Deep Phenotyping to Unravel Disease Mechanisms Responsible for Heart Failure Symptoms in Non-Obstructive Hypertrophic Cardiomyopathy

• Applicant: Dr. Alexander Schulz
• Subject Area: Cardiology, Angiology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563736895

The goal of the project is to investigate the mechanisms of heart failure in patients with non-obstructive hypertrophic cardiomyopathy (nHCM) during a two-year research fellowship at Harvard Medical School. nHCM is a genetically determined thickening of the heart muscle but without obstruction of blood outflow, as seen in obstructive HCM (oHCM). Up to 40% of patients with nHCM patients develop symptoms of heart failure, such as shortness of breath or reduced exercise capacity. However, unlike patients with oHCM, targeted therapies for nHCM patients are currently unavailable, as the underlying disease mechanisms are heterogeneous and insufficiently understood. The limited understanding of nHCM results from two main factors: a) Disease mechanisms are typically studied only at rest, even though heart failure symptoms primarily occur during exercise. b) The structure and function of the heart muscle are often analyzed separately, despite their close interrelation. Methodology and Objectives: To close these knowledge gaps, innovative non-invasive imaging techniques will be employed: 1. Exercise Cardiac MRI allows for the analysis of cardiac functional reserves under exercise conditions. 2. Diffusion-Weighted MRI provides insights into the microstructure of the heart muscle. The aim is to decipher the individual mechanisms of heart failure in nHCM. Exercise MRI will identify functional limitations, while diffusion-weighted MRI will detect microstructural abnormalities underlying functional limitations. This approach enables individualized phenotyping to facilitate the development of tailored therapies in the long term. Study Design: The study plans to enroll at least 80 patients with nHCM, who will undergo a standardized exercise protocol using an MRI-compatible bicycle. The necessary validation work for both imaging techniques has already been successfully completed to ensure their applicability at the research site. Expected Benefit: The study will address existing knowledge gaps regarding the mechanisms of nHCM and establish a foundation for future multicenter studies. By improving phenotyping, the study aims to enable targeted therapeutic approaches and optimize the treatment of these patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Reza Nezafat, Ph.D.