Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells

The Duchenne and Becker muscular dystrophies are caused by mutation of dystrophin gene and primarily affect skeletal and cardiac muscles. Cardiac involvement in dystrophic GRMD dogs has been demonstrated by electrocardiographic studies with the onset of a progressive cardiomyopathy similar to the cardiac disease in DMD patients. In this respect, GRMD is a useful model to explore cardiac and skeletal muscle pathogenesis and for developing new therapeutic protocols. Here we describe a protocol to convert GRMD canine fibroblasts isolated from heart and skin into induced cardiac-like myocytes (ciCLMs). We used a mix of transcription factors (GATA4, HAND2, TBX5, and MEF2C), known to be able to differentiate mouse and human somatic cells into ciCLMs. Exogenous gene expression was obtained using four lentiviral vectors carrying transcription factor genes and different resistance genes. Our data demonstrate a direct switch from fibroblast into ciCLMs with no activation of early cardiac genes. ciCLMs were unable to contract spontaneously, suggesting, differently from mouse and human cells, an incomplete differentiation process. However, when transplanted in neonatal hearts of SCID/Beige mice, ciCLMs participate in cardiac myogenesis.

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Cardiac tissue characterization with t1 and t2 mapping in anderson fabry patients: new pathophysiological concepts and early cardiac involvement

European Heart Journal ◽

10.1093/ehjci/ehaa946.0264 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R Zanoni ◽

V Ferrara ◽

G Lanati ◽

G Vitale ◽

F Di Nicola ◽

...

Keyword(s):

Cardiac Disease ◽

Tissue Characterization ◽

Cardiac Involvement ◽

Late Onset ◽

T2 Mapping ◽

Serum Levels ◽

Left Ventricular ◽

Control Group ◽

Funding Source ◽

T1 And T2

Abstract Background Anderson Fabry (AF) disease is a X-linked lysosomal storage disorder with multiorgan involvement. Cardiac disease, mainly represented by left ventricular hypertrophy (LVH) and arrhythmias, is the most frequent cause of premature death. It is well know that specific therapy is less effective after the development of LVH and myocardial fibrosis, therefore early cardiac detection (before LVH) is important. New cardiac magnetic resonance (CMR) parametric imaging techniques (T1 and T2 maps) enable myocardial tissue changes associated with AF disease. Purpose To evaluate the relationship between CMR tissue characterization and clinical and instrumental manifestations of AF disease to find early markers of cardiac involvement. Methods 31 AF patients (9 males, mean age 49±16 years) underwent ECG, echocardiogram and contrast CMR. TnI, BNP, pro-BNP and serum lyso-Gb3 were dosed. T1 mapping was performed in a pre-contrast acquisition with the modified Look-Locker inversion recovery (MOLLI) sequences. CMR results were compared with those of 43 healthy age and gender-matched controls. Results In AF patients native septal T1 values were significantly lower compared to healthy controls (median 949 vs 991 msec, p=0.0137) and were inversely related to Lyso-Gb3 serum levels (p=0.003). Patients with LVH had lower T1 septal values in comparison with patients without LVH (892 vs 981 msec; p=0.0012). Patients with classic form had abnormal low T1 values more frequently than pts with late onset variant (78 vs 23%; p=0.038). In AF patients native septal T2 values were significantly higher compared to the control group (53 vs 49 msec; p=0.0004) and correlated with troponin I (p=0.008) and NT-pro BNP (p=0.006) serum levels. No difference was found between pts with and without LVH (53.5 vs 52.5 ms; p=0.797) and the prevalence of abnormal high T2 values was similar between patients with late onset AF and pts with classical form (53% vs 50%; p=1.000). All patients with late onset AF and high T2 values were females. Conclusions CMR T1 (low values) and T2 (high values) mapping are useful tools to detect early cardiac involvement before LVH and to better understand the pathophysiology of cardiac disease in AF patients. Subclinical tissue inflammation, detectable through T2 maps, seems to be an additional pathogenetic mechanism related to the Gb3 storage that contributes to organ damage and precedes LVH, particularly in females patients with late onset phenotype. Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): Sant'Orsola-Malpighi Hospital

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15 Incidence of cardiac sarcoidosis in those with extra-cardiac disease without known cardiac involvement – a CMR study

Heart ◽

10.1136/heartjnl-2015-308621.15 ◽

2015 ◽

Vol 101 (Suppl 5) ◽

pp. A8.1-A8

Author(s):

T Murphy ◽

FD Waterhouse ◽

S James ◽

C Kenny ◽

R O’Hanlon

Keyword(s):

Cardiac Disease ◽

Cardiac Involvement ◽

Cardiac Sarcoidosis

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Dystrophin Gene-Editing Stability Is Dependent on Dystrophin Levels in Skeletal but Not Cardiac Muscles

Molecular Therapy ◽

10.1016/j.ymthe.2020.11.003 ◽

2020 ◽

Author(s):

Niclas E. Bengtsson ◽

Hichem Tasfaout ◽

Stephen D. Hauschka ◽

Jeffrey S. Chamberlain

Keyword(s):

Gene Editing ◽

Dystrophin Gene ◽

Cardiac Muscles

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Multicore Myopathy: Not Always a Benign Entity

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/s0317167100027098 ◽

1988 ◽

Vol 15 (1) ◽

pp. 10-14 ◽

Cited By ~ 23

Author(s):

Ashfaq Shuaib ◽

Justin M.E. Martin ◽

L. Brent Mitchell ◽

A. Keith W. Brownell

Keyword(s):

Heart Disease ◽

Cause Of Death ◽

Cardiac Disease ◽

Cardiac Involvement ◽

Significant Disability ◽

Multicore Myopathy

ABSTRACT:Four patients with Multicore Myopathy, a rare morphologically distinct myopathy, are described. Although previously considered to be a non-progressive or only slowly progressive myopathy, progression to significant disability was seen in three of our cases. The association of cardiac disease with Multicore Myopathy has not been previously emphasised. All four patients in this study had a cardiomyopathy, and heart disease was the cause of death in two of the patients. Multicore Myopathy is not always a benign entity. Cardiac involvement, when present, adversely affects prognosis.

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Cardiac Involvement in Dystrophin-Deficient Females: Current Understanding and Implications for the Treatment of Dystrophinopathies

Genes ◽

10.3390/genes11070765 ◽

2020 ◽

Vol 11 (7) ◽

pp. 765 ◽

Cited By ~ 1

Author(s):

Kenji Rowel Q. Lim ◽

Narin Sheri ◽

Quynh Nguyen ◽

Toshifumi Yokota

Keyword(s):

Muscular Dystrophy ◽

Molecular Mechanisms ◽

Cardiac Involvement ◽

Gene Mutations ◽

Dystrophin Gene ◽

Becker Muscular Dystrophy ◽

Female Carrier ◽

Daily Life Activities ◽

Cardiac Manifestations ◽

Available Information

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive condition caused primarily by out-of-frame mutations in the dystrophin gene. In males, DMD presents with progressive body-wide muscle deterioration, culminating in death as a result of cardiac or respiratory failure. A milder form of DMD exists, called Becker muscular dystrophy (BMD), which is typically caused by in-frame dystrophin gene mutations. It should be emphasized that DMD and BMD are not exclusive to males, as some female dystrophin mutation carriers do present with similar symptoms, generally at reduced levels of severity. Cardiac involvement in particular is a pressing concern among manifesting females, as it may develop into serious heart failure or could predispose them to certain risks during pregnancy or daily life activities. It is known that about 8% of carriers present with dilated cardiomyopathy, though it may vary from 0% to 16.7%, depending on if the carrier is classified as having DMD or BMD. Understanding the genetic and molecular mechanisms underlying cardiac manifestations in dystrophin-deficient females is therefore of critical importance. In this article, we review available information from the literature on this subject, as well as discuss the implications of female carrier studies on the development of therapies aiming to increase dystrophin levels in the heart.

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Improvement of Cardiac Vegetations in Antiphospholipid Syndrome with Enoxaparin and Corticosteroids after Rivaroxaban Failure

Case Reports in Hematology ◽

10.1155/2018/8097539 ◽

2018 ◽

Vol 2018 ◽

pp. 1-4

Author(s):

Eric Granowicz ◽

Kiyon Chung

Keyword(s):

Heart Failure ◽

Clinical Trials ◽

Autoimmune Disease ◽

Acute Heart Failure ◽

Antiphospholipid Syndrome ◽

Steroid Therapy ◽

Cardiac Disease ◽

Marked Improvement ◽

Cardiac Involvement

Cardiac disease is a well-known complication of antiphospholipid syndrome (APS), with many patients presenting with valvular thickening or vegetations, referred to as Libman–Sacks endocarditis (LSE). Because cases of APS with cardiac involvement are relatively rare, paucity of large clinical trials studying this complication has made management challenging. In the absence of acute heart failure and embolic events, a medical approach is usually selected, consisting of anticoagulation and possibly corticosteroids when another underlying autoimmune disease is present. However, the role of various anticoagulant classes and the duration of steroid therapy continue to be debated. Here, we present a 45-year-old woman who developed two vegetations in the setting of secondary APS while taking rivaroxaban before experiencing marked improvement with the use of enoxaparin and steroids.

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1176Hepatocyte growth factor has prognostic utility in light chain and transthyretin cardiac amyloidosis

European Heart Journal ◽

10.1093/eurheartj/ehz748.0018 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

K W Zhang ◽

A Kraja ◽

J Miao ◽

K Tomasek ◽

Y R Su ◽

...

Keyword(s):

Growth Factor ◽

Clinical Outcomes ◽

Cardiac Disease ◽

Cardiac Amyloidosis ◽

Cardiac Involvement ◽

Troponin T ◽

Left Ventricular ◽

Assist Device ◽

Ventricular Assist ◽

Left Ventricular Assist

Abstract Background With the advent of multiple novel therapeutics for light chain (AL) and transthyretin (ATTR) amyloidosis, there is a critical need for validated prognostic markers in cardiac amyloidosis. A discriminatory serum biomarker may improve prognostic and staging systems in AL and ATTR cardiac amyloidosis. Purpose Our objective was to test the hypothesis that hepatocyte growth factor (HGF) is associated with clinical outcomes in patients with AL and ATTR cardiac amyloidosis. Methods 102 patients with AL or ATTR and suspected cardiac involvement were prospectively enrolled. HGF, NT-proBNP, troponin-T, and eGFR were measured upon study enrollment. Cardiac involvement was established by 1) endomyocardial biopsy, or 2) non-cardiac biopsy with concentric hypertrophy on echocardiography, low voltage or pseudo-infarction on ECG, elevated NT-proBNP or troponin-T, or characteristic delayed myocardial enhancement on cardiac MRI. Patients were followed for the occurrence of all-cause mortality, cardiac transplantation, and left-ventricular assist device implantation. Results Of the total amyloidosis cohort, 72 had cardiac involvement while 30 had non-cardiac disease. HGF, NT-proBNP, and troponin-T levels were significantly higher in patients with cardiac involvement than in patients with non-cardiac disease (p<0.05 for all comparisons). Over a median follow-up period of 1.9 years there were 20 deaths, 1 cardiac transplant, and 1 left-ventricular assist device implant, all in patients with cardiac involvement. Patient stratification by cut-off levels of NT-proBNP (332 pg/mL), troponin-T (35 ng/L), and eGFR (45 mL/min/1.73m2) used in published staging models for AL and ATTR cardiac amyloidosis showed no association between abnormal biomarker level and adverse clinical outcome (p>0.05). In contrast, stratification by HGF level of 310 pg/mL (identified by the Youden Index for cardiac involvement by AL and ATTR in our cohort) showed that elevated HGF was associated with worse clinical outcomes (p=0.0211). Furthermore, event-free survival was worse in patients with elevated HGF, with survival curves diverging soon after enrollment (p=0.0730). HGF is Prognostic in Cardiac Amyloidosis Conclusions Elevated HGF is associated with worse clinical outcomes in patients with AL and ATTR cardiac amyloidosis and has potential for clinical utility.

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Cardiomyopathy in congenital disorders of glycosylation

Cardiology in the Young ◽

10.1017/s1047951103000702 ◽

2003 ◽

Vol 13 (4) ◽

pp. 345-351 ◽

Cited By ~ 36

Author(s):

Josef Gehrmann ◽

Kristina Sohlbach ◽

Michael Linnebank ◽

Hans-Josef Böhles ◽

Stephan Buderus ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Cardiac Disease ◽

Cardiac Death ◽

Cardiac Involvement ◽

The Other ◽

Congenital Disorders ◽

Congenital Disorders Of Glycosylation ◽

Congenital Disorder Of Glycosylation ◽

The Mean ◽

Cardiac Diagnosis

Congenital disorders of glycosylation are a group of inherited metabolic multisystem disorders characterized by defects in the glycosylation of proteins and lipids. In most cases, neuromuscular disease is present. The purpose of this study was to characterize the cardiological aspects in this disorder.From the literature, we identified six children with congenital disorders of glycosylation associated with cardiac disease. We then screened for cardiovascular manifestations 20 patients diagnosed with congenital disorders of glycosylation at our own institution.Of the 6 patients identified in the literature, 4 had hypertrophic cardiomyopathy, while in the other 2 the cardiac diagnosis was unclear. The mean age at cardiac diagnosis was 5 months, with a range from 34 weeks to 24 months. Of the patients, five had died at a mean age of 3.5 months, with a range from 1.5 to 6 months, with one documented cardiac death. Three of our 20 patients (15%) had coexistent cardiomyopathy, and in three additional patients presenting with cardiomyopathy we made the diagnosis of a congenital disorder of glycosylation. In our cohort, dilated cardiomyopathy was found in two-thirds of the patients, with hypertrophic cardiomyopathy in the other third. The mean age at cardiac diagnosis was 19 months, with a range from 0.5 to 84 months. Of these patients, two died in infancy at a mean age of 4 months, specifically at 1.5 and 7 months, due to cardiac disease, with one dying suddenly. The remaining four patients are alive with minor to severe cardiac dysfunction.We conclude that congenital disorders of glycosylation have to be considered in the differential diagnosis of children presenting with cardiomyopathy, and that all patients with congenital disorders of glycosylation should be screened for an associated cardiomyopathy. Cardiac involvement contributes significantly to morbidity and mortality, and probably to sudden cardiac death in this disorder.

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The natural course and the impact of therapies of cardiac involvement in the mucopolysaccharidoses

Cardiology in the Young ◽

10.1017/s1047951109003576 ◽

2009 ◽

Vol 19 (2) ◽

pp. 170-178 ◽

Cited By ~ 72

Author(s):

Vlasta Fesslová ◽

Paola Corti ◽

Giovanna Sersale ◽

Attilio Rovelli ◽

Pierluigi Russo ◽

...

Keyword(s):

Cardiac Disease ◽

Ventricular Hypertrophy ◽

Cardiac Involvement ◽

Left Ventricular ◽

Short Term ◽

Enzyme Replacement ◽

The Impact ◽

Delta Score ◽

Severe Cardiac Disease

AbstractObjectiveTo analyze cardiac involvement and its progression in mucopolysaccharidoses, and to assess the short term impact of new therapeutic strategies.Patients and methodsWe studied echocardiographically 57 patients with various types of mucopolysaccharidoses, specifically types I, II, III, IV and VI, with a median age at the diagnosis of cardiac involvement of 5 years, following them for a median of 4.6 years, with a range from 0.9 to 21.2 years. We used a scoring system, along with the so-called delta score, to quantify the severity of involvement at baseline and at last examination, and to chart their progression over time.ResultsCases with cardiac involvement increased from 59.6% to 87.3% at the last examination. The scores increased with age, and were significantly different according to the specific type of mucopolysaccharidosis. Involvement of the mitral valve was most common, often associated with an aortic valvar anomaly and/or left ventricular hypertrophy. Patients with the first and second types had more severe involvement than those with the third or fourth types. Patients undergoing transplantation of haematopoietic stem cells seem to stabilize after an initial worsening while, in contrast, we were unable to demonstrate an effect of enzyme replacement therapy on the progression of the cardiac disease, possibly because those receiving such treatment had a higher median age, more severe cardiac disease and shorter follow-up.ConclusionsCardiac involvement was present early in more than a half of the patients identified as having mucopolysaccharidosis, and generally progressed, being more frequent and severe in the first and second types of the disease. Longer follow-up is needed to demonstrate any significant improvement induced by new therapies.

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Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

Journal of Clinical Medicine ◽

10.3390/jcm10040820 ◽

2021 ◽

Vol 10 (4) ◽

pp. 820

Author(s):

Fernanda Fortunato ◽

Rachele Rossi ◽

Maria Sofia Falzarano ◽

Alessandra Ferlini

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Dystrophin Gene ◽

Orphan Drugs ◽

Therapeutic Approaches ◽

Anchoring Protein ◽

Cardiac Muscles ◽

Dystrophin Protein ◽

The Brain

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

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