Compound heterozygous loss-of-function mutations in KIF20A are associated with a novel lethal congenital cardiomyopathy in two siblings.

Congenital or neonatal cardiomyopathies are commonly associated with a poor prognosis and have multiple etiologies. In two siblings, a male and female, we identified an undescribed type of lethal congenital restrictive cardiomyopathy affecting the right ventricle. We hypothesized a novel autosomal recessive condition. To identify the cause, we performed genetic, in vitro and in vivo studies. Genome-wide SNP typing and parametric linkage analysis was done in a recessive model to identify candidate regions. Exome sequencing analysis was done in unaffected and affected siblings. In the linkage regions, we selected candidate genes that harbor two rare variants with predicted functional effects in the patients and for which the unaffected sibling is either heterozygous or homozygous reference. We identified two compound heterozygous variants in KIF20A; a maternal missense variant (c.544C>T: p.R182W) and a paternal frameshift mutation (c.1905delT: p.S635Tfs*15). Functional studies confirmed that the R182W mutation creates an ATPase defective form of KIF20A which is not able to support efficient transport of Aurora B as part of the chromosomal passenger complex. Due to this, Aurora B remains trapped on chromatin in dividing cells and fails to translocate to the spindle midzone during cytokinesis. Translational blocking of KIF20A in a zebrafish model resulted in a cardiomyopathy phenotype. We identified a novel autosomal recessive congenital restrictive cardiomyopathy, caused by a near complete loss-of-function of KIF20A. This finding further illustrates the relationship of cytokinesis and congenital cardiomyopathy.

Cardiovascular Magnetic Resonance in Heritable Cardiomyopathies.

Cardiovascular magnetic resonance represents the imaging modality of choice for the investigation of patients with heritable cardiomyopathies. The combination of gold-standard volumetric analysis with tissue characterization can deliver precise phenotypic evaluation of both cardiac morphology and the underlying myocardial substrate. Cardiovascular magnetic resonance additionally has an established role in risk-stratifying patients with heritable cardiomyopathy and an emerging role in guiding therapies. This article explores the application and utility of cardiovascular magnetic resonance techniques with specific focus on the major heritable cardiomyopathies.

Mutations in the accessory subunit NDUFB10 result in isolated complex I deficiency and illustrate the critical role of intermembrane space import for complex I holoenzyme assembly.

An infant presented with fatal infantile lactic acidosis and cardiomyopathy, and was found to have profoundly decreased activity of respiratory chain complex I in muscle, heart and liver. Exome sequencing revealed compound heterozygous mutations in NDUFB10, which encodes an accessory subunit located within the PD part of complex I. One mutation resulted in a premature stop codon and absent protein, while the second mutation replaced the highly conserved cysteine 107 with a serine residue. Protein expression of NDUFB10 was decreased in muscle and heart, and less so in the liver and fibroblasts, resulting in the perturbed assembly of the holoenzyme at the 830 kDa stage. NDUFB10 was identified together with three other complex I subunits as a substrate of the intermembrane space oxidoreductase CHCHD4 (also known as Mia40). We found that during its mitochondrial import and maturation NDUFB10 transiently interacts with CHCHD4 and acquires disulfide bonds. The mutation of cysteine residue 107 in NDUFB10 impaired oxidation and efficient mitochondrial accumulation of the protein and resulted in degradation of non-imported precursors. Our findings indicate that mutations in NDUFB10 are a novel cause of complex I deficiency associated with a late stage assembly defect and emphasize the role of intermembrane space proteins for the efficient assembly of complex I.

Animal Models of Congenital Cardiomyopathies Associated With Mutations in Z-Line Proteins.

The cardiac Z-line at the boundary between sarcomeres is a multiprotein complex connecting the contractile apparatus with the cytoskeleton and the extracellular matrix. The Z-line is important for efficient force generation and transmission as well as the maintenance of structural stability and integrity. Furthermore, it is a nodal point for intracellular signaling, in particular mechanosensing and mechanotransduction. Mutations in various genes encoding Z-line proteins have been associated with different cardiomyopathies, including dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, and left ventricular noncompaction, and mutations even within the same gene can cause widely different pathologies. Animal models have contributed to a great advancement in the understanding of the physiological function of Z-line proteins and the pathways leading from mutations in Z-line proteins to cardiomyopathy, although genotype-phenotype prediction remains a great challenge. This review presents an overview of the currently available animal models for Z-line and Z-line associated proteins involved in human cardiomyopathies with special emphasis on knock-in and transgenic mouse models recapitulating the clinical phenotypes of human cardiomyopathy patients carrying mutations in Z-line proteins. Pros and cons of mouse models will be discussed and a future outlook will be given. J. Cell. Physiol. 232: 38-52, 2017. © 2016 Wiley Periodicals, Inc.

Novel myosin-based therapies for congenital cardiac and skeletal myopathies.

The dysfunction in a number of inherited cardiac and skeletal myopathies is primarily due to an altered ability of myofilaments to generate force and motion. Despite this crucial knowledge, there are, currently, no effective therapeutic interventions for these diseases. In this short review, we discuss recent findings giving strong evidence that genetically or pharmacologically modulating one of the myofilament proteins, myosin, could alleviate the muscle pathology. This should constitute a research and clinical priority.

Sudden Death in a Male Infant Due to Histiocytoid Cardiomyopathy: An Autopsy Case and Review of the Literature.

Histiocytoid cardiomyopathy (HC) is a very rare cardiac disorder that mainly affects female infants younger than 2 years. It may manifest as ventricular tachycardia or dilated cardiomyopathy and frequently causes sudden death. The most common grossly change is multifocal uneven thickening of the endocardium, presenting a yellowish color, with some area forming nodular appearance, and histologically featured by scattered clusters of histiocytoid myocytes under the endocardium. Here, we present a 19-month-old male infant who died of heart failure, and an autopsy was performed and confirmed the diagnosis of HC. We also reviewed the literature and focused on the research progression of the origin and genetic/molecular features of HC in recent years.

A Rare Association of Non-Compaction of the Ventricular Myocardium, and Non-Immune Hydrops Fetalis.

Hydrops fetalis is a rare manifestation of severe congestive heart failure in a fetus, resulting in pathological fluid accumulation in fetal soft tissues and/or serous cavities. Non-compaction of the ventricular myocardium, frequently referred to as the left ventricular non-compaction (LVNC), is a very rare congenital cardiomyopathy. For LVNC, echocardiography is the diagnostic modality of choice. Various diagnostic criteria exist based on either echocardiography or MRI. Currently, nonimmune hydrops fetalis (NIHF) comprise almost 90% of all hydrops fetalis cases. Among cardiovascular conditions that contribute to NIHF (20%), structural malformations (especially hypoplastic left heart, endocardial cushion defect) and arrhythmias are the most frequent etiological factors. We describe an extremely preterm neonate who presented with features of non-Immune hydrops fetalis (NIHF) associated with LVNC and profound refractory systemic hypotension.

Cardiomyopathy in a dish: using human inducible pluripotent stem cells to model inherited cardiomyopathies.

Inherited cardiomyopathies, including hypertrophic cardiomyopathy, dilated cardiomyopathies, arrythmogenic right ventricular cardiomyopathy, and other inherited forms of heart failure, represent a unique set of genetically defined cardiovascular disease processes. Unraveling the molecular mechanisms of these deadly forms of human heart disease has been challenging, but recent groundbreaking scientific advances in stem cell technology have allowed for the generation of patient-specific human inducible stem cell (hiPSC)-derived cardiomyocytes (CMs). hiPSC-derived CMs retain the genetic blueprint of the patient, they can be maintained in culture, and they recapitulate the phenotypic characteristics of the disease in vitro, thus serving as a disease in a dish. This review provides an overview of in vitro modeling of inherited cardiomyopathies with the use of patient-specific hiPSC-derived CMs.

Abcc9 is required for the transition to oxidative metabolism in the newborn heart.

The newborn heart adapts to postnatal life by shifting from a fetal glycolytic metabolism to a mitochondrial oxidative metabolism. Abcc9, an ATP-binding cassette family member, increases expression concomitant with this metabolic shift. Abcc9 encodes a membrane-associated receptor that partners with a potassium channel to become the major potassium-sensitive ATP channel in the heart. Abcc9 also encodes a smaller protein enriched in the mitochondria. We now deleted exon 5 of Abcc9 to ablate expression of both plasma membrane and mitochondria-associated Abcc9-encoded proteins, and found that the myocardium failed to acquire normal mature metabolism, resulting in neonatal cardiomyopathy. Unlike wild-type neonatal cardiomyocytes, mitochondria from Ex5 cardiomyocytes were unresponsive to the KATP agonist diazoxide, consistent with loss of KATP activity. When exposed to hydrogen peroxide to induce cell stress, Ex5 neonatal cardiomyocytes displayed a rapid collapse of mitochondria membrane potential, distinct from wild-type cardiomyocytes. Ex5 cardiomyocytes had reduced fatty acid oxidation, reduced oxygen consumption and reserve. Morphologically, Ex5 cardiac mitochondria exhibited an immature pattern with reduced cross-sectional area and intermitochondrial contacts. In the absence of Abcc9, the newborn heart fails to transition normally from fetal to mature myocardial metabolism.-Fahrenbach, J. P., Stoller, D., Kim, G., Aggarwal, N., Yerokun, B., Earley, J. U., Hadhazy, M., Shi, N.-Q., Makielski, J. C., McNally, E. M. Abcc9 is required for the transition to oxidative metabolism in the newborn heart.

Exome sequencing of patients with histiocytoid cardiomyopathy reveals a de novo NDUFB11 mutation that plays a role in the pathogenesis of histiocytoid cardiomyopathy.

Histiocytoid cardiomyopathy (Histiocytoid CM) is a rare form of cardiomyopathy observed predominantly in newborn females that is fatal unless treated early in life. We have performed whole exome sequencing on five parent-proband trios and identified nuclear-encoded mitochondrial protein mutations in three cases. The molecular genetic basis of Histiocytoid CM remains unknown despite several hypotheses in medical literature. The findings presented in this manuscript may represent components of genetic etiologies for this heterogeneous disease. Two probands had de novo non-sense mutations in the second exon of the X-linked nuclear gene NDUFB11. A third proband was doubly heterozygous for inherited rare variants in additional components of complex I, NDUFAF2 and NDUFB9, confirming that Histiocytoid CM is genetically heterogeneous. In a fourth case, the proband with Histiocytoid CM inherited a mitochondrial mutation from her heteroplasmic mother, as did her brother who presented with cardiac arrhythmia. Strong candidate recessive or compound heterozygous variants were not found for this individual or for the fifth case. Although NDUFB11 has not been implicated before in cardiac pathology, morpholino-mediated knockdown of ndufb11 in zebrafish embryos generated defective cardiac tissue with cardiomegaly, looping defects, and arrhythmia which suggests the role of NDUFB11 in the pathogenesis of this abnormal cardiac pathology. Taken together, the unbiased whole exome sequencing approach confirms the suspected genetic heterogeneity of Histiocytoid CM. Therefore, the novel NDUFB11 mutation may cause a complex 1 deficiency in synergy with additional unknown mtDNA variants.

Protective effects of berberine against doxorubicin-induced cardiotoxicity in rats by inhibiting metabolism of doxorubicin.

1. The clinical use of doxorubicin, an effective anticancer drug, is severely hampered by its cardiotoxicity. Berberine, a botanical alkaloid, has been reported to possess cardioprotective and antitumor effects. In this study, we investigated the cardioprotective effect of berberine on doxorubicin-induced cardiotoxicity and the effect of berberine on the metabolism of doxorubicin. 2. Adult male Sprague-Dawley rats were administered doxorubicin in the presence or absence of berberine for 2 weeks. Administration of berberine effectively prevented doxorubicin-induced body weight reduction and mortality in rats. 3. Berberine reduced the activity of myocardial enzymes, including aspartate aminotransferase (AST), creatine kinase (CK), CK isoenzyme (CK-MB) and lactate dehydrogenase (LDH). Echocardiographic examination further demonstrated that berberine effectively ameliorated cardiac dysfunction induced by doxorubicin. 4. Berberine inhibited the metabolism of doxorubicin in the cytoplasm of rat heart and reduced the accumulation of doxorubicinol (a secondary alcohol metabolite of doxorubicin) in heart. 5. These data showed that berberine alleviated the doxorubicin-induced cardiotoxicity in rats via inhibition of the metabolism of doxorubicin and reduced accumulation of doxorubicinol selectively in hearts.

Mitochondrial mutations in patients with congenital heart defects by next generation sequencing technology.

It has been shown that mitochondrial deoxyribo nucleic acid mutations may play an important role in the development of cardiomyopathy, and various types of cardiomyopathy can be attributed to disturbed mitochondrial oxidative energy metabolism. Several studies have described many mutations in mitochondrial genes encoding for subunits of respiratory chain complexes. Thus, recent studies confirm that pathologic mitochondrial deoxyribo nucleic acid mutations are a major reason of diseases and determining them by next-generation sequencing will improve our understanding of dysregulation of heart development. To analyse mitochondrial deoxyribo nucleic acid mutations, the entire mitochondrial deoxyribo nucleic acid was amplified in two overlapping polymerase chain reaction fragments from the cardiac tissue of the 22 patients with congenital heart disease, undergoing cardiac surgery. Mitochondrial deoxyribo nucleic acid was deep sequenced by next-generation sequencing. A total of 13 novel mitochondrial deoxyribo nucleic acid mutations were identified in nine patients. Of the patients, three have novel mutations together with reported cardiomyopathy mutations. In all, 65 mutations were found, and 13 of them were unreported. This study represents the most comprehensive mitochondrial deoxyribo nucleic acid mutational analysis in patients with congenital heart disease.

The perfect storm? Histiocytoid cardiomyopathy and compound CACNA2D1 and RANGRF mutation in a baby.

A female baby suffered from a rare association between histiocytoid cardiomyopathy, left ventricular non-compaction, and Wolff-Parkinson-White syndrome causing severe and recurrent arrhythmic storms. Antiarrhythmic drugs, radiofrequency ablation of Purkinje tissue, and sympathetic denervation were ineffective. The implant of a cardiac defibrillator allowed her to survive till heart transplant. Compound mutation of CACNA2D1 and RANGRF genes were found. To the best of our knowledge, this is the first comprehensive description of the concurrence of these two mutations and histiocytoid cardiomyopathy.

[Left ventricular non compaction: A poorly known cardiomyopathy]. / LE CAS CLINIQUE DU MOIS. La non-compaction du ventricule gauche: une cardiomyopathie méconnue.

Left ventricular non compaction is a rare congenital cardiomyopathy. It is characterised by a thin compacted epicardial layer, prominent trabeculations and deep recesses that communicate with the left ventricular cavity. This condition may lead to chronic heart failure, life threatening ventricular arrhythmias and systemic embolic events.

[Histiocytoid cardiomyopathy concurrent with noncompact myocardium, myocarditis, and pericarditis].

The paper presents a practical case of histiocytoid cardiomyopathy concurrent with noncompact myocardium, atrial septal defects, myocarditis, and pericarditis in an 8-month-old girl, by describing their clinical presentations and a morphological examination.

Pregnancy in women with an implantable cardioverter-defibrillator: is it safe?

AIMS: To describe obstetric/neonatal and cardiac outcomes for a cohort of women carrying implantable cardioverter-defibrillators (ICDs) during pregnancy. METHODS AND RESULTS: All women in routine follow-up at our institution for ICD implantation who became pregnant between 2006 and 2013 were included in this study. All ICDs were pre-pectoral devices with bipolar endocardial leads. Obstetric/neonatal and cardiac outcomes were assessed during pregnancy and post-partum. Twenty pregnancies were conceived by 12 women carrying ICD devices, 14 of which resulted in live births and none in maternal death. Seven of these women had structural cardiomyopathies and five had channelopathies. No device-related complications were recorded. Twelve shocks (nine transthoracic and three from ICDs) were experienced during pregnancy by two women, one of whom miscarried shortly afterwards at 4 weeks gestation. One stillbirth, three miscarriages and one termination were recorded for women with long QT syndrome, repaired tetralogy of Fallot and repaired Laubry-Pezzi syndrome, respectively. Intrauterine growth restriction, low birth weight, and neonatal hypoglycaemia were recorded in four, three, and five pregnancies, respectively. CONCLUSIONS: Pregnancy had no effect on ICD operation and no evidence was found to link ICD carriage with adverse pregnancy outcomes, although one miscarriage may have been induced by ICD shock therapy. A worsening of cardiac condition occurs in specific cardiac diseases and ß-blocker therapy should be continued for all women carrying ICDs in pregnancy as the benefits outweigh the risks of taking this medication.

Assessment of tenascin-C levels in ventricular noncompaction/hypertrabeculation patients: a cross-sectional study.

PURPOSE: Ventricular noncompaction/hypertrabeculation (NC/HT) is a rare form of congenital cardiomyopathy. We aimed to investigate the presence of serum tenascin-C (TN-C) in adult patients with NC/HT and evaluate its value. METHODS AND RESULTS: Serum TN-C levels were measured by ELISA in 50 NC/HT patients both with/without systolic dysfunction and in 23 normal controls. Systolic dysfunction was defined as ejection fraction (EF) ≤ 40. Mann-Whitney U-test and ROC curve analysis were done. Of 49 NC/HT patients, 24 (49%) patients had systolic dysfunction (mean age 36 ± 15) and 25 patients (51%) had normal systolic function (mean age 36 ± 17). The ages between groups were not different. The mean levels of serum TN-C in patients with or without systolic dysfunction were 26 ± 10 ng/mL and 26 ± 8 ng/mL respectively, compared to normal controls, 7 ± 2 ng/mL (P < 0.001). No significance was observed between 2 groups of NC/HT patients regarding TN-C levels (P = 0.8). The ROC curve analysis revealed that a TN-C value of 11.7 ng/mL identified patients with NC/HT with 100% sensitivity and specifity. CONCLUSION: High serum TN-C levels are present in adult NC/HT cardiomyopathy even when left ventricular systolic function remains normal. Also, serum TN-C levels could be regarded as a candidate biomarker in the diagnosis of NC/HT which needs to be tested in larger prospective studies.

Left ventricular strain reduction is not confined to the noncompacted segments in noncompaction cardiomyopathy-insights from the three-dimensional speckle tracking echocardiographic MAGYAR-path study.

INTRODUCTION: Noncompaction cardiomyopathy (NCCM) is a new clinical entity characterized by prominent trabecular meshwork and deep intertrabecular recesses communicating with the left ventricular (LV) cavity due to arrest of the normal embryogenesis of the endomyocardium. The aim of the present study was to evaluate different contributions of noncompacted and compacted LV segments to the global LV dysfunction by three-dimensional (3D) speckle tracking echocardiography (3DSTE)-derived strain parameters in NCCM. PATIENTS AND METHODS: The present study comprised 9 patients with typical features of NCCM. Due to the limited image quality, one patient was excluded from the evaluations. Finally, 128 segments of 8 NCCM patients were assessed. Their results were compared to 176 segments of 11 healthy volunteers. Complete two-dimensional Doppler echocardiography extended with 3DSTE has been performed in all cases. RESULTS: Fifty-five of 128 LV segments (43%) proved to be noncompacted in NCCM patients. All strain parameters of segments of NCCM patients were significantly lower as compared to segments of controls. Only radial strain (6.99 ± 7.36% vs. 12.58 ± 12.78% vs. 25.24 ± 11.76%, P < 0.001 and P < 0.05, respectively) and 3D strain (7.79 ± 7.59% vs. 14.67 ± 14.04% vs. 27.78 ± 12.57%, P < 0.001 and P < 0.05, respectively) showed further reduction in noncompacted segments as compared to compacted segments. CONCLUSIONS: Left ventricular strain reduction is not confined to the nocompacted segments in NCCM. Radial and 3D strain parameters show further reduction in noncompacted segments compared to compacted segments.

Congenital and hereditary causes of sudden cardiac death in young adults: diagnosis, differential diagnosis, and risk stratification.

Sudden cardiac death is defined as death from unexpected circulatory arrest-usually a result of cardiac arrhythmia-that occurs within 1 hour of the onset of symptoms. Proper and timely identification of individuals at risk for sudden cardiac death and the diagnosis of its predisposing conditions are vital. A careful history and physical examination, in addition to electrocardiography and cardiac imaging, are essential to identify conditions associated with sudden cardiac death. Among young adults (18-35 years), sudden cardiac death most commonly results from a previously undiagnosed congenital or hereditary condition, such as coronary artery anomalies and inherited cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy [ARVC], dilated cardiomyopathy, and noncompaction cardiomyopathy). Overall, the most common causes of sudden cardiac death in young adults are, in descending order of frequency, hypertrophic cardiomyopathy, coronary artery anomalies with an interarterial or intramural course, and ARVC. Often, sudden cardiac death is precipitated by ventricular tachycardia or fibrillation and may be prevented with an implantable cardioverter defibrillator (ICD). Risk stratification to determine the need for an ICD is challenging and involves imaging, particularly echocardiography and cardiac magnetic resonance (MR) imaging. Coronary artery anomalies, a diverse group of congenital disorders with a variable manifestation, may be depicted at coronary computed tomographic angiography or MR angiography. A thorough understanding of clinical risk stratification, imaging features, and complementary diagnostic tools for the evaluation of cardiac disorders that may lead to sudden cardiac death is essential to effectively use imaging to guide diagnosis and therapy.