‘State-of-the-heart’ of cardiac laminopathies

Cattin, Marie-Elodie; Muchir, Antoine; Bonne, Gisèle

doi:10.1097/hco.0b013e32835f0c79

Cited by 61 publications

(79 citation statements)

References 58 publications

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“…Sudden cardiac death can occur and in some instances is the presenting manifestation; sudden cardiac death also can occur with little systolic dysfunction. 490 Genetic heterogeneity exists for autosomal dominant DCM or conduction system disease. 476,491 The genes identified to date primarily include genes encoding cytoskeletal and sarcomeric proteins, although some ion channel genes and others have also been identified.…”

Section: Clinical Statements and Guidelinesmentioning

confidence: 99%

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

Bozkurt¹,

Colvin²,

Cook³

et al. 2016

Circulation

602

663

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CLINICAL STATEMENTS AND GUIDELINEST he intent of this American Heart Association (AHA) scientific statement is to summarize our current understanding of dilated cardiomyopathies. There is special emphasis on recent developments in diagnostic approaches and therapies for specific cardiomyopathies. Recommendations in this document are based on published studies, published practice guidelines from the American College of Cardiology (ACC)/AHA 1 and other organizations, 2,3 and the multidisciplinary expertise of the writing group. Existing evidence in epidemiology, classification, diagnosis, and management of specific cardiomyopathies is usually derived from nonrandomized observational studies, registries, case reports, or expert opinion based on clinical experience, not large-scale randomized clinical trials or systematic reviews. Therefore, in this document, rather than using the standard ACC/AHA classification schema of recommendations and level of evidence, 4 we have included key management strategies at the end of each section and categorized our recommendations according to the level of consensus. Although the format of our recommendations might resemble the ACC/AHA classification of recommendations used in the ACC/AHA practice guidelines, because of the preponderance of expert opinion or level of evidence C evidence in our document, we elected to use different terminology to provide a distinction from the practice guidelines, in which stronger levels and quality of evidence with randomized clinical trials or meta-analyses are usually present. 4 The levels of evidence follow the AHA and ACC methods of classifying the level of certainty of the treatment effect. 4 DEfINITIoN of DILATED CArDIoMyopAThyThe term dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders that are characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. 5 In clinical practice, the pathogenesis of heart failure (HF) has often been placed into 2 categories: ischemic and nonischemic cardiomyopathy. The term nonischemic cardiomyopathy has been interchangeably used with DCM. Although this approach might be practical, it fails to recognize that nonischemic cardiomyopathy can include cardiomyopathies caused by volume or pressure overload (such as hypertension or valvular heart disease) that are not conventionally accepted under the definition of DCM. 1,5 Again, in general practice and clinical research trials, the term ischemic cardiomyopathy is defined as cardiomyopathy caused by ischemic heart disease. Current use of ischemic cardiomyopathy terminology implies ventricular dilation and depressed myocardial contractility caused by ischemia or infarction. CLASSIfICATIoN of CArDIoMyopAThIESThe first classification on this topic categorized cardiomyopathies as heart muscle diseases with dilated (DCM), hypertrophic, restrictive, arrhythmogenic right ventricular (ARVC), or nonclassifiable cardiomyopathy in 1980. 5 Subse...

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Section: Clinical Statements and Guidelinesmentioning

confidence: 99%

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

Bozkurt¹,

Colvin²,

Cook³

et al. 2016

Circulation

602

663

View full text Add to dashboard Cite

show abstract

“…In fact, analysis of skeletal muscle biopsies from two HCM patients showed a normal muscle fibre histology and biochemistry, and lacked any of the myopathological or electrophysiological abnormalities described in myofibrillar myopathy patients. These findings, together with previous reports showing that different mutations within the filamin C molecule result in different myopathological features 16 [19][20][21] . Similarly, mutations in FHL1, which usually cause skeletal muscle disease, have been shown to cause HCM with left ventricular diastolic dysfunction without skeletal muscle affection 22,23 .…”

Section: Discussionmentioning

confidence: 88%

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

et al. 2014

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Mutations in different genes encoding sarcomeric proteins are responsible for 50-60% of familial cases of hypertrophic cardiomyopathy (HCM); however, the genetic alterations causing the disease in one-third of patients are currently unknown. Here we describe a case with familial HCM of unknown cause. Whole-exome sequencing reveals a variant in the gene encoding the sarcomeric protein filamin C (p.A1539T) that segregates with the disease in this family. Sequencing of 92 HCM cases identifies seven additional variants segregating with the disease in eight families. Patients with FLNC mutations show marked sarcomeric abnormalities in cardiac muscle, and functional analysis reveals that expression of these FLNC variants resulted in the formation of large filamin C aggregates. Clinical studies indicate that FLNC-mutated patients have higher incidence of sudden cardiac death. On the basis of these findings, we conclude that mutations in the gene encoding the sarcomeric protein filamin C cause a new form of familial HMC.

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“…In support for this, heterozygous LMNA +/− mice, which express ∼50% less lamin A/C, have impaired activation of mechanosensitive genes (Cupesi et al, 2010), reduced contractility of cardiomyocytes and eventually develop atrioventricular block and DCM (Nikolova et al, 2004;Wolf et al, 2008). Therefore, the current hypothesis on the pathogenesis of DCM holds that LMNA mutation cause haploinsufficiency or/and dominant-negative structural effects leading to a mechanically unstable lamina and/or alterations in gene expression (Cattin et al, 2013). Both these features have also been observed in cells expressing p.S143P lamin A/C.…”

Section: Discussionmentioning

confidence: 99%

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

West

Gullmets

Virtanen

et al. 2016

Journal of Cell Science

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Mutation of the LMNA gene, encoding nuclear lamin A/C, is a common cause of familial dilated cardiomyopathy (DCM). Among Finnish DCM patients, the founder mutation c.427T>C (p.S143P) is the most frequently reported genetic variant. Here we show that p.S143P lamin A/C is more nucleoplasmic and soluble than wild type lamin A/C and accumulates into large intranuclear aggregates in a fraction of cultured patient fibroblasts as well as in cells ectopically expressing either FLAG- or GFP-tagged p.S143P lamin A. In fluorescence loss in photobleaching (FLIP) experiments, non-aggregated EGFP-tagged p.S143P lamin A is significantly more dynamic. In in vitro association studies p.S143P lamin A failed to form appropriate filament structures but instead assembled into disorganized aggregates similar to those observed in patient cell nuclei. A whole genome expression analysis revealed an elevated unfolded protein response (UPR) in p.S143P lamin A/C expressing cells. Additional endoplasmic reticulum (ER) stress induced by tunicamycin reduced the viability of mutant lamin expressing cells further. In summary, p.S143P lamin A/C affects normal lamina structure and influences the cellular stress response, homeostasis and viability.

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‘State-of-the-heart’ of cardiac laminopathies

Abstract: These recent findings suggest that targeting MAPK and Akt/mTOR pathways with potent and specific compounds represents a promising intervention for the treatment of LMNA DCM-CD.

Cited by 61 publications

References 58 publications

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

Current Diagnostic and Treatment Strategies for Specific Dilated Cardiomyopathies: A Scientific Statement From the American Heart Association

Mutations in filamin C cause a new form of familial hypertrophic cardiomyopathy

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

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