Disrobing the Emperor (Heart) Without Destroying the Dignity of Super-Normality
The familial hypertrophic heart is a hyperdynamic pump, not infrequently exhibited in the most elite of athletes, yet unexpectedly treacherous and magnificently deceptive of a defect present since its conception.
See p 2992
For an inherited disease, familial hypertrophic cardiomyopathy (FHCM) is relatively common, with an incidence of 1 in 500, and is the most common cause of sudden cardiac death in the young. All too often, sudden death is the first and only symptom in an otherwise healthy, energetic individual. Because these individuals manifest normal or supernormal ventricular function (ejection fraction 65% to 80%), it is not surprising that sudden death occurs unexpectedly and not infrequently in very fit athletes competing on a local, national, or international level. Our knowledge of the genetics of FHCM has advanced rapidly with at least 10 genes and >150 mutations identified.1 There are several barriers to the clinical application of this knowledge, however. Multiple genes with multiple mutations make screening for a mutation in a single individual a formidable task in terms of time and cost. Thus, there is a need to develop rapid, robust, and accurate techniques for detecting mutations. Mutations are most accurately detected by DNA sequencing on a research basis that remains both too expensive and time consuming for routine clinical use. Nevertheless, in the near future, genetic screening is likely to be incorporated into medical practice. Other techniques offer promise, such as the DNA chip technology and time of flight magnetic resonance. Unfortunately, assigning risk of developing disease, even when the mutation is known, is confounded by other genetic and clinical variables that may detract from the otherwise beneficial effects of this new knowledge. It is also too late to turn back.
The clinical diagnosis is based on echocardiographic detection of hypertrophy, the hallmark of the disease. However, like all single-gene disorders, the phenotype of FHCM results from interactions among the predominant gene, other genes (modifier genes), and the environment. FHCM is further confounded by the pattern of inheritance (namely, autosomal dominant), which is characterized by the variable age-dependent onset of the disease (variable penetrance) and variability in the clinical manifestations of the phenotype (variable expressivity). Genotype/phenotype correlation studies have been insightful, leading to the observation that FHCM seldom develops before puberty.1–4⇓⇓⇓ There are also certain age-dependent trends observed for specific genes. Myosin heavy chain mutations tend to be associated with a high incidence of sudden death, onset in the second and third decades of life, 90% to 100% penetrance, and significant hypertrophy. Unfortunately, troponin T mutations have a high incidence of sudden death with minimal hypertrophy. Onset of disease due to mutations in myosin binding protein C is often delayed until the fourth or fifth or even the seventh or eighth decade.5 The variability in age of onset and the varying extent of hypertrophy further decrease our diagnostic reliability, to say nothing of our ability to determine prognosis and whether and to what extent a detected mutation will be expressed. Tissue Doppler imaging (TDI) is a relatively new technique for detecting altered myocardial function and offers some promise for an earlier diagnosis independent of hypertrophy.6 Assessment of contractility by conventional echocardiography measures the transmural thickening of the myocardium and is less sensitive than TDI. TDI detects changes in contraction (systole) and relaxation (diastole) of the myocardium. Nagueh et al7 showed that transgenic rabbits expressing a β-myosin heavy chain mutation known to cause FHCM in humans exhibited abnormal TDI of the myocardium. This abnormality was present in all rabbits expressing the mutant gene. Surprisingly, 9 of these rabbits showed no echocardiographic evidence of hypertrophy and did not develop hypertrophy until several months later.
The above experimental results formed the basis for suspecting that TDI might provide a preclinical diagnosis of FHCM. To test this hypothesis, Nagueh et al8 performed a study involving 3 groups of individuals: patients with FHCM and hypertrophy, normal controls, and asymptomatic individuals positive for an FHCM mutation without hypertrophy or other known clinical features of FHCM. In the group with FHCM and hypertrophy, Nagueh et al observed decreased diastolic and systolic myocardial velocities on TDI. The 13 asymptomatic individuals positive for an FHCM mutation without hypertrophy (G+ LVH−) also had decreased systolic and diastolic myocardial velocities on TDI. These findings suggested TDI could be utilized for the preclinical diagnosis of FHCM. A preclinical diagnosis has obvious implications for the prevention and treatment of this disorder.
In this issue of Circulation, Ho et al9 publish the results of applying the same technique, TDI, with a similar protocol in a population of normal controls, patients with FHCM exhibiting hypertrophy, and 18 asymptomatic individuals positive for a β-myosin heavy chain mutation but without echocardiographic evidence of hypertrophy. With the use of TDI, Ho et al observed decreased systolic and diastolic myocardial velocities in patients with FHCM and hypertrophy. In the 18 individuals positive for the mutation without hypertrophy, they observed only a decrease in the diastolic myocardial velocity with varying sensitivity and specificity, depending on the cutoff value for velocity. Nagueh et al, in a similar group (G+ LVH−) with a lateral early diastolic (EA) velocity of ≤14 cm/s, showed a sensitivity of 100% and a specificity of 90%. In contrast, with an EA velocity of ≤13.5 cm/s, Ho et al observed a sensitivity of 75% and a specificity of 86% for predicting affected phenotype. They observed that combining an EA velocity of ≤13 cm/s with an ejection fraction of ≤68% had 100% specificity but a low sensitivity (44%). Although it remains to be determined, it is likely that whether one observes decreased diastolic (relaxation) or systolic (contraction) myocardial velocity most likely depends on the extent and duration of involvement of the myocardium. This is particularly so because both groups of investigators observed a consistent decrease in both diastolic and systolic myocardial velocities in patients with hypertrophy. The mean age of the G+ LVH− group in the Nagueh et al study was 35 years, which is 11 years older than the mean age of the same group (G+ LVH−) in the study by Ho et al. This may explain why Ho et al observed no decrease in systolic myocardial velocity. There is also the concern of penetrance. Does a TDI abnormality indicate the beginning of the disease? If so, a difference in the penetrance may account for the findings. We must also be cautious with sensitivity and specificity. What is the gold standard? Is it the presence of the mutation? Because penetrance may be incomplete, the mutation may not be expressed, and therefore, TDI abnormality will not be present despite the mutation. This is neither a false-negative nor a lack of sensitivity. Lastly, the number of individuals involved is small—13 in one study and 18 in the other. It might perhaps be more important to emphasize the positive findings rather than trying to reconcile them. Both studies suggest that TDI, whatever the appropriate future cutoff for the velocity, will identify a group of individuals without hypertrophy, presumably in an early or preclinical stage of the disease. There seems to be agreement that abnormal myocardial function is an early defect; whether it is decreased relaxation, contraction, or both may support the concept of secondary hypertrophy. Future studies will have to determine whether patients with only myocardial defects on TDI exhibit increased risk of sudden death, heart failure, or other clinical features, and to what extent prognosis is altered with this finding. Given the fact that the disease usually does not manifest itself until at least puberty and the age of onset is highly variable, this technique could play a significant role in the management of FHCM if it is confirmed to have adequate sensitivity and specificity. The possibility that TDI could provide an early diagnosis is exciting even if the sensitivity is low.
The significance of a preclinical diagnosis is further emphasized by the recent experimental studies. Placebo-controlled studies with losartan10 and simvastatin11 showed a marked reduction in the phenotype of fibrosis and hypertrophy and improved ventricular function in genetic animal models of human FHCM. Both drugs have approved safety profiles in humans for treatment of other diseases, which, if shown to be effective in clinical trials of patients with FHCM, would beckon the need for independent preclinical diagnosis. It is evident that whatever future therapies evolve, one would hope they would prevent or treat the disease at the earliest possible stage (eg, the stage at which TDI is positive but no other manifestations are evident). It would indeed be practical in families with the disease to screen relatives for prevention and early treatment.
The TDI findings also have implications for understanding the pathogenesis. On the basis of their data, Ho et al appropriately suggest diastolic dysfunction to be the initial defect with overall systolic ventricular function enhanced. Although the suggestion is reasonable, the studies by Ho et al do not exclude decreased systolic myocardial velocity as the trigger for hypertrophy because decreased diastolic velocity was observed only in individuals without hypertrophy, whereas those with hypertrophy consistently exhibited decreased diastolic and systolic myocardial velocities. The stage at which systolic velocity decreases may be the trigger. The issue of whether or not decreased diastolic myocardial velocity precedes decreased systolic velocity may require longitudinal studies from childhood. Both investigators showed in FHCM with hypertrophy that there is a supernormal ejection fraction with a decrease in both diastolic and systolic myocardial velocities. Thus, it remains to be explained why the dichotomy occurs in decreased diastolic and systolic myocardial velocities with an increased ejection fraction.
Is the myocardial abnormality observed on TDI due to sarcomere and/or myocyte disarray? If the primary defect is hyperfunction, sarcomeres made from the normal protein (heterozygote) will be under greater tension by the sarcomeres generated from the superfunctional mutant protein. Because sarcomeres turn over and reassemble every few days, it could lead to a malalignment (disarray), and this in turn could lead to the release of paracrine and intracrine growth factors leading to fibrosis and hypertrophy. The same nonuniformity of forces would exist if the mutant protein is hypofunctional, and it is likely that both hypo- and hyperfunctional mutations exist. The responsible culprit may be exposed with TDI without disrobing the emperor’s dignity of supernormality. FHCM has begun to shed its cloak, and the hidden secret behind the superfunction may be vulnerable. There is the combination of need, opportunity, and optimism for the cardiologist to make a difference with this disease as well as to understand and prevent sudden death in our young population and, in particular, in the young athlete.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- ↵Anan R, Greve G, Thierfelder L, et al. Prognostic implications of novel β cardiac myosin heavy chain gene mutations that cause familial hypertrophic cardiomyopathy. J Clin Invest. 1994; 93: 280–285.
- ↵Marian AJ, Mares A Jr, Kelly DP, et al. Sudden cardiac death in hypertrophic cardiomyopathy: Variability in phenotypic expression of β-myosin heavy chain mutations. Eur Heart J. 1995; 16: 368–376.
- ↵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: 1257.
- ↵Derumeaux G, Ovize M, Loufoua J, et al. Assessment of nonuniformity of transmural myocardial velocities by color-coded tissue doppler imaging: Characterization of normal, ischemic, and stunned myocardium. Circulation. 2000; 101: 1390–1395.
- ↵Nagueh SF, Kopelen H, Lim DS, 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.
- ↵Nagueh SF, Bachinski LL, 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.
- ↵Ho CY. Assessment of diastolic function with doppler tissue imaging to predict genotype in preclinical hypertrophy cardiomyopathy. Circulation. 2002; 105: 2992–2997.
- ↵Lim DS, Lutucuta S, Bachireddy P, et al. Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathy. Circulation. 2001; 103: 789–791.
- ↵Patel R, Nagueh SF, Tsybouleva N, et al. Simvastatin induces regression of cardiac hypertrophy and fibrosis and improves cardiac function in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circulation. 2001; 104: r27–r34.