Introduction and Epidemiology
Hypertrophic cardiomyopathy (HCM) is a complex cardiac disorder that has been the subject of intense scrutiny and scientific investigation for the past half century. HCM is a unique cardiac condition that has the potential to manifest during any phase of life, from infancy to the ninth decade. Despite the wide range of symptoms and ages of affected individuals, sudden and unexpected death in young people is perhaps the most devastating aspect of this disease. Despite a wealth of scientific data in this field, controversy continues with regard to diagnostic criteria, clinical course, and optimal management strategies for patients with HCM.
Since its first description in 1958, HCM has been referred to by a wide variety of names reflecting lapses in understanding of this complex disease and its clinical heterogeneity. The terms like idiopathic hypertrophic subaortic stenosis (IHSS) or hypertrophic obstructive cardiomyopathy (HOCM) are misleading, since they encompass only a subset of patients who have left ventricular outflow tract (LVOT) obstruction. In fact, roughly three fourths of the patients have no LVOT gradient at rest, and one third of patients do not demonstrate any LVOT gradient at rest, or with provocative maneuvers. With an improved understanding of the clinical heterogeneity of the disease, HCM is a more appropriate descriptive term that encompasses the overall disease spectrum.
HCM is a global disease and is the most common genetic cardiovascular disease encountered. The current prevalence of HCM in the adult population has been estimated to be 0.2% (1 : 500 adults), with similar estimates for other parts of the world. Approximately 600,000 adults are currently believed to be suffering from HCM. However, HCM patients constitute no more than 1% of outpatients in a routine cardiology practice, implying that a large majority of these patients remain undiagnosed. Due to the relatively infrequent prevalence of patients with HCM, most outpatient cardiologists care for only a few HCM patients and may not be aware of the contemporary management of this complex disease. This has led to an impetus for establishment of clinical programs of excellence, called “HCM Centers,” which would be staffed with cardiologists and cardiac surgeons familiar with the contemporary diagnostic and treatment options for HCM. These should include comprehensive history and physical examination followed by transthoracic echocardiography (TTE), cardiac magnetic resonance (CMR) imaging, both surgical septal myectomy (SM) and alcohol septal ablation (ASA), along with management of arrhythmias, and implantation of implantable cardiac defibrillators (ICD), genetic testing, and counseling.
Hallmarks and Differential Diagnosis
HCM has been defined as a disease state characterized by unexplained LV hypertrophy without chamber dilation in the absence of another cardiac or systemic disease that is capable of producing hypertrophy to the observed degree, with the caveat that patients who are genotypically positive may be phenotypically negative without manifest LV hypertrophy. HCM is usually recognized by a maximal septal hypertrophy ≥15 mm on echocardiography, particularly in the presence of other compelling information like family history of HCM. The LV septal thickness of 13 to 14 mm is considered borderline. Most of the current literature in the field of HCM has quantified LV septal thickness using echocardiography, although the use of CMR has been increasing over the last few years, and new data are likely to emerge in forthcoming years. In children, increased LV septal thickness is defined as thickness ≥2 standard deviations above the mean for age, sex, and body size. Despite these widely utilized cutoff points, it must be understood that any degree of LV wall thickness is compatible with the genetic substrate of HCM. An emerging subgroup within the broad clinical spectrum may be composed of family members with disease causing sarcomere mutations but without evidence of the disease phenotype. These individuals are generally referred to as “genotype positive or phenotype negative,” or as having “subclinical HCM.” In addition, a large number of patterns of LV hypertrophy, including segmental or diffuse involvement of LV, have been described in LV hypertrophy. It is possible that the LV wall hypertrophy may be limited to a small isolated segment that leads to a normal calculated LV wall mass using standard echocardiographic measurements.
The most common differential diagnoses of HCM include hypertensive heart disease and the physiologic remodeling of the heart seen among athletes (athlete’s heart). Mild morphologic expressions of HCM, or borderline HCM, pose the maximum degree of confusion with these diseases. In older individuals, HCM may even co-exist with hypertensive heart disease, which may pose further diagnostic challenges. The likelihood of HCM increases when the presentation is associated with a diagnostic sarcomere mutation, or inferred by marked LV thickness >25 mm and/or LVOT obstruction with systolic anterior motion (SAM) of the anterior mitral leaflet. The important distinction between pathologic LV hypertrophy seen in HCM and physiologic LV hypertrophy seen among athletes is the fact that the latter is usually associated with chamber enlargement (usually both LV and RV), and generally regresses when the high-level exercise routine is stopped. Besides ventricular dimensions, a detailed review of the family history, sarcomeric mutations, diastolic function, and pattern of LV hypertrophy may aid in the distinction of two states.
Several metabolic and infiltrative diseases may mimic HCM among babies, older children, and young adults—for example, mitochondrial diseases, Fabry disease, storage disease caused by mutations in genes encoding the γ-2 regulatory subunit of the adenosine monophosphate (AMP) activated protein kinase (PRKAG2), or the X-linked lysosome associated membrane protein gene (LAMP2; Danon disease). Other mimics of HCM may be encountered in the context of multisystem disorder such as Noonan syndrome (craniofacial and congenital heart malformations) as well as LV hypertrophy from mutations in genes of the RAt Sarcoma (RAS) pathway or distinct cardiomyopathies such as Pompe’s disease (glycogen storage disorder II, due to deficiency of α-1, 4-glucosidase).
Natural Course of Disease and Clinical Presentation
The understanding of the natural history of HCM has been hampered by a significant selection bias in published literature. Earlier published studies from the tertiary and quaternary centers reported a high annual mortality rate of 3% to 6%. Recent data from regional- and community-based centers suggest an annual mortality rate of ~1%. Selected subpopulations who have high-risk features, or those who are symptomatic, may have a higher annual mortality rate averaging ~5%. When mortality rates are reviewed, it is important to take into consideration the population that constitutes the denominator.
The clinical course of HCM is unpredictable in most scenarios. In addition, there are currently no therapies that prevent progression of this disease. Despite this, most affected individuals attain normal life expectancy without any disability or even a need for invasive therapeutic interventions. On the other hand, HCM disease progression may result in serious complications with a potential for premature death. Among those who do become symptomatic, there are three discrete clinical presentations of this disease.
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Sudden cardiac death (SCD) due to unpredictable and often refractory ventricular tachyarrhythmias. This is often encountered in young asymptomatic individuals <35 years of age (including competitive athletes).
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Heart failure with or without angina: This results in a progressively worsening exertional dyspnea. The earlier stages of HCM are characterized by diastolic heart failure without loss of systolic function. If left untreated, it may progress to the end-stage with LV remodeling and systolic dysfunction secondary to extensive myocardial scarring.
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Supraventricular tachycardia including atrial fibrillation (AF), which may be paroxysmal or permanent and leads to an increased risk of systemic thromboembolism including stroke. AF with rapid ventricular response may result in abrupt decompensation of an otherwise asymptomatic patient.
In the current era, the natural history of HCM can be altered by a number of therapeutic interventions: ICD implantation for prevention of SCD, medical therapy for managing heart failure symptoms, SM or ASA for progressive LVOT obstruction leading to sequelae, anti-arrhythmic or ablation therapies for management of AF, and lastly heart transplantation for end-stage HCM with refractory symptoms and systolic dysfunction.
Pathophysiology
The pathophysiology of HCM is complex and involves interplay of multiple factors. It is important to understand and quantify the contribution of each of the following mechanisms to an individual patient’s phenotype as the management strategies are largely dependent on these pathophysiologic mechanisms.
Left Ventricular Outflow Tract Obstruction
In patients with HCM, LVOT obstruction at rest has been demonstrated to be a strong, independent predictor of progression to severe symptoms of heart failure and of death. In HCM, the peak instantaneous gradient rather than the mean gradient holds greater prognostic significance and influences treatment decisions. Based on the extent of obstruction, the entire HCM cohort can be divided into three groups. The first group includes those who have obstruction (defined as LVOT gradient ≥30 mm Hg) at resting conditions. The second group includes those who have labile physiologically provoked gradients (defined as LVOT gradient <30 mm Hg at rest and ≥30 mm Hg with physiologic provocation). The final group includes those who have nonobstructive HCM, with LVOT gradient <30 mm Hg at rest and on provocation. Marked gradients ≥50 mm Hg at rest or with provocative maneuvers represent the conventional threshold for invasive management if symptoms are not controlled with medications alone.
LVOT obstruction in HCM is classically dynamic, varying with loading conditions and the loading conditions of the ventricle. Increased myocardial contractility, decreased ventricular volume, or decreased afterload increases the degree of LVOT obstruction. Patients with low LVOT gradients at rest may generate marked LVOT obstruction with exercise, Valsalva maneuver, or with pharmacologic provocation with amyl nitrite ( Figure 31-1 ). There may be a large variation in the degree of LVOT obstruction based on day-to-day activities, even minute to minute, based on heart rate and blood pressure, or even with food or alcohol intake; exacerbation of symptoms during the postprandial period is not uncommon.
LVOT obstruction leads to an increase in LV systolic pressure. This, in turn, leads to prolongation of ventricular relaxation, elevation of LV end-diastolic pressure, worsening mitral regurgitation (MR), myocardial ischemia, and a decrease in cardiac output. Although it was initially believed that LVOT obstruction primarily results from the systolic contraction of the hypertrophied basal ventricular septum encroaching on the LVOT, recent studies have demonstrated a greater involvement of the mitral valve leaflets in causing LVOT obstruction. LVOT obstruction generally occurs by virtue of systolic anterior motion (SAM) of anterior mitral leaflet and resultant mitral septal contact ( Figure 31-2 ). Ventricular systole in HCM causes an abnormal drag force on anterior mitral leaflet that “sucks in” this leaflet into the LVOT, causing obstruction. Occasionally, presence of hypertrophied papillary muscle abutting the septum, or anomalous papillary muscle insertion into the anterior mitral leaflet, may cause significant mid-cavitary obstruction.
The presence and degree of LVOT obstruction is assessed using two-dimensional echocardiography and continuous wave Doppler assessment ( Figure 31-1 ). The peak instantaneous gradient derived from the late-peaking systolic velocity is what reflects the subaortic obstruction. If the resting outflow gradient is <50 mm Hg, provocative measures are employed to ascertain if higher gradients can be obtained. This can be demonstrated using exercise (stress echocardiography) or Valsalva maneuver, or by inhalation of amyl nitrite. In equivocal cases, where there is a considerable discordance between clinical presentation and echocardiography data, cardiac catheterization with isoproterenol infusion may further aid in eliciting a provocable gradient.
Diastolic Dysfunction
Diastolic dysfunction is a major pathophysiologic mechanism in HCM that results in impairment of ventricular relaxation and chamber stiffness. The former results from systolic contraction against an obstructed LVOT, nonuniformity of ventricular contraction and relaxation, and a delayed inactivation caused by abnormal intracellular calcium reuptake. A marked increase in the LV wall thickness results in both impaired ventricular relaxation as well as increased chamber stiffness. Diffuse myocardial ischemia also potentiates the amount of diastolic dysfunction encountered in HCM. With exercise, there is a decrease in diastolic filling time and an increase in the amount of myocardial ischemia, which results in worsening of the diastolic dysfunction and may cause an increase in the pulmonary capillary wedge pressure resulting in dyspnea.
Myocardial Ischemia
Chest pain, both typical and atypical, is reported by roughly 80% of HCM patients. In many cases, heart catheterization reveals normal coronary arteries. Despite this observation, several studies with functional assessment of ischemia using single photon emission computed tomography (SPECT), positron emission tomography (PET), and CMR technologies have demonstrated significant reversible and irreversible myocardial perfusion defects in HCM patients. Autopsy data have reported that up to 15% of HCM patients may have findings of myocardial infarction, which may or may not be the reason for mortality. This discordance suggests that microvascular dysfunction may play an important role in the development of myocardial ischemia in these patients. The etiology of microvascular dysfunction is probably multifactorial. It may be partly due to arteriolar medial hypertrophy, resulting in reduced luminal diameter and an impaired coronary vasodilatory response. In addition, there is a demand supply mismatch that is created because of an abnormally thickened ventricle along with adverse loading conditions due to LVOT obstruction.
Autonomic Dysfunction
About a quarter of patients with HCM undergoing exercise stress testing demonstrate an abnormal blood pressure response to exercise characterized by a failure of systolic blood pressure to increase by at least 20 mm Hg at peak exercise, or a fall in systolic blood pressure. This subset of patients has been shown to have poorer prognosis compared with others. In addition to the potentiation of the dynamic LVOT gradient, it is speculated that autonomic dysregulation with resultant systemic vasodilation plays an important role in this phenomenon. It is believed that autonomic dysregulation is present in these patients and the fall in blood pressure, and associated bradycardia, may be an abnormal reflex response secondary to LVOT obstruction.
Mitral Regurgitation
Mitral regurgitation (MR) is common in patients with HCM and may play a primary role in mediating the symptoms of dyspnea ( Figure 31-3 ). The detailed mechanistic studies and the resolution of MR with SM suggest that MR is a secondary phenomenon in most patients with HCM. MR is usually caused by distortion of mitral valve apparatus from SAM-induced drag forces. In this case, the jet of MR is generally directed posterolaterally ( Figure 31-3 ). An anterior, or anteromedially, directed jet should suggest an intrinsic abnormality of the mitral valve apparatus. If the mechanism of MR is directly related to LVOT obstruction-induced SAM, changes in ventricular load and contractility would affect the degree of MR. It is very important to identify patients with intrinsic abnormality of mitral valve (prolapse or flail leaflets) because this finding has a major implication on the choice of treatment strategy.
Myocardial Fibrosis
Histopathologic examination of myocardium affected by HCM typically demonstrates myocardial fiber disarray with markedly thickened cardiomyocytes, arranged in whirls and branches and an increased amount of fibrosis, especially in advanced cases. It may be speculated that this cellular disarray reduces the contractile force of the affected myocardium, which in turn stimulates the myocardial hypertrophy process. Assessment of fibrosis may be performed using biomarkers as well as cardiac imaging modalities like echocardiography and CMR. In HCM, extracellular matrix turnover also seems to be a determinant of cardiac remodeling. Accordingly, the ratio of PICP (C-terminal propeptide of type I procollagen, a marker for collagen synthesis) to C-terminal telopeptide of type I collagen (collagen degradation product) was increased in subjects with HCM, suggesting that collagen synthesis exceeds degradation in these patients. The presence of fibrosis is suggested by late gadolinium enhancement (LGE) of affected myocardium observed on CMR ( Figure 31-4 ). LGE imaging detects accumulation of contrast in areas of fibrosis due to slower contrast kinetics and greater volume of distribution in the extracellular matrix. However, it should be noted that not all areas of LGE represent scar, especially in HCM. Areas of LGE identified in 40% to 80% of HCM patients may be helpful in the diagnosis of HCM versus other causes of LV wall thickening. Besides CMR, newer echocardiographic modalities like tissue Doppler imaging and speckle tracking can also help determine the extent of fibrosis in HCM. Low septal tissue velocity (<5 cm/s, normal >8 cm/s) corresponds to increased early diastolic stiffness of the fibrotic septum ( Figure 31-5 ). Speckle tracking often shows markedly reduced septal strain as opposed to the normal systolic function of the less fibrotic lateral wall.
Genetics and Role of Genetic Testing
Genetic studies have demonstrated that HCM is caused by dominant mutations in any one of the 11 or more genes encoding thick and thin contractile myofilament protein components of the sarcomere, or the adjacent Z-disc. Of patients who have been genotyped, about 70% have mutations in two genes: β-myosin heavy chain (MYH7) and myosin binding protein C (MYBPC3). Troponin T (TNNNT2), troponin I (TNNI3), and several other genes account for 5% or less of all cases. Despite few of these mutations accounting for a large majority of cases, more than 1400 mutations (largely missense) have been identified that may be responsible for causing HCM. Some of these include α-myosin heavy chain (MYH6), titin (TTN), muscle LIM protein (CSRP3), telethonin (TCAP), vinculin (VCL), and junctophilin 2 (JPH2).
Genetic mutations that cause HCM are transmitted in an autosomal dominant fashion, implying that each offspring of an affected individual has a 50% chance of inheriting this disease. Sporadic cases may arise due to de novo mutations. The phenotypic heterogeneity that exists between individual cases suggests that the mutations of the sarcomeres are probably not the only determinant of the HCM phenotype. It is possible that modifier genes or environmental factors affect the final phenotype. Age-related penetrance can occasionally result in delayed appearance of LV hypertrophy during adulthood. Nevertheless, LV wall thicknesses evident in mid-life and at older ages are generally modest. Extreme LV hypertrophy is rare at advanced ages.
Rapid, automated DNA sequencing provides opportunities for comprehensive genetic testing and identification of mutations causing HCM. However, pathogenic mutations can be identified in fewer than half of clinically affected probands. In addition, DNA-based testing frequently identifies novel DNA sequence variants for which pathogenicity is unresolved. Such ambiguous variants have virtually no clinical use for family screening and promote confusion in interpretation of genetic testing results.
The American College of Cardiology (ACC) and American Heart Association (AHA) recommend genetic testing for evaluation of familial inheritance for all patients with diagnosed HCM (Class I). Patients who undergo genetic testing should also undergo counseling by a cardiovascular genetics expert to review the implications of the results of their investigation (Class I). Genetic and/or clinical screening of all first-degree family members of patients with HCM is recommended to identify those with undiagnosed disease (Class I). Because familial HCM is a dominant disorder, the risk that an affected patient will transmit disease to each offspring is 50%. Because HCM mutations are highly penetrant, a mutation conveys substantial (>95%) risk for developing phenotypic expression of HCM. According to the current guidelines, the usefulness of genetic testing in the assessment of risk of SCD in HCM patients is considered uncertain (Class IIb). Genetic testing is not indicated in relatives when the index patient does not have a definitive pathogenic mutation (Class III).
Diagnosis
Echocardiography
Two-dimensional echocardiography is the most common method for establishing the clinical diagnosis of HCM via identification of a thickened nondilated LV in the absence of other co-morbidities known to cause LV hypertrophy. According to the latest ACC/AHA guidelines, TTE is recommended in the initial evaluation of all patients with suspected HCM (Class I). In addition, a TTE is recommended as a component of the screening algorithm for family members of patients with HCM (Class I). For family members between 12 and 21 years, screening should be performed every 12 to 18 months. For relatives older than 21 years, imaging should be performed either at the onset of symptoms or possibly at 5-year intervals. More frequent intervals may be appropriate among families, where a malignant clinical course or history of late-onset HCM exists. For children <12 years of age, screening is optional unless the child is a competitive athlete in an intensive training program, or is symptomatic, or there is a malignant family history of premature death from HCM, or other adverse complications are present.
Although classically thought to involve the upper septum, HCM can result in any pattern of LV thickening. While maximal wall thickness >15 mm is the traditional echocardiographic threshold utilized for defining HCM, the degree of LV hypertrophy often demonstrates considerable variability. It is important to note that the paucity of characteristic LV hypertrophy >15 mm on TTE does not exclude the presence of a gene mutation for HCM. Serial echocardiographic examinations are often necessary for monitoring the progression of LV hypertrophy and LVOT obstruction. In addition, there are considerable differences in the pattern of LV involvement between young and elderly patients. Elderly patients are often found to have an elliptical ventricular cavity with hypertrophy limited to the basal septum. In contrast, young patients often have a crescent-shaped LV cavity associated with diffuse hypertrophy of the interventricular septum.
Resting LVOT obstruction is observed in approximately one third of patients with HCM. Subaortic obstruction is usually dynamic in nature and is secondary to SAM of the anterior mitral leaflet leading to mitral-septal contact during mid-systole. Obstruction is not present in resting conditions in another third of all patients but can be provoked by pharmacological maneuvers (like amyl nitrite), or by physiological maneuvers (like Valsalva, exercise). Significant MR frequently accompanies SAM owing to distortion of the valvular apparatus and malcoaptation of the anterior and posterior mitral leaflets during systole. Up to 30% of the patients with HCM may have intrinsic mitral valve abnormalities such as leaflet prolapse, chordal rupture, or leaflet calcification/fibrosis. Less commonly, a mid-cavity gradient may be present because of anomalous insertion of the anterolateral papillary muscle directly onto the anterior mitral leaflet or an exaggerated proliferation of the mid-ventricular papillary musculature coming into apposition with the ventricular septum. It is important not to misinterpret the Doppler spectral display of MR for LVOT velocities given their close spatial orientations ( Figure 31-3 ). In the setting of SAM, the MR jet is generally posterolaterally directed into the left atrium, and it is often difficult to distinguish from the LVOT flow. It is useful to sweep anterior to posterior with continuous wave Doppler to distinguish these two flows.
Given the degree of LV hypertrophy seen in HCM, it is not uncommon to observe diastolic dysfunction on echocardiography. This may be manifested by reduced maximal flow velocity in early diastole (E wave), an increase in isovolumic relaxation time, and increased atrial contribution to the ventricular filling (A wave). Further, tissue Doppler imaging may demonstrate reduced velocities at the upper septal location suggestive of stiff fibrotic septum ( Figure 31-5 ). These changes are often present in patients without significant LVOT obstruction, suggesting that diastolic dysfunction may be an earlier clinical manifestation in the spectrum of the disease process.
Electrocardiography
Although increased voltages consistent with LV hypertrophy and early repolarization abnormalities are commonly encountered in HCM, electrocardiographic (ECG) findings in HCM are quite heterogeneous. Although >90% of patients have abnormal ECGs, no pattern is highly specific for the condition. Besides increased voltages and repolarization abnormalities, there may be left axis deviation, left atrial enlargement, T wave inversion, or nonspecific ST segment abnormalities. The degree of LV hypertrophy in HCM does not appear to correlate with the magnitude of hypertrophy when assessed using TTE. In a subset of Japanese patients with hypertrophy limited to the ventricular apex, giant T wave inversions are frequently noted in the anterior leads; these are often termed Yamaguchi’s disease. Pathological Q waves may be seen in the inferolateral leads in about 50% of patients with HCM. Moreover, approximately a third of patients have delayed His-Purkinje conduction noted on electrophysiological studies, possibly owing to the strain on the anterior fascicle, which overlies the hypertrophied ventricle.
According to the current ACC/AHA guidelines, 24-hour ambulatory ECG monitoring is recommended in the initial evaluation of patients with HCM to detect ventricular tachycardia (VT), and identify patients who may be candidates for ICD therapy (Class I). In addition, 24-hour ambulatory ECG monitoring or event recording is recommended in patients with HCM who develop palpitations or lightheadedness (Class I). Furthermore, a 12-lead ECG is recommended as a screening tool for first-degree relatives of patients with HCM (Class I). It is considered reasonable to perform serial ambulatory ECG monitoring on an annual or 2-year basis in patients who do not have ICDs, who are stable, and do not manifest arrhythmias on baseline 12-lead ECG and Holter monitoring (Class IIa).
Stress Testing
Treadmill exercise testing is considered reasonable to determine functional capacity and response to therapy in patients with HCM (Class IIa). In patients with HCM who do not have a resting LVOT gradient >50 mm Hg, exercise echocardiography is reasonable for detection and quantification of exercise-induced dynamic LVOT obstruction (Class IIa). Exercise testing is useful in assessment of patients with HCM, as abnormal blood pressure response to exercise (defined as failure to increase systolic blood pressure by at least 20 mm Hg, or a drop in systolic blood pressure at peak exercise) has been shown to be associated with the risk of SCD. Stress-testing modalities may include bicycle, treadmill testing using the Bruce protocol, or metabolic cardiopulmonary testing, with measurement of gradient either during or immediately after exercise.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance (CMR) imaging offers multiple advantages to better detect areas of LV hypertrophy that are not well visualized or missed by TTE. These include superior resolution with precise morphological characterization, enhanced tissue contrast capability, and production of three-dimensional images. The ACC/AHA currently recommend CMR for patients with suspected HCM, when echocardiography is inconclusive or equivocal for establishing diagnosis (Class I). In addition, CMR imaging is indicated in patients with known HCM when additional information that may have an impact on management of decision making regarding invasive management such as magnitude and distribution of hypertrophy, or anatomy of the mitral valve apparatus, or papillary muscles are not adequately defined with echocardiography (Class I). CMR imaging is considered reasonable in patients with suspected Yamaguchi’s disease to define apical hypertrophy (Class IIa).
The last few years have witnessed a growing use of contrast-enhanced CMR with LGE to identify areas of myocardial fibrosis in patients with HCM ( Figure 31-4 ). A substantial proportion of patients with HCM have been shown to have LGE suggestive of areas with fibrosis that may occupy a significant volume of the LV myocardium. Patients with presence of LGE on CMR imaging tend to have more markers of risk of SCD, such as nonsustained VT on ambulatory monitoring, as compared with those without LGE. It is currently hypothesized that areas of LGE represent a substrate for generation of malignant ventricular tachyarrhythmias, which might be responsible for SCD. Several studies have already demonstrated that presence of LGE (rather than extent) may be associated with adverse cardiovascular events among patients with HCM. The current evidence supports a potential role of contrast-enhanced CMR with LGE as an arbitrator in clinical decision making for primary prevention ICDs, where SCD risk stratification remains inconclusive.
Invasive Hemodynamic Assessment
Given the vast amount of diagnostic and prognostic information that can be derived with noninvasive modalities discussed above, cardiac catheterization is generally not required for the diagnosis of HCM. Invasive evaluation is generally employed in four scenarios, as follows:
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If noninvasive imaging is insufficient to qualify, or quantify, the degree of LVOT obstruction
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To rule out concomitant coronary artery disease among those that present with typical anginal chest discomfort, especially in presence of traditional cardiovascular risk factors for atherosclerotic heart disease (intermediate-high likelihood of coronary artery disease) (Class I)
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To evaluate the presence of coronary artery disease prior to planned surgical myectomy
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To evaluate the anatomy of the septal perforators prior to ASA
Coronary arteries are generally free of obstruction in patients with HCM. Due to significant hypertrophy of the septum, compression of the left anterior descending (LAD) artery may be seen during systole, resulting in a classically described “sawfish” appearance. Myocardial bridging (or tunneling) may be present in up to 40% of patients with HCM. Myocardial bridging may be responsible for causing angina in the absence of significant epicardial coronary artery stenosis. Although it has been suggested that intermittent ischemia as a result of myocardial bridging could be a potential mechanism for sudden death in HCM patients, there has been no convincing evidence to support this hypothesis in adults or children. Left ventriculography may demonstrate systolic cavity obliteration, MR, and occasionally hypertrophied septum prolapsing into the LVOT. Direct measurement and localization of the gradient may be performed by placing an end-hole catheter at the LV apex and then slowly withdrawing it while continuously monitoring the pressure waveform. Use of a wire placed via guide catheter helps maintain control during the pullback, and a more accurate determination of the level of obstruction. As opposed to aortic stenosis (AS), the gradient is seen to reduce before crossing the aortic valve. Measurement of gradient across the LVOT may also be performed by placement of a pigtail catheter in the aortic root and another pigtail catheter into the LV via the transseptal route, through the mitral valve, to allow for a simultaneous aortic and LV pressure waveform assessment, which is generally more accurate than the former technique.
Since the gradient across the LVOT is generally labile, various physiologic and pharmacologic maneuvers may need to be utilized to accentuate the LVOT obstruction. One of the classical signs described is the Brockenbrough-Braunwald-Morrow sign, or the postextrasystolic potentiation. This refers to the augmentation of the LV pressure with a concomitant decrease in the aortic systolic and pulse pressures as a result of increased LVOT obstruction in the cardiac cycle that follows a premature ventricular contraction (PVC) ( Figure 31-6 ). Postextrasystolic increase in the gradient between LV and aorta is seen in AS too, but unlike HCM, the pulse pressure (reflective of the stroke volume) does not decrease. This is because, in AS, a larger stroke volume of the postextrasystolic beat leads to a higher gradient with no change in the severity of obstruction.
Management of HCM
Management of patients with HCM requires a thorough understanding of the complex pathophysiology and often needs to be individualized to the patient. The management decisions are based on presence and extent of obstructive physiology, symptoms and their persistence, LV systolic function, surgical candidacy, co-morbidities, and patient preferences.
Asymptomatic Patients
A large proportion of patients with HCM are asymptomatic and a majority of those generally achieve a normal life expectancy. Risk stratification for SCD must be performed meticulously in all patients with HCM, irrespective of symptomatology. Education is key, and it is essential to counsel all patients and their families about the disease process, screening of all first-degree relatives, and avoidance of strenuous activity in competitive athletes. According to the current ACC/AHA guidelines, it is recommended that co-morbidities that contribute to atherosclerotic disease like hypertension, diabetes, hyperlipidemia, and obesity be aggressively treated in compliance with existing relevant guidelines (Class I). This is because concomitant CAD has a significant adverse impact on survival in patients with HCM. A low-intensity aerobic exercise regimen is reasonable to achieve optimal cardiovascular fitness.
It is important to avoid dehydration and environmental circumstances that promote vasodilation among all asymptomatic patients with resting or provocable LVOT gradient. Hence, high-dose diuretics and vasodilators should be avoided in patients with HCM, as these may promote a smaller LV cavity and exacerbate the degree of obstruction. Although the usefulness of β-blockade and calcium channel blockade to alter the natural course of disease is not well established in asymptomatic patients, these agents may be utilized to treat relevant co-morbidities like hypertension (Class IIb). Some preliminary data in animal models have demonstrated the efficacy of angiotensin-converting enzyme inhibitors or statins or calcium channel blockers in halting progression of LV hypertrophy. However, similar data are not available in humans. Therefore, these agents should not be utilized for the intent of altering HCM-related clinical outcomes, but only for the control of symptoms or for control of relevant co-morbidities.
Septal reduction therapies are currently not recommended for asymptomatic patients with HCM with normal exercise capacity regardless of the extent of LVOT obstruction (Class III). The indication of septal reduction therapy is to improve symptoms refractory to medical therapy resulting in significant impairment of quality of life. Therefore, they should not be performed in an asymptomatic patient solely based on the extent of resting or provocable LVOT gradient.
Symptomatic Patients
Medical Management
Medical therapy should be utilized as the initial therapeutic approach for treatment of symptomatic patients with HCM. Due to a relatively small number of cases, pharmacotherapy for HCM is largely based on expert opinion, clinical experience, and retrospective observational analyses. Patients with LVOT obstruction constitute the largest proportion of symptomatic obstruction. Besides these patients with manifest obstruction, a significant number of nonobstructing patients may also suffer consequences of diastolic dysfunction such as heart failure, angina, and atrial fibrillation, which may require pharmacologic treatment. Due a greater utilization of genetic markers and echocardiography in diagnosis of HCM, it has become increasingly clear that a vast majority of patients with HCM remain asymptomatic for an extended period of time. Most available data suggest that this population does not warrant empiric therapy until and unless symptoms develop.
Beta-Blockers
According to the current ACC/AHA guidelines, β-blockers should be utilized as primary pharmacologic therapy for treatment for symptoms in adult patients with obstructive or nonobstructive HCM, and with caution in patients with sinus bradycardia, or severe conduction disease (Class I). If low doses of β-blockers prove to be ineffective in controlling symptoms, it is often useful to titrate the dose to a resting heart rate <60 to 65 beats/minute (up to generally accepted and recommended maximum doses of individual agents) (Class I). β-blockers are effective due to their negative inotropic effects and their ability to attenuate adrenergic-induced tachycardia. These effects significantly reduce myocardial oxygen demand, thereby reducing myocardial ischemia. The reduction in resting heart rate prolongs the diastolic filling period, which allows for more efficient inactivation of myocardial contractile proteins and improving diastolic filling mechanics. Due to their negative chronotropic properties, these agents are especially helpful in patients with supraventricular tachycardia. The first agent initially utilized for treatment, propranolol, has largely been replaced by the newer generation, longer-acting, cardio-selective agents such as metoprolol.
Calcium Channel Blockers
Nondihydropyridine calcium channel blocker verapamil has been traditionally utilized in patients with HCM. According to the current guidelines, verapamil therapy (beginning in low doses and titrating up to 480 mg/d) is recommended for treatment of symptoms in patients with obstructive or nonobstructive HCM who do not respond to β-blockers, or who have adverse effects or contraindications to the use of β-blockers (Class I). In symptomatic patients, it is a common clinical practice to begin therapy using β-blockers rather than verapamil. Should the patient be intolerant of the side effects, or if symptoms persist despite adequate titration of the β-blocker therapy, consideration may be given to changing (or adding) therapy to verapamil. However, at the current time, there is no evidence to suggest that combination therapy with verapamil and β-blockers is more effective than either a β-blocker or verapamil alone. In case a decision for combination therapy is made, caution should be exercised because of the potential for high-grade atrioventricular (AV) conduction block.
Verapamil functions as a negative inotrope and a negative chronotope by blocking the intracellular migration of calcium ions. This results in a symptomatic improvement in patients, owing to increased diastolic filling time and enhanced diastolic ventricular relaxation without adversely affecting systolic function as well as ensuring reduced myocardial oxygen consumption. In addition, verapamil has been shown to increase absolute myocardial blood flow during pharmacologic stress testing, while also reducing ischemic burden and improving exercise tolerance in HCM patients. Although verapamil has classically been utilized in both obstructive as well as nonobstructive disease, caution should be exercised in those with a large resting LVOT gradient owing to reports of severe hemodynamic compromise resulting in cardiogenic shock and pulmonary edema. The current guidelines recommend against the use of verapamil in patients with obstructive HCM in the setting of systemic hypotension or severe dyspnea (Class III).
Although some preliminary data in animals have suggested the utility of diltiazem in preventing LV hypertrophy, there are scarce data in humans to suggest its usefulness in HCM. However, in patients who do not tolerate beta-blockers or verapamil, diltiazem may be considered (Class IIb). Nifedipine or other dihydropyridine calcium channel blockers are potentially harmful for treatment of symptoms in patients with HCM who have resting or provocable LVOT gradient (Class III). This is because their vasodilatory effects may exacerbate the outflow obstruction, possibly leading to worsening of current symptoms.
Disopyramide
Disopyramide has been in the armamentarium for HCM for over three decades. It is a Class IA anti-arrhythmic agent that also functions as a negative inotropic effect and leads to a relative increase in the systemic vascular resistance. The current ACC/AHA guidelines consider it reasonable to combine disopyramide with β-blockers or verapamil in treatment of symptomatic obstructive HCM, in patients who do not respond to β-blockers or verapamil alone (Class IIa). While it does not appear to have any effect on the diastolic dysfunction, disopyramide has been shown to effectively reduce the outflow obstruction due to SAM with improved symptomatic control in patients who are refractory to other forms of therapy. The initiation of disopyramide therapy should be performed in hospital with cardiac monitoring for arrhythmias due to its QT prolonging effects. Anti-cholinergic side effects like dry mouth, urinary retention, and constipation might occur, which may be managed with dose reduction. The use of disopyramide alone without β-blockers or verapamil is potentially harmful in HCM patients with AF because disopyramide may enhance AV conduction and increase the ventricular rate during episodes of AF (Class III).
Amiodarone
While current data appear to be conflicting with the use of amiodarone in HCM, it has been suggested that amiodarone might reduce the risk of SCD and improve survival in selected high-risk patients with nonsustained VT on ambulatory cardiac monitoring. Although some reports have demonstrated its efficacy in improvement of symptoms and functional capacity, amiodarone may have a pro-arrhythmic effect and may theoretically lead to an increased risk of SCD due to VT. However, recent data indicate that chronic low-dose amiodarone therapy (200 mg/d) in high-risk patients with recurrent nonsustained VT is not associated with any increase in long-term mortality. At this dose, amiodarone has been demonstrated to be effective therapy for treatment and prevention of VT in patients with HCM. Care should be exercised in selecting chronic VT suppression therapy with amiodarone, especially considering its attendant adverse effect profile, until more definitive data become available.
Other Agents
Although high-dose diuretics are generally contraindicated for fear of dehydration, it is considered reasonable to add low-dose oral diuretics in patients with nonobstructive or obstructive HCM when the symptoms of dyspnea persist despite the use of β-blockers or verapamil, or their combination (Class IIa). Diuretics often afford symptomatic relief in patients with pulmonary edema, but judicious use is certainly warranted. The usefulness of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in treatment of symptomatic HCM patients with preserved systolic function is not well established, and these drugs should be cautiously used (if at all) in patients with resting or provocable LVOT obstruction (Class IIa). Intravenous phenylephrine is recommended for treatment of acute hypotension in patients with obstructive HCM who fail to respond to intravenous fluid administration (Class I). Use of norepinephrine, dopamine, dobutamine, or other positive inotropic agents is potentially harmful for treatment of hypotension in patients with symptomatic HCM and is not recommended (Class III).
Invasive Management
The current ACC/AHA guidelines recommend that septal reduction therapy should be performed in eligible patients with severe drug refractory symptoms and LVOT obstruction as defined by the following core criteria
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Clinical: Severe angina or dyspnea (NYHA class III/IV) or other symptoms like syncope or near syncope that interfere with activities of daily living or adversely affect quality of life despite adequate medical therapy
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Hemodynamic: Resting or provocable LVOT gradient more than 50 mm Hg associated with septal hypertrophy and SAM of the mitral valve
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Anatomic: Targeted septal thickness sufficient to perform the procedure safely and effectively in the judgment of the individual operator.
Septal reduction therapy should not be done for patients who are asymptomatic with normal exercise tolerance or whose symptoms are minimized on optimal medical therapy (Class III). Septal reduction therapies include SM and ASA. Although these are methodologically very different approaches and interventions, they have been treated similarly in ACC/AHA guidelines as well as European guidelines as they are both accepted methods for relief of symptoms in patients with LVOT obstruction. There are some nuances in tailoring individual therapies among the affected population, which have been discussed further in this chapter. SM has been used for the last 50 years, and relief of LVOT obstruction can be achieved with minimal perioperative morbidity and mortality in experienced centers. Given the duration of experience, long-term results, and established safety in experienced hands, SM is considered as the treatment of choice in most patients who meet criteria for invasive management of HCM. Considerations that lead to the choice of SM include younger age, greater septal thickness, and concomitant cardiac disease that require surgical correction like intrinsic mitral valve disease or coronary artery disease. Specific abnormalities of mitral valve apparatus can contribute significantly to the generation of LVOT gradient, suggesting the potential value of additional surgical approaches (e.g., plication, papillary muscle relocation, valvuloplasty). Although ASA has been around only for the past two decades, the number of these procedures performed has surpassed the number of myectomies performed in the last five decades. ASA causes a regional infarction of the basal septum, thereby initially decreasing contractility and eventually causing thinning of the basal septum and consequent widening of the LVOT. Among patients who meet core criteria for septal reduction therapy, considerations that favor the use of ASA over SM include advanced age, significant noncardiac co-morbidities that increase surgical risk, and the patient’s desire to avoid open heart surgery after a thorough discussion of both options.
It has been recommended that both these procedures should only be performed by experienced operators, in the context of a comprehensive HCM clinical program. The ACC/AHA define an experienced operator as someone with a cumulative case volume of at least 20 procedures or an individual operator who is working in a dedicated HCM program with a cumulative total of at least 50 procedures. In addition, given the data available from experienced centers, operators should aim to achieve mortality rates <1% and major complication rates <3%, with documented improvement in hemodynamics and symptoms of their treated HCM patients. Therefore, septal reduction therapy should only be performed as part of a program dedicated to the longitudinal and multidisciplinary care of patients with HCM.
Septal Myectomy
Transaortic SM is currently considered the gold standard for the majority of patients with obstructive HCM and severe symptoms refractory to medical therapy. Although published literature demonstrate a considerable improvement in the surgical results over the last few decades, the data are limited to a relatively few centers with extensive experience and particular interest in the treatment of HCM. There has been a significant evolution in the spectrum of surgical therapy from the original isolated septal myotomy performed by Cleland in 1960, to the more modern, and widely utilized Morrow myectomy. The Morrow myectomy is performed via the transaortic approach so that the proximal septum is visualized and 5 to 15 g of myocardial tissue is resected from the base of the aortic valve to a region distal to the mitral leaflets such that the area of the mitral-septal contact that results in SAM is removed, consequently enlarging the LVOT. It is critically important to correctly identify the involved portion of the LV septum and resect enough myocardium to relieve the LVOT gradient. Therefore, most experienced centers utilize transesophageal echocardiography (TEE) to assist with the localization of the desired region for resection, and to monitor the effect of resection on the LVOT gradient intraoperatively.
Despite its more aggressive nature, an alteration of the classic Morrow procedure has been described, which involves an extended myectomy with a partial excision and mobilization of the papillary muscles. This procedure results in amelioration of the LVOT obstruction, reduced tethering of the subvalvular mitral structures, and a more individualized surgical resection depending on the extent and location of the patient’s LV hypertrophy. In patients with concomitant disorders like AF or coronary artery disease, SM may be combined with adjunctive procedures like surgical treatment for atrial fibrillation (MAZE) or coronary artery bypass grafting. Abnormalities of mitral valve apparatus such as elongated and flexible leaflets often contribute to the degree of LVOT obstruction in a minority of patients. These patients often benefit from leaflet plication at the time of myectomy to more effectively reduce the degree of LVOT obstruction that results from SAM and to reduce the associated MR. Mitral valve replacement is generally reserved for patients with significant primary valvular abnormalities such as myxomatous degeneration leading to mitral valve prolapse or severe MR. The surgical specimen obtained during the operation should be submitted for histopathological examination, not only to confirm the diagnosis of HCM, but also for special stains to rule out other storage disorders that can mimic HCM.
Patient Selection.
Since SM is considered to be a gold standard for the treatment of symptomatic obstructive HCM, clinicians should favor this procedure in all patients who are deemed surgical candidates. Subjective assessment of operative risk by clinicians often results in an overestimation of risk, resulting in the denial of SM for eligible patients. Considerations that lead to the choice of SM include younger age, greater septal thickness, and concomitant cardiac disease that require surgical correction like intrinsic mitral valve disease or coronary artery disease. Specific abnormalities of mitral valve apparatus can contribute significantly to the generation of LVOT gradient, suggesting the potential value of additional surgical approaches (e.g., plication, papillary muscle relocation, valvuloplasty).
Early Results.
Based on the results from several experienced centers, SM has been established as the most efficacious procedure for reversing the consequences of heart failure, relief of LVOT obstruction, as well as restoration of exercise capacity and good quality of life in HCM patients who were symptomatic on maximal tolerated pharmacologic therapy. Successful SM leads to an improvement in treadmill time, maximum workload, peak oxygen consumption, myocardial oxygen demand, and coronary blood flow. SM leads to basal septal thinning leading to an enlargement of the LVOT area. This leads to a redirection of forward flow and abolition of drag and Venturi effect on the mitral valve, leading to loss of SAM and mitral-septal contact. MR is usually eliminated without need for additional mitral valve surgery. With SM, the LA size (and the risk of subsequent AF) is reduced and LV end-diastolic pressure along with LV wall stress is normalized. In experienced centers the operative risk is particularly low and is estimated to be <1%.
Late Results.
It is believed that LVOT obstruction after SM might extend the longevity of patients with HCM. Although randomized controlled trials comparing SM with medical therapy do not exist, nonrandomized studies have demonstrated that SM resulted in excellent long-term survival similar to that in the general population. After SM, actuarial survival was 99%, 98%, and 95% at 1 year, 5 years, and 10 years postmyectomy, respectively. This survival rate did not differ from that expected in a matched general U.S. population and was superior to that achieved by patients with obstructed HCM who did not undergo SM. Although the rate of SCD or inappropriate ICD discharge following SM is very low (<0.9%), SM does not eliminate the need for individual SCD risk assessment and consideration of placement of ICD in those with a significant risk burden.
Complications.
In experienced hands, SM is a very safe procedure. The risk of operative mortality is <1%. Although left bundle branch block is relatively common after surgery, the risk of complete heart block is ~2% with SM. It is higher in patients with pre-existing right bundle branch block or those who have been subjected to alcohol septal ablation (ASA) in the past. In patients with prior ASA, the risk of complete heart block may be as high as 50% to 85%. Iatrogenic ventricular septal defect is rare and occurs in <1% of cases. Finally, the risk of aortic valve or mitral valve injury is also low (<1%), particularly when an experienced operator performs the procedure.
Important Considerations.
Abnormalities of the mitral valve apparatus may be identified preoperatively or intraoperatively using TEE. These include anomalous direct anterolateral papillary muscle insertion into anterior mitral leaflet or elongated mitral leaflets. These anomalies are generally correctable with modified mitral valve repair or extended myectomy without the need for valve replacement. With excellent early and late outcomes following extended SM for treatment of obstructive HCM, the requirement of mitral valve replacement has become rare. Concomitant degenerative mitral valve disease can be treated with adjunctive mitral valve repair at the time of myectomy. Mitral valve repair techniques need to be modified in HCM according to the degree of contribution of an abnormal mitral valve to LVOT obstruction or MR.
Mitral valve replacement has been performed rarely when septal reduction therapy was judged unsafe or felt to be ineffective. When the basal septum is mildly hypertrophied (<16 mm), the risk of either iatrogenic ventricular septal defect from excessive muscular resection or residual postoperative LVOT obstruction from inadequate resection increases considerably. Mitral valve replacement may be an option in these rare patients.
Alcohol Septal Ablation
First performed by Sigwart in 1995, ASA was intended for symptomatic patients who do not wish to undergo invasive open heart surgery, are suboptimal surgical candidates due to co-morbidities, or are located in areas without sufficient surgical expertise. Through the selective infusion of absolute (100%) ethanol into either the first or second septal perforator arteries, the ASA technique attempts to mimic the effect of the traditional Morrow myectomy by inducing a controlled infarction in the basal portion of the hypertrophied septum, resulting in scarring, thinning, and akinesis, leading to a significant reduction in the LVOT gradient and SAM of the anterior mitral valve leaflet. Although there are no randomized control trials comparing ASA to SM or medical therapy, short-term observational studies have demonstrated a significant reduction in LVOT gradient, and improvement in symptoms and functional capacity, with a reported mortality similar to or lower than the SM. The short-term success of this procedure combined with its minimally invasive character has led to a dramatic increase in the utilization of ASA for treatment of symptomatic obstructive HCM. It is estimated that ASA is performed 15 to 20 times more commonly than SM worldwide, relieving LVOT obstruction in symptomatic HCM patients.
Patient Selection.
ASA has the potential for a greater patient satisfaction because of its minimally invasive character, lack of surgical incision and general anesthesia, less overall discomfort, a much shorter recovery time, and a shorter hospital stay. It is well known that the perioperative risks and complications of cardiac surgery increase with age and therefore ASA might offer a selective advantage in older patients in whom surgical risk is high due to co-morbidities. ASA is not currently indicated in children.
There are several important considerations that physicians should discuss with their patients before a choice of ASA is made over SM. The likelihood of permanent pacemaker implantation postablation is 4 to 5 times higher as compared with SM. Clinical and hemodynamic benefit is achieved immediately after recovery from SM but may be delayed for up to 3 months after ASA; although a large majority of patients do achieve notable symptomatic benefit shortly after the procedure. In addition, patients with severe septal hypertrophy (>30 mm) derive limited or no benefit from ASA. In experienced hands, surgical myectomy is almost always predictable. However, the success of the ASA depends in part to distribution of the targeted septal perforator branch and the blood supply to the area of the septum that is aimed to be ablated. Before embarking on the choice of ASA, a thorough search should be made for concomitant abnormalities that are better addressed surgically. These include anomalous papillary muscle insertion into the mitral valve, anatomically abnormal mitral valve with long leaflet, co-existent coronary artery disease, primary valvular disease involving the mitral or aortic valve or subaortic membrane, or pannus, all of which would not be adequately addressed by ASA. In addition, abnormally elongated and flexible anterior mitral leaflet resulting in an anterior location of the co-aptation line and LVOT obstruction will not be correctable via ASA and would require SM with plication. Furthermore, an appropriate septal anatomy amenable to intervention is imperative for a successful ASA procedure.
Procedural Technique ( ).
The procedure is generally performed under conscious sedation with special attention to pain control at the time of alcohol infusion into the septal perforator. The first step of the procedure is to perform a standard diagnostic coronary angiogram to clearly define the coronary anatomy and evaluate for concomitant atherosclerotic disease ( Figure 31-7 ). For the clearest anatomical characterization of the septal anatomy coursing through the basal interventricular septum, the c-arm must be positioned in the right anterior oblique (RAO) cranial or the posteroanterior (PA) cranial projections. At times, the septal anatomy may vary such that one subdivision may run along the left side of the septum while another runs along the right side. Angiography in the left anterior oblique (LAO) cranial projection often helps determine the septal vessels’ course along the septum (leftwards or rightwards). Selection of the left-sided subdivision is advised as there is a significantly less likelihood of complete heart block during ethanol infusion into the leftward branches as compared with the rightward branches. While in a majority of cases the septal perforators arise from the LAD, substantial anatomical variation has been described in which the vessels may be seen to arise from the left main trunk (LMT), ramus intermedius (RI), left circumflex (LCX), the diagonal branches, or even from the branch of the right coronary artery (RCA). Once the image acquisition is completed, the operator should select the appropriate septal perforator branch to ablate.
