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Hypertrophic cardiomyopathy (HCM)

Introduction

Genetic disorder characterized by LV hypertrophy unexplained by secondary causes, and a non-dilated left ventricle with preserved/increased ejection fraction.

  • Diastolic dysfunction
  • M/C cause of sudden cardiac death (SCD) in adolescents and young adults, particularly in competitive athletes

History:

In 1957, Donald Teare of St. George’s Hospital in London described eight cases of asymmetric septal hypertrophy seen on autopsy with some bewilderment, noting that the tumors had “occurred in a group where cardiac incapacity … is rare.” He ultimately described “the eight tumours under discussion as hamartomata.” In 1959, Morrow and Braunwald published a case series of three patients with a clinical syndrome mimicking aortic stenosis. In the first two patients, “significant pressure gradients were demonstrated preoperatively but … no anatomic site of outflow obstruction could be detected at the time of open-heart operation.” When the third patient was taken to surgery, a discrete hypertrophy of the subaortic interventricular septum was resected, resulting in resolution of the stenosis and improvement of the patient’s symptoms. By the time of their 1964 case series of 64 patients with a condition they termed idiopathic hypertrophic subaortic stenosis, Braunwald’s group had launched a campaign now spanning more than five decades of clinical care and research of the condition we now know as hypertrophic cardiomyopathy (HCM). The first gene mutation for this condition was identified in a large French Canadian family cohort in 1989.


Aetiology

HCM is an archetypical single gene disorder with an autosomal dominant pattern of inheritance, whereby a single mutation is usually sufficient to cause the disease, albeit with variable penetrance and expression.

Determinants of phenotype in HCM Selected factors contributing to expression of cardiac phenotype in HCM are shown. The causal mutation imparts the main effect and several others, such as other pathogenic genetic variants (modifiers), genomics (such as non-coding RNAs), proteomics (such as post-translational modifications), and environmental factors (such as isometric exercises) contributing to expression of the phenotype. | Marian, A. J., & Braunwald, E. (2017). Hypertrophic Cardiomyopathy: Genetics, Pathogenesis, Clinical Manifestations, Diagnosis, and Therapy. Circulation research, 121(7), 749–770. https://doi.org/10.1161/CIRCRESAHA.117.311059

Pathophysiology

Characterized by an increase in left ventricular wall thickness (hypertrophy) which causes left ventricular outflow obstruction, diastolic dysfunction, myocardial ischemia, and mitral regurgitation.

Obstructive HCM: 70% cases

Defined as Left ventricular outflow tract (LVOT) ≥30 mmHg
Septal hypertrophy favors the occurrence of LVOT, resulting in a “suction” effect (Venturi effect), which leads to the traction of the anterior mitral valve leaflet towards the interventricular septum with consequent emergence of subaortic systolic gradient and LVOT obstruction.

Non-obstructive HCM:

Generally carry better prognosis
hypertrophic-cardiomyopathy
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Morphologic patterns of HCM:

Morphologic expression of HCM is widely variable and heterogeneous because HCM may affect any portion of the LV.
  • Asymmetric septal involvement (M/C form)
    • Midventricular HCM
    • Apical HCM
    • Concentric HCM
    • Basal interventricular septum HCM (M/severe)
HCM phenotypes. Diagrams show focal basal septum HCM (A), diffuse septum (B), concentric and diffuse HCM (C), midventricular HCM (D) and apical HCM (E). | Baxi A.J., Restrepo C.S., Vargas D. Hypertrophic cardiomyopathy from A to Z: genetics, pathophysiology, imaging, and management. Radiographics. 2016;36(2):335–354.

Clinical features

HCM is one of the few cardiovascular diseases that can manifest at any phase of life, from infancy to the seventh decade of life.

  • Exertional dyspnea (M/C)
  • Syncope, palpitations, angina, orthopnea, paroxysmal nocturnal dyspnea, dizziness

Physical examination:

  • Double apical impulse (d/t forceful left atrial contraction against a highly noncompliant left ventricle)
  • Normal s1 and split s2, s3 (d/t decompensated heart failure)
  • Prominent “a wave” of jugular venous pressure (JVP)
  • Laterally displaced apical impulse
  • Double carotid pulse
  • Systolic ejection murmur:
    • Crescendo-decrescendo type
    • ↓ intensity with ↑ preload (squatting) or ↑ afterload (handgrip)
    • ↑ intensity with ↓ preload (Valsalva maneuver, standing), and ↓ afterload (vasodilator administration)
Venous and arterial waveforms in HCM. JVP waveform in HCM showing an augmented a wave. Carotid impulse tracing in HCM demonstrating the spike (red arrow) and dome (blue arrow) pattern. | Goldstein JA. Cardiac tamponade, constrictive pericarditis, and restrictive cardiomyopathy. Curr Probl Cardiol. 2004;29(9):503–567.

Complications

  • Atrial and ventricular arrhythmias
  • Sudden cardiac death (SCD) (M/severe): Dreaded complication resulting from ventricular arrhythmias caused by autonomic hyperactivity secondary to LVOT obstruction, microvascular ischemia, myocardial fibrosis, and myocyte derangement
  • Left ventricular (LV) outflow tract obstruction (often dynamic and variable and may lead to syncope)
  • Heart failure (in the setting of preserved (HFpEF)/reduced (HFrEF) systolic function)

Diagnosis

HCM should be considered if a patient has unexplained symptoms, a family history of premature cardiac disease, or electrocardiographic abnormalities.

Diagnostic criteria:

  1. LV hypertrophy in the absence of another cardiac/systemic disease that could cause hypertrophy:
    • Wall thickness ≥ 1.5 cm (in adults) or equivalent relative to body surface area in children with a nondilated hyperdynamic left ventricle
    • Distribution of hypertrophy can be variable
  2. Electrocardiography:
    • LV hypertrophy with repolarization changes
    • T-wave inversions
    • Abnormal Q waves

Electrocardiogram (ECG): (M/sensitive)

M/practical technique for screening for HCM and is recommended at 12-month intervals during adolescence and every 5 years in adults as well as at the onset of symptoms suggestive of HCM

Combination of left ventricular hypertrophy (LVH) with right atrial enlargement is strongly suggestive of HCM

  • Localized/widespread repolarization changes (M/C):
    • Deep S waves in V1 and V2
    • Large R waves in V5 and V6 strain repolarization change
  • Deeply inverted T waves
  • Evidence of LVH (#2 M/C)
  • Pathological Q waves in inferior (II, III, and aVF) and lateral leads (I, aVL, and V4-V6)
  • Left atrial or biatrial enlargement
  • Left axis deviation
ECG of a 51-year old patient with HCM. Note the prominent precordial voltage, widespread repolarization abnormalities, Q-wave in the lateral lead (aVL), and p-wave abnormality suggesting left atrial enlargement. | Houston, B. A., & Stevens, G. R. (2015). Hypertrophic cardiomyopathy: a review. Clinical Medicine Insights. Cardiology, 8(Suppl 1), 53–65. https://doi.org/10.4137/CMC.S15717

Transthoracic echocardiogram (TTE):

Mainstay for imaging the HCM phenotype, and it remains the initial test for patients due to its portability, widespread access, and reliability in quantifying dynamic outflow tract gradients. It demonstrates cardiac morphology, systolic and diastolic function, the presence and severity of any LVOT gradient, and the degree of mitral regurgitation.
Imaging of HCM: (A) Transthoracic echocardiogram (TTE) in the parasternal long axis view showing basal septal hypertrophy (yellow line). (B) TTE in the apical view showing basal septal hypertrophy and SAM of the mitral valve (green arrow). (C) TTE in the apical view with color-flow Doppler showing turbulent flow in the outflow tract (white arrow) and mitral regurgitation because of mitral valve SAM. (D) Cardiac MRI in the apical view showing striking asymmetric basal septal hypertrophy (white arrow). All images are provided by Dr. Theodore Abraham, Johns Hopkins Hospital.

Cardiac magnetic resonance (CMR):

To establish the diagnosis of HCM in cases where areas of hypertrophy are technically difficult to assess by conventional echocardiography
An asymptomatic 36-year-old man with HCM. CMR images demonstrate mild asymmetric septal hypertrophy (A and B) and late gadolinium enhancement (arrows in C) in mid-septal wall and located near the right ventricular insertion points. | Antunes, M. O., & Scudeler, T. L. (2020). Hypertrophic cardiomyopathy. International journal of cardiology. Heart & vasculature, 27, 100503. https://doi.org/10.1016/j.ijcha.2020.100503

Ambulatory ECG monitoring:

Should be performed for 24 to 48 hours in all patients diagnosed with HCM for risk assessment of ventricular arrhythmias and sudden death.

Exercise stress testing:

For risk stratification and assessment of LV outflow tract (LVOT) gradient.
  • Assessment of functional capacity and therapeutic response;
  • Risk stratification for sudden cardiac death (SCD)
  • Assessment of the systolic blood pressure (sBP)
  • Assessment of latent obstructive forms when associated with ECG.

Cardiac catheterization:

Determines cardiac hemodynamic, the degree of left ventricular outflow obstruction, and anatomy of the coronary vessels.
LV angiogram of a patient with HCM | Prinz, C., Farr, M., Hering, D., Horstkotte, D., & Faber, L. (2011). The diagnosis and treatment of hypertrophic cardiomyopathy. Deutsches Arzteblatt international, 108(13), 209–215. https://doi.org/10.3238/arztebl.2011.0209

Management

HCM treatment is indicated in the presence of symptoms. Treatment requires a thorough understanding of the natural history and must be individualized to the patient.

Management of hypertrophic cardiomyopathy. Brackets indicate third-line therapy with, at best, borderline evidence to support their use. | ACE = angiotensin-converting-enzyme inhibitor, ARB = angiotensin receptor blocker, ICD = implantable cardioverter defibrillator, LVOT = left ventricular outflow tract. | Jacoby, D. L., DePasquale, E. C., & McKenna, W. J. (2013). Hypertrophic cardiomyopathy: diagnosis, risk stratification and treatment. CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne, 185(2), 127–134. https://doi.org/10.1503/cmaj.120138

Medical management:

First-line approach to symptomatic HCH. Goal of pharmacological therapy in HCM is to alleviate the symptoms of exertional dyspnea, palpitations, and angina and thereby improve patients’ quality of life.
  • β-blockers (first-line) and calcium channel blockers (CCB)
    • Improve exertional dyspnea and chest pain by inhibiting sympathetic heart stimulation; decreasing oxygen consumption by reducing heart rate, contractility, and myocardial stress during systole; and increasing the diastolic filling period.
  • Diuretics (pulmonary congestion)
  • Vitamin K antagonists (VKAs) (chronic anticoagulation in HCM and AF)

Surgical management:

Indicated in symptomatic patients (NYHA III-IV) despite optimal medical therapy with an LVOT gradient ≥50 mmHg (at rest or provoked)
Comparison between septal reduction therapies. | Antunes, M. O., & Scudeler, T. L. (2020). Hypertrophic cardiomyopathy. International journal of cardiology. Heart & vasculature, 27, 100503. https://doi.org/10.1016/j.ijcha.2020.100503

Surgical septal myectomy:

GOLD STANDARD for septal reduction
  • Morrow’s surgery: Removal of small portion of muscle from the basal ventricular septum to reduce the LVOT gradient

Alcohol septal ablation:

Alternative to surgical myectomy in select patients, such as those with advanced age, significant comorbidities, or who oppose open chest surgery

 Heart transplantation

Indicated in end-stage disease and LV dysfunction or in nonobstructive HCM with preserved systolic function (restrictive form) who develop refractory heart failure symptoms due to diastolic dysfunction

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