Echocardiography-Guided Genetic Testing in Hypertrophic Cardiomyopathy: Septal Morphological Features Predict the Presence of Myofilament Mutations

doi:10.4065/81.4.459

Mayo Clinic Proceedings

Volume 81, Issue 4, April 2006, Pages 459-467

https://doi.org/10.4065/81.4.459 Get rights and content

OBJECTIVE

To examine the relationship among age, septal morphological subtype, and presence of hypertrophic cardiomyopathy (HCM)-associated myofilament mutations.

PATIENTS AND METHODS

Comprehensive mutation analysis of the 8 HCM susceptibility genes that encode the myofilaments of the cardiac sarcomere was performed previously in 382 unrelated patients with HCM. Blinded to genotype status, we used echocardiography to characterize the left ventricular morphological features. Multivariate regression was used to assess the relationship among morphological subtypes, clinical data, and genetic variables.

RESULTS

The mean ± SD age of the patients was 41.6±19.0 years, with 126 patients 50 years or older at initial diagnosis. The septal morphological subtype was sigmoid in 181 (47%), reverse in 132 (35%), apical variant in 37 (10%), and neutral in 32 (8%). The HCM-associated myofilament mutations were identified in 143 patients (37%). Multivariate analysis showed that the reverse curvature septal morphological subtype was a strong predictor of genotype-positive status (odds ratio, 21; P<.001). Overall, the yield of HCM genetic testing was 79% in the setting of reverse curvature HCM but only 8% in sigmoid septal HCM.

CONCLUSION

In stark contrast to HCM in young patients, elderly patients with HCM display a predominantly sigmoid septal morphological subtype and uncommonly have perturbations of known HCM susceptibility genes. Independent of age, septal morphological subtype strongly predicts the presence or absence of HCM-associated myofilament mutations and may enable echocardiography-guided genetic testing for HCM.

Section snippets

PATIENTS AND METHODS

Written informed consent was obtained in accordance with a Mayo Foundation Institutional Review Board-approved protocol, and blood samples were obtained from 388 consecutively enrolled, unrelated patients evaluated at the Mayo Clinic's HCM Clinic in Rochester, Minn, between April 1997 and December 2001. The diagnosis of HCM was based on the echocardiographic demonstration of left ventricular (LV) hypertrophy in the absence of other disease processes known to promote hypertrophy.

Results from

Overall

Table 1 gives the baseline characteristics of the 382 unrelated patients with HCM analyzed in this study. The mean ± SD age was 41.6±19.0 years, with 126 patients 50 years or older at the time of initial diagnosis. The septal morphological subtype was classified as sigmoid septum in 181 patients (47%), reverse septal curvature in 132 patients (35%), apical variant in 37 patients (10%), and neutral contour in 32 patients (8%). Previous genetic testing established HCM-associated mutations that

DISCUSSION

The distribution of hypertrophy and distortion of septal anatomy is different among patients with a clinical diagnosis of HCM made later in life compared with younger patients.5, 6, 7, 8 These observations have generated widespread interest in regard to the pathophysiology, natural history, and pathogenic mechanisms of HCM in different age groups.5, 9 Indeed, this study demonstrates that the frequency of mutations among the 8 HCM-associated myofilament genes is much less common among older vs

CONCLUSION

We report that the presence or absence of HCM susceptibility mutations that involve the cardiac myofilaments, rather than age, is the principal determinant of septal morphological subtype and that the assessment of the septal contour may facilitate strategic genotyping. As shown herein, the yield of screening for mutations in these 8 HCM-associated genes approaches 80% in the setting of reverse curvature HCM but is less than 10% when the septal contour is sigmoidal. Furthermore, the genetic,

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A case of syncope after exertion due to sigmoid septum evaluated by exercise stress echocardiography
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A sigmoid septum is associated with sharp angulation and aging of the aortic root; however, it does not affect the pressure gradient in the left ventricular outflow tract and is generally asymptomatic. This report describes a 73-year-old woman who presented with syncope after exertion. Echocardiography revealed that the cause was left ventricular outflow tract stenosis associated with a sigmoid septum; her symptoms improved with beta-blocker therapy. Exercise stress echocardiography was performed to determine treatment efficacy. Sigmoid septum causes syncope on exertion; however, drug therapy is effective. Exercise stress echocardiography is effective in determining treatment efficacy. If syncope is present, a sigmoid septum should be considered as a cause.
- 1.
  A sigmoid septum is part of or resembles hypertrophic cardiomyopathy, resulting in left ventricular outflow tract (LVOT) stenosis that is exacerbated by exertion and may cause syncope.
- 2.
  A sigmoid septum is a differential diagnosis for the cause of syncope and is diagnosed using cardiac echocardiography.
- 3.
  LVOT stenosis due to a sigmoid septum can be improved with drug therapy such as beta-blockers.
- 4.
  The effects of beta-blocker therapy can be determined by exercise stress echocardiography.
Reversed Septal Curvature Is Associated With Nonsustained Ventricular Tachycardia in Hypertrophic Cardiomyopathy
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Sudden cardiac death (SCD) is associated with nonsustained ventricular tachycardia (NSVT) in patients with hypertrophic cardiomyopathy (HCM). Recently, differences regarding septal morphology have been reported, with an increased probability of sudden death in patients with HCM who had reverse septal curvature (RSC). This study aimed to examine the relation between RSC and NSVT in HCM. A total of 138 patients with HCM were enrolled. Of 138 patients, 47 (34.1%) were diagnosed with RSC and 42 patients (30.4%) had NSVT. Compared with the non-RSC group, those with RSC were much younger and had an increased incidence of NSVT, thicker septal thickness, larger mass, and a higher proportion of HCM or SCD family history. Furthermore, patients with RSC had a higher risk of SCD according to the European Society of Cardiology calculator (2.5 [1.6 to 4.6] vs 1.6 [1.1 to 2.3] [%/5 years], p <0.001). The multivariate analysis showed that RSC was a strong and independent risk factor for NSVT (odds ratio 2.756, 95% confidence interval 1.164 to 6.525, p = 0.021). In conclusion, the presence of RSC in patients with HCM is independently associated with NSVT. Further studies are needed to evaluate the role of RSC as a risk factor for SCD in this population.
Ethnic and sex-related differences at presentation in apical hypertrophic cardiomyopathy: An observational cross-sectional study
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We investigated whether ethnicity and sex are associated with different clinical presentations and cardiovascular magnetic resonance (CMR) findings in individuals with apical hypertrophic cardiomyopathy (ApHCM).
A retrospective observational cohort study of consecutive ApHCM patients from a large tertiary referral center in the United Kingdom (UK). Demographic, clinical, 12‑lead electrocardiogram (ECG) and CMR findings were collected. Participants presented in our clinics between 2010 and 2020. ‘Pure’ ApHCM was defined as isolated apical hypertrophy and ‘mixed’ with both apical and septal hypertrophy but with the apical segments of a greater wall thickness. Deep T-wave inversion was defined as ≥5 mm in any electrocardiogram lead.
A total of 150 consecutive ApHCM patients (75% men, 25% women; 37% White, 25% Black, 24% Asian and 15% of Mixed/Other ethnicity) were included. Females were diagnosed at an older age compared to men, had less prominent ECG changes, had higher left atrial area index, and were more hypertensive. Black patients had higher left ventricular mass index, more hypertension, and more of the ‘mixed’ type of ApHCM. The majority of hypertensive male patients showed the ‘mixed’ phenotype.
Individuals of Black ethnicity and hypertensive male patients are more likely to present with mixed apical and basal hypertrophy, whereas White, Asian and non-hypertensive male patients tend to have hypertrophy limited to the apex. Females present at an older age and are less likely to have deep T wave inversion on ECG.
First-in-Human Transapical Beating-Heart Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy
2023, Journal of the American College of Cardiology
To simplify surgical septal reduction therapy for hypertrophic obstructive cardiomyopathy (HOCM), we developed a novel transapical beating-heart septal myectomy (TA-BSM) procedure.
In this study, we sought to evaluate the clinical utility of TA-BSM in a first-in-human trial.
Patients with HOCM were enrolled if they presented with drug-refractory disabling symptoms. TA-BSM was performed via minithoracotomy with the use of our beating-heart myectomy device under echocardiographic guidance, without the use of cardiopulmonary bypass. Repeated resections were performed to tailor the extent of the septal myectomy for sufficient abolishment of left ventricular outflow tract (LVOT) obstruction and mitral regurgitation (MR). The primary outcome measure was procedural success, defined by resting/provoked LVOT gradient <30/50 mm Hg and residual MR grade ≤1+ (of 4+) at 3-month follow-up.
A total of 47 patients aged 12 to 77 years were enrolled. Of the 46 patients who were followed for 3 months, 42 achieved procedural success. The maximal LVOT gradient decreased from 86 mm Hg (IQR: 67-114 mm Hg) at baseline to 19 mm Hg (IQR: 14-28 mm Hg) at 3 months. MR grade was ≤1+ in 3 patients at baseline and in 45 patients at 3 months. One patient died on postoperative day 10 owing to device-unrelated reasons. Other major adverse events included 1 delayed ventricular septal perforation and 1 intraoperative left ventricular apical tear.
TA-BSM is a safe and efficient minimally invasive procedure for septal reduction of heterogeneous HOCM. Compared with conventional septal myectomy, TA-BSM provides real-time evaluation to guide resection while reducing surgical trauma. (Transapical Beating-Heart Septal Myectomy in Patients With Hypertrophic Obstructive Cardiomyopathy; NCT05332691)
Aorto-septal angle, isolated basal septal hypertrophy, and systolic murmur in 122 cats
2023, Journal of Veterinary Cardiology
Systolic murmurs in the absence of cardiac structural abnormalities are common in cats. Narrow aorto-septal angle (AoSA) and septal remodeling can be a cause of a systolic murmur in elderly human beings. The aim of this study was to measure the AoSA in cats and to investigate the association between the AoSA and the presence of a murmur and isolated basal septal hypertrophy (IBSH).
The study population comprised 122 cats.
A physical exam, blood pressure measurement, chest radiographs, and echocardiography were performed.
A systolic murmur was audible in 39/122 cats. A difference between cats with and without a murmur was found for age (P=0.0001), interventricular basal septal thickness (BIVSd) (P=0.004), AoSA (P=0.003), aortic (P<0.0001), and pulmonic (P=0.021) flow velocity, the presence of IBSH (P<0.0001), and systolic anterior motion of the mitral valve (P=0.0002). More than 50% of cats with a murmur had an AoSA ≤122°. Less than 25% of the cats with an AoSA ≥137° had a murmur. The AoSA narrowed 0.55°/year of age (P<0.001), whereas the BIVSd increased 0.11 mm/year of age (P<0.0001); the BIVSd increased as the AoSA narrowed. In all cats with AoSA < 120°, IBSH was present.
This study demonstrates that the probability of having a systolic murmur in cats is increased by the presence of a narrow AoSA. Aging was associated with a narrower AoSA and a thicker basal septum; these findings might represent an age-related heart remodeling.
Myocardial Bridge or Something Else?
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In this E-Challenge, the authors report on a patient with symptoms of exertional dyspnea and angina, scheduled to have surgical unroofing of an identified myocardial bridge (MB). An MB is very common in patients with hypertrophic cardiomyopathy (HCM). Intraoperative transesophageal echocardiography with provocative maneuvers revealed the patient had a systolic anterior motion of the mitral valve with septal contact and resulting outflow tract obstruction despite the notable absence of significant basal septal hypertrophy. HCM has many phenotypic variants that can make the identification of patients with latent left ventricular outflow tract obstruction difficult in the absence of a high index of suspicion. In this report, the authors discuss the association between MBs and HCM and the importance of recognizing phenotypic variants of HCM.

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: J.B. and S.R.O. contributed equally to this article

¹: Dr Ackerman's study is supported by a Mayo Foundation Clinical Research Award. Dr Ackerman is an Established Investigator of the American Heart Association.

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Original ArticleEchocardiography-Guided Genetic Testing in Hypertrophic Cardiomyopathy: Septal Morphological Features Predict the Presence of Myofilament Mutations

OBJECTIVE

PATIENTS AND METHODS

RESULTS

CONCLUSION

Section snippets

PATIENTS AND METHODS

Overall

DISCUSSION

CONCLUSION

Curr Probl Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Cell

Cell

Biochem Biophys Res Commun

J Am Coll Cardiol

Am J Cardiol

J Am Coll Cardiol

J Am Coll Cardiol

Mayo Clin Proc

Lancet

J Am Coll Cardiol

Mayo Clin Proc

J Mol Cell Cardiol

Am J Cardiol

Am J Cardiol

J Am Coll Cardiol

Hypertrophic cardiomyopathy: clinical spectrum and treatment

Circulation

Hypertrophic cardiomyopathy: a systematic review

JAMA

The “sigmoid septum”: variation in the contour of the left ventricular outt

Am J Roentgenol Radium Ther Nucl Med

Original Article
Echocardiography-Guided Genetic Testing in Hypertrophic Cardiomyopathy: Septal Morphological Features Predict the Presence of Myofilament Mutations