(Circulation. 2001;104:126.)
© 2001 American Heart Association, Inc.
Editorial |
Hypertrophic Cardiomyopathy
From Bedside to Bench ... And Now Back Again?
Key Words: Editorials • cardiomyopathy • echocardiography • genetics
Hypertrophic cardiomyopathy (HCM) is a fascinating disease that has intrigued and challenged cardiologists for decades. Initially a diagnosis made by master clinicians adept at translating bedside dynamic auscultation into hemodynamic pathophysiology, HCM continues to challenge the frontiers of diagnosis and technology. The development of 2D and Doppler echocardiography provided the greatest increment in understanding the complexity of HCM. While clinicians at large became skilled at the bedside detection of dynamic left ventricular outflow obstruction, echocardiography revealed that many more patients had unexplained left ventricular hypertrophy (LVH) consistent with HCM but without evidence of obstruction. In fact, the nonobstructive, "silent" forms are more frequent than the obstructive, "noisy" variants. The pattern and severity of LVH are now appreciated as heterogeneous and diastolic dysfunction as highly prevalent.
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The next frontier broached in terms of understanding the pathophysiology of HCM came in 1989 with the discovery that mutations in the genes coding for the proteins of the cardiac sarcomere were associated with familial HCM.1 Although long recognized clinically that a significant proportion of HCM occurred in a familial pattern, the gene discovery offered the potential for new insight to the pathophysiology of HCM. One particular challenge in the clinical management of HCM is the screening of family members, which has relied on echocardiographic and electrocardiographic evidence of LVH. The uncovering of the HCM mutation offered the potential of blood test screening that could be more accurate than clinical detection of LVH. However, the realization of the molecular complexity of HCM has exploded. More than 140 mutations in at least 9 different genes coding for cardiac sarcomeric proteins and 2 genes coding for cardiac mitochondria have been associated with clinical HCM.2,3 Each family seems to harbor a unique, family-specific mutation, and the clinical expression of mutations is highly variable, even within individual families. This molecular diversity renders blood test screening clinically impractical at present.
What Does This Mean for the Families of HCM Patients?
Screening for HCM among the family members of affected individuals continues to rely on history, examination, and electrocardiographic and echocardiographic detection of LVH in the absence of another cause for the LVH (ie, long-standing hypertension, aortic stenosis, etc.). In this regard, another important insight derived from molecular genetics is that mutations in myosin-binding protein C have been associated with HCM that may not manifest the typical phenotype until the fifth or sixth decade of life.4,5 This implies that screening for LVH should continue at periodic intervals throughout adulthood. Given concerns regarding the risk of sudden death, particularly in association with participation in competitive athletics, the detection of HCM before the development of LVH would be advantageous. If genetic screening is impractical, perhaps the common pathway that links the gene defects to the clinical expression of functional HCM could be used.
The exact mechanism by which mutations of the cardiac sarcomere lead to LVH in variable patterns has yet to be determined. The role of modifier genes and/or concomitant environmental stimuli has not been elucidated fully. However, the majority of models of HCM suggest that the mutations result in a dysfunctional sarcomere, with decreased force and/or velocity of contraction.2,6 Hypertrophy in this scenario could result as a compensatory response to the sarcomere/myocyte hypofunction; therefore, evidence of myocyte dysfunction should precede hypertrophy.2 Decreased myocyte function would seem to be contradictory to the relatively high ejection fractions (EF) that are seen in HCM. However, EF does not directly measure myocyte or even myocardial function. Rather, EF is a reflection of change in chamber dimensions. Compared with normal hearts, those with marked LVH and small chamber dimensions, as seen in HCM, can maintain EF with much less relative wall thickening. Therefore, measuring EF will not suffice to detect the subclinical, prehypertrophy phase of HCM; other measures will be needed.
In this issue, Nagueh and colleagues7 report on the utility of tissue Doppler velocities of the mitral annulus (speed of annular plane displacement) for the detection of individuals with HCM-causing mutations, even in the absence of LVH. Compared with individuals without gene defects, those with a mutation and no LVH had lower systolic and diastolic mitral annular velocities; however, the velocities were not as low as those in patients with full phenotypic HCM. This study, the first to report on the noninvasive detection of prehypertrophy HCM, is an extension of the authors’ previous work in a transgenic rabbit model of HCM.8 The tissue Doppler velocities of the mitral annulus have been shown to correlate with invasive measures of global systolic and diastolic left ventricular performance.9,10 This assessment of global function may have utility for detecting abnormal myocyte function in preclinical HCM. The tissue Doppler parameters proposed by Nagueh et al7 for the prediction of mutation status had 100% sensitivity and >90% specificity. Familial HCM is inherited in an autosomal-dominant pattern, thus predicting a 50% pretest probability of disease in first-degree relatives; thus, abnormal mitral annular velocities would be expected to have a positive predictive value of 91% and a negative predictive value of 100%.
Can We Now Use Tissue Doppler Echocardiography to Detect the Presence of HCM Gene Defects?
Clearly, this study of 73 patients divided among 3 groups (control; mutation-positive but LVH-negative; and mutation-positive, LVH-positive) serves as a preliminary investigation. In clinical practice, we are most concerned with establishing or excluding whether the family members of a known HCM patient are also affected. The current study suggests this possibility, but it does not have the breadth to answer this question clearly. If the individuals in this study with HCM mutations but no LVH were from different families or carried defects in completely different genes than the comparison groups, the results may indicate gene- or family-specific variance in myocardial velocity. Subsequent evaluations undoubtedly need to focus on individual genes (myosin heavy chain, myosin-binding protein C, troponin, etc), individual phenotypes, and/or individual kindreds.
It is not clear how early the tissue Doppler velocities can detect myocyte dysfunction, ie, do the tissue Doppler velocities decrease months, years, or decades before the development of LVH? If the lead-time is too short, then the comorbid conditions of adults will confound the results. HCM patients are often most concerned about whether their children also have the disease and whether it would be safe for them to participate in competitive athletics. It is not yet known if adolescents or preteens will demonstrate abnormal tissue Doppler profiles. Furthermore, it remains to be defined whether tissue Doppler of the mitral annulus is abnormal in HCM phenotypes such as the apical, midventricular, lateral free wall, and isolated anterior-basal septal hypertrophy variants. Greater relevance to clinical practice will be demonstrated if the tissue Doppler mitral annular velocities are also shown to be abnormal in the prehypertrophy phase of these morphological variants. Recently introduced Doppler strain-rate imaging is another form of myocardial imaging that may prove to be even more exciting as a screening tool for prehypertrophy genetic sarcomere dysfunction.11 Finally, it must be emphasized that other, more common conditions such as coronary artery disease, hypertension, diabetes mellitus, and aging alter myocardial function, tissue Doppler velocities, and Doppler strain, all of which may confound the screening for HCM in adults.
The preliminary observations reported by Nagueh and colleagues7 have just slightly opened the door to allow a glimpse of a possible tantalizing future. Their findings that noninvasive measures of left ventricular function can potentially predict HCM gene positivity before the development of hypertrophy, if widely substantiated, will truly revolutionize the understanding and management of HCM. In addition to facilitating appropriate counseling, the possibility of enacting therapy to prevent or hinder the progression to significant LVH, morbidity, and even mortality may be on the horizon. Although much work is still required to link genetic defects in the cardiac sarcomere with a clinical, noninvasive measure of global left ventricular performance, we may be headed back into the corridor connecting the molecular laboratory bench with the echocardiographic laboratory and ultimately back to the bedside.
References
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Niimura H, Bachinski LL, Sangwatanaroj S, et al. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med. 1998; 338: 1248–1257.
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Nagueh S, Bachinski L, Meyer D, et al. Tissue Doppler imaging consistently detects myocardial abnormalities in patients with hypertrophic cardiomyopathy and provides a novel means for an early diagnosis before and independently of hypertrophy. Circulation. 2001; 104: 128–130.
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Nagueh S, Kopelen H, Lim D, et al. Tissue Doppler imaging consistently detects myocardial contraction and relaxation abnormalities, irrespective of cardiac hypertrophy, in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2000; 102: 1346–1350.
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Zamorano J, Wallbridge DR, Ge J, et al. Non-invasive assessment of cardiac physiology by tissue Doppler echocardiography: a comparison with invasive haemodynamics. Eur Heart J. 1997; 18: 330–339.
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Sohn DW, Chai IH, Lee DJ, et al. Assessment of mitral annulus velocity by Doppler tissue imaging in the evaluation of left ventricular diastolic function. J Am Coll Cardiol. 1997; 30: 474–480.[Abstract]
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