Increased preload and echocardiographic assessment of diastolic function.

AIMS: Echocardiographic diastolic parameters are used to diagnose and monitor increased left ventricular filling pressure (LVFP) and we hypothesized that increased loading conditions cause increased E/e'. Our aim was to assess the effect of preload augmentation on diastolic parameters among both healthy subjects and subjects with known cardiac disease. METHODS AND RESULTS: We included 129 subjects merged from two cohorts; one dialysis cohort (n = 47) and one infusion cohort (n = 82). Echocardiography was performed immediately before and after hemodialysis (HD) or saline infusion, under low and high loading conditions. Elevated LVFP was defined as septal E/e' ≥ 15 and/or lateral E/e' ≥ 13 at high-loading conditions. The population was divided according to elevated LVFP (n = 31) and normal LVFP (n = 98). The load difference for the population was 972 ± 460 mL, with no differences in load difference between elevated and normal LVFP (p NS). The subjects with elevated LVFP were older (63 ± 11 vs. 46 ± 16 years, p < .001), and had lower LV ejection fraction (50 ± 14 vs. 59 ± 8.1%, p < .01). After augmented preload, EDV increased in the normal LVFP group (p < .01) but remained unchanged in the elevated LVFP group (p NS). Both E and e' increased among the subjects with normal LVFP, whereas E/e' remained unchanged (∆E/e' +.1 [-.5-1.2]), p NS). Among the subjects with elevated, LVFP we observed increased E but not e', resulting in significantly increased E/e' (∆ average E/e' +2.4 [0-4.0], p < .01). CONCLUSION: Augmented preload does not seem to affect E/e' among subjects with normal LVFP, whereas E/e' seems to increase significantly among subjects with elevated LVFP.

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.

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.

Preload responsiveness-guided fluid removal in mechanically ventilated patients with fluid overload: A comprehensive clinical-physiological study.

This study investigated fluid removal strategies for critically ill patients with fluid overload on mechanical ventilation. Traditionally, a negative fluid balance (FB) is aimed for. However, this approach can have drawbacks. Here, we compared a new approach, namely removing fluids until patients become fluid responsive (FR) to the traditional empiric negative balance approach. Twelve patients were placed in each group (n = 24). FR assessment was performed using passive leg raising (PLR). Both groups maintained stable blood pressure and heart function during fluid management. Notably, the FR group weaned from the ventilator significantly faster than negative FB group (both for a spontaneous breathing trial (14 h vs. 36 h, p = 0.031) and extubation (26 h vs. 57 h, p = 0.007); the difference in total ventilator time wasn't statistically significant (49 h vs. 62 h, p = 0.065). Additionally, FR group avoided metabolic problems like secondary alkalosis and potential hypokalemia seen in the negative FB group. FR-guided fluid-removal in fluid overloaded mechanically ventilated patients was a feasible, safe, and maybe superior strategy in facilitating weaning and disconnection from mechanical ventilation than negative FB-driven fluid removal. FR is a safe endpoint for optimizing cardiac function and preventing adverse consequences during fluid removal.

Seismocardiography and echocardiography: the correlation in the systolic complex.

Aim. This study aimed to investigate the correlation between seismocardiographic and echocardiographic systolic variables and whether a decrease in preload could be detected by the seismocardiography (SCG).Methods. This study included a total of 34 subjects. SCG and electrocardiography were recorded simultaneously followed by echocardiography (echo) in both supine and 30◦head-up tilted position. The SCG signals was segmented into individual heartbeats and systolic fiducial points were defined using a detection algorithm. Statistical analysis included correlation coefficient calculations and paired sample tests.Results. SCG was able to measure a decrease in preload by almost all of the examined systolic SCG variables. It was possible to correlate certain echo variables to SCG time intervals, amplitudes, and peak to peak intervals. Also, changes between supineand tilted position of some SCG variables were possible to correlate to changes in echo variables. LVET, IVCT, S', strain, SR, SV, and LVEF were significantly correlated to relevant SCG variables.Conclusion. This study showed a moderate correlation, between systolic echo and systolic SCG variables. Additionally, systolic SCG variables were able to detect a decrease in preload.

Plasma catecholamines in patients undergoing invasive cardiopulmonary exercise test for exercise intolerance.

BACKGROUND: Invasive cardiopulmonary exercise testing (iCPET) combines traditional cardiopulmonary exercise testing with invasive hemodynamic measurements to assess exercise intolerance, which can be caused by preload insufficiency (PI), characterized by low ventricular filling pressures and reduced cardiac output during exertion. We hypothesize that plasma catecholamine levels at rest and during exercise correlate with hemodynamic parameters in PI. METHODS: We included adult patients who underwent iCPET for exercise intolerance and had plasma catecholamines measured at rest and peak exercise. RESULTS: Among 84 patients, PI was identified in 57 (67.8 %). Compared to patients without PI, those with PI were younger [median (IQR) 37 (28, 46) vs 47 (39,55) years, p = 0.005] and had lower workload at peak exercise [81 (66, 96) vs 95 (83.5, 110.50) Watts, p = 0.006]. Patients with PI had higher heart rates at rest and peak exercise [87 (78, 97) vs 79 (74, 87) bpm, p = 0.04; and 167 (154, 183) vs 156 (136, 168) bpm, p = 0.01, respectively]. In all patients, epinephrine and norepinephrine at peak exercise directly correlated with peak workload (r:0.41, p < 0.001 and r:0.47, p < 0.001, respectively). Resting epinephrine was higher in patients with PI [136 (60, 210) vs 77 (41, 110) pg/mL, p = 0.02]. There was no significant difference in the change in catecholamines from rest to peak exercise between patients with or without PI. CONCLUSION: PI patients exhibited elevated heart rate and epinephrine at rest, indicating increased sympathetic activity. We did not find strong associations between catecholamines and cardiac filling pressures, suggesting that catecholamine levels are predominantly influenced by peak workload.

Comparison of Pressure vs Volume Overload Ventricular Wall Stress in Patients With Valvular Heart Disease.

BACKGROUND: Aortic stenosis (AS) and mitral regurgitation (MR) result in different patterns of left ventricular remodeling and hypertrophy. OBJECTIVES: We characterized left ventricular wall stress (LVWS) profiles in pressure and volume-overloaded systems, examined the relationship between baseline LVWS and cardiac remodeling, and assessed the acute effects of valve intervention on LVWS using invasive pressures combined with cardiac magnetic resonance (CMR) imaging measures of left ventricular volumes/mass. METHODS: A total of 47 patients with severe AS undergoing transcatheter aortic valve replacement (TAVR) and 15 patients with severe MR undergoing MitraClip (MC) underwent a 6-minute walk test (6MWT), transthoracic echocardiogram, and CMR before their procedures. Catheters in the left ventricle were used to record hemodynamic changes before and after valve/clip deployment. This was integrated with CMR data to calculate LVWS before and after intervention. RESULTS: The TAVR group demonstrated significant reductions in systolic LVWS post procedure (median 24.7 Pa [IQR: 14 Pa] pre vs median 17.3 Pa [IQR: 12 Pa] post; P < 0.001). The MC group demonstrated significant reductions in diastolic LVWS (median 6.4 Pa [IQR: 5 Pa] pre vs median 4.3 Pa [IQR: 4.1 Pa] post; P = 0.021) with no significant change in systolic LVWS (30.6 ±1.61 pre vs 33 ±2.47 Pa post; P = 0.16). There was an inverse correlation between baseline systolic LVWS and 6MWT in the TAVR group (r = -0.31; P = 0.04). CONCLUSIONS: TAVR results in significant reductions in systolic LVWS acutely. MC results in significant reductions in diastolic LVWS. Higher baseline systolic LVWS in TAVR is associated with shorter 6MWT suggesting that in AS, LVWS may be a useful marker of early decompensation.

Preload Influence on the Dynamic Properties of a Polyurethane Elastomeric Foam.

Polymeric foams are widely used in engineering applications for vibration attenuation. The foams usually work preloaded and it is known that the dynamic properties and attenuation ability of these polymers depend on the preload. In this paper, experimental characterization of a polyurethane elastomeric foam is performed in a frequency range between 1 and 60 Hz, a temperature range between -60 and 30 °C and a preload range between 2 and 12 N, using a Dynamic Mechanical Analyzer. When going from the minimum to the maximum preload, results show the linear viscoelastic range increases 57%. In the frequency sweeps, the storage modulus increases 58% on average, while the loss factor remains unaffected by preload. Moreover, the glassy transition temperature of the material decreases for greater preloads. From the curve-fitting of a four-parameter fractional derivative model using the experimental data, a seven-parameter mathematical model is developed, reducing the number of parameters needed to describe the influence of frequency and preload on the dynamic properties of the material. Hence, it has been established that the relaxation time, relaxed modulus and unrelaxed modulus depend on the exponential of the squared prestress. In contrast, the fractional parameter does not depend on preload for the range under study.

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.

Bias, trending ability and diagnostic performance of a non-calibrated multi-beat analysis continuous cardiac output monitor to identify fluid responsiveness in critically ill patients.

Objective: To evaluate the accuracy of non-calibrated multi-beat analysis continuous cardiac output (CCOMBA), against calibrated pulse-contour analysis continuous cardiac output (CCOPCA) during a passive leg raise (PLR) and/or a fluid challenge (FC). Design: Observational, single-centre, prospective study. Setting: Tertiary academic medical intensive care unit, Lyon, France. Participants: Adult patients receiving norepinephrine, monitored by CCOPCA, and in which a PLR and/or a FC was indicated. Main outcome measures: CCOMBA and CCOPCA were recorded prior to and during the PLR/FC to evaluate bias and evaluate changes in CCOMBA and CCOPCA (∆%CCOMBA and ∆%CCOPCA). Fluid responsiveness was identified by an increase >15% in calibrated cardiac output after FC, to identify the optimal ∆%CCOMBA threshold during PLR to predict fluid responsiveness. Results: 29 patients (median age 68 [IQR: 57-74]) performed 28 PLR and 16 FC. The bias between methods increased with higher CCOPCA values, with a percentage error of 64% (95%confidence interval: 52%-77%). ∆%CCOMBA adequately tracked changes in ∆%CCOPCA with an angular bias of 2 ± 29°. ∆%CCOMBA during PLR had an AUROC of 0.92 (P < 0.05), with an optimal threshold >14% to predict fluid responsiveness (sensitivity: 0.99, specificity: 0.87). Conclusions: CCOMBA showed a non-constant bias and a percentage error >30% against calibrated CCOPCA, but an adequate ability to track changes in CCOPCA and to predict fluid responsiveness.

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.

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.

Comparison of Left Ventricular End-Diastolic Volume Approximated from Mean Blood Pressure and Stroke Volume and End-Diastolic Volume Calculated from Left Ventricular-Aortic Coupling.

Objectives: The purpose of this study was to compare left ventricular end-diastolic volume (EDV), derived from left ventricular arterial coupling (Ees/Ea), and mean arterial blood pressure. Both of these methods of measuring EDV require some invasive procedure. However, the method of measuring EDV approximate is less invasive than the EDV coupling measuring method. This is because EDV approximate only requires arterial pressure waveform as an invasive procedure. Methods: This study included 14 patients with normal cardiac function who underwent general anesthesia. The point when blood pressure stabilized after the induction of anesthesia was taken as a baseline according to the study protocol. At the point when systolic arterial blood pressure fell 10% or more from the baseline blood pressure, 300 mL of colloid solution was administered over 15 min. EDV approximate and EDV coupling were calculated for each of the 14 patients at three points during the course of anesthetic. Each value was obtained by calculating a 5 min average. The timing of these three points was 5 min before, 5 min during, and 5 min after infusion loading. Results: The total number of comparable points was 42; 3 points were taken from each of the 14 participants. Both EDV approximate and EDV coupling increased through the infusion load testing. Scatter plots were prepared, and regression lines were calculated from the obtained values. A high correlation was shown between EDV approximate and EDV coupling (R2 = 0.96, p < 0.05). Conclusions: In patients with good cardiac function, EDV approximate can be substituted for EDV coupling, suggesting the possibility that EDV can be continuously and less invasively calculated under the situation of general anesthesia.

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.

Dynamic changes of hepatic vein Doppler velocities predict preload responsiveness in mechanically ventilated critically ill patients.

BACKGROUND: Assessment of dynamic parameters to guide fluid administration is one of the mainstays of current resuscitation strategies. Each test has its own limitations, but passive leg raising (PLR) has emerged as one of the most versatile preload responsiveness tests. However, it requires real-time cardiac output (CO) measurement either through advanced monitoring devices, which are not routinely available, or echocardiography, which is not always feasible. Analysis of the hepatic vein Doppler waveform change, a simpler ultrasound-based assessment, during a dynamic test such as PLR could be useful in predicting preload responsiveness. The objective of this study was to assess the diagnostic accuracy of hepatic vein Doppler S and D-wave velocities during PLR as a predictor of preload responsiveness. METHODS: Prospective observational study conducted in two medical-surgical ICUs in Chile. Patients in circulatory failure and connected to controlled mechanical ventilation were included from August to December 2023. A baseline ultrasound assessment of cardiac function was performed. Then, simultaneously, ultrasound measurements of hepatic vein Doppler S and D waves and cardiac output by continuous pulse contour analysis device were performed during a PLR maneuver. RESULTS: Thirty-seven patients were analyzed. 63% of the patients were preload responsive defined by a 10% increase in CO after passive leg raising. A 20% increase in the maximum S wave velocity after PLR showed the best diagnostic accuracy with a sensitivity of 69.6% (49.1-84.4) and specificity of 92.8 (68.5-99.6) to detect preload responsiveness, with an area under curve of receiving operator characteristic (AUC-ROC) of 0.82 ± 0.07 (p = 0.001 vs. AUC-ROC of 0.5). D-wave velocities showed worse diagnostic accuracy. CONCLUSIONS: Hepatic vein Doppler assessment emerges as a novel complementary technique with adequate predictive capacity to identify preload responsiveness in patients in mechanical ventilation and circulatory failure. This technique could become valuable in scenarios of basic hemodynamic monitoring and when echocardiography is not feasible. Future studies should confirm these results.

Endurance Training Provokes Arrhythmogenic Right Ventricular Cardiomyopathy Phenotype in Heterozygous Desmoglein-2 Mutants: Alleviation by Preload Reduction.

Desmoglein-2 mutations are detected in 5-10% of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). Endurance training accelerates the development of the ARVC phenotype, leading to earlier arrhythmic events. Homozygous Dsg2 mutant mice develop a severe ARVC-like phenotype. The phenotype of heterozygous mutant (Dsg2mt/wt) or haploinsufficient (Dsg20/wt) mice is still not well understood. To assess the effects of age and endurance swim training, we studied cardiac morphology and function in sedentary one-year-old Dsg2mt/wt and Dsg20/wt mice and in young Dsg2mt/wt mice exposed to endurance swim training. Cardiac structure was only occasionally affected in aged Dsg20/wt and Dsg2mt/wt mice manifesting as small fibrotic foci and displacement of Connexin 43. Endurance swim training increased the right ventricular (RV) diameter and decreased RV function in Dsg2mt/wt mice but not in wild types. Dsg2mt/wt hearts showed increased ventricular activation times and pacing-induced ventricular arrhythmia without obvious fibrosis or inflammation. Preload-reducing therapy during training prevented RV enlargement and alleviated the electrophysiological phenotype. Taken together, endurance swim training induced features of ARVC in young adult Dsg2mt/wt mice. Prolonged ventricular activation times in the hearts of trained Dsg2mt/wt mice are therefore a potential mechanism for increased arrhythmia risk. Preload-reducing therapy prevented training-induced ARVC phenotype pointing to beneficial treatment options in human patients.

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.