Hypertrophic cardiomyopathy: Sudden cardiac death risk stratification in adults

Jordà, Paloma; García‐Álvarez, Ana

doi:10.21542/gcsp.2018.25

Cited by 18 publications

(29 citation statements)

References 57 publications

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“…Hypertrophic cardiomyopathy (HCM) is one of the most prevalent genetic diseases of the heart, affecting over 1 in 200 individuals [1, 2], and is a leading cause of sudden cardiac death [3]. HCM is characterized by cardiomyocyte hypertrophy, myofibril disarray, hypercontractility, and diastolic dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Hypertrophic cardiomyopathy ß-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state

Roest

Liu

Morck

et al. 2020

Preprint

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Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1000 mutations, many in β-cardiac myosin (MYH7). Molecular studies of myosin with different HCM mutations have revealed a diversity of effects on ATPase and load-sensitive rate of detachment from actin. It has been difficult to predict how such diverse molecular effects combine to influence forces at the cellular level and further influence cellular phenotypes. This study focused on the P710R mutation that dramatically decreases in vitro motility and actin-activated ATPase, in contrast to other MYH7 mutations. Optical trap measurements of single myosin molecules revealed that this mutation reduced the step size of the myosin motor and the load-sensitivity of the actin detachment rate. Conversely, this mutation destabilized the super-relaxed state in larger, two-headed myosin constructs, freeing more heads to generate force. Micropatterned hiPSC-cardiomyocytes CRISPR-edited with the P710R mutation produced significantly increased force (measured by traction force microscopy) compared with isogenic control cells. The P710R mutation also caused cardiomyocyte hypertrophy and cytoskeletal remodeling, as measured by immunostaining and electron microscopy. Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt. Finally, we used a computational model that integrates measured molecular changes to demonstrate that closely predict the measured traction forces. These results confirm a key role for regulation of the super-relaxed state in driving hypercontractility in HCM and demonstrate the value of a multiscale approach in revealing key mechanisms of disease.Significance StatementHeart disease is the leading cause of death world wide, and hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, affecting over 1 in 200 people. Mutations in myosin, the motor protein responsible for contraction of the heart, are a common cause of HCM but have diverse effects on the biomechanics of the myosin protein that can make it difficult to predict the combined effects of each mutation. We demonstrate that complex biomechanical effects of mutations associated with heart disease can be effectively studied and understood using a multi-scale experimental and computational modeling approach. This work can be extended to aid in the development of new targeted therapies for patients with different mutations.

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Section: Introductionmentioning

confidence: 99%

Hypertrophic cardiomyopathy ß-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state

Roest

Liu

Morck

et al. 2020

Preprint

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“…However, as the number of sequenced genes increases, variant analysis becomes difficult, so firstly, candidate genes with a high mutation detection rate can be searched. It is known that 53-85% of HCM is caused by pathogenic variants in the MYH7, MYBPC3 and TNNT2 genes (2,3,11). The molecular diagnosis rate of this study was 66%, as in the expected range.…”

Section: Discussionmentioning

confidence: 48%

“…The autosomal dominant inherited HCM is a complex disease that is characterized by an heterogenous clinical and genetic expression. It is caused primarily by missense mutations, although causative nonsense, frame-shift, and in-frame insertion/deletion mutations have also been observed, particularly in sarcomeric genes (3,17). As a matter of fact, we have identified missense pathogenic variants in this study.…”

Section: Discussionmentioning

confidence: 76%

“…In our study, the pathogenic variants were not detected in 4 of 12 patients with familial HCM, possibly because disease-causing variants can be found in other HCM-associated genes. In NGS studies applied in recent years, it has been determined that pathogenic variants in both the exonic and intronic regions of more than 40 candidate genes were found to cause the HCM phenotype (3,(8)(9)(10). The use of next generation sequencing for the diagnosis of multigenic diseases such as HCM appears to be advantageous to identify all variants.…”

Section: Discussionmentioning

confidence: 99%

“…Although, in recent times, more than 40 genes have been identified in HCM patients by new genetic sequencing (NGS) (8,10), HCM is mostly due to pathogenic single nucleotide variants (SNVs) (53-85%) in the MYH7 gene encoding cardiac ß-myosin heavy chain (ß-MyHC), the MYBPC3 gene encoding cardiac myosin binding protein-C (cMyBP-C) and the TNNT2 gene encoding cardiac troponin T (cTnT) (2,3,11).…”

Section: Introductionmentioning

confidence: 99%

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Contribution of Sarcomeric Gene Variants to the Prediction of Sudden Cardiac Death Risk in Familial Hypertrophic Cardiomyopathy

Kömürcü-Bayrak¹,

Geyik²,

Kahveci³

et al. 2020

J Istanb Fac Med

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Amaç: Hipertrofik kardiyomiyopati (HKM), ani kardiyak ölümün (AKÖ) nedenlerinden biridir. Bu çalışmada, HKM'de en sık mutasyon bulunan üç sarkomerik gende, AKÖ için yüksek riskli patojenik varyantların belirlenmesi amaçlandı. Gereç ve Yöntem: Çalışmaya, AKÖ ve/veya HKM için aile öyküsü olan 12 yetişkin HKM'li indeks vaka ve 31 aile üyesi dahil edildi. Tüm katılımcılar, kardiyolojik olarak değerlendirildi. MYH7, MYBPC3 ve TNNT2 genlerinin ekzonik bölgeleri, CorTAG HCM1 dizileme sistemi kullanılarak analiz edildi. Bulgular: HKM'li indeks vakaların 8'inde, amino asit değişimine neden olan 6 farklı patojenik varyant bulundu. Bunlardan beşinin, MYH7 genindeki Val698Ala, Arg719Trp, Met822Leu ve Arg-663Cys (üç vakada) ve TNNT2 genindeki Arg102Trp değişimlerinin daha önce tanımlanmış yanlış anlamlı patojenik varyantlar olduğu belirlendi. İleri yaşta AKÖ öyküsü olan bir HKM ailesinde, MYBPC3 geninde Tyr525Asn ve c.*27-21G>A varyantlar bileşik heterozigot olarak ilk defa tanımlandı. Bu varyantlar, Türk popülasyonu kontrol örneklerinde (n=777) saptanmadı. Sonuç: Bu çalışmada, AKÖ öyküsü olan bir HKM ailesinde yeni varyantlar tanımlandı. Ancak, HKM ailelerinde saptanan patojenik varyantlar ile AKÖ riski arasında net bir ilişki bulunamadı.

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Comparing long‐term outcomes of septal myectomy and mitral valve replacement in hypertrophic cardiomyopathy patients: A retrospective cohort study in Iran

Ayati,

Khoshfetrat,

Davoodi

et al. 2024

Health Science Reports

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BackgroundHypertrophic cardiomyopathy (HCM) affects millions of individuals worldwide. In severe cases, it can cause life‐threatening conditions such as left ventricular outflow tract (LVOT) obstruction, mitral regurgitation (MR), and sudden cardiac death, making surgical treatment necessary. This study aimed to report the long‐term outcomes of HCM patients undergoing septal myectomy or mitral valve replacement (MVR) and compare the results between different types of surgeries.MethodsThis was a retrospective cohort study on HCM patients who underwent surgical treatment in an Iranian referral center between 2005 and 2021. Patients were divided into three groups according to the type of surgery received: septal myectomy, MVR, or a combination of both surgeries. Patient characteristics, surgical and echocardiographic features, and in‐hospital and long‐term outcomes were reported and compared between the three groups.ResultsA total of 102 patients with an average age of 53.3 ± 16.9 were included. Twenty‐six patients had septal myectomy, 23 had MVR, and 53 had combined septal myectomy and MVR surgery. All surgeries were associated with a significant reduction in interventricular septum thickness and LVOT gradients. After a median of 6.8‐year follow‐up time, patients with an isolated septal myectomy had significantly lower mortality and major adverse cardiac and cerebrovascular events rates than the other groups.ConclusionIsolated septal myectomy showed better long‐term survival rates and can correct HCM‐related MR, while MVR should be preserved only for intrinsic valve defects. More extensive studies are needed to confirm these findings and achieve a comprehensive guideline on surgical treatment of HCM.

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Hypertrophic cardiomyopathy: Sudden cardiac death risk stratification in adults

Cited by 18 publications

References 57 publications

Hypertrophic cardiomyopathy ß-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state

Hypertrophic cardiomyopathy ß-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super-relaxed state

Contribution of Sarcomeric Gene Variants to the Prediction of Sudden Cardiac Death Risk in Familial Hypertrophic Cardiomyopathy

Comparing long‐term outcomes of septal myectomy and mitral valve replacement in hypertrophic cardiomyopathy patients: A retrospective cohort study in Iran

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