From Benchtop to Beside: Patient-specific Outcomes Explained by Invitro Experiment

Study: Recent analyses show that females have higher early postoperative (PO) mortality and right ventricular failure (RVF) than males after left ventricular assist device (LVAD) implantation; and that this association is partially mediated by smaller LV size in females. Benchtop experiments allow us to investigate patient-specific (PS) characteristics in a reproducible way given the fact that the PS anatomy and physiology is mimicked accurately. With multiple heart models of varying LV size, we can directly study the individual effects of titrating the LVAD speed and the resulting bi-ventricular volumes, shedding light on the interplay between LV and RV as well as resulting inter-ventricular septum (IVS) positions, which may cause the different outcomes pertaining to sex. Methods: In vitro, we studied the impact of the heart size to IVS position using two smaller and two larger sized PS silicone heart phantoms derived from clinical CT images (Fig. 1A). With ultrasound crystals that were integrated on a placeholder inflow cannula, the IVS position was measured during LV and RV volume changes (dV) mimicking varying ventricular loading states (Fig. 1B). Figure 1 A Two small (blue) and two large PS heart phantoms (orange) on B benchtop. C Median septum curvature results. LVEDD/LVV/RVV: LV enddiastolic diameter/LV and RV volume. Results: Going from small to large dV, at zero curvature, the septum starts to shift towards the left; for smaller hearts at dV = -40 mL and for larger hearts at dV = -50 mL (Fig. 1C). This result indicates that smaller hearts are more prone to an IVS shift to the left than larger hearts. We conclude that smaller LV size may therefore mediate increased early PO LVAD mortality and RVF observed in females compared to males. Novel 3D silicone printing technology enables us to study accurate, PS heart models across a heterogeneous patient population. PS relationships can be studied simultaneously to clinical assessments and support the decision-making prior to LVAD implantation

Measurement Principles for a real-time Cardiac Volume Sensor

Patients suffering from heart failure cannot provide sufficient cardiac output for organ perfusion, such that effective medical treatment is required. Three therapies for the treatment of heart failure have been clinically established: pharmacological treatment, heart transplantation, and implantation of a left-ventricular assist device (LVAD). Despite the efficacy of these therapies, survival rates remain unsatisfactorily low. The continuous monitoring of hemodynamic parameters can improve survival, as it supports timely and effective clinical decision making. The hemodynamics of the healthy heart are very sensitive to the left-ventricular (LV) volume. Hence, the LV volume is a promising hemodynamic parameter for clinical decision making. In addition, an LV volume measurement could be used for physiological feedback control of an LVAD, presumably increasing his or her quality of life and reducing the probability of adverse events. The aim of this thesis was to identify key requirements for an LV volume sensor, investigate possible measurement principles and evaluate the three most promising sensor concepts in terms of their sensitivity and accuracy. The LV volume cannot easily be measured remotely, because the requirements for a real-time portable sensor are highly complex. An LV volume sensor needs to be implemented in such a way that traumatic injury is avoided and the areas of foreign surfaces in the body are not increased. The sensor should be small enough to be safely implanted or attached to the body surface. The LV volume measurement should be continuous and robust to changes in heart geometry, posture or hematocrit. Computer tomography, magnetic resonance imaging, various forms of impedance measurement, pressure measurement, echocardiography and strain sensors have been proposed to estimate the LV volume. However, none of them meets all of the above requirements. An implantable, biocompatible and robust LV volume sensor remains to be developed. Three concepts for the real-time LV volume measurement are proposed in this thesis: Acoustic resonance, ultrasonic distance and the QRS amplitude of the electrocardiogram. The concepts were evaluated in a testing environment suitable to their current stage of development: in-silico, in-vitro, in-vivo and in the setting of an experimental clinical study. All measurement priniciples were sensitive to the LV volume. The achievable LV volume accuracies were assessed using a Bland-Altman analysis. The accuracies for the acoustic concept could not be evaluated as the principle was only assessed in-silico and lacked the possibility to account for noise. The ultrasonic distance approach yielded estimation accuracies for the LV volume smaller than 20% in human heart phantoms in vitro. The QRS-amplitude in vivo measurement rendered LV volume estimation accuracies smaller than 20%. The experimental clinical study revealed a small, but significant correlation between the QRS amplitude on the body surface and the mean pulmonary arterial pressure. The three concepts presented are all atraumatic, small enough, capable of real-time measurement and should be sufficiently robust as they can be placed close to the heart. The QRS amplitude is the most promising concept to be implemented in the near future, particularly because of the electrode size. The ultrasonic distance measurement is equally convincing in terms of accuracy, but requires more effort for miniaturization and efficient data processing. The influence of hematocrit changes on both measurement principles should be investigated carefully in subsequent studies. In conclusion, continuous measurement of LV volume is possible and will likely increase survival rates in heart failure patients in the future

Spontaneous Cardiac-Locomotor Coupling in Healthy Individuals During Daily Activities

During exercise, the locomotor and the cardiovascular system work in synergy to control the blood flow through the body. In particular, the muscle contraction generates rhythmic raising and lowering of intramuscular pressure, which in synergy supports cardiovascular function. This study aims to analyze spontaneous cardiac-locomotor coupling (CLC) events during daily activities using weareable sensors. We analyze the dataset PMData, containing recordings from sixteen healthy subjects during five months. The data were acquired with a smartwatch and consist of step rate (SR), heart rate (HR) and daily surveys reporting the training sessions. Coupling is defined as being present when SR and HR are within 1% of each other (strong coupling) and within the 10% of each other (weak coupling). The results show that every subject presents occurrences of CLC while performing normal daily activities. In particular, strong coupling occurs more likely for longer activities (111 ± 34 min), at moderate intensity (100 steps/min &lt; SR &gt; 130 steps/min). The presence of CLC during daily activities rises the question whether there is a physiological mechanism controlling this phenomenon, that should be investigated in future.QC 20230608</p

Does Size Matter for Female Continuous-flow LVAD Recipients? A Translational Approach to a Decade Long Question

Females have increased risk of right-ventricular failure (RVF) and 3 month mortality after left-ventricular assist device (LVAD) implantation. In this translational study, we tested the hypothesis that sex differences in outcomes are driven by pump-induced LV size-volume mismatch, due to a negative impact on interventricular septal (IVS) interdependence. Adult continuous-flow LVAD recipients from the International Society For Heart And Lung Transplantation Mechanically Assisted Circulatory Support registry (n = 15,498) were studied to determine association of female sex with outcomes of 3 month mortality and RVF. Female sex was associated with smaller preimplant left-ventricular end-diastolic diameter (6.5 vs. 6.9 cm, p \u3c 0.001), increased 3 month mortality (odds ratio [OR]: 1.42, p \u3c 0.001) and RVF (OR: 1.18, p = 0.005). Smaller left-ventricular end-diastolic diameter was associated with worse outcomes after LVAD implantation (OR for mortality: 1.20, p \u3c 0.001; RVF: 1.09, p \u3c 0.001), and attenuated the association of female sex with these outcomes. In test bench heart phantoms (n = 4), the IVSs of smaller hearts demonstrated abnormal leftward shift earlier than larger hearts (volume change at IVS shift: 40 [95% confidence interval: 30-52] vs. 50 [95% confidence interval: 48-69] ml). Smaller LV size partially mediates worse post-LVAD outcomes for female patients, due to lower volume thresholds for adverse IVS shifting

Decoupling Transmission and Transduction for Improved Durability of Highly Stretchable, Soft Strain Sensing: Applications in Human Health Monitoring

This work presents a modular approach to the development of strain sensors for large deformations. The proposed method separates the extension and signal transduction mechanisms using a soft, elastomeric transmission and a high-sensitivity microelectromechanical system (MEMS) transducer. By separating the transmission and transduction, they can be optimized independently for application-specific mechanical and electrical performance. This work investigates the potential of this approach for human health monitoring as an implantable cardiac strain sensor for measuring global longitudinal strain (GLS). The durability of the sensor was evaluated by conducting cyclic loading tests over one million cycles, and the results showed negligible drift. To account for hysteresis and frequency-dependent effects, a lumped-parameter model was developed to represent the viscoelastic behavior of the sensor. Multiple model orders were considered and compared using validation and test data sets that mimic physiologically relevant dynamics. Results support the choice of a second-order model, which reduces error by 73% compared to a linear calibration. In addition, we evaluated the suitability of this sensor for the proposed application by demonstrating its ability to operate on compliant, curved surfaces. The effects of friction and boundary conditions are also empirically assessed and discussed

Real-Time Ventricular Volume Measured Using the Intracardiac Electromyogram

Left ventricular end-diastolic volume (EDV) is an important parameter for monitoring patients with left ventricular assist devices (LVADs) and might be useful for automatic LVAD work adaptation. However, continuous information on the EDV is unavailable to date. The depolarization amplitude (DA) of the noncontact intracardiac electromyogram (iEMG) is physically related to the EDV. Here, we show how a left ventricular (LV) volume sensor based on the iEMG might provide beat-wise EDV estimates. The study was performed in six pigs while undergoing a series of controlled changes in hemodynamic states. The LV volume sensor consisted of four conventional pacemaker electrodes measuring the far-field iEMG inside the LV blood pool, using a novel unipolar amplifier. Simultaneously, noninvasive measurements of EDV and hematocrit were recorded. The proposed EDV predictor was tested for statistical significance using a mixed-effect model and associated confidence intervals. A statistically significant (p = 3e–07) negative correlation was confirmed between the DA of the iEMG and the EDV as measured by electric impedance at a slope of –0.069 (–0.089, –0.049) mV/mL. The DA was slightly decreased by increased hematocrit (p = 0.039) and moderately decreased with the opening of the thorax (p = 0.003). The DA of the iEMG proved to be a significant, independent predictor of EDV. The proposed LV volume sensor is simple to integrate into the inflow cannula of an LVAD and thus has the potential to inform the clinician about the state of LV volume in real time and to automatically control the LVAD.ISSN:1058-2916ISSN:1538-943

Right Ventricular Function and T1‐Mapping in Boys With Duchenne Muscular Dystrophy

BackgroundClinical management of boys with Duchenne muscular dystrophy (DMD) relies on in-depth understanding of cardiac involvement, but right ventricular (RV) structural and functional remodeling remains understudied.PurposeTo evaluate several analysis methods and identify the most reliable one to measure RV pre- and postcontrast T1 (RV-T1) and to characterize myocardial remodeling in the RV of boys with DMD.Study typeProspective.PopulationBoys with DMD (N&nbsp;=&nbsp;27) and age-/sex-matched healthy controls (N&nbsp;=&nbsp;17) from two sites.Field strength/sequence3.0 T using balanced steady state free precession, motion-corrected phase sensitive inversion recovery and modified Look-Locker inversion recovery sequences.AssessmentBiventricular mass (Mi), end-diastolic volume (EDVi) and ejection fraction (EF) assessment, tricuspid annular excursion (TAE), late gadolinium enhancement (LGE), pre- and postcontrast myocardial T1 maps. The RV-T1 reliability was assessed by three observers in four different RV regions of interest (ROI) using intraclass correlation (ICC).Statistical testsThe Wilcoxon rank sum test was used to compare RV-T1 differences between DMD boys with negative LGE(-) or positive LGE(+) and healthy controls. Additionally, correlation of precontrast RV-T1 with functional measures was performed. A P-value &lt;0.05 was considered statistically significant.ResultsA 1-pixel thick RV circumferential ROI proved most reliable (ICC &gt; 0.91) for assessing RV-T1. Precontrast RV-T1 was significantly higher in boys with DMD compared to controls. Both LGE(-) and LGE(+) boys had significantly elevated precontrast RV-T1 compared to controls (1543 [1489-1597] msec and 1550 [1402-1699] msec vs. 1436 [1399-1473] msec, respectively). Compared to healthy controls, boys with DMD had preserved RVEF (51.8 [9.9]% vs. 54.2 [7.2]%, P&nbsp;=&nbsp;0.31) and significantly reduced RVMi (29.8 [9.7]&nbsp;g vs. 48.0 [15.7]&nbsp;g), RVEDVi (69.8 [29.7]&nbsp;mL/m2 vs. 89.1 [21.9]&nbsp;mL/m2 ), and TAE (22.0 [3.2]&nbsp;cm vs. 26.0 [4.7]&nbsp;cm). Significant correlations were found between precontrast RV-T1 and RVEF (β&nbsp;=&nbsp;-0.48%/msec) and between LV-T1 and LVEF (β&nbsp;=&nbsp;-0.51%/msec).Data conclusionPrecontrast RV-T1 is elevated in boys with DMD compared to healthy controls and is negatively correlated with RVEF.Level of evidence1 TECHNICAL EFFICACY: Stage 2

Elucidating tricuspid Doppler signal interpolation and its implication for assessing pulmonary hypertension

Doppler echocardiography plays a central role in the assessment of pulmonary hypertension (PAH). We aim to improve quality assessment of systolic pulmonary arterial pressure (SPAP) by applying a cubic polynomial interpolation to digitized tricuspid regurgitation (TR) waveforms. Patients with PAH and advanced lung disease were divided into three cohorts: a derivation cohort (n = 44), a validation cohort (n = 71), an outlier cohort (n = 26), and a non-PAH cohort (n = 44). We digitized TR waveforms and analyzed normalized duration, skewness, kurtosis, and first and second derivatives of pressure. Cubic polynomial interpolation was applied to three physiology-driven phases: the isovolumic phase, ejection phase, and “shoulder” point phase. Coefficients of determination and a Bland−Altman analysis was used to assess bias between methods. The cubic polynomial interpolation of the TR waveform correlated strongly with expert read right ventricular systolic pressure (RVSP) with R2 &gt; 0.910 in the validation cohort. The biases when compared to invasive SPAP measured within 24 h were 6.03 [4.33; 7.73], −2.94 [1.47; 4.41], and −3.11 [−4.52; −1.71] mmHg, for isovolumic, ejection, and shoulder point interpolations, respectively. In the outlier cohort with more than 30% difference between echocardiographic estimates and invasive SPAP, cubic polynomial interpolation significantly reduced underestimation of RVSP. Cubic polynomial interpolation of the TR waveform based on isovolumic or early ejection phase may improve RVSP estimates.QC 20230607</p