A 17-year-old adolescent boy presented to the general cardiology clinic for family screening after a maternal aunt had been diagnosed with hypertrophic cardiomyopathy (HCM). He had no history of chest pain, breathlessness, or syncope. He reported mild symptoms of postural hypotension. Examination revealed normal first and second heart sounds with an audible and palpable fourth heart sound, but no murmurs. His electrocardiogram (ECG) demonstrated left ventricular hypertrophy (LVH) with repolarization abnormalities, and echocardiographic and cardiac magnetic resonance imaging (MRI) features of severe asymmetric LVH are noted in this patient (Figure 10-1). He had no evidence of arrhythmia on ambulatory Holter monitoring, but exercise testing demonstrated an abnormal blood pressure response on exercise. Familial genetic testing was performed and identified a pathogenic mutation in the sarcomere gene MYL3. Given his risk factor profile for sudden cardiac death (SCD), an automatic implantable cardioverter defibrillator (AICD) was implanted for primary prevention.

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  HCM represents the most common inherited cardiac disorder and is a global disease with no racial or ethnic preponderance.¹ A reported prevalence of approximately 0.2% (1:500) has been reported consistently in epidemiological studies.¹

  
  
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  Age-related penetrance is a key feature of the disease, with onset and progression of hypertrophy occurring at virtually any age.

  
  
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  Importantly, it is the most common cause of SCD in young people (<35 years of age) and athletes.²

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  HCM represents a primary disease of the myocardium. The hallmark of the disease is the presence of increased left ventricular (LV) wall thickness in the absence of another cardiac or systemic disease that could result in a similar degree of myocardial hypertrophy.

  
  
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  On a microscopic level there is extensive disarray of myocytes and myofibrils, as well as thickening of the intramural microvessels and interstitial fibrosis.

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  In adults and adolescents, the disease typically exhibits an autosomal dominant pattern of inheritance. In around 40% to 60% of cases, a mutation in 1 of the genes encoding sarcomeric proteins is identified.

  
  
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  In up to 10% of cases in adults another underlying genetic disorder may be the cause of the HCM phenotype. In addition, nongenetic causes also account for some cases of unexplained LVH.^3,4

DIFFERENTIAL DIAGNOSIS

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  LVH can represent either a physiologic (athlete’s heart) or pathologic cardiac response that can occur in a variety of cardiac, genetic, and systemic diseases (Figure 10-2), or in response to hemodynamic loading of the ventricle (arterial hypertension and aortic stenosis).

  
  
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  Accurate identification of the underlying etiology is critical given that HCM is a common cause of premature SCD and can lead to considerable morbidity. Specific therapeutic strategies are available for certain mimics of HCM, such as the inborn errors of metabolism, Anderson-Fabry disease, and amyloidosis; early and accurate diagnosis allows timely institution of appropriate therapy.

The symptoms and clinical presentation in patients with HCM result from a complex interplay between several structural and hemodynamic underlying abnormalities.

DIASTOLIC DYSFUNCTION

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  Hypertrophy and fibrosis of the myocardium result in an increase in myocardial stiffness, ultimately causing an impairment in LV relaxation. Delayed LV relaxation results both in an inability to increase stroke volume during exercise and an increase in left ventricular end-diastolic pressure (LVEDP).

  
  
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  Impaired passive filling of the left ventricle due to stiffness leads to an increased reliance on active filling during atrial systole, which is why atrial fibrillation is often poorly tolerated.

  
  
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  The chronic increase in LVEDP and atrial pressures results in left atrial dilatation over time.

LEFT VENTRICULAR OUTFLOW TRACT OBSTRUCTION

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  Left ventricular outflow tract (LVOT) obstruction is an important and frequent manifestation of HCM. While in most cases the level of obstruction is subvalvular in the outflow tract, in a subset of patients the obstruction is primarily at the midventricular level (resulting from a combination of septal hypertrophy and hypertrophy of the papillary muscles).⁵

  
  
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  Obstruction is a major cause of symptoms such as dyspnea, chest pain, presyncope, and syncope, and is associated with a higher risk of progressive heart failure (HF) and death.⁶

  
  
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  LVOT obstruction is classically dynamic and variable, affected by the hemodynamic changes that occur in day-to-day life (heart rate, inotropic or contractile state of the heart, systemic vascular resistance, and loading conditions).

  
  
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  The cause is multifactorial and includes both vigorous ejection of the left ventricle as well as the alterations in chamber geometry and morphology caused by hypertrophy. Hypertrophy of the interventricular septum and systolic anterior motion of the mitral valve contribute to obstruction. Abnormalities of the mitral valve and subvalvular apparatus/papillary muscles frequently coexist and further aggravate obstruction.

MYOCARDIAL ISCHEMIA

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  Unlike common forms of ischemia related to epicardial coronary artery disease, ischemia in HCM is multifactorial. It arises not only from a supply/demand mismatch (as a result of increased myocardial mass), but also due to abnormalities of the myocardial microvasculature.

  
  
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  A reduction in arteriolar density, small intracoronary arteriole dysplasia (SICAD), vessel intimal and/or medial thickening, and proliferation and disorganization of smooth muscle cells have all been described (Figure 10-3). The reduction in luminal cross-sectional area of the small vessels is further aggravated by dense perivascular collagen and increased collagen content in the media of the vessels.

  
  
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  Raised intracavitary left ventricular end-diastolic pressure (LVEDP) also serve to cause a reduction in transcoronary perfusion gradient, which further compromises coronary blood flow.

AUTONOMIC DYSFUNCTION

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  Disturbances of reflex control of the vasculature and systemic vascular resistance have been demonstrated in HCM. Inappropriate firing of LV mechanoreceptors can occur, particularly during exercise. The resulting sudden and inappropriate vasodilatation can precipitate a fall in blood pressure.⁷ These episodes of hypotension may lead to recurrent presyncope, syncope, or even act as a trigger for SCD.

  
  
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  Approximately 30% of patients demonstrate an abnormal blood pressure response to exercise (failure to increase systolic pressure by >20 mm Hg, or even a fall in blood pressure).^8,9

ARRHYTHMIA

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  Supraventricular arrhythmias are common, with up to 20% to 25% of patients experiencing episodes of atrial fibrillation. Risk factors for atrial fibrillation include the presence of LVOT obstruction, significant mitral regurgitation, and diastolic dysfunction. The risk of atrial fibrillation is related to the degree of left atrial dilatation and to abnormalities of left atrial function.^10-12

  
  
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  Bradycardias secondary to sinus node dysfunction or atrioventricular block are relatively uncommon. In younger patients, they may suggest the presence of certain genotypes (desmin, FHL1, PRKAG2). In older patients, they should raise the suspicion of a mimic of HCM such as cardiac amyloidosis or Anderson-Fabry disease.

  
  
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  Nonsustained ventricular tachycardia (NSVT; defined as ≥3 ventricular extrasystoles at a rate of ≥120 bpm, of <30 seconds duration) is a relatively common finding on ambulatory Holter monitoring. NSVT increases in frequency with age, occurring in around 25% of patients over the age of 40 years. NSVT is a risk factor for SCD (particularly in adults and young children),¹³ and is related to the degree of LVH and myocardial fibrosis.

  
  
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  Sustained ventricular tachycardia, in contrast, is uncommon. However, in high-risk patients in whom an AICD has been fitted for primary prevention of SCD, sustained monomorphic ventricular tachycardia is seen more frequently on device interrogation.

  
  
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  Exercise-induced ventricular arrhythmias are rare, but when present have been associated with a significantly increased risk of sudden death or AICD discharge.¹⁴

SYSTOLIC DYSFUNCTION

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  A small proportion of patients can develop systolic impairment, with a reported prevalence of between 2.4% and 15%.^15,16 A left ventricular ejection fraction (LVEF) of <50% represents significant impairment of LV function, given that these patients typically have a supranormal LVEF. Similar to other causes of LV dysfunction, there is progressive wall thinning and chamber dilatation (end-stage or burnt-out HCM).

AGE

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  Age is important and may give a clue to the underlying cause of HCM. Inherited metabolic disorders and congenital syndromes (eg, Noonan syndrome) are much more common in neonates and infants. Similarly, transthyretin cardiac amyloidosis is more common with advancing age.

FAMILY HISTORY

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  A thorough family history spanning 3 to 4 generations is crucial in order to establish and confirm the genetic nature of the disease (Figure 10-4). Most genetic forms of HCM are autosomal dominant and an affected individual will be present in every generation. When transmission occurs only from the mother, a mitochondrial DNA mutation should be suspected.

  
  
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  Family history should include a history of premature SCD, unexplained HF, pacemaker or defibrillator implantation, or heart transplantation.

Many patients are either asymptomatic or minimally symptomatic, with severe medically refractory symptoms occurring in only a small proportion. Asymptomatic patients may come to attention due to the incidental finding of a heart murmur or an abnormal ECG. An increasing number of cases come to attention through family screening of an affected individual.

DYSPNEA

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  Breathlessness is common in patients with HCM, and is typically the result of diastolic dysfunction and LVOT obstruction.

  
  
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  An increase in breathlessness and NYHA class may be precipitated by the acute onset of atrial fibrillation, or more insidiously by the development of LV systolic dysfunction.

CHEST PAIN

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  Chest pain may present as typical angina (often with postprandial exacerbation, typically in patients with obstructive physiology) or as atypical pain, and is caused by episodes of myocardial ischemia.

PALPITATIONS

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  Palpitations are most commonly associated with the development of atrial fibrillation, particularly if paroxysmal. In addition, NSVT and sustained ventricular arrhythmias may be the underlying cause.

PRESYNCOPE AND SYNCOPE

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  Episodes can occur at rest or with exertion.

  
  
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  The underlying causes are myriad, including arrhythmia, outflow tract obstruction, and autonomic dysfunction resulting in episodic hypotension.

  
  
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  Syncope, particularly if recent (within the preceding 6 months) or recurrent, is associated with an increased risk of SCD.¹⁷

STROKE

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  Occasionally the first presentation of HCM may be a stroke in the setting of atrial fibrillation or thrombus associated with an LV apical aneurysm.

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  In many patients the clinical examination may be entirely normal, particularly in patients without obstruction.

  
  
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  The apex beat is typically sustained and forceful, and a palpable fourth heart sound (S₄) may be present.

  
  
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  In patients with obstruction, an ejection systolic murmur, which is heard best at the left sternal edge, is present. The murmur will increase in intensity in the standing position and with performance of a Valsalva maneuver (reduction in preload), and will decrease in intensity with squatting and handgrip maneuvers (increase in afterload/systemic vascular resistance).

  
  
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  If significant mitral regurgitation is present, a pansystolic murmur will be heard best at the apex, with radiation to the axilla.

  
  
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  A thorough clinical examination may give clues to the underlying etiology of hypertrophy, with certain clinical signs associated with specific underlying conditions (angiokeratoma in Anderson-Fabry disease, multiple lentigines in LEOPARD syndrome, neuropathic pain and parasthesia in Anderson-Fabry disease and amyloidosis).

ELECTROCARDIOGRAPHY

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  The resting ECG may be normal in a minority of patients, but typically demonstrates a combination of LVH, ST segment and T-wave changes (typically T-wave inversion), and pathological Q waves (Figure 10-5). In apical HCM there is giant negative T-wave inversion (>10 mm).

  
  
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  Left atrial enlargement may be surmised by the presence of a P-mitrale pattern.

  
  
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  The presence of a short PR interval and pre-excitation may give a clue to the underlying etiology (storage disorders, mitochondrial disorders, and Anderson-Fabry disease).

  
  
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  Ambulatory Holter monitoring is recommended in all patients at first clinical assessment and subsequently at periodic intervals for both risk stratifications for SCD (NSVT) and stroke (paroxysmal or sustained atrial fibrillation).