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ORIGINAL RESEARCH
Ahead of print publication  

Echocardiography Study of Hypertrophic Cardiomyopathy Phenotypes: An Indian Perspective


 Department of Cardiology, Hero DMC Heart Institute, Ludhiana, Punjab, India

Date of Submission18-Oct-2020
Date of Acceptance14-Jan-2021
Date of Web Publication23-May-2021

Correspondence Address:
Rohit Tandon,
Hero DMC Heart Institute, Ludhiana, Punjab
India

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jiae.jiae_71_20

  Abstract 

Background: Hypertrophic cardiomyopathy (HCM) is a genetic disorder with a heterogeneous phenotype. Historically, only obstructive and nonobstructive forms have been described. Improvements in imaging techniques have led to elaborative description of various new phenotypes, although there are limited epidemiological data regarding these phenotypes from within our population. Aims and Objectives: •To identify HCM patients from a cohort of cardiomyopathy patients. •To describe their demographic profile and mode of presentation based on the presenting symptoms. •To subclassify the selected HCM population into various phenotypes based on echocardiography. Results: There were 233 patients of HCM in this study. The mean age of the patients was 53 ± 14.5 years with male preponderance (70%). Thirty-six percent patients were asymptomatic, 37% mildly symptomatic (in class I-II), and 27% severely symptomatic (in class III-IV). Patients were classified into six phenotypes consisting of five classically described phenotypes and one atypical phenotype. Reverse curvature phenotype was most prevalent (49%) and symptomatic phenotype with 19.3% having significant resting left ventricular outflow tract (LVOT) obstruction. Other phenotypes were 19% apical mid, 11% neutral, 6% sigmoid, and 4% atypical. Male: female ratio for reverse curvature phenotype was 3:1, apical (mid) phenotype 2.4:1, and both apical and neutral phenotypes 2:1. Sigmoid phenotype had female-to-male ratio of 2.5:1. Conclusion: HCM patients require phenotype specific approach for complete assessment. Transthoracic echocardiography with myocardial contrast plays a pivotal role in identifying morphological phenotypes, effects on cardiac remodeling and hemodynamics which consequently influence mode of presentation. Reverse curvature, apical mid, and sigmoid phenotypes are comparatively more symptomatic, have larger left atrial size and segment thickness compared to less symptomatic apical and neutral phenotypes. Symptom status of the patient seems to be dependent on age, septal contour, severity of LVOT obstruction, left atrial volume, and maximal segment thickness.

Keywords: Echocardiography, hypertrophic cardiomyopathy, phenotype



How to cite this URL:
Tandon R, Dutt S, Bansal N, Singh G, Singh B, Goyal A, Chabbra ST, Aslam N, Mohan B, Wander GS. Echocardiography Study of Hypertrophic Cardiomyopathy Phenotypes: An Indian Perspective. J Indian Acad Echocardiogr Cardiovasc Imaging [Epub ahead of print] [cited 2021 Oct 17]. Available from: https://www.jiaecho.org/preprintarticle.asp?id=316638


  Introduction Top


Hypertrophic cardiomyopathy (HCM) is a genetic disorder having a heterogeneous phenotype. Originally, only two phenotypes of HCM were described; a more common obstructive type (70%) and a less common, nonobstructive type (30%). Advances in cardiac imaging have led to the identification of new phenotypes besides the already known obstructive and nonobstructive forms. In 2006, American Heart Association Working Group suggested that HCM should be defined genetically and not morphologically.[1] Recently, European Society of Cardiology Working Group on Myocardial and Pericardial Diseases recommended a morphological classification stressing that clinical evaluation of patients starts with the finding of a hypertrophied heart rather than a genetic mutation.[2] Echocardiography remains a principal tool for the diagnosis and morphological characterization of HCM. It is imperative to identify the different HCM phenotypes to help treating physician choose an appropriate management protocol in a given patient.

Aims and objectives

  • To identify HCM patients from a cohort of cardiomyopathy population
  • To describe their demographic profile and mode of presentation based on presenting symptoms
  • To subclassify the selected HCM population into various phenotypes based on echocardiography.



  Materials and Methods Top


This was a retrospective, observational study of HCM patients which was done at a tertiary care cardiac center over 5 years (January 2015 to December 2019).

Inclusion criteria

All patients with a diagnosis of HCM having age more than 18 years with echocardiography data available for offline analysis were included.

Exclusion criteria

Patients with HCM phenocopies, i.e., abnormal left ventricular (LV) hypertrophy as seen in aortic stenosis (valvular/supravalvular/subvalvular), chronic kidney disease, cardiac amyloidosis, hypereosinophilic disorders, Fabry disease, and phaechromocytoma were excluded.

Data collection

Demographic data including age and gender, and details of presenting symptoms, family history of HCM or HCM-related sudden cardiac death (SCD), h/o hypertension and diabetes mellitus were collected. Echocardiography was performed by two-trained physician echocardiographers. A comprehensive transthoracic echocardiography examination was done, including measurement of maximal LV wall thickness at end diastole, maximal to minimum wall thickness ratio, maximal left atrial volume in end systole, early (E) and late (A) diastolic mitral inflow velocities, and E/A ratio using pulsed-wave Doppler and ratio of mitral E to average mitral annular early diastolic velocity (E') using tissue Doppler recordings at both medial and lateral annulus. Resting LV outflow tract (LVOT) gradient >30 mm of Hg was considered significant. Provocable LVOT obstruction was sought using standard Valsalva maneuver wherever deemed necessary.

Patients were subcategorized into following morphological phenotypes, namely reverse curvature, sigmoid variant, neutral, apical, apical with mid segment involvement and atypical phenotypes based on the septal contour, location, and extent of myocardial segment hypertrophy [Figure 1] [Figure 2] [Figure 3].[3]

In reverse curvature phenotype, there is predominantly mid-septal convexity toward the LV cavity resulting in a crescent-shaped cavity.
Figure 1: Showing hypertrophic cardiomyopathy phenotypes based on septal contour and aorto septal angle. (a) Reverse curvature type- blue arrow points toward septal curvature convexity toward left ventricular cavity, (b) neutral variant showing straight asymmetrically hypertrophied septum, and (c and d) sigmoid variant with arrow pointing to isolated basal septum hypertrophy and aorto septal angle >110°

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Figure 2: Shows classification of hypertrophy cardiomyopathy variants based on apical segment involvement. (a and b) Apical mid variants with and without contrast echocardiography, and (c) isolated apical variant

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Figure 3: Shows rare variants and hemodynamic alterations. (a) Mitral stenosis with reverse curvature morphology, (b) posterolateral hypertrophy with normal septal thickness, (c) significant turbulence in left ventricular outflow tract associated with moderate mitral regurgitation, both these complications are related to systolic anterior motion of anterior mitral leaflet, and (d) massive septal hypertrophy with septal thickness up to 4.3 cm

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In sigmoid phenotype, septum shows a prominent basal septal bulge convex to the LV cavity having aorto-septal angle >110° resulting in an ovoid LV cavity. Dynamic resting LVOT obstruction may be present in these phenotypes.

In neutral phenotypes, there is an overall straight septum that is neither predominantly convex nor concave toward the LV cavity.

For these above-mentioned three phenotypes, asymmetrical septal hypertrophy was defined as septal-to-posterior wall thickness ratio ≥1.3 (or ≥1.5 in hypertensive patients) in diastole.

In apical phenotype, there is predominantly apical distribution of hypertrophy that is confined to the LV apex with an apical wall thickness ≥15 mm and a ratio of maximal apical to basal segment thickness ≥1.5 in diastole.

In apical phenotype with midsegment involvement, there is mid and apical LV segment involvement with or without LV apical aneurysm.

Atypical phenotype had asymmetrical hypertrophy of posterior or lateral wall of the LV without septum hypertrophy.

Myocardial contrast echocardiography was used to delineate hypertrophied segments whenever deemed appropriate [Figure 1] [Figure 2] [Figure 3].

Statistical analysis

Demographic variables such as age, gender, symptoms at presentation, and echocardiography variables were collected and tabulated for each patient using SPSS 21.0 (IBM Corp., Armonk, NY, USA). Measurements are presented as mean ± standard deviation for the continuous variables and frequency and percentages for the categorical variables. For interobserver variability, measurements were carried out by a second operator on previously acquired images. For intraobserver variability, two sets of measurements were carried out by the same operator, 1 month apart. Variability was calculated as the absolute differences between two measurements divided by the mean of the two measurements.


  Results Top


A total of 900 patients with a diagnosis of cardiomyopathy were identified from January 2015 to December 2019 at our institution. Etiological diagnosis of cardiomyopathies was as follows: ischemic cardiomyopathy (n = 350, 38.9% patients), dilated cardiomyopathy (n = 290, 32.2% patients), HCM (n = 233, 25.9% patients), and restrictive cardiomyopathy (n = 27, 9%) patients.

Clinical characteristics

Patients with HCM presented in the fourth to sixth decades, and mean age at presentation was 53.21 ± 14.5 years. There were 70% males and 30% females with similar age at presentation 52 ± 14 and 54 ± 15 years, respectively. There were 12% hypertensive and 5% diabetics.

Distribution of patients according to the symptoms at presentation

Thirty-six percent patients were asymptomatic, 37% were mildly symptomatic (class I-II), and 27% were severely symptomatic (class III-IV). In mildly symptomatic group, the most common symptom on the presentation was dyspnea (57% patients), followed by palpitations (25.6%), and angina (16%). Among severely symptomatic patients, 28% had class III/IV dyspnea, 25% had class III/IV angina, 20% had syncope, 12.2% had cardio-embolic stroke, and 7.9% had ventricular/atrial arrhythmias at presentation [Table 1].
Table 1: General characteristics of the study population (n=233)

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Gender distribution and phenotypes based comparison

[Figure 4] depicts phenotype distribution of HCM patients. All phenotypes except sigmoid phenotype had male preponderance. Male and female gender ratio was as follows: in reverse curvature 3:1; apical (mid) phenotype 2.4:1 and both apical and neutral phenotypes 2:1. Sigmoid phenotype had female-to-male ratio of 2.5:1. Neutral and reverse curvature phenotypes had youngest patients (50 ± 10 years), whereas sigmoid phenotype had oldest age group patients (64 ± 10 years). Up to 70% patients were symptomatic in reverse curvature phenotype and least symptomatic patients were in the neutral phenotype (up to 35%).
Figure 4: Pie chart showing distribution of different hypertrophic cardiomyopathy phenotypes

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Echocardiographic characteristics

Patients had enlarged left atria and increased and asymmetric wall thickness with moderately increased E/E' ratio [Table 2]. Reverse curvature phenotypes had the largest while apical and neutral phenotypes had the smallest left atrial volumes. Reverse curvature phenotypes also had maximal LV segment thickness. Massive hypertrophy, i.e., septal thickness >30 mm was seen in 30% patients, out of which 85% were of reverse curvature and 15% apical-mid phenotypes [Figure 5].
Figure 5: Bar chart comparing different echocardiographic variables and age (years) in hypertrophic cardiomyopathy phenotypes. Max LA vol: Maximum left atrium volume in ml, MLWT: Maximum left ventricle wall thickness in mm, RC: Reverse curvature

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Table 2: Echocardiography findings in hypertrophic cardiomyopathy patients

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19.3% patients had significant resting LVOT obstruction, i.e., >30 mm of Hg. 79.7% patients had no LVOT obstruction at rest or after provocable measures. Eight percent patients had high risk features for SCD including severe resting LVOT obstruction or ventricular arrhythmias at presentation. 0.8% patients developed severe mitral regurgitation owing to systolic anterior motion of mitral valve.

Although a significant difference was observed in maximal segment thickness and left atrial volume in different phenotypes, Doppler variables including mitral flow velocities and ratios did not differ much among phenotypes [Table 3]. Interobserver variability in echocardiography findings was <5%.
Table 3: Phenotype-based Doppler echocardiography variables

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  Discussion Top


This study aimed at describing the symptoms on presentation and echocardiography findings of specific phenotypes of HCM and following findings were observed. Patients presented in the fourth to sixth decade with a mean age at presentation 53.21 ± 14.5 years. There was male preponderance (70% males and 30% females) with similar age at presentation 52 ± 14 and 54 ± 15 years, respectively. Tanjore et al. in a series of 127 HCM patients reported the mean age at presentation 42 ± 12 years with male-to-female ratio 3.7:1.[4] Rangaraju et al. in a study of 100 HCM patients reported the mean age at the diagnosis 45.5 ± 13.8 years for males and 41.2 ± 20.2 years for females with sex ratio of 3.1:1.[5] Biswas et al. in a study of 59 patients of HCM patients reported mean age at diagnosis 43.8 ± 15.3 years and sex ratio of 5.5:1.[6] In a study of 21 HCM patients by Teple and Kalra, there was 6:1 male-to-female ratio, with a mean age of 44.9 ± 14.9 years.[7] In our study, 37% patients were mildly symptomatic (class I-II), 27% were severely symptomatic (class III-IV), whereas 36% were asymptomatic. The most common symptom in outpatient presentation was dyspnea (57% patients), followed by palpitations (25.6%), and angina (16%). Reason for admission was acute onset dyspnea in 28% of patients, angina in 25% of cases, syncope in 20%, cardioembolic stroke in 12.2%, and ventricular/atrial arrhythmias in 7.9% of patients.

In the Epidemiology of Cardiomyopathy Study- HCM study (EPOCH-H) study, the authors reported chest pain in 64%, shortness of breath in 62.5%, palpitations in 53.5%, syncope in 21.4%, presyncope in 7.4%, New York Heart Association class III/IV at presentation 23.7%, and SCD in 3.4%.[6] Teple and Kalra noted 28.6% asymptomatic, 33% class II dyspnea, 28.6% angina, 23% palpitations, 14% syncope, 9.5% class IV dyspnea and 9.5% having atrial fibrillation on presentation.[7] Rangaraju et al. described dyspnea class II in 75%, palpitations in 56%, angina in 30%, and syncope in 22% patients.[5]

Echocardiography findings in our study documented maximum average segment thickness 25.3 ± 8.8 mm, mean left atrial volume 44.38 ± 14.6 ml, average LVOT gradient 52.64 ± 26.2 mm of Hg, and average E/E' 15.7 ± 5.6. The EPOCH-H study noted maximum average segment thickness 21.0 ± 8.3 mm, whereas Rangaraju et al. noted maximum average segment thickness 19.3 ± 0.51 mm and LVOT gradient 58.5 ± 29.5 mm of Hg.[5],[6] Reverse curvature phenotype is the most common HCM phenotype described and is also more likely to be associated with gene mutations. Similar results were seen in our study- reverse curvature was the dominant phenotype (48.5%) comprising predominantly males. Apical (mid) phenotype was the second most common phenotype with 18.9% patients in our study. This phenotype was characterized by males in the fifth decade with moderately enlarged left atria, significantly thick apical, and mid segments with moderately increased LV end diastolic pressure (LVEDP) (average E/E'>16), signifying moderate diastolic impairment. Apical phenotype contributed 10.7% patients. Apical phenotypes required myocardial contrast echocardiography for confirming the diagnosis in most of the cases. It was characterized by males in their late fifth decade who were either asymptomatic or mildly symptomatic at the presentation. Echocardiography showed mildly dilated left atrium with maximum LV wall thickness at apex in the range of 18–22 mm with moderately increased LVEDP.

Nearly 11.6% patients were of neutral phenotype characterized by males in their late fourth decade who were either asymptomatic or mildly symptomatic at presentation and having minimally dilated left atria with minimally increased maximum LV wall thickness with mild or no diastolic function impairment.

Six percent patients were of sigmoid phenotype comprising predominantly of elderly females in their sixth decade who were mostly in symptomatic class III/IV and had moderately enlarged left atria and moderately increased LVEDP (moderate diastolic impairment) with least increased maximum LV wall thickness and moderate LVOT obstruction.

Asymmetric posterior LV wall hypertrophy was seen in 4% patients. This morphological entity was first described in 1991 by Lewis and Maron as an unusual morphologic pattern with asymmetric thickening of the posterior LV free wall with/without LVOT obstruction.[8]

Tanjore et al. reported phenotypic distribution as 48% nonobstructive, 40% obstructive, 5.5% apical, and 2.3% each concentric and mid cavitary phenotypes.[4] Rangaraju reported phenotypic distribution as nonobstructive 52.6%, obstructive 22.3%, asymmetrical septal hypertrophy 15.7%, apical 6.5%, and mid cavitary 2.6%.[5] Biswas et al. reported 64% nonobstructive and 34% obstructive variety.[6] Teple reported 52% as nonobstructive, 23.8% obstructive, and 47% apical phenotype[7] [Table 4]. Our study was in concordance with studies conducted by Rangaraju et al. and Tanjore et al. as the other two studies had small sample size and were having specific patient sampling. Our study was unique as it aimed at detailed elaborative description of HCM phenotypes in accordance with septal contour and site of maximal LV segment thickness.
Table 4: Comparison with previous echocardiography studies on hypertrophic cardiomyopathy from India

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Nearly 19.3% patients in our study had significant LVOT obstruction. Dyspnea and angina class II-III were predominant symptoms. These patients had higher left atrial volumes with moderately increased LVEDP and thicker maximum LV wall thickness compared to non-LVOT obstruction patients.

Eight percent patients demonstrated high risk features, i.e., massive hypertrophy >30 mm of Hg, severe resting LVOT obstruction, and malignant ventricular arrhythmias at presentation. Massive LV hypertrophy (wall thickness ≥30 mm) generally affects about 10% of HCM patients. We found massive hypertrophy in 30% of our cases, 90% were of reverse curvature phenotypes and 10% patients were of apical (mid) variant. An Italian study of 480 HCM patients found that the risk of SCD had a correlation with LV wall thickness: 0% for ≤15 mm and 1.8% per year for ≥30 mm. The incidence of SCD doubled with every 5 mm increase in LV wall thickness.[9],[10]

In HCM, diastolic dysfunction seems to be independent of morphological patterns. The main correlates of diastolic dysfunction include LVOT obstruction, age, degree of hypertrophy, and mitral regurgitation. Based on the symptom presentation in various phenotypes, we conclude that once significant LVOT obstruction develops, the patient's symptoms are dictated by the degree of obstruction as LVOT obstruction increases left atrial size and causes further impairment in LV diastolic function. Degree of septal contour explains the severity of symptoms as in neutral contour mild symptoms were observed, whereas the patients with sigmoid phenotype had moderate symptoms. In apical (mid) phenotype, there is clustering of hypertrophy in apical segments, resulting in reduced cavity size, impaired diastology parameters and thereby, increasing risk of atrial arrhythmias and thromboembolic events. In earlier studies, a positive linear relationship between left atrial diameter and the 5-year risk of thromboembolism was observed up to 45–50 mm, at which point it became exponential.[11],[12]

Limitations of this study

It is a single center referral study of HCM patients. Cardiac magnetic resonance imaging and genotyping could have further enhanced our phenotype classification. Symptom evaluation was done subjectively rather than using objective tools (cardiopulmonary exercise testing), especially in mildly symptomatic and asymptomatic patients.


  Conclusion Top


HCM patients require phenotype specific approach for complete assessment. Transthoracic echocardiography with myocardial contrast has a pivotal role in identifying various morphological phenotypes, cardiac remodeling, and hemodynamics which consequently influence the mode of presentation. Reverse curvature, apical mid and sigmoid phenotypes are comparatively more symptomatic, have larger left atrial size and segment thickness compared to less symptomatic apical and neutral phenotypes. Symptom status of the patient is dependent on age, septal contour, degree of LVOT obstruction, left atrial size, and maximal segment thickness.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Maron BJ, Towbin JA, Thiene G, Antzelevitch C, Corrado D, Arnett D, et al. Contemporary definitions and classification of the cardiomyopathies: An American Heart Association Scientific Statement from the Council on Clinical Cardiology, Heart Failure and Transplantation Committee; Quality of Care and Outcomes Research and Functional Genomics and Translational Biology Interdisciplinary Working Groups; and Council on Epidemiology and Prevention. Circulation 2006;113:1807-16.  Back to cited text no. 1
    
2.
Elliott P, Andersson B, Arbustini E, Bilinska Z, Cecchi F, Charron P, et al. Classification of the cardiomyopathies: A position statement from the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J 2008;29:270-6.  Back to cited text no. 2
    
3.
Syed IS, Ommen SR, Breen JF, Tajik AJ. Hypertrophic cardiomyopathy: Identification of morphological subtypes by echocardiography and cardiac magnetic resonance imaging. JACC Cardiovasc Imaging 2008;1:377-9.  Back to cited text no. 3
    
4.
Tanjore RR, Thakkar B, Sikindlapuram AD, Narasimhan C, Kerkar PG, Vajjha HV, et al. Epidemiology and genetics of hypertrophic cardiomyopathy. Indian J Hum Genet 2006;12:26-33.  Back to cited text no. 4
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5.
Rangaraju RA, Calambur N, Nallari P. Epidemiological and clinical analyses of hypertrophic cardiomyopathy. J Med Sci Res 2015;3:9-16.  Back to cited text no. 5
    
6.
Biswas A, Das S, Kapoor M, Seth S, Bhargava B, Rao VR. Epidemiology of cardiomyopathy-A clinical and genetic study of hypertrophic cardiomyopathy: The EPOCH-H study. J Pract Cardiovasc Sci 2015;1:143-9.  Back to cited text no. 6
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Teple K, Kalra R. Clinical profile and echocardiography findings of patients with cardiomyopathy at tertiary care hospital. J Mar Med Soc 2016;18:17-24.  Back to cited text no. 7
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8.
Lewis JF, Maron BJ. Hypertrophic cardiomyopathy characterized by marked hypertrophy of the posterior left ventricular free wall: Significance and clinical implications. J Am Coll Cardiol 1991;18:421-8.  Back to cited text no. 8
    
9.
Spirito P, Bellone P, Harris KM, Bernabò P, Bruzzi P, Maron BJ. Magnitude of left ventricular hypertrophy and risk of sudden death in hypertrophic cardiomyopathy. N Engl J Med 2000;342:1778-85.  Back to cited text no. 9
    
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Lu DY, Ventoulis I, Liu H, Kudchadkar SM, Greenland GV, Yalcin H, et al. Sex-specific cardiac phenotype and clinical outcomes in patients with hypertrophic cardiomyopathy. Am Heart J 2020;219:58-69.  Back to cited text no. 10
    
11.
Klues HG, Schiffers A, Maron BJ. Phenotypic spectrum and patterns of left ventricular hypertrophy in hypertrophic cardiomyopathy: Morphologic observations and significance as assessed by two-dimensional echocardiography in 600 patients. J Am Coll Cardiol 1995;26:1699-708.  Back to cited text no. 11
    
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Parato VM, Olivotto I, Maron MS, Nanda NC, Pandian NG. Left ventricular apex involvement in hypertrophic cardiomyopathy. Echocardiography 2015;32:1575-80.  Back to cited text no. 12
    


    Figures

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