Cardiac power output is a central haemodynamic measure which describes pumping capability and performance of the heart. This is a unique measure as it accounts for both, flow- and pressure-generating capacities of the heart. Cardiac power output (CPO) is calculated from mean arterial pressure and cardiac output. Popular noninvasive methods for cardiac output measurement today include rebreathing methods. From the practical and clinical perspective it is important to know which of the commonly measured cardio-respiratory variables, obtained from a cardiopulmonary exercise test, are good predictors of peak CPO in healthy but also in heart failure populations. Until now there has been no measurement of cardiac power output in patients implanted with a left ventricular assist device (LVAD) and those explanted (recovered) patients. In a comparison study design it has been shown that peak cardiac power output differentiates well during cardiac restoration using LVADs and emphasizes the benefits of this therapy. It seems that CPO has the potential to be a key physiological marker of heart failure severity and can guide the management of LVAD patients. Furthermore as a consequence of acute reduction of LVAD support, there is a decrease in cardiac pumping capability and exercise performance. A decrease at rest and at peak exercise, expressed in percentages, was higher in central haemodynamics, particularly in CPO, than in the conventionally measured peak oxygen consumption. This suggests that CPO is more sensitive to acute reduction of LVAD support than oxygen consumption. In patients with severe heart failure and those implanted with an LVAD, the relationship between peak CPO and peak oxygen consumption is only modest. In healthy adults and LVAD explanted patients this relationship was high. No strong relationship was found between peak CPO and anaerobic threshold, circulatory power, oxygen pulse or ventilatory efficiency in LVAD implanted and patients with severe heart failure. Finally, regarding di fferent modalities of exercise training, in contrast with resistance training, aerobic exercise training may increase both maximal flow-generating capacity of the heart and peak oxygen consumption and also delays anaerobic metabolism in patients with stable chronic heart failure. Improved peak oxygen consumption, following aerobic exercise training, is closely associated with an exercise-induce increase in cardiac output.

Polydimethylsiloxane (POMS)-based (Generation 1) and glass-based (Generation 2) microfluidic devices for heart tissue maintenance have been developed. Rat and human heart biopsies were electrically-paced in a 37 QC environment constantly perfused with oxygenated media, and waste products were continuously removed, mimicking the in vivo conditions. Tissue damage was indicated by assaying the lactate dehydrogenase (LOH) activity in the effluent samples. Heart tissues were kept viable in the biomimetic microenvironment within these devices once optimised, for up to 3.5 hours (human, Generation 1); 5 hours (rat, Generation 1), and 24 hours (rat, Generation 2). Mechanical contraction was observed in some of the tissue biopsies, suggesting that they were functioning as it is in the body. Sensitive, accurate and robust electrochemical analytical probes were established to measure the total reactive oxygen species (ROS) and creatine kinase MB (CK-MB) concentration in the effluent from the tissue biopsies. The total ROS probe was integrated with the Generation 1 microfluidic device to give a real-time measurement of the tissue insult. Both of these devices were also used to investigate the effects of on-chip ischaemia reperfusion (IR) procedures on the expression levels of a series of genes, which were analysed off-chip by semi-quantitative PCR. In addition, mixing within the Generation 1 microfluidic device was induced by redox-magnetohydrodynamics (redox-MHO), where a redox species, hexamineruthenium (Ill) chroride (Ruhex) and magnet were used to generate a magnetic force, thus causing the fluid to rotate around the electrodes. Qualitative microscopy recordings on polystyrene microbeads movement were provided in the supplementary OVO, showing the effects of MHO and Ruhex-MHO. This application could be of particular importance when the tissue sample is exposed to certain therapeutic drugs during perfusion for defined periods of time, to test the responsiveness of cardiac tissue to treatment. This proof-of-principle microfluidic technique will hopefully serve as a platform technology for future cardiac research and may also be exploited and modified for investigation of other clinical tissues, hence reducing reliance on animal models. The full potential of this technology remains to be discovered as other groups adopt this approach to analyse diseased and normal tissues.

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Next-generation sequencing methods now allow rapid and cost-effective sequencing of DNA on a scale not previously possible. This offers great opportunities for the research of Mendelian disorders, but also significant challenges. The sequencing of exomes, or whole genomes, has emerged as a powerful clinical research tool, with targeted gene analyses generally being preferred in the clinical diagnostic setting. These methods have been employed here with the aim of identifying novel genetic causes of inherited heart disorders and to gain insights into the utility and limitations of these techniques for clinical diagnosis in these disorders. Data produced from the introduction of a targeted multi-gene next-generation sequencing test into clinical practice has been studied. Variation within the mitochondrial genome has been analysed to assess the importance of mitochondrial DNA variants in patients with hypertrophic cardiomyopathy. The m.4300A>G mutation is identified as an important cause of this disorder, with other previously cardiomyopathy-associated and novel variants also identified. Such multi-gene tests can facilitate interpretable and phenotype-relevant results, but at the expense of limiting more extensive data acquisition. Whole-genome sequencing has been performed in five families with different autosomal dominant inherited heart disease phenotypes of unknown genetic aetiology. In two of these likely pathogenic variants were identified, one in the gene encoding titin (TTN) and the other in the calcium channel subunit gene CACNA1C. In vitro studies were undertaken to support the pathogenicity of the TTN variant and understand the functional effects of this. In the other three families either multiple candidate gene variants were identified or no clear candidate variant was identified. This highlights the difficulties in interpreting these results, even in carefully selected families. Overall, although the research benefits of exome or genome studies are evident, the interpretation and validation of genetic variant data produced remains highly challenging for clinical diagnosis.