Hypertrophic Cardiomyopathy: An Overview of Genetics and Management

Hypertrophic cardiomyopathy (HCM) is a genetically heterogeneous cardiac muscle disorder with a diverse natural history, characterized by unexplained left ventricular hypertrophy (LVH), with histopathological hallmarks including myocyte enlargement, myocyte disarray and myocardial fibrosis. Although these features can cause significant cardiac symptoms, many young individuals with HCM are asymptomatic or mildly symptomatic. Sudden cardiac death (SCD) may occur as the initial clinical manifestation. Over the past few decades, HCM has been considered a disease of sarcomere, and typically as an autosomal dominant disease with variable expressivity and incomplete penetrance. Important insights into the genetic landscape of HCM have enhanced our understanding of the molecular pathogenesis, empowered gene-based diagnostic testing to identify at-risk individuals, and offered potential targets for the development of therapeutic agents. This article reviews the current knowledge on the clinical genetics and management of HCM.

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Novel Aspects of Classification, Prognosis and Therapy in Takotsubo Syndrome

European Cardiology Review ◽

10.15420/ecr.2019.27.3 ◽

2019 ◽

Vol 14 (3) ◽

pp. 191-196

Author(s):

Chiara Di Filippo ◽

Beatrice Bacchi ◽

Carlo Di Mario

Keyword(s):

Acute Phase ◽

Current Knowledge ◽

Ventricular Outflow Tract ◽

Left Ventricular ◽

Takotsubo Syndrome ◽

Coronary Syndrome ◽

Cardiac Symptoms ◽

Left Ventricular Outflow ◽

Life Threatening ◽

Physiological Abnormalities

Takotsubo syndrome (TTS) can be considered a transient form of acute heart failure that mimics an acute coronary syndrome. Although many hypotheses have been formulated, the precise physiopathology of TTS remains unknown. TTS is associated with a heterogeneous clinical course, which ranges from benign to poor outcome, comprising life-threatening phenotypes. In the acute phase, TTS patients may experience complications including left ventricular outflow tract obstruction, cardiogenic shock, arrhythmias and thromboembolic events. Furthermore, after the acute episode, physiological abnormalities can persist and some patients continue to suffer cardiac symptoms. To recognise patients at higher risk earlier, many variables have been proposed and risk stratifications suggested. There is no solid evidence regarding specific therapy and the proper management of TTS patients, either in the acute phase or long term. This review describes the current knowledge regarding diagnostic criteria, prognosis and therapy in TTS.

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Heritability and Pedigree Analyses of Hypertrophic Cardiomyopathy in Rhesus Macaques (Macaca Mulatta)

Frontiers in Veterinary Science ◽

10.3389/fvets.2021.540493 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yu Ueda ◽

Samantha Kovacs ◽

Rachel Reader ◽

Jeffrey A. Roberts ◽

Joshua A. Stern

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Rhesus Macaques ◽

Phenotypic Expression ◽

Pedigree Analysis ◽

Left Ventricular ◽

Incomplete Penetrance ◽

Recessive Trait ◽

Primate Research ◽

Pedigree Data ◽

Mode Of Inheritance

In a colony of rhesus macaques at California National Primate Research Center (CNPRC), naturally occurring hypertrophic cardiomyopathy (HCM) classified by left ventricular hypertrophy without obvious underlying diseases has been identified during necropsy over the last two decades. A preliminary pedigree analysis suggested a strong genetic predisposition of this disease with a founder effect. However, the mode of inheritance was undetermined due to insufficient pedigree data. Since 2015, antemortem examination using echocardiographic examination as well as other cardiovascular analyses have been performed on large numbers of rhesus macaques at the colony. Based on antemortem examination, HCM was diagnosed in additional 65 rhesus macaques. Using HCM cases diagnosed based on antemortem and postmortem examinations, the heritability (h2) was estimated to determine the degree of genetic and environmental contributions to the development of HCM in rhesus macaques at the CNPRC. The calculated mean and median heritability (h2) of HCM in this colony of rhesus macaques were 0.5 and 0.51 (95% confidence interval; 0.14–0.82), respectively. This suggests genetics influence development of HCM in the colony of rhesus macaques. However, post-translational modifications and environmental factors are also likely to contribute the variability of phenotypic expression. Based on the pedigree analysis, an autosomal recessive trait was suspected, but an autosomal dominant mode of inheritance with incomplete penetrance was also possible. Further investigation with more data from siblings, offspring, and parents of HCM-affected rhesus macaques are warranted. Importantly, the findings of the present study support conducting genetic investigations such as whole genome sequencing to identify the causative variants of inherited HCM in rhesus macaques.

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P890Gene carriers of hypertrophic cardiomyopathy, what to expect over time

European Heart Journal ◽

10.1093/eurheartj/ehz747.0487 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

P Poveda Velazquez ◽

J Basu ◽

T Homfray ◽

M Papadakis ◽

E Behr ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Family History ◽

Age Groups ◽

Gene Mutations ◽

Left Ventricular ◽

Cascade Screening ◽

Cardiac Symptoms ◽

History Of ◽

Mybpc3 Gene

Abstract Background Data on the natural history of genotype positive/phenotype negative (G+/P-) hypertrophic cardiomyopathy (HCM) patients identified as a part of genetic cascade screening in different age groups is limited. Purpose To describe the rate of conversion to overt HCM phenotype in G+/P- subjects in relation with the age who were identified in a specialized clinic in a single center. Methods We retrospectively identified 56 consecutive HCM G+/P− subjects followed in our center specialized clinic between Jan 2012-Jan 2019. Demographics, family history of sudden cardiac death (SCD) and presence of symptoms were collected. All of them underwent baseline investigations including ECG, echocardiogram and/or cardiac magnetic resonance (CMR) and 24 hour monitor at baseline and during follow up. Overt HCM phenotype was defined as left ventricular hypertrophy (LVH) ≥13mm in the echocardiogram or CMR. Results We identified 56 HCM G+/P− subjects from 34 different families. 22 subjects were ≤18 years old with a mean age of 11.6±0.9 years (IQR [P25-P75] 9–16 years) and 32 subjects were >18 years old with a mean age of 38.1±2.2 years (IQR [P25-P75] 27–48 years). Mean time of follow up was 35.2±34.4 months (IQR [P25-P75] 4.25–50.25 years). 60.7% (34) of them were female and 82.1% (46) were of Caucasian ethnicity. Most of the subjects with no evidence LVH were asymptomatic but small number had symptoms, 8.9% (5), and 3.6% (2) were treated with betablockers for palpitations. Family history of SCD was present in 57.1% (32) of the subjects and 35.7% (20) had a relative with an implantable cardiac defibrillator (ICD). MYBPC3 gene mutations were identified in 62.5% (35) of subjects, followed by MYH7 gene mutation in 23.2% (13) of the cases. None of the subjects under 18 year old developed HCM during the period of observation, however 7 subjects (21.9%), mean age 48.6±10.5 years, 71.4% (5) females, showed progression to HCM in the >18 years old group. All of them had pathogenic MYBPC3 gene variants. No differences were found in gender, ethnicity, symptoms or family history of SCD in the G+/P− vs HCM group. There were no differences on the presence of ECG abnormalities and no episodes of NSVT were recorded in any of the groups. Baseline E/e' values of those with new HCM vs G+/P− were higher (8.2±3.3 vs 5.6±1.7, p=0.014). Conclusions In our cohort, rate of progression to HCM phenotype was 21.9% of >18 years old HCM G+/P- subjects. The mean age at the time of developing the phenotype was 48.6±10.5 years old and all the patients were asymptomatic for cardiac symptoms. Echocardiographic E/e' values were increased. This data supports the need of life long follow up of this group of patients with ongoing clinical evaluation. Acknowledgement/Funding ESC clinical grant

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Apical hypertrophic cardiomyopathy associated with circumflex to left ventricular fistulae: a case report of two rare subtypes of rare conditions occurring together

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytaa552 ◽

2021 ◽

Vol 5 (2) ◽

Author(s):

Samuel Conway ◽

Anna S Herrey ◽

Roby D Rakhit

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Systolic Function ◽

Beta Blockers ◽

Left Ventricular ◽

Wave Inversion ◽

Cardiac Symptoms ◽

Coronary Steal ◽

Artery Disease ◽

Apical Hypertrophy ◽

Cavity Obliteration

Abstract Background Coronary arterial fistulae are rare yet have been associated with hypertrophic cardiomyopathy (HCM). We present a patient who was found to have a left circumflex (LCx) to left ventricular (LV) fistula in combination with apical HCM. Case summary A 72-year-old female presented with syncope after exercise. She sustained facial injuries including fracture of her nasal bones. There were no previous episodes, no cardiac history, and she denied chest pain or anginal symptoms. Electrocardiogram showed sinus rhythm with T-wave inversion throughout the chest leads. Echocardiography suggested apical HCM with hypertrophy of the LV apex but good systolic function. This was confirmed on cardiac magnetic resonance imaging with a characteristically spade-shaped LV cavity. Coronary angiography demonstrated a distal LCx to LV fistula from the apical hypertrophy but no coronary artery disease. She was started on beta-blockers and has had no further episodes, remaining well. Discussion Coronary fistulae are present in 0.002% of the population but clinical outcomes are poorly understood. The majority are asymptomatic but anginal chest pains can occur through the ‘coronary steal’ phenomenon. Apical HCM is a subtype of HCM characterized by spade-shaped LV cavity obliteration. It is unclear whether the association between fistulae and HCM occur because of the increased vascularization and fibrosis associated with HCM or whether congenital malformation leads to hypertrophy. Both can produce a constellation of cardiac symptoms. Our patient has the previously unreported combination of apical HCM and an LCx fistula; two rarer subtypes of rare conditions appearing together.

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Left Ventricular Remodeling in Hypertrophic Cardiomyopathy: An Overview of Current Knowledge

Journal of Clinical Medicine ◽

10.3390/jcm10081547 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1547

Author(s):

Beatrice Musumeci ◽

Giacomo Tini ◽

Domitilla Russo ◽

Matteo Sclafani ◽

Francesco Cava ◽

...

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Ventricular Remodeling ◽

Current Knowledge ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Lv Remodeling ◽

Definition Of ◽

And Function ◽

Specific Impact ◽

Pathophysiologic Mechanisms

While most patients with hypertrophic cardiomyopathy (HCM) show a relatively stable morphologic and clinical phenotype, in some others, progressive changes in the left ventricular (LV) wall thickness, cavity size, and function, defined, overall, as “LV remodeling”, may occur. The interplay of multiple pathophysiologic mechanisms, from genetic background to myocardial ischemia and fibrosis, is implicated in this process. Different patterns of LV remodeling have been recognized and are associated with a specific impact on the clinical course and management of the disease. These findings underline the need for and the importance of serial multimodal clinical and instrumental evaluations to identify and further characterize the LV remodeling phenomenon. A more complete definition of the stages of the disease may present a chance to improve the management of HCM patients.

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An overview of the current genetic and phenotypical selection strategies to reduce the prevalence of feline hypertrophic cardiomyopathy

Vlaams Diergeneeskundig Tijdschrift ◽

10.21825/vdt.v89i2.16355 ◽

2020 ◽

Vol 89 (2) ◽

pp. 69-80

Author(s):

T. Schipper ◽

L. J. Peelman ◽

P. Smets ◽

B. J. G. Broeckx

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Ventricular Hypertrophy ◽

Negative Impact ◽

Left Ventricular ◽

The Other ◽

Incomplete Penetrance ◽

Optimal Selection ◽

Selection Strategies ◽

High Prevalence ◽

Stringent Selection

Hypertrophic cardiomyopathy (HCM) is a common and potentially lethal heart disease in cats. To reduce its prevalence, breeding cats are frequently screened on the basis of their phenotype or genotype. Although echocardiography is the most reliable phenotypical method, its efficacy is limited by the incomplete penetrance of HCM and by difficulties in distinguishing primary HCM from other causes of left ventricular hypertrophy. On the other hand, genetic testing is hampered by the genetic heterogeneity of the disease. Genetic tests are currently only available for Maine Coons and Ragdolls. Because of the high prevalence of HCM, stringent selection may have a negative impact on the genetic diversity of a breed. A more optimal selection would therefore be a slow and careful exclusion of phenotypically and/or genetically positive cats.

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Diagnostic testing for SARS-CoV-2 infection in HHT patients: nasopharyngeal versus oropharyngeal swab

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01628-w ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Fabio Pagella ◽

Roberta Lizzio ◽

Sara Ugolini ◽

Giuseppe Spinozzi ◽

Eugenia Maiorano ◽

...

Keyword(s):

Current Knowledge ◽

Diagnostic Testing ◽

Nasopharyngeal Swab ◽

Global Pandemic ◽

Recurrent Epistaxis ◽

Rapid Spread ◽

Dominant Disease ◽

History Of ◽

Oropharyngeal Swab ◽

Novel Coronavirus

AbstractOn March 11, 2020, WHO has defined the novel coronavirus disease SARS-CoV-2 (COVID-19) outbreak as a pandemic that still today continues to affect much of the world. Among the reasons for the rapid spread of SARS-CoV-2 infection, there is the role of asymptomatic or minimally symptomatic carriers. Therefore diagnostic testing is central to contain the global pandemic. Up to now real-time reverse transcriptase polymerase chain reaction-based molecular assays for detecting SARS-CoV-2 in respiratory specimens is the current reference standard for COVID-19 diagnosis. Based on current knowledge regarding the sensitivity of the molecular test, the highest positive detection rate is from lower respiratory tract specimens; alternatively it is possible to perform a nasopharyngeal or oropharyngeal swab. Nasopharyngeal swab is the preferred choice for SARS-CoV-2 testing since it seems to have a greater sensitivity; however the procedure is not always free of complications and an epistaxis can occur. Among patients with greatest risk of massive nosebleed there are HHT patients. Hereditary hemorrhagic telangiectasia is an autosomal dominant disease that leads to multiregional mucocutanous telangiectases and visceral arteriovenous malformations. Clinically, the presence of telangiectases in nasal mucosa is the cause of recurrent epistaxis. In HHT patients the execution of the nasopharyngeal swab can determine from little or no consequences to a massive epistaxis leading to the necessity of nasal packing generally followed by hospital admission. In HHT patients undergoing a diagnostic test to evaluate the SARS-CoV-2 infection status, especially in those patients with frequent epistaxis with a history of anemia and repeated hospitalizations, it is therefore advisable to perform an oropharyngeal swab. This, compared to the nasopharyngeal swab, exposes to a lower risk of severe nosebleeds related treatments, such as blood transfusions or invasive procedures. According to the risk-benefit assessment and based on our experience, we consider that, despite a lower diagnostic sensitivity, oropharyngeal swab is preferable to nasopharyngeal swab for the diagnosis of SARS CoV-2 infection in patients with HHT.

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MicroRNAs Based Therapy of Hypertrophic Cardiomyopathy: The Road Traveled So Far

BioMed Research International ◽

10.1155/2015/983290 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Catarina Roma-Rodrigues ◽

Luís R. Raposo ◽

Alexandra R. Fernandes

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Posttranslational Modifications ◽

Current Knowledge ◽

Heart Diseases ◽

Mirna Expression Profile ◽

The Road ◽

Small Noncoding Rnas ◽

Diagnosis And Prognosis ◽

Dominant Disease ◽

The Stability

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by variable expressivity, age penetrance, and a high heterogeneity. The transcriptional profile (miRNAs, mRNAs), epigenetic modifications, and posttranslational modifications seem to be highly relevant for the onset of the disease. miRNAs, small noncoding RNAs with 22 nucleotides, have been implicated in the regulation of cardiomyocyte function, being differentially expressed in several heart diseases, including HCM. Moreover, a different miRNA expression profile in the various stages of HCM development is also observed. This review summarizes the current knowledge of the profile of miRNAs characteristic of asymptomatic to overt HCM patients, discussing alongside their potential use for diagnosis and therapy. Indeed, the stability and specificity of miRNAs make them suitable targets for use as biomarkers for diagnosis and prognosis and as therapeutical targets.

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Quantifying the contribution of recessive coding variation to developmental disorders

10.1101/201533 ◽

2017 ◽

Cited By ~ 2

Author(s):

Hilary C. Martin ◽

Wendy D. Jones ◽

James Stephenson ◽

Juliet Handsaker ◽

Giuseppe Gallone ◽

...

Keyword(s):

Developmental Disorders ◽

Disease Gene ◽

De Novo ◽

European Ancestry ◽

Compound Heterozygous ◽

Clinical Genetics ◽

Incomplete Penetrance ◽

Loss Of Function ◽

Dominant Disease ◽

Coding Variants

Large exome-sequencing datasets offer an unprecedented opportunity to understand the genetic architecture of rare diseases, informing clinical genetics counseling and optimal study designs for disease gene identification. We analyzed 7,448 exome-sequenced families from the Deciphering Developmental Disorders study, and, for the first time, estimated the causal contribution of recessive coding variation exome-wide. We found that the proportion of cases attributable to recessive coding variants is surprisingly low in patients of European ancestry, at only 3.6%, versus 50% of cases explained by de novo coding mutations. Surprisingly, we found that, even in European probands with affected siblings, recessive coding variants are only likely to explain ~12% of cases. In contrast, they account for 31% of probands with Pakistani ancestry due to elevated autozygosity. We tested every gene for an excess of damaging homozygous or compound heterozygous genotypes and found three genes that passed stringent Bonferroni correction: EIF3F, KDM5B, and THOC6. EIF3F is a novel disease gene, and KDM5B has previously been reported as a dominant disease gene. KDM5B appears to follow a complex mode of inheritance, in which heterozygous loss-of-function variants (LoFs) show incomplete penetrance and biallelic LoFs are fully penetrant. Our results suggest that a large proportion of undiagnosed developmental disorders remain to be explained by other factors, such as noncoding variants and polygenic risk.

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Hypertrophic obstructive cardiomyopathy and its outcome following surgical myectomy: a retrospective study

International Surgery Journal ◽

10.18203/2349-2902.isj20200563 ◽

2020 ◽

Vol 7 (3) ◽

pp. 655

Author(s):

Vedanth Gopalan ◽

Pavaneel Bhandari ◽

Anant A. Takalkar

Keyword(s):

Hypertrophic Cardiomyopathy ◽

Valve Replacement ◽

Artery Bypass ◽

Ventricular Outflow Tract ◽

Hypertrophic Obstructive Cardiomyopathy ◽

Left Ventricular ◽

Female Ratio ◽

Septal Myectomy ◽

Cardiac Symptoms ◽

Left Ventricular Outflow

Background: Hypertrophic cardiomyopathy is highly heterogeneous with a diverse anatomy, pathophysiology, and clinical course. It is obstruction to left ventricular outflow that has become the major hallmark of the disease. Septal myectomy has been the gold standard treatment for the relief of left ventricular outflow tract obstruction and cardiac symptoms in both adults and children with obstructive hypertrophic cardiomyopathy. Objective of the study was to evaluate effect of Myomectomy and its impact on survival for a period of one year.Methods: The study design is a retrospective record based observational study. Data was retrieved from previous records both electronic as well as manual records of all the patients who underwent myectomy with or without concomitant procedures such as mitral valve replacement or aortic valve replacement or coronary artery bypass surgery during 2014 to 2018.Results: Majority of the patients 11 (52.4%) in fourth decade i.e. 40-59 years age group. majority were males i.e. 16 (76.2%) and remaining 5 i.e. 23.8% were females. Male to female ratio was 3.2:1. Dyspnoea was present 81% and chest pain in 76.2%. Preoperative LVOT gradient was 86.86±20.33 and post-operative gradient was 23.47±20.49.Conclusions: Operative techniques have evolved from simple myotomy to the present method of extended septal myectomy which can be done in all adult cases of hypertrophic obstructive cardiomyopathy.

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