Hypertrophic cardiomyopathy (HCM) may be defined as left ventricular (LV) hypertrophy in the absence of an underlying cause such as systemic hypertension or valvular aortic stenosis.¹ Left ventricular outflow tract obstruction (LVOTO) is caused by septal hypertrophy combined with abnormal systolic anterior motion (SAM) of the mitral valve, and this, in turn, produces variable degrees of mitral valve regurgitation (MR). LVOTO in HCM is distinct in morphology and prognosis from congenital membranous subaortic stenosis, which is rarely associated with SAM. Some patients with HCM will have symptoms due to mid ventricular obstruction. Hypertrophic obstructive cardiomyopathy (HOCM) is important for surgeons because obstruction may occur in over 70 percent of patients with HCM,² and transaortic septal myectomy is highly effective in the management of HOCM.

Morphology

Distribution of Hypertrophy

As shown in Figure 46-1 distribution of LV hypertrophy is variable in patients with HCM. For example, subaortic stenosis may be associated with diffuse ventricular hypertrophy (Fig. 46-1E), or the hypertrophy may be limited to the septum (asymmetric septal hypertrophy, ASH) (Fig. 46-1B). In other patients, there may be obstruction in the mid-ventricle where hypertrophy of the papillary muscles leads to obstruction of ejection of blood, and in other patients, there may be an apical distribution of hypertrophy (Fig. 46-1F). It is important to note that neither the phenotype of the disease nor the appearance and severity of hypertrophy correlates with genotype; multiple ventricular morphologies may be found in the same family.

Mitral Valve

In the classic form of HOCM, the mitral valve, especially the anterior leaflet of the valve, moves anteriorly during systole, and the posterior leaflet closes against the mid- and free-edge third of the anterior leaflet instead of at the free edge as occurs normally. The free edge of the anterior leaflet is then displaced upward and narrows the left ventricular outflow tract (LVOT). Anterior displacement of the valve leaflets produces MR of variable degree, and the jet is oriented in a posterolateral direction. MR is an important pathophysiologic component of HOCM and contributes to the symptoms of dyspnea and fatigability. Apposition of the anterior leaflet to the bulging septum produces a contact lesion, a whitish endocardial scar, which is useful in guiding septal myectomy. It is important to note that occurrence of SAM is often dynamic, and provocative maneuvers such as Valsalva, squatting, exercise, and, in some cases, adrenergic stimulation may be necessary to elicit SAM, MR, and LVOTO.

Anomalies of papillary muscles are present in 15 to 20 percent of patients with HCM who undergo myectomy. These abnormalities include anomalous papillary muscles, direct insertion of papillary muscles into the anterior mitral valve leaflet, fusion of the papillary muscle to the ventricular septum or LV free wall, and accessory muscles and accessory anomalous chordae (false cords). In most cases, these abnormalities do not complicate myectomy or contribute to outflow tract obstruction, but in some patients, anomalous papillary muscles, especially those that insert directly into the anterior leaflet, can contribute to outflow tract obstruction.³

Coronary Arteries

Coronary arteries are larger than normal in patients with HCM, and basal coronary flow is increased in the resting state. Coronary flow reserve (CFR), however, is decreased in symptomatic patients with HCM compared with controls, and phasic flow is abnormal with a greater amount of flow during diastole, the presence of flow reversal in systole, and a more rapid deceleration of diastolic blood flow compared with normal patients. Decreased flow reserve is associated with a reduction in coronary resistance, suggesting that the mechanism is not due to narrowing of intramyocardial small arteries or compression of the microcirculation; indeed, the reduction in CFR in patients with HCM may be the result of near maximal vasodilation of the microcirculation in the basal state.

Atherosclerotic coronary artery disease (CAD) is present in approximately 5 to 15 percent of patients with HCM depending upon the population studied. At the Mayo Clinic, significant CAD was detected in half of patients who were selected for coronary angiography, and disease was severe in 26 percent.⁴ Survival of HCM patients with obstructive CAD is reduced compared with HCM patients without CAD, and survival is also poorer than in patients without HCM who have comparable CAD and normal ventricular function.

Muscular bridging of the left anterior descending coronary artery (LAD) is not uncommon, occurring in 15 percent of patients with HCM undergoing coronary angiography at our clinic. It is unclear whether bridging of the LAD plays a role in the pathophysiology of the disease and associated symptoms of angina, but for adult patients, risk of death and, in particular, sudden cardiac death, is not increased among patients with HCM with myocardial bridging. In contrast, Yetman and coworkers⁵ reported that among children with HCM, systolic compression of the LAD was present in 285 cases and was associated with a greater incidence of chest pain (60 vs 19 percent, P = 0.04), cardiac arrest with subsequent resuscitation (50 vs 4 percent, P = 0.004), and ventricular tachycardia (80 vs 8 percent, P < 0.001). Myocardial ischemia was postulated to be the cause of this poor outcome.

Histopathology

Myocardial Fiber Disarray

A characteristic histologic feature of HCM is myocardial fiber disarray, which consists of short runs of severely hypertrophied fibers interspersed by connective tissue. Myocytes show large, bizarre nuclei with degenerating muscle fibers and fibrosis. It is the disorganized whirling of muscle fibers that is characteristic of HCM. Myocardial disarray is not pathognomonic for HCM and may be present in the myocardium for any conditions in which there is pressure overload.

HCM has a prevalence of 0.2 percent for phenotypically expressed disease. Approximately 60 to 80 percent of cases are familial and the remainder result from de novo mutations.⁶ HCM is genetically diverse, involving sarcomeric and nonsarcomeric proteins, and over 400 mutations in over 15 genes have been identified; indeed, double and compound heterozygosity and homozygosity have been reported.⁷ Most patients with familial disease have mutations in three protein-encoding genes: β-myosin heavy chain (MYH7) in 35 to 50 percent, myosin-binding protein C (MYBPC3) in 15 to 25 percent, and cardiac troponin T type 2 (TNNT2) in 15 to 20 percent. In current practice, the clinical value of genetic testing is uncertain.

A potential benefit of genetic analysis is the preclinical diagnosis in patients with a family history of SCD or in those carrying a “malignant” mutation that predisposes them to a severe phenotype. Also, it may be useful to know the precise genetic defect in HCM among asymptomatic family members who carry the mutation and might be at risk for SCD.

Diastolic Dysfunction

Diastolic dysfunction with elevation of the LV end-diastolic pressure is the principal pathophysiologic feature in HCM. The resulting increase in left atrial and pulmonary venous pressures accounts for the common symptoms of effort dyspnea and limited aerobic capacity. With worsening diastolic function, LV filling becomes more dependent on atrial contraction, and occurrence of atrial arrhythmias, especially atrial fibrillation (AF), can cause an acute and profound decrease in cardiac output and worsening of symptoms.

LVOTO has a direct effect of increasing end-diastolic pressure and an indirect effect on hemodynamics through the often associated MR. Thus, while surgical myectomy has a minimal immediate effect on overall LV mass, symptoms related to diastolic dysfunction are immediately improved when outflow gradients and MR are relieved. A secondary effect of septal myectomy on diastolic function is regression of hypertrophy.

In some patients, concentric ventricular hypertrophy is so severe that muscle mass encroaches upon the ventricular cavity and reduces normal cavity size. This is particularly striking in patients with the apical form of HCM where the distal one-third to distal one-half of the left ventricle may be obliterated (during diastole and systole) by muscle. Surgical remodeling by apical myectomy may increase end-diastolic volume and thus improve diastolic function.

Left Ventricular Outflow Obstruction

Surgical treatment of HCM consists primarily of relief of LVOTO. Previously, there was debate on the importance of outflow tract obstruction as a mechanism for symptoms in patients with HCM because of the lability of the finding and the question of catheter entrapment when gradients were measured by invasive catheterization. It is now recognized that outflow obstruction is much more common than previously thought, correlates importantly with development of symptoms, and may negatively influence long-term survival.

Among 320 patients with HCM, Maron found resting outflow tract gradients of ≥50 mm Hg in 37 percent and, more importantly, found exercise-induced gradients (mean 80 ± 43 mm Hg) in an additional 106 patients. Thus, as many as 70 percent of patients with HCM who come to clinical evaluation will have significant outflow tract obstruction.⁸ Another important finding in this study was the relative unreliability of the Valsalva maneuver (sensitivity 40 percent) compared with exercise Doppler echocardiography in detecting these dynamic gradients. Latent obstruction can also be documented during hemodynamic catheterization by isoproterenol challenge, and the technique may be useful in patients who are unable to exercise or in patients in whom reliable Doppler echocardiographic parameters cannot be measured.⁹

Mitral Valve Regurgitation

As is true with outflow gradients, the degree of MR is often dynamic. Symptomatic patients with moderate or severe degrees of MR associated with HOCM are excellent candidates for operation because the MR and associated symptoms (dyspnea and fatigability) are almost always abolished or significantly improved with adequate septal myectomy.

Intrinsic mitral valve disease may contribute to valvular regurgitation in patients with HOCM. Rupture of chordae with resultant leaflet prolapse can precipitate congestive heart failure, and hemodynamics may worsen if HCM is not recognized and patients are managed medically with afterload reduction.

Echocardiogram

Two-dimensional and Doppler echocardiography is the essential tool for the diagnosis of HCM, providing information on ventricular morphology, hemodynamics, and valve function. The most common pattern of hypertrophy is diffuse involvement of the ventricular septum. In patients with HCM, the average maximal LV-wall thickness is 20 to 22 mm, and in 5 to 10 percent of patients, LV wall thickness is dramatically increased measuring 30 to 50 mm. Morphology of the septum appears to vary according to age, and older patients with HCM often demonstrate a sigmoid configuration.

The echocardiographic findings of increased wall thickness should prompt a search for other causes including systemic hypertension (especially in patients on dialysis), valvular aortic stenosis, and infiltrative and glycogen storage diseases such as cardiac amyloidosis, Fabry’s disease, and Friedreich’s ataxia.

On continuous-wave Doppler echocardiography, LVOTO is seen as a high-velocity, late-peaking, “dagger-shaped” signal. In patients with low velocity at rest (less than 3 m/s), maneuvers such as Valsalva, inhalation of amyl nitrate, or exercise may demonstrate latent obstruction. Presence and severity of MR can be determined by Doppler color-flow imaging. It is important to differentiate the true outflow tract velocity from the MR jet.

MR that results from SAM is eccentric and directed posterolaterally during late systole. A centrally directed jet should raise suspicion of a primary leaflet abnormality contributing to valve leakage. Preoperative transesophageal echocardiography (TEE) is unnecessary in most patients, but TEE is critically important intraoperatively in assessing the results of myectomy.

Cardiac MRI

Cardiac MRI is useful in identifying regions of LV hypertrophy not easily recognized by echocardiography, specifically the anterolateral free wall and the apical area. In addition, MRI can detect the presence and severity of myocardial fibrosis that appears to be an important risk factor for subsequent ventricular arrhythmias and sudden cardiac death.

Invasive Catheterization

In current practice, cardiac catheterization is rarely necessary for the diagnosis of HCM. Coronary angiography is indicated for patients with symptoms of angina and for patients at risk for CAD (strong family history, abnormal lipids, older age) who undergo myectomy. A hemodynamic study with isoproterenol provocation can be useful in identifying patients with labile obstruction gradients that cannot be elicited during echocardiography.

Symptom Course

The clinical course of HCM is variable, but the onset of symptoms is often associated with development of LVOTO. It is uncertain what causes this in adult patients who have had no gradients until the fourth, fifth, or sixth decade of life. Onset of AF can also precipitate symptoms and predispose to systemic embolism, which occurs in 6 percent of patients.¹⁰ AF is noted in 30 percent of older patients with HCM.

Infective endocarditis may occur with HCM, and the reported incidence is 1.4 cases/1000 person-years. But the important feature is that in virtually all cases of endocarditis, there is LVOTO. Indeed, among HCM patients with obstruction, the incidence of endocarditis is 3.8 per 1000 person-years, or a 4 percent likelihood of developing this complication over 10 years.