Cardiovascular disease is a global burden and the leading cause of death worldwide. In context, more than 18 million people die from cardiovascular disease each year while the COVID-19 pandemic has resulted in 2.5 million deaths to date.
Sudden cardiac death is a tragic and devastating complication of cardiovascular disease particularly when it impacts the young. Sudden cardiac death accounts for about half of all heart disease-related deaths and structural heart disease such as familial hypertrophic cardiomyopathy (HCM) is the leading cause of death from cardiac causes in people aged 5-15 years.
HCM is a primary disorder of the myocardium characterised by cardiac hypertrophy in the absence of other loading conditions such as hypertension and may be as prevalent as 1 in 500. It is an autosomal-dominant condition caused by defects in at least 12 genes for contractile proteins. Mutations in cardiac ß myosin heavy chain, cardiac myosin binding protein C, and cardiac troponin T account for approximately 80% to 90% of described cases of familial hypertrophic cardiomyopathy.
The clinical course of the cardiomyopathy is variable, ranging from benign asymptomatic disease to a malignant phenotype with a high-risk of cardiac failure or sudden cardiac death.
Treatment for familial hypertrophic cardiomyopathy includes ß-blockers or calcium channel inhibitors that target symptoms. Arrhythmias are managed with antiarrhythmic drug therapy such as sodium or potassium channel blockers or insertion of an implantable cardioverter defibrillator. Surgical myotomy or myectomy may be required to reduce left ventricular outflow tract obstruction.
The challenge has been to prevent the enlarged heart from developing because the presence of hypertrophy is associated with increased risk of sudden death. Patients present with increased interventricular septal and posterior wall thickness on echocardiography and hearts are hypercontractile with normal or high fractional shortening.
It is not fully understood how the heart becomes large and why the heart is hypercontractile and consumes so much oxygen. In the heart, mitochondria are responsible for meeting the cellular energy demands required to maintain excitation and contraction on a beat-to-beat basis. Calcium uptake is integral to mitochondrial function in order to maintain ATP production.
A research program at the University of Western Australia is significantly impacting management of genetically inherited cardiomyopathies by closing an important gap in treatment using novel approaches.
A novel mechanism by which a calcium channel regulates energetics in the heart has been identified. By targeting the calcium channel, the therapy reduces energy consumption and prevents the development of the hypertrophy. We are also optimising the treatment to reverse the hypertrophy once it has established.
The therapy is estimated to enter phase 1 clinical trials in 24 months. It will offer an alternative to a small molecule inhibitor of myosin, Mavacamten that completed Phase 3 clinical trials last year and is now seeking FDA regulatory approval. Once efficacy is established, the availability of the novel calcium channel inhibitor will be welcome news for patients with a family history of hypertrophic sarcomere gene mutations because no therapy has been available that can prevent the development of the hypertrophy.
Key messages
- HCM is the leading cause of cardiac deaths in the 5-15 years age group
- Thus far no treatment has influenced its development
- Novel treatments are being trialled at UWA.
ED: Professor Hool is head of the Cardiovascular Electrophysiology Laboratory and Faculty-at-Large Victor Chang Cardiac Research Institute, Sydney.
Author competing interests – the author leads the research described