Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy

Olivotto, Iacopo; Girolami, Francesca; Ackerman, Michael J.; Nistri, Stefano; Bos, J. Martijn; Zachara, Elisabetta; Ommen, Steve R.; Theis, Jeanne L.; Vaubel, Rachael A.; Re, Federica; Armentano, Corinna; Poggesi, Corrado; Torricelli, Francesca; Cecchi, Francesca

doi:10.1016/s0025-6196(11)60890-2

Cited by 296 publications

(150 citation statements)

References 38 publications

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“…Previous studies analyzing a similar number of sarcomeric genes in large series of unrelated patients with the classic form of HCM found a positive genotype in no more than 50-60% of cases. [6][7][8] Similar results have been reported by a recent study on patients with end-stage HCM. In particular, genetic analysis of 10 HCM-related genes disclosed a positive genotype in 58% of the patients with a 13% of double mutations.…”

Section: Discussionsupporting

confidence: 88%

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

et al. 2012

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A 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage evolution). She was recently diagnosed elsewhere because of palpitations. Her 7-year-old daughter underwent familiar screening and she was diagnosed with classic HCM. She was completely asymptomatic without extracardiac or systemic manifestations. During the following years, they both experienced a similar clinical course with worsening dyspnoea and progressive deterioration of LV systolic function. They both underwent heart transplantation, the mother at the age of 47 and the daughter at the age of 23, respectively. Many diagnostic hypotheses, including sarcomeric HCM, Anderson-Fabry disease, glycogen storage diseases and mitochondrial cardiomyopathies have been taken into account. The diagnostic work-up included serial electrocardiogram and echocardiographic assessments, pathologic evaluation of the explanted hearts and genetic analysis of 8 sarcomeric and 3 metabolic genes. Even if a shared HCM phenotype (LV systolic dysfunction in two first-degree female family members associated with a likely autosomal dominant inheritance and absence of extracardiac or multisystemic manifestations) could support a temptative diagnosis of sarcomeric HCM, a definitive diagnosis could not be reached, due to the lack of genetic analysis to confirm such diagnosis. Case ReportA 35-year-old woman was referred to our centre for clinical management of hypertrophic cardiomyopathy (HCM) with left ventricular (LV) systolic dysfunction (end-stage phase). This condition was recently diagnosed in a different hospital because of palpitations.The electrocardiogram (ECG) showed sinus rhythm and negative T waves in the lateral leads ( Figure 1A). Echocardiography showed LV hypertrophy (maximal wall thickness 14 mm) associated with LV enlargement (enddiastolic diameter 56 mm) and LV ejection fraction (EF) of 30%. Of note, a relative wall thinning localized at the basal segment of the interventricular septum with marked akinesia was present ( Figure 1B and 1C, arrows). At that time she was mildly symptomatic, showing dyspnoea on mild efforts (NYHA functional class II). No other clinical manifestations were present and laboratory parameters were unremarkable. Medical therapy with beta-blockers and ACE-inhibitors was started.The patient's 7-year-old daughter underwent familiar screening with ECG and echocardiography. She was completely asymptomatic. No mental retardation or other extracardiac manifestations were detected and laboratory parameters were normal. The ECG showed extreme LV hypertrophy with infero-lateral pseudonecrosis and negative T waves in the infero-lateral leads (Figure 2A). Two-dimensional echocardiography disclosed a classical form of HCM with a maximal wall thickness of 16 mm at the postero-lateral wall level, a LV end-diastolic diameter of 35 mm and a LV ejection fraction of 78%. As the mother, a relative and localized wall thinning associated with hypo...

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Section: Discussionsupporting

confidence: 88%

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

et al. 2012

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“…More than 600 mutations have been discovered to be associated with HCM with all but a few in the genes coding for the contractile apparatus of the myofibril, predominantly myosin-binding protein C and ␤-myosin heavy chain (3)(4)(5)(6). Eleven mutations have been identified in the cardiac actin gene, ACTC (7)(8)(9)(10)(11), including the E99K mutation that has been intensively investigated as it has been shown to co-segregate with an unusual apical hypertrophic phenotype (12,13). HCM is defined clinically as the presence of unexplained ventricular hypertrophy; usually the thickening is most prominent in the interventricular septum, but other pathologies can also occur, such as apical and concentric hypertrophy or left ventricular noncompaction.…”

Section: Hypertrophic Cardiomyopathy (Hcm)mentioning

confidence: 99%

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Song

Dyer

Stuckey

et al. 2011

Journal of Biological Chemistry

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We generated a transgenic mouse model expressing the apical hypertrophic cardiomyopathy-causing mutation ACTC E99K at 50% of total heart actin and compared it with actin from patients carrying the same mutation. The actin mutation caused a higher Ca 2؉ sensitivity in reconstituted thin filaments measured by in vitro motility assay (2.3-fold for mice and 1.3-fold for humans) and in skinned papillary muscle. The mutation also abolished the change in Ca 2؉ sensitivity normally linked to troponin I phosphorylation. MyBP-C and troponin I phosphorylation levels were the same as controls in transgenic mice and human carrier heart samples. ACTC E99K mice exhibited a high death rate between 28 and 45 days (48% females and 22% males). At 21 weeks, the hearts of the male survivors had enlarged atria, increased interstitial fibrosis, and sarcomere disarray. MRI showed hypertrophy, predominantly at the apex of the heart. End-diastolic volume and end-diastolic pressure were increased, and relaxation rates were reduced compared with nontransgenic littermates. End-systolic pressures and volumes were unaltered. ECG abnormalities were present, and the contractile response to ␤-adrenergic stimulation was much reduced. Older mice (29-week-old females and 38-week-old males) developed dilated cardiomyopathy with increased end-systolic volume and continuing increased end-diastolic pressure and slower contraction and relaxation rates. ECG showed atrial flutter and frequent atrial ectopic beats at rest in some ACTC E99K mice. We propose that the ACTC E99K mutation causes higher myofibrillar Ca 2؉ sensitivity that is responsible for the sudden cardiac death, apical hypertrophy, and subsequent development of heart failure in humans and mice.

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“…Here we tested the easily generalizable idea to prevent the disease phenotype by adding full-length Mybpc3 by gene therapy in a Mybpc3-targeted knock-in (KI) mouse model 21,22 that genetically mimics the severe neonatal HCM cases 21,22 . These mice carry at the homozygous state the human c.772G4A MYBPC3 transition, which is one of the most frequent HCM mutations (13% in a large Italian cohort) 23 and is associated with a bad prognosis 19 . Homozygous KI mice develop systolic dysfunction after postnatal day 1 and LVH at postnatal day 3 (refs 21,22), but are born with an apparently normal heart, providing the opportunity to treat prior to the onset of the disease phenotype.…”

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confidence: 99%

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

et al. 2014

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Homozygous or compound heterozygous frameshift mutations in MYBPC3 encoding cardiac myosin-binding protein C (cMyBP-C) cause neonatal hypertrophic cardiomyopathy (HCM), which rapidly evolves into systolic heart failure and death within the first year of life. Here we show successful long-term Mybpc3 gene therapy in homozygous Mybpc3-targeted knock-in (KI) mice, which genetically mimic these human neonatal cardiomyopathies. A single systemic administration of adeno-associated virus (AAV9)-Mybpc3 in 1-day-old KI mice prevents the development of cardiac hypertrophy and dysfunction for the observation period of 34 weeks and increases Mybpc3 messenger RNA (mRNA) and cMyBP-C protein levels in a dose-dependent manner. Importantly, Mybpc3 gene therapy unexpectedly also suppresses accumulation of mutant mRNAs. This study reports the first successful long-term gene therapy of HCM with correction of both haploinsufficiency and production of poison peptides. In the absence of alternative treatment options except heart transplantation, gene therapy could become a realistic treatment option for severe neonatal HCM.

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Myofilament Protein Gene Mutation Screening and Outcome of Patients With Hypertrophic Cardiomyopathy

Cited by 296 publications

References 38 publications

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

An Unusual Case of Familial Hypertrophic Cardiomyopathy with Left Ventricular Systolic Dysfunction: A Still Unsolved Diagnosis

Molecular Mechanism of the E99K Mutation in Cardiac Actin (ACTC Gene) That Causes Apical Hypertrophy in Man and Mouse

Mybpc3 gene therapy for neonatal cardiomyopathy enables long-term disease prevention in mice

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