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Published online before print December 4, 2008
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Commentary |
From the Division of Cardiology,
* Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland; the Department of Human Anatomy and Physiology,
University of Padova, Padova, Italy; and the Department of Clinical Medicine,
Section of General Pathology, University of Perugia, Perugia, Italy
Abstract
This Commentary discusses the potential of angiotensin II type 1 receptor blockade as a treatment option for patients with hypertrophic cardiomyopathy
As recently stated by Elliott and Spirito, "the prevention of premature death from ventricular tachyarrhythmia, heart failure and stroke remains a major aim of clinical management in what is now called hypertrophic cardiomyopathy."1 Hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease, the first myocardial affliction for which a genetic basis was identified and, in essence, a disease of the contractile sarcomeric proteins. The stigmata of the disease are myocardial hypertrophy, often asymmetric and with any possible diffuse or segmental pattern of left ventricle (LV) thickening, and impaired LV contractile and diastolic function. HCM can be classified as obstructive or non obstructive. In the 25% of HCM patients with LV outflow tract obstruction, there is the presence of a dynamic ventricular gradient. A pronounced LV outflow tract obstruction directly correlates with the severity of the clinical manifestations while adversely impacting the prognosis.2
HCM results from excessive cardiac growth, increased number of fibroblasts with secretion of collagen (fibrosis), and disruption of the characteristic cell-to-cell alignment of the sarcomere and myocyte. Electrical instability (ie, atrial and ventricular arrhythmias) is another prominent feature of HCM and a leading cause of death, particularly in young athletes.3 Although HCM is a relatively benign syndrome in adult populations, with an annual frequency of sudden cardiac death (SCD) of 0.5% to 1%, HCM still remains the most common cause of death among children and adolescents (1% to 2%).4 Early age of onset, family history of SCD, malignant arrhythmias and exercise-induced hypotension, in addition to specific genetic mutations, all contribute to a higher risk for SCD.5, 6 As a matter of fact, "the major clinical challenge is the identification of the small number of individuals who are prone to serious complications and rapid disease progression."2
Typical clinical manifestations of HCM include chest pain, exertion-related dyspnea (exercise intolerance), palpitations and, less frequently, syncope. However, HCM is clinically variable, with some patients remaining asymptomatic throughout their lifetime, while others experience the most serious complications. This heterogeneity is likely one of the major reasons for the complexity of HCM management. Unfortunately, SCD is quite often the presenting manifestation in young individuals.3
Current treatments focus on relieving the symptoms of HCM, treating arrhythmias (ie, atrial fibrillation and nonsustained ventricular tachycardia) that occur commonly in HCM, and, foremost, preventing SCD. These interventions include changes in lifestyle (ie, diet and exercise) and pharmacological tools such as β-blockers, Ca2+ channel blockers and diuretics. The implantation of cardiac defibrillators is also a valid option, particularly for those patients that are at the highest risk for sudden death.
HCM is caused by mutations in one of a number of genes. Approximately 450 different mutations have been discovered in genes for functional/structural proteins in the sarcomere (13 related genes) and myofilaments.2 Most of the alterations are missense, with a single amino acid residue substituted for another. The majority of HCM molecular defects lie in genes encoding functional and regulatory sarcomeric proteins such as β-myosin heavy chain (β-MHC), actin, cardiac troponin T and I, and tropomyosin, as well as structural proteins, ie, myosin binding protein C (MYBPC) and titin.2
Identifying the specific gene mutation underlying the disease in individuals has more than an etiological relevance, as specific gene mutations may contribute to the different phenotypic and functional outcomes in patients suffering from HCM. For example, disease due to mutations in β-MHC appears to manifest at a younger age and is associated with more pronounced hypertrophy and a higher risk of SCD when compared to HCM caused by mutations in MYBPC or 
-tropomyosin genes.7
Hearts from subjects harboring a TnT mutation, however, exhibit a mild hypertrophic phenotype, despite the association with high incidence of SCD.8
While HCM is a monogenic disorder in nature, the ultimate phenotype is likely the result of the complex blend of the primary causal mutation with alterations in other genes and the surrounding environment.6
To predict the severity of HCM outcome, possibly prevent SCD, and describe "genotype-phenotype" connections, other "modifying factors" that may influence HCM phenotypic expression should be considered and studied as well.
In addition to the genetic defects affecting functional and structural sarcomeric proteins, polymorphisms in the renin–angiotensin–aldosterone system are considered potential disease modifiers in HCM. The renin–angiotensin–aldosterone system plays a pivotal role in cardiovascular physiology and pathology. Gene polymorphisms of the angiotensin-converting enzyme (ACE) and angiotensin II type 1 receptor (ATR-1) are associated with the severity of hypertrophy9 and the prognosis of HCM patients.6, 10 ACE is a zinc metallopeptidase, converting angiotensin I into the vasoactive and aldosterone-stimulating peptide angiotensin II (a potent pro-hypertrophic agent), and inactivating bradykinin (a weapon against hypertrophy). ACE activity is highly variable among individuals, mainly due to the presence of an insertion/deletion polymorphism in intron 16, consisting of a 287-bp Alu repeat sequence, with three genotypes: insertion, insertion/deletion, and deletion (DD). Patients with the DD genotype have increased tissue and plasma levels of ACE and may therefore have increased levels of angiotensin II, fueling hypertrophy and fibrosis. DD-ACE is considered a ‘pro-LVH’ modifier in HCM.
However, assessing the modulatory role of angiotensin II in the setting of HCM is more complex than a simple "gene specificity." One study of families with mutations in MYBPC and β-MHC by Tesson and colleagues has shown that a significant correlation between the DD-ACE genotype and hypertrophy was observed in the presence of Arg403 codon mutations of β-MHC, but not for other mutations of either MYBPC or β-MHC.11 Conversely, Perkins and colleagues observed DD-ACE only in patients harboring MYBPC.12 This inconsistency highlights another potential problem for the modulatory role of angiotensin II in the HCM setting—the "codon-specificity" (within the same gene) for this angiotensin II effect. Importantly, the frequency of the ACE insertion/deletion polymorphism shows wide diversity among geographical areas and populations, thus making comparison of studies performed in different countries more difficult.13
Inhibiting ACE or blocking ATR-1 might reverse hypertrophy and fibrosis in experimental and human cardiac afflictions such as hypertension, congestive heart failure and metabolic syndrome. In these conditions, ACE inhibitors are known to improve LV diastolic function and coronary blood flow. Several studies have assessed the potential benefits of ATR-1 antagonism in human HCM. In one study, Araujo and colleagues have shown that 6 months’ treatment with losartan (100 mg/day) improved diastolic function and decreased LV filling pressure in 20 patients with nonobstructive HCM, although no changes were observed in the thickness of LV wall.14 More recently, the administration of losartan (50 mg/day) for a 1-year period was able to reduce LV mass to some extent (6.4%).15 Kawano et al demonstrated that 12 months’ treatment with valsartan (100 mg/day) reduced collagen synthesis in HCM patients, with no favorable effects on LV diastolic function, filling pressures, or degree of hypertrophy.16 In each of the studies mentioned above, the primary HCM-causing genetic mutation was never reported. The different genetic backgrounds or ethnicity of the HCM patients enrolled in these studies may have contributed to the divergent impact of this class of compounds on LV hypertrophy and could prove important in understanding different therapeutic outcomes with the same drug regimen.
The study conducted by Penicka and colleagues17
in the current issue of the Journal of Molecular Diagnostics addresses these issues. These authors first hypothesized that a long-term (12 months) administration of the angiotensin II type I receptor antagonist candesartan in patients with HCM is able to reduce LV hypertrophy as well as improve LV function and exercise tolerance. They aimed to demonstrate that the magnitude of the impact of the AT1-blocker on patients harboring HCM is a function of the specific sarcomeric mutation that is present. To test this hypothesis, they performed a double-blind, placebo-controlled, randomized and multicenter study, enrolling 24 genetically independent, adult patients with nonobstructive HCM, normal ejection fraction (
60%), and sinus rhythm. HCM was diagnosed by echocardiography showing a non-dilated, hypertrophied LV (wall thickness >15 mm), and absence of LV hypertrophy caused by hypertension and valvular diseases. Treatment with ACE inhibitors or AT1-R antagonists at any time in the past was one of the major exclusion criteria.
Investigating "genotype-phenotype" correlations in HCM has been a topic of intense study. These authors look at the condition from a different angle, asking whether "the efficacy of AT-1 blockade on LV mass and function in HCM subjects can be predicted on the basis of the intrinsic gene mutation harbored?" The investigators first performed baseline molecular genetic testing, revealing that the majority of the patients enrolled in the study were affected by mutations in β-MHC, MYBPC, and cardiac troponin T and I genes. Then, they assessed tolerance to exercise by bicycle ergometry, the presence of malignant arrhythmias by Holter monitoring, the extent of LV hypertrophy by 2D echocardiography and LV outflow tract pressure gradient by Doppler echocardiography. The patient cohort was subsequently divided in two groups (n = 12 each), randomly assigned to receive the AT1-R blocker candesartan (32 mg/day) or matching placebo for 12 months. The authors performed a titration of the candesartan dose to be used, with 67% of the patients reaching the target dose of 32 mg daily. The same structural and functional end-points were re-evaluated after the drug (or placebo) treatment. Despite similar baseline symptoms between the groups, including exercise tolerance, systo-diastolic LV function, and hypertrophy magnitude, patients under candesartan treatment showed a significant reduction in mean LV thickness and mass when compared to those receiving placebo. These morphological changes were concomitant with a better functional outcome both in terms of systolic and diastolic function and with reduced LV filling pressures. This beneficial impact was absent in patients receiving placebo. Despite no change in LV ejection fraction was reported between the groups, six patients receiving candesartan showed a 1-point decrease in NYHA class compared to only one patient receiving placebo. The reduction of LV mass (–15.5%) and improvement in LV systolic and diastolic function in the candesartan group were also associated with an increase in total exercise time.
Besides showing that long-term treatment with AT1-R blockers are safe, in face of their vasodilative action, the most salient aspect of the present study is that the heterogeneous response in terms of LV reduction after candesartan treatment is in part dependent on the specific sarcomeric protein gene mutation. All patients displaying mutations in β-MHC showed the most marked decrease in LV mass, while carriers of the MYBPC genotype showed moderate responses. Conversely, no regression of hypertrophy was observed in patients harboring the cardiac troponin I gene mutation. This pilot study is the first attempt to associate the effects of AT1-R blockade with the significant mutation-specific regression of hypertrophy.
Other studies have been published using different angiotensin II receptor blockers from the same family, but the present approach uses a new combination of tools, ie, cardiac functional assessment and mutation analysis. Mutational analysis by Penicka et al shows that the beneficial effects of the AT1-R blocker candesartan might be mutation specific, with better hypertrophy regression in patients with mutations in β-MHC and MYBPC. This must be considered a pilot study, and increasing the population size is necessary to draw confident conclusions regarding the correlation of AT1-R blockade and genetic mutations involved in HCM. The hypothesis of a "genetic basis" as the explanatory factor for the conflicting results in AT1-R blockade on HCM progression still remains speculative, particularly because the causative genetic mutations identified here were not examined in the previous studies,14, 16, 15 making the comparison between studies rather problematic.
The concept that a heterogeneous genetic background in HCM patients enrolled in long-term studies with AT1-R blockers is responsible for the different response in terms of LV hypertrophy magnitude must be validated. Ideally, a comparison should be made studying different patient cohorts from the same geographical area. The authors noted that HCM-causing mutations may also depend on the genetic (and so "geographical") background of the cohort of individuals. Another major limitation is that neither ACE nor AT1-R polymorphisms were assessed. In theory, carriers of the DD-ACE or AT1-R C (increased angiotensin II effect) should get the most beneficial effects after candesartan (or similar compounds). Finally, the specific molecular mechanisms linking beneficial effects of candesartan to specific sarcomere protein gene mutations should be explored.
Setting aside these intrinsic limitations, the work by Penicka and co-workers17
introduces a number of new intriguing questions and starting points for future more in-depth investigations. Half of the patients with unexplained LV hypertrophy do not have a sarcomere or sarcomere-related gene mutation.2
For instance, recent studies of mouse models of mutations in the 
2 subunit of AMP-dependent protein kinase and in the lysosomal-associated membrane protein 2 have been shown to cause unexplained LV hypertrophy.18
The 2 subunit of AMP-dependent protein kinase mutations lead to marked accumulation of glycogen within myocytes,19
whereas, lysosomal-associated membrane protein 2 mutations cause accumulation of authophagic vacuoles that contain undegraded cellular products.20
The rate of progression from hypertrophy to dilation and overt heart failure is higher in storage cardiomyopathies than in HCM,2
and interstitial fibrosis is a major component in most of HCM cardiac phenotypes. Would AT1-R antagonists still be able to provide beneficial effects in patients affected by HCM based on non-sarcomeric mutation? Would collagen neo-synthesis and fibrosis still be a crucial factor? Is the role of oxidative stress, particularly when the heart rapidly progresses from LV wall thickening to overt dilation, relevant?
Certainly, the balance between oxidants and antioxidants is important for maintenance of normal collagen homeostasis. Thiol-reducing agents such as N-acetylcysteine are effective in reducing myocardial oxidative stress, stress-responsive signaling kinases, and fibrosis in a mouse model of HCM.21 Based on existing literature with other ATR-1 blockers,22 one could anticipate that patients receiving candesartan may have better preserved cardiac tissue redox conditions. However, there is no direct link between reactive oxygen species, changes in LV morphology, and gene mutations, at either the sarcomeric or the non-sarcomeric level. Other drugs could therefore be effective in reducing LV mass and improving function in HCM patients on a "specific genetic mutation" basis. These issues highlight the need to understand the exact mechanism by which gene mutations are translated into clinical HCM phenotype.
A positive impact of candesartan on exercise tolerance has been demonstrated in patients with mild diastolic dysfunction at rest and a hypertensive response to exercise.23 In the present study Doppler-echocardiography measurements were not performed immediately after exercise, but only at rest. The data are consistent with previous observations, which showed improved exercise tolerance correlated with an improvement in myocardial systo-diastolic function.24 Again, decrease in LV mass seems to be a major determinant for this change. This might be related to improved myocardial contraction and relaxation in presence of decreased LV filling pressures. Moreover, the systolic blood pressure at peak exercise tended to be lower in the candesartan versus placebo group. Ultimately, this systemic effect may have accounted for some of the observed positive impact of candesartan on exercise tolerance. In addition, it is likely that reduced collagen synthesis (deposition) associated with AT1-R antagonism could have contributed to increased myocardial function. These questions still remain unanswered, although the present study provides an excellent and intriguing basis for a better understanding of the pathophysiological features of HCM and for improvements in its clinical management.
"Critical mass" is a concept used in different disciplines, including sociodynamics and physics. It usually designates the existence of a sufficient momentum or a minimum amount of given material, respectively, such that the momentum itself (or the material) becomes self-sustaining and fuels further growth. In nuclear physics reaching this point starts a fission chain reaction under stated conditions. In both cases, this initial "critical" nucleus (or quantum) is, at the same time, igniting a reaction and subjected to external factors that may influence the further development (orientation) of this "tipping point." Adopting, by analogy, this conceptual frame in the HCM setting is indeed very tempting. However, what if "mass becomes critical?" After all, the present study reiterates one central mainstay of the pathophysiology, clinical outcome, and possible therapeutic success in HCM patients: the magnitude of LV hypertrophy is one key determinant of symptoms and prognosis.
Young patients with "critical," extreme hypertrophy (even with few or no symptoms at all) have substantial risk for SCD.25
The present study suggests that β-MHC (and MYBPC to a lesser extent) may be more "critical" than other proteins, as all patients displaying a candesartan-induced marked decrease in LV mass (>100g) were positive for a mutation in β-MHC. Previous studies have demonstrated that the magnitude of LV hypertrophy is not only a strong and independent predictor of prognosis, but in young patients the LV mass becomes really "critical" when, in absence of other generally accepted risk factors, the maximal wall thickness is 30 mm.25
Thus, we may have the threshold for its "criticality," and possibly a structural/molecular diagnostic marker for predicting HCM outcome and the efficacy of a given intervention.
We are left with several unresolved questions. We know that genetic mutations are major determinants of HCM, but the molecular links between the causal sarcomeric mutations and the phenotype of HCM remain to be fully understood. Putative mutations and the prevalence of modifying factors, such as ACE and ATR-1 polymorphisms, may differ between ethnic groups. However, in addition to genetic and geographical influences, geometry should be also considered. More specifically, how would the conceptual framework of predicting the efficacy of a given drug based on the specific gene mutation apply and work for HCM with LV outflow tract obstruction? This dynamic condition exhibits poorer overall survival, complex LV kinetics and requires a completely different palette of drugs, avoiding agents endowed with some vasodilative properties such as ACE inhibitors, ATR-1 blockers, and certain Ca2+ channel blockers.26 Since β-adrenergic antagonists are the front-line therapy in obstructive HCM, perhaps a polymorphism in β-adrenergic receptor genes would apply as a modifying factor in patients suffering from obstructive HCM. Whether and how the possible cross talk between specific gene mutations, modifying factors and spatial distribution of the LV mass may influence HCM phenotype and the efficacy of a given intervention remains to be fully resolved.
Footnotes
Address reprint requests to Nazareno Paolocci, M.D., Ph.D., 858 Ross, Division of Cardiology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD, 21205. E-mail npaoloc1{at}jhmi.edu
See related article on page 35
Supported by a Post-Doctoral Fellowship Grant from the American Heart Association (N.K.) and NIH (HL075265 to N.P.).
Accepted for publication October 24, 2008.
References
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