"Hypertrophic cardiomyopathy (HCM) is associated with more than 1500 genetic variants," commented Andrew Wang, MD, as we began our discussion on HCM pathophysiology. "So, it's fascinating that a single mechanism -- the abnormal activation of myosin heads -- could be a unifying cause for HCM-related left ventricular hypertrophy (LVH) and its sequelae."

Dr Wang is a professor of medicine and director of the hypertrophic cardiomyopathy clinic at Duke University. Dr Wang is renowned for his expertise in the care of patients with HCM, which affects at least 1 out of every 500 individuals and is the most common inherited monogenic cardiovascular disease.^[1]

Medscape: What is HCM?

Andrew Wang, MD: HCM is a heterogeneous myocardial disease typically caused by sarcomeric mutations that result in LVH, fibrosis, hypercontractility, and reduced compliance.^[2,3] HCM is not an uncommon disease, but its recognition is poor.^[4] Often, patients are not diagnosed for many years, despite having symptoms.

The diagnosis of HCM is confirmed by the presence of an LV wall thickness of ≥ 15 mm that is otherwise unexplained by abnormal loading conditions (eg, hypertension, valvular disease, congenital heart disease) or infiltrative cardiomyopathies.^[5-7] In patients with a family history of HCM, this diagnostic criteria lowers to ≥ 13 mm. Approximately 70% of patients with HCM present with left ventricular outflow tract (LVOT) obstruction at rest or upon provocation (eg, exercise) -- this subtype of HCM is known as obstructive HCM.^[8]

Medscape: How can more than 1500 different sarcomeric gene mutations all lead to a similar phenotype?^[1]

Dr Wang: Great question. Sarcomeres are the smallest functional units of cardiomyocytes, or heart muscle cells. The sarcomere contains a highly organized arrangement of contractile, regulatory, and structural proteins, including myosin-containing thick filaments and actin-containing thin filaments.^[9] The contraction cycle is triggered when calcium ions bind the troponin complex exposing the active site on actin. The myosin head then forms a cross-bridge with actin that is necessary for myocyte contraction. Adenosine triphosphate (ATP) breaks the myosin-actin cross-bridge, freeing myosin for the next contraction. (Figure 1.) The prevailing thought is that most HCM-causing gene mutations affect the structure of the myosin head.^[10,11]

Figure 1. HCM Is a Disease of Sarcomere Proteins

 

ADP = adenosine diphosphate.

During relaxation, the myosin head assumes 1 of 2 conformations: either a super relaxed (SRX) state in which both ATP-binding domains cannot bind actin or a disordered relaxed (DRX) state in which only 1 myosin head is positioned to interact with actin.^[12] In HCM, the myosin head becomes unstable in its relaxed state and more readily available to form a cross-bridge with actin. (Figure 2.) Increasing the number of actin-myosin cross-bridges increases the sarcomere's force production, power stroke, work, and ATP consumption, ultimately leading to myocardial hypercontractility and a depleted energy state. A high calcium concentration within the myocyte signals the upregulation of actin-myosin interactions and ATPase activity manifesting as LVH.^[9]

Figure 2. Myosin Head Formations^[13]

 

Notably, the abnormal cellular processes caused by sarcomeric gene mutations, not the LVH, are what lead to the hypercontractility commonly present in HCM.^[14] Abnormal cellular processes found in HCM are as follows:

• Actin-myosin cross-bridging
• Myocardial metabolism
• Sodium and calcium channels
• Hyperdynamic LV function
• Impaired LV relaxation and compliance
• Myocardial disarray, fibrosis, and adverse remodeling

Medscape: How is obstructive HCM currently treated?

Dr Wang: Current pharmacological treatments for symptomatic, obstructive HCM aim to reduce LVOT obstruction and LV contractility by negative inotropic effect.^[5,6] The most commonly used therapeutics include β-adrenergic receptor blockers and Ca2+ channel blockers. Disopyramide is effective as an add-on therapy, although it may have side effects and contraindications. Available treatment options were not designed specifically for HCM, and although guideline-recommended, they were never studied in large, randomized trials with HCM patients. Despite some symptom relief with current therapies, their use can have pleiotropic effects and produce inconsistent therapeutic responses. Many patients will continue to have symptoms that limit their physical activity and affect their quality of life while on treatment.^[15] Symptoms may include shortness of breath or dyspnea with exertion, chest discomfort, and presyncope or syncope related to the LVOT.^[5]

Septal reduction therapy, including septal myectomy and alcohol septal ablation (ASA), benefits patients with obstructive HCM and drug-refractory symptoms when performed at experienced centers.^[5,6] At high-volume centers with multidisciplinary teams, surgical myectomy has demonstrated near-complete resolution of resting and inducible LVOT gradients and long-term survival similar to demographic-matched controls.^[16,17] However, myectomy is invasive and associated with risks that may be prohibitive or undesirable for certain patients.^[5,6] An increase in overall mortality from < 1% to 5.2% has been reported when septal myectomy is performed outside of experienced centers.^[16-18] ASA can have similar efficacy to myectomy, if patients have suitable coronary anatomy. For example, 1 study found that 15% of patients had septal perforators unsuitable for ASA intervention.^[19] Periprocedural (< 30 days) mortality is approximately 1% with ASA; however, ASA is associated with a 10% to 15% rate of complete heart block, reintervention, and a possible increased risk of ventricular arrhythmia related to ablation scarring.^[20,21]

Medscape: What is the rationale for new treatments that target cardiac myosin?

Dr Wang: A medical therapy targeting the underlying abnormality in HCM has long-been sought, and a new drug class of cardiac myosin inhibitors is showing promise. This class of agents blocks the ATP-converting enzyme on the myosin head, which normalizes the level of myosin activation and causes reversible inhibition of actin-myosin cross bridging to reduce contractility.^[22,23] In short, these agents target the pathway shared by sarcomeric genetic variants thought to lead to myosin activation, hypercontractility, and HCM. The benefit of myosin inhibitors does not appear related to the presence or absence of a genotype based on the evaluation of a small number of patients with pathogenic sarcomeric mutations.^[24]

The myosin inhibitor that has been the most studied to date is mavacamten. The randomized phase 3 EXPLORER-HCM trial found that mavacamten improved exercise capacity, LVOT obstruction, and heart failure symptoms in patients with symptomatic, obstructive HCM.^[24] A second cardiac myosin inhibitor, CK-274, is currently undergoing investigation for symptomatic obstructive HCM in a phase 2 clinical trial (REDWOOD-HCM, NCT04219826).^[25] Initial data are anticipated for release in mid-2021.

Medscape: Any parting comments that you'd like to share with your colleagues?

Dr Wang: The myosin inhibitor trials in HCM have generally included patients with obstructive HCM who are symptomatic despite ongoing medical treatment, and have a resting gradient ≥ 30 mmHg, a provoked LVOT gradient ≥ 50 mmHg, and an LVEF ≥ 55%.^[24,25] As clinicians, these are the clinical criteria to consider when thinking about either enrolling a patient in a clinical trial, or in the future, treating patients with a myosin inhibitor. Medication that attenuates contractility needs to be used with caution. Patients must be monitored closely to assess their response and changes in cardiac function. Myosin inhibitors should be titrated to dose levels that block just enough of the myosin head's activation to reduce contractility and LVOT obstruction without causing the patient to have a reduced ejection fraction or develop systolic dysfunction.

Again, the clinician must be mindful about attenuating contractility; but these targeted therapies may prove extremely beneficial for patients with obstructive HCM. And on a quick side note, several mouse models have supported the hypothesis that myosin inhibition may reverse the degree of LVH by normalizing myocardial energetics.^[26] Now, that would be amazing for HCM patients but longer term studies will be needed.

Dr Wang's Points to Remember

• HCM is the most common inherited monogenic cardiovascular disease, yet it's still frequently overlooked as a cause of cardiac symptoms. Evaluating patients with HCM for provocable LVOT obstruction can help to identify one-third more patients with treatable obstructive disease.
• HCM is a disease of the sarcomere. Sarcomeric mutations cause hypercontractility and LV wall thickening that manifest as HCM.
• Myosin hydrolyzes ATP in the sarcomere and forms cross-bridges with actin to propel myocardial contraction. Sarcomeric HCM mutations cause hypercontractility by increasing the number of myosin heads in their active form.
• Myosin inhibitors are investigational agents that reversibly block the ATP-converting enzyme on the myosin head to reduce the level of myosin activation, resulting in reduced myocardial contractility and less outflow tract obstruction. Ongoing studies are evaluating the effect of myosin inhibitors on left ventricular mass and diastolic function.
• The benefits associated with myosin inhibitors in HCM do not appear to be dependent on the presence of a specific sarcomeric gene or protein variant.
• Myosin inhibitors are potentially efficacious for HCM patients with hypercontractile and obstructive phenotypes, including both genotype-positive and genotype-negative HCM.