The regulatory light chain mediates inactivation of myosin motors during active shortening of cardiac muscle

The normal function of heart muscle depends on its ability to contract more strongly at longer length. Increased venous filling stretches relaxed heart muscle cells, triggering a stronger contraction in the next beat- the Frank-Starling relation. Conversely, heart muscle cells are inactivated when they shorten during ejection, accelerating relaxation to facilitate refilling before the next beat. Although both effects are essential for the efficient function of the heart, the underlying mechanisms were unknown. Using bifunctional fluorescent probes on the regulatory light chain of the myosin motor we show that its N-terminal domain may be captured in the folded OFF state of the myosin dimer at the end of the working-stroke of the actin-attached motor, whilst its C-terminal domain joins the OFF state only after motor detachment from actin. We propose that sequential folding of myosin motors onto the filament backbone may be responsible for shortening-induced de-activation in the heart.

Peripheral arterial filling time and peripheral retina fluorescence features in ultra-widefield angiography

AIM: To evaluate the peripheral arterial filling time (PAFT) and venous filling time (VFT) in eyes without known diseases that may influence filling process using ultra-widefield (UWF) fluorescein angiography (FA), and to review the peripheral retina fluorescence features. METHODS: A total of 30 eyes of 30 patients were retrospectively reviewed in this observational study. UWF-FA was performed using Optos 200Tx. PAFT and VFT was recorded. The interval between the arterial or venous filling completion and the previous photo was documented. The appearance of the far peripheral retina was described as either granular background fluorescence or mottled fluorescent band or vascular leakage. Terminal vascular patterns was described as loop pattern or branching pattern. Microvascular abnormalities such as arteriovenous shunting, vessels crossing the horizontal raphe, right angle vessels, terminal networks, capillary nonperfusion, drusen or microaneurysms were evaluated. RESULTS: The normal limits of PAFT was 3.397-8.984s and 4.399-11.753s for VFT. The appearance of the far peripheral retina, defined as granular background (63%), mottled fluorescence (20%), or vascular leakage (17%), was symmetrical between both eyes. Capillary nonperfusion (23%) and microaneurysms (40%) were more frequently found in eyes with loop pattern than in eyes with branching pattern. Other peripheral signs such as right-angle vessels (73%), and terminal networks (80%) were commonly seen on UWF-FA in the normal peripheral retina. CONCLUSION: The main courses of retinal artery and vein filling time are overlapping with each other on UWF-FA. Notably, the arterial filling process is completed in the arteriovenous phase rather than the traditionally named arterial phase. There are various manifestations in the peripheral retina of normal eyes.

Inferring the Frank–Starling Curve From Simultaneous Venous and Arterial Doppler: Measurements From a Wireless, Wearable Ultrasound Patch

The Frank–Starling relationship is a fundamental concept in cardiovascular physiology, relating change in cardiac filling to its output. Historically, this relationship has been measured by physiologists and clinicians using invasive monitoring tools, relating right atrial pressure (Pra) to stroke volume (SV) because the Pra-SV slope has therapeutic implications. For example, a critically ill patient with a flattened Pra-SV slope may have low Pra yet fail to increase SV following additional cardiac filling (e.g., intravenous fluids). Provocative maneuvers such as the passive leg raise (PLR) have been proposed to identify these “fluid non-responders”; however, simultaneously measuring cardiac filling and output via non-invasive methods like ultrasound is cumbersome during a PLR. In this Hypothesis and Theory submission, we suggest that a wearable Doppler ultrasound can infer the Pra-SV relationship by simultaneously capturing jugular venous and carotid arterial Doppler in real time. We propose that this method would confirm that low cardiac filling may associate with poor response to additional volume. Additionally, simultaneous assessment of venous filling and arterial output could help interpret and compare provocative maneuvers like the PLR because change in cardiac filling can be confirmed. If our hypothesis is confirmed with future investigation, wearable monitors capable of monitoring both variables of the Frank–Starling relation could be helpful in the ICU and other less acute patient settings.

Evaluating the Velocity and Extent of Cortical Venous Filling in Patients With Severe Middle Cerebral Artery Stenosis or Occlusion

Objective: To investigate the velocity and extent of cortical venous filling (CVF) and its association with clinical manifestations in patients with severe stenosis or occlusion of the middle cerebral artery (MCA) using dynamic computed tomography angiography (CTA).Methods: Fifty-eight patients (36 symptomatic and 22 asymptomatic) with severe unilateral stenosis (≥70%) or occlusion of the MCA M1 segment who underwent dynamic CTA were included. Collateral status, antegrade flow, and CVF of each patient were observed using dynamic CTA. Three types of cortical veins were selected to observe the extent of CVF, and the absence of CVF (CVF-) was recorded. Based on the appearance of CVF in the superior sagittal sinus, instances of CVF, including early (CVF1), peak (CVF2), and late (CVF3) venous phases, were recorded. The differences in CVF times between the affected and contralateral hemispheres were represented as rCVFs, and CVF velocity was defined compared to the median time of each rCVF.Results: All CVF times in the affected hemisphere were longer than those in the contralateral hemisphere (p < 0.05). Patients with symptomatic MCA stenosis had more ipsilateral CVF- (p = 0.02) and more delayed CVF at rCVF2 and rCVF21 (rCVF2-rCVF1) (p = 0.03 and 0.001, respectively) compared to those with asymptomatic MCA stenosis. For symptomatic patients, fast CVF at rCVF21 was associated with poor collateral status (odds ratio [OR] 6.42, 95% confidence interval [CI] 1.37–30.05, p = 0.02), and ipsilateral CVF- in two cortical veins was associated with poor 3-month outcomes (adjusted OR 0.025, 95% CI 0.002–0.33, p = 0.005).Conclusions: Complete and fast CVF is essential for patients with symptomatic MCA stenosis or occlusion. The clinical value of additional CVF assessment should be explored in future studies to identify patients with severe MCA stenosis or occlusion at a higher risk of stroke occurrence and poor recovery.

Early Venous Filling Following Thrombectomy: Association With Hemorrhagic Transformation and Functional Outcome

Background and Purpose: Previous studies have noted the angiographic appearance of early venous filling (EVF) following recanalisation in acute ischemic stroke. However, the prognostic implications of EVF as a novel imaging biomarker remain unclear. We aimed to evaluate the correlation between EVF with (i) the risk of subsequent reperfusion hemorrhage (RPH) and (ii) the association of EVF on both the NIHSS score at 24 h and functional outcome as assessed with the Modified Rankin Scale (mRS) score at 90 days.Methods: We conducted a retrospective cohort study of patients presenting with an acute ischemic stroke due to a proximal large-vessel occlusion of the anterior circulation treated by thrombectomy. Post-reperfusion digital subtraction angiography was reviewed to look for EVF as evidenced by the contrast opacification of any cerebral vein before the late arterial phase.Results: EVF occurred in 22.4% of the 147 cases included. The presence of EVF significantly increased the risk of RPH (p = 0.0048), including the risk of symptomatic hemorrhage (p = 0.0052). The presence of EVF (p = 0.0016) and the absence of RPH (p = 0.0021) were independently associated with a better outcome as defined by the NIHSS difference at 24 h, most significantly in the EVF+RPH− group. No significant relationship was however found between either EVF or RPH and a mRS score ≤ 2 at 90 days.Conclusion: Early venous filling on angiographic imaging is a potential predictor of reperfusion hemorrhage. The absence of subsequent RPH in this sub-group is associated with better outcomes at 24 h post-thrombectomy than in those with RPH.

Abstract P375: Cortical Venous Opacification Patterns and Outcome in Patients With Tandem Carotid Occlusion - Results From the ESCAPE NA1-Trial

Background: The degree of cortical venous opacification could reflect the degree of ischemia in tandem occlusions strokes. We assessed the association between asymmetric cortical vein opacification and outcome among patients with acute ischemic stroke and tandem occlusion. Methods: ESCAPE NA1 was a multicenter randomized-controlled trial comparing medical treatments nerinetide vs. placebo in patients with acute ischemic stroke and large vessel occlusion who underwent EVT. Tandem carotid occlusion was defined as complete occlusion of the ICA on catheter angiography. We assessed cortical venous opacification on baseline CTA using the COVES score (Jansen, et al. Radiology 2019, ranging from 0-6 with lower numbers indicating poor cortical venous filling, and dichotomized to 0 vs. 1-6). The influence of cortical venous opacification on functional outcome was analyzed using regression modelling with adjustment for age, baseline NIHSS and ASPECTS, thrombolysis and treatment allocation. Results: We assessed 115 patients with tandem occlusion. Median COVES score was 2 (IQR 1-3) with 9 patients (8%) scoring 0 (complete absence of cortical venous filling). Patients with COVES 0 were less likely to have good leptomeningeal collaterals (good collaterals: COVES 0: 0/9 (0%) vs. COVES 1-6: 19/102 (18%), p = 0.007). Patients with COVES 0 were less likely to achieve good outcome (mRS 0-2, COVES 0: 3/9 patients (33%) vs. COVES 1-6: 79/106 (74%), p=0.016). Cortical venous filling was significantly associated with good functional outcome on univariable analysis (OR 5.9, 95%CI 1.4 - 25.0), and after adjustment for baseline variables (OR 8.6, 95%CI 1.4 - 51.0). Cervical carotid angioplasty and/or stenting did not modify functional outcome after adjustment for COVES score. Conclusion: Impaired venous drainage is a marker of poor pial collaterals and is associated with poorer outcome in tandem occlusion patients.

Influence of Superficial Venous Ablation on Deep Venous Dilation and Reflux in Patients With Saphenous Varicose Veins

Background: To investigate the influence of superficial venous ablation on deep venous dilation and reflux in patients with saphenous varicose veins, and to elucidate the association between superficial venous reflux and deep venous morphology and hemodynamics. Methods: The data of 154 patients with 223 limbs, who underwent endovenous radiofrequency ablation (RFA) of the great saphenous vein for primary varicose veins between September 2014 and March 2016 in Eniwa Midorino Clinic, were retrospectively analyzed. Overall venous hemodynamics of the leg, including functional venous volume (VV) and venous filling index (VFI), was assessed using air-plethysmography. Saphenous and deep vein reflux and diameter were evaluated with duplex scanning. Results: Hemodynamic and morphologic changes were evaluated before and 1 month after RFA. The VV and VFI were significantly decreased in postoperative values than in preoperative values ( P < .001). Limbs with deep venous reflux significantly decreased postoperatively than preoperatively ( P < .001). There were significant differences in the diameter of the common femoral vein (CFV) and popliteal vein (PV) between the preoperative and postoperative values ( P < .001). There were strong to moderate correlations between the VV and the diameter of the CFV or PV (CFV, r = 0.47, P < .001; PV, r = 0.35, P < .001), while there were moderate to weak correlations between the VFI and the diameter of the CFV or PV (CFV, r = 0.23, P < .001; PV, r = 0.33, P <.001). Conclusions: Superficial venous ablation significantly reduced deep venous dilation and reflux in patients with saphenous varicose veins. Significant correlations existed between the VV or VFI, which reflected superficial venous reflux, and the diameter of the deep veins. These findings reveal that volume overload due to superficial venous reflux is associated with deep venous morphology and hemodynamics.