Cardiomiopatia Hipertrófica: uma revisão pelo olhar da ressonância magnética / Hypertrophic Cardiomyopathy: a review using magnetic resonance imaging

A cardiomiopatia hipertrófica é a cardiopatia genética mais frequente na população geral e é caracterizada por uma hipertrofia ventricular esquerda assimétrica. Entretanto, as alterações fenotípicas desta cardiomiopatia vão muito além da hipertrofia ventricular, e incluem alterações do aparato valvar mitral, dos músculos papilares e do ventrículo direito. Devido à dificuldade no diagnóstico diferencial entre as múltiplas causas de hipertrofia, a ressonância magnética cardíaca vem cumprindo um papel fundamental na avaliação diagnóstica e prognóstica desta cardiomiopatia. A cineressonância magnética na definição da localização e extensão da hipertrofia, o realce tardio, na detecção das áreas de fibrose miocárdica e técnicas mais recentes como o Mapa de T1 que avalia a fibrose intersticial e o volume extracelular; e finalmente o Tissue Tracking na análise da deformação miocárdica.(AU)

Hypertrophic cardiomyopathy, the most common genetic cardiopathy in the general population, is characterized by asymmetric left ventricular hypertrophy. However, the phenotypic changes in this cardiomyopathy extend beyond ventricular hypertrophy and include changes in the mitral valve apparatus, papillary muscles, and right ventricle. Due to the difficult differential diagnosis among multiple causes of hypertrophy, cardiac magnetic resonance has played a fundamental role in its diagnostic and prognostic evaluation; magnetic cine-resonance in defining the location and extent of hypertrophy; late enhancement, in the detection of areas of myocardial fibrosis; more recent techniques such as T1 mapping that assesses interstitial fibrosis and extracellular volume; and finally tissue tracking in the analysis of myocardial deformation. (AU)

Novel frameshift variant in MYL2 reveals molecular differences between dominant and recessive forms of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by thickening of the ventricular muscle without dilation and is often associated with dominant pathogenic variants in cardiac sarcomeric protein genes. Here, we report a family with two infants diagnosed with infantile-onset HCM and mitral valve dysplasia that led to death before one year of age. Using exome sequencing, we discovered that one of the affected children had a homozygous frameshift variant in Myosin light chain 2 (MYL2:NM_000432.3:c.431_432delCT: p.Pro144Argfs*57;MYL2-fs), which alters the last 20 amino acids of the protein and is predicted to impact the most C-terminal of the three EF-hand domains in MYL2. The parents are unaffected heterozygous carriers of the variant and the variant is absent in control cohorts from gnomAD. The absence of the phenotype in carriers and the infantile presentation of severe HCM is in contrast to HCM associated with dominant MYL2 variants. Immunohistochemical analysis of the ventricular muscle of the deceased patient with the MYL2-fs variant showed a marked reduction of MYL2 expression compared to an unaffected control. In vitro overexpression studies further indicate that the MYL2-fs variant is actively degraded. In contrast, an HCM-associated missense variant (MYL2:p.Gly162Arg) and three other MYL2 stop-gain variants (p.E22*, p.K62*, p.E97*) that result in loss of the EF domains are stably expressed but show impaired localization. The degradation of the MYL2-fs can be rescued by inhibiting the cell's proteasome function supporting a post-translational effect of the variant. In vivo rescue experiments with a Drosophila MYL2-homolog (Mlc2) knockdown model indicate that neither the MYL2-fs nor the MYL2:p.Gly162Arg variant supports normal cardiac function. The tools that we have generated provide a rapid screening platform for functional assessment of variants of unknown significance in MYL2. Our study supports an autosomal recessive model of inheritance for MYL2 loss-of-function variants in infantile HCM and highlights the variant-specific molecular differences found in MYL2-associated cardiomyopathy.

Clinical and functional characterization of a novel RASopathy-causing SHOC2 mutation associated with prenatal-onset hypertrophic cardiomyopathy.

SHOC2 is a scaffold protein mediating RAS-promoted activation of mitogen-activated protein kinase (MAPK) signaling in response to extracellular stimuli. A recurrent activating mutation in SHOC2 (p.Ser2Gly) causes Mazzanti syndrome, a RASopathy characterized by features resembling Noonan syndrome and distinctive ectodermal abnormalities. A second mutation (p.Met173Ile) supposed to cause loss-of-function was more recently identified in two individuals with milder phenotypes. Here, we report on the third RASopathy-causing SHOC2 mutation (c.807_808delinsTT, p.Gln269_His270delinsHisTyr), which was found associated with prenatal-onset hypertrophic cardiomyopathy. Structural analyses indicated a possible impact of the mutation on the relative orientation of the two SHOC2's leucine-rich repeat domains. Functional studies provided evidence of its activating role, revealing enhanced binding of the mutant protein to MRAS and PPP1CB, and increased signaling through the MAPK cascade. Differing from SHOC2 S2G , SHOC2 Q269_H270delinsHY is not constitutively targeted to the plasma membrane. These data document that diverse mechanisms in SHOC2 functional dysregulation converge toward MAPK signaling upregulation.

[Modern genetic counselling : Practical aspects exemplified by hypertrophic cardiomyopathy]. / Moderne humangenetische Beratung : Praktische Aspekte am Beispiel der hypertrophen Kardiomyopathie.

Genetic counselling and subsequent molecular genetic testing should be performed in patients when an inherited monogenic form of heart disease is suspected. For the individual patient as well as for the (possibly asymptomatic) relatives, molecular diagnostics is important for an early diagnosis, (preventive) therapy and prognosis assessment. Using the example of hypertrophic cardiomyopathy (HCM), the most common monogenic form of structural heart disease, essential aspects of modern genetic counselling are elucidated. Specific examples of one case with a classical form of hypertrophic obstructive cardiomyopathy and one case of congenital HCM with Noonan's syndrome are discussed.

Radiofrequency ablation of fast ventricular tachycardia causing an ICD storm in an infant with hypertrophic cardiomyopathy.

An implantable cardioverter defibrillator (ICD) storm involves very frequent arrhythmia episodes and ICD shocks, and it is associated with poor short-term and long-term prognosis. Radiofrequency catheter ablation can be used as an effective rescue treatment for patients with an ICD storm. To our knowledge, this is the first report of an infant with hypertrophic cardiomyopathy presenting with an ICD storm and undergoing successful radiofrequency catheter ablation salvage treatment for the fast left posterior fascicular ventricular tachycardia.

New non-renal congenital disorders associated with medullary sponge kidney (MSK) support the pathogenic role of GDNF and point to the diagnosis of MSK in recurrent stone formers.

Medullary sponge kidney (MSK) is a congenital renal disorder. Its association with several developmental abnormalities in other organs hints at the likelihood of some shared step(s) in the embryogenesis of the kidney and other organs. It has been suggested that the REarranged during Transfection (RET) proto-oncogene and the Glial cell line-Derived Neurotrophic Factor (GDNF) gene are defective in patients with MSK, and both RET and GDNF are known to have a role in the development of the central nervous system, heart, and craniofacial skeleton. Among a cohort of 143 MSK patients being followed up for nephrolithiasis and chronic kidney disease at our institution, we found six with one or more associated non-renal anomalies: one patient probably has congenital hemihyperplasia and hypertrophic cardiomyopathy with adipose metaplasia and mitral valve prolapse; one has Marfan syndrome; and the other four have novel associations between MSK and nerve and skeleton abnormalities described here for the first time. The discovery of disorders involving the central nervous system, cardiovascular system and craniofacial skeleton in MSK patients supports the hypothesis of a genetic alteration on the RET-GDNF axis having a pivotal role in the pathogenesis of MSK, in a subset of patients at least. MSK seems more and more to be a systemic disease, and the identification of extrarenal developmental defects could be important in arousing the suspicion of MSK in recurrent stone formers.

The role of imaging in the diagnosis and management of hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy, affecting approximately 1:500 people. As the yield of genetic testing is only about 35-60%, the diagnosis of HCM is still clinical and based on the demonstration of unexplained and usually asymmetric left ventricular (LV) hypertrophy by imaging modalities. In the past, echocardiography was the sole imaging modality used for the diagnosis and management of HCM. However, in recent years other imaging modalities such as cardiac magnetic resonance have played a major role in the diagnosis, management and risk stratification of HCM, particularly when the location of left ventricular hypertrophy is atypical (apex, lateral wall) and when the echocardiographic imaging is sub-optimal. However, the most unique contribution of cardiac magnetic resonance is the quantification of myocardial fibrosis. Exercise stress echocardiography is the preferred provocative test for the assessment of LV outflow tract obstruction, which is detected only on provocation in one-third of the patients.

Persistent Pulmonary Hypertension in a Neonate With Transposition of Great Arteries and Intact Ventricular Septum: A Case Report and Review of the Literature.

Transposition of the great arteries (TGA) with intact ventricular septum (IVS) has very favorable short- and long-term surgical outcome. Although rare, when associated with persistent pulmonary hypertension (PPH), it exhibits significant mortality risk and management challenges. We report the case of a neonate with TGA with IVS and PPH who underwent successful early surgical repair with emphasis on clinical management and review of the literature.

Fatal congenital hypertrophic cardiomyopathy and a pancreatic nodule morphologically identical to focal lesion of congenital hyperinsulinism in an infant with costello syndrome: case report and review of the literature.

Costello syndrome is characterized by constitutional mutations in the proto-oncogene HRAS, causing dysmorphic features, multiple cardiac problems, intellectual disability, and an increased risk of neoplasia. We report a male infant with dysmorphic features, born prematurely at 32 weeks, who, during his 3-month life span, had an unusually severe and ultimately fatal manifestation of hypertrophic cardiomyopathy and hyperinsulinemic hypoglycemia. Molecular studies in this patient demonstrated the uncommon Q22K mutation in the HRAS gene, diagnostic of Costello syndrome. The major autopsy findings revealed hypertrophic cardiomyopathy, congenital myopathy, and a 1.4-cm pancreatic nodule that was positive for insulin expression and morphologically identical to a focal lesion of congenital hyperinsulinism. Sequencing of KCNJ11 and ABCC8, the 2 most commonly mutated genes in focal lesion of congenital hyperinsulinism, revealed no mutations. While hyperinsulinism is a recognized feature of RASopathies, a focal proliferation of endocrine cells similar to a focal lesion of hyperinsulinism is a novel pathologic finding in Costello syndrome.

Whole-exome sequencing identifies a mutation in the mitochondrial ribosome protein MRPL44 to underlie mitochondrial infantile cardiomyopathy.

BACKGROUND: The genetic complexity of infantile cardiomyopathies is remarkable, and the importance of mitochondrial translation defects as a causative factor is only starting to be recognised. We investigated the genetic basis for infantile onset recessive hypertrophic cardiomyopathy in two siblings. METHODS AND RESULTS: Analysis of respiratory chain enzymes revealed a combined deficiency of complexes I and IV in the heart and skeletal muscle. Exome sequencing uncovered a homozygous mutation (L156R) in MRPL44 of both siblings. MRPL44 encodes a protein in the large subunit of the mitochondrial ribosome and is suggested to locate in close proximity to the tunnel exit of the yeast mitochondrial ribosome. We found severely reduced MRPL44 levels in the patient's heart, skeletal muscle and fibroblasts suggesting that the missense mutation affected the protein stability. In patient fibroblasts, decreased MRPL44 affected assembly of the large ribosomal subunit and stability of 16S rRNA leading to complex IV deficiency. Despite this assembly defect, de novo mitochondrial translation was only mildly affected in fibroblasts suggesting that MRPL44 may have a function in the assembly/stability of nascent mitochondrial polypeptides exiting the ribosome. Retroviral expression of wild-type MRPL44 in patient fibroblasts rescued the large ribosome assembly defect and COX deficiency. CONCLUSIONS: These findings indicate that mitochondrial ribosomal subunit defects can generate tissue-specific manifestations, such as cardiomyopathy.

Pulmonary interstitial glycogenosis associated with pulmonary hypertension and hypertrophic cardiomyopathy.

A neonate with pulmonary interstitial glycogenosis, pulmonary hypertension, and hypertrophic cardiomyopathy is described. The fatal outcome for this patient contrasts with the reported favorable prognosis associated with isolated pulmonary interstitial glycogenosis. To the authors' knowledge, the association of pulmonary interstitial glycogenosis and hypertrophic cardiomyopathy has not been reported previously. The authors have broadened the phenotype of pulmonary interstitial glycogenosis and demonstrate the diagnostic value of lung biopsy in cases of unexplained neonatal pulmonary hypertension.

Utilization of extracorporeal membrane oxygenation in congenital hypertrophic cardiomyopathy caused by maternal diabetes.

Extracorporeal membrane oxygenation (ECMO) is an advanced strategy utilized in many neonatal intensive care units for a specific list of indications. This case illustrates a rare but effective use of this therapy for a newborn infant with severe hypertrophic cardiomyopathy induced by maternal diabetes. Such infants who are unresponsive to conventional therapies may benefit from ECMO support, if it is used in conjunction with management strategies that optimize cardiac output.

A rasopathy phenotype with severe congenital hypertrophic obstructive cardiomyopathy associated with a PTPN11 mutation and a novel variant in SOS1.

The RAS-MAPK pathway is critical for human growth and development. Abnormalities at different steps of this signaling cascade result in neuro-cardio-facial-cutaneous syndromes, or the RASopathies, a group of disorders with overlapping yet distinct phenotypes. RASopathy patients have variable degrees of intellectual disability, poor growth, relative macrocephaly, ectodermal abnormalities, dysmorphic features, and increased risk for certain malignancies. Congenital heart disease, particularly hypertrophic cardiomyopathy (HCM) and pulmonic stenosis, are prominent features in these disorders. Significant locus heterogeneity exists for many of the RASopathies. Traditionally, these diseases were thought to be inherited in an autosomal dominant manner. However, recently patients with defects in two components of this pathway and overlapping features of various forms of Noonan syndrome and neurofibromatosis 1 and have been reported. Here we present a patient with severe, progressive neonatal HCM, elevated urinary catecholamine metabolites, and dysmorphic features in whom we identified a known LEOPARD syndrome-associated PTPN11 mutation (c.1403 C > T; p.T468M) and a novel, potentially pathogenic missense SOS1 variant (c.1018 C > T; p.P340S) replacing a rigid nonpolar imino acid with a polar amino acid at a highly conserved position. We describe detailed clinical manifestations, cardiac histopathology, and the molecular genetic findings. Oligogenic models of inheritance with potential synergistic effects should be considered in the RASopathies.

Hypertrophic cardiomyopathy with cardiac rupture and tamponade caused by congenital disorder of glycosylation type Ia.

Hypertrophic cardiomyopathy (HCM) is a rare presenting feature of congenital disorder of glycosylation type Ia (CDG-Ia). We report two female siblings with CDG-Ia and cardiomyopathy. Patient no. 1 died at 12 days of age from cardiac rupture and tamponade, which has not previously been reported in CDG-Ia. The second patient died at 2 months of age from HCM. The severe cardiac manifestations seen in our patients emphasize the importance of early cardiac assessment in all patients with CDG-Ia.

Supernumerary umbilical vein in a hydropic neonate with hypertrophic cardiomyopathy.

The anomalies of the umbilical vessels are uncommon, with the exception of a single umbilical artery. We report a term female infant with fetal hydrops, hypertrophic cardiomyopathy, and a four-vessel umbilical cord consisting of two umbilical arteries and two umbilical veins. The presence of two veins in the umbilical cord has been attributed to persistence of both the normal left umbilical vein and the caudal part of the right umbilical vein. This fetal vascular pathology has been reported very rarely and may be associated with increased risk of congenital malformations and adverse perinatal outcome.

A fetal dilated and hypertrophic cardiomyopathy associated with maternal gestational diabetes--a case report.

There is an increased risk of a hypertrophic cardiomyopathy and congenital heart defects among newborns of diabetic mothers. We report a case of hypertrophic cardiomyopathy preceded with dilated cardiomyopathy in a fetus of a diabetic mother. The fetal echocardiography at the 23rd week of gestation revealed signs of dilated cardiomyopathy with signs of cardiac failure. Under the echocardiographic monitoring the successful treatment was performed. In spite of poor prognosis, the child was born at the 39th gestation week in a good condition.