Hypertrophic cardiomyopathy (HC), a common genetic heart disorder associated with substantial clinical and genetic heterogeneity, is the most frequent cause of sudden death in the young (including competitive athletes). HC is generally characterized by unexplained left ventricular (LV) hypertrophy, although with the aid of molecular diagnosis, it has become evident that disease-causing mutations can be associated with virtually any LV wall thickness. Indeed, many genetically affected children (and even some adults) in HC families do not demonstrate LV hypertrophy at some point in their clinical courses, with incomplete penetrance of the phenotype. Laboratory investigations over the past 2 decades have defined HC as a primary myocardial disease caused by >1,000 mutations in ≥13 genes encoding proteins within and associated with the sarcomere. This has led to an increasing recognition of a novel patient subset within the vast and ever expanding HC disease spectrum: genetically affected family members without clinical or morphologic evidence of the disease. Such patients are usually referred to as “preclinical” or “genotype-positive (+)–phenotype-negative (−)” (G+ P−), and they present the paradox of a rapidly evolving new patient subgroup that requires a long period of follow-up to develop clear guidelines with regard to management.
Definition of Genotype-Positive (+)–Phenotype-Negative (−)
G+ P− patients carry mutations in genes encoding proteins of the cardiac sarcomere, judged (or known) to be disease causing for HC. Such patients are usually asymptomatic, often with 12-lead electrocardiographic abnormalities but no evidence of the HC phenotype (i.e., LV hypertrophy) on 2-dimensional echocardiography and cardiovascular magnetic resonance (CMR) imaging.
CMR is emerging as a highly relevant imaging modality for the identification of the HC phenotype, because of its tomographic high–spatial resolution characteristics. CMR is not encumbered by certain well-recognized limitations of echocardiography with respect to measurements of LV wall thickness, justifying its inclusion in the assessment of G+ P− patients. For example, CMR can provide LV wall thickness measurements with greater precision, particularly relevant to hypertrophy in the borderline zone of 12 to 15 mm. Also, in selected patients, CMR may identify segmental regions of LV hypertrophy in the anterolateral LV free wall (or apex), not reliably detected or often underestimated in magnitude by echocardiography.
It has not been our practice to define the HC phenotype solely by abnormalities on 12-lead electrocardiography. This consideration is due to certain predictable limitations of electrocardiography as a screening test for the clinical HC spectrum : (1) difficulty in establishing absolute and strict partitions for normality at all ages and body sizes (particularly in children), (2) potential confusion created by nonspecific alterations unrelated to cardiovascular disease, (3) unpredictable variability in electrocardiographic patterns over time, (4) the documented weak relation between electrocardiographic voltages and LV wall thickness, and (5) the occurrence of normal results on electrocardiography in up to 25% of phenotypically expressed HC and in about 50% of G+ P− family members.
In contrast, 2-dimensional echocardiography and CMR provide reproducible, quantitative measures of LV wall thickness for comparison to established normal values. On the basis of these considerations, it appears most appropriate to define the HC phenotype with respect to LV hypertrophy (as identified directly by contemporary imaging), while an indirect measure with 12-lead electrocardiography would likely be associated with a large number of false-positive test results.
Family Studies
In Figure 1 , we present 4 families demonstrating significant challenges that arise in G+ P− family members, which are cornerstones of HC clinical decision making: eligibility versus disqualification from intense competitive sports and the prevention of sudden death with prophylactic implantable cardioverter-defibrillators (ICDs).
Family A highlights the issue of sports eligibility in G+ P− children. Two young female children aged 10 and 12 years (III:3 and III:4) are both elite gymnasts. They showed no evidence of HC on electrocardiography and echocardiography, but both carry the causative gene mutation, Arg810His in the MYBPC3 gene, also identified in other clinically affected individuals in the family (II:1 and II:3). Should these children (III:3 and III:4) be removed from competitive sports?
Family B targets the issue of whether decisions regarding sports eligibility in G+ P− patients should be further influenced by a family history of a sudden death event. This family presented for evaluation after a resuscitated cardiac arrest occurred in an 11-year-old female patient (III:2). With subsequent clinical screening and genetic testing, the causative gene mutation, Arg495Gln in the MYBPC3 gene, was identified in each clinically affected family member, as well as the 9-year-old sibling (III:3), with no evidence of the disease phenotype. Should this 9-year-old G+ P− brother be excluded from future involvement in competitive sports, and furthermore, should an ICD for primary prevention even be considered in a patient of this age?
Family C explores and extends the potential role for ICDs in young G+ P− patients with family histories of sudden death. In the first generation, a 30-year-old man (I:1) died suddenly while jogging, but without a confirmed HC diagnosis. All 3 adult children are clinically affected, and 2 have elected prophylactic ICDs (II:1 and II:4). Genetic screening identified the Gly733Glu mutation in the MYH7 gene in each of the 3 siblings, as well as the 14-year-old grandson of the proband, with no evidence of LV hypertrophy but extensive involvement in competitive athletics (III:2). Should this 14-year-old be withdrawn from sports and/or considered for an ICD on the basis of the sudden death event occurring decades earlier in his grandfather?
Family D illustrates the dilemma for a G+ P− relative (III:2), who carries the Lys97Asn mutation in the TNNT2 gene. At 38 years of age, she is the sole survivor affected by HC in a family with malignant outcomes, including 4 sudden death events (III:3, III:4, III:5, and IV:1) and 2 deaths due to end-stage progression (II:1 and II:3). Should this adult relative elect a prophylactic ICD, despite absence of the HC phenotype?
Family Studies
In Figure 1 , we present 4 families demonstrating significant challenges that arise in G+ P− family members, which are cornerstones of HC clinical decision making: eligibility versus disqualification from intense competitive sports and the prevention of sudden death with prophylactic implantable cardioverter-defibrillators (ICDs).
Family A highlights the issue of sports eligibility in G+ P− children. Two young female children aged 10 and 12 years (III:3 and III:4) are both elite gymnasts. They showed no evidence of HC on electrocardiography and echocardiography, but both carry the causative gene mutation, Arg810His in the MYBPC3 gene, also identified in other clinically affected individuals in the family (II:1 and II:3). Should these children (III:3 and III:4) be removed from competitive sports?
Family B targets the issue of whether decisions regarding sports eligibility in G+ P− patients should be further influenced by a family history of a sudden death event. This family presented for evaluation after a resuscitated cardiac arrest occurred in an 11-year-old female patient (III:2). With subsequent clinical screening and genetic testing, the causative gene mutation, Arg495Gln in the MYBPC3 gene, was identified in each clinically affected family member, as well as the 9-year-old sibling (III:3), with no evidence of the disease phenotype. Should this 9-year-old G+ P− brother be excluded from future involvement in competitive sports, and furthermore, should an ICD for primary prevention even be considered in a patient of this age?
Family C explores and extends the potential role for ICDs in young G+ P− patients with family histories of sudden death. In the first generation, a 30-year-old man (I:1) died suddenly while jogging, but without a confirmed HC diagnosis. All 3 adult children are clinically affected, and 2 have elected prophylactic ICDs (II:1 and II:4). Genetic screening identified the Gly733Glu mutation in the MYH7 gene in each of the 3 siblings, as well as the 14-year-old grandson of the proband, with no evidence of LV hypertrophy but extensive involvement in competitive athletics (III:2). Should this 14-year-old be withdrawn from sports and/or considered for an ICD on the basis of the sudden death event occurring decades earlier in his grandfather?
Family D illustrates the dilemma for a G+ P− relative (III:2), who carries the Lys97Asn mutation in the TNNT2 gene. At 38 years of age, she is the sole survivor affected by HC in a family with malignant outcomes, including 4 sudden death events (III:3, III:4, III:5, and IV:1) and 2 deaths due to end-stage progression (II:1 and II:3). Should this adult relative elect a prophylactic ICD, despite absence of the HC phenotype?
Commentary
These HC families underscore emerging dilemmas in clinical HC practice, that is, whether the management of sudden death risk in this new subset of genetically affected relatives without clinical evidence of disease (i.e., G+ P−) should be similar to more typical patients with HC with LV hypertrophy. As seen in families B and C, the issue of disqualification from competitive sports participation and the advisability of prophylactic ICDs for G+ P− members of HC families are often interwoven, making many of these clinical decisions particularly complex and challenging.
Sports Eligibility
Family A raises the question of whether all G+ P− patients with HC should be disqualified from intense competitive sports, an obvious consideration given that HC is the most common cause of sudden death in young athletes. Also, intense competitive sports increase the likelihood of these catastrophic events, and withdrawal from this vigorous lifestyle may well reduce this risk.
Nevertheless, this issue remains unsettled. Notably, the 2 available consensus expert panel documents present diametrically opposed recommendations, with both unavoidably based on clinical inferences with little or no hard evidence. For example, the European Society of Cardiology guidelines are particularly conservative, recommending disqualification from competitive sports for all gene carriers. In contrast, the United States–based Bethesda Conference 36 permits G+ P− patients to participate in all competitive sports until LV hypertrophy appears. These divergent recommendations regarding the same clinical scenario cannot be resolved without longitudinal follow-up studies in this select subset.
Families B and C raise the consideration of whether sports disqualification for G+ P− athletes is even more relevant when there is a family history of HC-related sudden death in a close relative. The question of sports eligibility or disqualification in such subjects is increasing in frequency as more of these families pursue genetic testing in response to catastrophic events occurring in relatives. However, this particular clinical issue is not specifically addressed in the aforementioned recommendations of either the United States or European consensus panel.
A family history of sudden death in a close relative is an acknowledged risk factor in HC, although available data relate only to phenotype-positive patients with LV hypertrophy and clinically defined disease. While it is unresolved as to whether this risk marker can (or should) be extrapolated to genetically affected subjects without LV hypertrophy, it nevertheless seems most prudent to discourage young G+ P− relatives with family histories of HC sudden death from engaging in intense competitive sports at an early age.
ICDs For Primary Prevention
The question of whether G+ P− patients should be considered for primary prevention ICDs because of a family history of sudden death arises most frequently in adults who are part of malignant families with multiple sudden deaths (such as family D). As demonstrated by families B and C, this treatment consideration may also arise with respect to G+ P− children and adolescents. However, the considerable frequency of device-related complications in young patients over long follow-up periods of decades is often a mitigating factor for prophylactic implants in such G+ P− relatives.
Nevertheless, ICDs have proved effective in terminating life-threatening ventricular tachyarrhythmias in high-risk patients with HC with overt disease expression. However, it is largely unresolved as to whether non-hypertrophied LV muscle in patients with HC-causing mutations can constitute an electrically unstable substrate capable of potentially lethal sustained ventricular tachyarrhythmias. Therefore, prophylactic ICDs are most likely to be considered after LV hypertrophy has appeared, thereby justifying close clinical surveillance with echocardiography (and CMR imaging, if available), probably at 12-month intervals, to identify changes in LV wall thickness.
The overwhelming difficulty surrounding this (and other) key questions related to management of G+ P− HC family members is the paucity of available outcome data. The prevailing perception has been that sudden death risk in HC is virtually always linked to the presence of LV hypertrophy. Notably, however, 2 cases have been reported recently in 37-year-old and 43-year-old (nonathlete) patients with MHY7 mutations (but without clinical or phenotypic evidence of HC), who survived ventricular fibrillation. In addition, a few family members reported in the pre-genotyping era may represent similar sudden deaths in the absence of LV hypertrophy. Although rare, such isolated cases suggest the possibility that susceptible G+ P− relatives can harbor arrhythmogenic substrates at a cellular and molecular level capable of triggering life-threatening ventricular tachyarrhythmias.
This observation is consistent with other clinical findings that support the notion that the nonhypertrophied LV myocardium in some G+ P− relatives may be electrically or functionally abnormal, that is, with evidence of diastolic dysfunction, or abnormal 12-lead electrocardiographic patterns, as well as risk markers such as nonsustained ventricular tachycardia on ambulatory (Holter) electrocardiography, abnormal blood pressure response to exercise, delayed gadolinium enhancement.
In contrast, we found no evidence of important arrhythmias on ambulatory (Holter) electrocardiographic monitoring in our G+ P− patients, including in the 4 families reported here. Whether or not the occurrence of arrhythmic events would be enhanced by intense physical activity (such as competitive sports) is unresolved. Supportive evidence that lethal events are probably exceedingly rare in G+ P− patients can be derived from those HC patients with only mild phenotypic expression who have generally favorable prognosis and low sudden death risk. However, it is certainly possible that the true prevalence of lethal HC-related events in G+ P− patients has been underestimated, given that at autopsy, these patients would have structurally normal hearts and probably not be assigned postmortem cardiac diagnoses.
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