Hypertrophic cardiomyopathy: A complex disease

Laboratory testing for phenocopies of HCM

A metabolic panel will show derangements in liver function and glucose levels in patients with glycogen storage disorders such as Pompe disease. 

Serum creatinine. Renal dysfunction will be seen in patients with Fabry disease or amyloidosis.

Creatine kinase may be elevated in patients with Danon disease.

Electrocardiographic findings are common

More than 90% of HCM patients have electrocardiographic abnormalities. Although the findings can vary widely, common manifestations include:

• Left ventricular hypertrophy
• A pseudoinfarct pattern with Q waves in the anterolateral leads
• Repolarization changes such as T-wave inversions and horizontal or down-sloping ST segments.

Apical HCM, seen mainly in Asian populations, often presents with giant T-wave inversion (> 10 mm) in the anterolateral leads, most prominent in V₄, V₅, and V₆.

Notably, the degree of electrocardiographic abnormalities does not correlate with the severity or pattern of hypertrophy.⁹ Electrocardiography lacks specificity for definitive diagnosis, and further diagnostic testing should therefore be pursued.

Echocardiography: Initial imaging test

Transthoracic echocardiography is the initial imaging test in patients with suspected HCM, allowing for cost-effective quantitative and qualitative assessment of left ventricular morphology and function. Left ventricular hypertrophy is considered pathologic if wall thickness is 15 mm or greater without a known cause. Transthoracic echocardiography also allows for evaluation of left atrial volume and mitral valve anatomy and function.

Speckle tracking imaging is an advanced echocardiographic technique that measures strain. Its major advantage is in identifying early abnormalities in genotype-positive, phenotype-negative HCM patients, ie, people who harbor mutations but who have no clinical symptoms or signs of HCM, potentially allowing for modification of the natural history of HCM.¹² Strain imaging can also differentiate between physiologic hypertrophy (“athlete’s heart”) and hypertension and HCM.^13,14

The utility of echocardiography in HCM is heavily influenced by the sonographer’s experience in obtaining adequate acoustic windows. This may be more difficult in obese patients, patients with advanced obstructive lung disease or pleural effusions, and women with breast implants.

Magnetic resonance imaging

MRI has an emerging role in both diagnosing and predicting risk in HCM, and is routinely done as an adjunct to transthoracic echocardiography on initial diagnosis in our tertiary referral center. It is particularly useful in patients suspected of having apical hypertrophy (Figure 2), in whom the diagnosis may be missed in up to 10% on transthoracic echocardiography alone.¹⁵ MRI can also enhance the assessment of left ventricular hypertrophy and has been shown to improve the diagnostic classification of HCM.¹⁶ It is the best way to assess myocardial tissue abnormalities, and late gadolinium enhancement to detect interstitial fibrosis can be used for further prognostication. While historically the primary role of MRI in HCM has been in phenotype classification, there is currently much interest in its role in risk stratification of HCM patients for ICD implantation.

MRI with late gadolinium enhancement provides insight into the location, pattern, and extent of myocardial fibrosis; the extent of fibrosis has been shown to be a strong independent predictor of poor outcomes, including sudden cardiac death.^17–20 However, late gadolinium enhancement can be technically challenging, as variations in the timing of postcontrast imaging, sequences for measuring late gadolinium enhancement, or detection thresholds can result in widely variable image quality. Cardiac MRI should therefore be performed at an experienced center with standardized imaging protocols in place.

Current guidelines recommend considering cardiac MRI if a patient’s risk of sudden cardiac death remains inconclusive after conventional risk stratification, as discussed below.^9,21

Stress testing for risk stratification

Exercise stress electrocardiography. Treadmill exercise stress testing with electrocardiography and hemodynamic monitoring was one of the first tools used for risk stratification in HCM.

Although systolic blood pressure normally increases by at least 20 mm Hg with exercise, one-quarter of HCM patients have either a blunted response (failure of systolic blood pressure to increase by at least 20 mm Hg) or a hypotensive response (a drop in systolic blood pressure of 20 mm Hg or more, either continuously or after an initial increase). Studies have shown that HCM patients who have abnormal blood pressure responses during exercise have a higher risk of sudden cardiac death.^22–24

Exercise stress echocardiography can be useful to evaluate for provoked increases in the left ventricular outflow tract gradient, which may contribute to a patient’s symptoms even if the resting left ventricular outflow tract gradient is normal. Exercise testing is preferred over pharmacologic stimulation because it can provide functional assessment of whether a patient’s clinical symptoms are truly related to hemodynamic changes due to the hypertrophied ventricle, or whether alternative mechanisms should be explored.

Cardiopulmonary stress testing can readily add prognostic value with additional measurements of functional capacity. HCM patients who cannot achieve their predicted maximal exercise value such as peak rate of oxygen consumption, ventilation efficiency, or anaerobic threshold have higher rates of morbidity and mortality.^25,26 Stress testing can also be useful for risk stratification in asymptomatic patients, with one study showing that those who achieve more than 100% of their age- and sex-predicted metabolic equivalents have a low event rate.²⁷