Cuando la genética estaba oculta: miocardiopatía hipertrófica por variante MYBPC3 c. 1102A>T (p.Lys368*) refractaria a manejo médico: reporte de un caso / When genetics were hidden: hypertrophic cardiomyopathy due to MYBPC3 c. 1102A>T (p.Lys368*) variant refractory to medical management: case report / Quando a genética estava oculta: cardiomiopatia hipertrófica por variante MYBPC3 c. 1102A>T (p.Lys368*) refractária à manejo médico: reporte de um caso

La miocardiopatía hipertrófica es cada vez más diagnosticada. Es una condición genética que genera hipertrofia miocárdica, fibrosis, isquemia y apoptosis con obstrucción del tracto de salida del ventrículo izquierdo. Puede generar síncope, falla cardíaca y muerte súbita. El tratamiento es farmacológico y se requiere cirugía si hay refractariedad. Se presenta un caso de miocardiopatía hipertrófica asociada a variante genética patogénica en un paciente no respondedor a manejo médico óptimo. La importancia de este artículo radica en lo determinante que es la genética para el abordaje diagnóstico y el establecimiento del origen y pronóstico de esta enfermedad.

Hypertrophic cardiomyopathy is increasingly diagnosed. It is a genetic condition that leads to myocardial hypertrophy, fibrosis, ischemia, and apoptosis with obstruction of the left ventricular outflow tract. It can result in syncope, heart failure, and sudden death. Treatment is pharmacological, and surgery is required in cases of refractoriness. A case of hypertrophic cardiomyopathy associated with a pathogenic genetic variant is presented in a patient unresponsive to optimal medical management. The importance of this article lies in how crucial genetics is for the proper diagnostic approach and the establishment of the origin and prognosis of this disease.

A miocardiopatia hipertrófica está sendo diagnosticada cada vez mais. É uma condição genética que leva à hipertrofia miocárdica, fibrose, isquemia e apoptose com obstrução do trato de saída do ventrículo esquerdo. Pode resultar em síncope, insuficiência cardíaca e morte súbita. O tratamento é farmacológico e a cirurgia é necessária em casos de refratariedade. Apresenta-se um caso de miocardiopatia hipertrófica associada a uma variante genética patogênica em um paciente não responsivo ao manejo médico ótimo. A importância deste artigo reside na determinante genética para a abordagem diagnóstica adequada e para o estabelecimento da origem e prognóstico desta doença.

MicroRNA expression profiles in familial hypertrophic cardiomyopathy with myosin-binding protein C3 (MYBPC3) gene mutations.

Familial hypertrophic cardiomyopathy (FHCM) is an autosomal dominant inherited disease caused by mutations in genes encoding cardiac sarcomere proteins. MicroRNAs (miRNAs) play an important role in the pathogenesis of FHCM. In the present study, we aimed to determine the miRNA profile in FHCM patients with myosin-binding protein C3 (MYBPC3) gene mutations. We recruited three FHCM patients and age- and sex-matched controls. The three probands all had hypertrophic obstructive cardiomyopathy with severe myocardial hypertrophy, and two of the three had a history of sudden cardiac death, representing a "malignant" phenotype. We then compared the miRNA expression profiles of three FHCM patients carrying MYBPC3 gene mutations with those of the normal control group using miRNA sequencing technology. Differentially expressed miRNAs were verified using real-time polymerase chain reaction (qPCR). Target genes and signaling pathways of the identified differentially expressed miRNAs were predicted using bioinformatics analysis. A total of 33 significantly differentially expressed miRNAs were detected in the peripheral blood of the three probands, of which 28 were upregulated, including miR-208b-3p, and 5 were downregulated. Real-time PCR confirmed the upregulated expression of miR-208b-3p in FHCM patients (P < 0.05). Bioinformatics analysis showed that miR-208b-3p was mainly enriched in 79 target genes including UBE2V2, MED13, YBX1, CNKSR2, GATA4, andSOX5/6, et al. Gene ontology (GO) analysis of target genes showed that miR-208b was mainly involved in the processes of negative regulation of transcription from RNA polymerase II promoter, and regulation of transcription, DNA templated. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that the target genes regulated by miR-208b-3p were mainly involved in the Wnt signaling pathway. These findings suggest that FHCM patients with MYBPC3 gene mutations have a specific miRNA expression profile, and that miR-208b-3p is significantly upregulated in cardiac hypertrophy. Our results also indicate that miRNA-208b-3p activates the Wnt signaling pathway through its target gene to promote cardiac hypertrophy.

Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. METHODS: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. RESULTS: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. CONCLUSIONS: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.

Myocardial Perfusion Defects in Hypertrophic Cardiomyopathy Mutation Carriers.

Background Impaired myocardial blood flow (MBF) in the absence of epicardial coronary disease is a feature of hypertrophic cardiomyopathy (HCM). Although most evident in hypertrophied or scarred segments, reduced MBF can occur in apparently normal segments. We hypothesized that impaired MBF and myocardial perfusion reserve, quantified using perfusion mapping cardiac magnetic resonance, might occur in the absence of overt left ventricular hypertrophy (LVH) and late gadolinium enhancement, in mutation carriers without LVH criteria for HCM (genotype-positive, left ventricular hypertrophy-negative). Methods and Results A single center, case-control study investigated MBF and myocardial perfusion reserve (the ratio of MBF at stress:rest), along with other pre-phenotypic features of HCM. Individuals with genotype-positive, left ventricular hypertrophy-negative (n=50) with likely pathogenic/pathogenic variants and no evidence of LVH, and matched controls (n=28) underwent cardiac magnetic resonance. Cardiac magnetic resonance identified LVH-fulfilling criteria for HCM in 5 patients who were excluded. Individuals with genotype-positive, left ventricular hypertrophy-negative had longer indexed anterior mitral valve leaflet length (12.52±2.1 versus 11.55±1.6 mm/m2, P=0.03), lower left ventricular end-systolic volume (21.0±6.9 versus 26.7±6.2 mm/m2, P≤0.005) and higher left ventricular ejection fraction (71.9±5.5 versus 65.8±4.4%, P≤0.005). Maximum wall thickness was not significantly different (9.03±1.95 versus 8.37±1.2 mm, P=0.075), and no subject had significant late gadolinium enhancement (minor right ventricle‒insertion point late gadolinium enhancement only). Perfusion mapping demonstrated visual perfusion defects in 9 (20%) carriers versus 0 controls (P=0.011). These were almost all septal or near right ventricle insertion points. Globally, myocardial perfusion reserve was lower in carriers (2.77±0.83 versus 3.24±0.63, P=0.009), with a subendocardial:subepicardial myocardial perfusion reserve gradient (2.55±0.75 versus 3.2±0.65, P=<0.005; 3.01±0.96 versus 3.47±0.75, P=0.026) but equivalent MBF (2.75±0.82 versus 2.65±0.69 mL/g per min, P=0.826). Conclusions Regional and global impaired myocardial perfusion can occur in HCM mutation carriers, in the absence of significant hypertrophy or scarring.

Clinical characteristics of hypertrophic cardiomyopathy in children: An 8-year single center experience.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the second most common pediatric cardiomyopathy. Although there is a large body of literature about HCM in adults, there is limited information on HCM in childhood. We evaluated various aspects of pediatric HCM patients treated at our center. METHODS: We identified 152 pediatric patients with HCM between October 2011 and October 2019. Clinical history, invasive (ICD, pacemaker, electrophysiologic study, catheter ablation therapy) and non-invasive (ECG, holter moniterization, echocardiography, cardiac MR, genetic study, medicam treatment) data were collected and evaluated. RESULTS: The mean ± standard deviation age of patients was 8.9 ± 5.7 years (1 month-18 years) and 67.8% were male. The most frequent clinical symptoms were murmur and palpitations. Three cases (2%) had aborted sudden death as the first manifestation of HCM. Of these patients, 120 (78.9%) had non-syndromic HCM and 32 (27.2%) had syndromic HCM. Asymmetric septal hypertrophy was common (48.3%) in the non-syndromic group, whereas concentric hypertrophy was common (56.2%) in syndromic group. Left ventricular outflow tract obstruction (LVOTO) occurred in 39 (25.6%) patients. Nine (5.9%) patients underwent electrophysiologic study and/or ablation and 16 patients underwent surgical intervention. Implantable cardioverter defibrillator (ICD) insertion was performed in 38 patients (26 transvenous, 12 epicardial). ICDs were inserted in three (7.9%) patients for secondary prevention; in the remaining patients (92.1%) the devices were placed for primary prevention. Mean SD follow-up time was 27.1 ± 22 months. Five (3.3%) patients died during the follow-up. No patient had heart transplantation or a long-term assistive device. CONCLUSION: The etiology of HCM is heterogeneous and present at any age. It is important to determine the timing of surgery and potential risks for sudden cardiac arrest. As most cases of HCM are familial, evaluation of family members at risk should be a routine component of clinical management.

Ecoestresse físico na cardiomiopatia hipertrófica: como, quando e por quê? / Exercise stress echocardiography in hypertrophic cardiomyopathy: how, when and why?

Resumo Historicamente, o papel do ecocardiograma de estresse físico no manejo da cardiomiopatia hipertrófica tem sido negligenciado na prática clínica, de acordo com a análise das diretrizes do American College of Cardiology/ American Heart Association de 2002, que recomendavam cautela no uso dessa metodologia, em portadores de cardiomiopatia hipertrófica, devido ao risco de possível ocorrência tanto de arritmia cardíaca, como de colapso hemodinâmico no esforço. Atualmente, o estresse físico na cardiomiopatia hipertrófica integra a avaliação rotineira de pacientes sintomáticos com ou sem gradiente da via de saída do ventrículo esquerdo < 50 mmHg, em repouso. Para este grupo, é um método seguro e confiável para medir o gradiente da via de saída do ventrículo esquerdo durante o esforço e sólido diferenciador de pacientes com cardiomiopatia hipertrófica não obstrutivos (gradiente ausente, tanto em repouso quanto no esforço) daqueles com gradientes lábeis (gradiente ausente no repouso e presente no esforço). Portanto, na avaliação da cardiomiopatia hipertrófica, o estresse físico é igualmente útil na quantificação do grau de regurgitação mitral, nas alterações da contratilidade segmentar do ventrículo esquerdo e na avaliação da função diastólica do ventrículo esquerdo, diante do esforço, sendo capaz de predizer o futuro desenvolvimento de sintomas de insuficiência cardíaca. O método é também importante na determinação das diferentes estratégias de tratamento para cada paciente, desde a miomectomia cirúrgica ou a ablação septal alcoólica, para aqueles com gradiente lábil, com sintomas limitantes e refratários ao tratamento medicamentoso versus transplante cardíaco para aqueles sem gradiente.(AU)

Gap junction protein beta 4 plays an important role in cardiac function in humans, rodents, and zebrafish.

AIMS: GJB4 encodes a transmembrane connexin protein (Cx30.3) that is a component of gap junctions. This study investigated whether GJB4 plays an important role in human heart disease and function. METHODS AND RESULTS: We examined a patient and her older brother who both presented with complicated severe hypertrophic cardiomyopathy (HCM) and whose parents are healthy married cousins. The gene exome analysis showed 340 single nucleotide polymorphisms (SNPs) that caused amino acid changes for which the patient was homozygous and both parents were heterozygous. After excluding all known common (>10%) SNP gene mutations, the gene for GJB4 was the only identified gene that is possibly associated with cardiac muscle. The resultant E204A substitution exists in the 4th transmembrane domain. GJB4-E204A impaired the binding with gap junction protein A1 (GJA1) compared with GJB4-WT. The expression of GJB4 was induced in rat disease models of left and right ventricle hypertrophy and mouse disease models of adriamycin-induced cardiomyopathy and myocardial infarction, while it was not detected at all in control. An immunohistochemical study was performed for autopsied human hearts and the explanted heart of the patient. GJB4 was expressed and colocalized with GJA1 in intercalated discs in human diseased hearts, which was extensively enhanced in the explanted heart of the patient. The abnormal expression and localization of GJB4 were observed in beating spheres of patient's induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs). We generated knockout zebrafish of GJB4 by CRISPR/Cas9 and the endodiastolic volume and the ventricular ejection fraction were significantly lower in GJB4-deficient than in wild-type zebrafish at five days post-fertilization. CONCLUSIONS: These results indicate both that GJB4 is defined as a new connexin in diseased hearts, of which mutation can cause a familial form of HCM, and that GJB4 may be a new target for the treatment of cardiac hypertrophy and dysfunction.

Familial evaluation reveals a distinct genetic cause in a large Spanish family with neurofibromatosis 1 and hypertrophic cardiomyopathy.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder characterized by café-au-lait spots, intertriginous freckling, and multiple neurofibromas. Classically, it has been described that hypertrophic cardiomyopathy (HCM) may be a cardiovascular manifestation of neurofibromatosis 1, although the relationship between these two entities has not been fully established. We report a large Spanish family carrying a pathogenic truncating variant in NF1 (p.Arg2258Ter) causing neurofibromatosis 1, and a pathogenic missense variant in MYH7 (p. Arg453Cys), causing hypertrophic cardiomyopathy independently. A complete penetrance was observed in both genetic diseases, reinforcing the notion of deleterious effects of both rare variants. According to our report, hypertrophic cardiomyopathy in patients with NF1 should not be considered as part of the clinical spectrum in all cases. A careful and comprehensive assessment, including family evaluation and genetic testing for HCM should be considered as part of the diagnostic work-up in individuals presenting with both phenotypes.

The Fabry disease-causing mutation, GLA IVS4+919G>A, originated in Mainland China more than 800 years ago.

The Fabry disease-causing mutation, the GLA IVS4+919G>A (designated GLA IVS4), is very prevalent in patients with hypertrophic cardiomyopathy in Taiwan. This X-linked mutation has also been found in patients in Kyushu, Japan and Southeast Asia. To investigate the age and the possible ancestral origin of this mutation, a total of 33 male patients with the GLA IVS4+919G>A mutation, born in Taiwan, Japan, Singapore, Malaysia, Vietnam, and the Fujian and Guangdong provinces of China, were studied. Peripheral bloods were collected, and the Ilumina Infinium CoreExome-24 microarray was used for dense genotyping. A mutation-carrying haplotype was discovered which was shared by all 33 patients. This haplotype does not exist in 15 healthy persons without the mutation. Rather, a wide diversity of haplotypes was found in the vicinity of the mutation site, supporting the existence of a single founder of the GLA IVS4 mutation. The age of the founder mutation was estimated by the lengths of the mutation-carrying haplotypes based on the linkage-disequilibrium decay theory. The first, second, and third quartile of the age estimates are 800.7, 922.6, and 1068.4 years, respectively. We concluded that the GLA IVS4+919G>A mutation originated from a single mutational event that occurred in a Chinese chromosome more than 800 years ago.

Hypertrophic cardiomyopathy masked by pericarditis

Hypertrophic cardiomyopathy used to be regarded as a rare untreatable cause of sudden death in young male athletes. This report is the case of a middle-aged female patient with hereditary hypertrophic cardiomyopathy masked by superimposed pericarditis and revealed by autopsy. This case report illustrates how co-morbidity can hide a crucial diagnosis. This case report also illustrates the value of autopsy disclosing a familial disease that is increasingly recognized and dramatically more treatable than a few decades ago. Sudden death due to hypertrophic cardiomyopathy has become preventable, if the diagnosis is made soon enough. The lessons for patient care from this case include the importance of not missing the diagnosis of hypertrophic cardiomyopathy in female patients.

Caracterización clínica y molecular de niños con síndrome de Noonan y otras RASopatías en Argentina / Clinical and molecular characterization of children with Noonan syndrome and other RASopathies in Argentina

Introducción. Las RASopatías son un conjunto de síndromes fenotípicamente superpuestos causados por mutaciones en genes implicados en la vía RAS/MAPK. La herencia es autosómica dominante, presentan características clínicas comunes, como baja talla, dismorfias craneofaciales, cardiopatia congénita, manifestaciones ectodérmicas y mayor riesgo de cáncer. El diagnóstico molecular es clave. Objetivo. Identificar mutaciones en los genes PTPN11, SOS1,RAF1, BRAFy HRAS,y comparar las principales características clínicas en pacientes con confirmación molecular. Población y métodos. Se estudiaron niños con diagnóstico clínico de RASopatía evaluados entre agosto de 2013 y febrero de 2017. Resultados. Se identificaron mutaciones en el 71 % (87/122) de los pacientes. El estudio molecular confirmó el diagnóstico en el 73 % de los pacientes con síndrome de Noonan. La mutación más prevalente fue c.922A>G (p.Asn308Asp) en el gen PTPN11. Se detectó una variante no descrita en RAF1, c.1467G>C (p.Leu489Phe). Se confirmó el sindrome cardiofaciocutáneo en el 67 % de los casos con mutaciones en el gen BRAF. El síndrome de Costello y el síndrome de Noonan con múltiples lentigos se confirmaron en todos los casos. Conclusión. La confirmación del diagnóstico clínico permitió un diagnóstico diferencial más preciso. Se determinó la prevalencia de las mutaciones en PTPN11 (el 58 %), SOS1 (el 10 %) y RAF1 (el 5 %) en niños con síndrome de Noonan, en PTPN11 (el 100 %) en el sindrome de Noonan con múltiples lentigos, en BRAF (el 67 %) en el síndrome cardiofaciocutáneo y en HRAS (el 100 %) en el sindrome de Costello.

Introduction. RASopathies are a set of syndromes with phenotypic overlapping features caused by gene mutations involved in the RAS/MAPK pathway. They are autosomal dominantly inherited and share common clinical characteristics, including short stature, craniofacial dysmorphisms, congenital heart disease, ectodermal manifestations, and a higher risk for cancer. A molecular diagnosis is a key factor. Objective. To identify PTPN11, SOS1, RAF1, BRAF, and HRAS mutations and compare the main clinical characteristics of patients with molecular confirmation. Population and methods. Children with a clinical diagnosis of RASopathy assessed between August 2013 and February 2017. Results. Mutations were identified in 71 % (87/122) of patients. The molecular test confirmed diagnosis in 73 % of patients with Noonan syndrome. The most prevalent mutation was c.922A>G (p.Asn308Asp) in the PTPN11 gene. A previously undescribed variant in RAF1 was detected: c.1467G>C (p.Leu489Phe). Cardiofaciocutaneous syndrome was confirmed in 67 % of cases with BRAF mutations. Costello syndrome and Noonan syndrome with multiple lentigines were confirmed in all cases. Conclusion. The confirmation of clinical diagnosis allowed for a more accurate differential diagnosis. The prevalence of PTPN11 (58 %), SOS1 (10 % ), and RAF1 mutations (5 %) in children with Noonan syndrome, of PTPN11 mutations (100 %) in those with Noonan syndrome with multiple lentigines, of BRAF mutations (67 %) in those with cardiofaciocutaneous syndrome, and of HRAS mutations (100 %) in those with Costello syndrome was determined.

Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2 mouse model of HCM.

Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by ventricular hypertrophy, myofibrillar disarray, and fibrosis, and is primarily caused by mutations in sarcomeric genes. With no definitive cure for HCM, there is an urgent need for the development of novel preventive and reparative therapies. This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at Ser15-RLC phosphorylation site (S15D-RLC) into the hearts of humanized HCM-D166V mice. Improvement of heart function was monitored by echocardiography, invasive hemodynamics (PV-loops) and muscle contractile mechanics. A significant increase in cardiac output and stroke work and a decrease in relaxation constant, Tau, shown to be prolonged in HCM mice, were observed in AAV- vs. PBS-injected HCM mice. Strain analysis showed enhanced myocardial longitudinal shortening in AAV-treated vs. control mice. In addition, increased maximal contractile force was observed in skinned papillary muscles from AAV-injected HCM hearts. Our data suggest that myosin RLC phosphorylation may have important translational implications for the treatment of RLC mutations-induced HCM and possibly play a role in other disease settings accompanied by depressed Ser15-RLC phosphorylation. KEY MESSAGES: HCM-D166V mice show decreased RLC phosphorylation and decompensated function. AAV9-S15D-RLC gene therapy in HCM-D166V mice, but not in WT-RLC, results in improved heart performance. Global longitudinal strain analysis shows enhanced contractility in AAV vs controls. Increased systolic and diastolic function is paralleled by higher contractile force. Phosphomimic S15D-RLC has a therapeutic potential for HCM.

The False-negative Phenotype.

Ethical controversies may arise when genome sequencing reveals a genetic variant that is thought to be pathogenic, but the patient has no symptoms. This could be due to variable penetrance or expressivity. It could also result from a misclassification of the gene as pathogenic. In this article, I analyze 2 possibilities when such a situation occurs. The first is straightforward. We could conclude that the sequencing results should be considered a "false-positive" test result. The second is a bit more counterintuitive. In some cases, we could consider the test result to be a true-positive but in way that has not yet led to phenotypic findings. Somewhat playfully, we imagine that, in such cases, we could consider the patient's phenotype to be falsely negative. Sometimes, as odd as it seems, we act is if that is what we believe.

Qual o valor da cintilografia de perfusão e PET cardíaco na miocardiopatia hipertrófica / What is the value of perfusion scintigraphy and cardiac PET in hypertrophic cardiomyopathy

A miocardiopatia hipertrófica é a cardiopatia hereditária mais comum e acomete cerca de 1:500 indivíduos na população geral. O diagnóstico, que nem sempre é simples pela variação fenotípica e pela concomitância de outras patologias, baseia-se, inicialmente, em critérios eletrocardiográficos e ecocardiográficos, e na ausência de outras doenças que cursem com hipertrofia ventricular. Tendo como base celular o desarranjo miofibrilar e a fibrose com alterações hemodinâmicas decorrentes, a miocardiopatia hipertrófica pode revelar isquemia miocárdica (não relacionada à aterosclerose) e morte súbita. Assim, a avaliação da repercussão funcional por meio da cintilografia de perfusão miocárdica pela técnica Single Photon Emission Computed Tomography (SPECT) tem ganhado espaço, uma vez que 25% dos pacientes com miocardiopatia hipertrófica demonstram defeitos de perfusão fixos ou isquêmicos. Neste âmbito, notam-se alterações perfusionais que não estão necessariamente associadas ao tipo de miocardiopatia hipertrófica, mas conseguem predizer morbimortalidade nestes indivíduos. Outra técnica cintilográfica mais recente é a tomografia por emissão de pósitrons (PET), que se destaca na avaliação da microcirculação, na reserva de fluxo coronário e no metabolismo miocárdico. Em pacientes com miocardiopatia hipertrófica, estudos têm demonstrado resultados desfavoráveis quanto menores o fluxo sanguíneo miocárdico e a reserva de fluxo coronário. A avaliação miocárdica metabólica pela PET parece útil no entendimento fisiopatológico desta doença e na avaliação prognóstica da ablação alcoólica, procedimento realizado em formas obstrutivas graves. Assim, esta revisão aborda o papel da cardiologia nuclear pelas técnicas SPECT e PET miocárdico na avaliação diagnóstica, prognóstica e terapêutica da miocardiopatia hipertrófica

[Gene screening and phenotype analysis in a pedigree with familial hypertrophic cardiomyopathy from Yunnan Province].

Objective: To identify the disease-causing mutations in a pedigree with familial hypertrophic cardiomyopathy (HCM) from Yunnan province, and analyze the relationship between the genotype and the phenotype. Methods: The blood samples and the clinical data of the HCM family members were collected.The coding exons and their flanking intronic regions of 28 previously reported genes related to HCM were screened in the proband by high-throughput sequencing. The mutations in proband were confirmed and detected in all family members as well as in 159 healthy controls by Sanger sequencing.The relationship between the genotype and the phenotype was analyzed in this pedigree. Results: Two missense mutations of Arg1045His and Ala26Val in ß myosin heavy chain gene(MYH7) were identified. Genetic screening showed that the mother and brother of the proband carried Arg1045His mutation.Both mutations were absent in other family members and in 159 healthy controls.Disease onset age was less than 50 years old in this pedigree, chest pain, exertional dyspnea and syncope were the major symptoms, and all accompanied by severe left ventricular hypertrophy and left ventricular outflow tract stenosis.The grandma of the proband suffered sudden cardiac death. The proband had the worst symptoms and the earliest disease onset in this pedigree. Conclusions: We find a pedigree with familial HCM from Yunnan province carrying MYH7 Arg1045His and Ala26Val mutations. The study suggests that Arg1045His mutation in MYH7 gene caused HCM is malignant with early onset, severe ventricular hypertrophy and poor prognosis. Arg1045His and Ala26Val double-mutant might have dosage effects and aggravate the clinical phenotype of the patient.

Mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin.

We used transient biochemical and structural kinetics to elucidate the molecular mechanism of mavacamten, an allosteric cardiac myosin inhibitor and a prospective treatment for hypertrophic cardiomyopathy. We find that mavacamten stabilizes an autoinhibited state of two-headed cardiac myosin not found in the single-headed S1 myosin motor fragment. We determined this by measuring cardiac myosin actin-activated and actin-independent ATPase and single-ATP turnover kinetics. A two-headed myosin fragment exhibits distinct autoinhibited ATP turnover kinetics compared with a single-headed fragment. Mavacamten enhanced this autoinhibition. It also enhanced autoinhibition of ADP release. Furthermore, actin changes the structure of the autoinhibited state by forcing myosin lever-arm rotation. Mavacamten slows this rotation in two-headed myosin but does not prevent it. We conclude that cardiac myosin is regulated in solution by an interaction between its two heads and propose that mavacamten stabilizes this state.

Asn391Thr Mutation of ß-Myosin Heavy Chain in a Hypertrophic Cardiomyopathy Family.

The present study was performed to identify the genetic abnormalities in a family with familial hypertrophic cardiomyopathy.Peripheral blood samples were collected from 22 members of a Chinese family with hypertrophic cardiomyopathy and 307 healthy controls. A total of 26 candidate pathogenic genes were analyzed in the proband using targeted capture sequencing. Identified mutations were analyzed using Sanger sequencing in all family members and healthy controls.A missense mutation (c.1172A>C, p. Asn391Thr) in exon 12 of MYH7 was identified in eight family members, among which six of them were hypertrophic cardiomyopathy carriers. Three carriers presented with cardiac dysfunction. Four members of this pedigree died suddenly, three of whom were diagnosed with hypertrophic cardiomyopathy.From the results of this study, we concluded that the Asn391Thr mutation of MYH7 is a malignant mutation for HCM and that mutation carriers should get effective treatment to prevent sudden death.

Surgical pathology of subaortic septal myectomy: histology skips over clinical diagnosis.

BACKGROUND: Subaortic septal myectomy is usually performed to mitigate obstruction in patients with the obstructive form of hypertrophic cardiomyopathy (HCM) or in those with congenital subaortic stenosis. Moreover, it is combined with aortic valve replacement in patients with severe aortic valve stenosis (SAS) and asymmetrical septal hypertrophy causing concomitant left ventricular outflow tract obstruction. When both conditions coexist, it is conceptually difficult to identify a cardiomyopathy beyond an adaptive myocardial hypertrophy, strictly related to pressure overload. Myectomy histopathology might be useful to enlighten the cause of the obstruction and establish the diagnosis. AIM: The aim was to describe the pathological findings of surgical septal myectomy specimens obtained from a group of patients with diverse clinical diagnosis, including HCM, severe aortic stenosis, and asymmetrical septal hypertrophy. METHODS: This was a retrospective study of 56 patients undergoing septal myectomy along a 10-year period at a tertiary cardiac surgical center. Clinical, interventional, and anatomopathological findings between patients with and without a preoperative diagnosis of HCM were analyzed and compared. RESULTS: Mean age at intervention was 67.5±20.5 years; 37 (66.1%) were female Preoperative diagnosis of sarcomeric obstructive HCM was assumed in 23 (41.1%) patients. All the other patients (58.9%) were referred for surgery with preoperative diagnosis of asymmetric septal hypertrophy, mainly in the context of severe aortic stenosis (24 patients). Twenty-seven (48.2%) patients had a greater than 30 mmHg intraventricular gradient at rest. Patients with presumed HCM were significantly younger (56.5±15.8 vs. 70.2±13.3 years, P<.001), had higher prevalence of significant intraventricular obstruction at rest [20 (87.0%) vs. 8 (34.8%), P<.001], and more frequently had moderate or severe mitral regurgitation [9 (39.1%) vs. 5(15.1%), P=.043]. All patients with aortic valve stenosis underwent both aortic valve replacement and septal myectomy. Twelve (52.1%) of the patients with obstructive HCM had isolated septal myectomy, while in the remaining 11, the procedure was combined with intervention on the mitral valve. Histopathological final diagnosis was of nonspecific reactive myocardial hypertrophy in all but 4 (92.2%) patients. In those, 2 (3.6%) had the final diagnosis of HCM and 2 (3.6%) the diagnosis of congenital subaortic membranous stenosis with reactive myocardial hypertrophy. Different grades of subendocardial fibroelastosis and myocardial fibrosis, mainly interstitial, were present [27 (48.2%) and 18 (32%) patients, respectively]. When microscopic data were compared between patients with or without a preoperative clinical diagnosis of HCM, no significant differences were found. CONCLUSION: In patients submitted to surgical septal myectomy, histology was mostly indistinctive among different clinical entities. Since different myocardial hypertrophy etiologies may share similar pathological expression, there is a need for detailed clinical assessment when trying to define the best strategy for clinical management.