The Effect of PEEP on Pulmonary Vascular Resistance Depends on Lung Recruitability in ARDS Patients.

Rationale. A U-shape relationship should exist between lung volume and pulmonary vascular resistance (PVR), with minimal PVR at functional residual capacity. Thus, positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome (ARDS) should increase PVR if it induces significant lung distension compared to recruitment. However, this has never been proven in patients. Objectives. To study the effects of PEEP on PVR according to lung recruitability, evaluated by the recruitment-to-inflation (R/I) ratio. Methods. In patients with ARDS, we measured hemodynamic (pulmonary artery catheter), echocardiographic and ventilatory variables (including esophageal pressure), at both low PEEP and higher PEEP by 10 cmH2O. Preload responsiveness was assessed by the passive leg raising test at high PEEP. Measurements and Main Results. We enrolled 23 patients, including 10 low recruiters (R/I <0.5) and 13 high recruiters (R/I ≥0.5). Raising PEEP from 4 (2-5) to 14 (12-15) cmH2O increased PVR in low recruiters (from 160 (120-297) to 243 (166-380) dyn.s/cm5, p<0.01), while PVR was unchanged in high recruiters (from 224 (185-289) to 235 (168-300) dyn.s/cm5, p=0.55). Right-to-left ventricular end-diastolic areas ratio simultaneously increased in low recruiters (from 0.54 (0.50-0.59) to 0.64 (0.56-0.70), p<0.01), while remaining stable in high recruiters (from 0.70 (0.65-0.79) to 0.68 (0.58-0.80), p=0.48). Raising PEEP decreased cardiac index only in preload responsive patients. Conclusions. PEEP increases PVR only when it induces significant lung distension compared to recruitment according to the recruitment-to-inflation ratio. Tailoring PEEP on this recruitability index should mitigate its hemodynamic effects.

Impact of the timing of metformin administration on glycaemic and glucagon-like peptide-1 responses to intraduodenal glucose infusion in type 2 diabetes: a double-blind, randomised, placebo-controlled, crossover study.

AIMS/HYPOTHESIS: Metformin lowers postprandial glycaemic excursions in individuals with type 2 diabetes by modulating gastrointestinal function, including the stimulation of glucagon-like peptide-1 (GLP-1). The impact of varying the timing of metformin administration on postprandial glucose metabolism is poorly defined. We evaluated the effects of metformin, administered at different intervals before an intraduodenal glucose infusion, on the subsequent glycaemic, insulinaemic and GLP-1 responses in metformin-treated type 2 diabetes. METHODS: Sixteen participants with type 2 diabetes that was relatively well-controlled by metformin monotherapy were studied on four separate days in a crossover design. On each day, participants were randomised to receive a bolus infusion of metformin (1000 mg in 50 ml 0.9% saline) via a nasoduodenal catheter at t = -60, -30 or 0 min (and saline at the other timepoints) or saline at all timepoints (control), followed by an intraduodenal glucose infusion of 12.56 kJ/min (3 kcal/min) at t = 0-60 min. The treatments were blinded to both participants and investigators involved in the study procedures. Plasma glucose, insulin and total GLP-1 levels were measured every 30 min between t = -60 min and t = 120 min. RESULTS: There was a treatment-by-time interaction for metformin in reducing plasma glucose levels and increasing plasma GLP-1 and insulin levels (p<0.05 for each). The reduction in plasma glucose levels was greater when metformin was administered at t = -60 or -30 min vs t = 0 min (p<0.05 for each), and the increases in plasma GLP-1 levels were evident only when metformin was administered at t = -60 or -30 min (p<0.05 for each). Although metformin did not influence insulin sensitivity, it enhanced glucose-induced insulin secretion (p<0.05), and the increases in plasma insulin levels were comparable on the 3 days when metformin was given. CONCLUSIONS/INTERPRETATION: In well-controlled metformin-treated type 2 diabetes, glucose-lowering by metformin is greater when it is given before, rather than with, enteral glucose, and this is associated with a greater GLP-1 response. These observations suggest that administration of metformin before meals may optimise its effect in improving postprandial glycaemic control. TRIAL REGISTRATION: www.anzctr.org.au ACTRN12621000878875 FUNDING: The study was not funded by a specific research grant.

Residual force depression is not related to positive muscle fascicle work during submaximal voluntary dorsiflexion contractions in humans.

Residual force depression (rFD) following active muscle shortening is assumed to correlate most strongly with muscle work, but this has not been tested during voluntary contractions in humans. Using dynamometry, we compared steady-state ankle joint torques (N = 16) following tibialis anterior (TA) muscle-tendon unit (MTU) lengthening and shortening to the time-matched torque during submaximal voluntary fixed-end dorsiflexion reference contractions (REF) at a matched MTU length and EMG amplitude. Ultrasound revealed significantly reduced (P < 0.001) TA fascicle shortening amplitudes during MTU lengthening without a preload over small and medium amplitudes, respectively, relative to REF. MTU lengthening with a preload over a large amplitude significantly (P < 0.001) increased fascicle shortening relative to REF, as well as stretch amplitudes relative to MTU lengthening without a preload (P = 0.001). Significant (P = 0.028) steady-state fascicle force enhancement relative to REF was observed following MTU lengthening, and was similar among MTU lengthening-hold conditions (3-5%). MTU shortening with and without a preload over small and large amplitudes significantly (P < 0.001) increased positive fascicle and MTU work relative to REF, but significant (P = 0.006) rFD was observed following MTU shortening with a preload (7-10%) only. rFD was linearly related to positive MTU work [rrm (47) = 0.48, P < 0.001], but not positive fascicle work [rrm (47) = 0.16, P = 0.277]. Our findings indicate that MTU lengthening without substantial fascicle stretch enhances steady-state force output, which might arise from less shortening-induced rFD. Our findings also indicate similar rFD following different amounts of positive fascicle/MTU work, which cautions against using work to predict rFD during submaximal voluntary contractions. KEY POINTS: Accurately predicting muscle force is challenging because active muscle shortening depresses force output. The residual force depression (rFD) that exists following active muscle shortening is commonly assumed to correlate strongly and positively with muscle work. We found that tibialis anterior muscle fascicle work and muscle-tendon unit work did not accurately predict rFD during submaximal voluntary dorsiflexion contractions. Fascicle shortening during fixed-end reference contractions also potentially induced rFD of 3-5%, which was similar to the rFD following muscle-tendon unit shortening without a preload. A higher number of active muscle fibres during shortening probably increased rFD, which suggests that motor unit recruitment during shortening might predict rFD.

Preload-Induced Switchable Adhesion.

Animals with robust attachment abilities commonly exhibit stable attachment and convenient detachment. However, achieving an efficient attachment-detachment function in bioinspired adhesives is challenging owing to the complexity and delay of actuators. In this study, a class of multilayer adhesives (MAs) comprising backing, middle, and bottom layers is proposed to realize rapid switching by only adjusting the preload. At low preload, the MAs maintain intimate contact with the substrate. By contrast, a sufficiently large preload results in significant deformation of the middle layer, causing underside buckling and reducing adhesion. By optimizing the structural parameters of the MAs, a high switching ratio (up to 136×) can be achieved under different preloads. Furthermore, the design of the MAs incorporates a film-terminated structure, which prevents the embedding of dirt particles, simplifies cleaning, and maintains the separation and uprightness of the microstructures. Consequently, the MAs demonstrate practical potential for simple and efficient transportation applications, as they achieve switchable adhesion through their structure, exhibiting a high switching ratio and fast switching.

Validation of Preload Assessment Technologies at Altitude in a Porcine Model of Hemorrhage.

INTRODUCTION: Dynamic preload assessment measures including pulse pressure variation (PPV), stroke volume variation (SVV), pleth variability index (PVI), and hypotension prediction index (HPI) have been utilized clinically to guide fluid management decisions in critically ill patients. These values aid in the balance of correcting hypotension while avoiding over-resuscitation leading to respiratory failure and increased mortality. However, these measures have not been previously validated at altitude or in those with temporary abdominal closure (TAC). METHODS: Forty-eight female swine (39 ± 2 kg) were separated into eight groups (n = 6) including all combinations of flight versus ground, hemorrhage versus no hemorrhage, and TAC versus no TAC. Flight animals underwent simulated aeromedical evacuation via an altitude chamber at 8000 ft. Hemorrhagic shock was induced via stepwise hemorrhage removing 10% blood volume in 15-min increments to a total blood loss of 40% or a mean arterial pressure of 35 mmHg. Animals were then stepwise transfused with citrated shed blood with 10% volume every 15 min back to full blood volume. PPV, SVV, PVI, and HPI were monitored every 15 min throughout the simulated aeromedical evacuation or ground control. Blood samples were collected and analyzed for serum levels of serum IL-1ß, IL-6, IL-8, and TNF-α. RESULTS: Hemorrhage groups demonstrated significant increases in PPV, SVV, PVI, and HPI at each step compared to nonhemorrhage groups. Flight increased PPV (P = 0.004) and SVV (P = 0.003) in hemorrhaged animals. TAC at ground level increased PPV (P < 0.0001), SVV (P = 0.0003), and PVI (P < 0.0001). When TAC was present during flight, PPV (P = 0.004), SVV (P = 0.003), and PVI (P < 0.0001) values were decreased suggesting a dependent effect between altitude and TAC. There were no significant differences in serum IL-1ß, IL-6, IL-8, or TNF-α concentration between injury groups. CONCLUSIONS: Based on our study, PPV and SVV are increased during flight and in the presence of TAC. Pleth variability index is slightly increased with TAC at ground level. Hypotension prediction index demonstrated no significant changes regardless of altitude or TAC status, however this measure was less reliable once the resuscitation phase was initiated. Pleth variability index may be the most useful predictor of preload during aeromedical evacuation as it is a noninvasive modality.

Myocardial strain is regulated by cardiac preload in the early stage of sepsis.

BACKGROUND: Owing to a lack of data, this study aimed to explore the effect of cardiac preload on myocardial strain in patients with sepsis. METHODS: A total of 70 patients with sepsis in intensive care unit (ICU) of a tertiary teaching hospital in China from January 2018 to July 2019 and underwent transthoracic echocardiography were enrolled. Echocardiographic data were recorded at ICU admission and 24 h later. Patients were assigned to low left ventricular end-diastolic volume index (LVEDVI) and normal LVEDVI groups. We assessed the impact of preload on myocardial strain between the groups and analyzed the correlation of echocardiographic parameters under different preload conditions. RESULTS: Thirty-seven patients (53%) had a low LVEDVI and 33 (47%) a normal LVEDVI. Those in the low LVEDVI group had a faster heart rate (121.7 vs. 95.3, p < 0.001) and required a greater degree of fluid infusion (3.67 L vs. 2.62 L, P = 0.019). The left ventricular global strain (LVGLS) (-8.60% vs. -10.80%, p = 0.001), left ventricular global circumferential strain (LVGCS) (-13.83% vs. -18.26%, p = 0.006), and right ventricular global longitudinal strain (RVGLS) (-6.9% vs. -10.60%, p = 0.001) showed significant improvements in the low LVEDVI group after fluid resuscitation. However, fluid resuscitation resulted in a significantly increased cardiac afterload value (1172.00 vs. 1487.00, p = 0.009) only in the normal LVEDVI group. Multivariate backward linear regression showed that LVEDVI changes were independently associated with myocardial strain-related improvements during fluid resuscitation. The baseline LVEDVI was significantly negatively correlated with the LVGLS and RVGLS (r = -0.44 and - 0.39, respectively) but not LVGCS. LVEDVI increases during fluid resuscitation were associated with improvements in the myocardial strain degree. CONCLUSIONS: Myocardial strain alterations were significantly influenced by the cardiac preload during fluid resuscitation in sepsis.

Head-down tilt reduces the heart rate in postural tachycardia syndrome in acute setting: a pilot study.

BACKGROUND: Reduced preload and thoracic blood volume accompany postural tachycardia syndrome (POTS). Head-down tilt (HDT) increases both preload and intrathoracic blood volume. The objective of this study was to assess the safety and efficacy of HDT in POTS in acute settings. METHODS: This retrospective study evaluated POTS patients. Analyzed data included heart rate, blood pressure, cerebral blood flow velocity (CBFv) in the middle cerebral artery, and capnography. The baseline supine hemodynamic data were compared with the data obtained at the second minute of the -10° HDT. A linear mixed-effects model was used to assess the effect of HDT on hemodynamic variables. RESULTS: The HDT was explored in seven POTS patients and an additional seven POTS patients without HDT served as controls. In the HDT arm, four POTS patients had overlapping diagnoses of myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) and one patient had comorbidity of post-acute sequelae of SARS-CoV-2 infection (PASC). HDT lowered heart rate by 10% and increased end-tidal CO2 by 8%. There was no change in other cardiovascular variables. CONCLUSIONS: In the acute setting, HDT is safe. HDT reduces the heart rate presumably by modulating baroreflex by enhancing preload and stroke volume, which in turn increases thoracic blood volume with a net effect of parasympathetic cardiovagal activation and/or sympathetic withdrawal. This pilot study provides a foundation to proceed with longitudinal studies exploring the long-term effect of repetitive HDT in conditions associated with preload failure such as POTS, ME/CSF, and PASC.

The effects of bolus isosorbide dinitrate on pulmonary hypertension with cardiopulmonary comorbidities.

Lowering mean pulmonary arterial pressure (mPAP) without reducing cardiac output is essential in treating pulmonary hypertension (PH). Isosorbide dinitrate (ISDN) potentially achieves this in post-capillary PH but can decrease cardiac output and blood pressure (BP), especially in pre-capillary PH. However, post-capillary PH and pre-capillary PH can overlap, and their clear discrimination is difficult. The aim of the study was to examine to what extent bolus ISDN injection reduces mPAP and BP, and changes mixed venous oxygen saturation (SvO2), an indicator of cardiac output in PH with various cardiopulmonary comorbidities in the context of treatment modifications. We retrospectively examined the hemodynamic effects of bolus ISDN injection in patients with PH who underwent right heart catheterization and their subsequent treatment modification. Our sample comprised 13 PH patients. In seven with pre-capillary PH, ISDN significantly lowered mPAP from the median 34 (interquartile range 32-39) to 28 (28-30) mmHg and the mean BP (mBP) from 90 (79-92) to 72 (68-87) mmHg. In six with post-capillary PH, ISDN lowered mPAP from 40 (29-44) to 27 (23-31) mmHg and mBP from 91 (87-110) to 87 (82-104) mmHg. There was a significant decrease in SvO2 from 69.8% (64.9%-78.1%) to 63.9% (60.5%-71.5%) in pre-capillary PH, but not in post-capillary PH including combined post- and pre-capillary PH and some patients showed a large increase in SvO2. In all patients showing an SvO2 increase, diuretics or hemodialysis were up-titrated or continued. Bolus ISDN injection lowered mPAP. However, in pre-capillary PH, it caused a significant decrease in SvO2 and a notable reduction in blood pressure. In post-capillary PH, including combined post- and pre-capillary PH, it clarified whether systemic preload and afterload reduction increased or decreased SvO2 in each patient, which may aid in treatment modification.

Determinants of Urine Output Using Advanced Hemodynamic Monitoring in Critically Ill Patients Undergoing Continuous Renal Replacement Therapy.

INTRODUCTION: Low cardiac output and hypovolemia are candidate macrocirculatory mechanisms explanatory of de novo anuria in intensive care unit (ICU) patients undergoing continuous renal replacement therapy (CRRT). We aimed to determine the hemodynamic parameters and CRRT settings associated with the longitudinal course of UO during CRRT. METHODS: This is an ancillary analysis of the PRELOAD CRRT observational, single-center study (NCT03139123). Enrolled adult patients had severe acute kidney injury treated with CRRT for less than 24 h and were monitored with a calibrated continuous cardiac output monitoring device. Hemodynamics (including stroke volume index [SVI] and preload-dependence, identified by continuous cardiac index variation during postural maneuvers), net ultrafiltration (UFNET), and UO were reported 4-hourly, over 7 days. Two study groups were defined at inclusion: non-anuric participants if the cumulative 24 h UO at inclusion was ≥0.05 mL kg-1 h-1, and anuric otherwise. Quantitative data were reported by its median [interquartile range]. RESULTS: Forty-two patients (age 68 [58-76] years) were enrolled. At inclusion, 32 patients (76%) were not anuric. During follow-up, UO decreased significantly in non-anuric patients, with 25/32 (78%) progressing to anuria within 19 [10-50] hours. Mean arterial pressure (MAP) and UFNET did not significantly differ between study groups during follow-up, while SVI and preload-dependence were significantly associated with the interaction of study group and time since inclusion. Higher UFNET flow rates were significantly associated with higher systemic vascular resistances and lower cardiac output during follow-up. Multivariate analyses showed that (1) lower UO was significantly associated with lower SVI, lower MAP, and preload-independence; and (2) higher UFNET was significantly associated with lower UO. CONCLUSIONS: In ICU patients treated with CRRT, those without anuria showed a rapid loss of diuresis after CRRT initiation. Hemodynamic indicators of renal perfusion and effective volemia were the principal determinants of UO during follow-up, in relation with the hemodynamic impact of UFNET setting.

Signal Processing Using a Circular Sensor Array to Measure the Torsional Angle of a Bolted Joint.

This study presents a new approach to determining the preload force of bolted joints. The concept involves measuring the torsional angle without contact. For this purpose, we present a circular magnetic sensor array integrated into the torque wrench. The torsional angle in bolted joints depends on the dimensions of the screw and the materials used and is typically less than four degrees. For this reason, one requirement is a high angular resolution so that a continuous recording of the torsion angle is feasible during the assembly process. This can be achieved using the circular sensor array and adapted signal processing methods. Two signal processing approaches are utilized. First, the direct method uses the discrete Fourier transformation to calculate the rotation angle from the signal phase. This approach is robust to signal distortion and does not depend on signal amplitude. Second, the method with a learning phase employs Gaussian process regression to minimize the angle error. In an experiment, both approaches were applied within a test bench and showed promising results. The direct method demonstrated a very good angular resolution without training and calibration. For mobile and less-complex applications where a reference system is unavailable, the direct method is preferable. However, in complex measurement systems where reference systems can be utilized initially, significant enhancements to an excellent resolution can be achieved through prior training.

PMUT-Based System for Continuous Monitoring of Bolted Joints Preload.

In this paper, we present a bolt preload monitoring system, including the system architecture and algorithms. We show how Finite Element Method (FEM) simulations aided the design and how we processed signals to achieve experimental validation. The preload is measured using a Piezoelectric Micromachined Ultrasonic Transducer (PMUT) in pulse-echo mode, by detecting the Change in Time-of-Flight (CTOF) of the acoustic wave generated by the PMUT, between no-load and load conditions. We performed FEM simulations to analyze the wave propagation inside the bolt and understand the effect of different configurations and parameters, such as transducer bandwidth, transducer position (head/tip), presence or absence of threads, as well as the frequency of the acoustic waves. In order to couple the PMUT to the bolt, a novel assembly process involving the deposition of an elastomeric acoustic impedance matching layer was developed. We achieved, for the first time with PMUTs, an experimental measure of bolt preload from the CTOF, with a good signal-to-noise ratio. Due to its low cost and small size, this system has great potential for use in the field for continuous monitoring throughout the operative life of the bolt.

Vasoconstriction with phenylephrine increases cardiac output in preload dependent patients.

General Anaesthesia (GA) is accompanied by a marked decrease in sympathetic outflow and thus loss of vasomotor control of cardiac preload. The use of vasoconstriction during GA has mainly focused on maintaining blood pressure. Phenylephrine (PE) is a pure α1-agonist without inotropic effects widely used to correct intraoperative hypotension. The potential of PE for augmenting cardiac stroke volume (SV) and -output (CO) by venous recruitment is controversial and no human studies have explored the effects of PE in preload dependent circulation using indicator dilution technique. We hypothesized that PE-infusion in patients with cardiac stroke volume limited by reduced preload would restore preload and thus augment SV and CO. 20 patients undergoing GA for gastrointestinal surgery were monitored with arterial catheter and LiDCO unity monitor. Upon stable haemodynamics after induction patients were placed in head-up tilt (HUT). All patients became preload responsive as verified by a stroke volume variation (SVV) of > 12%. PE-infusion was then started at 15-20mikrg/min and adjusted until preload was restored (SVV < 12%). Li-dilution cardiac output (CO) was initially measured after induction (baseline), again with HUT in the preload responsive phase, and finally when preload was restored with infusion of PE.At baseline SVV was 10 ± 3% (mean ± st.dev.), CI was 2,6 ± 0,4 L/min*m2, and SVI 43 ± 7mL/m2. With HUT SVV was 19 ± 4%, CI was 2,2 ± 0,4 L/min*m2, SVI 35 ± 7mL/m2. During PE-infusion SVV was reduced to 6 ± 3%, CI increased to 2,6 ± 0,5 L/min*m2, and SVI increased to 49 ± 11mL/m2. All differences p < 0,001. In conclusion: Infusion of phenylephrine during preload dependency increased venous return abolishing preload dependency as evaluated by SVV and increased cardiac stroke volume and -output as measured by indicator-dilution technique. (ClinicalTrials.gov NCT05193097).

Differential Cardiac Responses after Passive Leg Raising.

This study retrospectively examined the hemodynamic effects of passive leg raising (PLR) in mechanically ventilated patients during fluid removal before spontaneous breathing trials. In previous studies, we noticed varying cardiac responses after PLR completion, particularly in positive tests. Using a bioreactance monitor, we recorded and analyzed hemodynamic parameters, including stroke volume and cardiac index (CI), before and after PLR in post-acute ICU patients. We included 27 patients who underwent 60 PLR procedures. In preload-unresponsive patients, no significant CI changes were observed (CI_t-6 = 3.7 [2.6; 4.7] mL/min/m2 vs. CI_t9 = 3.3 [2.5; 3.4] mL/min/m2; p = 0.306), while in preload-responsive patients, two distinct CI response types to PLR were identified: a transient peak with immediate return to baseline (CI_t-6 = 2.7 [2.5; 3.1] mL/min/m2 vs. 3.3 [2.6; 3.8] L/min/m2; p = 0.119) and a sustained CI elevation lasting beyond the PLR maneuver (CI_t-6 = 2.8 [2.3; 2.9] L/min/m2 vs. 3.3 [2.8; 3.9] ml/min/m2; p = 0.034). The latter was particularly noted when ΔCI during PLR exceeded 25%. Our findings suggest that in certain preload-responsive patients, PLR can induce a more sustained increase in CI, indicating a possible persistent hemodynamic effect. This effect could be due to a combination of autotransfusion and sympathetic activation affecting venous return and vascular tone. Further research in larger cohorts and more comprehensive hemodynamic assessments are warranted to validate these observations and elucidate the possible underlying mechanisms.The Fluid unLoading On Weaning (FLOW) study was prospectively registered under the ID NCT04496583 on 2020-07-29 at ClinicalTrials.gov.

Diamond-Like Carbon Coating Reduces Connection Screw Head Stripping After Multiple Tightening Instances.

The stability of implant-abutment joint is fundamental for the long-term success of implant rehabilitation. The screw loosening, fracture, and head deformation are among the most common mechanical complications. Several surface treatments of titanium screws have been proposed to improve their resistance and stability. Diamond-like carbon (DLC) coating of the materials is widely used to increase their wear resistance and durability. The present study aimed to evaluate the effect of carbon fiber coating on the screw head on screw removal torque and screw head stripping. One hundred titanium implant screws were used, 50 without coating (Group 1) and 50 with DLC coating of the screw head (Group 2). Each screw was tightened with a torque of 25 Ncm and unscrewed 10 times. The removal torque was measured with a digital cap torque tester for each loosening. Optical 3d measurement of the screw head surface was performed by a fully automatic machine before and after multiple tightening to investigate surface modifications. The reverse torque values decreased with repeated tightening and loosening cycles in both groups without significant differences (P > .05). Optical measurements of surface dimensions revealed average changes of 0.0357 mm in Group 1 and 0.02312 mm in Group 2, which resulted to be statistically significant (P < .001). The DLC coating of the retention screw head can prevent its distortion and wear, especially after multiple tightening.

Chronic diastolic stretch unmasks conduction defects in an in vitro model of arrhythmogenic cardiomyopathy.

We seek to elucidate the precise nature of mechanical loading that precipitates conduction deficits in a concealed-phase model of arrhythmogenic cardiomyopathy (ACM). ACM is a progressive disorder often resulting from mutations in desmosomal proteins. Exercise has been shown to worsen disease progression and unmask arrhythmia vulnerability, yet the underlying pathomechanisms may depend on the type and intensity of exercise. Because exercise causes myriad changes to multiple inter-dependent hemodynamic parameters, it is difficult to isolate its effects to specific changes in mechanical load. Here, we use engineered heart tissues (EHTs) with iPSC-derived cardiomyocytes expressing R451G desmoplakin, an ACM-linked mutation, which results in a functionally null model of desmoplakin (DSP). We also use a novel bioreactor to independently perturb tissue strain at different time points during the cardiac cycle. We culture EHTs under three strain regimes: normal physiological shortening; increased diastolic stretch, simulating high preload; and isometric culture, simulating high afterload. DSPR451G EHTs that have been cultured isometrically undergo adaptation, with no change in action potential parameters, conduction velocity, or contractile function, a phenotype confirmed by global proteomic analysis. However, when DSPR451G EHTs are subjected to increased diastolic stretch, they exhibit concomitant reductions in conduction velocity and the expression of connexin-43. These effects are rescued by inhibition of both lysosome activity and ERK signaling. Our results indicate that the response of DSPR451G EHTs to mechanical stimuli depends on the strain and the timing of the applied stimulus, with increased diastolic stretch unmasking conduction deficits in a concealed-phase model of ACM.

Assessing maternal cardiac function by obstetricians: technique and reference ranges.

BACKGROUND: A strong body of evidence has now coalesced indicating that some obstetrical syndromes may result from maladaptive responses of the maternal cardiovascular system. Longitudinal studies have shown that these changes are complex and present before the clinical recognition of preeclampsia and fetal growth restriction, suggesting that hemodynamic maladaptation may play an etiologic role in obstetrical complications. Chronic hypertension is one of the most frequent complications of pregnancy, and recent evidence suggests that control of mild hypertension in early pregnancy improves outcome. The management of chronic hypertension can be improved by understanding specific cardiovascular hemodynamic abnormalities such as increased cardiac output or increased systemic vascular resistance, which can respond to either beta or calcium channel blockers, depending on the hemodynamic findings. Evaluation of maternal cardiac function has not been previously available to obstetrical healthcare providers using diagnostic ultrasound equipment used for fetal evaluation. OBJECTIVE: Obstetrical ultrasound machines may be configured for various probes (endovaginal, abdominal, 3D/4D, and cardiac). This study used a cardiac probe placed in the suprasternal notch to image and measure the descending aorta diameter and the velocity time integral using pulsed and continuous wave Doppler ultrasound in normal pregnant women between 11 and 39 weeks of gestation. These measurements were followed by computation of maternal left ventricular preload, afterload, contractility, and blood flow. STUDY DESIGN: This was a prospective cross-sectional study. A total of 400 pregnant women were recruited between 11 and 39 weeks of gestation. Imaging of the maternal aortic arch was performed by placing a cardiac probe in the suprasternal notch to identify the aortic arch using 2D and color Doppler ultrasound. The end-systolic diameter of the aorta was measured at the junction of the left subclavian artery with the descending aorta, which was followed by insonation of the descending aorta to obtain the Doppler waveform. Following insonation of the descending aorta, measurements of the aortic diameter, velocity time integral, ejection time, mean pressure gradient, heart rate, maternal weight and height, and systolic and diastolic blood pressures were entered into an Excel spreadsheet to compute the following: (1) preload measurements of stroke volume, stroke volume index, and stroke work index; (2) afterload measurements of systemic vascular resistance and the potential-to-kinetic energy ratio; (3) contractility measurements of inotropy and the Smith-Madigan inotropy index; and (4) blood flow measurements of cardiac output and the cardiac output index. Fractional polynomial regression analysis was performed for each of the above measurements using gestational age as the independent variable. RESULTS: The diastolic and mean arterial blood pressure decreased from 11 to 18 weeks of gestation and then increased until term. The afterload measurements demonstrated similar characteristics, as all values decreased from 11 weeks until the mid and late second trimester, after which all values increased until term. Changes in contractility demonstrated an increase from 11 weeks to 25 to 28 weeks, followed by a decline until term. Changes in blood flow demonstrated an increase from 11 to 27 weeks and then declined until term. The continuous wave Doppler values were greater than the pulsed Doppler values except for the contractility measurements. Examples of abnormal cardiac measurements were identified in pregnant patients with hypertension and fetal growth restriction. An Excel calculator was created to provide quick computation of z-score measurements and their corresponding centiles described in this study. CONCLUSION: The technique for evaluation of maternal cardiac function described in this study would allow screening of maternal left ventricular preload, afterload, contractility, and blood flow in the obstetrical clinical milieu once a cardiac probe is acquired for obstetrical ultrasound machines used for fetal evaluation. The above measurements would allow the clinician to select appropriate hypertensive medication on the basis of the results of the evaluation of the maternal left ventricle.

Perioperative changes in fluid distribution and haemodynamics in acute high-risk abdominal surgery.

BACKGROUND: Understanding the pathophysiology of fluid distribution in acute high-risk abdominal (AHA) surgery is essential in optimizing fluid management. There is currently no data on the time course and haemodynamic implications of fluid distribution in the perioperative period and the differences between the surgical pathologies. METHODS: Seventy-three patients undergoing surgery for intestinal obstruction, perforated viscus, and anastomotic leakage within a well-defined perioperative regime, including intraoperative goal-directed therapy, were included in this prospective, observational study. From 0 to 120 h, we measured body fluid volumes and hydration status by bioimpedance spectroscopy (BIA), fluid balance (input vs. output), preload dependency defined as a > 10% increase in stroke volume after preoperative fluid challenge, and post-operatively evaluated by passive leg raise. RESULTS: We observed a progressive increase in fluid balance and extracellular volume throughout the study, irrespective of surgical diagnosis. BIA measured variables indicated post-operative overhydration in 36% of the patients, increasing to 50% on the 5th post-operative day, coinciding with a progressive increase of preload dependency, from 12% immediately post-operatively to 58% on the 5th post-operative day and irrespective of surgical diagnosis. Patients with overhydration were less haemodynamically stable than those with normo- or dehydration. CONCLUSION: Despite increased fluid balance and extracellular volumes, preload dependency increased progressively during the post-operative period. Our observations indicate a post-operative physiological incoherence between changes in the extracellular volume compartment and inadequate physiological preload control in patients undergoing AHA surgery. Considering the increasing overhydration during the observational period, our findings show that an indiscriminate correction of preload dependency with intravenous fluid bolus could lead to overhydration. Trial registration clinicaltrials.gov. (NCT03997721), Registered 23 May 2019, first participant enrolled 01 June 2019.

Apple preload increased postprandial insulin sensitivity of a high glycemic rice meal only at breakfast.

PURPOSE: The possible impact of preload food on insulin sensitivity has yet been reported. This study aimed to investigate the glycemic and insulinemic effect of an apple preload before breakfast, lunch and early supper, based on high glycemic index (GI) rice meals. METHODS: Twenty-three healthy participants in Group 1 and 14 participants in Group 2 were served with the reference meal (white rice containing 50 g of available carbohydrate) or experimental meals (apple preload and rice, each containing 15 and 35 g of available carbohydrate). The meals were either served at 8:00 for breakfast, 12:30 for lunch or 17:00 for early supper to explore the possible effect of time factor. The group 1 assessed the postprandial and subsequent-meal glycemic effect of the test meals by continuous glucose monitoring (CGM), along with subjective appetite; The group 2 further investigated the glycemic and insulin effect by blood collection. RESULTS: The apple preload lowered the blood glucose peak value by 33.5%, 31.4% and 31.0% in breakfast, lunch and supper, respectively, while increased insulin sensitivity by 40.5% only at breakfast, compared with the rice reference. The early supper resulted significantly milder glycemic response than its breakfast and lunch counterparts did. The result of CGM tests was consistent with that of the fingertip blood tests. CONCLUSION: Apple preload performed the best at breakfast in terms of enhancing the insulin sensitivity. The preload treatment could effectively attenuate postprandial GR without increasing the area under insulin response curve in any of the three meals.

Detection of physiological control inputs preload and afterload from intrinsic pump parameters in total artificial heart.

BACKGROUND: In the total artificial heart (TAH), the inputs to the physiological control unit, preload, and afterload, are detected from intrinsic pump parameters (e.g., motor current). Within this study, their detection techniques are developed, and their reliability in pre- and afterload prediction is mapped for a broad range of cardiovascular system states. METHODS: We used ReinHeart TAH which is a fully implantable TAH with a plunger coil drive that is alternately emptying the left and right chambers. From the coil currents we first derived a force generated by the piston with respect to its position and then analyzed its pattern to detect (1) preload-chamber filling, found as piston position at begin ejection and (2) afterload-mean outflow pressures, determined as linearly calibrated average piston force during ejection. TAH is then integrated into a mock loop circulation (MLC) which is set to 135 different steady operating points varying in chamber filling (0%-100%, five steps), mean outflow pressures (system circulation: 60-90-120 mm Hg, pulmonary circulation: 15-30-45 mm Hg), and heart cycle duration (171-600 ms in seven non-equidistant steps). The detected preload and afterload are compared to MLC set values, and the errors are mapped. RESULTS: Respectively for the left and right chambers, the preload was detectable in 134 and 118 operating points and the mean error was ±3% and ±2%. The afterload was detectable in 135 and 87 operating points and the mean error was 37% and 30% respectively for left and right circulation. The operational points that are further away from homeostatic equilibrium values generally yielded larger errors. The largest errors were observed for right circulation at long cycle duration, low afterload, and low filling. CONCLUSIONS: The study yields reliable preload estimation in a broad range of physiological states, particularly for left circulation. Detection of afterload needs further improvements. The study revealed a need for piston movement optimization within the ReinHeart TAH during the early phase of systole.

Balancing the ventricular outputs of pulsatile total artificial hearts.

BACKGROUND: Maintaining balanced left and right cardiac outputs in a total artificial heart (TAH) is challenging due to the need for continuous adaptation to changing hemodynamic conditions. Proper balance in ventricular outputs of the left and right ventricles requires a preload-sensitive response and mechanisms to address the higher volumetric efficiency of the right ventricle. METHODS: This review provides a comprehensive overview of various methods used to balance left and right ventricular outputs in pulsatile total artificial hearts, categorized based on their actuation mechanism. RESULTS: Reported strategies include incorporating compliant materials and/or air cushions inside the ventricles, employing active control mechanisms to regulate ventricular filling state, and utilizing various shunts (such as hydraulic or intra-atrial shunts). Furthermore, reducing right ventricular stroke volume compared to the left often serves to balance the ventricular outputs. Individually controlled actuation of both ventricles in a pulsatile TAH seems to be the simplest and most effective way to achieve proper preload sensitivity and left-right output balance. Pneumatically actuated TAHs have the advantage to respond passively to preload changes. CONCLUSION: Therefore, a pneumatic TAH that comprises two individually actuated ventricles appears to be a more desirable option-both in terms of simplicity and efficacy-to respond to changing hemodynamic conditions.