In this episode of BeatWise The Podcast, I am joined by Professor Joseph Selvanayagam to explore cardiac metabolism in hypertrophic cardiomyopathy (HCM), the evolving treatment landscape in HCM, and the findings of the RESOLVE-HCM trial investigating perhexiline in non-obstructive disease.

We explore the heterogeneity of HCM, including the differences between obstructive and non-obstructive forms of the condition, why symptoms are not always explained by LV outflow tract obstruction alone, and how treatment strategies are beginning to move beyond symptom management toward disease-modifying therapies.

We also discuss the role of myocardial energetics and metabolic dysfunction in HCM, how perhexiline works as a CPT1 inhibitor to shift myocardial metabolism toward more oxygen-efficient glucose use, and why this may be particularly relevant in non-obstructive HCM where treatment options remain limited.

Professor Selvanayagam takes us inside the design of the randomized, double-blind RESOLVE-HCM trial, including the use of cardiac MRI imaging and maximal LV wall thickness as the primary endpoint over 12 months. We review the trial findings, where several endpoints including diastolic function, NT-proBNP, and quality-of-life measures favored perhexiline, with mental health quality-of-life outcomes reaching statistical significance.

We also explore the importance of therapeutic drug monitoring given perhexiline’s narrow therapeutic index, the risks of hepatotoxicity and neurotoxicity, and the future direction of metabolic therapies in cardiomyopathy.

Key topics discussed: 

• Obstructive vs non-obstructive HCM
• What drives symptoms in hypertrophic cardiomyopathy
• The evolution of HCM therapies
• Cardiac metabolism and myocardial energetics
• How perhexiline works
• The RESOLVE-HCM trial
• Cardiac MRI endpoints in HCM research
• Therapeutic drug monitoring and safety
• Disease-modifying therapies in cardiomyopathy

EPISODE HIGHLIGHTS:

00:00 Welcome to Beatwise

00:27 Why metabolism matters

01:59 Meet Professor Selvanayagam

02:29 HCM types and symptoms

04:29 Treatment landscape update

05:42 Why RESOLVE-HCM

07:20 How perhexiline works

08:44 Trial design and imaging

12:53 RESOLVE-HCM results

14:43 Clinical use and safety

17:15 Future trials and wrap up

18:54 Final takeaways

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