Patrick Most, MD

Contact Dr. Most

Center for
Translational Medicine
1025 Walnut Street, Suite 308
Philadelphia, PA 19107

(215) 955-8990

Medical School
University of Heidelberg, Germany

Residency
S100A1: A novel regulator of cardiac contractility (summa cum laude)

Board Certification
M.D., University of Heidelberg, Germany

University Appointment
Assistant Professor of Medicine (2006)

Research and Clinical Interests
Our lab focuses on the discovery, development and clinical translation of novel targets for heart failure (HF) therapy. HF, the disability of the cardiac muscle to provide sufficient circulatory support at rest and exercise, currently has limited treatment options and patients suffering from severe HF (NYHA III/IV) face a 5-year mortality > 50%.

In light of this therapeutic dilemma, our research efforts are targeted toward innovative treatments emerging from the investigation of the physiological role, pathophysiological relevance and therapeutic potential of S100 proteins in cardiac and vascular disease.

In the last decade, our group pioneered research focusing on the role of S100 proteins in cardiovascular physiology and disease. In particular, we characterized S100A1, being the cardiac specific S100 isoform, as a novel calcium-dependent inotrope with anti-arrhythmic and anti-apoptotic properties. S100A1 unique inotropic actions in the heart are independent and additive to beta-adrenergic stimulation and cAMP-PKA dependent signaling.

Our work shows that loss of S100A1 in diseased myocardium is a critical factor in heart failure development and progression. Based on these results, we have successfully developed viral- and peptide-based therapeutic approaches to restore S100A1 protein function that can rescue heart failure in different experimental cardiac disease models. Our gene therapy approaches are currently tested in a large animal heart failure model in order to enter clinical testing.

An exciting new option stems from our recent insight into therapeutic options of S100A1 derived peptides. Given the unresolved biological concerns regarding viral-based approaches, S100A1 derived peptides with the identical therapeutical profile than the native protein enable novel and exciting therapeutic options that are currently tested in cellular and small animal HF models

In addition, we have extended our research focus into S100A1 function in endothelial cells and pertinent regulation of vascular function and blood pressure. Although expressed at significantly lower levels than in cardiomyoctes, our lab most recently provided evidence for a crucial role of endothelial S100A1 in endothelial cell NO-homeostasis and RR regulation.

Given the world-wide significance of hypertensive disease, our translational efforts are directed towards development of novel S100A1-based anti-hypertensive therapeutic strategies.

Due to known extracellular S100 functions, we have most recently identified S100A1 as a novel cardiac alarmin being released upon ischemic damage from cardiomyocytes in the extracellular environment and circulation. S100A1 participates in MI infarct healing through modulation of post-MI inflammation and recruitment of stem cells to the site of cardiac injury.

Our efforts are directed towards therapeutic use and manipulation of MI-released S100A1 to improve post-MI healing and regeneration.

Publications

Most Recent Peer-reviewed Publications

1. S100A1 in cardiovascular health and disease: Closing the gap between basic science and clinical therapy
2. Endothelial S100A1 modulates vascular function via nitric oxide
3. Ca2+-dependent interaction of S100A1 with F,-ATPase leads to an increased ATP content in cardiomyocytes
4. Stable myocardial-specific AAV6-S100A1 gene therapy results in chronic functional heart failure rescue
5. S100A1 decreases calcium spark frequency and alters their spatial characteristics in permeabilized adult ventricular cardiomyocytes
6. Cardiac S100A1 protein levels determine contractile performance and propensity toward heart failure after myocardial infarction
7. S100A1 gene therapy preserves in vivo cardiac function after myocardial infarction
8. Transgenic Overexpression of the Ca2+-binding Protein S100A1 in the Heart Leads to Increased in Vivo Myocardial Contractile Performance
9. S100A1: A regulator of myocardial contractility
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