Hypertrophic Cardiomyopathy Case File

Hypertrophic Cardiomyopathy Case File

Eugene C. Toy, Md, Michael d . Faulx, Md

Case 8

A 21-year-old man is evaluated during a routine medical examination prior to employment. He voices no active complaints and has no medical problems and takes no medications or illicit drugs. On review of symptoms (ROS) he tells you that 9 months ago he experienced an episode of syncope after playing volleyball with some friends. He attributed the episode to dehydration and did not seek medical attention for it. He has no family histoiy of cardiovascular disease but reports that his father died at the age of 40 years for unclear reasons. On physical examination, blood pressure is 116/72 mmHg, pulse rate is 58 bpm, and respiration rate is 16 breaths/mim BMI is 28 kg/m². There is no jugular venous distention. Carotid upstrokes are brisk. There is a grade 2/6 early systolic murmur along the left lower sternal border. A Valsalva maneuver increases the intensity of the murmur. Moving from a standing position to a squatting position. performing a passive leg lift while recumbent, and performing isometric handgrip exercises

decrease the intensity of the murmur. An S4 gallop is also noted. Electrocardiogram shows sinus bradycardia and left ventricular hypertrophy by voltage.

c What is the most likely diagnosis?

c What is the best next diagnostic step?

c What is the best therapy for this patient?

Answer to Case 8:

Hypertrophic Cardiomyopathy

Summary: A 21-year-old healthy man with no active complaints but with a history of unexplained syncope is found to have brisk carotid upstrokes, a grade 2/6 early systolic murmur along the left lower sternal border whose intensity increases on a Valsalva maneuver and decreases when the patient moves from a standing position to a squatting position, performing a passive leg lift while recumbent and performing isometric handgrip exercises. An S4 gallop is also noted. Electrocardiogram (ECG) shows sinus bradycardia and left ventricular hypertrophy (LVH) by voltage. His review of systems and family history raises concern for an increased risk for sudden cardiac death.

• Most likely diagnosis: Hypertrophic cardiomyopathy (HCM).
• Best diagnostic step: Transthoracic echocardiogram (TTE).
• Best therapy: Implantable cardioverter defibrillator (ICD).

ANALYSIS

Objectives

1. Recognize the clinical presentation and physical exam findings in HCM.
2. Understand the physiology of HCM and how changes in left ventricular loading conditions influence the degree of outflow obstruction.
3. Review the diagnostic approaches, treatments, and complications related to HCM.

Considerations

This 21-year-old asymptomatic man is found to have a systolic murmur on a routine physical examination. The most common diagnoses to consider include primary valve abnormalities (ie, bicuspid aortic valve, aortic stenosis, mitral valve prolapse), a benign flow-related murmur, HCM, ventricular septal defect, and aortic coarctation. In this patient, the physical examination is most consistent with HCM. The systolic murmur of HCM is caused by turbulent flow and obstruction in the left ventricular outflow tract (LVOT) from the thickened interventricular septum. In severe cases, systolic anterior motion (SAM) of the mitral valve apparatus into the LVOT also contributes the dynamic obstruction of left ventricular outflow. There may be concurrent mitral regurgitation (MR) if mitral valve leaflet coaptation is affected. The Valsalva maneuver and the squat-to-stand maneuver transiently decreases venous return, with the septum and anterior mitral leaflet brought closer together, thereby increasing the turbulent flow and the murmur intensity. The reasons for mitral leaflet SAM in HCM are incompletely understood, but changes in ventricular flow mechanics and the Venturi effect are felt to be drivers of this phenomenon.

The stand-to-squat maneuver and passive leg lift transiently increase venous return (preload), which increases left ventricular chamber size and volume, leading to less relative obstruction and turbulence in the LVOT, thus decreasing murmur intensity. Handgrip exercise increases afterload and decreases the relative pressure gradient across the LVOT, so murmur intensity for HCM is decreased. TTE can confirm a diagnosis of HCM.

Approach To:

Hypertrophic Cardiomyopathy

DEFINITIONS

HYPERTROPHIC CARDIOMYOPATHY (HCM): Myocardial hypertrophy (diffuse or focal) in the absence of other cardiac or systemic causes such as systemic hypertension or aortic valve stenosis.

SYSTOLIC ANTERIOR MOTION (SAM): Motion of the closed mitral valve leaflets or chordae toward the interventricular septum during systole. SAM contributes to dynamic left ventricular outflow tract obstruction in HCM.

CLINICAL APPROACH

Introduction

Hypertrophic cardiomyopathy, the most common genetically determined cardiovascular disease, is a primary disorder of the myocardium caused by mutations in several genes encoding proteins of cardiac sarcomere. Inheritance is autosomal dominant; however, only about 50% of patients have a family history of the disease, most likely the result of variable penetrance and new mutations. HCM occurs with equal frequency in men and women. Women have greater risk than men for progression to advanced heart failure, although there is no relation between gender and sudden death. HCM has been reported in many races, but it is underrecognized in African Americans.

Hypertrophic cardiomyopathy is the most common cause of sudden death in young persons, including competitive athletes. Along with diffuse or focal myocardial hypertrophy and dynamic outflow obstruction, it is also responsible for heart failure–related disability at virtually any age. The course is benign in most patients, but it can cause significant morbidity, including syncope, arrhythmia, ischemia, heart failure, and stroke. Annual mortality is as high as 3–6% in high-risk patients.

Pathophysiology

Hypertrophic cardiomyopathy can be considered obstructive or nonobstructive, depending on the presence of a left ventricular outflow tract (LVOT) gradient, either at rest or with provocative maneuvers. Depending on the site and extent of cardiac hypertrophy, HCM patients can develop one or more clinical abnormalities detailed as follows.

LV Outf ow Obstruction Marked asymmetric septal hypertrophy results in narrowing of the LVOT in many patients with HCM. In some cases obstruction is driven by the abnormal location of the mitral valve or a papillary muscle. The dynamic pressure gradient across the LVOT appears to be related to further narrowing of an already small outflow tract by the SAM of the mitral valve against the hypertrophied septum. Mitral regurgitation is a secondary consequence of SAM. The jet is usually mild to moderate in degree and directed posteriorly. Consequently, the left ventricle has to generate higher pressures to overcome the outflow obstruction. Premature closure of the aortic valve may occur and is caused by the decline in pressure distal to the LVOT obstruction.

Unlike the fixed obstructions of aortic stenosis and subvalvular aortic membranes, HCM-associated obstruction is dynamic. In dynamic obstruction, the degree of obstruction depends more on cardiac contractility and loading conditions than on fixed obstructions. An underfilled left ventricle experiences greater obstruction because there is less separation between the interventricular septum and mitral valve. Augmenting cardiac contractility also increases LVOT obstruction because a more vigorous contraction is more likely to cause the obstructing components to come together (coalesce).

Apparently there are distinct forms of HCM at different ages. Younger patients often have more diffuse hypertrophy and reversal of septal curvature, whereas older patients tend to have focal proximal septal hypertrophy, with a sigmoid septal morphology. These may be two different disease processes; subjects with reversal of septal curvature were found to have an almost 80% yield for screening for HCMassociated genetic mutations, but those with a sigmoid septum had less than a 10% yield. Hypertrophy often develops or worsens during the adolescent growth spurt. An apical variant of HCM also exists.

Older patients with severe concentric left ventricular hypertrophy and dynamic left ventricular systolic function can generate midcavity dynamic obstruction that mimics the LVOT obstruction in HCM. These patients can actually be protected from their dynamic LVOT obstruction by disorders that increase left ventricular afterload such as hypertension or severe aortic stenosis. In such patients the severity of their dynamic LV cavity obstruction sometimes becomes apparent after their hypertension is treated (particularly if diuretics or direct vasodilators are used) or following aortic valve replacement, where the effect of the unhindered dynamic outflow obstruction can be abrupt and dramatic (the “suicide left ventricle”).

Diastolic Dysfunction Most patients with HCM have abnormal diastolic function, which impairs ventricular filling and increases filling pressure, despite a normal or small ventricular cavity. Diastolic dysfunction is likely to be the fundamental mechanism by which heart failure occurs in nonobstructive HCM with preserved LV systolic function.

Myocardial Ischemia Patients with HCM have abnormal calcium kinetics and myocardial ischemia, which are related to the profound hypertrophy, LV myocardial scarring, remodeling, and the myopathic process, and hence affect the clinical course. Active ischemia, demonstrable with positron emission tomography, is a determinant of progressive heart failure and cardiovascular mortality.

Clinical Presentation

The clinical course of HCM is variable. It is typically asymptomatic in childhood and adolescence. Symptomatic patients may have chest pain that is either typical angina pectoris or atypical in character. Patients may also have symptoms of heart failure such as dyspnea, fatigue, orthopnea, paroxysmal nocturnal dyspnea, and leg edema. Other symptoms may represent arrhythmia, including palpitations, presyncope/syncope, and lightheadedness. Sudden death (likely secondary to ventricular arrhythmias) can often be the initial manifestation occurring commonly in asymptomatic patients.

Physical Examination

Hypertrophic cardiomyopathy patients may have characteristic brisk carotid upstrokes. Arterial pulses usually rise rapidly with bisferiens contour because of an early systolic wave followed by dynamic obstruction and a later systolic wave (the “spike and dome” waveform). Lungs are usually clear to auscultation unless the patient has underlying heart failure, when crackles might be heard. The point of maximal impulse will be forceful and sustained, and a palpable S4 gallop may be present prior to a biphasic pulsation during systolic ejection (the “triple ripple”). Jugular venous pressures are usually normal. Initial clinical suspicion of HCM may be triggered by an incidental finding of a medium-pitched systolic ejection murmur at the lower left sternal border and apex on routine examination or before sports participation. Maneuvers that increase venous return (eg, leg elevation) diminish the murmur, and those that decrease preload (eg, Valsalva maneuver) enhance the murmur (see Table 8-1).

Abbreviations: LVOT, left ventricular outf ow tract; PVC, premature ventricular complex.

Differential Diagnosis

The differential diagnosis for HCM is somewhat broad and includes the athlete’s heart, hypertension-related hypertrophy, aortic stenosis, restrictive and infiltrative cardiomyopathies such as Fabry’s disease, and amyloidosis.

Diagnosis

The ECG is typically abnormal, showing increased QRS voltage consistent with LVH and ST-T changes, including marked T wave inversion in the lateral precordial leads, left atrial enlargement, deep and narrow Q waves, and diminished R waves in the lateral precordial leads.

Echocardiography (see Figure 8-1) usually yields the diagnosis, showing increased left ventricular mass, disproportionate left ventricular hypertrophy (particularly of the septum), hyperdynamic or preserved ejection fraction, diastolic dysfunction, small LV cavity, and atrial enlargement. Tissue Doppler echocardiography measures velocity of myocardial contraction and relaxation, and may allow disease detection before development of hypertrophy and has prognostic importance. Exercise echocardiography is useful to unmask labile obstruction. Compared with HCM, athlete’s heart is more apt to manifest concentric hypertrophy, less marked hypertrophy (wall thickness ≤15 mm), an enlarged left ventricular cavity (>55 mm end diastolic diameter), lack of marked left atrial enlargement, and normal diastolic function. Hypertension and Fabry disease cause concentric wall thickening.

Cardiovascular magnetic resonance imaging (cMRI) adds incremental diagnostic information if HCM cannot be confirmed or differentiated from other etiologies. cMRI detects focal areas of hypertrophy and fibrosis, which have been associated with a greater risk for arrhythmia and sudden cardiac death.

Figure 8-1. HCM by echocardiogram. This parasternal long-axis image was obtained during systole and reveals systolic anterior motion (SAM) of the mitral valve (arrow) in a patient with marked thickening of the interventricular septum (bracket) (Ao, aorta; LA. left atrium: LV left ventricle). (Reproduced, with, permission, from Michael Faulx, MD.)

Treatment

Asymptomatic patients should be counselled to avoid particularly strenuous activities or competitive athletics. These patients should also receive screening for risk factors for sudden cardiac death. Septal reduction therapy is not recommended in asymptomatic patients. Various medications can help relax the muscle and slow the rate to enable the heart to pump more efficiently. Some of the drugs include beta-blockers, calcium channel blockers, or the antiarrhythmic medications disopyramide and amiodarone. Diuretics can be cautiously used in case of fluid overload.

The thickened part of the septum is surgically removed in cases of progressive heart failure symptoms refractory to medications. Comprehensive surgical management of HCM sometimes includes mitral valve repair and even relocation of abnormally situated papillary muscles in order to properly relieve obstruction. In select patients who are not ideal candidates for surgical septal myectomy, a small portion of the thickened heart muscle may be destroyed by injecting alcohol through a catheter into a septal perforator branch of the left anterior descending coronary artery (alcohol septal ablation). Complications with this procedure include heart block, which may require implantation of a permanent pacemaker. The role of right ventricular pacing to induce dyssynchronous left ventricular activation to lessen LVOT obstruction is unclear and somewhat controversial. It is generally not as effective as surgical options, but it is sometimes used in older people who want to avoid more invasive procedures.

Some HCM patients are at risk of sudden cardiac death because of abnormal heart rhythms that an ICD can detect and restore by delivering precisely calibrated electrical shocks. In these patients implantation of an implantable cardioverter defibrillator (ICD) may be required. ICD placement is recommended in the highrisk individuals (Table 8-2). Cardiac transplantation for HCM is the only available treatment for end-stage heart failure if done before sequelae such as pulmonary hypertension, kidney dysfunction, and venous thromboembolism occur.

CASE CORRELATION

• See also Case 1 (acute coronary syndrome/STEMI) and Case 2 (acute coronary syndrome/NSTEMI).

COMPREHENSION QUESTIONS

8.1 A 19-year-old man with no past medical history is evaluated after the recent sudden death of his father at age 45 years. He is asymptomatic and does not smoke or take illicit drugs. On physical examination, he is afebrile, blood pressure is 120/60 mmHg, pulse rate is 60/min, and respiration rate is 14/min. No jugular venous distention is present. A grade 2/6 midsystolic murmur that increases during the strain phase of the Valsalva maneuver is heard; brisk carotid upstrokes are present. An electrocardiogram shows sinus rhythm and increased QRS voltage of precordial leads and also symmmetric basal and midseptal hypertrophy, and a 36-mm left ventricular end diastolic wall thickness of the septum. Which of the following is the most appropriate management?

A. Alcohol septal ablation

B. Electrophysiology testing

C. Measurement of blood pressure response to exercise

D. Placement of implantable cardioverter-defibrillator

E. Start amiodarone

8.2 A 32-year-old man is evaluated in the emergency department after being involved in a motor vehicle accident 30 minutes ago. He was confused at the scene, with a forehead laceration. On arrival, blood pressure is 165/90 mmHg and pulse rate is 80/min. Head CT is unremarkable. Over the course of 1 hour, blood pressure decreases to 70/45 mmHg and pulse rate increases to 110/min. Blood pressure increases to 75/50 after a normal saline bolus. Despite dopamine, blood pressure progressively declines. A medical alert bracelet notes a history of HCM. On physical exam grade 3/6 midsystolic murmur is heard at the left sternal border. ECG shows sinus rhythm, increased QRS voltage, and inverted T waves. TTE reveals small left and right ventricular cavities, hyperdynamic left ventricular function, asymmetric basilar septal hypertrophy, prolonged SAM of the mitral valve, and moderate MR. In addition to saline boluses and discontinuing dopamine, which of the following is the most appropriate treatment?

A. Epinephrine

B. Phenylepherine

C. Milrinone

D. Dobutamine

ANSWERS

8.1 D. Two major risk factors for sudden cardiac death: family history of premature sudden death in a first-degree relative and left ventricular wall thickness of ≥30 mm in this HCM patient warrants placement of ICD.

8.2 B. In HCM patients with LVOT obstruction inotropic agents (eg, dopamine, dobutamine) may precipitate hemodynamic collapse and are contraindicated. Phenylephrine is an α-agonist and raises afterload by peripheral vasoconstriction, which decreases the LVOT pressure gradient and increases blood pressure. Milrinone has vasodilator effects and will reduce the blood pressure. 

CLINICAL PEARLS

C HCM is the most common genetic cardiovascular disease.

C It is the most frequent cause of sudden cardiac death in young people.

C Presentation varies from asymptomatic to heart failure symptoms.

C Family history may be present. TTE should be used to screen first-degree relatives.

C Use of CMRI for diagnosis and prognosis of HCM is growing.

C An lCd should be implanted in any HCM patient who lias an increased risk for sudden death.

References

Carasso S, Rakowski H. Hypertrophic Cardiomyopathy. In: Klein AL and Garcia MJ, eds. Diastology: Clinical Approach to Diastolic Heart Failure. Philadelphia, PA. Elsevier, Saunders; 2008:287–299. 

Gersh BJ, Maron BJ, Bonow RO, et al. 2011 ACCF/AHA guideline for the diagnosis and treatment of hypertrophic cardiomyopathy: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg. 142(6):1303–1338. 

Maron BJ. Hypertrophic cardiomyopathy. In: Bonow O, Braunwald E, eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine. 9th ed. Philadelphia, PA: Elsevier, Saunders; 2012:1582–1594.

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