End-systolic Pressure-volume Relationship Research Articles

A Lumped Two-Compartment Model for Simulation of Ventricular Pump and Tissue Mechanics in Ischemic Heart Disease.

Introduction: Computational modeling of cardiac mechanics and hemodynamics in ischemic heart disease (IHD) is important for a better understanding of the complex relations between ischemia-induced heterogeneity of myocardial tissue properties, regional tissue mechanics, and hemodynamic pump function. We validated and applied a lumped two-compartment modeling approach for IHD integrated into the CircAdapt model of the human heart and circulation. Methods: Ischemic contractile dysfunction was simulated by subdividing a left ventricular (LV) wall segment into a hypothetical contractile and noncontractile compartment, and dysfunction severity was determined by the noncontractile volume fraction (). Myocardial stiffness was determined by the zero-passive stress length ( and nonlinearity () of the passive stress-sarcomere length relation of the noncontractile compartment. Simulated end-systolic pressure volume relations (ESPVRs) for 20% acute ischemia were qualitatively compared between a two- and one-compartment simulation, and parameters of the two-compartment model were tuned to previously published canine data of regional myocardial deformation during acute and prolonged ischemia and reperfusion. In six patients with myocardial infarction (MI), the was automatically estimated using the echocardiographic LV strain and volume measurements obtained acutely and 6 months after MI. Estimated segmental values at the baseline and 6-month follow-up were compared with percentage late gadolinium enhancement (LGE) at 6-month follow-up. Results: Simulation of 20% of shifted the ESPVR rightward while moderately reducing the slope, while a one-compartment simulation caused a leftward shift with severe reduction in the slope. Through tuning of the , , and , it was found that manipulation of the alone reproduced the deformation during acute ischemia and reperfusion, while additional manipulations of and were required to reproduce deformation during prolonged ischemia and reperfusion. Out of all segments with LGE>25% at the follow-up, the majority (68%) had higher estimated at the baseline than at the follow-up. Furthermore, the baseline correlated better with percentage LGE than did at the follow-up. Conclusion: We successfully used a two-compartment model for simulation of the ventricular pump and tissue mechanics in IHD. Patient-specific optimizations using regional myocardial deformation estimated the in a small cohort of MI patients in the acute and chronic phase after MI, while estimated values closely approximated the extent of the myocardial scar at the follow-up. In future studies, this approach can facilitate deformation imaging–based estimation of myocardial tissue properties in patients with cardiovascular diseases.

The Underlying Cardiovascular Mechanisms of Resuscitation and Injury of REBOA and Partial REBOA.

Introduction: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is used for aortic control in hemorrhagic shock despite little quantification of its mechanism of resuscitation or cardiac injury. The goal of this study was to use pressure-volume (PV) loop analysis and direct coronary blood flow measurements to describe the physiologic changes associated with the clinical use of REBOA. Methods: Swine underwent surgical and vascular access to measure left ventricular PV loops and left coronary flow in hemorrhagic shock and subsequent placement of occlusive REBOA, partial REBOA, and no REBOA. PV loop characteristics and coronary flow are compared graphically with PV loops and coronary waveforms, and quantitatively with measures of the end systolic and end pressure volume relationship, and coronary flow parameters, with accounting for multiple comparisons. Results: Hemorrhagic shock was induced in five male swine (mean 53.6 ± 3.6 kg) as demonstrated by reduction of stroke work (baseline: 3.1 vs. shock: 1.2 L*mmHg, p < 0.01) and end systolic pressure (ESP; 109.8 vs. 59.6 mmHg, p < 0.01). ESP increased with full REBOA (178.4 mmHg; p < 0.01), but only moderately with partial REBOA (103.0 mmHg, p < 0.01 compared to shock). End systolic elastance was augmented from baseline to shock (1.01 vs. 0.39 ml/mmHg, p < 0.01) as well as shock compared to REBOA (4.50 ml/mmHg, p < 0.01) and partial REBOA (3.22 ml/mmHg, p = 0.01). Percent time in antegrade coronary flow decreased in shock (94%–71.8%, p < 0.01) but was rescued with REBOA. Peak flow increased with REBOA (271 vs. shock: 93 ml/min, p < 0.01) as did total flow (peak: 2136, baseline: 424 ml/min, p < 0.01). REBOA did not augment the end diastolic pressure volume relationship. Conclusion: REBOA increases afterload to facilitate resuscitation, but the penalty is supraphysiologic coronary flows and imposed increase in LV contractility to maintain cardiac output. Partial REBOA balances the increased afterload with improved aortic system compliance to prevent injury.

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.

Apical Myectomy in HCM: Time to Let the Rubber of the Operation Meet the Road of a Randomized Trial

In the context of the Batista operation, Mark Ratcliffe1 suggested that success of remodeling the left ventricle (LV) depends on how it affects both end-systolic pressure-volume (elastance) and diastolic pressure-volume (compliance) relationships. In this manuscript and in a 2020 manuscript, the authors suggest that in patients with nonobstructive hypertrophic cardiomyopathy (nHCM), an apical myectomy alters the LV diastolic properties by augmenting LV volume while decreasing LV end-diastolic pressure, thus increasing stroke volume.

Sex related differences in exercise performance in patients with hypertrophic cardiomyopathy: Hemodynamic insights through non-invasive pressure volume analysis

BackgroundWomen with HCM have worse cardiopulmonary exercise performance compared to men. We used non-invasive pressure-volume (PV) analysis to delineate sex related hemodynamic differences in HCM. MethodsPV loops were constructed from echocardiograms using left ventricular (LV) volumes indexed to body surface area, Doppler estimates of LV end-diastolic pressure and blood pressure. The end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR) were derived from validated single-beat techniques. The area between the ESPVR and EDPVR (isovolumetric PV area), was indexed to an LV end-diastolic pressure of 30 mmHg (PVAiso30), as the integrated metric of LV function. LV volume at an end-diastolic pressure of 30 mmHg (V30) indexed ventricular capacity. Results202 patients were included, 56 women. Women were older (51 vs 44 years, p = 0.012) and had reduced exercise capacity (5.6 vs 6.9 METs, p < 0.001). Only 32 patients (16%) had a peak gradient >30 mmHg at rest with no sex differences. Women had significantly lower indexed PVAiso30 (9094 vs 10,255 mmHg*mL/m2, p = 0.02) driven by reduced ventricular capacitance (V30 54 vs 62 mL/m2, p < 0.001). In multivariable linear regression indexed V30 was an independent predictor of exercise capacity. ConclusionImpaired exercise capacity in women with HCM appears associated with abnormalities in passive diastolic properties, suggesting a unique pathophysiology compared to men, and a potential difference in viable therapeutic molecular targets.

Pressure-volume relationship by pharmacological stress cardiovascular magnetic resonance.

The variation between rest and peak stress end-systolic pressure-volume relation (ΔESPVR) is an index of myocardial contractility, easily obtained during routine stress echocardiography and never tested during dipyridamole stress-cardiac magnetic resonance (CMR). We assessed the ΔESPVR index in patients with known/suspected coronary artery disease (CAD) who underwent dipyridamole stress-CMR. One-hundred consecutive patients (24 females, 63.76 ± 10.17years) were considered. ESPVR index was evaluated at rest and stress from raw measurement of systolic arterial pressure and end-systolic volume by biplane Simpson's method. The ΔESPVR index showed a good inter-operator reproducibility. Mean ΔESPVR index was 0.48 ± 1.45mmHg/mL/m2. ΔESPVR index was significantly lower in males than in females. ΔESPVR index was not correlated to rest left ventricular end-diastolic volume index or ejection fraction. Forty-six of 85 patients had myocardial fibrosis detected by the late gadolinium enhancement technique and they showed significantly lower ΔESPVR values. An abnormal stress CMR was found in 25 patients and they showed significantly lower ΔESPVR values. During a mean follow-up of 56.34 ± 30.04months, 24 cardiovascular events occurred. At receiver-operating characteristic curve analysis, a ΔESPVR < 0.02mmHg/mL/m2 predicted the presence of future cardiac events with a sensitivity of 0.79 and a specificity of 0.68. The noninvasive assessment of the ΔESPVR index during a dipyridamole stress-CMR exam is feasible and reproducible. The ΔESPVR index was independent from rest LV dimensions and function and can be used for a comparative assessment of patients with different diseases. ΔESPVR indexby CMR can be a useful and simple marker for additional prognostic stratification.

Abstract 11209: KER-012, a Novel Modified ActrII Ligand Trap, Attenuated Cardiac Pathology in a Pulmonary Arterial Banding Model of Right Ventricle Overload

Pulmonary arterial hypertension (PAH) is a debilitating disorder, characterized by right ventricle (RV) pressure overload, cardiac hypertrophy, and progressive RV dysfunction. PAH is associated with unbalanced TGFß signaling, favoring signaling of SMAD2/3 and opposing SMAD1/5/9. The result is an increase in vascular proliferation and disruption of vascular homeostasis. KER-012 is a modified ActRII ligand trap designed to inhibit ligands that signal through SMAD2/3 to promote restoration of vascular homeostasis. To investigate the cardio-protective effects of RKER-012, a research version of KER-012, we evaluated the effect of treatment in a pulmonary arterial banding (PAB) model. In this study, 8-week-old, male C57BL/6 mice underwent sham or PAB surgery to increase RV pressure and induce cardiac remodeling. The sham cohort received vehicle (VEH) treatment and PAB mice received either vehicle (VEH) or 10 mg/kg RKER-012 twice weekly for 3 weeks. Relative to sham mice, all PAB mice had elevated pulmonary arterial pressures on day 1 (all ps&lt;0.0001) that persisted until day 21 (all ps&lt;0.01), indicating that the PAB procedure was effective. VEH PAB mice also exhibited diminished cardiac function, including increased end systolic pressure volume relationship (ESPVR; +79.3%; p&lt;0.001) and increased myocardial performance index (MPI; +45.6%; p&lt;0.0001) compared to Sham VEH. Additionally, VEH PAB mice had markers of cardiac remodeling, including increased Fulton Indices (+54.8%; p&lt;0.0001), increased RV free wall thickness (RVFWT; +95.8%; p&lt;0.0001) and increased cardiac fibrotic tissue (+529.9%; p&lt;0.0001). In contrast, RKER-012 treatment was cardioprotective and prevented changes in cardiac function and tissue remodeling. In treated mice, there was a trend for decreased ESPVR (-14.2%), decreased MPI (-13.2%, p&lt;0.01), decreased Fulton Index (-13.5%; p&lt;0.01), and decreased RVFWT (-22.9%; p&lt;0.0001) compared to VEH PAB. Treated mice also had reduced cardiac fibrotic tissue (-38.9%, p&lt;0.01). Taken together, these data provide evidence that KER-012 has the potential to reduce cardiac remodeling and improve cardiac performance in pathologies involving constricted pulmonary arterial blood flow and could provide benefit in diseases such as PAH.

Sex related differences in exercise performance in patients with hypertrophic cardiomyopathy: hemodynamic insights through non-invasive pressure volume analysis

Abstract Background Women with HCM have worse cardiopulmonary exercise performance compared to men. We used non-invasive pressure-volume (PV) analysis to delineate sex related hemodynamic differences in HCM. Methods PV loops were constructed from echocardiograms using left ventricular (LV) volumes indexed to body surface area, Doppler estimates of LV end-diastolic pressure and blood pressure. The end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR) were derived from validated single-beat techniques. The area between the ESPVR and EDPVR (isovolumetric PV area), was indexed to an LV end-diastolic pressure of 30mmHg (PVAiso30), as the integrated metric of LV function. LV volume at an end-diastolic pressure of 30mmHg (V30) indexed ventricular capacity. Results 202 patients were included, 56 women. Women were older (51 vs 44 yrs, p=0.012) and had reduced exercise capacity (5.6 vs 6.9 METs, p&amp;lt;0.001). Only 32 patients (16%) had a peak gradient &amp;gt;30mmHg at rest with no sex differences. Women had significantly lower indexed PVAiso30 (6577 vs 7767 mmHg·mL/m2, p&amp;lt;0.001) driven by reduced ventricular capacitance (V30 54 vs 62 ml/m2, p&amp;lt;0.001). In multivariable linear regression indexed V30 was an independent predictor of exercise capacity. Conclusion Impaired exercise capacity in women with HCM appears strongly related to abnormalities in passive diastolic properties, suggesting a unique pathophysiology compared to men, and a potential difference in viable therapeutic molecular targets Funding Acknowledgement Type of funding sources: None.

Inflammasome-mediated neurodegeneration following heart disease.

BackgroundMyocardial infarction (MI) has been suggested as a critical predisposing factor for Alzheimer’s disease (AD); however, the underlying mechanisms remain unknown. PYD domains-containing protein 3 (NLRP3) is a key factor to mediate inflammasome formation. Previous studies have shown that NLRP3 activation in brain microglia is required for AD; however, its possible role in MI-induced future development of neurodegeneration is not yet understood. These questions were addressed in the current study.MethodsWe generated microglia-specific NLRP3 mutation mice in the AD-prone APP/PS1 background (APP/PS1/NLRP3MKO), and studied the neurodegeneration in these mice after MI compared to the control wild-type C57/BL6J or APP/PS1 mice. NLRP3, IL-1β and caspase-1 levels were determined by Enzyme-linked immunoassay (ELISA). The heart function was determined by the slope of end systolic pressure-volume relationship, left ventricular end diastolic pressure, the positive maximal pressure derivative as well as the degree of fibrosis by Masson’s trichrome staining. Mouse behavior measurement includes Morris water-maze test and motor assessment.ResultsWe found that compared with the control wild-type C57/BL6J or APP/PS1 mice, the effects of MI on the subsequent development of defected spatial reference memory and motor activity were all attenuated in APP/PS1/NLRP3MKO mice, likely resulting from the reduced formation of amyloid-beta peptide aggregates (Aβ) plaques.ConclusionsNLRP3 may play a non-redundant role in the MI-induced future development of AD.

A finite element model of the cardiac ventricles with coupled circulation: Biventricular mesh generation with hexahedral elements, airbags and a functional mockup interface to the circulation

IntroductionFinite element (FE) mechanics models of the heart are becoming more sophisticated. However, there is lack of consensus about optimal element type and coupling of FE models to the circulation. We describe biventricular (left (LV) and right (RV) ventricles) FE mechanics model creation using hexahedral elements, airbags and a functional mockup interface (FMI) to lumped-parameter models of the circulation. MethodsCardiac MRI (CMR) was performed in two healthy volunteers and a single patient with ischemic heart disease (IHD). CMR images were segmented and surfaced, meshing with hexahedral elements was performed with a “thin butterfly with septum” topology. LV and RV inflow and outflow airbags were coupled to lumped-parameter circulation models with an FMI interface. Pulmonary constriction (PAC) and vena cava occlusion (VCO) were simulated and end-systolic pressure-volume relations (ESPVR) were calculated. ResultsMesh construction was prompt with representative contouring and mesh adjustment requiring 32 and 26 min Respectively. The numbers of elements ranged from 4104 to 5184 with a representative Jacobian of 1.0026 ± 0.4531. Agreement between CMR-based surfaces and mesh was excellent with root-mean-squared error of 0.589 ± 0.321 mm. The LV ESPVR slope was 3.37 ± 0.09 in volunteers but 2.74 in the IHD patient. The effect of PAC and VCO on LV ESPVR was consistent with ventricular interaction (p = 0.0286). ConclusionSuccessful co-simulation using a biventricular FE mechanics model with hexahedral elements, airbags and an FMI interface to lumped-parameter model of the circulation was demonstrated. Future studies will include comparison of element type and study of cardiovascular pathologies and device therapies.

Novel insights into the athlete's heart: is myocardial work the new champion of systolic function?

AimsWe sought to investigate the correlation between speckle-tracking echocardiography (STE)-derived myocardial work (MW) and invasively measured contractility in a rat model of athlete's heart. We also assessed MW in elite athletes and explored its association with cardiopulmonary exercise test (CPET)-derived aerobic capacity.Methods and resultsSixteen rats underwent a 12-week swim training program and were compared to controls (n = 16). STE was performed to assess global longitudinal strain (GLS), which was followed by invasive pressure-volume analysis to measure contractility [slope of end-systolic pressure–volume relationship (ESPVR)]. Global MW index (GMWI) was calculated from GLS curves and left ventricular (LV) pressure recordings. In the human investigations, 20 elite swimmers and 20 healthy sedentary controls were enrolled. GMWI was calculated through the simultaneous evaluation of GLS and non-invasively approximated LV pressure curves at rest. All subjects underwent CPET to determine peak oxygen uptake (VO2/kg). Exercised rats exhibited higher values of GLS, GMWI, and ESPVR than controls (−20.9 ± 1.7 vs. −17.6 ± 1.9%, 2745 ± 280 vs. 2119 ± 272 mmHg·%, 3.72 ± 0.72 vs. 2.61 ± 0.40 mmHg/μL, all PExercise < 0.001). GMWI correlated robustly with ESPVR (r = 0.764, P < 0.001). In humans, regular exercise training was associated with decreased GLS (−17.6 ± 1.5 vs. −18.8 ± 0.9%, PExercise = 0.002) but increased values of GMWI at rest (1899 ± 136 vs. 1755 ± 234 mmHg·%, PExercise = 0.025). GMWI exhibited a positive correlation with VO2/kg (r = 0.527, P < 0.001).ConclusionsGMWI precisely reflected LV contractility in a rat model of exercise-induced LV hypertrophy and captured the supernormal systolic performance in human athletes even at rest. Our findings endorse the utilization of MW analysis in the evaluation of the athlete’s heart.

Patisiran Stabilizes Cardiac Mechanics in Patients with Hereditary Transthyretin-Mediated Amyloidosis: Post-hoc Analysis of the APOLLO Study

Hereditary transthyretin-mediated (hATTR) amyloidosis is caused by deposition of transthyretin (TTR) fibrils in the heart, nerves and other organs. Patisiran is a siRNA that inhibits hepatic synthesis of TTR. This post-hoc analysis used single-beat pressure-volume (PV) techniques to delineate the effects of patisiran on cardiac function in the APOLLO trial. Noninvasive PV loops were constructed from core laboratory echocardiograms using LV volumes, Doppler estimates of LV pressure and blood pressure. The end-systolic PV relationship (ESPVR) and end-diastolic PV relationship (EDPVR) were derived from previously validated techniques. The area between the ESPVR and EDPVR, the isovolumetric PV area, was indexed to a LV end-diastolic pressure of 30 mmHg (PVAiso30), as the metric of LV function over time. ANCOVA was used to assess significance in the least squares mean change from baseline in PVAiso30 between treatment arms at 9 and 18 months. At 9 months, the least squares mean change in PVAiso30 was -100 mmHg*mL on patisiran and -2013 mmHg*mL on placebo ( P < 0.001). At 18 months, the least squares mean change in PVAiso30 was -867 mmHg*mL on patisiran and -2314 mmHg*mL on placebo ( P = 0.019). PVAiso30 decline was driven by a decline in LV capacitance at both timepoints. Patisiran may delay progression of LV chamber dysfunction over 18 months of treatment. The safety and efficacy of patisiran is being studied in ATTR amyloidosis with cardiomyopathy in the APOLLO-B study.

V alidity of Assessing in vivo Cardiac Contractility Using A “Less‐Invasive” Approach during Mechanical Ventilation: Insights from Small and Large Animal Models

Background and Aims End-systolic elastance (Ees) derived from sequential pressure-volume (PV) loops acquired during inferior vena cava occlusion (IVCO) is the reference for quantification of in vivo left ventricular (LV) contractile performance. Given the challenges associated with midline laparotomy surgeries in animal models and the barriers of performing such measures in clinical practice, a number of single-beat estimations of LV contractile function have been proposed. Here, we examined the agreement between two single-beat estimates of Ees obtained from basal LV and arterial hemodynamics in rats and pigs and the Ees obtained from IVCO (Ees(IVC)). We also tested whether a novel approach of leveraging the respiratory-induced oscillations in cardiac PV (i.e., changes in intrathoracic pressure) during mechanical ventilation enables a “naturally” occurring change in cardiac preload and the subsequent estimation of Ees (Ees(RES)). Methods 38 Wistar rats (300-350g; aged 10 wks) and 22 Yucatan mini-pigs (20-25 kg, aged 8-12 wks) were used. Once anesthetized and ventilated, animals were instrumented with 1) a LV PV catheter for assessments of LV Ees(IVC) during IVCO and LV hemodynamics, and 2) a femoral arterial catheter to record basal systemic hemodynamics. Basal LV and arterial indices, including end-systolic volume (ESV), end-systolic pressure (ESP), and arterial systolic blood pressure (SBP), were averaged over a 30s (rats) or 60s period (pigs). Ees(IVC) was measured as the slope of end-systolic PV relationship (ESPVR). From the basal LV and arterial data we then calculated single-beat estimation of Ees(IVC), including the ESP and ESV ratio (EesSB1), and the ESP (SBP × 0.9) and EDV ratio (EesSB2). Estimation of Ees(RES) was analogous to Ees(IVC) however, respiratory-induced oscillations in cardiac preload, rather than an IVCO, was used to calculate the slope of the ESPVR. Absolute agreement between metrics was examined using intra-class correlation coefficients (ICC). Results In rats, while we found a moderate agreement between Ees(SB1) (ICC = 0.685, P < 0.001), Ees(SB2) (ICC = 0.685, P < 0.001) and Ees(IVC), there was excellent agreement between Ees(RES) and Ees(IVC) (ICC = 0.934 P < 0.001). In pigs, although a moderate agreement was observed between Ees(RES) and Ees(IVC) (ICC = 0.572, P = 0.033), no agreements were noted between Ees(SB1) (ICC = 0.352, P = 0.101), Ees(SB2) (ICC = 0.320, P = 0.0741) and Ees(IVC). Conclusion Thesefindings demonstrate that the single-beat estimates of Ees show moderate agreement with Ees(IVC) in rats. Utilizing the respiratory-induced changes in cardiac preload during mechanical ventilation, however, may provide a better less-invasive approach for estimation of cardiac contractile performance, especially in a small animal model.

Incorporating the anterior mitral leaflet to the annulus impairs left ventricular function in an ovine model

ObjectivesTranscatheter mitral valve prostheses are designed to capture the anterior leaflet and surgical techniques designed to fully preserve the subvalvular apparatus at prosthetic valve insertion both serve to shorten the anterior mitral leaflet height, thus effectively incorporating it into the anterior annulus. This study quantifies the acute effects of incorporating the anterior mitral leaflet into the annulus on left ventricular function. MethodsFourteen adult sheep (weight, 48.7 ± 6.2 kg) underwent a mechanical mitral valve insertion on normothermic beating-heart cardiopulmonary bypass, with full retention of the native mitral valve but with placement of exteriorized releasable snares around the anterior mitral leaflet. Continuous measurements of left ventricular mechano-energetics were recorded throughout, alternating incorporating and releasing of the anterior mitral leaflet to the mitral annulus. Echocardiography confirmed the incorporation into the annulus and release. ResultsThe independent indices of left ventricular contractility (ie, end systolic pressure volume relationship and preload recruitable stroke work) were both significantly impaired when the anterior mitral leaflet was incorporated to the annulus and restored after release, as were the hemodynamic parameters: cardiac output, stroke volume, stroke work, and left ventricular pressure decreased by 15%, 17%, 23%, and 11%, respectively. Echocardiography demonstrated increased sphericity of the left ventricle during anterior mitral leaflet incorporation. ConclusionsIncorporating the anterior mitral leaflet to the anterior annulus adversely affected left ventricular contractility, caused distortion of the left ventricle in the form of increased sphericity, and impaired hemodynamic parameters in normal ovine hearts.

High Oxygen is Likely to be Beneficial on Cardiac Contractility after Normothermic Regional Perfusion after Circulatory Death in a Porcine Model

<h3>Purpose</h3> The impact of high versus low oxygenation during normothermic regional perfusion (NRP) after anoxic circulatory death on donor heart contractility in a porcine model. <h3>Methods</h3> The animals were anaesthetized, pressure-volume catheters were placed in both ventricles and a pulmonary artery catheter was inserted percutaneously. Through a midline sternotomy, the heparinized animals were cannulated for extracorporeal circulation. Baseline data were obtained. Mechanical ventilation was withdrawn. After 15 minutes of warm ischemia, the aortic arch vessels and infrarenal aorta were clamped before NRP was commenced using a standard heart-lung machine. The animals were randomized to receive either FiO2 of 1.0 (HOX) or 0.21 (LOX) with a gradual increase to 0.40 during NRP. The NRP protocol includes early volume loading of the right ventricle and gradual wean over 35 minutes. Dobutamine and norepinephrine infusions were started during NRP for circulatory support. The animals were observed for 180 minutes after weaning from NRP. <h3>Results</h3> 15 of 19 animals were successfully weaned from NRP; 8/9 in the HOX and 7/10 in the LOX group, (p = 0.58). All weaned animals displayed acceptable cardiac function during the observation period and sustained a mean arterial pressure >60 mmHg with low filling pressures and cardiac index >2.5 L/min/m². The preload independent end-systolic pressure volume relationship as an index of contractility was preserved in both groups. The HOX RV contractility was higher than the LOX group (p=0.035); and not significantly in the LV (p=0.37) (Fig. 1). Biochemestry showed lower lactate levels in the HOX group. There was no difference in norepinephrine requirement between groups. <h3>Conclusion</h3> There were minimal haemodynamic and biochemical differences between the groups as all weaned animals demonstrated acceptable cardiac function. The high oxygenation group showed marginally better cardiac performance and lower lactate concentrations.

Improvement of Left but Not Right Ventricular Contractility after Circulatory Death and Normothermic Regional Perfusion in a Porcine Model

<h3>Purpose</h3> To investigate the impact of cerebral reperfusion on cardiac contractile function after normothermic regional perfusion (NRP) after anoxic circulatory death in a porcine model. <h3>Methods</h3> The animals were anaesthetized and biventricular pressure-volume catheters and a pulmonary artery catheter were inserted percutaneously. Through a midline sternotomy, the heparinised animals were cannulated for extracorporeal circulation. Baseline data were obtained before cessation of mechanical ventilation. Death was determined 5 minutes after mechanical asystole and after additional 3 minutes of warm ischemia NRP was started using a heart-lung machine. The animals were randomized before reperfusion to either clamping (CL) (n=8) or non-clamping (NCL) (n=8) of the aortic arch vessels; the infrarenal aorta was clamped in both groups. The NRP-protocol includes early volume loading of the right ventricle, infusion of dobutamine and norepinephrine and gradual wean over 30 minutes. The animals were observed for 180 minutes after weaning from NRP. <h3>Results</h3> All animals were successfully weaned from NRP. Both groups demonstrated an acceptable cardiac function after weaning with a mean arterial blood pressure above 75 mmHg and low filling pressures. The NCL group received significantly more norepinephrine (p=0.0484) than the CL group. The left ventricle End-systolic pressure-volume relationship as an index of contractility showed improvement in both groups after wean from NRP compared to baseline (p=0.0009). In the CL group, LV contractility showed a tendency to a better improvement compared to the NCL group (p=0.226) (Fig. 1). The RV showed preserved contractility in both groups. <h3>Conclusion</h3> LV contractility but not RV contractility improves after circulatory death and weaning from NRP. The improvement of the left ventricular contractility tends to be better when the aortic arch vessels are clamped compared to upper-body perfusion.

Angiotensin II blockers improve cardiac coronary flow under hemodynamic pressure overload.

Coronary flow velocity (CFV) is reduced in pathologic cardiac hypertrophy. This functional reduction is linked to adverse cardiac remodeling, hypertension and fibrosis, and angiotensin II (AngII) is a key molecular player. Angiotensin receptor blockers (ARBs) are known to attenuate adverse cardiac remodeling and fibrosis following increased afterload, while the mechanism by which these drugs offer clinical benefits and regulate hemodynamics remains unknown. To establish a direct connection between coronary flow changes and angiotensin-induced hypertension, we used a Doppler echocardiographic method in two distinct disease models. First, we performed serial echocardiography to visualize coronary flow and assess heart function in patients newly diagnosed with hypertension and currently on ARBs or calcium channel blockers (CCBs). CFV improved significantly in the hypertensive patients after 12 weeks of ARB treatment but not in those treated with CCBs. Second, using murine models of pressure overload, including Ang II infusion and aortic banding, we mimicked the clinical conditions of Ang II- and mechanical stress-induced hypertension, respectively. Both Ang II infusion and aortic banding increased the end-systolic pressure-volume relationship and cardiac fibrosis, but interestingly, only Ang II infusion resulted in a significant reduction in CFV and corresponding activation of pressure-sensitive proteins, including connective tissue growth factor, hypoxia-inducible factor 1α and signal transducer and activator of transcription 3. These data support the existence of a molecular and functional link between AngII-induced hemodynamic remodeling and alterations in coronary vasculature, which, in part, can explain the clinical benefit of ARB treatment in hypertensive patients.

Myocardial repair of bioengineered cardiac patches with decellularized placental scaffold and human-induced pluripotent stem cells in a rat model of myocardial infarction

BackgroundThe creation of a bioengineered cardiac patch (BCP) is a potential novel strategy for myocardial repair. Nevertheless, the ideal scaffold for BCP is unknown.ObjectiveWe investigated whether the decellularized placenta (DP) could serve as natural scaffold material to create a BCP for myocardial repair.Methods and resultsA BCP was created by seeding human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs; 1 × 106/cm2) onto DP. The functional and electrophysiological properties of the BCP were first characterized by in vitro analysis and optical mapping. Next, in vivo therapeutic efficacy of the BCP was evaluated in a rat model of myocardial infarction (MI), created by left descending coronary artery ligation (MI + BCP group), and compared with MI alone (MI group), transplantation of DP (MI + DP group), and hiPSC-CMs (MI + CM group). Cytokine profiling demonstrated that the BCP contained multiple growth and angiogenic factors, including vascular endothelial growth factor, platelet-derived growth factor, insulin-like growth factor-1, basic fibroblast growth factor, angiogenin, and angiopoietin-2. In vitro optical mapping showed that the BCP exhibited organized mechanical contraction and synchronized electrical propagation. RNA sequencing showed that DP enhanced the maturation of hiPSC-CMs compared with the monolayer of cultured hiPSC-CMs. At 4 weeks follow-up, the BCP significantly improved left ventricular (LV) function, as determined by LV ejection fraction, fractional shortening, + dP/dtmax, and end-systolic pressure-volume relationship, compared with the MI, MI + DP, and MI + CM groups. Moreover, histological examination revealed that engraftment of the BCP at the infarct zone decreased infarct size and increased cell retention and neovascularization compared with the MI, MI + DP, and MI + CM groups.ConclusionsOur results demonstrate that a DP scaffold contains multiple growth and angiogenic factors that enhance the maturation and survival of seeded hiPSC-CMs. Transplantation of a BCP is superior to DP or hiPSC-CMs alone in reducing infarct size and improving cell retention and neovascularization, thus providing a novel therapy for myocardial repair following MI.

Abstract 16282: The Development of the New Treatment for Distressed Microvascular Dysfunction in Porcine Dilated Cardiomyopathy Model Using Induced Pluripotent Stem Cell Derived Cardiomyocyte Sheet

Introduction: The progression of dilated cardiomyopathy (DCM) mainly involves genetic mutations or ischemia at the cellular level, leading to microvascular dysfunction associated with cell death, interstitial fibrosis, and high wall stress. Radical treatment of DCM requires how to ameliorate its microcirculation and integrate cardiomyocytes created ex vivo into recipient myocardium. Hypothesis: The induced pluripotent stem cell derived cardiomyocyte sheets (iPS-sheet) has therapeutic potential by the improvement of microcirculation in a porcine DCM model. Methods: The iPS-sheets were generated from clinical grade human iPS cells. A DCM model was created by tachycardia pacing, and iPS-sheet was transplanted with immunosuppressive agents 1 month after the initiation of the pacing. We compared the therapeutic efficacy functionally and pathologically between the iPS-sheet transplant group (iPS-group) and the sham group after 1 month of transplantation. Results: On echocardiography, the iPS group showed a significant improvement in contractility compared to the sham group (LVEF 4 weeks after transplantation iPS vs. sham 49.0±6.5% vs. 36.4±3.3%, p&lt;0.05, Figure A). Pressure-volume loop analysis revealed that a significant decrease in left ventricular end diastolic pressure and an improvement in end-systolic pressure-volume relationship in the iPS group (Figure B). Ammonia PET showed improvement in myocardial blood flow at both rest and stress in iPS group (Figure C). Histological analysis revealed that the density of CD31-positive capillaries in transplanted area was significantly greater in the iPS group than the sham group. Immunostaining revealed iPS-sheet were detected on the epicardium of the distressed myocardium (Figure D). Conclusions: The iPS sheet showed engraftment in distressed myocardium, leading to amelioration in cardiac function through improving microcirculation with angiogenesis in porcine DCM model.