Management in Patients with Duchenne Muscular Dystrophy. J Neuromuscul Dis. 2017;4(1):17-23. doi: 10.3233/JND-160194 - 22.
Soslow JH, Xu M, Slaughter JC, Stanley M, Crum K, Markham LW, Parra DA.Evaluation of Echocardiographic Measures of Left Ventricular Function in Patients with Duchenne Muscular Dystrophy: Assessment of Reproducibility and Comparison to Cardiac Magnetic Resonance Imaging. J Am Soc Echocardiogr. 2016 Oct;29(10):983-991. doi: 10.1016/j.echo.2016.07.001 - 23.
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 Aug;28(8):999-1008. doi: 10.1016/j.echo.2015.03.003 - 24.
Vincenti M, De La Villeon G, Lavastre K, Barrea C, Guillaumont S, Bredy C, Gamon L, Meli AC, Cazorla O, Fauconnier J, Meyer P, Rivier F, Adda J, Mura T, Lacampagne A. Speckle-Tracking Echocardiography in Children With Duchenne Muscular Dystrophy: A Prospective Multicenter Controlled Cross-Sectional Study. J Am Soc Echocardiogr. 2019 Mar;32(3):412-422. doi: 10.1016/j.echo.2018.10.017 - 25.
Power A, Poonja S, Disler D, Myers K, Patton DJ, Mah JK, Fine NM, Greenway SC. Echocardiographic Image Quality Deteriorates with Age in Children and Young Adults with Duchenne Muscular Dystrophy. Front Cardiovasc Med. 2017 Dec 20;4:82. doi: 10.3389/fcvm.2017.00082 - 26.
Florian A, Ludwig A, Engelen M, Waltenberger J, Rösch S, Sechtem U, Yilmaz A. Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients. J Cardiovasc Magn Reson. 2014 Sep 25;16(1):81. doi: 10.1186/s12968-014-0081-1 - 27.
Olivieri LJ, Kellman P, McCarter RJ, Cross RR, Hansen MS, Spurney CF. Native T1 values identify myocardial changes and stratify disease severity in patients with Duchenne muscular dystrophy. J Cardiovasc Magn Reson. 2016 Oct 28;18(1):72. doi: 10.1186/s12968-016-0292-8 - 28.
Duboc D, Meune C, Lerebours G, Devaux JY, Vaksmann G, Bécane HM. Effect of perindopril on the onset and progression of left ventricular dysfunction in Duchenne muscular dystrophy. J Am Coll Cardiol. 2005 Mar 15;45(6):855-7. doi: 10.1016/j.jacc.2004.09.078 - 29.
Raman SV, Hor KN, Mazur W, Halnon NJ, Kissel JT, He X, Tran T, Smart S, McCarthy B, Taylor MD, Jefferies JL, Rafael-Fortney JA, Lowe J, Roble SL, Cripe LH. Eplerenone for early cardiomyopathy in Duchenne muscular dystrophy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015 Feb;14(2):153-61. doi: 10.1016/S1474-4422(14)70318-7 - 30.
Raman SV, Hor KN, Mazur W, Cardona A, He X, Halnon N, Markham L, Soslow JH, Puchalski MD, Auerbach SR, Truong U, Smart S, McCarthy B, Saeed IM, Statland JM, Kissel JT, Cripe LH. Stabilization of Early Duchenne Cardiomyopathy With Aldosterone Inhibition: Results of the Multicenter AIDMD Trial. J Am Heart Assoc 2019, 8, e013501. DOI: 10.1161/JAHA.119.013501 - 31.
Allen HD, Flanigan KM, Thrush PT, Dvorchik I, Yin H, Canter C, Connolly AM, Parrish M, McDonald CM, Braunlin E, Colan SD, Day J, Darras B, Mendell JR. A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in Duchenne muscular dystrophy. PLoS Curr 2013, 5. DOI: 10.1371/currents.md.2cc69a1dae4be7dfe2bcb420024ea865 - 32.
Rhodes J, Margossian R, Darras BT, Colan SD, Jenkins KJ, Geva T, Powell AJ. Safety and efficacy of carvedilol therapy for patients with dilated cardiomyopathy secondary to muscular dystrophy. Pediatr Cardiol 2008, 29, 343-351. DOI: 10.1007/s00246-007-9113-z - 33.
Matsumura T, Tamura T, Kuru S, Kikuchi Y, Kawai M. Carvedilol can prevent cardiac events in Duchenne muscular dystrophy. Intern Med 2010, 49, 1357-1363. DOI: 10.2169/internalmedicine.49.3259 - 34.
Ogata H, Ishikawa Y, Ishikawa Y, Minami R. Beneficial effects of beta-blockers and angiotensin-converting enzyme inhibitors in Duchenne muscular dystrophy. J Cardiol 2009, 53, 72-78. DOI: 10.1016/j.jjcc.2008.08.013 - 35.
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013, 62, 147-239. DOI: 10.1016/j.jacc.2013.05.019 - 36.
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P; Authors/Task Force Members; Document Reviewers. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Eur J Heart Fail 2016, 18, 891-975. DOI: 10.1002/ejhf.592 - 37.
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 - 38.
Mullens W, Damman K, Harjola VP, Mebazaa A, Brunner-La Rocca HP, Martens P, Testani JM, Tang WHW, Orso F, Rossignol P, Metra M, Filippatos G, Seferovic PM, Ruschitzka F, Coats AJ. The use of diuretics in heart failure with congestion - a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 2019 Feb;21(2):137-155. doi: 10.1002/ejhf.1369 - 39.
Kirk R, Dipchand AI, Rosenthal DN, Addonizio L, Burch M, Chrisant M, Dubin A, Everitt M, Gajarski R, Mertens L, Miyamoto S, Morales D, Pahl E, Shaddy R, Towbin J, Weintraub R. The International Society for Heart and Lung Transplantation Guidelines for the management of pediatric heart failure: Executive summary. J Heart Lung Transplant 2014, 33, 888-909. DOI: 10.1016/j.healun.2014.06.002 - 40.
Amodeo A, Adorisio R. Left ventricular assist device in Duchenne cardiomyopathy: can we change the natural history of cardiac disease? Int J Cardiol. 2012 Nov 29;161(3):e43. doi: 10.1016/j.ijcard.2012.04.009 - 41.
Perri G, Filippelli S, Adorisio R, Iacobelli R, Iodice F, Testa G, Paglietti MG, D'Amario D, Massetti M, Amodeo A. Left ventricular assist device as destination therapy in cardiac end-stage dystrophinopathies: Midterm results. J Thorac Cardiovasc Surg. 2017 Mar; 153(3):669-674. doi:10.1016/j.jtcvs.2016.08.016 - 42.
Wittlieb-Weber CA, Villa CR, Conway J, Bock MJ, Gambetta KE, Johnson JN, Lal AK, Schumacher KR, Law SP, Deshpande SR, West SC, Friedland-Little JM, Lytrivi ID, McCulloch MA, Butts RJ, Weber DR, Knecht KR. Use of advanced heart failure therapies in Duchenne muscular dystrophy. Prog Pediatr Cardiol. 2019 Jun;53:11-14. doi: 10.1016/j.ppedcard.2019.01.001 - 43.
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; Working Group of the National Heart, Lung, and Blood Institute; Parent Project Muscular Dystrophy. 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 May 5;131(18):1590-8. doi: 10.1161/CIRCULATIONAHA.114.015151 - 44.
Bello L, Gordish-Dressman H, Morgenroth LP, Henricson EK, Duong T, Hoffman EP, Cnaan A, McDonald CM; CINRG Investigators. Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology. 2015 Sep 22;85(12):1048-55. doi: 10.1212/WNL.0000000000001950 - 45.
Markham LW, Kinnett K, Wong BL, Woodrow Benson D, Cripe LH. Corticosteroid treatment retards development of ventricular dysfunction in Duchenne muscular dystrophy. Neuromuscul Disord. 2008 May;18(5):365-70. doi: 10.1016/j.nmd.2008.03.002 - 46.
Schram G, Fournier A, Leduc H, Dahdah N, Therien J, Vanasse M, Khairy P. All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol. 2013 Mar 5;61(9):948-54. doi: 10.1016/j.jacc.2012.12.008 - 47.
Heier CR, Yu Q , Fiorillo AA, Tully CB, Tucker A, Mazala DA, Uaesoontrachoon K, Srinivassane S, Damsker JM, Hoffman EP, Nagaraju K, Spurney CF. Life Sci Alliance. 2019 Feb 11;2(1):e201800186. doi: 10.26508/lsa.201800186. Print 2019 Feb - 48.
Meyers TA, Townsend D. Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy. Int J Mol Sci. 2019 Aug 22;20(17):4098. doi: 10.3390/ijms20174098 - 49.
Finsterer J, Stollberger C. Muscle, cardiac, and cerebral manifestations in female carriers of dystrophin variants. J. Neurol. Sci. 2018;388:107-108. doi: 10.1016/j.jns.2018.03.01 - 50.
Wexberg P, Avanzini M, Mascherbauer J, Pfaffenberger S, Freudenthaler B, Bittner R, Bernert G, Weidinger F. Myocardial late gadolinium enhancement is associated with clinical presentation in Duchenne muscular dystrophy carriers. J Cardiovasc Magn Reson. 2016 Sep 22;18(1):61. doi: 10.1186/s12968-016-0281-y