A Machine Learning-Derived Score to Effectively Identify Heart Failure With Preserved Ejection Fraction.

Background: The diagnosis of heart failure with preserved ejection fraction (HFpEF) in the clinical setting remains challenging, especially in patients with obesity. Objectives: This study aimed to identify novel predictors of HFpEF well suited for patients with obesity. Methods: We performed a retrospective analysis of a well-characterized cohort of patients with obesity with HFpEF (n = 404; mean body mass index [BMI] 36.6 kg/m2) and controls (n = 67). We used the machine learning algorithm Gradient Boosting Machine to analyze the association of various parameters with the diagnosis of HFpEF and subsequently created a multivariate logistic model for the diagnosis. Results: Gradient Boosting Machine identified BMI, estimated glomerular filtration rate, left ventricular mass index, and left atrial to left ventricular volume ratio as the strongest predictors of HFpEF. These variables were used to build a model that identified HFpEF with a sensitivity of 0.83, a specificity of 0.82, and an area under the curve (AUC) of 0.88. Internal validation of the model with optimism-adjusted AUC showed an AUC of 0.87. Within the studied cohort, the novel score outperformed the H2FPEF score (AUC: 0.88 vs 0.74; P < 0.001). Conclusions: In a HFpEF cohort with obesity, BMI, estimated glomerular filtration rate, left ventricular mass index, and left atrial to left ventricular volume ratio most correlated with the identification of HFpEF, and a score based on these variables (HFpEF-JH score) outperformed the currently used H2PEF score. Further validation of this novel score is warranted, as it may facilitate improved diagnostic accuracy of HFpEF, particularly in patients with obesity.

Race and Socioeconomic Status Impact Diagnosis and Clinical Outcomes in Transthyretin Cardiac Amyloidosis.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is associated with significant mortality. The Val122Ile variant, highly prevalent in Black patients, portends poorer survival compared with other ATTR-CM subtypes. Although Val122Ile is biologically more aggressive, the contribution of race and socioeconomic status (SES) to disease outcomes in patients with ATTR-CM is undefined. Objectives: The aim of this study was to evaluate the impact of race and SES on clinical outcomes in patients with ATTR-CM. Methods: Patients with ATTR-CM who received care at Johns Hopkins Hospital between 2006 and 2022 were included. SES was assessed using area deprivation index (ADI). Associations of race and ADI with heart failure (HF) hospitalization and/or death were measured using multivariable logistic or Cox proportional hazards models. Results: Of 282 patients, 225 (80%) were men, and 129 (46%) were Black. Black vs White patients disproportionately constituted the highest ADI (most deprived) category (66% vs 28%; P = 0.004), and Black patients were more likely to have HF hospitalization or death over 5 years compared with White patients (log-rank P < 0.001). Among those with ADI >25, Black patients had a significantly greater hazard of HF hospitalization or death compared with White patients, independent of disease stage at diagnosis (HR: 2.77; 95% CI: 1.45-5.32; P = 0.002). Conclusions: Black patients with low SES may be at greater risk for underdiagnosis and adverse outcomes compared with White patients. Ongoing efforts are needed to improve outcomes in this subset of patients with ATTR-CM.

Poor cardiac output reserve in pulmonary arterial hypertension is associated with right ventricular stiffness and impaired interventricular dependence.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterised by poor exercise tolerance. The contribution of right ventricular (RV) diastolic function to the augmentation of cardiac output during exercise is not known. This study leverages pressure-volume (P-V) loop analysis to characterise the impact of RV diastology on poor flow augmentation during exercise in PAH. METHODS: RV P-V loops were measured in 41 PAH patients at rest and during supine bike exercise. Patients were stratified by median change in cardiac index (CI) during exercise into two groups: high and low CI reserve. Indices of diastolic function (end-diastolic elastance (E ed)) and ventricular interdependence (left ventricular transmural pressure (LVTMP)) were compared at matched exercise stages. RESULTS: Compared to patients with high CI reserve, those with low reserve exhibited lower exercise stroke volume (36 versus 49 mL·m-2; p=0.0001), with higher associated exercise afterload (effective arterial elastance (E a) 1.76 versus 0.90 mmHg·mL-1; p<0.0001), RV stiffness (E ed 0.68 versus 0.26 mmHg·mL-1; p=0.003) and right-sided pressures (right atrial pressure 14 versus 8 mmHg; p=0.002). Higher right-sided pressures led to significantly lower LV filling among the low CI reserve subjects (LVTMP -4.6 versus 3.2 mmHg; p=0.0001). Interestingly, low exercise flow reserve correlated significantly with high afterload and RV stiffness, but not with RV contractility nor RV-PA coupling. CONCLUSIONS: Patients with poor exercise CI reserve exhibit poor exercise RV afterload, stiffness and right-sided filling pressures that depress LV filling and stroke work. High afterload and RV stiffness were the best correlates to low flow reserve in PAH. Exercise unmasked significant pathophysiological PAH differences unapparent at rest.

A mathematical model of tissue axial and radial diffusion in the microvasculature for intravascular microscopy and phosphorescence quenching data.

This study aims to extend earlier Krogh Cylinder Models of an oxygen profile by considering axial diffusion and analytically solving Fick's Law Partial Differential Equation with novel boundary conditions via the separation of variables. We next prospectively collected a total of 20 animals, which were randomly assigned to receive either fresh or two-week-old stored red blood cell (RBC) transfusions and PQM oxygen data were measured acutely (90 min) or chronically (24 h). Transfusion effects were evaluated in vivo using intravital microscopy of the dorsal skinfold window chamber in Golden Syrian Hamsters. Hamsters were initially hemorrhaged by 50% of total blood volume and resuscitated 1-h post hemorrhage. PQM data were subsequently collected and fit the derived 2D Krogh cylinder model. Systemic hemodynamics (mean arterial pressure, heart rate) were similar in both pre and post-transfusion with either stored or fresh cells. Transfusion with stored cells was found to impair axial and radial oxygen gradients as quantified by our model and consistent with previous studies. Specifically, we observed a statistically significant decrease in the arteriolar tissue radial oxygen gradient after transfusion with stored RBCs at 24 h compared with fresh RBCs (0.33 ± 0.17 mmHg µ m-1 vs, 0.14 ± 0.12 mmHg µ m-1; p = 0.0280). We also observed a deficit in the arteriolar tissue oxygen gradient (0.03 ± 0.01 mmHg µ m-1 fresh vs. 0.018 ± 0.007 mmHg µ m-1 stored; p = 0.0185). We successfully derived and validated an analytical 2D Krogh cylinder model in an animal model of microhemodynamic oxygen diffusion aberration secondary to storage lesions.

Optimal Method for Assessing Right Ventricular to Pulmonary Arterial Coupling in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

Right ventricular (RV) to pulmonary arterial (PA) coupling describes the ability of the RV to augment contractility in response to increased afterload. Several echocardiographic indexes of RV-PA coupling have been defined; however, the optimal numerator in the coupling ratio is unclear. We sought to establish which of these ratios is best for assessing RV-PA coupling based on their relations with 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the Kansas City Cardiomyopathy Questionnaire (KCCQ) in aging adults. In this study of 1,611 Multi-Ethnic Study of Atherosclerosis participants who underwent echocardiography at Exam 6, we evaluated the association between different numerators, including tricuspid annular planar systolic excursion (TAPSE), fractional area change (FAC), RV free wall strain, and tissue Doppler imaging S' velocity to pulmonary artery systolic pressure (PASP) with 6MWD, NT-proBNP, and KCCQ score, adjusted for socioeconomic and cardiovascular disease risk factors. Our cohort had a mean age of 73 ± 8 years, 54% female, 17% Chinese American, 22% African American, 22% Hispanic, and 39% White participants. The mean ( ± SD) TAPSE/PASP, FAC/PASP, tissue Doppler imaging S' velocity/PASP, and RV free wall strain:PASP ratios were 0.7 ± 0.2, 1.3 ± 0.3, 0.5 ± 0.1, and 0.8 ± 0.2, respectively. All RV-PA coupling indices decreased with age (p <0.0001 for all). TAPSE:PASP ratio was lower in older (³85 years) female (0.59 ± 0.14) versus male (0.65 ± 0.17) participants (p = 0.01), whereas FAC/PASP ratio was higher in the same female versus male participants (p <0.01). TAPSE/PASP and FAC/PASP ratios were significantly and strongly associated with all NT-proBNP, 6MWD, and KCCQ scores in fully adjusted and receiver operating characteristic analysis. In older community-dwelling adults free of heart failure and pulmonary hypertension, both FAC/PASP and TAPSE:PASP ratios are optimal for assessment of RV-PA coupling based on its association with 6MWD, NT-proBNP, and KCCQ score. FAC/PASP ratio has the additional benefit of reflecting age and gender-related geometric and functional changes.

Neonates and Infants with Left Heart Obstruction and Borderline Left Ventricle Undergoing Biventricular Repair: What Do We Know about Long-Term Outcomes? A Critical Review.

BACKGROUND: The decision to perform biventricular repair (BVR) in neonates and infants presenting with either single or multiple left ventricle outflow obstructions (LVOTOs) and a borderline left ventricle (BLV) is subject to extensive discussion, and limited information is known regarding the long-term outcomes. As a result, the objective of this study is to critically assess and summarize the available data regarding the prognosis of neonates and infants with LVOTO and BLV who underwent BVR. METHODS: In February 2023, we conducted a review study with three different medical search engines (the National Library of Medicine, Science Direct, and Cochrane Library) for Medical Subject Headings and free text terms including "congenital heart disease", "outcome", and "borderline left ventricle". The search was refined by adding keywords for "Shone's complex", "complex LVOT obstruction", "hypoplastic left heart syndrome/complex", and "critical aortic stenosis". RESULTS: Out of a total of 51 studies, 15 studies were included in the final analysis. The authors utilized heterogeneous definitions to characterize BLV, resulting in considerable variation in inclusion criteria among studies. Three distinct categories of studies were identified, encompassing those specifically designed to evaluate BLV, those focused on Shone's complex, and finally those on aortic stenosis. Despite the challenges associated with comparing data originating from slightly different cardiac defects and from different eras, our results indicate a favorable survival rate and clinical outcome following BVR. However, the incidence of reintervention remains high, and concerns persist regarding residual pulmonary hypertension, which has been inadequately investigated. CONCLUSIONS: The available data concerning neonates and infants with LVOTO and BLV who undergo BVR are inadequate and fragmented. Consequently, large-scale studies are necessary to fully ascertain the long-term outcome of these complex defects.

The structural OFF and ON states of myosin can be decoupled from the biochemical super- and disordered-relaxed states.

There is a growing awareness that both thick-filament and classical thin-filament regulations play central roles in modulating muscle contraction. Myosin ATPase assays have demonstrated that under relaxed conditions, myosin may reside either in a high-energy-consuming disordered-relaxed (DRX) state available for binding actin to generate force or in an energy-sparing super-relaxed (SRX) state unavailable for actin binding. X-ray diffraction studies have shown that the majority of myosin heads are in a quasi-helically ordered OFF state in a resting muscle and that this helical ordering is lost when myosin heads are turned ON for contraction. It has been assumed that myosin heads in SRX and DRX states are equivalent to the OFF and ON states, respectively, and the terms have been used interchangeably. In this study, we use X-ray diffraction and ATP turnover assays to track the structural and biochemical transitions of myosin heads, respectively, induced with either omecamtiv mecarbil (OM) or piperine in relaxed porcine myocardium. We find that while OM and piperine induce dramatic shifts of myosin heads from the OFF to the ON state, there are no appreciable changes in the population of myosin heads in the SRX and DRX states in both unloaded and loaded preparations. Our results show that biochemically defined SRX and DRX can be decoupled from structurally defined OFF and ON states. In summary, while SRX/DRX and OFF/ON transitions can be correlated in some cases, these two phenomena are measured using different approaches, reflect different properties of the thick filament, and should be investigated and interpreted separately.

Deep learning for automatic volumetric segmentation of left ventricular myocardium and ischaemic scar from multi-slice late gadolinium enhancement cardiovascular magnetic resonance.

AIMS: This study details application of deep learning for automatic volumetric segmentation of left ventricular (LV) myocardium and scar and automated quantification of myocardial ischaemic scar burden from late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR). METHODS AND RESULTS: We included 501 images and manual segmentations of short-axis LGE-CMR from over 20 multinational sites, from which 377 studies were used for training and 124 studies from unique participants for internal validation. A third test set of 52 images was used for external evaluation. Three models, U-Net, Cascaded U-Net, and U-Net++, were trained with a novel adaptive weighted categorical cross-entropy loss function. Model performance was evaluated using concordance correlation coefficients (CCCs) for LV mass and per cent myocardial scar burden. Cascaded U-Net was found to be the best model for the quantification of LV mass and scar percentage. The model exhibited a mean difference of -5 ± 23 g for LV mass, -0.4 ± 11.2 g for scar mass, and -0.8 ± 7% for per cent scar. CCC were 0.87, 0.77, and 0.78 for LV mass, scar mass, and per cent scar burden, respectively, in the internal validation set and 0.75, 0.71, and 0.69, respectively, in the external test set. For segmental scar mass, CCC was 0.74 for apical scar, 0.91 for mid-ventricular scar, and 0.73 for basal scar, demonstrating moderate to strong agreement. CONCLUSION: We successfully trained a convolutional neural network for volumetric segmentation and analysis of LV scar burden from LGE-CMR images in a large, multinational cohort of participants with ischaemic scar.

The structural OFF and ON states of myosin can be decoupled from the biochemical super-relaxed and disordered-relaxed states.

There is a growing awareness that both thick filament and classical thin filament regulation play central roles in modulating muscle contraction. Myosin ATPase assays have demonstrated that under relaxed conditions, myosin may reside in either a high energy-consuming disordered-relaxed (DRX) state available for binding actin to generate force, or in an energy-sparing super-relaxed (SRX) state unavailable for actin binding. X-ray diffraction studies have shown the majority of myosin heads are in a quasi-helically ordered OFF state in a resting muscle and that this helical ordering is lost when myosin heads are turned ON for contraction. It has been assumed that myosin heads in SRX and DRX states are equivalent to the OFF and ON state respectively and the terms have been used interchangeably. Here, we use X-ray diffraction and ATP turnover assays to track the structural and biochemical transitions of myosin heads respectively induced with either omecamtiv mecarbil (OM) or piperine in relaxed porcine myocardium. We find that while OM and piperine induce dramatic shifts of myosin heads from the OFF to ON states, there are no appreciable changes in the population of myosin heads in the SRX and DRX states in both unloaded and loaded preparations. Our results show that biochemically defined SRX and DRX can be decoupled from structurally-defined OFF and ON states. In summary, while SRX/DRX and OFF/ON transitions can be correlated in some cases, these two phenomena are measured using different approaches, do not necessarily reflect the same properties of the thick filament and should be investigated and interpreted separately.

Semi-automated quantification of tricuspid valve dynamics and structure in tetralogy of Fallot and hypoplastic left heart syndrome using three-dimensional echocardiography.

Anomalies of the tricuspid valve (TV) are associated with worsened prognosis in congenital heart disease (CHD). Here, we present a descriptive study examining changes in TV morphology in two CHD conditions-repaired tetralogy of Fallot (rTOF) and hypoplastic left heart syndrome (HLSH), using three-dimensional echocardiography. Full volume acquisitions of the TV and right ventricle (RV) were performed from an RV-focused apical view using ECG gating over 2-5 consecutive cardiac cycles using 3D echocardiography, from which TV annulus and leaflet parameters were quantified. A total of 40 rTOF patients (age 14 ± 9.8 years), 40 HLHS patients (age1.0 ± 1.5 years) and 80 age and gender matched controls were included. Among leaflet parameters, antero-posterior and posterior-septal TV coaptation heights were smaller in rTOF (p < 0.001) vs. control. Conversely, only the short-axis TV height was different in HLHS vs. controls (HLHS 1.6 ± 0.4 cm vs. control 1.4 ± 0.3 cm). TV leaflet parameters tended to be larger in HLHS, while leaflet coaptation distances were similar between groups. We demonstrate that 3D echocardiography for assessment of the TV is feasible in rTOF and HLHS patients and identifies unique differences in TV morphology. Future studies should clarify the clinical significance of TV morphology in these patient populations.

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure With Pulmonary Hypertension.

BACKGROUND: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in patients with heart failure with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. We thus sought to characterize RV myocyte contractile depression in HFrEF-PH, identify those components reflected by clinical RV indices, and uncover underlying biophysical mechanisms. METHODS: Resting, calcium-, and load-dependent mechanics were prospectively studied in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 patients with HFrEF-PH undergoing cardiac transplantation and 9 organ donor controls. RESULTS: Unsupervised machine learning using myocyte mechanical data with the highest variance yielded 2 HFrEF-PH subgroups that in turn mapped to patients with decompensated or compensated clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in decompensated clinical RV function, whereas surprisingly, many other major myocyte contractile measures including peak power and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick filament defects, myofibrillar structure was assessed by x-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in decompensated clinical RV function, but not compensated clinical RV function, as compared with controls. This corresponded to reduced myosin ATP turnover in decompensated clinical RV function myocytes, indicating less myosin in a crossbridge-ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Last, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human heart failure. CONCLUSIONS: Although there are many RV myocyte contractile deficits in HFrEF-PH, commonly used clinical indices only detect reduced isometric calcium-stimulated force, which is related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.

Prony Analysis of Left Ventricle Pressure and Volume.

Direct measurement of cardiac pressure-volume (PV) relationships is the gold standard for assessment of ventricular hemodynamics, but few innovations have been made to "multi-beat" PV analysis beyond traditional signal processing. The Prony method solves the signal recovery problem with a series of dampened exponentials or sinusoids. It achieves this by extracting the amplitude, frequency, dampening, and phase of each component. Since its inception, application of the Prony method to biologic and medical signal has demonstrated a relative degree of success, as a series of dampened complex sinusoids easily generalizes to multifaceted physiological processes. In cardiovascular physiology, the Prony analysis has been used to determine fatal arrythmia from electrocardiogram signals. However, application of the Prony method to simple left ventricular function based on pressure and volume analysis is absent. We have developed a new pipeline for analysis of pressure volume signals recorded from the left ventricle. We propose fitting pressure-volume data from cardiac catheterization to the Prony method for pole extraction and quantification of the transfer function. We implemented the Prony algorithm using open-source Python packages and analyzed the pressure and volume signals before and after severe hemorrhagic shock, and after resuscitation with stored blood. Each animal (n = 6 per group) underwent a 50% hemorrhage to induce hypovolemic shock, which was maintained for 30 min, and resuscitated with 3-week-old stored RBCs until 90% baseline blood pressure was achieved. Pressure-volume catheterization data used for Prony analysis were 1 s in length, sampled at 1000 Hz, and acquired at the time of hypovolemic shock, 15 and 30 min after induction of hypovolemic shock, and 10, 30, and 60 min after volume resuscitation. We next assessed the complex poles from both pressure and volume waveforms. To quantify deviation from the unit circle, which represents deviation from a Fourier series, we counted the number of poles at least 0.2 radial units away from it. We found a significant decrease in the number of poles after shock (p = 0.0072 vs. baseline) and after resuscitation (p = 0.0091 vs. baseline). No differences were observed in this metric pre and post volume resuscitation (p = 0.2956). We next found a composite transfer function using the Prony fits between the pressure and volume waveforms and found differences in both the magnitude and phase Bode plots at baseline, during shock, and after resuscitation. In summary, our implementation of the Prony analysis shows meaningful physiologic differences after shock and resuscitation and allows for future applications to broader physiological and pathophysiological conditions.

Characterization of Aortic Flow Patterns by High-Frame-Rate Blood Speckle Tracking Echocardiography in Children.

Background Blood speckle tracking echocardiography allows for direct quantification of interventricular and aortic flow profiles, principally in children. Here, we sought to demonstrate the feasibility and reproducibility of blood speckle tracking echocardiography in the aortas of healthy children. Methods and Results One hundred healthy White children evaluated for the screening of congenital heart disease were prospectively enrolled. Echocardiographic examinations were performed using a Vivid E 95 ultrasound system, with blood speckle tracking from a focused and zoomed view of the aortic root and the ascending aorta. Vortex position, height (mm), width (mm), sphericity index, and area (cm2) were measured and indexed by body surface area. Median (interquartile range) age was 8.2 (5.6-11.0) years, median (interquartile range) weight was 28 (19-35) kg, and median (interquartile range) body surface area was 1.01 (0.79-1.16) m2. Vortices were visualized in only a single phase of the cardiac cycle in 25 subjects-14 (56.0%) were evident in early diastole and 11 (44.0%) in late systole. Vortices visualized in diastole had a mean area of 0.27±0.1 cm2/m2, while those in systole had a mean area of 0.34±0.12 cm2/m2. In a subset of 20 patients, inter- and intraobserver coefficient of variation and intraclass correlation coefficients were determined and showed good reproducibility. Conclusions We demonstrate feasibility and reproducibility of blood speckle tracking and identified vortical flow patterns in the aortic root and ascending aorta in healthy children. These data may serve as a baseline for evaluating aortic flow patterns in children with congenital and acquired heart disease.

Characteristics of Right Ventricular to Pulmonary Arterial Coupling and Association With Functional Status Among Older Aged Adults from the Multi-Ethnic Study of Atherosclerosis.

Although the echocardiographic:derived ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary arterial systolic pressure (PASP) is an important prognostic tool in heart failure (HF), the relation with 6-minute walk distance (6MWD) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) is less established. We sought to establish the normative values of TAPSE:PASP among older adults without cardiovascular disease (CVD) and evaluate the relation with NT-proBNP and 6MWD. Among 1,542 participants of the Multi-Ethnic Study of Atherosclerosis-HF ancillary study, the cross-sectional association of TAPSE:PASP with the outcomes of 6MWD and NT-proBNP was analyzed using multivariable linear regression, with progressive adjustment for sociodemographic and CVD risk factors. Our cohort had a mean age (SD) of 73 ± 8 years, 55% women, and a mean TAPSE:PASP ratio of 0.68 ± 0.16. In the unadjusted analysis, increasing tertiles of TAPSE:PASP were associated with younger age, less diabetes, higher estimated glomerular filtration rate, and less antihypertensive medication use. The TAPSE:PASP ratio significantly correlated with both 6MWD and NT-proBNP in the fully adjusted models. A 1-unit increment in TAPSE:PASP was associated with an adjusted 9.9% (4.8% to 15.2%) higher 6MWD, whereas a 1-unit increment in TAPSE:PASP was associated with an adjusted 38.0% (16.0% to 54.2%) lower NT-proBNP. There was a significant gender interaction of the association of TAPSE:PASP ratio and 6MWD, with stronger association seen in women. Among multiethnic older adults free of clinical CVD, the TAPSE:PASP ratio decreased with age, especially in women and was associated with decreased 6MWD and increasing NT-proBNP, the markers of subclinical HF.

Modification of a Transvalvular Microaxial Flow Pump for Instantaneous Determination of Native Cardiac Output and Volume.

BACKGROUND: The current Impella cardiopulmonary (CP) pump, used for mechanical circulatory support in patients with cardiogenic shock (CS), cannot assess native cardiac output (CO) and left ventricular (LV) volumes. These data are valuable in facilitating device management and weaning. Admittance technology allows for accurate assessment of cardiac chamber volumes. OBJECTIVES: This study tested the ability to engineer admittance electrodes onto an existing Impella CP pump to assess total and native CO as well as LV chamber volumes in an instantaneous manner. METHODS: Impella CP pumps were fitted with 4 admittance electrodes and were placed in the LVs of adult swine (n = 9) that were subjected to 3 different hemodynamic conditions, including Impella CP speed adjustments, administration of escalating doses of dobutamine and microsphere injections into the left main artery to result in cardiac injury. CO, according to admittance electrodes, was calculated from LV volumes and heart rate. In addition, CO was calculated in each instance via thermodilution, continuous CO measurement, the Fick principle, and aortic velocity-time integral by means of echocardiography. RESULTS: Modified Impella CP pumps were placed in swine LVs successfully. CO, as determined by admittance electrodes, was similar by trend to other methods of CO assessment. It was corrected for pump speed to calculate native CO, and calculated LV chamber volumes trended as expected in each experimental protocol. CONCLUSIONS: We report, for the first time, that an Impella CP pump can be fitted with admittance electrodes and used to determine total and native CO in various hemodynamic situations. CONDENSED ABSTRACT: Transvalvular mechanical circulatory support devices such as the Impella CP do not have the ability to provide real-time information on native cardiac output (CO) and left ventricular (LV) volumes. This information is critical in device management and in weaning in patients with cardiogenic shock. We demonstrate, for the first time, that Impella CP pumps coupled with admittance electrodes are able to determine native CO and LV chamber volumes in multiple hemodynamic situations such as Impella pump speed adjustments, escalating dobutamine administration and cardiac injury from microsphere injection.

Right Ventricular Sarcomere Contractile Depression and the Role of Thick Filament Activation in Human Heart Failure with Pulmonary Hypertension.

Rationale: Right ventricular (RV) contractile dysfunction commonly occurs and worsens outcomes in heart failure patients with reduced ejection fraction and pulmonary hypertension (HFrEF-PH). However, such dysfunction often goes undetected by standard clinical RV indices, raising concerns that they may not reflect aspects of underlying myocyte dysfunction. Objective: To determine components of myocyte contractile depression in HFrEF-PH, identify those reflected by clinical RV indices, and elucidate their underlying biophysical mechanisms. Methods and Results: Resting, calcium- and load-dependent mechanics were measured in permeabilized RV cardiomyocytes isolated from explanted hearts from 23 HFrEF-PH patients undergoing cardiac transplantation and 9 organ-donor controls. Unsupervised machine learning using myocyte mechanical data with the highest variance yielded two HFrEF-PH subgroups that in turn mapped to patients with depressed (RVd) or compensated (RVc) clinical RV function. This correspondence was driven by reduced calcium-activated isometric tension in RVd, while surprisingly, many other major myocyte contractile measures including peak power, maximum unloaded shortening velocity, and myocyte active stiffness were similarly depressed in both groups. Similar results were obtained when subgroups were first defined by clinical indices, and then myocyte mechanical properties in each group compared. To test the role of thick-filament defects, myofibrillar structure was assessed by X-ray diffraction of muscle fibers. This revealed more myosin heads associated with the thick filament backbone in RVd but not RVc, as compared to controls. This corresponded to reduced myosin ATP turnover in RVd myocytes, indicating less myosin in a cross-bridge ready disordered-relaxed (DRX) state. Altering DRX proportion (%DRX) affected peak calcium-activated tension in the patient groups differently, depending on their basal %DRX, highlighting potential roles for precision-guided therapeutics. Lastly, increasing myocyte preload (sarcomere length) increased %DRX 1.5-fold in controls but only 1.2-fold in both HFrEF-PH groups, revealing a novel mechanism for reduced myocyte active stiffness and by extension Frank-Starling reserve in human HF. Conclusions: While there are multiple RV myocyte contractile deficits In HFrEF-PH, clinical indices primarily detect reduced isometric calcium-stimulated force related to deficits in basal and recruitable %DRX myosin. Our results support use of therapies to increase %DRX and enhance length-dependent recruitment of DRX myosin heads in such patients.