Journal of Physiology-London最新文献

Type 2 diabetes is a highly prevalent metabolic disease that significantly impacts the heart and contributes to an increased risk of cardiac complications, notably heart failure with preserved ejection fraction and cardiac arrhythmias, which can cause sudden cardiac death. In type 2 diabetes chronic hyperglycaemia and insulin resistance lead to subcellular changes, including dysregulation of calcium/calmodulin-dependent protein kinase II (CaMKII), intracellular sodium and calcium handling and potassium currents, all of which impair cardiac contractility and repolarisation. Type 2 diabetes induces diffuse myocardial fibrosis and anatomical remodelling, which contribute to diastolic and systolic dysfunction, and the formation of a pro-arrhythmic substrate. Impaired connexin 43-mediated conduction and cardiac autonomic neuropathy further promote cardiac electrophysiological and mechanical dysfunction. Clinical studies using the ECG and cardiac imaging modalities have been successful in detecting some of these changes; however our mechanistic understanding of type 2 diabetes-driven cardiac disorders remains limited. Recent advances in multiscale computational modelling and simulation of human cardiac electrophysiology and mechanics provide new opportunities to study diabetes-induced cardiac remodelling in silico by unravelling disease mechanisms across different scales and assisting in the development of novel therapies. Here we review key pathophysiological mechanisms of electrophysiological, structural and nervous cardiac remodelling in type 2 diabetes; their clinical implications; and the cardiac effects of common glucose-lowering pharmacological agents commonly taken by diabetes patients. We discuss the potential of human-based computational cardiac modelling and simulation in this context to deepen our mechanistic understanding, and guide more precise prevention and treatment of diabetes-driven cardiac arrhythmias and diastolic dysfunction.

We know that ischaemic cardiomyopathy leads to compensatory changes in the cardiovascular system to offset the reduction in cardiac output; there is a marked increase in cardiac sympathetic drive, as measured by noradrenaline spillover, and a marked increase in sympathetic vasoconstrictor drive to the skeletal muscle vascular bed, as measured by recording muscle sympathetic nerve activity from a peripheral nerve. Conversely based on assessment of heart rate variability there is believed to be a decrease in cardiac parasympathetic drive. Accordingly we might expect a decrease in ongoing neural activity in the vagus nerve. To test this we performed microelectrode recordings from the right vagus nerve in 14 patients with ischaemic cardiomyopathy and left ventricular ejection fractions ranging from 30%-48%. Multiple intrafascicular sites were analysed in each participant, with 57 multiunit sites being identified in which ongoing neural activity exhibited cardiac rhythmicity. Construction of cross-correlation histograms between the neural activity and the ECG demonstrated that there was no reduction in cardiac-modulated neural activity when compared to a group of healthy controls. Rather the magnitude of cardiac modulation of vagal activity was significantly elevated in ischaemic cardiomyopathy: 30.8% ± 13.7% (mean ± SD) vs. 18.1% ± 18.0% (P < 0.0001). Conversely there was no significant difference in the magnitude of respiratory modulation of vagal activity (48.0 ± 24.6% vs. 40.7% ± 22.7%, P = 0.1122). We conclude that ongoing cardiac-modulated activity in the right vagus nerve is elevated in ischaemic cardiomyopathy. Given that most of the vagus nerve is sensory we interpret this as reflecting an increase in afferent activity from the failing heart. KEY POINTS: Intraneural recordings from the cervical vagus were obtained in awake patients with ischaemic cardiomyopathy via tungsten microelectrodes inserted into the nerve through ultrasound guidance. Cross-correlation analysis of multiunit vagal activity revealed cardiac and respiratory modulation, from which the amplitude of modulation could be computed. We expected cardiac-locked vagal activity to be reduced, given the evidence for an overall reduction in heart rate variability in heart failure and the interpretation that this largely reflects an increase in cardiac sympathetic drive and a decrease in parasympathetic drive. However compared to data obtained in healthy participants the magnitude of cardiac modulation of vagal activity was significantly elevated in ischaemic cardiomyopathy (31% vs. 18%), but there was no significant difference in the magnitude of respiratory modulation of vagal activity (48% vs. 41%). We interpret this as reflecting an increase in afferent activity from the failing heart.

Resistance exercise training (RET) leads to marked interindividual heterogeneity in the hypertrophic response. Whether such heterogeneity is due to endogenous (i.e. inherent biological factors) or exogenous variables (i.e. external load) has not been firmly established. Twenty healthy young male participants completed thrice-weekly resistance exercise sessions for 10 weeks. Each participant had their legs and arms randomly assigned to perform unilateral bicep curls or knee extensions with either a higher (heavier) load (HL: 8-12 repetitions; ∼70%-80% of one-repetition maximum (1RM)) or, in the contralateral limb, lower load (LL: 20-25 repetitions at ∼30%-40% 1RM) for three sets to volitional fatigue during each session. Fat- and bone-free mass (dual-energy X-ray absorptiometry), muscle size (ultrasonography and muscle biopsies) and strength were measured pretraining and at 10 weeks. Skeletal muscle biopsies were obtained from the vastus lateralis, and we used ingested deuterated water to assess myofibrillar protein synthesis (MyoPS) at weeks 1 and 10 during training. Despite considerable interindividual variability in hypertrophic responses, we observed that muscle hypertrophy following RET was relatively well conserved within versus between subjects and was unaffected by load. Rates of MyoPS in weeks 1 and 10 of training were increased relative to rest (Week 1: Δ0.27 ± 0.11, P < 0.0001; Week 10: Δ0.10 ± 0.14%/d, P = 0.009); however, MyoPS was attenuated in week 10 versus week 1 (Δ0.16 ± 0.18%/d, P < 0.001). MyoPS rates were less heterogenous within versus between individuals. Variation in RET-induced muscle hypertrophy occurred independent of external load and was relatively well conserved (i.e., retention of the hypertrophic response) across different anatomical limbs within an individual. KEY POINTS: Considerable interindividual variability exists in resistance exercise training (RET)-induced muscle hypertrophy. However we observed that RET-induced muscle hypertrophy is relatively conserved within an individual (i.e. between the upper- and lower body) and is independent of external load when RET is performed to volitional fatigue. Changes in myofibrillar protein synthesis (MyoPS) rates are comparable with both higher and lower loads but are blunted following a period of RET despite progressive overload. There is negligible shared variance between RET-induced increases in muscle size and strength. Additionally, there are limited relationships between measures used to assess RET-induced muscle hypertrophy. We conclude that when effort is matched (i.e. working to volitional muscular fatigue), RET-induced hypertrophy is mediated to a far greater degree by inherent endogenous biological factors, which account for a large proportion of the heterogeneity between individuals.