Special Interview with Dr. Erik Blackwood, Youth Editorial Board Member of The Journal of Cardiovascular Aging

In May 2025, the Editorial Office of The Journal of Cardiovascular Aging had the pleasure of interviewing Dr. Erik Blackwood from the University of Utah to discuss his insights on heart failure with preserved ejection fraction (HFpEF), proteostasis, and cardiovascular aging.

Below are the details of the interview:

1. Research Focus on HFpEF

My research on HFpEF stems from its strong association with protein misfolding disorders, such as transthyretin amyloidosis. During my postdoctoral training with Dr. Chris Combosti, we studied proteostasis—how proteins are synthesized, folded, and degraded in cardiac cells. This work naturally led me to HFpEF, a condition marked by clear proteostatic dysfunction.  
A key challenge in modeling HFpEF is replicating its clinical features, particularly its age-dependent prevalence in women. The "two-hit" model (high-fat diet + hypertensive stress) developed by the Joe Hill lab was groundbreaking, but it lacked components related to aging and sex differences. Our lab adapted this model by incorporating aging, enabling studies in both male and female mice to better mirror human disease.

2. Proteostasis and ER Stress in Cardiac Aging

My understanding of protein regulation in aging hearts has been deeply influenced by the work of Dr. Litsa Kranias and the late Dr. Jeff Robbins, who laid the groundwork for understanding proteasome function and ER stress in cardiomyocytes. Under Dr. Combosti’s mentorship, I explored how ER-associated degradation (ERAD) maintains proteostasis. Surprisingly, we found that 60-70% of ERAD substrates in cardiomyocytes are cytosolic, challenging the prevailing view that ERAD only degrades ER-resident proteins. This discovery led to our concept of "ERAD-OUT," revealing new pathways for therapeutic intervention.

3. A Systems-Level Perspective in Cardiovascular Aging

HFpEF is not just a cardiac disease—it’s a multisystem disorder involving metabolic organs (such as the liver, kidneys, and adipose tissue). Unlike traditional "inside-out" models (e.g., myocardial infarction), HFpEF requires an "outside-in" approach, where systemic metabolic dysfunction drives cardiac pathology. This perspective explains why treatments such as SGLT2 inhibitors and GLP-1 agonists benefit HFpEF patients: improving extra-cardiac organ function indirectly enhances heart health.  
Our lab uses BioID-based tools to trace organ crosstalk, identifying secreted proteins that modulate disease progression. This approach opens new avenues for multi-organ therapeutics.

4. ERAD-OUT and Novel Therapeutic Strategies

The ERAD-OUT pathway revealed that cytosolic proteins can also be degraded via ERAD, expanding the range of potential targets for proteostasis modulation. We’re now developing peptide-based inhibitors to enhance the degradation of pro-hypertrophic substrates, offering an alternative approach to traditional kinase inhibitors.
This work underscores the importance of inter-organelle crosstalk (ER-mitochondria-lysosome) in maintaining cardiac health. Future therapies may need to target these integrated cellular networks rather than isolated signaling pathways.

5. Gene Therapy for Age-Related Heart Failure

At the University of Utah, I collaborate with Drs. Robin Shaw and TingTing Hong on AAV-based gene therapies, including targeting S100A1 for heart failure. While challenges remain—such as long-term safety and patient acceptance—gene therapy offers durable solutions compared to small molecules.  
Key hurdles include:

• Ensuring target specificity across physiological (e.g., exercise) and pathological states
• Scaling up from mouse models to large-animal studies before clinical trials

6. Vision for The Journal of Cardiovascular Aging

As a Youth Editorial Board Member, I aim to highlight the following areas:

• Interorgan and intercellular communication in aging (e.g., cardiomyocyte-fibroblast crosstalk)
• Atrial dysfunction in HFpEF, given its strong link to atrial fibrillation and metabolic disease
• Innovative models (single-cell omics, targeted organelle studies) to bridge basic and clinical research

By fostering interdisciplinary collaboration, we can accelerate translational breakthroughs for aging-related cardiovascular diseases.

Editor: Fiona Zhao
Language Editor: Catherine Yang
Production Editor: Ting Xu
Respectfully submitted by the Editorial Office of The Journal of Cardiovascular Aging