Hypertrophic cardiomyopathy (HC) is the most common genetic heart disease, with currently ≥13 genes encoding proteins of the cardiac sarcomere (>1,500 mutations) associated with HC and responsible for the enormous heterogeneity observed in phenotypic expression and natural history. During the past half century, the principle of “heterogeneity” has emerged as one of the dominant unifying principles of this complex genetic cardiomyopathy. However, this vast spectrum in disease expression has also created significant clinical challenges, including the ability to reliably identify patients at increased risk of adverse disease-related consequences, such as heart failure symptoms and sudden death.

In the case report “Dramatically Different Phenotypic Expressions of Hypertrophic Cardiomyopathy in Male Cousins Undergoing Cardiac Transplantation with Identical Disease-Causing Gene Mutation,” published in the Journal, Roberts et al have expanded on our understanding of the diverse morphologic expression observed within the enormous HC disease spectrum. Two family members with a longstanding history of HC each developed progressive heart failure refractory to advanced medical therapies and, ultimately, required heart transplantation (at nearly the same age). However, the most striking aspect of their report is that these relatives developed severe heart failure symptoms, each associated with a completely different and unique HC phenotype (i.e., nonobstructive HC with preserved ejection fraction [65%] in 1 patient and the “end-stage” phase associated with systolic dysfunction [ejection fraction 20%] in 1 patient). These dramatically different expressions in HC morphology occurred despite each family member having the identical troponin I gene mutation.

This case report draws attention to a number of important HC disease-related concepts that remain largely underappreciated within contemporary cardiovascular practice. Perhaps most importantly is the principle that the determinants of heart failure symptoms in patients with HC are complex and can vary substantially among the patients. Although left ventricular (LV) outflow obstruction (≥30 mm Hg) is the most common disease feature responsible for the generation of limiting symptoms (present in 2/3 of patients at rest or with exercise), ≥1/3 of patients with HC will have the nonobstructive form, with no outflow gradient (<30 mm Hg) and with preserved systolic function. The development of exertional dyspnea in these patients with HC is considered to be largely a consequence of diastolic dysfunction resulting from restrictive physiology.

However, a paradoxical observation noted among these patients has been the lack of any substantial amount of fibrosis, often considered to be 1 of the major components of the underlying myocardial substrate promoting abnormal compliance of the left ventricle. Previous cardiovascular magnetic resonance imaging with late gadolinium enhancement studies have demonstrated that patients with HC who develop moderate to severe limiting heart failure symptoms have no or very little late gadolinium enhancement. This was the case observed in the report by Roberts et al, in which the HC family member who underwent transplantation for advanced heart failure symptoms in the setting of normal systolic function was observed to have only a trivial amount of fibrosis in the native explanted heart.

Therefore, at present, the precise pathophysiologic mechanism responsible for the development of progressive limiting symptoms in this subset of patients with HC remains uncertain. Fortunately, it is extremely uncommon for patients with nonobstructed HC (with preserved systolic function) to develop severe progressive heart failure during their clinical course. The management strategies for these patients include atrioventricular nodal blocking agents (e.g., β blockers, verapamil) and, if clinically indicated, judicious use of diuretics. No data are available supporting the use of angiotensin-converting enzyme or aldosterone inhibitors in this subset of patients with HC, and the lack of any substantial amount of myocardial fibrosis suggests these antiremodeling drugs would have limited utility. We also wish to underscore that it remains difficult to assess the severity of diastolic function in the presence of HC, because noninvasive measures do not reliably reflect the LV filling pressures. Thus, discordance is often present between a specific patient’s magnitude of symptoms and the results of objective testing. Therefore, for the small minority of patients with nonobstructive HC in whom limiting symptoms progress despite drug therapy, advanced therapeutic options such as heart transplantation should be considered as the only long-term management option.

On the other end of the HC disease spectrum is the most advanced form of heart failure, the “end-stage” (or “burned out”) phase, occurring in a small subset of patients with nonobstructive HC (prevalence 3%). End-stage HC is characterized by systolic dysfunction (ejection fraction <50%) with ventricular dilation and diffuse myocardial fibrosis and is associated with a generally unfavorable clinical course owing to an increased risk of sudden death and progressive heart failure symptoms. The identification of patients with HC and systolic dysfunction is important, triggering consideration of the use of conventional therapies aimed at improving the adverse LV remodeling, including angiotensin-converting enzyme and aldosterone inhibitors. Once patients with HC develop systolic dysfunction, the rapid progression of heart failure symptoms can occur; therefore, early consideration should be given to heart transplantation listing. However, LV assist devices can also be used successfully as a bridge to transplantation (i.e., in particular, in select patients with a substantially dilated LV chamber size), just as was demonstrated for the patient with “end-stage” HC described in the report by Roberts et al.

Although these 2 cases have highlighted the important role for cardiac transplantation in the treatment of young patients with HC, transplantation is still uncommon within the vast spectrum of clinically identified patients with HC (the prevalence of transplantation for HC has been approximately 1% annually in the United States). However, for those patients with HC who do require this therapy, the post-transplant survival has been favorable (75% at 5 years and 60% at 10 years) and comparable to that of patients transplanted because of other cardiovascular diseases.

The report by Roberts et al has also highlighted the role of genetic testing in the contemporary treatment of patients with HC and their family members. Although the introduction in 1992 of commercial genetic testing for HC resulted in a substantial amount of optimism that molecular biology would lead to a new paradigm in the clinical management of HC, these expectations have generally not been realized. Specifically, among large cohorts of both related and unrelated patients with HC, the individual sarcomere mutations do not appear to reliable predict the pattern of LV hypertrophy (e.g., specific phenotypes) nor the clinical course. Thus, the results of genetic testing cannot be used to “predict the future” for individual patients with HC. For these reasons, specific sarcomere mutations are not currently used in routine clinical practice to identify individual patients with HC at future risk of adverse heart failure events (e.g., end-stage heart failure and/or the need for transplantation) or patients at high risk of sudden death who might benefit from implantable cardioverter defibrillator therapy.

Nevertheless, a powerful role still exists for genetic testing in HC; however, this is primarily as a test to definitely screen at-risk relatives if a mutation can be identified in a family proband. Those relatives who do not carry the mutation will have no future risk of developing HC and therefore no further testing would be necessary. Likewise, for relatives identified as having a mutation but without LV hypertrophy (i.e., genotype positive but phenotype negative), the likelihood is very high that the patients will develop phenotypic evidence of disease during early adulthood.

What then could be a possible explanation for the lack of a relation between genotype and phenotype in this disease, including the incredibly diversity in phenotypic expression among related subjects? It is likely that numerous, as yet undefined, environmental factors and modifier genes are important elements that influence expression of the primary sarcomere gene mutation. However, the precise complex pathophysiology responsible for the diversity of morphologic expression observed in HC remains uncertain. However, perhaps future investigations will yield important insights in this area.

Since its initial description >50 years ago, HC remains a complex and challenging heart disease associated with enormous diversity in phenotypic expression, perhaps greater than any other cardiovascular disease. The case presented in the report by Roberts et al of 2 family members requiring heart transplantation, each with a distinctly unique morphologic expression of HC, further substantiates the principle that heterogeneity “rules the day” in HC.