A single neuron subset governs a single coactive neuron circuit in Hydra vulgaris, representing a possible ancestral feature of neural evolution

The last common ancestor of Bilateria and Cnidaria is believed to be one of the first animals to develop a nervous system over 500 million years ago. Many of the genes involved in the neural function of the advanced nervous system in Bilateria are well conserved in Cnidaria. Thus, the cnidarian Hydra vulgaris is a good model organism for the study of the putative primitive nervous system in its last common ancestor. The diffuse nervous system of Hydra consists of several peptidergic neuron subsets. However, the specific functions of these subsets remain unclear. Using calcium imaging, here we show that the neuron subsets that express neuropeptide, Hym-176, function as motor circuits to evoke longitudinal contraction. We found that all neurons in a subset defined by the Hym-176 gene (Hym-176A) or its paralogs (Hym-176B) expression are excited simultaneously, followed by longitudinal contraction. This indicates not only that these neuron subsets have a motor function but also that a single molecularly defined neuron subset forms a single coactive circuit. This is in contrast with the bilaterian nervous system, where a single molecularly defined neuron subset harbors multiple coactive circuits, showing a mixture of neurons firing with different timings. Furthermore, we found that the two motor circuits, one expressing Hym-176B in the body column and the other expressing Hym-176A in the foot, are coordinately regulated to exert region-specific contraction. Our results demonstrate that one neuron subset is likely to form a monofunctional circuit as a minimum functional unit to build a more complex behavior in Hydra. This simple feature (one subset, one circuit, one function) found in Hydra may represent the simple ancestral condition of neural evolution.

Electro-mechanical and mechano-electrical interactions in healthy and drug-induced LQTS rabbit hearts

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): German Research Foundation Background Electrical and mechanical heterogeneities and their interactions (electro-mechanical and mechano-electrical coupling; EMC / MEC) are essential for normal cardiac function. Alterations in these can result in increased arrhythmia formation. Purpose With this study, we aim to investigate EMC and MEC under physiological and pathological conditions to better understand their roles in arrhythmia development. Methods Multi-channel ECG and TPM-MRI were used to measure regional differences in EMC in healthy ("control") and IKr-blocker E-4031 induced acute LQTS ("E-4031") rabbit hearts in vivo. MEC was studied in both groups by acutely changing mechanical function (increased preload by 6 ml/kg BW bolus of NaCl). Results In acute LQTS hearts (E-4031 10µg/kg bolus + 1µg/(kg*min) iv), cardiac repolarization was markedly prolonged compared to healthy controls, (p < 0.0001; n = 13), with increased QT-dispersion (Max-Min), a marker for regional heterogeneity of repolarization (p < 0.01; n = 13). Changing electrical function by E-4031 resulted in changes of mechanical features (EMC): in acute LQTS hearts, diastolic longitudinal velocity (Vz) was reduced in all basal (p = 0.003; n = 19) and 4/6 mid segments (p = 0.006; n = 19). Longitudinal diastolic TTP was prolonged significantly in 5/6 basal and 4/6 mid segments by E-4031. These alterations led to an increased apicobasal heterogeneity of longitudinal contraction duration (basal-apical Vz_dia_TTP [ms] 2.9 ± 10.6 vs. 21.1 ± 21.3; p = 0.01; n = 9). Increased preload acutely prolonged QTc in both "control" and "E-4031" hearts (‘control’ 156.6 ± 11.6 to 198.3 ± 20.3; p < 0.0001 vs. ‘E-4031’ 193.9 ± 19.6 to 256.0 ± 37.5; p < 0.0001; n = 13) (MEC). This effect was more pronounced in "E-4031" acute LQTS hearts than in healthy hearts (Figure 1; delta QTc [ms] ‘control’ 41.6 ± 14.9 vs. ‘E4031’ 62.1 ± 32.1; p < 0.006, n = 13). QT-dispersion (Max-Min) was increased significantly upon mechanical change only in "E-4031" (‘E-4031’ 25.8 ± 5.5 to 32.7 ± 12.3; p < 0.03, n = 13). Conclusion E-4031-induced changes in electrical function resulted in marked alterations in mechanical features via EMC. Similarly, acute changes in mechanical function (increased preload) resulted in electrical changes via MEC. Importantly, QT-prolonging effects of acutely increased preload, as well as its effects on regional heterogeneity of repolarization, were more pronounced in E-4031-induced acute LQTS hearts, indicating that cardiac repolarization in LQTS may be more susceptible to acute MEC effects than in healthy hearts. Acute MEC effects may thus play an additional role in LQT-related arrhythmogenesis. Abstract Figure.

Regional shape, global function and mechanics in right ventricular volume and pressure overload conditions: a three-dimensional echocardiography study

Our aim was to assess the regional right ventricular (RV) shape changes in pressure and volume overload conditions and their relations with RV function and mechanics. The end-diastolic and end-systolic RV endocardial surfaces were analyzed with three-dimensional echocardiography (3DE) in 33 patients with RV volume overload (rToF), 31 patients with RV pressure overload (PH), and 60 controls. The mean curvature of the RV inflow (RVIT) and outflow (RVOT) tracts, RV apex and body (both divided into free wall (FW) and septum) were measured. Zero curvature defined a flat surface, whereas positive or negative curvature indicated convexity or concavity, respectively. The longitudinal and radial RV wall motions were also obtained. rToF and PH patients had flatter FW (body and apex) and RVIT, more convex interventricular septum (body and apex) and RVOT than controls. rToF demonstrated a less bulging interventricular septum at end-systole than PH patients, resulting in a more convex shape of the RVFW (r = − 0.701, p < 0.0001), and worse RV longitudinal contraction (r = − 0.397, p = 0.02). PH patients showed flatter RVFW apex at end-systole compared to rToF (p < 0.01). In both groups, a flatter RVFW apex was associated with worse radial RV contraction (r = 0.362 in rToF, r = 0.482 in PH at end-diastole, and r = 0.555 in rToF, r = 0.379 in PH at end-systole, respectively). In PH group, the impairment of radial contraction was also related to flatter RVIT (r = 0.407) and more convex RVOT (r = − 0.525) at end-systole (p < 0.05). In conclusion, different loading conditions are associated to specific RV curvature changes, that are related to longitudinal and radial RV dysfunction.

A single neuron subset governs a single coactive neuron circuit in Hydra vulgaris, representing a prototypic feature of neural evolution

The last common ancestor of Bilateria and Cnidaria is believed to be one of the first animals to develop a nervous system over 500 million years ago. Many of the genes involved in the neural function of the advanced nervous system in Bilateria are well conserved in Cnidaria1. Thus, Cnidarian representative species, Hydra, is considered to be a living fossil and a good model organism for the study of the putative primitive nervous system in its last common ancestor. The diffuse nervous system of Hydra consists of several peptidergic neuron subsets. However, the specific functions of these subsets remain unclear. Using calcium imaging, here we show that the neuron subsets that express neuropeptide, Hym-1762,3 function as motor neurons to evoke longitudinal contraction. We found that all neurons in a subset defined by the Hym-176 gene (Hym-176A) or its paralogs (Hym-176B) expression4 are excited simultaneously, which is then followed by longitudinal contraction. This indicates not only that these neuron subsets are motor neurons but also that a single molecularly defined neuron subset forms a single coactive motor circuit. This is in contrast with the Bilaterian nervous system, where a single molecularly defined neuron subset harbors multiple coactive circuits, showing a mixture of neurons firing with different timings5. Furthermore, we found that the two motor circuits, one expressing Hym-176B in the body column and the other expressing Hym-176A in the foot, are coordinately regulated to exert region-specific contraction. Our results demonstrate that one neuron subset is likely to form a monofunctional circuit as a minimum functional unit to build a more complex behavior in Hydra. We propose that this simple feature (one subset, one circuit, one function) found in Hydra is a fundamental trait of the primitive nervous system.

Abstract 15411: Healthy Aging Reduces Stroke Volume but Not Longitudinal Pumping at Rest or During Exercise

Background: Healthy sedentary aging is accompanied by cardiac atrophy and decreases in left ventricular (LV) size, but its effects on longitudinal motion are unclear. Longitudinal pumping, generated by descent of the mitral annulus, efficiently contributes to the LV stroke volume (SV). This study aimed to determine the relative contribution of longitudinal motion to stroke volume at rest and exercise in healthy young and senior adults. Methods: Cardiopulmonary exercise testing with concurrent 3D echocardiography was performed in 22 subjects free of cardiovascular disease (Young n=12, age 32±2 years, Senior n=10, age 70±4 years) at rest and during submaximal exercise at a targeted heart rate of 100 bpm (Young 104±35 watts, Senior 83±36 watts, p = 0.18). Mitral annular excursion (MAE) and LV SV were measured using multi-beat 3D echo acquisition at rest and during sub-maximal exercise. MAE volume (MAEV) was measured by multiplying MAE by short axis area at the base of the LV. Relative longitudinal pumping was measured by dividing the MAEV and SV (%). Results: MAE and MAEV were similar between the young and senior groups at rest (Figure) and both increased with exercise (MAE Young: Δ4.0mm vs Δ Senior 3.3 mm, group x exercise p = 0.459, MAEV Young: 10.2 ml vs Δ Senior 7.1 ml, group x exercise p = 0.280). SV was lower in the senior group at both rest and exercise (group p = 0.024, group x exercise p = 0.029). While the relative contribution of longitudinal pumping to stroke volume during rest was higher in the senior group (group p = 0.013), there was no differential change with exercise (Young: Δ7.6% vs Senior Δ 7.9%, group x exercise p = 0.938). Conclusions: With sedentary aging, mitral annular excursion volume, a novel measure of systolic function, remains unchanged and results in higher relative contribution to a diminished stroke volume. Yet, the response to exercise is identical across the age groups, suggesting that efficient longitudinal contraction is preserved despite cardiac atrophy.

P4687Relevance of TAPSE and FAC, and their relationship to PASP as echo-derived measures for RV-PA coupling in heart failure: a comparative analysis with invasive RV-pressure volume loop data

Background Right ventricular (RV) to pulmonary artery (PA) coupling (C), quantified by pressure volume (PV) loop analysis, predicts RV function, and is independently associated with long term survival in systolic heart failure (HFrEF). However, the PV loop technique is invasive and complex to carry out, especially when used to do RV functional analyses. Different echo-surrogate parameters are proposed to measure RV-PA-C, such as the tricuspid annular plane systolic excursion, TAPSE/PAsystolic pressure (SP) and FAC (fractional area change)/PASP as the most promising parameters. However, up to now, no validation of these non-invasive coupling indices with the invasive gold standard method of RV-PV-loops has been done. Methods In 111 patients with advanced HFrEF (Post-hoc analysis of Magdeburger CRT Responder Trial, DRKS00011133), echo-derived TAPSE and FAC, and their relationship to PASP were related to the RV PV-loop-derived parameters of intrinsic RV contractility (Ees), pulmonary load (Ea), and the RV-PA-C efficiency (Ees/Ea) by linear regression analysis. Within a MRI substudy (n=49 patients) we examined the relationship of pure longitudinal contraction (MRI-TAPSE) and radial free wall to septum contraction (area change of 5 RV segments from tricuspid valve to apex in the short axis view) to the invasive RV-PA-C. Results The MRI analysis demonstrated that radial RV contraction (R2=0.77, p<0.001) correlated better to invasive RV-PA-C than pure longitudinal shortening (R2=0.37, p<0.001) (radial vs. longitudinal: p<0.00). Echo data for the entire patient cohort confirmed the MRI data. The FAC (R2=0.8, p<0.001) was significantly better associated with RV-PA-C than TAPSE (R2=0.57, p<0.001) (TAPSE vs FAC, p<0.001). Placing TAPSE or FAC into a quotient with PASP did not at all (TAPSE vs. TAPSE/PASP, p=0.1) or significantly attenuated (FAC vs. FAC/PASP R2=0.8 vs 0.58, p<0.001) their association to RV-PA-C. However, FAC/PASP and TAPSE/PASP correlated significantly better with global afterload (Eea), PA compliance, and pressure volume area (PVA), (p<0.001). In ROC analysis for all-cause mortality, all 4 tested parameters were prognostic relevant, however, with higher AUC values for FAC/PASP (AUC=0.74, p<0.001) and TAPSE/PASP (AUC=0.74, p<0.001) than for single TAPSE (AUC= 0.71, p=0.001) or FAC (AUC=0.7, p=0.001). Within a multivariate Cox regression analysis, only the FAC/PASP remained an independent predictor for long term survival. Conclusion FAC, an echo parameter that includes a predominant radial with a smaller part of longitudinal contraction, correlated significantly better to the invasively derived RV-PA-C-ratio than pure longitudinal RV shortening (TAPSE). Combining FAC or TAPSE with PASP did not improve the non-invasive RV-PA coupling information. However, it provided more comprehensive information on pulmonary vascular load and RV oxygen consumption, which seems to be translated into a higher prognostic power. Acknowledgement/Funding scientific grant from Boston Scientific