Hypertrophic Cardiomyopathy (2005)

HYPERTROPHIC cardiomyopathy (HCM) is a genetic cardiac disorder caused by mutations in one of at least 12 sarcomeric or nonsarcomeric genes and is recognized as the most common cause of sudden cardiac death (SCD) in the young and an important substrate for disability at any age.1,2The broad phenotypic expression and disease complexity have consistently generated uncertainty regarding this disorder. Technological developments coupled with advanced understanding of epidemiology, clinical course, and molecular defects responsible for HCM have promoted new diagnostic management strategies.2Anesthesia providers caring for patients with this heterogeneous disease should be aware of its potential life-threatening nature and should be familiar with new clinical insights to afford optimal treatment during the perioperative period. Conversely, anesthesiologists may be confronted with clinically unrecognized HCM and should be prepared to anticipate the hemodynamic changes and cardiovascular instability that such patients may impose.Hypertrophic cardiomyopathy is unique among cardiovascular diseases by virtue of its potential for clinical presentation during any phase of life, from infancy to older than 90 yr.3Although adverse clinical consequences of the disease, particularly sudden cardiac death, are well documented, a more balanced perspective regarding prognosis has recently evolved in which normal longevity is recognized in a substantial proportion of patients.3Clinical diagnosis of HCM is usually established with two-dimensional echocardiography by demonstrating left ventricular (LV) hypertrophy, typically asymmetric in distribution, and associated with a nondilated chamber in the absence of another cardiac or systemic disease capable of producing the magnitude of hypertrophy evident.2,4This definition of HCM is independent of whether LV outflow obstruction or cardiac symptoms are present.During the past few decades, numerous investigations have led to an evolution in our understanding of the clinical, genetic, and pathologic spectrum of HCM.1In the process, the disease has acquired a myriad of names largely related to its substantial clinical, functional, and morphologic diversity. Hypertrophic cardiomyopathy is the preferred name because it describes the overall disease extent without introducing the misleading inference that outflow tract obstruction is an invariable feature.1,2,4Epidemiologic studies with a variety of study designs have shown similar estimates for the prevalence of phenotypically expressed HCM in the adult general population of approximately 0.2% (1:500).5Therefore, HCM is not rare and, in fact, is the most common genetic cardiovascular disease transmitted as an autosomal dominant trait.2It is now apparent, based on discrepancies between the prevalence of HCM in the general population compared with cardiology practice, that most patients affected by this disease are unrecognized clinically, including many at high-risk for SCD.1–3Furthermore, because more than 30 million patients undergo a surgical procedure each year in North America, it may be expected that a substantial number of HCM patients will receive perioperative and anesthetic care at least one time during their lives.It is possible to regard most of the HCM clinical spectrum as a single, unified disease entity and a primary disorder of the sarcomere. Mutations in the β-myosin heavy chain and myosin-binding protein C genes comprise almost one half of the genotyped patients to date, whereas six other sarcomere genes each account for a small number of cases, i.e. , cardiac troponin T, cardiac troponin I, α, tropomyosin, cardiac α-actin myosin regulatory light chain, myosin essential light chain.2This genetic diversity is compounded by intragenic heterogeneity, with more than 400 mutations now identified.2These are most commonly missense mutations with a single amino acid residue substituted for another but also include insertions, deletions, and splice (split site) mutations encoding truncated sarcomeric proteins.Most recently, mutations in two nonsarcomeric genes have been recognized as causing diseases with LV hypertrophy (often associated with Wolff-Parkinson-White pattern on electrocardiogram) that mimic HCM but are due to glycogen storage in the myocardium, i.e. , the gene encoding the γ2-regulatory subunit of the adenosine monophosphate-activated protein kinase (PRKAG2) and a mutant gene for Danon disease involving the lysosome-associated membrane protein 2-α-galactosidase or acid α-1,4-glucosidase, usually with massive degrees of hypertrophy.6The phenotypic expression of HCM is believed to be the product not only of a disease-causing mutation, but also of modifier genes and environmental factors. Therefore, a large number of genes and mutations (including many not yet identified) may influence the expression of the HCM phenotype.Recent studies have recognized the role of genetics in the genesis of electrophysiologic abnormalities associated with HCM. For example, increased risk of atrial fibrillation in HCM has been linked to a particular missense mutation in the β-myosin heavy chain gene. However, many adolescents (and some adults) harboring a genetic defect for HCM do not necessarily express typical clinical and phenotypic features, although electrocardiographic abnormalities or evidence of diastolic dysfunction by tissue Doppler imaging may precede appearance of LV hypertrophy on echocardiogram.7Although laboratory DNA analysis for mutant genes is the most definitive method for establishing the HCM diagnosis, important obstacles remain for translating such research-based genetic technology into practical clinical strategies on a widespread and routine basis. These factors include the aforementioned genetic heterogeneity of HCM, as well as the methodologic difficulties associated with identifying a single disease-causing mutation among a total of at least 12 possible HCM genes. However, when a HCM mutation is identified in a proband, definition of genetic status can be achieved in all family members efficiently and inexpensively. Diagnostic molecular laboratories§have recently begun to address these challenges by offering rapid, direct DNA sequencing for a subset of HCM disease genes.8Nonetheless, a significant potential remains for false-negative results (i.e. , in which HCM diagnosis cannot be ruled out).Virtually all possible patterns of LV wall thickening occur in the HCM patient population, and none can be regarded as classic or typical of the disease, although anterior ventricular septum is usually the predominant region of hypertrophy.1,4Distribution of LV hypertrophy is almost always asymmetric, although a small proportion (approximately 1%) show a concentric or symmetric form.1,4A large proportion of affected patients show diffuse involvement of the septum and LV free wall, but that is not invariable, and approximately 30% of patients have only localized (usually mild) thickening confined to a single segment of the wall, including unusual areas such as the LV apex, anterolateral free wall, or posterior portion of the septum4(fig. 1).Many cardiac muscle cells in both the ventricular septum and the LV free wall show increased transverse diameter and bizarre shapes, as well as disorganized architectural patterns with adjacent cells arranged at oblique and perpendicular angles. Cardiac muscle cell disarray is present in 95% of patients who die of HCM and usually occupies substantial portions of the LV (average area, approximately 33%).9These histopathologic findings are not confined to the hypertrophied regions of LV but are also present in areas of normal wall thickness. In addition, there is substantial collagen distribution within the LV wall as part of an expanded interstitial (matrix) compartment.9Abnormal intramural coronary arterioles with thickened walls and narrow lumen may account for bursts of myocardial ischemia.10The degree to which there is a mismatch between myocytes and arterioles depends largely on the magnitude of LV mass. Therefore, disorganized myocardial architecture and myocardial replacement scarring as a repair process after ischemia due to small vessel disease (and consequently cell death), as well as the large collagen matrix compartment, probably serve as the electrically unstable arrhythmogenic substrate predisposing some susceptible patients to life-threatening reentrant ventricular tachyarrhythmias10(fig. 1).Primary malformations of the mitral valve apparatus, responsible for dynamic LV outflow tract obstruction, are present in at least two thirds of patients in an HCM population.11,12These abnormalities include enlargement and elongation of the mitral leaflets in a variety of patterns with increased mitral valve tissue area (ranging up to twice normal), as well as anomalous papillary muscle insertion directly into the anterior mitral leaflet, producing muscular midcavity obstruction.11,12These structural malformations of the mitral apparatus expand the morphologic definition of HCM by demonstrating that the disease process is not confined to cardiac muscle alone (fig. 2).It is generally believed (in the absence of genetic testing) that when both LV hypertrophy on echocardiogram and electrocardiographic abnormalities are not present in HCM family members by the time full growth has been achieved at the age of approximately 18 yr, it is unlikely that the disease phenotype will develop. Such clinical judgments have generally proved reasonable because, in the majority of affected individuals, virtually complete penetrance of the phenotype is evident by the end of the adolescent growth period. However, recent genotype-phenotype investigations have shown, in fact, that de novo LV remodeling and development of the HCM phenotype may extend into midlife or even beyond, particularly in patients with myosin-binding protein C gene mutations.13Paradoxically, a subtle decrease in LV wall thickness seems to be associated with aging in the adult HCM population, particularly in women.2,3Extreme reduction in wall thickness associated with systolic dysfunction and chamber enlargement represents evolution into the end-stage phase (for which heart transplantation is the only treatment option).3Hypertrophic cardiomyopathy is the most common cause of SCD in young competitive athletes.14Relevant to this consideration is the clinical dilemma frequently encountered in distinguishing HCM from physiologic (and benign) LV hypertrophy due to athletic training.Increased LV wall thickness (in the “gray zone” of 13–15 mm) in trained athletes may trigger the differential diagnosis between a mild morphologic form of HCM and an extreme expression of “athlete's heart.” This important distinction can be resolved clinically by documenting HCM in a relative or by noninvasive testing of other clinical variables.14Clinical identification of HCM continues to be customarily based on transthoracic two-dimensional echocardiographic recognition of the disease phenotype with LV hypertrophy (wall thickness ≥ 15 mm), unassociated with ventricular cavity enlargement. However, genotype-phenotype correlations in family members have demonstrated that virtually any LV wall thickness (including normal) is compatible with the presence of a mutant HCM gene.4Maximum LV wall thicknesses show a particularly wide range, extending up to 60 mm and the most substantial in any cardiac disease. Mean LV wall thickness in a population of HCM patients is 21–22 mm, far exceeding on average that observed in systemic hypertension or valve degree of LV outflow tract obstruction is by Doppler at or with physiologic by virtue of the usually mild to in outflow obstruction with the typically and Doppler the mitral from that of LV myocardial due to hypertrophied is time is of is and time echocardiography has only a clinical role in HCM but is in the for outflow obstruction and hemodynamic changes associated with management and as well as and of the results during is in of patients with HCM, a variety of none of which is or for this disease. common are with LV hypertrophy, and left atrial and or in the left there is between electrocardiographic and magnitude of LV hypertrophy by the heterogeneous patterns observed on have for clinical may have diagnostic by of HCM in young family members who do not yet show LV hypertrophy on cardiac imaging of the LV and represents an diagnostic in HCM. is particularly in patients with echocardiographic studies or when hypertrophy is confined to unusual within the LV wall , anterolateral free wall or Therefore, has an role as a clinical imaging and may be to echocardiography in HCM of clinical and disease in HCM include dynamic obstruction to LV outflow due to mitral valve systolic anterior and ventricular diastolic associated with increased from LV and of a hypertrophied and coronary and myocardial and and ventricular , atrial fibrillation and ventricular (fig. to there is now widespread that the and associated in LV to outflow and are of to HCM recent study LV outflow obstruction to be an independent of heart and heart and death, although associated with sudden a large proportion of HCM patients are susceptible to LV outflow tract with including many without systolic anterior or obstruction obstruction in HCM is by a number of structural including small LV outflow tract area, degree of into the outflow tract and and mitral leaflets in with LV the mitral valve the is i.e. , most patients do not obstruction although many have development of of magnitude with a variety of that include or but also by such as of and , or outflow in HCM may also be and may even with or of a heavy or of are responsible for systolic at the left and apex, which may be present in the or with and are with anterior is responsible not only for obstruction, but also for mitral due to consequences related to outflow such as heart are by increased LV wall myocardial and death and replacement to the and perioperative outflow obstruction in HCM can be dynamic and occur and or by that myocardial , and or decrease and ventricular , and in HCM to in a to that observed in disease. Therefore, in HCM, with a in whereas decrease obstruction and in and are present in approximately of HCM an important of clinical course, particularly in the absence of LV outflow phase of is and results in a and of there is a in the of atrial to overall ventricular increased LV for any LV the diastolic coronary the of heart symptoms due to diastolic dysfunction outflow tract are not directly related to the magnitude of LV symptoms are more in patients with massive LV hypertrophy than in patients with degrees of dysfunction and myocardial ischemia are common of HCM and the of a variety of including relative to magnitude of LV hypertrophy, myocardial and diastolic of myocardial to on HCM patients to myocardial which has been in the of to LV systolic and diastolic and recent study that the degree of dysfunction in patients with HCM is an independent of heart symptoms and death and may precede clinical by many fibrillation is the most common in HCM and usually or occur in of HCM are linked to left atrial and show with is well by approximately one of patients and is not an independent of sudden is associated with heart death, of and and disease of may also be responsible for clinical with or heart from diastolic and cardiac as a of increased ventricular and with of atrial in a hypertrophied and or are in patients within of that the presence of atrial can be is generally regarded as the most for of for is in HCM because of the of with the aforementioned disease and (and have proved in heart although and ventricular may be in clinical of HCM is typically and patients may remain of with a significant proportion normal adverse clinical including death, are well documented, a more balanced perspective regarding prognosis has recently of HCM have been by on from up to recent studies during the past from or HCM patient overall of approximately not to that expected in the general adult HCM may be associated with important symptoms and death, but with or mild disability and without the for who symptoms as a of HCM have a clinical that one or more heart with and evolution to end-stage and sudden death high-risk associated with of ≥ death frequently as the disease in or young and remains the most common of and most and of high-risk patients only a of the overall disease a has been clinical identification of this important patient subset by risk factors (fig. are on of risk and a large of understanding has been for identification of all high-risk patients by clinical risk are not substantial of HCM patients who die are with or only one risk such as and have been to heart symptoms of and in patients with of on are due largely to decrease in heart with of the diastolic period. who do not of symptoms with or may from the other but of these is not should be regarding of to some patients with LV outflow obstruction and heart with increased are few regarding of other such as and (in with a has been into the treatment of patients with HCM who are to and and has been shown to heart symptoms and outflow without are generally in HCM due to their potential for or dynamic LV outflow the past yr, based on the of many the ventricular has been established as the primary for and with HCM ≥ at or with physiologic and These patients a small (i.e. , although important subset of the overall HCM is an and of a small of muscle from the ventricular extending from the of the valve to the of mitral leaflets and the of obstruction due to the LV outflow tract is and the to LV and mitral is usually of LV to of heart symptoms and in the majority of patients and represents a form of heart also capable of extending is now 1%) in most the past yr, treatment for patients with symptoms and outflow obstruction have that the optimal outflow and symptoms in many HCM that the clinical of in HCM most with a by which are not well although of the seems to a role by the of ventricular has now been largely as an to the recent for has in the past as a potential to surgical in of into a of the left anterior coronary to a myocardial within the ventricular by thickness and and also the LV outflow systolic anterior and mitral with to is the potential risk for (including sudden directly to the to which usually left but not an commonly results in and a large treatment strategies to high-risk HCM patients SCD due to ventricular have been on of such as or , and more recently there is evidence that of such to HCM patients is in the for Therefore, that when risk is to be the is the most treatment with the potential for the of HCM in some is for of SCD in patients with cardiac or ventricular and for primary in patients with high-risk status by noninvasive are regarding cardiovascular for patients with coronary disease for there is regarding such for HCM is probably largely because of the relative with which patients with a HCM diagnosis are encountered by HCM patients or without LV outflow not adverse perioperative include heart myocardial systemic and or ventricular and of are of adverse cardiac in HCM death and myocardial to be such during in young patients with HCM to a to the with unrecognized HCM may sudden and systemic , due to and and trigger dynamic LV outflow tract may be by the or appearance of a systolic and on the or to and anesthetic In such HCM should be and to the such as and (i.e. , with and and (i.e. , with should be heart in HCM patients probably related to diastolic the of identification of HCM to management the prevalence of HCM in the general population, the with which this disease is clinically, and the number of year in the it may be expected that a not subset of HCM patients will present for and without an established This a for the with the clinical for HCM patients who are and usually and family (i.e. , cardiac symptoms of or family of and the (i.e. , systolic particularly increased with and with may the clinical of HCM, a full cardiovascular with the diagnosis by echocardiography is form of HCM may be to the absence of a heart for and LV are important in HCM patients should be to to be in a may status as a of diastolic echocardiography with Doppler imaging regarding the of LV outflow tract as well as mitral valve and chamber and may management by on development of dynamic obstruction to the LV mitral and diastolic dysfunction as well as evidence of myocardial ischemia virtue of LV wall These may be important to that changes precede abnormalities by patients with HCM, clinical should on the potential for dynamic LV obstruction, and myocardial ischemia to which these patients may be particularly in the perioperative and the influence of and that myocardial and and systemic are the in of LV outflow tract increased or the patient with HCM, and in an to may have consequences by heart without of LV outflow obstruction at should not be regarded as free from the of dynamic obstruction with the of anesthetic there is evidence that the magnitude of LV wall thickness is directly related to risk of a perioperative a massive degree of LV hypertrophy (wall thickness ≥ 30 mm) is an independent risk for sudden it is a reasonable that such HCM patients be susceptible to in the are to although of such as or should be because of a potential for is to a on heart and when in with other of or increased should be when an and of these should be of the should be achieved at the time muscle are consideration should be to the consequences of and and of that these In this seems to be an myocardial is generally during the of are in patients with HCM, although for sudden hemodynamic changes or is has the to heart to systemic when in seems to both heart and can cause and increased whereas when a sudden in can to and systemic hypertension as well as is a mild myocardial and its results in a more decrease in systemic and than encountered with or at the time causing only small or in heart and are in perioperative management because an in is in HCM. in as with by is and may LV outflow and should be to is particularly important these of in the replacement and of , with such as or are because increased and associated with their are to LV outflow tract obstruction and myocardial hypertension should be by the of or by such as or are not to decrease because and systemic cardiomyopathy the potential for a variety of during or anesthetic including (including and ventricular of is important because ventricular is largely on left atrial and patients may be in In the or should be with direct than during from and in the with to increased remains a to or can to increased myocardial dynamic LV outflow obstruction, and after cardiac in HCM patients an of the disease are in HCM because these patients a and to outflow tract obstruction, diastolic and myocardial and decrease and and may HCM patients to dynamic obstruction, with all its in HCM patients management because of the unique cardiovascular changes that may In the of or during and may decrease the and of cause heart and which in can to a hemodynamic studies that with HCM is and seems to be confined to who are at particularly risk because of of and occur only and are largely related to the clinical is evidence that risk in with HCM when during general and have been without for in with of and and have been in the past decades, a and has regarding HCM, an autosomal dominant genetic cardiac disease caused largely by a variety of mutations in genes encoding sarcomeric and by an hypertrophied and nondilated LV with a broad and clinical that HCM, although an important cause of sudden cardiac death and not prognosis (and is in compatible with normal a large of for many when HCM patients are to the of and and perioperative occur not and include heart myocardial diastolic and should be aware of and that may trigger or dynamic LV outflow obstruction and, in strategies to and this and other potential from the of with HCM. These are to and to perioperative when during to patients with HCM.