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Hypertrophic Cardiomyopathy: Diagnosis and Therapeutic Options
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Abstract
Hypertrophic cardiomyopathy is an underdiagnosed genetic disorder, resulting from mutations in sarcomeric proteins. It has a highly variable clinical presentation, with some individuals remaining asymptomatic and others having significant limitation of functional status. The disorder is typically characterized by left ventricular hypertrophy that is not explained by another cause. Patients are further classified based on whether there is obstruction of the left ventricular outflow tract. To-date, there are no pharmacologic therapies that alter the natural history of the disease. Therapeutic approaches have instead focused on symptom relief and prevention of sudden cardiac death. Newer therapies under investigation represent potential means to improve limiting symptoms.
Am J Manag Care. 2021;27(suppl 6):S111-S117. https://doi.org/10.37765/ajmc.2021.88628
Introduction
Hypertrophic cardiomyopathy (HCM) is the most common monogenetic cardiovascular disorder.1 It is observed globally and inherited in an autosomal dominant pattern. Despite being equally distributed by sex, men are diagnosed more frequently than women.2 The prevalence of HCM depends on whether a patient has subclinical or overt disease, and varies by age, race, and ethnicity.3 While the prevalence of asymptomatic HCM ranges between 1:200 and 1:500,4 symptoms are noted in fewer than 1 of 3000.2,5 This discrepancy helps to explain why only about 100,000 of the estimated 750,000 Americans with HCM have been diagnosed. Sadly, this diagnosis gap disproportionately affects women and underserved populations (particularly Blacks/African Americans).1,6
HCM was first reported in the early 1960s as idiopathic hypertrophic subaortic stenosis.7 For decades that followed, various names were used to describe this condition.8 Terms such as hypertrophic obstructive cardiomyopathy have proven confusing, as roughly one-third of patients do not develop left ventricular outflow tract obstruction. Preference has been given to the term HCM.2
Understanding of HCM has evolved significantly over the past 15 years, driven by greater appreciation of diagnostic features, genetic factors, and the disease’s clinical course.9 The purpose of this article is to review HCM’s diagnosis and management.
Etiology and Genetics
Genetic mutations involving one or more cardiac sarcomere, Z-disc, and calcium-controlling proteins underlie most cases of HCM.10-12 To-date, more than 200 mutations involving 20 genes have been reported.13 Most common among them are those involving beta myosin heavy chain 7 (MYH7) and myosin-binding protein C3 (MYBPC3), affecting about 70% of patients who are variant positive.2
While between 30% and 60% of individuals with HCM have an identifiable genetic variant, a significant number of individuals lack a known pathologic genotype or related family history.2,14 Importantly, patients with HCM and a known sarcomeric mutation, such as MYH7, have a 3-fold greater risk of adverse outcomes compared with those without.15 In addition, as many as 5% of patients have 2 distinct pathogenic mutations and fewer than 1% have three.16,17 Those with multiple mutations typically have more severe phenotypes that are more likely to manifest at an earlier age.13
Even among families with the same variant, age of onset and the timing of disease expression can be variable.2 This phenotypic heterogeneity suggests that other factors beyond the sarcomere mutation itself likely play a role.2,8 As an example, morphologic features (eg, mitral-valve enlargement and microvascular abnormalities) can vary in those with a given variant, suggesting that there may be contribution by other modifier genes or environmental factors.8
Pathophysiology
The pathophysiology of HCM has multiple underlying drivers, including left ventricular outflow tract obstruction (LVOTO), mitral regurgitation, diastolic dysfunction, myocardial ischemia, arrhythmias, and autonomic dysfunction.2 Depending on the patient, one of these may predominate or there may be a complex interplay between these contributors.2 A majority of patients present with left ventricular hypertrophy (LVH) and myofibrillar disarray with fibrosis, which contribute to diastolic dysfunction.18 Importantly, though, diastolic dysfunction may be secondary to a number of hemodynamic derangements (eg, prolonged and nonuniform ventricular relaxation, loss of ventricular suction, decreased chamber compliance, and abnormal uptake of intracellular calcium).18
LVOTO is typically present in approximately 75% of individuals with HCM and usually results from 2 primary mechanisms: (1) septal hypertrophy with narrowing of the left ventricular outflow tract (LVOT) and (2) anatomic alterations in the mitral valve apparatus.2 Increased left ventricular pressure ensues, which may further exacerbate LVH, produce myocardial ischemia, and prolong ventricular relaxation. LVOTO is also associated with impaired stroke volume (SV) and increased risk of heart failure (HF), as well as decreased survival.19,20 LVOTO in HCM, however, is extremely labile and can vary based on volume status, autonomic nervous system activity, pharmacotherapy, exercise, and physical positioning, even during a single diagnostic evaluation.21
In general, individuals with HCM, but without LVOTO (aka nonobstructive HCM), usually have a more favorable prognosis, with symptoms typically resulting from diastolic dysfunction.22,23 There is the potential, though, for this and other types of HCM to “burn out,” transitioning to a dilated cardiomyopathy with a worse prognosis.18
Clinical Course
Unlike many other cardiovascular disorders, HCM can appear at any life phase, from infancy to the seventh decade or later.13 It is characterized predominantly by LVH in the absence of other cardiac, systemic, or metabolic disorders capable of producing similar hypertrophy, along with an identified or suspected pathogenic variant.2
The clinical course for those with HCM can be highly variable. For example, some patients lack symptoms, with little need for treatment; in contrast, others may exhibit a progressive course, requiring targeted treatment to improve morbidity and mortality.1,9,24 Approximately 30% to 40% of those with HCM will experience adverse effects such as sudden cardiac death (SCD), progressive symptoms due to LVOTO or diastolic dysfunction, HF symptoms associated with systolic dysfunction, and/or atrial fibrillation (AF) with increased risk of thromboembolism.2 Long-term studies have demonstrated significant benefit with conventional therapies and interventions, with a decrease in the annualized mortality rate to less than 1%, whether a patient has increased risk or develops one of these HCM-related complications.2
Diagnosis and Prognosis
Evaluation for HCM may follow report of a positive family history, presence of clinical symptoms, incidental detection of a heart murmur, an abnormal electrocardiogram (ECG), or echocardiography for a different reason altogether.2 Regardless of the prompting, if a clinical suspicion for HCM exists, patients should undergo evaluation with a comprehensive cardiac history (going back 3 family generations) and physical examination.2 Classic physical exam findings include a systolic murmur, prominent apical point of maximal impulse, abnormal carotid pulse, and a fourth heart sound.2 If LVH is suspected, individuals should also receive an ECG and cardiac imaging for diagnostic confirmation.2
In general, HCM is confirmed by the presence of increased left ventricular wall thickness (>15 mm up to 21-22 mm on average), most commonly by echocardiography.8 More limited wall thickening (13-14 mm) can also be diagnostic when observed in those with an affected family member.2 LVH is the hallmark of HCM and frequently is not concentric; rather, various asymmetrical patterns may be found.8 If imaging by echocardiography is inconclusive, cardiovascular magnetic resonance (CMR) imaging is indicated. CMR can be helpful in many ways, including its ability to distinguish HCM from infiltrative or storage diseases and an athlete’s heart.2
Some family members may have a positive genotype for HCM but are phenotype negative.8 Importantly in these individuals, subclinical cardiac changes may still be found. These include ECG abnormalities, myocardial fibrosis, mitral leaflet elongation, diastolic dysfunction, and blood-filled myocardial crypts.8
Severity of LVH plays a significant role in HCM prognosis and risk of SCD.18 In general, SCD with HCM is uncommon, with an annual event rate of 1%, but it does occur more often in younger as compared with older individuals.2 It is also the most highly visible and devastating complication of HCM. SCD is thought to be due to ventricular arrhythmias resulting from autonomic overactivity secondary to LVOTO, microvascular ischemia, myocardial fibrosis, and myocyte disarray.25 Multiple factors increase this risk further, including left ventricular wall thickness ≥30 mm (so called “massive” hypertrophy) and a personal history of cardiac arrest, ventricular fibrillation, or sustained ventricular tachycardia (VT).18
There has been keen interest in identifying markers of SCD to help stratify implantable cardioverter defibrillator (ICD) use for primary prevention in HCM.2 Because risk of SCD extends over one’s lifetime, it is recommended that it be reassessed every 1 to 2 years (Figure 1).1 Tools to estimate risk are available; however, they may not account for newer risk markers including presence of systolic dysfunction, an apical aneurysm, and late gadolinium enhancement.26-28 Risk stratification algorithms are also limited by low-positive-predictive values. As such, there is a growing need to leverage larger prospective HCM registries to better stratify risk, particularly in pediatric and non-White populations.2
Clinical judgment is required when assessing the prognostic strength of conventional SCD risk markers for individual patients.2 Several major risk markers have been associated with increased risk of SCD.1,2,29 Similarly, additional potential risk mediators have been identified that can inform the risk discussion. Based on current guideline recommendations, individuals with HCM and one or more major risk markers should be considered for ICD placement for primary prevention.2,18 In addition, an ICD is recommended for anyone with a previous documented cardiac arrest or sustained VT.2,30,31 An ICD is not recommended, however, solelyfor participation in competitive athletics.29,32
Current Treatment Guidelines and Management
The 2020 American Heart Association/American College of Cardiology (AHA/ACC) Guideline for the Diagnosis and Treatment of Patients with Hypertrophic Cardiomyopathy largely categorizes management decisions based on whether a patient’s HCM is obstructive or nonobstructive and whether AF, ventricular arrhythmias, and HF are present.2 To this end, treatment must be individualized and requires a thorough understanding of the natural history of HCM. It is also important to remember that currently available pharmacologic therapy does not alter the natural history of HCM; instead, the primary goals involve relief of symptoms (eg, exertional dyspnea, palpitations, angina) and improvement in quality of life (QOL).13
Obstructive HCM
LVOTO in HCM can be quite labile. Nonetheless, treatment success is tightly tied to improvement in the patient’s LVOT gradient. It is critical that caution be exercised when introducing therapies for coexisting conditions that can cause or worsen LVOTO.2 Diuretics, for example, decrease preload and can augment LVOTO. While they may be considered in asymptomatic patients or at low doses for patients with signs and symptoms of congestion, they can be highly problematic in those with symptomatic HCM. Beyond this, positive inotropic agents and pure vasodilators also have relative contraindication in symptomatic patients with obstructive HCM.2
Non-vasodilating β-blockers (eg, atenolol, propranolol) are usually utilized first line for symptom relief and should be titrated as tolerated (typically to a resting heart rate of 60 bpm) (Figure 22).2,13,33-35β-blockers are effective at improving exertional dyspnea and chest pain, largely by inhibiting sympathetic heart stimulation, decreasing oxygen consumption (through reduced heart rate, contractility, and myocardial stress during systole), and increasing diastolic filling.13 Although β-blockers help to alleviate symptoms, they have not been shown to decrease the incidence of ventricular arrhythmias or SCD in HCM.26,36-38
Non-dihydropyridine calcium channel blockers (CCBs) [eg, verapamil and diltiazem] represent an alternative to β-blockers for symptom relief (Figure 22). Because of their vasodilating39,40 and afterload reducing effects, they should be used cautiously in patients with very high resting gradients (>80-100 mm Hg) and/or signs of congestive heart failure.2 For those with significant obstruction and severe associated symptoms, it may be best to avoid CCBs altogether.2,39,41 While combination therapy with β-blockers and CCBs for HCM is generally not recommended, this approach may be considered when used to manage concomitant hypertension.2,42,43
If patients with HCM fail to respond to β-blockers and non-dihydropyridine CCBs, advanced therapies such as disopyramide (a class 1a antiarrhythmic) and septal reduction therapy (SRT) may be considered. Although used infrequently as an antiarrhythmic, disopyramide is an important option in HCM due to its negative inotropic properties.2,39 Because disopyramide can enhance conduction through the atrioventricular (AV) node and potentially facilitate rapid conduction with AF, it is important to use it in conjunction with AV nodal blocking agents such as β-blockers or non-dihydropyridine CCBs.2 If patients experience limiting anticholinergic effects from disopyramide, pyridostigmine can be added to make it more tolerable.2 In general, disopyramide is used for symptom relief and reserved for patients who fail first-line therapies and are not good SRT candidates.38,39,44
SRT is usually reserved for patients who fail to achieve symptom relief from guideline-directed medical therapy (GDMT) and continue to experience impaired QOL.2 Because SRT performed in centers with limited experience addressing LVOTO is associated with increased morbidity, mortality, and need for mitral valve replacement,eligible patients should be referred to advanced HCM centers for evaluation and treatment.2,45-47 In some patients, preference may be given to SRT over escalation of GDMT in follow-up to shared decision making. This is likely to be more common in patients with a low risk of procedural complications and a higher likelihood of medication-related adverse effects. Importantly, SRT is not recommended for patients with HCM who are asymptomatic, with a normal exercise capacity.2
Preference is given to surgical myectomy in patients with symptomatic obstructive HCM who have associated cardiac disease that requires surgical treatment.48,49 Likewise, preference is given to alcohol septal ablation in patients with symptomatic obstructive HCM and contraindication to surgery, advanced age, or limiting comorbidities.45,50,51
Nonobstructive HCM With Preserved Ejection Fraction
Diagnosis and treatment of nonobstructive HCM can prove particularly challenging given variability in disease onset, severity, and risk of adverse outcomes.15 In spite of this, the risk of HCM-related death appears to be no different from that with LVOTO. Similarly, dyspnea and chest pain are common symptoms in this population.2
Treatment of chest pain and dyspnea in those with nonobstructive HCM most commonly involves β-blockers and non-dihydropyridine CCBs. These agents help to slow heart rate, improve diastolic function, decrease left ventricular filling pressures, and reduce myocardial oxygen demand. Verapamil and diltiazem have also been shown to improve exercise capacity and stress myocardial perfusion defects.2,20 Given that these agents have only been evaluated in very small trials, use largely reflects extrapolation from studies of patients with LVOTO.26,36
Loop and thiazide diuretics may be used to improve dyspnea and volume overload when congestion exists.2 As with obstructive HCM, however, judicious use is recommended (ie, low-dose therapy or intermittent dosing) to mitigate the risk of symptomatic hypotension and hypovolemia.52,53
HCM With Atrial Fibrillation
AF occurs in up to 20% of people with HCM, likely as a result of increased left ventricular end-diastolic pressure from LVOTO.2 AF in the setting of HCM is associated with significant risks, including stroke and impaired QOL. Beyond therapies directed at symptom control, prevention of thromboembolism in this population is a priority. Unfortunately, traditional tools used to estimate stroke risk (eg, CHA2DS2-VASc score) fall short in patients with HCM and should not be used.2,13
An oral anticoagulant is recommended in all patients with HCM and AF, as thromboembolism occurs in up to 30%.1,26,36 Similar to those without HCM, preference is given to a direct-acting oral anticoagulant (DOAC), with use of a vitamin K antagonist (VKA) second line. For those on a VKA, an international normalized ratio (INR) of 2 to 3 is sought.2,29 For patients with subclinical AF (detected by an internal or external device), use of an oral anticoagulant for durations longer than 5 minutes but less than 24 hours is reasonable, informed by the duration of AF, the total AF burden, underlying risk factors, and bleeding risk. If an oral anticoagulant is to be used in this group, preference should be given to a DOAC first line.54
Restoration of sinus rhythm should be considered in those with AF, particularly in the presence of poorly tolerated symptoms. Options include antiarrhythmic drug (AAD) therapy (eg, amiodarone and sotalol), catheter ablation, and/or surgical ablation (particularly in those undergoing surgery).13,55,56 In general, ablation is reserved for patients with inability to maintain sinus rhythm on AAD therapy or those in whom it is contraindicated.2 Rate control usually involves a β-blocker, verapamil, or diltiazem, with therapy choice based on patient preference and comorbid conditions.36
HCM With Ventricular Arrhythmias
Because ICD shocks are associated with worse outcomes and impaired QOL in HCM, prevention of VT is an important goal.2 Most patients who have concomitant HCM and VT are already on a β-blocker. Therefore, if VT persists or recurrent ICD shocks occur, AAD therapy should be initiated, with therapy choice based on age, underlying comorbidities, severity of disease, patient preference, and efficacy/safety.2 If VT persists in spite of maximally tolerated AAD therapy, catheter ablation can be useful to reduce the arrhythmia burden.2
HCM and Advanced HF
Left ventricular systolic dysfunction is uncommon in HCM (≈5%) and should invite a comprehensive evaluation for other potential causes such as coronary artery disease, valvular heart disease, and metabolic disorders.2,57 Current guideline recommendations endorse use of GDMT in patients with HCM and a left ventricular ejection fraction under 50%.2 In addition, it is reasonable to discontinue negative inotropic agents (eg, verapamil, diltiazem, or disopyramide) in this population. For those with nonobstructive HCM and advanced HF, it is reasonable to pursue evaluation for heart transplantation or mechanical circulatory support (ie, left ventricular assist device [LVAD]).20,26 Finally, it is reasonable to pursue ICD placement or cardiac resynchronization therapy (CRT) in patients with HCM and a left ventricular ejection fraction under 50%.2,22
Investigational Treatments
Presently, there are no disease-modifying nor preventive therapies for HCM. Treatments, such as valsartan, gene editing (CRISPR/Cas9), gene replacement therapy, and allele-specific silencing remain under investigation,2,58 with uncertain efficacy and safety.2
Mavacamten
Mavacamten is a first-in-class, small molecule selective inhibitor of cardiac myosin ATPase59 that reduces actin-myosin cross-bridge formation.60,61 It can improve the LVOT gradient and left ventricular filling61-63 and was shown to significantly decrease post-exercise LVOT gradients in a small phase 2 trial (PIONEER-HCM) of patients with symptomatic obstructive HCM.64 Individuals in this study who received mavacamten were also noted to have increased exercise capacity and improved New York Heart Association (NYHA) functional class.64
In follow-up to this, a phase 3, randomized, double-blind, placebo-controlled trial (EXPLORER-HCM) was initiated. Patients with symptomatic obstructive HCM were randomized 1:1 (n = 251) to receive once-daily oral mavacamten or placebo for 30 weeks.59 The primary end point was a 1.5 mL/kg/min or greater increase in peak oxygen consumption (assessed by cardiopulmonary exercise test) and at least one NYHA class reduction or 3 mL/kg/min or greater oxygen consumption increase without NYHA class worsening. Treatment with mavacamten in this study was associated with a significant improvement in the primary efficacy end point (37% of patients treated with mavacamten vs 22% of patients treated with placebo; 95% CI, 8.7-30.1; P = .0005). There was also greater reduction in the post-exercise LVOT gradient (–36 mm Hg; 95% CI, –43.2 to –28.1; P <.0001), oxygen consumption (+1.4 mL/kg per min; 0.6-2.1; P = .0006), and symptom scores (KCCQ-CSS +9.1; 5.5-12.7; HCMSQ-SoB, –1.8, –2.4 to –1.2; P <.0001). Finally, 34% more patients in the mavacamten group saw improvement by at least one NYHA class (95% CI, 22.2-45.4; P <.0001). Mavacamten was well tolerated, with a comparable safety profile to placebo. A single case of SCD was noted in the placebo group.59
Given mavacamten’s ability to improve myocardial relaxation, it was also evaluated in a phase 2 double-blind, placebo-controlled, dose-ranging study of patients with nonobstructive HCM (MAVERICK-HCM).65 This study enrolled symptomatic patients without LVOTO, with a left ventricular ejection fraction of 55% or above, and a N-terminal pro-B type natriuretic peptide (NT-proBNP) level greater than or equal to 300 pg/mL.65 Participants were randomized 1:1:1 (n = 59) to one of 2 doses of mavacamten (200 ng/mL or 500 ng/mL) or placebo, with stratification based on treatment with a β-blocker and cardiopulmonary exercise testing. Serious adverse effects were observed in 10% and 21% of those receiving mavacamten and placebo, respectively. Patients treated with mavacamten had a significant reduction in NT-proBNP (53%, P = .0005) and cardiac troponin (34%, P = .009) levels, indicating improvement in myocardial wall stress.65 These results have set the stage for potential future investigation in nonobstructive HCM.
Recently, a phase 3 randomized, double-blind, placebo-controlled trial (VALOR-HCM) was initiated to assess the effect of mavacamten on reducing SRT procedures in patients with symptomatic obstructive HCM (NCT04349072).66 The study will include approximately 100 participants and use a parallel group treatment. The primary outcome measure is the number of individuals who decide to continue with SRT before or at week 16 and the number of participants who remain guideline eligible for SRT at week 16.66
CK-3773274 (CK-274)
Another investigational therapy, CK-274, is an oral cardiac myosin inhibitor under development for HCM.67 This agent’s mechanism of action is similar to mavacamten; however, its half-life is much shorter (12 hours for CK-274 compared with ≈9 days for mavacamten).68 A phase 2, randomized, double-blind, placebo-controlled, dose-finding trial (REDWOOD-HCM) began in January 2020 (NCT04219826).67 The purpose of the study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of CK-274. Due to the COVID-19 pandemic, the study was temporarily suspended.67
Conclusions
In summary, while HCM is the most common monogenetic cardiovascular disorder, it remains widely underdiagnosed, with a large number of pathologic variants. It has a highly variable clinical presentation, with some patients being asymptomatic and others having significant limitation of functional status. Diagnosis requires a thorough evaluation, including risk stratification for SCD. Treatment depends on symptom status, the presence of LVOTO, and coexistence of other cardiac conditions including AF, ventricular arrhythmias, and HF. While there are no approved disease-modifying therapies for HCM, it remains an area of ongoing investigation.
Author affiliation: Ty J. Gluckman, MD, is the Medical Director, Center for Cardiovascular Analytics, Research and Data Science (CARDS), Providence Heart Institute, Portland, OR.
Funding source: This activity is supported by an educational grant from MyoKardia, Inc, a wholly owned subsidiary of Bristol Myers Squibb.
Author disclosure: Dr Gluckman has no relevant financial relationships with commercial interests to disclose.
Author information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.
Address correspondence to: tyler.gluckman@providence.org
Medical writing and editorial support provided by: Brittany Hoffmann-Eubanks, PharmD, MBA
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