Contemporary Therapies and Future Directions in the Management of Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM), a myocardial disorder characterized by increased ventricular wall thickness, is one of the most common inherited cardiovascular diseases. Since the initial discovery of HCM in the 1950s, there has been significant advancement in our understanding of the etiology and pathophysiology of the disease. This knowledge has fueled an evolution in the approach to treatment, from minimizing symptoms to slowing disease progression to developing targeted molecular therapies to alter the natural history of the disease. In this article, we will review the major phenotypes of HCM, describe conventional treatment strategies, and discuss emerging novel therapies that will allow for disease-specific treatment and change the future management of HCM (Fig. 1).

HCM is defined by a left ventricular wall thickness of > 15 mm in the absence of secondary causes, and is estimated to have a prevalence of at least 1 case per 500 persons in the general population, and perhaps as high as 1 in 250 if genotype positive, phenotype negative individuals are included [1, 2]. HCM is inherited in an autosomal dominant pattern, and between 30% and 60% of HCM in adults is caused by variants in genes that encode thick and thin myofilament components of the cardiac sarcomere [3, 4]. Genetic variation in genes that encode sarcomeric proteins accounts for the majority of genetic HCM. Pathogenic variants in the MYH7 (myosin heavy chain 7) and MYBPC3 (myosin binding protein C3) genes comprise approximately half of the causal variants in patients with familial HCM [5‐7]. Some inherited metabolic diseases (Danon disease, Anderson–Fabry disease), neuromuscular diseases (Friedreich ataxia), and mitochondrial diseases demonstrate a clinical phenotype with left ventricular hypertrophy that mimics that of sarcomeric HCM. However, it is important to differentiate these phenocopies from HCM as the causal genetics, pathogenesis, prognosis, and treatment are different, and these conditions will not be reviewed herein. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

HCM has heterogeneous phenotypic expression, and as such, clinical manifestations are highly variable. The majority of patients with HCM are currently undiagnosed. For those who are asymptomatic, diagnosis may only be made after incidental discovery of a heart murmur, abnormal electrocardiogram (EKG), or suggestive family history [2]. Symptoms secondary to HCM are commonly attributed to left ventricular outflow tract (LVOT) obstruction, diastolic ventricular dysfunction, an imbalance between myocardial oxygen supply and demand, or arrhythmia. Common symptoms include exertional dyspnea, chest pain, fatigue, palpitations, dizziness, and syncope.

HCM has been historically classified into two hemodynamic subsets: obstructive and nonobstructive. Obstructive hypertrophic cardiomyopathy is characterized by dynamic LVOT obstruction with an LVOT peak pressure gradient > 30 mmHg. [8] Approximately one-third of patients with HCM have resting LVOT obstruction, predominantly due to systolic anterior motion of the mitral valve [2, 9, 10]. Other causes of LVOT obstruction include severe interventricular septal hypertrophy, papillary muscle hypertrophy and displacement, and intrinsic mitral leaflet abnormalities [4]. Another one-third of patients with HCM have obstruction with provocation only (i.e., latent obstruction) [11]. In these patients, LVOT obstruction may be provoked by a decrease in preload/afterload, such as with Valsalva maneuver and nitrate administration, or with an increase in contractility during exercise. The remaining one-third of patients with HCM have no significant obstruction either at rest or with provocation, with a peak LVOT gradient < 30 mmHg.

With the recent progress in treatment modalities and surgical techniques, the mortality associated with HCM has significantly reduced. HCM-related death has been reduced from approximately 6% per year to 0.5% per year [12]. Although the overall mortality rate has decreased, there remains a significant burden of disease from morbidity, most commonly from atrial fibrillation and heart failure. Continued advances towards targeted therapies is essential to limit disease progression and adverse outcomes, especially in younger populations with known causal genetic variants who are at highest risk for HCM-related morbidity and mortality. [13]

The discovery of the genetic mechanisms of HCM has led to accelerating interest in the development of targeted molecular therapeutics to improve symptoms and cardiac function, and to potentially positively alter the disease course (Table 1).

Cardiac myosin inhibitors are a new class of disease-specific therapies that target left ventricular hypercontractility. Cardiac contractility is mediated by myosin, a motor protein containing ATPase, which hydrolyzes ATP to form actin-myosin cross bridges [30]. This process ultimately leads to sarcomere shortening and muscle contraction. In HCM, most causal genetic variants lead to an increase in actin-myosin cross bridge formation and thus hyperdynamic contraction [31]. MYH7 (cardiac B-myosin heavy chain) is the predominant myosin isoform expressed in the heart, and MYBPC (myosin-binding protein C) is a modulator of cardiac contraction [32]. Deleterious variants in the genes that encode these and other sarcomeric proteins cause increased myosin involvement in the cardiac cycle and hypercontractility.

Mavacamten (MYK-461), is a reversible, selective allosteric inhibitor of myosin ATPase, thereby reducing cardiac contractility [33, 34]. It was initially studied in a murine HCM model, in which it demonstrated decreased hypercontractility as well as blunted development of ventricular hypertrophy [33]. In the phase 2 proof-of-concept PIONEER-HCM, mavacamten significantly reduced post-exercise LVOT gradients and symptoms while improving exercise capacity in patients with obstructive HCM [35]. Based on these results, the phase 3 EXPLORER-HCM trial, a multicenter, randomized, double-blind, placebo-controlled trial, enrolled 251 patients with severe symptomatic obstructive HCM with LVOT gradient > 50 mm Hg. Patients were randomized to mavacamten or placebo in addition to their prior beta-blocker or calcium channel blocker. After 30 weeks of treatment, twice as many patients on mavacamten met the primary endpoint of improved functional capacity measured by cardiopulmonary exercise testing and symptom burden. Additionally, 34% more patients in the mavacamten group experienced symptom improvement by at least one NYHA class [36]. Overall, this study demonstrated that mavacamten is superior to placebo with regard to the study endpoints, is well tolerated, and is associated with a significant reduction in post-exercise LVOT gradient. Furthermore, in the recent phase 3 clinical trial VALOR-HCM studying patients with symptomatic obstructive HCM on maximal medical therapy and referred for SRT, treatment with mavacamten for 16 weeks was shown to significantly improve symptoms and reduce the need for SRT [37]. In April 2022, mavacamten was approved by the US Food and Drug Administration as a first-in-class therapy for the treatment of adult patients with obstructive HCM and NYHA class II–III symptoms. Mavacamten is primarily metabolized through CYP2C19 and CYP3A4, and therefore caution should be used with concomitant administration of CYP inhibitors and inducers. As mavacamten reduces cardiac contractility, it carries a risk of systolic heart failure and as such it is only available under a Risk Evaluation and Mitigation Strategy (REMS). This restricted program ensures that there is monitoring for systolic dysfunction with periodic echocardiograms and screening for drug interactions prior to each dispense.

Aficamten (CK-274) is a next-generation selective cardiac myosin inhibitor. Similar to mavacamten, aficamten binds to the ATP binding pocket of myosin to stabilize a myosin off-state and theoretically reduce cardiac contractility [38]. Compared with mavacamten, it has a shorter half-life, achieves steady state within 2 weeks, and may have a wider therapeutic window [39, 40]. Additionally, studies have shown that it has no substantial CYP450 induction or inhibition, potentially providing less drug–drug interaction compared with mavacamten. In the phase 2, randomized placebo-controlled REDWOOD-HCM trial, nearly all patients treated with aficamten for 10 weeks had elimination of resting LVOT gradients (93% response rate in the high-dose cohort) compared with 8% in the placebo arm. A substantial number of patients also achieved improvement in NYHA class [40]. A phase 3 clinical trial, SEQUOIA-HCM, is an ongoing international, multicenter clinical trial designed to evaluate aficamten in patients with symptomatic obstructive HCM on background medical therapy for 24 weeks. It began enrolling patients in February 2022 and is expected to enroll 270 patients [41].

With the landmark findings of mavacamten, it is likely that there will be further development of other selective myosin inhibitors in the near future. MYK-581 and MYK-224 are two other small molecule myosin inhibitors with similar properties to mavacamten and are under investigation [42, 43]. MYK-224 is in a phase 1 trial, and MYK-581 is collecting preliminary preclinical data [4].

HCM cardiomyocytes have enhanced late sodium current activity due to enzyme-induced sodium-channel phosphorylation [45]. This leads to increased levels of intracellular calcium via ion exchange, which ultimately leads to increased arrhythmogenicity [46].

Both ranolazine and eleclazine inhibit late sodium current activity, and thus could in theory counteract diastolic and microvascular dysfunction and promote myocardial relaxation [46]. A small pilot study, the RHYME trial, treated symptomatic HCM patients with ranolazine for 2 months and found improvement in angina and heart failure symptoms [47]. A larger, multicenter double-blind randomized controlled trial (RCT) (RESTYLE HCM) was performed that enrolled 80 patients randomized to placebo or ranolazine, but investigators did not find a significant difference in the end point (exercise capacity assessed by VO2) between the ranolazine and placebo groups [48]. A similar study, LIBERTY-HCM, was conducted to compare the more potent late sodium current activity inhibitor, eleclazine, to placebo, but it was found to be ineffective [49].

While currently no drugs that target ion channels have proven to be effective treatment for HCM, it is certainly a possible area for future novel therapeutics.

Sarcomeric HCM in mouse models have shown that myocardial hypertrophy and fibrosis is largely mediated by transforming growth factor-beta (TGF-b) [50, 51]. Angiotensin II receptor blockers (ARBs) are known to inhibit TGF-b activation, and thus it has been theorized that this class of medications may help slow the progression or even prevent the emergence of HCM. The INHERIT trial, a large single-center randomized trial of losartan in obstructive and nonobstructive patients, failed to demonstrate a beneficial effect on LV mass or exercise capacity [52]. It was theorized that the lack of benefit was because the hypertrophy was already established with full phenotypic expression [53, 54]. The VANISH trial, a multicenter, double-blind, placebo-controlled clinical trial, enrolled 178 patients with early-stage sarcomeric HCM and randomized them to valsartan or placebo. Treatment with valsartan improved the primary composite outcome of cardiac structure/function and remodeling (based on nine distinct measures) compared with placebo [54]. Additional recent meta-analyses have shown that ARB treatment was associated with significant reduction in left ventricular mass in patients with HCM [55]. While additional randomized control trials with larger sample sizes are being conducted to assess the validity and applicability of these results, early initiation of ARB therapy should be considered to potentially slow disease progression.

In addition to novel pharmacotherapy, there have been recent advances in invasive techniques to treat patients with drug-refractory obstructive symptoms. Both ASA and septal myectomy have limitations with regard to patient selection and requisite septal anatomy [56]. This has led to a desire to develop alternative invasive techniques to reduce LVOT obstruction.

Radiofrequency ablation is a technique that has been used for many years for the treatment of various cardiac arrhythmias [57]. The technique utilizes electroanatomic mapping systems for specified myocardial targeting, which helps to limit complications necessitating pacemaker placement [58]. The first reported study using radiofrequency septal ablation was in 2011 and consisted of 19 inoperable patients with drug-refractory symptoms. Patients had a small reduction in septal width, but a significant reduction in resting gradient from 77 to 27 mmHg, as well as provoked gradient 158 to 164 mmHg. [59] A recent large, open-label, single-arm study recruited 200 patients with HCM with drug-refractory symptoms, LVOT gradient > 50 mmHg, and NYHA class II or higher. At the median time of follow-up (19 months), maximal septal thickness was reduced from 24 to 17 mm, LVOT gradient was decreased from 79 to 14 mmHg, and over 96% of patients were NYHA class I or II at follow-up [60]. These results are encouraging, and further study to compare this invasive technique with the other established septal reduction techniques will be necessary.

Transcatheter myotomy is another novel technique under investigation to help reduce LVOT obstruction, particularly as an alternative for patients who are poor surgical candidates. Prior to septal myectomy, the surgical technique involved a myotomy in which circumferential myofibers were splayed apart to reduce septal encroachment and ultimately improve LVOT obstruction [61]. Based on this idea, a novel transcatheter procedure known as Septal Scoring Along the Midline Endocardium (SESAME) was recently developed [62]. This procedure utilizes coronary guiding catheters and guidewires to mechanically enter the basal interventricular septum, and then lacerates the myocardium with transcatheter electrosurgery to create the myotomy. A recent preclinical study performed this procedure in five naïve pigs and five pigs with percutaneous aortic banding-induced left ventricular hypertrophy, and achieved increased left ventricular outflow tract area (753–854 mm², P = 0.008) in all animals [62]. Additionally, no ventricular septal defects developed in the hypertrophy model pigs, there was no evidence of conduction block on electrocardiography, and coronary artery branches were intact on angiography [62]. The first human case of transcatheter septal myotomy was reported as of May 2022 in an 80-year old woman with obstructive HCM for whom surgery was risk prohibitive. SESAME was successfully used to enlarge the LVOT, relieve the LVOT gradient from the hypertrophied septum, and allow for total mitral valve replacement without complication [63].

The appeal of gene therapy as a means to permanently cure hereditary disease has led to numerous international clinical trials for various diseases. HCM is predominantly an autosomal dominant disorder, and research has shown a majority of causal variants to be in MYBPC3 and MYH7. As such, these may serve as intriguing targets for cardiac gene therapy [64]. This is particularly true for patients who have double or compound heterozygosity (i.e., two distinct variants in the same or different sarcomere genes) who have been shown to have earlier onset and more severe disease progression [65].

Over the past decade, there has been significant development in different gene therapy strategies. These include genome editing, allele-specific silencing, spliceosome-mediated RNA trans-splicing, exon skipping, and gene replacement [64]. Cardiac gene therapy utilizes adeno-associated viruses (AAV) as the viral vectors as they have very low pathogenicity in human hosts [66]. Of the various strategies, gene replacement with AAV9 has shown promise for HCM-associated MYBPC3 variants. Studies have shown success with both mice and human pluripotent stem cell-derived cardiomyocytes [67‐69]. While further testing with large animal models are still required to test AAV doses and delivery before human testing, this may be a potential therapeutic option in the future for a selected subset of patients with genetic HCM.

Approximately one-third of patients with HCM do not have evidence of obstruction at rest or with provocation. Pharmacotherapy has typically been reserved for symptomatic patients, and includes beta-blockers or calcium channel blockers with the addition of diuretics if congestion is present. Those who develop end-stage heart failure may have a hypokinetic and/or restrictive phenotype associated with a poor prognosis and typically responds poorly to conventional systolic heart failure treatment [13]. For these patients, transplantation is often the only definitive option.

While it was previously thought that nonobstructive was more benign than obstructive HCM, a recent meta-analysis of 7731 patients showed no difference in the risk of heart failure-associated deaths in patients with nonobstructive compared with obstructive disease [70]. Annual mortality among patients with nonobstructive HCM has been shown to be low (0.5% per year), with a 10‐year survival rate of 97%. However, recent studies have shown that these patients have high rates of morbidity and adverse cardiac events similar to those with obstructive HCM. Notably, patients with nonobstructive HCM have been shown to have higher risk of arrhythmia [71]. Therefore, it is crucial to develop targeted therapies for patients with symptomatic nonobstructive HCM as well.

One trial designed to address this unmet need is IMPROVE-HCM. This phase 2 clinical trial investigates the drug IMB-101 in patients with nonobstructive hypertrophic cardiomyopathy. IMB-101 is a cardiac mitotrope that is a partial fatty acid oxidation (pFOX) inhibitor. It improves myocardial metabolic efficiency by reducing fatty acid oxidation in favor of glucose oxidation to generate more ATP per unit of oxygen [72]. The efficacy of the drug will be measured by the change from baseline of peak oxygen consumption and oxygen uptake efficiency slope by cardiopulmonary exercise testing after 12 weeks. IMPROVE-HCM is currently enrolling patients with an estimated completion date of November 2022.

The phase 2, dose finding MAVERICK-HCM trial of mavacamten in nonobstructive HCM showed that myosin inhibitors are well tolerated in patients without obstruction, and also resulted in significant reductions in N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin levels, suggesting an improvement in filling pressures and wall stress [73]. The REDWOOD-HCM cohort 4 study of aficamten in nonobstructive HCM is ongoing [74].

The therapeutic landscape of HCM management has seen rapid expansion in the last 5 years, with multiple novel therapies under investigation and the regulatory approval of a first-in-class cardiac myosin inhibitor designed specifically to treat obstructive HCM. There are also existing therapies being studied as potential therapeutic options for HCM, including the effects of both sodium–glucose co-transporter 2 (SGLT2) inhibitors and sacubitril/valsartan on cardiac remodeling (Table 2) [75, 76]. Localized ionizing radiation that is commonly used to target tumors is also being investigated as an alternative to conventional septal reduction therapy [77]. With continued research into the genetic architecture underlying HCM, there will be continued progress towards the development of targeted therapies that have the ability to attenuate and, ideally, change the natural course of the disease.