Abstract
We demonstrate the synergistic benefits of using multiple technologies to investigate complex multi-scale biological responses. The combination of reductionist and integrative methodologies can reveal novel insights into mechanisms of action by tracking changes of in vivo phenomena to alterations in protein activity (or vice versa). We have applied this approach to electrical and mechanical remodelling in right ventricular failure caused by monocrotaline-induced pulmonary artery hypertension in rats.We show arrhythmogenic T-wave alternans in the ECG of conscious heart failure animals. Optical mapping of isolated hearts revealed discordant action potential duration (APD) alternans. Potential causes of the arrhythmic substrate; structural remodelling and/or steep APD restitution and dispersion were observed, with specific remodelling of the Right Ventricular Outflow Tract. At the myocyte level, [Ca2+]i transient alternans were observed together with decreased activity, gene and protein expression of the sarcoplasmic reticulum Ca2+-ATPase (SERCA). Computer simulations of the electrical and structural remodelling suggest both contribute to a less stable substrate.Echocardiography was used to estimate increased wall stress in failure, in vivo. Stretch of intact and skinned single myocytes revealed no effect on the Frank-Starling mechanism in failing myocytes. In isolated hearts acute stretch-induced arrhythmias occurred in all preparations. Significant shortening of the early APD was seen in control but not failing hearts. These observations may be linked to changes in the gene expression of candidate mechanosensitive ion channels (MSCs) TREK-1 and TRPC1/6. Computer simulations incorporating MSCs and changes in ion channels with failure, based on altered gene expression, largely reproduced experimental observations.
Highlights
To simulate mechanosensitive ion channels (MSCs) in failure within 3e4 weeks (FAIL), we reduced gMSCNS by 11% and gMSCK by 87% based on mRNA changes (Fig. 10) and TRPC 1:TRPC6 abundance which was scaled at 8:1 based on the cycle threshold in real time RT-PCR experiments being 3 higher in TRPC6 (32 1⁄4 8 fold reduced initial copy number)
action potential duration (APD) alternans are more likely to arise when there is increased dispersion of repolarisation (Fig. 1C, D) and/or steeper APD restitution (Fig.1E): both conditions were found in MCTtreated hearts
It was observed that while the APD in the Right Ventricular Outflow Tract (RVOT) region was typically shorter than the APD measured midway between Right ventricular (RV) apex and base in CON rats it was significantly longer in MCT hearts (Fig. 1C, D)
Summary
While Systems Biology has been interpreted by some as confined to the study of genes and proteins, there is no necessity for such a narrow definition (Kohl et al, 2010; Kuster et al, 2011). In addition the overall goals of Systems Biology seem similar to those long held by Integrative Physiologists (Greenhaff and Hargreaves, 2011). The approach described here is in keeping with ideas presented in the above articles. It stems from the self-evident conviction that combining technologies to allow a reductionist (organism to gene) and/or integrative approach (gene to organism) to the study of a complex problem, such as heart failure, will reveal more information about ‘the system’ than study at a single level.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
