End-diastolic Pressure-volume Relationship Research Articles

Effect of patisiran on stroke volume in hereditary transthyretin-mediated amyloidosis: insights from pressure-volume analysis of the APOLLO study.

Transthyretin-mediated (ATTR) amyloidosis is caused by deposition of transthyretin protein fibrils in the heart, nerves, and other organs. Patisiran, an RNA interference therapeutic that inhibits hepatic synthesis of transthyretin, was approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy based on the phase 3 APOLLO study. We use left ventricular (LV) stroke volume (SV) to quantify LV function overtime and non-invasive pressure-volume techniques to delineate the effects of patisiran on LV mechanics in the pre-specified cardiac subpopulation of the APOLLO study. Left ventricular SV was assessed by transthoracic echocardiography at baseline, and after 9 and 18 months of therapy. To determine the mechanisms underlying changes in LV SV, non-invasive pressure-volume parameters, including the end-systolic and end-diastolic pressure-volume relationship, were derived using single beat techniques. At baseline, the mean SV was 51 ± 14ml. At 9months, the least-squares mean change in SV was -0.3 ± 1.2ml for patisiran and -5.4 ± 1.9ml for placebo (p= 0.021). At 18 months, the least-squares mean change in SV was -1.7 ± 1.3ml for patisiran and - 8.1 ± 2.3ml for placebo (p= 0.016). Decline in LV SV was driven by diminished LV capacitance in placebo relative to patisiran. Patisiran may delay progression of LV chamber dysfunction starting at 9months of therapy. These data elucidate the mechanisms by which transthyretin-reducing therapies modulate progression of cardiac disease and need to be confirmed in ongoing phase 3 trials.

Myocardial viscoelasticity impairs late-filling in working myocardial slice preparations.

Heart failure with preserved ejection fraction (HFpEF) is linked to diabetes and obesity and has become the dominant form of heart failure in western cultures. Both impaired relaxation and increased myocardial stiffness impede ventricular filling which manifests in patients as exercise intolerance early in disease progression. The observation of elevated end-diastolic pressure (EDP) in exercising HFpEF patients implies that the passive viscoelasticity of the heart may reduce exercise performance, but no direct experimental methods can assess this ex-vivo. To determine if the passive viscoelastic properties of the myocardium were capable of influencing EDP in exercise, we have developed a myocardial slice-based protocol that permits long-duration mechanical testing with controllable end-diastolic filling velocity. The role of myocardial viscoelasticity on work output is determined by conducting work-loops at varying speeds of end-diastolic filling. Our results demonstrate an increase in the slope of the end diastolic pressure volume relationship (EDPVR) with filling speed in healthy Wistar-Kyoto rats (WKY) suggesting viscoelasticity can limit myocardial filling ex-vivo. To determine if the viscoelastic contribution was predominantly due to myocytes or extracellular matrix (ECM), the passive mechanical properties of the tissue were assessed before and after decellularization. The results indicate that in WKY rats, the ECM contributes minimally to tissue performance under the experimental working conditions. Together, these results suggest that increased myocardial viscoelasticity may contribute to diastolic dysfunction through myocyte stiffening in the absence of overt fibrosis.

Tevar Acutely Increases Left Ventricular Work In An Animal Model

Thoracic aortic stent-grafts are thought to decrease aortic compliance and may contribute to hypertension and heart failure post-TEVAR. Left ventricular (LV) biomechanics post-TEVAR have not been quantified. The aim of this study is to use LV pressure-volume (PV) loops to characterize the end systolic pressure (ESP)-volume relationship (ESPVR) and end diastolic pressure (EDP)-volume relationship (EDPVR) in a large animal model.

Computational analysis of ventricular mechanics in hypertrophic cardiomyopathy patients

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease that is associated with many pathological features, such as a reduction in global longitudinal strain (GLS), myofiber disarray and hypertrophy. The effects of these features on left ventricle (LV) function are, however, not clear in two phenotypes of HCM, namely, obstructive and non-obstructive. To address this issue, we developed patient-specific computational models of the LV using clinical measurements from 2 female HCM patients and a control subject. Left ventricular mechanics was described using an active stress formulation and myofiber disarray was described using a structural tensor in the constitutive models. Unloaded LV configuration for each subject was first determined from their respective end-diastole LV geometries segmented from the cardiac magnetic resonance images, and an empirical single-beat estimation of the end-diastolic pressure volume relationship. The LV was then connected to a closed-loop circulatory model and calibrated using the clinically measured LV pressure and volume waveforms, peak GLS and blood pressure. Without consideration of myofiber disarray, peak myofiber tension was found to be lowest in the obstructive HCM subject (60 kPa), followed by the non-obstructive subject (242 kPa) and the control subject (375 kPa). With increasing myofiber disarray, we found that peak tension has to increase in the HCM models to match the clinical measurements. In the obstructive HCM patient, however, peak tension was still depressed (cf. normal subject) at the largest degree of myofiber disarray found in the clinic. The computational modeling workflow proposed here can be used in future studies with more HCM patient data.

Cardiac hemodynamics and ventricular stiffness of sea-run cherry salmon (Oncorhynchus masou masou) differ critically from those of landlocked masu salmon.

Ventricular diastolic mechanical properties are important determinants of cardiac function and are optimized by changes in cardiac structure and physical properties. Oncorhynchus masou masou is an anadromous migratory fish of the Salmonidae family, and several ecological studies on it have been conducted; however, the cardiac functions of the fish are not well known. Therefore, we investigated ventricular diastolic function in landlocked (masu salmon) and sea-run (cherry salmon) types at 29-30 months post fertilization. Pulsed-wave Doppler echocardiography showed that the atrioventricular inflow waveforms of cherry salmon were biphasic with early diastolic filling and atrial contraction, whereas those of masu salmon were monophasic with atrial contraction. In addition, end-diastolic pressure-volume relationship analysis revealed that the dilatability per unit myocardial mass of the ventricle in cherry salmon was significantly suppressed compared to that in masu salmon, suggesting that the ventricle of the cherry salmon was relatively stiffer (relative ventricular stiffness index; p = 0.0263). Contrastingly, the extensibility of cardiomyocytes, characterized by the expression pattern of Connectin isoforms in their ventricles, was similar in both types. Histological analysis showed that the percentage of the collagen accumulation area in the compact layer of cherry salmon increased compared with that of the masu salmon, which may contribute to ventricle stiffness. Although the heart mass of cherry salmon was about 11-fold greater than that of masu salmon, there was no difference in the morphology of the isolated cardiomyocytes, suggesting that the heart of the cherry salmon grows by cardiomyocyte proliferation, but not cell hypertrophy. The cardiac physiological function of the teleosts varies with differences in their developmental processes and life history. Our multidimensional analysis of the O. masou heart may provide a clue to the process by which the heart acquires a biphasic blood-filling pattern, i.e., a ventricular diastolic suction.

Attenuation of Myocardial Dysfunction in Hypertensive Cardiomyopathy Using Non-R-Wave-Synchronized Cardiac Shock Wave Therapy.

Cardiac shock wave therapy (CSWT) is a novel therapeutic procedure for patients with angina that is refractory to conventional therapy. We investigated the potential mechanism and therapeutic efficacy of non-R-wave-triggered CSWT to attenuate myocardial dysfunction in a large animal model of hypertensive cardiomyopathy. Sustained elevated blood pressure (BP) was induced in adult pigs using a combination of angiotensin-II and deoxycorticosterone acetate (DOCA). Two sessions of non-R-wave-triggered CSWT were performed at 11 and 16 weeks. At 10 weeks, systolic and diastolic blood pressure, LV posterior wall thickness and intraventricular septum thickness significantly increased in both the hypertension and CSWT groups. At 20 weeks, +dP/dt and end-systolic pressure-volume relationship (ESPVR) decreased significantly in the hypertension group but not the CSWT group, as compared with week 10. A significant improvement in end-diastolic pressure-volume relationship (EDPVR) was observed in the CSWT group. The CSWT group exhibited significantly increased microvascular density and vascular endothelial growth factor (VEGF) expression in the myocardium. Cytokine array demonstrated that the CSWT group had significantly reduced inflammation compared with the hypertension group. Our results demonstrate that non-R-wave-triggered CSWT is safe and can attenuate LV systolic and diastolic dysfunction via enhancement of myocardial neovascularization and anti-inflammatory effect in a large animal model of hypertensive cardiomyopathy.

Prognostic value of left ventricular chamber stiffness and heart failure in patients with severe aortic stenosis undergoing aortic valve replacement

Abstract Background Increased left ventricular (LV) stiffness (LVStiffn) was shown to be associated with mortality in patients with severe aortic stenosis (AS), despite aortic valve replacement (AVR), and may contribute to future heart failure (HF) symptoms. The aim was to assess whether preoperative LVStiffn is a risk factor of HF in these patients. Methods A retrospective analysis was done in patients with severe AS who underwent AVR (93% surgical). LV end-diastolic pressure-volume relations (P=aVb) were reconstructed from LV end-diastolic volumes and estimated end-diastolic pressures (from E/e'); LVStiffn at 30 mmHg (CS30) and capacitance (V30) were then derived. Primary endpoint was development of symptomatic HF at >1 month post AVR. Results 1,837 patients were studied (age 76±10 years, 62% males, LVEF 61±12%; Table). Mean CS30 was 2.2±1.3 mmHg/mL and V30 64±17 mL/m2. Patients with higher CS30 ≥3 mmHg/mL were older, more frequently female, and had more comorbidities. During a median follow-up of 5.0 [3.0–7.9] years, 607 (33%) patients developed HF. A higher CS30 (≥3 mmHg/mL), but not V30 (P=0.32), was associated with higher risk of HF events (HR 1.86 [95% CI 1.52–2.27], P<0.0001), along with other clinical and echo predictors (Table). In multivariate analysis, adjusting for age, sex, comorbidities, advanced NYHA class III–IV, creatinine >1.5 mg/dL, medication use, severity of AS, reduced LVEF <50%, diastolic dysfunction grade ≥2, right ventricular size and pulmonary hypertension, a higher CS30 ≥3 mmHg/mL remained independently associated with HF events (adjusted HR 1.61 [1.29–2.01], P<0.0001; Figure). Conclusion Increased LVStiffn in patients with severe AS undergoing AVR is associated with HF at follow-up, despite the benefits brought by AVR, and can help identify patients with poorer outcomes who may need closer monitoring/more intensive treatment of comorbidities Funding Acknowledgement Type of funding sources: None.

A pacing-controlled protocol for frequency-diastolic relations distinguishes diastolic dysfunction specific to a mouse HFpEF model.

Heart failure with preserved ejection fraction (HFpEF), characterized by diastolic dysfunction and insufficient exercise capacity, is a growing health problem worldwide. One major difficulty with experimental research on HFpEF is the lack of methods to consistently detect diastolic dysfunction in mouse models. We developed a pacing-controlled pressure-volume (PV) loop protocol for the assessment of diastolic function at different heart rates in mice and tested if the protocol could detect diastolic dysfunction specific to a HFpEF model. A HFpEF model was generated by high-fat diet (HFD) feeding with concomitant NG-nitro-l-arginine methyl ester administration, and a pressure-overload hypertrophy (PO) model was produced by surgical constriction of the transverse aorta (TAC). Heart rate (HR) was slowed below 400 beats/min by intraperitoneal injection of ivabradine. PV loop data were acquired and analyzed at HR incrementing from 400 to 700 beats/min via atrial pacing using a miniature pacing catheter inserted into the esophagus, and comparisons were made among control, HFpEF, and PO mice. At baseline without pacing, no diastolic abnormalities were detected in either PO or HFpEF models. Frequency-diastolic relations, however, revealed the significant diastolic impairment specific to the HFpEF model; both relaxation time constant (Tau) and end-diastolic pressure-volume relationship (EDPVR) were worsened as heart rate increased. Peak positive first derivative of left ventricular pressure (dP/dtmax) was significantly lower in HFpEF versus controls only at a high HR of 700 beats/min. A pacing-controlled protocol would be a feasible and potent method to detect diastolic dysfunction specific to a mouse HFpEF model.NEW & NOTEWORTHY We developed a pacing-controlled PV loop protocol for the assessment of diastolic function at different heart rates in mice, which is a feasible and potent method for the characterization of diastolic dysfunction in a murine HFpEF model whose diastolic dysfunction might be difficult to be detected under resting conditions without pacing.

Impairment of left ventricular diastolic function and exercise capacity after yoyo dieting in female mice with or without ovariectomy-induced post-menopausal condition

Follow-up studies show that weight gain in women proportionally increases the risk of coronary heart disease and that weight cycling is associated with adverse cardiometabolic markers. Moreover, women after menopause are prone to weight gain. To work out a protocol responsible for weight fluctuation and to measure the cardiac functional consequences after a final weight loss, in mice having undergone or not an ovariectomy (OVX). Five-month-old female underwent OVX or not. Starting 5 days after surgery, mice were subjected to Yoyo dieting with successive periods (I, II, III) of a biphasic alternation of a high fat diet (HFD) (4-week constant phase of HFD60%) followed by standard diet (SD) (phase of 4, 6, 10 weeks for period I, II, III, respectively). Non-OVX control (CTL) mice were maintained on SD. At the end of the last SD phase, the global metabolism was evaluated by an insulin tolerance test and echo-MRI, the blood pressure was measured by plethysmography, the exercise capacity was evaluated on treadmill, then the left ventricular (LV) function was assessed by ultrasound and invasive hemodynamics. Body weight in Yoyo and OVX-Yoyo mice was higher to that of CTL mice at the end of period III. Moreover, the first phase of HFD resulted in a higher weight gain in OVX-yoyo mice, which kept bigger than Yoyo mice until the end of the protocol, however without difference in body composition. There was decreased insulin sensitivity in both Yoyo and Yoyo-OVX mice compared to CTL. There was no difference in blood pressure nor in LV fractional shortening between groups. Invasive hemodynamics showed no difference in LV-end diastolic pressure (LVEDP) but an increased LV end-diastolic pressure volume relation (LVEDPVR) in OVX-Yoyo mice, indicating decreased compliance. LV weight was increased in Yoyo mice only. Treadmill stress test showed decreased running duration for OVX-Yoyo mice only ( Fig. 1 ). In female mice subjected to the same Yoyo diet protocol, those in post-menopausal condition after OVX show an increased risk of developing heart failure with preserved ejection fraction and reduced exercise capacity.

Quantifying the Cardiovascular Physiology of REBOA and Partial REBOA: How REBOA Facilitates Resuscitation but Also Strains the Left Ventricle

Resuscitative endovascular balloon occlusion of the aorta (REBOA) is increasingly used as an endovascular approach to aortic occlusion. This can provide complete or partial aortic occlusion and is thereby known to augment afterload relative to the extent of occlusion. Despite the increasing use of this tool, little cardiovascular physiology has been quantified across clinically relevant REBOA transitions: placement of occlusive REBOA, then transition to partially occlusive REBOA, and lastly, REBOA removal. The goal of this study is to use pressure-volume loop analysis and direct left coronary artery blood flow measurements to capture these transitions in a swine model of hemorrhagic shock to elucidate the underlying physiologic mechanism of clinical REBOA use. Swine underwent complex surgical and vascular access instrumentation to capture real-time left ventricular pressure-volume loops and directly measure left coronary flow (Figure 1). Animals were hemorrhaged to 45 mmHg with subsequent placement of fully occlusive REBOA, followed by transition to partial REBOA while these data were captured. A full methodological protocol has been published: https://doi.org/10.21203/rs.3.pex-1646/v1. Five male swine underwent this protocol (mean weight, 53.6 ± 3.6 kg). Hemorrhagic shock was induced and maintained with reduction of stroke work (baseline: 3.1 L × mmHg vs shock: 1.2 L × mmHg; P < .01) and average end systolic pressure (109.8 vs 59.6 mmHg; P = .02). REBOA augmented the end systolic pressure volume relationship. Stroke work evolved with placement of occlusive REBOA (1.2 vs 4.3 mmHgL; P < .01). End systolic elastance was augmented from baseline by shock and REBOA placement (1.01 vs 0.39 vs 4.50 mL/mmHg; P < .01) and remained elevated with transition to partial REBOA (3.22 mL/mmHg) (Figure 2). Percent time in antegrade coronary blood flow decreased during shock (94% to 71.8%; P < .01) and was rescued with REBOA, but REBOA also increased peak coronary flow compared with shock (271 vs 93 mL/min; P < .01) and total coronary flow, even beyond baseline (peak: 2136 vs baseline: 424 mL/min; P < .01). No REBOA state augmented the end diastolic pressure volume relationship. REBOA maintains the end diastolic pressure volume relationship, but increases afterload, thereby augmenting the end systolic pressure volume relationship and left ventricle contractility with partial REBOA. REBOA alters coronary artery blood flow by reversing shock-induced retrograde coronary flow, and increasing peak coronary artery flow, therefore increasing total flow. The afterload modulation from REBOA underlies its resuscitative capability but may drive the mechanism of cardiovascular injury. Partial REBOA with resuscitation balances the afterload improvement against undue left ventricle strain.Fig 2End systolic elastance (Ees; the slope of the end systolic pressure volume relationship) evolution across study periods. *P = .003; **P = .048; ***P = .01; ****P = .015.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Robust and efficient fixed-point algorithm for the inverse elastostatic problem to identify myocardial passive material parameters and the unloaded reference configuration

Image-based computational models of the heart represent a powerful tool to shed new light on the mechanisms underlying physiological and pathological conditions in cardiac function and to improve diagnosis and therapy planning. However, in order to enable the clinical translation of such models, it is crucial to develop personalized models that are able to reproduce the physiological reality of a given patient. There have been numerous contributions in experimental and computational biomechanics to characterize the passive behavior of the myocardium. However, most of these studies suffer from severe limitations and are not applicable to high-resolution geometries. In this work, we present a novel methodology to perform an automated identification of in vivo properties of passive cardiac biomechanics. The highly-efficient algorithm fits material parameters against the shape of a patient-specific approximation of the end-diastolic pressure-volume relation (EDPVR). Simultaneously, an unloaded reference configuration is generated, where a novel line search strategy to improve convergence and robustness is implemented. Only clinical image data or previously generated meshes at one time point during diastole and one measured data point of the EDPVR are required as an input. The proposed method can be straightforwardly coupled to existing finite element (FE) software packages and is applicable to different constitutive laws and FE formulations. Sensitivity analysis demonstrates that the algorithm is robust with respect to initial input parameters.

Binge drinking‐like behavior in juvenile rats causes long‐lasting cardiorespiratory dysfunction that persists until adulthood

Harmful alcohol abuse is associated with serious psychosocial and health damage, including cardiac and neurological morbidities. Americans drink 40% more than the global average and adolescents are the heaviest drinkers, displaying a pathological consumption pattern termed “binge drinking”, consisting in short episodes of heavy alcohol intake followed by long withdrawal periods. Despite adolescent binge drinking (ABD) drives severe impairments in neurological and cardiorespiratory function, there are no current health policies to prevent ABD or its physiological consequences. Indeed, little is known about the long‐term consequences of ABD in adulthood physiology. Therefore, we aimed to investigate the potential harmful effects of ABD on cardiac and respiratory (patho)physiology in the adult life. Sixteen male juvenile Sprague‐Dawley rats underwent ABD‐like alcohol administration protocol or control treatment, consisting of 2‐days “ON” and 2‐days “OFF” doses of ethanol (3.0 g/kg, 25% w/v in saline administered i. p.) beginning on post‐natal day (PND) 25 until PND 38. Once rats reached adulthood (PND80), respiratory and cardiac function were respectively assessed by whole‐body plethysmography and intraventricular pressure‐volume loops. Compared to controls, adult rats exposed to ABD displayed no differences in resting blood pressure, heart rate and pulmonary ventilation, but they showed a significant (p&lt;0.05) increase in the breath‐to‐breath interval variability (40.8 ± 2.8 vs. 25.6 ± 2.3 ms; ABD vs. Control, respectively) and in the incidence of apneas/hypoapneas (AHI: 5.83 ± 0.40 vs. 2.50 ± 0.37 events/h; ABD vs. Control, respectively). Intraventricular cardiac function analysis using PV‐loops revealed a reduction in left ventricular compliance in ABD animals, evidenced by the augmented slope of the end diastolic pressure‐volume relationship (EDPVR: 0.0303 ± 0.006 vs. 0.009 ± 0.001 mmHg/µL; ABD vs. Control). Also, we found that ABD induced cardiac autonomic imbalance estimated by low/high frequency ratio of heart rate variability (LFHRV/HFHRV: 1.59 ± 0.23 vs. 1.01 ± 0.08) and increased arrhythmia incidence (53.6 ± 12.7 vs. 21.7 ± 5.7 events/h; ABD vs. Control). Our results shows that binge drinking in adolescence causes long‐lasting cardiorespiratory dysfunction that includes at least cardiac diastolic dysfunction, autonomic imbalance, and generation of irregular breathing all of them persisting until the adulthood.1Laboratory of Cardiorespiratory Control, Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile. 2Biomedical Department, Facultad of Health Science, Universidad de Antofagasta. 3Centro de Excelencia de Biomedicina en Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas, Chile. 4Centro de Envejecimiento y Regeneración CARE‐UC, Pontificia Universidad Católica de Chile, Santiago, Chile.

The effects of positive end-expiratory pressure on cardiac function: a comparative echocardiography-conductance catheter study

BackgroundEchocardiographic parameters of diastolic function depend on cardiac loading conditions, which are altered by positive pressure ventilation. The direct effects of positive end-expiratory pressure (PEEP) on cardiac diastolic function are unknown.MethodsTwenty-five patients without apparent diastolic dysfunction undergoing coronary angiography were ventilated noninvasively at PEEPs of 0, 5, and 10 cmH2O (in randomized order). Echocardiographic diastolic assessment and pressure–volume-loop analysis from conductance catheters were compared. The time constant for pressure decay (τ) was modeled with exponential decay. End-diastolic and end-systolic pressure volume relationships (EDPVRs and ESPVRs, respectively) from temporary caval occlusion were analyzed with generalized linear mixed-effects and linear mixed models. Transmural pressures were calculated using esophageal balloons.Resultsτ values for intracavitary cardiac pressure increased with the PEEP (n = 25; no PEEP, 44 ± 5 ms; 5 cmH2O PEEP, 46 ± 6 ms; 10 cmH2O PEEP, 45 ± 6 ms; p < 0.001). This increase disappeared when corrected for transmural pressure and diastole length. The transmural EDPVR was unaffected by PEEP. The ESPVR increased slightly with PEEP. Echocardiographic mitral inflow parameters and tissue Doppler values decreased with PEEP [peak E wave (n = 25): no PEEP, 0.76 ± 0.13 m/s; 5 cmH2O PEEP, 0.74 ± 0.14 m/s; 10 cmH2O PEEP, 0.68 ± 0.13 m/s; p = 0.016; peak A wave (n = 24): no PEEP, 0.74 ± 0.12 m/s; 5 cmH2O PEEP, 0.7 ± 0.11 m/s; 10 cmH2O PEEP, 0.67 ± 0.15 m/s; p = 0.014; E’ septal (n = 24): no PEEP, 0.085 ± 0.016 m/s; 5 cmH2O PEEP, 0.08 ± 0.013 m/s; 10 cmH2O PEEP, 0.075 ± 0.012 m/s; p = 0.002].ConclusionsPEEP does not affect active diastolic relaxation or passive ventricular filling properties. Dynamic echocardiographic filling parameters may reflect changing loading conditions rather than intrinsic diastolic function. PEEP may have slight positive inotropic effects.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT02267291, registered 17. October 2014.Graphical abstract

Interventricular Interactions and Right Ventricular Function in LVAD Recipients: Insights from Pressure Volume Analyses

<h3>Purpose</h3> Data supporting the hypothesis that interventricular interaction contribute to right ventricular (RV) failure after left ventricular assist device (LVAD) implantation are lacking. <h3>Methods</h3> Patients underwent a protocolized hemodynamic ramp test where RV pressure-volume (PV) loops were recorded with a conductance catheter. The end-systolic PV relationship was characterized by the ratio of end-systolic pressure and volume (R_es). The end-diastolic PV relationship (EDPVR) was characterized by the V₁₀ index (i.e., the volume at which the EDPVR reaches a pressure of 10 mmHg). ΔR_es and ΔV₁₀ (i.e., the maximal change across the range of tested LVAD speeds) were used to compare systolic and diastolic function between patients. <h3>Results</h3> Six adult males with HeartMate3 LVADs completed the study protocol (Fig. 1). ΔR_es and ΔV₁₀ both exhibited minimal changes in 3 subjects (mean ΔR_es=7.24%, mean ΔV₁₀=8.14 mL), suggesting neither RV systolic nor diastolic function was impacted by LV unloading. In contrast, 2 subjects showed predominantly diastolic responses to changing LVAD speed (mean ΔV₁₀=17.4), but no significant systolic response (mean ΔR_es=5.47%). The final subject's ramp study was stopped prematurely because of suction events: ΔR_es and ΔV₁₀ were 23.2% and 1.4 mL, respectively, indicating a significant decrement in systolic function with greater LVAD speed. The mean PA systolic pressures were significantly greater in the 3 participants without systolic or diastolic changes relative to their counterparts (42.3 vs. 25.3 mmHg, p=0.038). <h3>Conclusion</h3> Interventricular interaction exerts a heterogenous influence on RV performance: Systolic interactions diminish RV contractile function, while diastolic interactions improve RV compliance. Further work is required to establish whether interventricular interaction is, indeed, a rare cause of post-LVAD RV dysfunction, and if chronic exposure to afterload blunts the RV's sensitivity to interventricular interaction.

A machine learning model to estimate myocardial stiffness from EDPVR

In-vivo estimation of mechanical properties of the myocardium is essential for patient-specific diagnosis and prognosis of cardiac disease involving myocardial remodeling, including myocardial infarction and heart failure with preserved ejection fraction. Current approaches use time-consuming finite-element (FE) inverse methods that involve reconstructing and meshing the heart geometry, imposing measured loading, and conducting computationally expensive iterative FE simulations. In this paper, we propose a machine learning (ML) model that feasibly and accurately predicts passive myocardial properties directly from select geometric, architectural, and hemodynamic measures, thus bypassing exhaustive steps commonly required in cardiac FE inverse problems. Geometric and fiber-orientation features were chosen to be readily obtainable from standard cardiac imaging protocols. The end-diastolic pressure-volume relationship (EDPVR), which can be obtained using a single-point pressure-volume measurement, was used as a hemodynamic (loading) feature. A comprehensive ML training dataset in the geometry-architecture-loading space was generated, including a wide variety of partially synthesized rodent heart geometry and myofiber helicity possibilities, and a broad range of EDPVRs obtained using forward FE simulations. Latin hypercube sampling was used to create 2500 examples for training, validation, and testing. A multi-layer feed-forward neural network (MFNN) was used as a deep learning agent to train the ML model. The model showed excellent performance in predicting stiffness parameters a_f and b_f associated with fiber direction (R^2_{a_f}=99.471% and R^2_{b_f}=92.837%). After conducting permutation feature importance analysis, the ML performance further improved for b_f (R^2_{b_f}=96.240%), and the left ventricular volume and endocardial area were found to be the most critical geometric features for accurate predictions. The ML model predictions were evaluated further in two cases: (i) rat-specific stiffness data measured using ex-vivo mechanical testing, and (ii) patient-specific estimation using FE inverse modeling. Excellent agreements with ML predictions were found for both cases. The trained ML model offers a feasible technology to estimate patient-specific myocardial properties, thus, bridging the gap between EDPVR, as a confounded organ-level metric for tissue stiffness, and intrinsic tissue-level properties. These properties provide incremental information relative to traditional organ-level indices for cardiac function, improving the clinical assessment and prognosis of cardiac diseases.

Allogeneic Cell Combination Therapy Ameliorates Chronic Kidney Disease-Induced Heart Failure with Preserved Ejection Fraction.

BackgroundLeft ventricular hypertrophy and heart failure with preserved ejection fraction (HFpEF) are primary manifestations of the cardiorenal syndrome in patients with chronic kidney disease (CKD). Therapies that improve morbidity and mortality in HFpEF are lacking. Cell-based therapies promote cardiac repair in ischemic and non-ischemic cardiomyopathies. We hypothesized that cell-based therapy ameliorates CKD-induced HFpEF.Methods and ResultsYorkshire pigs (n = 26) underwent 5/6 embolization-mediated nephrectomy. CKD was confirmed by increased creatinine and decreased glomerular filtration rate (GFR). Mean arterial pressure (MAP) was not different between groups from baseline to 4 weeks. HFpEF was evident at 4 weeks by increased LV mass, relative wall thickening, end-diastolic pressure, and end-diastolic pressure-volume relationship, with no change in ejection fraction (EF). Four weeks post-embolization, allogeneic (allo) bone marrow-derived mesenchymal stem cells (MSC; 1 × 107 cells), allo-kidney-derived stem cells (KSC; 1 × 107 cells), allo-cell combination therapy (ACCT; MSC + KSC; 1:1 ratio; total = 1 × 107 cells), or placebo (Plasma-Lyte) was delivered via intra-renal artery. Eight weeks post-treatment, there was a significant increase in MAP in the placebo group (21.89 ± 6.05 mmHg) compared to the ACCT group. GFR significantly improved in the ACCT group. EF, relative wall thickness, and LV mass did not differ between groups at 12 weeks. EDPVR improved in the ACCT group, indicating decreased ventricular stiffness.ConclusionsIntra-renal artery allogeneic cell therapy was safe in a CKD swine model manifesting the characteristics of HFpEF. The beneficial effect on renal function and ventricular compliance in the ACCT group supports further research of cell therapy for cardiorenal syndrome.

On the interplay of loading, myocardial stiffness and contractility in transthoracic acoustic radiation force-induced shear wave measurements in pigs

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Research Foundation Flanders (FWO grant number 1211620N) &amp; TTW-Dutch Heart Foundation partnership program "Early recognition of cardiovascular diseases" (project number 14740) Background Acoustic radiation force-based shear wave elastography (SWE) is a promising technique to non-invasively assess mechanical properties of the heart based on the propagation speed of acoustically induced shear waves. However, the interpretation of cardiac SWE measurements remains complex, and it is unclear how other factors such as loading affect shear wave propagation speed (SWS) measurements in diastole and systole. Purpose We applied transthoracic SWE in a pig model to investigate the dependencies of diastolic and systolic SWS on pressure-volume (PV) loop derived indices of loading, myocardial stiffness and contractility. Methods In 7 pigs, loading conditions were altered (increasing or decreasing preload; increasing afterload) and myocardial stiffness was changed (LAD occlusion for 60-100 minutes followed by 40 minutes of reperfusion). For each intervention, transthoracic SWE measurements were performed in a parasternal long-axis view with a high frame rate ultrasound system (&amp;gt; 6.2 kHz). Recordings of 28 ms were repeated at 34 Hz during 1.5 s to track shear waves throughout the cardiac cycle. To determine systolic and diastolic SWS in a robust manner, a piecewise linear model was fitted to the SWS data of each intervention representing multiple acquisitions, heartbeats and M-lines (fig. 1a). PV loops were recorded simultaneously with SWE measurements to estimate end-diastolic pressure (EDP), end-systolic pressure (ESP), end-diastolic pressure volume relation (EDPVR with exponential coefficient β in fig. 1b) and preload-recruitable stroke work (PRSW). Passive chamber stiffness was evaluated as the local slope of the EDPVR, i.e. β·EDP. Linear regressions and Pearson’s correlation coefficients were calculated. Results Diastolic SWS was significantly correlated to EDP when altering loading (blue in fig. 2a: R = 0.55; p &amp;lt; 0.01) and stiffness (orange in fig. 2a: R = 0.66; p &amp;lt; 0.01). A similar correlation is found between SWS and passive chamber stiffness β·EDP (fig. 2b). Diastolic SWS is more sensitive to changes in stiffness than in loading, as reflected by the larger slope of the regression line (0.79 vs. 0.28 in fig. 2b). Furthermore, systolic SWS significantly correlated with measures of contractility during loading alterations: ESP in fig. 2c (R = 0.69; p &amp;lt; 0.001) and PRSW in fig. 2d (R = 0.63; p = 0.02). However, no significant correlation was found between systolic SWS and contractility during infarct/reperfusion. Conclusion This study shows that diastolic SWS reflects the instantaneous stiffness of the myocardium, but is not a load-independent measure of the intrinsic passive mechanical properties of the heart. Instantaneous stiffness, and thus diastolic SWS, might be altered by loading (due to material non-linearity) or intrinsic mechanical changes. Furthermore, loading experiments suggest that systolic SWS is related to contractility. The relation between SWS and contractility in the presence of myocardial infarct deserves further study. Abstract Figure. Fig. 1: SWS and PV analysis. Abstract Figure. Fig. 2: SWS vs. PV-derived indices.

Myocardial stiffness assessed by shear wave elastography relates to pressure-volume loop derived measurements of chamber stiffness

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundations Flanders Background Increased myocardial stiffness is an important cause of diastolic dysfunction. Currently, invasive pressure-volume loop analysis is the gold standard method for the assessment of the left ventricular (LV) chamber stiffness. Its non-invasive assessment in the clinic is cumbersome, requires the combination of several parameters and has limited reliability. Shear wave elastography (SWE) is a novel method that evaluates the propagation of shear waves travelling along the myocardium using high frame rate echocardiography. The propagation speed is directly related to myocardial stiffness. Shear waves can be induced naturally by mitral valve closure (MVC). So far, the in vivo validation of SWE against an invasive gold standard reference method is still lacking. Purpose To compare myocardial stiffness assessed by shear wave propagation speed after MVC to invasive pressure-volume loop derived measurements of chamber stiffness. Methods Fifteen pigs (31.2 ± 4.1 kg) were included in the study. The instantaneous stiffness of the myocardium was altered by performing the following interventions: 1) preload reduction, 2) afterload increase, 3) preload increase and 4) induction of ischemia/reperfusion (I/R) injury by balloon occlusion of the proximal LAD for 90 min. with subsequent reperfusion of 40 min. To obtain the end-diastolic pressure-volume loop relation (EDPVR), a set of pressure-volume loops was acquired under preload reduction. From the EDPVR, the chamber stiffness constant β and operating chamber stiffness dP/dV were derived. SWE datasets in a parasternal long-axis view were acquired with an experimental ultrasound scanner at an average frame rate of 1304 ± 115 Hz. Shear waves after MVC were visualized on tissue acceleration maps by drawing an M-mode line along the interventricular septum (Figure 1A). The propagation speed was calculated by semi-automatically measuring the spatiotemporal slope. Results The chamber stiffness constant β significantly increased after the induction of the I/R injury (0.05 ± 0.01 1/ml vs. 0.09 ± 0.03 1/ml; p &amp;lt; 0.001). The operating chamber stiffness dP/dV decreased by reducing preload and increased by increasing afterload, increasing preload or by inducing an I/R injury (0.50 ± 0.18 mmHg/ml vs. 0.09 ± 0.05 mmHg/ml, 0.67 ± 0.19 mmHg/ml, 0.78 ± 0.35 mmHg/ml and 1.09 ± 0.38 mmHg/ml, respectively; p &amp;lt; 0.01). Likewise, shear wave propagation speed after MVC increased by increasing pre- and afterload (p = 0.001) and by inducing I/R injury (p &amp;lt; 0.001) (Figure 1B). Preload reduction had no significant influence (p = 0.118). Shear wave speed had a strong positive correlation with β (r = 0.63; p &amp;lt; 0.001) (Figure 1C) and dP/dV (r = 0.81; p &amp;lt; 0.001) (Figure 1D). Conclusions Shear wave speed after MVC is strongly related to invasive pressure-volume loop derived measures of chamber stiffness. The results of this study indicate the potential of SWE as a novel non-invasive method for the assessment of the instantaneous stiffness of the myocardium. Abstract Figure.

Impaired Diastolic Function Predicts Improved Ischemic Myocardial Flow by Mechanical Left Ventricular Unloading in a Swine Model of Ischemic Heart Failure.

Background: Impact of mechanical left ventricular (LV) unloading on myocardial tissue perfusion and its regulating factors remain unclear. This study was conducted to elucidate the predictors of regional blood flow (RBF) improvement by mechanical LV unloading.Materials and Methods: One to four weeks after percutaneous induction of myocardial infarction (MI), Yorkshire pigs (n = 15) underwent mechanical LV unloading using Impella CP. Hemodynamic parameters were collected prior to LV unloading. RBF in infarct, border and remote myocardium were measured by fluorescent microsphere injections before and 120 min after LV unloading.Results: RBF showed variable responses to mechanical LV unloading. While infarct RBF improved in general (0.33 ± 0.13 to 0.42 ± 0.19 mL/min/g, p = 0.06), there were a few pigs that showed little improvement. Meanwhile, there were no clear trends in the border (1.07 ± 0.47 to 1.02 ± 0.65 mL/min/g, p = 0.73) and remote myocardial RBF (1.25 ± 0.52 to 1.23 ± 0.68 mL/min/g, p = 0.85). In the simple linear regression analysis, cardiac output, mean pulmonary arterial wedge pressure, mean left atrial pressure, minimum LV pressure, end-diastolic LV pressure, maximum dP/dt, slope of end-diastolic pressure-volume relationship (EDPVR) and end-diastolic wall stress were significantly associated with % change of infarct RBF. In the multiple regression model, slope of EDPVR and maximum dP/dt remained as independent predictors of infarct RBF change.Conclusion: Steeper EDPVR and lower maximum dP/dt were associated with increased blood perfusion in the infarct area after LV unloading. Our data suggests mechanical LV unloading is more beneficial in post-MI patients with high diastolic pressure associated with increased LV stiffness and in those with worse cardiac contractility.

Transplantation of Fibroblast Sheets with Blood Mononuclear Cell Culture Exerts Cardioprotective Effects by Enhancing Anti-Inflammation and Vasculogenic Potential in Rat Experimental Autoimmune Myocarditis Model.

Simple SummaryFulminant myocarditis (FM) is a serious inflammatory lesion of the myocardium accompanied by cardiac dysfunction, transitioning to end-stage heart failure. Due to such a difficult pathology, a therapeutic strategy that exerts a steadfast effect has yet to be developed. Blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. The aim of this study was to investigate whether transplantation therapy with hybrid cell sheets of fibroblasts and QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM) induced by purified porcine cardiac myosin. The transplanted hybrid cell sheet exerts cardioprotective effects against EAM, resulting in limited left ventricular remodeling and partially improved cardiac functions due to revascularization, anti-inflammation, and anti-fibrosis. Thus, tissue engineering using hybrid cell sheets of fibroblasts constructed with QQMNCs is expected to provide an effective therapeutic option for patients with severe FM.Fulminant myocarditis causes impaired cardiac function, leading to poor prognosis and heart failure. Cell sheet engineering is an effective therapeutic option for improving cardiac function. Naïve blood mononuclear cells (MNCs) have been previously shown to enhance the quality and quantity of cellular fractions (QQMNCs) with anti-inflammatory and vasculogenic potential using the one culture system. Herein, we investigated whether autologous cell sheet transplant with QQMNCs improves cardiac function in a rat model with experimental autoimmune myocarditis (EAM). Fibroblast sheets (F-sheet), prepared from EAM rats, were co-cultured with or without QQMNCs (QQ+F sheet) on temperature-responsive dishes. QQ+F sheet induced higher expression of anti-inflammatory and vasculogenic genes (Vegf-b, Hgf, Il-10, and Mrc1/Cd206) than the F sheet. EAM rats were transplanted with either QQ+F sheet or F-sheet, and the left ventricular (LV) hemodynamic analysis was performed using cardiac catheterization. Among the three groups (QQ+F sheet, F-sheet, operation control), the QQ+F sheet transplant group showed alleviation of end-diastolic pressure–volume relationship on a volume load to the same level as that in the healthy group. Histological analysis revealed that QQ+F sheet transplantation promoted revascularization and mitigated fibrosis by limiting LV remodeling. Therefore, autologous QQMNC-modified F-sheets may be a beneficial therapeutic option for EAM.