INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a primary autosomal-dominant disorder of the myocardium caused by mutations in several genes encoding cardiac contractile proteins ( Fig. 23-1 ). Histopathologically it is associated with myocardial hypertrophy, fiber disarray, increased loose connective tissue, and fibrosis, which are all thought to interfere with the generation of force and relaxation of the cardiac muscle ( Fig. 23-2 ). Although HCM has been traditionally described as a hyperdynamic systolic disorder causing obstruction of the left ventricular outflow tract (LVOT), a large fraction of patients with HCM experience heart failure symptoms with a normal-appearing systolic function and without obstruction. This emphasizes the importance of myocardial relaxation and left ventricular (LV) filling in symptom generation in this disorder. The origin of diastolic dysfunction in HCM is multifactorial, with changes at the molecular, myocardial tissue, and global LV levels.
PATHOPHYSIOLOGY
Molecular Level: Mutations and Calcium Economy
The mutations related to HCM result in the production of abnormal myocardial sarcomeric proteins that have altered contraction and relaxation characteristics. These include changes in the affinity between the various contractile proteins and in the sensitivity to Ca 2+ , as well as in the efficiency of energy utilization (from ATP) and its expenditure.
Changes in Diastolic Calcium Levels
Myosin Heavy Chain Mutations
Mysosin heavy chain (MHC) mutations represent approximately 35% of HCM patients, and more than 50 different point mutations have been described in families or probands with HCM. These are clustered in four particular locations in the S1 (head/rod junction) of the protein. The Arg403Gln has been extensively studied and is an example of a high-risk mutation. It lies close to the actin-binding interface and is a common severe mutation (100% penetrance and high incidence of sudden death). Its primary result is in reduction of filament sliding velocity and diminished rate of actin-activated myosin-ATPase activity, leading to a hypocontractile state. Diastolic function in patients with the Arg403Gln mutation is often impaired, with an end diastolic pressure (EDP) greater than 15 mmHg in most patients. Studies in mice showed two forms of diastolic dysfunction during inotropic stimulation: an increase in EDP and a slower maximal rate of relaxation (−dP/dt). The most direct explanation for impaired relaxation in αMHC 403/+ hearts is that the arginine-to-glutamine amino acid switch has slowed the kinetics of actin-myosin dissociation and led to prolonged activation of the thin filament. These observations indicate that the relaxation dysfunction is due to altered myosin binding kinetics. At high work loads, αMHC 403/+ hearts reach an energetic state where sarcoplasmic/endoplasmic reticulum Ca 2+ -ATPase (SERCA) is unable to maintain the cytoplasm-sarcoplasmic reticulum Ca 2+ gradient, causing diastolic Ca 2+ overload due to a fall in the free energy stored in the high-energy phosphate bonds of ATP. Taken together, these observations indicate that the relaxation dysfunction is a primary consequence of altered myosin binding kinetics.
Changes in Sensitivity to Calcium
Myosin Binding Protein C
As with MHC, there are a large number of HCM-causing mutations (both missense and truncation mutations) affecting variable regions of the protein. Myosin binding protein C (MyBPC) has modules responsible for binding to myosin filaments and to titin. MyBPC does not have a solely structural role but is also able to participate in regulatory signals, potentially in several pathways, linked through protein kinase cascades. In young and adult homozygous cardiac-MyBPC knockout mice, isovolumic relaxation time (IVRT) was shown to be increased, indicating that relaxation was significantly impaired. Skinned fibers from LV papillary muscle from MyBPC mutant transgenic mice showed increased calcium sensitivity of force development and decreased maximum power compared with control fibers.
Cardiac Troponin T
At least 10 mutations have been recognized in cardiac troponin T (cTnT), including missense, truncation, and deletion mutations. Their effects include several aspects of increased function (higher sliding or shortening speed, higher Ca 2+ affinity) and decreased force (altered Ca 2+ sensitivity, impairment of folding/thin filament binding/sarcomere structure). Ca 2+ sensitivity of force development increased moderately in some mutations and more dramatically in others. In one mutation, TnT(In16), both the activation and the inhibition of force were significantly decreased, and the mutation substantially decreased the activation and inhibition of actin-Tm-activated myosin-ATPase activity. ATPase activation was also impaired by other TnT mutations. These observed changes in the Ca 2+ regulation of force development would likely cause altered contractility and contribute to the development of HCM. The relaxation in these fibers was also significantly impaired. One could speculate that this mutation could result in altered stoichiometry of the thin filament proteins and lead to dysfunctional interactions between the thick and thin filaments and change Ca 2+ -dependent interactions that would ultimately result in reduced activation and relaxation during muscle contraction. The data demonstrate that TnT can alter the rate of myosin cross-bridge detachment, and thus the troponin complex plays a significant role in modulating muscle contractile performance.
α-Tropomyosin
Four HCM-related mutations are known, two of which change Ca 2+ sensitive troponin binding, while the other two alter actin binding. In transgeneic mice, work performing ex vivo heart preparations demonstrated dramatically decreased rate of relaxation (−dP/dt) and increased diastolic and end diastolic pressures. Skinned fiber bundle measurements showed an increase in maximum tension and in Ca 2+ sensitivity that corresponded to a slight increase in +dP/dt and slowing of relaxation as reflected in −dP/dt, respectively.
Troponin I
Five missense mutations were reported, along with a mutation causing the deletion of one codon. Troponin I (TnI) is the inhibitory component of the troponin complex and is involved in the Ca 2+ regulation of muscle contraction in both skeletal and cardiac muscle. HCM TnI mutations result in (1) reduced inhibition of actin-tropomyosin-activated myosin ATPase by the troponin complex under relaxing conditions and (2) increased Ca 2+ sensitivity of actin-tropomyosin-activated myosin ATPase regulation. These functional differences may manifest themselves in vivo as impairment of relaxation of cardiac muscle and may provide a hypertrophic stimulus leading to the disease state.
Myosin Regulatory Light Chain
Regulatory light chains (RLCs) play an important role in the maintenance of integrity of the thick filaments and their relaxed, ordered arrangement of myosin heads. Deltoid muscle biopsies from HCM patients with an RLC substitution mutation demonstrated increased calcium sensitivity and loss of relaxed order of thick filaments. The conformational change in peptide shape caused by the mutation may alter the degree to which the RLC can support the partially naked α-helical heavy chain core.
Tissue Level: Hypertrophy, Fibrosis, and Disarray
Microscopically, hypertrophy, fibrosis, and myocardial fiber dis-array are hallmarks of HCM, but they also exist in other forms of cardiac hypertrophy. Studies comparing hypertensive hypertrophy to HCM correlating histopathology findings to diastolic function showed that in both hypertensive and HCM patients, IVRT was significantly longer, and the rapid filling volume index (RFVI) tended to be smaller than in the controls. While the mean myocyte size and percentage of myocardial interstitial fibrosis did not differ significantly, quantitative disarray of myocytes in HCM was significantly greater than that in hypertensive subjects. Multiple regression analysis showed that the percentage of fibrosis was the most significant factor related to diastolic LV dysfunction in hypertensive subjects, while disarray was the most significant in HCM. In HCM patients, significant positive correlations were observed between IVRT and wall thickness, diameter of myocytes, and the percentage of fibrosis, with negative correlations with disarray. There was a significantly negative correlation between RFVI and wall thickness, and a significantly positive correlation between RFVI and disarray. Multiple regression analyses showed that the diameter of myocytes, the percentage of fibrosis, and disarray all correlated significantly with IVRT ( r = 0.821) and RFVI ( r = 0.604). These results indicate that diastolic dysfunction in HCM is related to the degree of myocardial hypertrophy, increased interstitial fibrosis, and especially myocardial disarrangement, including disorganization.
Geometry
Dynamic diastolic pressure-volume (P-V) curves measured during filling (PVR fill ) in patients with HCM are often considerably shallower than would be anticipated if one assumed high chamber stiffness, and they markedly deviate from the passive end diastolic pressure-volume relationship (EDPVR) recorded during balloon catheter obstruction of inferior vena cava inflow. This is in contrast to the concordance of dynamic and passive curves in normal subjects, hypertensive hypertrophy, and dilated cardiomyopathy. The unusual behavior in HCM cannot be attributed directly to increased viscosity, enhanced pericardial constraint, or preload dependence of isovolumic relaxation. Regional heterogeneity of relaxation may play a role, but probably the major mechanism involves the end systolic distal chamber being virtually emptied, so that unfolding of the chamber in early diastole can accommodate substantial volumes by pure shape change without increasing the endocardial surface area and thus without stretching the myocardium. This may account for the fact that there was very little change in LV pressure during early filling in HCM hearts, yielding shallow PVR fill . This in turn may be directly related to the unique fiber and chamber architecture seen with HCM and possibly to enhanced ventricular interaction. These observations complicate the interpretation of diastolic P-V data in HCM, as well as conclusions regarding the influence of therapies based on analysis of single cardiac cycles.
Ischemia
In HCM, exercise-induced ischemia and reduced LV distensibility were demonstrated when studied by stress redistribution 201 Tl myocardial scintigraphy and biventricular cardiac catheterization and echocardiography at rest and during exercise. The LVEDP was significantly increased in HCM patients with ischemia, while the end diastolic dimensions did not differ from patients without it, indicating reduced LV diastolic distensibility.
When LVEDP was measured serially, two distinct patterns were shown. In one, LVEDP steadily increased continuously throughout exercise. In contrast, in the second pattern, LVEDP exhibited biphasic changes rising until a critical heart rate was achieved, after which it declined. Importantly, the LVEDP at peak exercise in group 1 was similar to that at the critical heart rate in group 2 patients. Patients with this pattern had less exercise-induced filling defects in 201 Tl scintigraphy, suggesting a lower ischemic burden in this group. The biphasic pattern was lost with administration of a beta-blocker prior to exercise. The biphasic changes in LVEDP seen during exercise may be related to improved coronary microcirculation in response to beta-adrenergic stimulation in patients with mild to moderate HCM.
CLINICAL PRESENTATION AND PROGNOSIS
Phenotypic Heterogeneity of Hypertrophic Cardiomyopathy
The cardiac phenotype of HCM shows great diversity in the extent and pattern of hypertrophy, which may be asymmetric (involving mainly the interventricular septum, with or without LVOT obstruction), concentric, or apical, as well as in its penetrance. The clinical course is also very variable, especially in age of onset, existence of symptoms, disability, and predisposition to sudden death. With age, the hearts of affected individuals undergo further remodeling, manifested by changes in the chamber size and the extent of hypertrophy. A small subset of affected individuals progress to LV dilatation associated with end-stage heart failure (usually referred to as “burnt-out” HCM).
Progression of HCM to the burnt-out phase of disease represents unfavorable remodeling characterized by loss of function; wall thinning and chamber dilatation cause combined systolic and diastolic dysfunction. Although this progression occurs in only about 10% of individuals with HCM, there is evidence that certain mutation populations are at greater risk for this clinical deterioration. In addition, the burnt-out phase of HCM may be evoked by a “second hit” in another gene, as has been reported in individuals with both sarcomere protein gene and mitochondrial mutations.
Genotype/Phenotype Relations
Variability in the clinical course is explained in part by the different roles that mutant proteins play in the sarcomere (see Fig. 23-2 ) and the effect of the mutation on protein structure and function. The β-MHC gene was the first to be identified as a cause of familial HCM, and almost 100 disease-causing mutations have been defined to date that are responsible for about 35% of HCM cases. Most β-MHC mutations are located in the head and head/rod junction, and some of these mutations are recognized as causing severe hypertrophy that presents clinically early in life and demonstrate an increased risk for outflow obstruction, heart failure, and sudden death.
Other β-MHC mutations may cause less severe clinical disease. MyBPC mutations (accounting for 15%-30% of HCM cases) are a leading cause of late-onset HCM and are generally associated with a good prognosis. TnT mutations (∼15% of HCM) generally cause less marked hypertrophy, with poor survival. Near-normal life expectancy has been reported with most α-tropomyosin (∼5% of HCM) and MyBPC mutations. Although this variation in clinical consequences most likely reflects differences in the biophysical properties of mutant and normal peptide, factors other than these structural changes can also influence disease expression. It has been demonstrated that the identical sarcomere mutation in different populations can cause distinct hypertrophic morphologies and divergent clinical courses.
Thus, although HCM-causing mutations can be identified, clinical diversity exists and is probably related to other genetic phenotypes, environment, gender, and acquired conditions. These data also raise the possibility that some (genetic or environmental or a combination of both) modifiers account for unfavorable cardiac remodeling and predisposition to adverse outcomes in HCM. Evaluation of candidate molecules as genetic modifiers of HCM, particularly those that influence the extent of hypertrophy, including the renin-angiotensin-aldosterone axis, endothelin, and tumor necrosis factor (TNF), have shown conflicting results and appear only partially to explain the observed clinical diversity in the extent of hypertrophy in HCM. Polymorphisms within the angiotensin converting enzyme (ACE) gene have been reported to be associated with increased risk for sudden death. The complexities of defining genetic modifiers in human HCM populations remain considerable, given the substantial heterogeneity of genetic causes that may independently influence hypertrophy.
Origin of Symptoms
Symptoms leading to considerable disability in HCM patients are caused by obstruction (LVOT, RVOT, or LV midventricular), diastolic dysfunction with impaired relaxation and elevated filling pressures, coronary artery disease, independent mitral regurgitation (MR), and arrhythmia.
Patients with obstructive HCM typically complain of dyspnea, angina, presyncope, syncope on exertion, or a combination thereof. Patients with nonobstructive HCM present with these symptoms less frequently, and usually the symptoms are milder. Congestive heart failure is uncommon in HCM in normal sinus rhythm, but it may be seen with severe obstruction to outflow or severe systolic or diastolic dysfunction, and of course it is common in the presence of atrial fibrillation (AF).
Patients with HCM and impaired relaxation, including those with apical HCM, develop progressive LA enlargement and AF, which results in severe hemodynamic deterioration because of the importance of atrial systole in the presence of impaired relaxation.
Myocardial ischemia has been repeatedly demonstrated in both obstructive and nonobstructive HCM by means of fixed and reversible thallium perfusion defects; by measurement of myocardial lactate production, particularly during rapid atrial pacing; and by positron emission tomography. Although the exact cause of the ischemia is in some doubt, it may be related to small-vessel disease with decreased vasodilator capacity. Other factors that could cause or contribute to ischemia are septal perforator artery compression, myocardial bridging, decreased coronary perfusion pressure, obstruction to LV outflow, and decreased capillary myocardial fiber ratio. Impaired relaxation of the myocardium during the isovolumic and rapid filling periods could impair coronary filling and result in ischemia. On the other hand, myocardial ischemia could act to impair relaxation by a number of mechanisms. Indeed, a vicious cycle may exist in HCM that relates diminished coronary perfusion and myocardial ischemia with impaired diastolic relaxation and vice versa.
In about 20% of patients with subaortic obstruction in HCM, MR is to a variable extent independent of the systolic anterior motion, in which case other abnormalities of the mitral valve are present, such as anomalous papillary muscle attachment to the anterior leaflet, mitral valve prolapse, extensive anterior leaflet fibrosis due to repeated mitral leaflet/septal contact, mitral annular calcification, and other, rarer abnormalities. These independent abnormalities of the mitral valve at times cause pansystolic MR, which is often anteriorly or centrally directed into the left atrium and is quite different from the late-onset, posteriorly directed MR that is the result of anterior mitral leaflet systolic anterior motion.
AF in the vast majority of cases of HCM is related to an increase in LA size (usually >50 mm). Obstructive HCM with concomitant MR is the most common cause of increased LA size and AF, but both systolic and diastolic dysfunction may also lead to significant LA enlargement and atrial arrhythmias. The onset of AF in both obstructive and nonobstructive HCM may result in cardiac failure, syncope, and systemic emboli.
Prognosis
In an unselected population followed prospectively, three distinctive modes of death were identified: (1) sudden and unexpected (51%; age 45 ± 20), (2) progressive heart failure (36%; age 56 ± 19), and (3) HCM-related stroke associated with AF (13%; age 73 ± 14). Sudden death was most common in young patients, whereas heart failure and stroke-related deaths occurred more frequently in midlife and beyond. However, neither sudden nor heart failure-related death showed a disproportionate age distribution. Stroke-related death did occur disproportionately in older patients, 91% of whom had AF and 64% of whom had LVOT obstruction.
Even in patients with latent LVOT obstruction and apical HCM, the most frequent morbid event was AF. LA enlargement on baseline echo was identified as the only predictor of AF. Impaired LV relaxation in patients with HCM, including apical, has been previously proposed as a mechanism for progressive LA enlargement and subsequent AF. Thus, HCM patients appear to have a four- to sixfold greater likelihood of developing AF compared with the general population, and it will occur in about a third of them. AF prevalence increased progressively with age and LA size, which in turn is related to the degree of hypertrophy, severity of MR, and diastolic dysfunction. It is predominant in patients older than 60 years, but it is not rare in younger patients (<50 years), in whom it is associated with higher risk for clinical deterioration and HCM-related death.
Diagnosis
Conventional Doppler Echocardiography
Mitral and Pulmonary Venous Flow Velocities
Estimation of LV filling pressures by flow Doppler echocardiographic methods is unreliable in HCM. Mitral flow velocity curve variables and mean LA pressure were not related in HCM patients, even when the extremes of age were excluded ( Figs. 23-3 and 23-4 ). This may be due to a dominant influence of impaired relaxation on mitral inflow that overshadows the effect of increased filling pressures. During left-heart catheterization, diastolic pressures before atrial contraction were weakly related to velocities of mitral or pulmonary venous flow in HCM patients, whereas they correlated strongly with E/e′ and with E/Vp (e′ is the early diastolic longitudinal velocity recorded at the lateral mitral annulus; Vp is the flow propagation velocity of ventricular filling).
Left Atrial Volumes
LA volumes have been previously shown to relate to LV filling pressures. A higher incidence of abnormal diastolic filling, a higher early diastolic velocity to early diastolic mitral annular velocity ratio, and a higher calculated LA pressure were found in HCM patients with an LA volume index (LAVI) of at least 34 m 3 /m 2 . Moreover, LA volumetric remodeling predicts exercise capacity in nonobstructive HCM and may reflect chronic LV diastolic burden. This simple, noninvasive measure of LA size may provide a long-term indication of the effects of chronically elevated filling pressures in patients with HCM.
Newer Doppler Echocardiographic Indices
Myocardial Velocities by Tissue Doppler Imaging
Patients with HCM demonstrate delayed and reduced longitudinal myocardial velocities and time-velocity integrals during early diastole. They also have lower velocities during atrial contraction and prolonged regional deceleration times and IVRTs. Larger changes in regional diastolic function were found in patients with mitral inflow E/A ratio below 1, and the difference in duration between mitral inflow and retrograde pulmonary venous flow during atrial systole (Ar-A) correlates with elevated LA pressure and with abnormal collagen metabolism in patients with HCM.
Myocardial Velocity Gradient
A reduced myocardial velocity gradient (MVG), defined as the difference in myocardial velocity between the endocardium and the epicardium divided by myocardial wall thickness during diastole in HCM, reflects prolonged relaxation. It may also reflect an elevated LV EDP ( Fig. 23-5 ). MVG is less affected by preload alterations than by mitral inflow velocity pattern. During simultaneous LV pressures with tissue Doppler waveforms comparing HCM patients with controls, the peak negative MVG during rapid filling was lower in HCM, and a cutoff value of 3.2/s discriminated well. HCM patients had higher EDPs (mean, 19.6 mmHg vs. 6.5 mmHg) and longer time constants of LV pressure decay (Tau, τ); MVG correlated inversely with both. In HCM patients, τ has been reported to inversely correlate with the myocardial peak early diastolic motion velocity.
Echocardiographic Indices of Mechanical Dyssynchrony
In HCM, longitudinal velocities around the LV base vary considerably, and a “heterogeneity index” (the average difference between individual velocity measurements and their means) can be calculated. Patients with HCM exhibit increased regional variations or asynchrony in the time to peak systolic velocity and in the duration of ejection. Diastolic function is also asynchronous, since patients with HCM have a high myocardial E/A heterogeneity index and more variation in the times from aortic valve closure to peak myocardial E velocity in different segments. These observations are supported by a study of color kinesis in patients with HCM, using time curves of regional LV filling in a short-axis view. The percent filling fractions at 25%, 50%, and 75% of total filling were averaged for all segments in each patient, and the standard deviation of each mean was used as an “asynchrony index.” In subjects with HCM compared with controls, asynchrony was increased in mid- and late diastole, and regional filling times were prolonged even in nonhypertrophied segments.
Myocardial Strain and Strain Rate
The assessment of myocardial muscle shortening (strain) and its rate are new tools in cardiac imaging. Strain may be evaluated noninvasively by tagging on magnetic resonance imaging (MRI) and by echocardiography. MRI studies have shown reduced longitudinal strain and early diastolic strain rate. Circumferential strain was less documented and was found to be either normal or slightly reduced in HCM. Strain rate imaging by tissue Doppler calculates velocity differences between two adjacent points to generate a strain rate/time curve, which is then integrated to calculate strain ( Fig. 23-6 ). This method is restricted mostly to the evaluation of longitudinal indices by the alignment of the interrogation beam. By this method, longitudinal strain in patients has been shown to be reduced compared with controls.
Newer methods analyze two-dimensional B-mode images by tissue tracking and allow for direct measurement of regional tissue displacement, shortening (strain) and strain rate both longitudinally and circumferentially and combining them into a three-dimensional model. Circumferential LV rotation can also be calculated. Our data are in support of the reduction of the longitudinal strain shown previously, while the circumferential strain was found to be increased. Longitudinal strain rate E was decreased by 23%, and circumferential strain rate E was increased by 37%, reflecting the decreased longitudinal strain and strain rate S and their increased circumferential values in HCM ( Fig. 23-7A ). Both longitudinal and circumferential strain rate E/S ratio decreased significantly, indicating impaired relaxation. Functional status (New York Heart Association class greater than I) was found to be related to decreased basal and midlongitudinal strain rate E. The LV twist angle (maximal instantaneous basal to apical angle difference) was similar, but time to peak twist was decreased by 13%, and untwist time (peak to trough twist) was lengthened by 16%, also implying delayed relaxation (see Fig. 23-7B ).
