Cardiomyopathy, Hypertrophic

• Christopher P. Blomberg, D.O.
• Marc Paul Waase, M.D., PH.D.

 Basic Information

Definition

Hypertrophic cardiomyopathy (HCM) is most commonly an autosomal dominant myocardial disorder characterized by disorganized myocyte architecture and marked thickening (hypertrophy) of the left ventricular wall (≥15 mm), without dilation, not explained by another cardiac or systemic disorder. The interventricular septum is the most common site of enlargement, though hypertrophy may involve other focal regions or may be concentric. HCM may result in hemodynamically significant obstruction within the left ventricular outflow tract (LVOT) and/or impairment of the diastolic function of the left ventricle. However, about one third of patients have no obstruction at rest or with provocation.

Synonyms

1. HCM

2. Hypertrophic cardiomyopathy

3. Idiopathic hypertrophic subaortic stenosis (IHSS)

4. Hypertrophic obstructive cardiomyopathy (HOCM)

5. Hypertrophic nonobstructive cardiomyopathy

6. Asymmetric septal hypertrophy (ASH)

7. Familial hypertrophic cardiomyopathy

ICD-10CM CODES
I42.1	Obstructive hypertrophic cardiomyopathy (Includes hypertrophic subaortic stenosis)
I42.2	Other hypertrophic cardiomyopathy (Includes nonobstructive hypertrophic cardiomyopathy)
I42.8	Other cardiomyopathies
I42.9	Cardiomyopathy, unspecified (includes cardiomyopathy [primary] [secondary] NOS)

Epidemiology & Demographics

1. •

   Prevalence in the general population in the U.S., China, and Japan is estimated to be between 1/500 to 1/200 (the most common genetically transmitted cardiovascular disease).

2. •

   HCM is the most common cause of sudden cardiac death in young athletes (more commonly among blacks).

3. •

   There is equal prevalence in men and women (probably underdiagnosed in women).

4. •

   It occurs across ethnicities, perhaps underdiagnosed among blacks.

5. •

   Mortality rate is approximately 1%/yr, as high as to 2%/yr in children.

6. •

   The most common form of the disease is familial (60%-70% of cases), and it follows an autosomal dominant inheritance pattern with variable expression.

7. •

   Spontaneous mutations can also occur, accounting for approximately 20% of cases. It is otherwise indistinguishable from the familial form.

8. •

   A variant form seen in the elderly (5%-10% of cases) has a better prognosis, and it is not typically associated with sudden cardiac death.

9. •

   The familial form is usually diagnosed in young patients. It is most often caused by a mutation in one of the contractile protein genes of the cardiac sarcomere. See “Etiology” or more details.

10. •

    Nonsarcomeric genetic mutations that cause storage disease (e.g., Fabry disease) have a very similar clinical presentation.

11. •

    Apical HCM is a variant more common among Asians: as many as 41% of Chinese HCM and 15% of Japanese HCM patients. Clinically there is no LVOT obstruction.

Physical Findings & Clinical Presentation

Patients may have subtle symptoms of progressive congestive heart failure (CHF). At time of diagnosis, most patients are asymptomatic, referred and diagnosed based on family history. HCM may be suspected on the basis of abnormalities found on physical examination. Classic findings include:

1. •

   Harsh, systolic, crescendo–decrescendo murmur at the left sternal border or apex. The murmur increases with maneuvers that decrease venous return or LV size (Valsalva, standing), and decreases with those that increase venous return or afterload (squatting, hand grip, post-Valsalva release).

2. •

   Paradoxical splitting of S2 (if left ventricular obstruction is present).

3. •

   S4 may be present.

4. •

   Double or triple LV apical impulse (“triple ripple”: atrial contraction, early rapid ejection, and late slow ejection).

5. •

   Pulsus bisferiens (double pulsation on palpation of the carotid pulse).

Increased obstruction can occur with:

1. •

   Drugs: digitalis, β-adrenergic stimulators (isoproterenol, dopamine, epinephrine), nitroglycerin, vasodilators, diuretics, alcohol, inhalation of amyl nitrate

2. •

   Hypovolemia

3. •

   Tachycardia

4. •

   Valsalva maneuver

5. •

   Standing position

Decreased obstruction is seen with:

1. •

   Drugs: β-adrenergic blockers, calcium channel blockers, disopyramide, α-adrenergic stimulators

2. •

   Volume expansion

3. •

   Bradycardia

4. •

   Hand-grip exercise

5. •

   Squatting position

6. •

   Release phase of the Valsalva maneuver

Clinical manifestations are as follows:

1. •

   Syncope or presyncope (usually seen with exercise)

2. •

   Angina

3. •

   Palpitations

4. •

   Sudden cardiac death

5. •

   Heart failure (typically with advanced stages): dyspnea on exertion, orthopnea, edema, increased jugular venous pressure, paroxysmal nocturnal dyspnea

Etiology

1. •

   Genetic: Autosomal dominant trait with variable penetrance caused by mutations in multiple genes encoding proteins of the cardiac sarcomere and calcium regulation. To date, >1400 mutations have been identified among at least 13 genes, with variable phenotypes, expressivity, and penetrance. The most vigorous evidence indicates that 8 genes are known to definitively cause HCM: beta myosin heavy chain, myosin binding protein C, troponin T, troponin I, tropomyosin alpha-1 chain, actin, regulatory light chain, and essential light chain. HCM may be caused by a single mutation in one of two alleles; however, 5% of patients have at least two mutations. Sarcomeric protein gene mutations account for up to 60% of cases of HCM.

2. •

   Metabolic: Most are autosomal recessive, but some are X-linked. Most commonly, they are due to Anderson-Fabry disease (a lysosomal storage disease). Other metabolic etiologies include the glycogen storage diseases Pompe and Danon, AMP-kinase (PRKAG2), and carnitine disorders.

3. •

   Mitochondrial: These comprise autosomal dominant, autosomal recessive, X-linked, and maternally inherited traits. Most frequently, they are due to mutations in the respiratory chain protein complexes. The age of onset and severity of involvement are variable.

4. •

   Neuromuscular: These are most commonly associated with Friedreich’s ataxia, but they are also associated with FHLI.

5. •

   Malformation syndromes: These etiologies include Noonan, LEOPARD, Costello, and cardiofasciocutaneous.

6. •

   Amyloidosis: These include familial ATTR, wild-type TTR (senile), and amyloid light-chain (AL) amyloidosis.

7. •

   Drug-induced: Tacrolimus, hydroxychloroquine, and steroids.

8. •

   Sporadic occurrence.

Diagnosis

Differential Diagnosis

1. •

   Hypertensive heart disease

2. •

   Aortic stenosis

3. •

   Subaortic stenosis

4. •

   Athlete’s heart

5. •

   Volume depletion

Workup

1. •

   Medical history: Unexplained clinical manifestations and/or family history of sudden death.

2. •

   Physical exam: See “Physical Findings & Clinical Presentation.”

3. •

   Genetic counseling with or without testing.

4. •

   ECG is abnormal in 75% to 95% of patients, although there are no pathognomonic findings. Typical findings include:

   1. 1.

      LV hypertrophy (abnormally tall R waves in the precordial leads) in up to 80% of patients (Fig. 1)

      

   2. 2.

      Abnormal Q waves in lateral and inferior leads

   3. 3.

      T wave inversions (associated with the apical hypertrophy predominant variant)

5. •

   Echocardiography (Fig. 2) is usually diagnostic as the majority of patients have significant LV hypertrophy (See “Imaging Studies” for details) and should be repeated every 12 to 24 months or as clinically needed.

   

6. •

   24-hour Holter monitor to screen for potentially lethal ventricular arrhythmias (principal cause of syncope or sudden death in obstructive cardiomyopathy) should be performed at the initial diagnosis and in patients that subsequently develop palpitations, lightheadedness, or syncope. The presence of these arrhythmias identifies patients who are candidates for ICD therapy.

7. •

   In the absence of significant LVOT obstruction, exercise testing is indicated at diagnosis and annually thereafter to evaluate for symptoms and response to exercise. A drop in systolic blood pressure by at least 20 mm Hg or failure to augment by at least 20 mm Hg with exercise are markers of poor prognosis and are indicators for referral for myotomy/myomectomy. Cardiopulmonary exercise testing can provide objective evidence for worsening diseases, but need only be performed every 2 to 3 years.

8. •

   Biomarkers of myocardial fibrosis in HCM include BNP and high-sensitivity cardiac troponin T and I. Other labs include CBC, BMP, LFTs, TSH, SPEP, UPEP, Kappa/Lambda.

9. •

   Screening for sarcomere protein gene mutations in family members of patients with HCM can identify a broad subgroup of patients with increased propensity toward long-term impairment of left ventricular function and adverse outcome, irrespective of the myofilament (thick, intermediate, or thin) involvement.

10. •

    In individuals with pathogenic mutations who do not express the HCM phenotype, it is recommended to perform serial electrocardiogram (ECG), transthoracic echocardiogram (TTE), and clinical assessment at periodic intervals (12 to 18 months in children and adolescents and about every 5 years in adults), based on the patient’s age and change in clinical status.

11. •

    Endomyocardial biopsy may be helpful to rule out diseases other than HCM if a diagnosis remains inconclusive after extensive testing.

Imaging Studies

1. •

   Chest x-ray may be normal or show cardiomegaly.

2. •

   Two-dimensional echocardiography is used to establish the diagnosis and assess the severity of obstruction when present. LV wall thickness will usually be ≥15 mm (although some may be genetically positive but phenotype negative), and most patients (up to 95%) will have asymmetric (ratio of septum thickness to left ventricular wall thickness >1.3:1) LV wall hypertrophy. Symmetric LV hypertrophy is less common. The septum is most often affected, followed by the left ventricular mid-cavity and apex. In addition, 25% to 30% of patients will manifest systolic anterior motion (SAM) of the anterior leaflet of the mitral valve, causing obstruction of the LVOT and mitral regurgitation. Two-dimensional strain imaging echocardiography is useful for differentiation of HCM and cardiac amyloidosis from other causes of ventricular wall thickening. Up to 80% of HCM patients will also have diastolic dysfunction as evidenced by pulsed mitral valve inflow pattern and tissue Doppler.

3. •

   Cardiac MRI or cardiac CT may be of diagnostic value when echocardiographic studies are technically inadequate. MRI is also useful in identifying unusual segmental hypertrophy undetectable by standard echocardiography and can detect myocardial replacement fibrosis (an independent predictor of adverse cardiac outcomes and ventricular arrhythmias) using late gadolinium enhancement. CMR evaluation may be considered every 5 years or every 2 to 3 years in patients with progressive disease.

Treatment

Nonpharmacologic Therapy

1. •

   Avoid volume depletion: HCM patients experience decrease in stroke volume and consequent increase in left ventricular outflow gradient with exercise. This may lead to hypotension, dizziness, and syncope.

2. •

   Exercise restriction: The risk of sudden cardiac death is increased by exercise in HCM patients. Participation in competitive sports and intense physical activity should be avoided. As a part of a healthy lifestyle, low-intensity aerobic exercise is reasonable.

3. •

   Avoidance of alcohol: Alcohol use (even in small amounts) may result in increased obstruction of the left ventricular outflow tract. Other stimulants such as cocaine and other sympathomimetic recreational drugs should also be avoided.

General Rx

1. •

   Therapy for HCM is directed at blocking the effect of catecholamines and avoiding vasodilator or diuretic agents that can exacerbate the dynamic left ventricular outflow tract obstruction.

2. •

   Beta-blockers’ beneficial effects on symptoms (principally dyspnea and chest pain) and exercise tolerance appear to be largely a result of a decrease in the heart rate with consequent prolongation of diastole and increased passive ventricular filling. By reducing the inotropic response, beta-blockers may also reduce myocardial oxygen demand and decrease the outflow gradient during exercise, when sympathetic tone is increased.

3. •

   Nondihydropyridine calcium channel blockers (e.g., verapamil is the preferred agent, diltiazem) can also decrease left ventricular outflow obstruction through a mechanism similar to beta-blockers. However, they are mainly second-line agents used in patients who cannot tolerate beta-blockers as they also theoretically have vasodilatory properties that may worsen severe outflow tract gradients.

4. •

   Disopyramide is an antiarrhythmic that is also a negative inotrope, resulting in further decrease in outflow gradient. It is sometimes used in combination with beta-blockers.

5. •

   Prophylactic antibiotics before dental, GI, and genitourinary procedures are no longer recommended according to the 2007 American Heart Association (AHA) guidelines.

6. •

   Avoid use of digitalis, intravenous inotropes, dihydropyridine calcium channel blockers (e.g., nifedipine, amlodipine), nitrates, and vasodilators.

7. •

   Diuretics, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers should be used with caution.

8. •

   Intravenous phenylephrine (or another pure vasoconstricting agent) is recommended for the treatment of acute hypotension in patients with obstructive HCM who do not respond to fluid administration.

9. •

   Implantable cardiac defibrillators (ICDs) are a safe and effective therapy in HCM patients prone to ventricular arrhythmias. In their practice guidelines, the major cardiology societies (AHA/ACC/HRS) give a strong recommendation (Class I) for ICD implantation in all patients with HCM who have had an episode of sustained ventricular tachycardia or fibrillation. In addition, they endorse the prophylactic placement of an ICD (Class IIa recommendation) for patients with one or more of the major risk factors for sudden cardiac death (outlined in “Disposition”).

10. •

    Dual-chamber pacing may provide symptomatic relief of symptoms attributable to LVOT obstruction and refractory to medical therapy.

11. •

    HCM patients are at an increased risk of atrial fibrillation (AF) as well as systemic thromboembolization. AF occurs in over 20% of the HCM population. AF is an important source of symptoms, morbidity, and mortality and correlates to a worse prognosis. AF therapy is indicated independent of CHA₂DS₂-VASc score and should aim for thromboembolic risk mitigation with a vitamin K antagonist (unless contraindicated) and symptom alleviation via rhythm (generally preferred due to poor tolerance of AF with HCM) or rate control. If a vitamin K antagonist cannot be used in a patient (due to inability to maintain a therapeutic INR, inability to adequately perform INR monitoring, or other side effects), the 2014 ESC HCM (Class Ib) and 2014 ACC/AHA/HRS AF (Class Ic) guidelines recommend the use of direct thrombin or factor Xa inhibitors, even though there is no data on their use in patients with HCM.

Disposition

HCM is not a static disease. Some adults may experience subtle regression in wall thickness, whereas others (∼5%-10%) paradoxically evolve into an end-stage cardiomyopathy resembling dilated cardiomyopathy, characterized by cavity enlargement, left ventricular wall thinning, and systolic dysfunction. Patients with HCM are at increased risk for sudden death, especially if the onset of symptoms began during childhood. Severe left ventricular outflow obstruction at rest is also a strong, independent predictor of severe symptoms of heart failure and death. ICD implantation for primary prevention should be considered if patients (particularly the young) have any of the following high risk features:

1. •

   Personal history of sudden cardiac death or out of hospital cardiac arrest (major risk factor)

2. •

   Spontaneous sustained ventricular tachycardia or ventricular fibrillation (major risk factor)

3. •

   Family history of premature death in a first-degree relative possibly caused by HCM

4. •

   Unexplained syncope

5. •

   Nonsustained ventricular tachycardia during Holter monitoring

6. •

   Substantial septal hypertrophy (>30 mm)

7. •

   Abnormal blood pressure response during exercise

8. •

   Increased delayed gadolinium enhancement on cardiac magnetic resonance imaging is suggested in some recent studies as a marker of increased SCD risk

Referral

1. •

   Surgical treatment (septal myectomy involving resection of the basal septum) is now the gold standard for relieving outflow tract obstruction in patients with large outflow gradient (≥50 mm Hg) and moderate to severe symptoms unresponsive to medical therapy. The risk for sudden death from arrhythmias is not altered by surgery. When this operation is performed by experienced surgeons in tertiary referral centers, the operative mortality rate is <1%, and many patients are able to achieve near-normal exercise capacity after surgery. Mitral valvuloplasty or plication in combination with myectomy may be necessary in <5% of patients. Risks of surgery include AV nodal block, ventricular septal defect, and aortic regurgitation (AR).

2. •

   Alcohol septal ablation is a nonsurgical alternative to reduce the size of the interventricular septum. This can be done in patients with HCM refractory to pharmacologic treatment, particularly in those who are not candidates for myectomy due to high surgical risk or patient preference. This technique involves the injection of ethanol in a septal perforator branch of the left anterior descending coronary artery (Fig. 3), producing a controlled myocardial infarction of the interventricular septum, and thereby reducing septal mass and consequently the left ventricular outflow tract gradient. This method may lead to improvement in both subjective and objective measures of exercise capacity, but results are not as effective as surgery because they are associated with a high incidence of heart block, requiring permanent pacing in approximately one fourth of patients, and/or recurrence of obstruction and symptoms. This should be done only at centers with experienced operators.

   

3. •

   Refractory end-stage HF symptoms can be treated with LVAD, BiVAD, or heart transplant.

Pearls & Considerations

Comments

1. •

   Clinical screening of first-degree relatives with two-dimensional echocardiography and ECG is indicated. Starting at the age of 12, periodic screening at 12- to 18-month intervals is recommended for children of patients with HCM and in competitive athletes. Periodic screening of first-degree adult family members not in competitive athletics is recommended at 5-yr intervals because hypertrophy may not be detected until the sixth decade of life. Genetic testing is not indicated in relatives of index patients who do not have a definite pathogenic mutation.

2. •

   Genetic counseling and screening (Fig. 4) is recommended in first-degree relatives of patients with HCM. Genetic screening of first-degree relatives can refine or eliminate the need for periodic clinical screening. At least 13 genes are known to cause HCM, among them: cardiac myosin binding protein-C, beta-myosin heavy chain, troponin T, troponin I, alpha tropomyosin, actin regulatory light chain, and essential light chain. Clinical predictors of positive genotype, such as the presence of ventricular arrhythmias, age at diagnosis, degree of left ventricular wall hypertrophy, and family history of HCM, may aid in patient selection for genetic testing and increase the yield of cardiac sarcomere gene screening. Currently a mutation can be identified in 40% to 60% of all cases, sporadic or familial.

   

3. •

   All HCM patients who wish to become pregnant should be given prenatal counseling about the risk of transmission (about 50%) to their offspring and should be followed at a tertiary care center that specializes in high-risk pregnancies. Most patients with HCM tolerate pregnancy well due to the higher circulating blood volume.

4. •

   The mortality rate in HCM is approximately 1% to 2% per yr.

5. •

   About one third of HCM patients will not have a resting or labile outflow gradient (i.e., nonobstructive form of HCM), but it is important to note that lethal ventricular arrhythmias can occur in the absence of obstruction or symptoms.

6. •

   Myocardial fibrosis is a hallmark of hypertrophic cardiomyopathy. Biomarkers of collagen metabolism such as serum C-terminal propeptide of type I procollagen (PICP) are significantly higher in mutation carriers without left ventricular hypertrophy and in subjects with overt hypertrophic cardiomyopathy than in controls, indicating that a probiotic state precedes the development of hypertrophy of fibrosis identifiable with cardiac MRI.

 

Suggested Readings

• P.M. Elliott, et al.: 2014 ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy. Eur Heart J. 35 (39):2733–2779 2014 25173338

• B.J. Gersh, et al.: 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: a report of the American College of Cardiology Foundation/American Health Association Task Force on practice guidelines. Circulation. 124:e783–e831 2011 22068434

• C.Y. Ho, et al.: Myocardial fibrosis as an early manifestation of hypertrophic cardiomyopathy. N Engl J Med. 363:552–563 2010 20818890

• B.J. Maron: Hypertrophic cardiomyopathy, a systematic review. JAMA. 287:1308 2002 11886323

• B.J. Maron, et al.: Genetics of hypertrophic cardiomyopathy after 20 years: clinical perspectives. J Am Coll Cardiol. 60 (8):705–715 2012 22796258

• C. Semsarian, et al.: New perspectives on the prevalence of hypertrophic cardiomyopathy. J Am Coll Cardiol. 65 (12):1249–1254 2015 25814232

• H.G. van Venlzen, et al.: Value of genetic testing for the prediction of long-term outcome in patients with hypertrophic cardiomyopathy. Am J Cardiol. 118:881–887 2016 27476098

• L. Wang, et al.: Narrative review: harnessing molecular genetics for the diagnosis and management of hypertrophic cardiomyopathy. Ann Intern Med. 152:13 2010

• H. Watkins, et al.: Inherited cardiomyopathies. N Engl J Med. 364:1643–1656 2011 21524215

• W. Wilson, et al.: Prevention of infectious endocarditis: guidelines from the American Heart Association. Circulation. 116:1736 2007 17446442

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