Abstract

Fabry Cardiomyopathy: Early Detection and Intervention

Frank Weidemann

Fabry (or Anderson-Fabry) disease is a rare x-linked lysosomal storage disorder leading to an accumulation of globotriaosylceramides in all tissues and organs including the heart. Cardiac involvement is of major prognostic importance in Fabry disease. Left ventricular hypertrophy represents the dominant cardiac feature. The clinical diagnosis must be confirmed by assay of α-galactosidase A activity in leukocytes or plasma and should be followed by molecular genetic analysis. In addition, new biomarkers like LysoGb3 might be helpful for the clinical understanding of the found genetic abnormalities. Specific treatment with enzyme replacement therapy with agalsidase beta (Fabrazyme^®, Genzyme, USA) became available since 2001. In early randomized trials using Fabrazyme^® a clearance of globotriaosylceramides from the myocardium (mainly the vascular endothelium) could be shown by sequential myocardial biopsies. Furthermore clinical studies showed a reduction of left ventricular wall thickness/mass and improvement of regional myocardial function during enzyme replacement therapy. Lately it became obvious that early therapy at least in male patients might be appropriate. In advanced cardiomyopathies with typically located replacement fibrosis an additional therapy is necessary. This presentation will focus on typically signs of the cardiomyopathy which might be helpful for an early intervention.

The Therapeutic Potential of Purinergic Signalling

Geoffrey Burnstock

The talk will begin with a review of the main conceptual steps involved in the development of purinergic signalling. The focus will then be on the pathophysiology of purinergic signalling in a wide variety of systems, including urinogenital, cardiovascular, airways, musculoskeletal and gastrointestinal. There will also be consideration of the involvement of purinoceptors in pain, cancer and diseases of the central nervous system. Purinergic therapeutic approaches for the treatment of some of these diseases will be discussed.

Human Skin Resident T Cells in Health and Disease

Rachael A. Clark

One of the most exciting recent discoveries in T cell immunobiology is the discovery of non-recirculating resident memory cells (T_RM). These cells remain long-term in peripheral tissues and provide frontline protection against infections. The healthy skin surface of a healthy adult contains 20 billion memory T cells, nearly twice as many as are present in the entire circulation. Approximately 80% of these cells are nonrecirculating T_RM. These cells are critically important in defending against infection but when they become autoreactive or malignant, they give rise to dermatologic diseases such as psoriasis and mycosis fungoides (MF), respectively. The antigen specificity of T_RM in human gut, lung and skin are largely nonoverlapping and are enriched for organisms encountered through that particular barrier tissue. We find also that human skin cancers, including squamous cell carcinoma, Merkel cell carcinoma and melanoma have evolved mechanisms to either exclude or inactivate skin T_RM. Lastly, we find that MF and Sézary syndrome, two subtypes of cutaneous T-cell lymphoma (CTCL), are derived from distinct T-cell subsets. MF has markers suggesting it derives from nonrecirculating, sessile T_RM. This is consistent with the tendency of inflammatory plaques to remain fixed for many years and to recur after cessation of therapy. In contrast, L-CTCL derives from central memory T cells, a type of T cell that actively recirculates between the blood skin and lymph nodes. In response, we have begun to use therapies that selectively deplete T_RM vs. T_CM to selectively kill malignant cells while sparing benign T cells.

Human Pluripotent Stem Cells: Tools for Cardiovascular Medicine

Timothy J. Kamp

Human pluripotent stem cells have opened powerful new avenues for innovations in cardiovascular medicine. The basic properties of human pluripotent stem cells will be reviewed. Technologies to differentiate human stem cells to functional cardiomyocytes will be described with particular attention to the role of the extracellular matrix. Modeling of human disease with iPS cell-derived cardiomyocytes is rapidly advancing, and an example of modeling long QT syndrome will be provided. The promise and status of iPS cells for cardiovascular therapies will be described. Current roadblocks to human pluripotent stem cell applications as well as strategies to overcome these challenges will be discussed.