Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ANATOMY-FOUND (Novel Imaging of the heart for new structural and metabolic diagnosis)

Teaser

What are the overall objectives?Each year cardiovascular disease (CVD) causes over 4 mio deaths in Europe. Predictions suggest that 80% of premature heart disease and stroke is preventable, but ~20% of CVDs are misdiagnosed, and in elderly patients up to 60% of CVDs remain...

Summary

What are the overall objectives?
Each year cardiovascular disease (CVD) causes over 4 mio deaths in Europe. Predictions suggest that 80% of premature heart disease and stroke is preventable, but ~20% of CVDs are misdiagnosed, and in elderly patients up to 60% of CVDs remain undiagnosed. We need to develop new technologies and strategies for early and accurate diagnosis of the biggest killer in western society. Early CVD processes begin in heart cells, before evolving to the ’macro’ pathology recognisable by traditional techniques. Clinicians desire a non-invasive technique that can provide high-resolution micro-anatomy in 3-dimensions, and organ specific regional metabolic assessment. However the intricate micro-anatomy of the heart and its dynamic relationship with cardiac function is still fiercely debated. We set out to investigate the following questions: 1) what is the true micro-anatomy of the heart, and how is it remodelled in disease? 2) What is the role of 3-dimensional micro-anatomy in 4-dimensional pump function? 3) Does micro-anatomical remodelling correlate with regional changes in metabolism? Using state-of-the-art non-invasive 3d and 4d ex-vivo and in-vivo imaging methodologies, we attempted to answer these questions. In this regard, we have provided novel information regarding the 3D disposition of the cardiac conduction system in normal and congenitally malformed human hearts. We have shed light on the true micro-anatomy of the working myocardium, challenging traditional views, and providing new insight into how the micro-structure of the heart facilitates contraction and is modified in disease. We also confirmed the efficacy of in-vivo metabolic imaging for the assessment of metabolic impairment in heart failure. With initial results suggesting micro-anatomical remodelling does accompany regional metabolic remodelling.
We now have an improved understanding of the micro-anatomy of the heart in 3-dimensions and its relationship with contraction and metabolism in disease. We hope that our findings and on-going research will aid in detecting and correlating novel morphological and metabolic changes upstream of the macro-anatomical and non-specific metabolic changes, providing the foundation for a step-wise change in diagnosis of CVD.

Work performed

We used numerous state-of-the-art non-invasive ex-vivo and in-vivo imaging methodologies to investigate our research questions.
Using contrast micro-CT we produced, for the first time, 3D representations of the cardiac conduction system in normal and congenitally malformed human hearts. This data was then used to create 3D printed hearts showing the precise 3D disposition of the cardiac conduction system. The prints were fabricated with transparent flexible myocardium and coloured cardiac conduction system in a cuttable and suturable material. Collectively these data formed the basis for three peer-reviewed publications in high impact open access Journals. The data was presented at numerous meetings and conferences, and gained considerable media attention in the form of magazine articles, interviews and online videos.
We also used micro-CT, synchro-CT, nano-CT and diffusion tensor magnetic resonance imaging (DTMRI) to investigate the micro-structure of the contractile myocardium. We confirmed the existence of our hypothesised ‘cardiac mesh’ morphology across multiple species, thus challenging the widely accepted ‘helical ventricular myocardial band’ model. Using novel myocyte orientation analysis we confirmed that the cellular arrangement of the myocardium is modified in diseased and malformed hearts. We showed that the major contributor to myocardial deformation is the rearrangement of the aggregated units of myocytes, and not shortening of the individual myocyte chains. This information allowed us to gain new insight into how the heart contracts. For example, the existence and antagonistic function of the transmural orientated component of the myocardial wall was elucidated. This body of work resulted in 5 publications in leading cardiology journals and will act to challenge the ‘text-book’ understanding of cardiac morphology and function.
We observed a reduction in resting bicarbonate production in failing hearts compared with controls, accompanied by an increase in pyruvate conversion to lactate in pulmonary-banded pigs. This suggests the hearts shifted to an undesirable anaerobic metabolic state. Lactate metabolite intensity maps suggest the failing heart underwent regional specific changes in cardiac metabolism. Initial visualisation of ex-vivo micro-CT data from the same hearts suggests micro-anatomical remodelling does correlate with regional metabolic remodelling but analysis is on-going. Our data will allow us to answer the important question of whether metabolic remodelling precedes micro-anatomical remodelling. Thus providing further support for the use of in-vivo magnetic resonance based metabolic imaging as a new tool for early diagnosis of heart disease.

Final results

Novel 3D printed hearts for improved patient outcomes:
Using micro-CT we produced the first time 3D representations of the cardiac conduction system in in-tact normal and congenitally malformed human hearts. This data was then used to create 3D printed hearts showing the cardiac conduction system. These print were the frist of their kind, showing the coloured cardiac conduction system in the setting of a flexible, transparent, cuttable and suturable myocardium. 3D-printing has allowed us to create physical models to aid understanding, teaching, patient consultations and to aid planning and practice of complex surgeries.

New anatomy to validate future clinical screening of heart disease:
We continued to improve the understanding of cardiac microanatomy and its role in 4D pump-function. This provides us with the opportunity to validate the potential use of DTMRI in the clinical assessment of cardiac remodelling and pump dysfunction. DTMRI offers a resolution that is an order of magnitude poorer than micro-CT but still allows analysis of the mean arrangement of myocyte chains and lamellar units. Previously, DT-MRI findings have been ‘validated’ by serial histology; in our view, validating 3D data with a 2D technique is erroneous, especially considering the heterogeneous 3D micro-anatomy. Micro-CT provides high resolution images in which individual myocyte chains are resolved. So far we have provided rudimentary validation of DTMRI for use in assessment of myocardial microstructure in 3D using high resolution tomographic imaging. DTMRI has the potential to be a powerful diagnostic and prognostic tool in the assessment of myocardial remodelling in disease.

Metabolic imaging for early diagnosis of heart failure:
Clinicians desire an objective non-invasive technique to provide high-resolution morphological data, with organ specific regional metabolic assessment. During the development heart failure, disease processes begin at the intracellular level before macro-anatomic pathology can be recognised. Changes in cardiac metabolism therefore offer an attractive diagnostic target. Our study confirms the efficacy of in-vivo [113C]pyruvate MRI imaging for assessment of metabolic impairment in heart failure. In addition, our data suggests morphological and metabolic remodelling are linked, and these data will allow us to answer the important question of whether metabolic remodelling precedes micro-anatomical remodelling.