Targeting immunomodulation following cardiac injury

Cardiovascular diseases cause more than a quarter of all deaths in the UK, (approximately 170,000 deaths each year - an average of 460 deaths each day or one every three minutes). Of these, coronary heart disease is the most common and is the leading cause of heart attack. Heart attack manifests as massive death of muscle cells, upwards of around one billion, accounting for around 25% loss of the total heart muscle. There is no means to replace these lost cells and consequently the injury is patched-up by the formation of a non-contractile, scar to prevent rupture of the wall of the heart. This, in turn, increases the burden on survived muscle and results in increased cell size, wall thinning, dilation of the chambers and ultimately progression to heart failure. Currently there are around 900,000 people living in the UK with heart failure; organ transplantation is the only current long-term solution, but is complicated by immune rejection and the fact that demand continually outstrips the availability of donor hearts. Alternative regenerative approaches have centred on the replacement of lost cells generated from a variety of sources (bone marrow, fat tissue and skeletal muscle), however, these have largely failed, with disappointing clinical trial results. One reason for this is that the local environment of the injured heart becomes highly inflamed and scarred due to the invasion of immune cells which in turn leads to further cell death and failure to support the integration of new cells into survived tissue. Elsewhere in the body immune cells are cleared to draining lymph nodes by lymphatic vessels after injury (for eg. following skin excision injury). We recently discovered that the lymphatics of the heart respond to injury in mice by sprouting and further identified that these expanding vessels function to clear immune cells which, when increased by growth factor treatment, improved the outcome after a heart attack. In this proposal, we seek to determine whether timed stimulation of the growth of cardiac lymphatics can define the optimal window for intervention after injury and which types of immune cells are best retained in the heart versus cleared lymph nodes to optimise heart repair and function after a heart attack. Correlating timed clearance of precisely defined immune cells with outcome, will enable us to uniquely attribute function to different subsets of immune cells as an important insight. We will also model human lymphatic vessels and their interactions with immune cells and screen these models for drug compounds which might activate the lymphatics. This will represent the first stage of a drug-discovery pipeline targeting the local environment, to enable cell repopulation and tissue restoration, as part of a combined therapy to treat heart attack patients.