Mechanosensitive regulation of cardiac excitation-contraction coupling: The role of localized beta-adrenergic receptors and calcium channels

When a heart fails to function properly it may be possible to reduce its workload and assist its role in providing blood to the different organs in the body by the use of mechanical pumps, known as left ventricular assist devices. The devices induce profound changes in the heart leading, in some cases, to significant improvements in heart function. It is thought that one of the elements that respond promptly to this treatment is the cardiac cell. In this project we aim to investigate how this cell changes in response to treatment with left ventricular assist devices. We will study isolated cells from the hearts of rats that are exposed to a reduction in mechanical load, in a similar fashion to hearts treated with left ventricular assist devices. Using sophisticated microscopic techniques we will study the response of molecules that are involved in the function of the cells and determine if they are responsible for changes in function. This research will help understanding the mechanisms responsible for poor function of the heart and provide potential targets for the treatment of patients.

There is emerging interest in the potential of mechanical unloading of failing hearts using Left Ventricular Assist Device (LVAD) therapy to improve myocardial function. Recently it has been shown that LVAD support restores beta-adrenergic responsiveness and reverses receptor downregulation in failing human hearts. In this project we aim to study cAMP -beta receptors signalling in cardiomyocytes (CMs) isolated from rat hearts after mechanical unloading using a novel SICM/FRET technique. Mechanical unloading for periods of different duration will be induced in normal and failing rat hearts by heterotopic abdominal heart transplantation. The localized dynamics of cAMP-beta-receptors and the compatmentalisation of the signalling will be determined in isolated cardiomyocytes from control and unloaded hearts.

In the second part of the project we will investigate the role of L type Calcium channels in the recovery of unloaded cells. We will look at the distribution of channels and correlate this with restoration of cellular architecture and membrane topography.

This project will provide a mechanistic insight in the relationship between chronic changes in load and functional properties of the myocardium, and provide new information on the molecular and signalling effects of mechanical unloading during myocardial remodelling in heart failure.

The proposed study is fundamental in its nature, aiming to understand basic mechanisms of cardiac myocyte reaction to mechanical unloading. This study will generate new knowledge that would be of immediate interest to researchers in heart failure and in cardiac biology in general. In the longer term this should help define new strategies to ameliorate cellular function in failing hearts. This work will be of interest to researchers in translational medicine and finally will result in more specific health care and therapeutic approaches. This would be highly beneficial to human health and wealth both within and outside the UK.

Besides publication in specialized scientific journals we anticipate that the results of this work will be widely publicised as they have substantial value for the general public.
Dr Julia Gorelik's recent work, first published in "Science " magazine, has been covered extensively on many news websites including the Pharma Times, US Clinical Researcher, Medical Device Guru, Cordis News and Science Daily. It is also covered on the Wellcome Trust's website and in the 15th of March edition of 360, the newspaper of Imperial College Healthcare NHS Trust. Links to some examples of the coverage are below.

Examples of coverage:

Bear chemical brings heart hope - BBC News Health;

Bear chemical could help to prevent arrhythmia in heart attack sufferers- The Daily Mail;

Synthesized Compound Also Found in Bear Bile Chemical Could Help Keep Hearts in Rhythm - Science Daily;

New microscopy technique could mean more effective beta-blockers - PharmaTimes

Nanotech scanning used to assess heart damage - British Standards Institution

New microscopy technique could mean more effective beta-blockers - US Clinical Researcher

Detailed insight into failing heart cells gained using new nano ... - Science Daily

Researchers gain detailed insight into failing heart cells using ... - PhysOrg

Nano-imaging technique gives clues to failing hearts | Wellcome Trust - Wellcome Trust

Nanoscale heart imaging - Medical Device Guru