Ventricular Pressure-volume Relationship Research Articles

Application of Cardiovascular Physiology to the Critically Ill Patient.

To use the ventricular pressure-volume relationship and time-varying elastance model to provide a foundation for understanding cardiovascular physiology and pathophysiology, interpreting advanced hemodynamic monitoring, and for illustrating the physiologic basis and hemodynamic effects of therapeutic interventions. We will build on this foundation by using a cardiovascular simulator to illustrate the application of these principles in the care of patients with severe sepsis, cardiogenic shock, and acute mechanical circulatory support. Publications relevant to the discussion of the time-varying elastance model, cardiogenic shock, and sepsis were retrieved from MEDLINE. Supporting evidence was also retrieved from MEDLINE when indicated. Data from relevant publications were reviewed and applied as indicated. The ventricular pressure-volume relationship and time-varying elastance model provide a foundation for understanding cardiovascular physiology and pathophysiology. We have built on this foundation by using a cardiovascular simulator to illustrate the application of these important principles and have demonstrated how complex pathophysiologic abnormalities alter clinical parameters used by the clinician at the bedside.

Noninvasive Assessment of Left Ventricular Pressure-Volume Relations: Inter- and Intraobserver Variability and Assessment Across Heart Failure Subtypes

A novel method to derive pressure-volume (PV) loops noninvasively from cardiac magnetic resonance images has recently been developed. The aim of this study was to evaluate inter- and intraobserver variability of hemodynamic parameters obtained from noninvasive PV loops in healthy controls, subclinical diastolic dysfunction (SDD), and patients with heart failure with preserved ejection fraction, mildly reduced ejection fraction, and reduced ejection fraction. We included 75 subjects, of whom 15 were healthy controls, 15 subjects with SDD (defined as fulfilling 1 to 2 echocardiographic criteria for diastolic dysfunction), and 15 patients with preserved ejection fraction, 15 with mildly reduced ejection fraction, and 15 with reduced ejection fraction. PV loops were computed using time-resolved left ventricular volumes from cardiac magnetic resonance images and a brachial blood pressure. Inter- and intraobserver variability and intergroup differences of PV loop-derived hemodynamic parameters were assessed. Bias was low and limits of agreement were narrow for all hemodynamic parameters in the inter- and intraobserver comparisons. Interobserver difference for stroke work was 2 ± 9%, potential energy was 4 ± 11%, and maximal ventricular elastance was -4 ± 7%. Intraobserver for stroke work was -1 ± 7%, potential energy was 3 ± 4%, and maximal ventricular elastance was 1 ± 5%. In conclusion, this study presents a fully noninvasive left ventricular PV loop analysis across healthy controls, subjects with SDD, and patients with heart failure with preserved or impaired systolic function. In conclusion, the method for PV loop computation from clinical-standard manual left ventricular segmentation was rapid and robust, bridging the gap between clinical and research settings.

An Investigation of Left Ventricular Valve Disorders and the Mechano-Electric Feedback Using a Synergistic Lumped Parameter Cardiovascular Numerical Model.

Cardiac diseases and failure make up one of largest contributions to global mortality and significantly detriment the quality of life for millions of others. Disorders in the valves of the left ventricle are a prominent example of heart disease, with prolapse, regurgitation, and stenoses—the three main valve disorders. It is widely known that mitral valve prolapse increases the susceptibility to cardiac arrhythmia. Here, we investigate stenoses and regurgitation of the mitral and aortic valves in the left ventricle using a synergistic low-order numerical model. The model synergy derives from the incorporation of the mechanical, chemical, and electrical elements. As an alternative framework to the time-varying elastance (TVE) method, it allows feedback mechanisms at work in the heart to be considered. The TVE model imposes the ventricular pressure–volume relationship using a periodic function rather than calculating it consistently. Using our synergistic approach, the effects of valve disorders on the mechano-electric-feedback (MEF) are investigated. The MEF is the influence of cellular mechanics on the electrical activity, and significantly contributes to the generation of arrhythmia. We further investigate stenoses and regurgitation of the mitral and aortic valves and their relationship with the MEF and generation of arrhythmia. Mitral valve stenosis is found to increase the sensitivity to arrhythmia-stimulating systolic stretch, and reduces the sensitivity to diastolic stretch. Aortic valve stenosis does not change the sensitivity to arrhythmia-stimulating stretch, and regurgitation reduces it. A key result is found when valve regurgitation is accompanied by diastolic stretch. In the presence of MEF disorder, ectopic beats become far more frequent when accompanied by valve regurgitation. Therefore, arrhythmia resulting from a disorder in the MEF will be more severe when valve regurgitation is present.

Effect of Classic or Delayed Ischemic Conditioning on Left Ventricular Pressure-Volume Relations in Dogs

Objective: Non-pharmacologic interventions such as ischemic conditioning (IC) markedly reduce infarct size but it remains unclear whether this protection translates to a significant attenuation of ischemia-mediated LV contractile dysfunction. In this study we evaluated pressure-volume (P-V) data obtained by the load-insensitive conductance catheter method, to examine LV pressure-volume (LVP-V), diastolic function and ventricular-arterial coupling in anesthetized dogs exposed to ischemic conditioning (IC) or delayed IC (dIC; 48h prior to ischemia). The objective was to determine if IC, or dIC pre-treatment could influence post-ischemic recovery of LV contractile function. Methods: Three groups were studied – nIC, IC and dIC; all dogs underwent 90-min acute coronary occlusion (CO) followed by 180-min reperfusion (REP). IC consisted of 4 cycles of 5-min CO and 5-min REP of the left main coronary artery. LV P-V relations were constructed under steady-state conditions (by transient occlusion of the inferior vena cava) prior to IC treatment and at the end of the experiment; P-V loop data was also acquired at different points during the experiment to evaluate changes in end-systolic and end-diastolic parameters. Results: During CO dP/dtmax and dP/dtmin (indicator of rate of LV relaxation) decreased significantly compared to baseline in the IC group; these variables were unchanged in the dIC group. LVEF decreased during CO and REP in the nIC and IC groups but was stable in the dIC group. Tau was increased only in the IC group during CO and REP. ESV and EDV increased significantly in all groups during CO and REP; none of these negative effects was resorbed by the end of the experimental period. Conclusions: Diminished LV contractile function caused by CO did not improve with IC, or dIC pre-treatment, despite significant reduction in infarct size.

Impact of Acute Ischemia-Reperfusion Injury on Left Ventricular Pressure-Volume Relations in Dogs

Objective: Ischemic conditioning (IC) limits myocyte necrosis after acute myocardial ischemia-reperfusion; however, controversy persists regarding its potential to attenuate LV contractile dysfunction. Pressure-volume (P-V) loop analysis, via the load-insensitive conductance catheter method, was used to evaluate LV contractility, diastolic function, and ventriculo-arterial coupling. The goal of this study was to evaluate the ability of IC to improve post-ischemic recovery of LV contractile function. Methods: Twelve anesthetized dogs were randomly distributed to either the IC or the non-IC group; all dogs were subject to 60-min acute coronary occlusion followed by 180-min reperfusion. IC consisted of 4 repeated cycles of 5-min occlusion and 5-min reperfusion of the left main coronary artery. LV P-V relations were constructed under steady-state conditions (by inferior vena cava occlusion) at the beginning and end of the experiments; P-V loops were acquired at different time points before and during ischemia-reperfusion. Results: During ischemia and reperfusion, dP/dtmax decreased significantly compared to baseline in both groups; dP/dtmin, an indicator of the rate of LV relaxation rate was not affected for either group. Significant changes in several parameters of LV function including LVEF, SW, tPFR, ESV, and EDV caused by ischemia were also identified; none of these negative effects were resorbed, even in part, during reperfusion. Conclusions: Diminished LV contractile efficiency during systole and diastole produced by ischemia-reperfusion did not improve with IC pre-treatment despite significant endogenous protection against tissue necrosis.

Abstract 10486: Single-Beat Estimation Right Ventricular End Diastolic Pressure Relationship

Introduction: An abnormal right ventricular (RV) end-diastolic pressure-volume relationship (EDPVR) is an early marker of poor prognosis in pulmonary arterial hypertension (PAH). Prior studies assessing RV diastolic impairment utilized pressure (P) measured at right heart catheterization (RHC) and non-simultaneous volume (V) measured by cardiac magnetic resonance imaging (cMRI), which serves as the current reference standard for V. Our aims were: (a) to validate a single-beat (SB) method to assess RV EDPVR in an animal model against multi-beat (MB) measurements during preload variation, and (b) to use V obtained via transthoracic 3D echocardiography (3DE) during simultaneous RHC. Methods: In six anesthetized swine under an Institutional Animal Care & Use Committee-approved protocol, a SB method was used to derive EDPVR as V 15 , the previously described predicted ventricular V at a theoretical EDP of 15 mmHg. A multi-beat (MB) reference EDPVR was defined using conductance/micromanometer catheter-measured RVP and V during preload variation. The V 15 value derived from the SB method was compared by Bland-Altman analysis to that defined by the reference EDPVR. Clinically, the SB method was applied to 13 patients with PAH and 10 age- and gender-matched controls who underwent RHC with simultaneous transthoracic 3DE. V 15 values between groups were compared by t-test. Results: In the animal model there was strong correlation between MB and SB estimates of V 15 (r=0.95; p<0.0001) with acceptable accuracy and precision (bias -4.2±6.1 mL, overall error 8.4%). Consistent with previous reports using cMRI, PAH patients exhibited greater V 15 (166±43 mL vs. 131±30 mL; p=0.04) (Figure 1) . Conclusion: This study demonstrates validity of a SB assessment of RV EDPVR using data obtained from transthoracic 3DE performed during RHC, obviating the need for non-simultaneous cMRI. Further studies are needed to examine SB assessment of RV EDPVR across the spectrum of PH phenotypes.

A Targeted Treatment Opportunity for HFpEF: Taking Advantage of Diastolic Tone.

A Targeted Treatment Opportunity for HFpEF: Taking Advantage of Diastolic Tone.

Automated non-invasive pressure-volume loop analysis of cardiac aging in a large cohort of healthy community dwellers

Abstract Background/Introduction Pressure-volume loops (PVloops) provide a wealth of information on cardiac function that is not readily available from cardiac imaging alone. Methods To estimate left ventricular (LV) PVloops non-invasively have been available, but have so far not been used to interrogate ventricular function in large patient cohorts, due to the complexity of estimating PVloops. A new method was recently validated that construct PVloops non-invasively from cine cardiac magnetic resonance (CMR), based on the time-varying elastance model [1]. At the same time, we have validated a framework for automated, quality controlled analysis of cine CMR in large cohorts of patients/subjects [2]. Combining these two methods could automated PVloop estimation, enabling analysis of ventricular pressure-volume relationships in large study populations. Purpose Evaluate if CMR-based non-invasive PVloops can be used to interrogate the impact of cardiac ageing on LV function occurring in a large population of healthy community dwellers. Methods Non-invasive PVloops were calculated from a full cardiac cycle LV volume curve and brachial blood pressure data using a recently validated method based on the time-varying elastance model [1], in 7,650 healthy community dwellers from the UKBiobank population study. The LV volume curve was automatically obtained using our state-of-the-art, quality controlled deep learning (DL) based cine CMR analysis framework [2]. External Work, pressure-volume-area (PVA), end-systolic pressure (Pes), ventricular elastance (Ees, an estimate of contractility) and arterial elastance (Ea) and energy per ejected volume (EEV: PVA/ stroke volume) were calculated from the PVloops. We performed univariate regression between PVloop parameters and age. We also calculated the additional impact of cardiovascular risk-factors in a multivariate analysis. Results See results in table 1. With age, LV volumes fall (p<0.001) in healthy subjects, while systolic blood pressure and Pes increases (both p<0.001). As a result of the higher afterload, PVA (p=0.894) and EW (p=0.499) do not significantly change with age despite a lower SV. Arterial elastance (Ea) increased, and so did contractility, as measured by Ees (p<0.001). Due to all these changes, EEV increased with age (p<0.001). In multivariate analysis, cardiovascular risk factors hypercholesterolemia and hypertension negatively impacted Pes, PVA, Ees and EEV. Diabetes and smoking habits did not. Conclusion Non-invasive CMR-based PVloop analyses capture the impact of known changes occurring during cardiac ageing on cardiac work, contractility and energetic expenditure. Obtaining PVloops automatically using our AI analysis system in this large cohort of healthy subjects allows to formulate reference for assessment of cardiac disease. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The authors acknowledge financial support (support) the National Institute for Health Research (NIHR) Cardiovascular MedTech Co-operative (previously existing as the Cardiovascular Healthcare Technology Co-operative 2012 - 2017) award to the Guy's and St Thomas' NHS Foundation Trust, in partnership with King's College London and the NIHR comprehensive Biomedical Research Centre of the Guy's & St Thomas' NHS Foundation Trust. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health Univariate regression analysisExample of estimated PV loop

Acute Impact of Prone Positioning on the Right Ventricle in COVID-19-Associated Acute Respiratory Distress Syndrome.

HomeCirculation: Heart FailureVol. 14, No. 8Acute Impact of Prone Positioning on the Right Ventricle in COVID-19–Associated Acute Respiratory Distress Syndrome Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBAcute Impact of Prone Positioning on the Right Ventricle in COVID-19–Associated Acute Respiratory Distress Syndrome Nils C. Kremer, MD, Manuel J. Richter, MD, Zvonimir A. Rako, MD and Khodr Tello, MD Nils C. KremerNils C. Kremer https://orcid.org/0000-0002-5615-0214 Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Germany. Search for more papers by this author , Manuel J. RichterManuel J. Richter Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Germany. Search for more papers by this author , Zvonimir A. RakoZvonimir A. Rako https://orcid.org/0000-0003-0539-0362 Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Germany. Search for more papers by this author and Khodr TelloKhodr Tello Correspondence to: Khodr Tello, MD, Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Klinikstr 33, 35392 Giessen, Germany. Email E-mail Address: [email protected] https://orcid.org/0000-0002-5557-623X Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Germany. Search for more papers by this author Originally published30 Jul 2021https://doi.org/10.1161/CIRCHEARTFAILURE.121.008810Circulation: Heart Failure. 2021;14:e008810Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: July 30, 2021: Ahead of Print A 48-year-old patient was admitted to our intensive care unit with severe acute respiratory distress syndrome (Pao2/fraction of inspired oxygen, 97 mm Hg) due to a severe acute respiratory syndrome coronavirus 2 infection with a documented N501Y mutation (B.1.1.7 lineage). The medical history included obesity (body mass index, 31.1 kg/m2), type II diabetes, and arterial hypertension. The patient received pressure-controlled ventilation (bilevel positive airway pressure) with a positive end-expiratory pressure of 10 cm H2O, a driving pressure of 14 cm H2O, and a fraction of inspired oxygen of 70%. The patient required vasopressor therapy with norepinephrine (0.55 µg/kg per min) and vasopressin (0.02 µg/kg per min). In accordance with current recommendations,1,2 prone positioning was initiated. Before and after moving the patient from supine to prone positioning, we measured right ventricular pressure-volume loops and pulmonary hemodynamics (Figures 1 and 2).Download figureDownload PowerPointFigure 1. Chest radiograph showing bilateral infiltrates, acute respiratory failure due to severe acute respiratory syndrome coronavirus 2.Download figureDownload PowerPointFigure 2. Right ventricular pressure-volume loops during supine and prone positioning.When the patient was supine, we observed precapillary pulmonary hypertension associated with acute respiratory distress syndrome (mean pulmonary arterial pressure, 31 mm Hg; central venous pressure, 18 mm Hg; pulmonary arterial wedge pressure, 15 mm Hg). After moving the patient to a prone position, we observed a substantial increase in end-systolic pressure (from 37 to 47 mm Hg), end-diastolic pressure (from 16 to 28 mm Hg), end-systolic volume (from 92 to 118 mL), and end-diastolic volume (from 179 to 217 mL; values represent the averages of all loops). Stroke volume decreased from 98 to 88 mL right ventricular ejection fraction from 58% to 44%. Furthermore, mean pulmonary arterial pressure increased to 39 mm Hg and central venous pressure to 22 mm Hg.To our knowledge, this is the first case demonstrating a substantial impact of prone positioning on the right ventricular pressure-volume relationship in acute respiratory distress syndrome. Further in-depth studies are needed to evaluate the impact on the right ventricle of this widely accepted approach.Sources of FundingCollaborative Research Center CRC 1213 and Sonderforschungsbereiche SFB Project B08.Disclosures None.FootnotesCorrespondence to: Khodr Tello, MD, Department of Internal Medicine, Justus-Liebig-University Giessen, Universities of Giessen and Marburg Lung Center, Klinikstr 33, 35392 Giessen, Germany. Email khodr.[email protected]med.uni-giessen.de

Abstract 214: Cardiac Arrest and Extracorporeal Cardiopulmonary Resuscitation Impairs Left Ventricle Hemodynamic Function in a Ventricular Fibrillation Cardiac Arrest Model in Rats

Introduction: Extracorporeal Cardiopulmonary Resuscitation (ECPR) may achieve ROSC after prolonged CA when conventional cardiopulmonary resuscitation fails. We investigated the impact of ECPR on cardiac hemodynamic recovery and hypothesized, that left ventricular hemodynamic function is impaired in resuscitated hearts. Methods: Adult male Sprague-Dawley rats (500 g, n=36) were subjected to 6 or 8 min of ventricular fibrillation CA, thereafter resuscitated with ECPR (open reservoir, roller pump, membrane oxygenator, draining catheter in the right jugular vein, inflow catheter in the right femoral artery; custom made bypass system), mechanical ventilation and drugs (epinephrine, bicarbonate, heparin). After defibrillation and ROSC, rats survived for 14 days and were compared to 7 sham animals. The hearts were isolated and mounted onto an erythrocyte-perfused, isolated working heart (WH) system. Cardiac output, left ventricular systolic pressure (LVSP), coronary flow and pressure-volume (P-V) relationships (by increasing the afterload in 10 mmHg increments) were measured. Myocardium of all rats was evaluated pathohistological in hematoxylin-eosin staining. Results: ROSC was achieved in 18 animals after 6 min of CA, of which 10 survived 14 d and 7 were investigated in WH, in 8 min CA group 15 achieved ROSC of which 5 survived to 14 d and 2 were investigated in WH and compared to the hearts of 7 sham animals. At defined afterload (60 mm Hg; baseline) there was no difference in cardiac hemodynamics between sham and 6 min CA group. In contrast, 8 min CA rats showed a tendency towards decrease in cardiac output and LVSP compared to sham animals. Notably, both CA groups showed impaired P-V loop relationship and subsequently less tolerance to hemodynamic stress. Histologically all 8 min CA rats showed multiple foci of myocardial scarring. Conclusions: CA led to impaired left ventricular hemodynamics in 8 min CA rats resuscitated with ECPR. In addition, hearts were more vulnerable to hemodynamic stress after successful resuscitation. For investigating the effects of future therapy approaches during and after resuscitation from CA on the heart function, isolated WH might be a promising approach in resuscitation research.

Methane supplementation improves graft function in experimental heart transplantation

Maintenance of cell viability during cold storage is a key issue in organ transplantation. Methane (CH4) bioactivity has recently been recognized in ischemia/reperfusion conditions; we therefore hypothesized that cold storage in CH4-enriched preservation solution can provide an increased defense against organ dysfunction during experimental heart transplantation (HTX). The hearts of donor Lewis rats were stored for 60 minutes in cold histidine-tryptophan-ketoglutarate (Custodiol [CS]) or CH4-saturated CS solution (CS-CH4) (n = 12 each). Standard heterotopic HTX was performed, and 60 minutes later, the left ventricular (LV) pressure-volume relationships LV systolic pressure (LVSP), systolic pressure increment (dP/dtmax), diastolic pressure decrement, and coronary blood flow (CBF) were measured. Tissue samples were taken to detect proinflammatory parameters, structural damage (by light microscopy), endoplasmic reticulum (ER) stress, and apoptosis markers (CCAAT/enhancer binding protein [C/EBP] homologous protein, GRP78, glycogen synthase kinase-3β, very low-density lipoprotein receptor, caspase 3 and 9, B-cell lymphoma 2, and bcl-2-like protein 4), whereas mitochondrial functional changes were analyzed by high-resolution respirometry. LVSP and dP/dtmax increased significantly at the largest pre-load volumes in CS-CH4 grafts as compared with the CS group (114.5 ± 16.6 mmHg vs 82.8 ± 4.6 mmHg and 3,133 ± 430 mmHg/s vs 1,739 ± 169 mmHg/s, respectively); the diastolic function and CBF (2.4 ± 0.4 ml/min/g vs 1.3 ± 0.3 ml/min/g) also improved. Mitochondrial oxidative phosphorylation capacity was more preserved (58.5 ± 9.4 pmol/s/ml vs 27.7 ± 6.6 pmol/s/ml), and cytochrome c release was reduced in CS-CH4 storage. Signs of HTX-caused myocardial damage, level of ER stress, and the transcription of proapoptotic proteins were significantly lower in CS-CH4 grafts. The addition of CH4 during 1 hour of cold storage improved early in vitro graft function and reduced mitochondrial dysfunction and activation of inflammation. Evidence shows that CH4 reduced ER stress-linked proapoptotic signaling.

Abstract 244: Post- But Not Pre-menopausal Female Smoothelin-like 1 Deficient Mice Develop Diastolic Dysfunction Unlike Their Male Counterparts

Diastolic dysfunction is a core characteristic of heart failure with preserved ejection fraction (HFpEF), which accounts for half of all HF cases. Our group revealed a novel impact of the smoothelin-like 1 (SMTNL1) protein which when subjected to genetic deletion drives alterations in endothelial and cardiovascular performances. Of note, previous cardiac hemodynamic profiling showed that young male SMTNL1 knockout (KO) mice developed diastolic dysfunction as evidenced by increased end diastolic pressure (EDP), left ventricular relaxation time constant (Tau) and steeper end diastolic pressure-volume relationship (EDPVR). A majority of HFpEF patients are post-menopausal women, so this study examined the impact of SMTNL1 silencing on endothelial and cardiac function with increasing age in a novel female murine model. The cardiac function of SMTNL1 global KO mice (3-, 12- and 18-month old, male and female) was assessed by echocardiography and pressure-volume loop. Unlike young males, 3-month old female KO mice did not develop diastolic dysfunction. However, ageing provided progressive impairment of diastolic function in female KO mice with increased EDP (8.4±1.1 vs 12.2±0.8 mmHg, p<0.02) and EDPVR (0.22±0.05 vs 0.51±0.05, p=0.02) at 18 months; an elevated E/E′ (20.8±1.6 vs 28.3±2.2, p=0.02) and decreased E′/A′ (1.49±0.19 vs 0.97±0.14, p<0.05) at 12 months in comparison to their WT counterparts, along with a normal ejection fraction (>60%) for all age groups. Furthermore, while flow-mediated dilation was continuously impaired in male KO cohorts from 3-month age, female KO showed impairment only at 12-months. Aging was also associated with altered cardiac morphology and fibrotic levels in the aged female KO cohort. Taken together, we have identified pathophysiologic effects of SMTNL1 silencing on vascular and cardiac function with ageing in female mice. The SMTNL1 KO model for the first time recapitulates the sex dimorphic onset of diastolic dysfunction that is central to HFpEF clinical phenotypes and represents a novel preclinical model to study the etiology of the HFpEF condition. Furthermore, the absence of diastolic dysfunction in KO female mice until post-menopausal age reveals a protective role of female sex hormones and warrants further study.

Deep phenotyping of cardiac function in heart transplant patients using cardiovascular system models.

Right heart catheterization data from clinical records of heart transplant patients are used to identify patient-specific models of the cardiovascular system. These patient-specific cardiovascular models represent a snapshot of cardiovascular function at a given post-transplant recovery time point. This approach is used to describe cardiac function in 10 heart transplant patients, five of which had multiple right heart catheterizations allowing an assessment of cardiac function over time. These patient-specific models are used to predict cardiovascular function in the form of right and left ventricular pressure-volume loops and ventricular power, an important metric in the clinical assessment of cardiac function. Outcomes for the longitudinally tracked patients show that our approach was able to identify the one patient from the group of five that exhibited post-transplant cardiovascular complications. Heart transplant patients are followed with periodic right heart catheterizations (RHCs) to identify post-transplant complications and guide treatment. Post-transplant positive outcomes are associated with a steady reduction of right ventricular and pulmonary arterial pressures, toward normal levels of right-side pressure (about 20mmHg) measured by RHC. This study shows that more information about patient progression is obtained by combining standard RHC measures with mechanistic computational cardiovascular system models. The purpose of this study is twofold: to understand how cardiovascular system models can be used to represent a patient's cardiovascular state, and to use these models to track post-transplant recovery and outcome. To obtain reliable parameter estimates comparable within and across datasets, we use sensitivity analysis, parameter subset selection, and optimization to determine patient-specific mechanistic parameters that can be reliably extracted from the RHC data. Patient-specific models are identified for 10 patients from their first post-transplant RHC, and longitudinal analysis is carried out for five patients. Results of the sensitivity analysis and subset selection show that we can reliably estimate seven non-measurable quantities; namely, ventricular diastolic relaxation, systemic resistance, pulmonary venous elastance, pulmonary resistance, pulmonary arterial elastance, pulmonary valve resistance and systemic arterial elastance. Changes in parameters and predicted cardiovascular function post-transplant are used to evaluate the cardiovascular state during recovery of five patients. Of these five patients, only one showed inconsistent trends during recovery in ventricular pressure-volume relationships and power output. At the four-year post-transplant time point this patient exhibited biventricular failure along with graft dysfunction while the remaining four exhibited no cardiovascular complications.

Methane-Enriched Custodiol Preservation Solution Improves Graft Function in Experimental Model of Heterotopic Heart Transplantation

The key goal of cold storage is to maintain cell viability for a prolonged time during solid organ transplantation. Methane (CH4) has been recognized as novel therapeutic gas exerting anti-inflammatory effects in ischemia-reperfusion (IR) injuries. We aimed to investigate whether cold storage of donor hearts in CH4-enriched Custodiol preservation solution could protect against IR and preserve myocardial function in a rat model of heterotopic heart transplantation (HTX). The hearts of donor Lewis rats were explanted and stored for 1 h in cold Custodiol (CS group, n=12) or in CH4-saturated (0.054 mg/100 ml) Custodiol (CS-CH4 group, n=12). 60 min after HTX left ventricular (LV) pressure-volume relations and coronary blood flow (CBF) were assessed to evaluate early post-transplant graft function. At the end of haemodynamic measurements, samples were taken for qPCR of endoplasmic reticulum (ER) stress and mitochondria-related apoptosis markers (CHOP, GRP78, GSK3β, VLDR, Caspase 3 and 9, Bcl2, Bax), biochemical parameters and mitochondrial functional analysis with high-resolution respirometry (Oxygraph2K, Austria). LV contractility (LV systolic pressure at 120µl of LV volume: 86±6 vs. 57±7mmHg, p=0.01; dP/dtmax: 2326±167 vs. 1583±139mmHg, p=0.007) and active relaxation (dP/dtmin at 120µl of LV volume: -1660±185 vs. -1043±169mmHg, p=0.04) improved significantly after an hour of reperfusion, while alteration of CBF standardized to heart weight (2.11±0.35 vs. 1.13±0.2ml/min/g, p=0.04) was also significantly improved following pretreatment. CS-CH4 storage significantly reduced the transcription of pro-apoptotic proteins and Bcl2/Bax ratios as compared to CS grafts. Increased mitochondrial oxidative phosphorylation, reduced leak respiration and cytochrome c release were demonstrated in response to CS-CH4 preservation. These results might provide reliable evidence for the benefit of CH4-enriched preservation solution during HTX, through a mechanism which involves the inhibition of pro-apoptotic signals. Hence CH4-enriched preservation solution could be a potential cardioprotective agent in the inventory of heart transplantation surgery and other cardiac surgical procedures requiring prolonged cardioplegia.

Stimulation of soluble guanylate cyclase improves donor organ function in rat heart transplantation

Heart transplantation remains the definitive therapy of end-stage heart failure. Ischemia-reperfusion injury occurring during transplantation is a primary determinant of long-term outcome of heart transplantation and primary graft insufficiency. Modification of the nitric oxide/soluble guanylate cyclase/cyclic guanosine monophosphate signaling pathway appears to be one of the most promising among the pharmacological interventional options. We aimed at characterizing the cardio-protective effects of the soluble guanylate cyclase stimulator riociguat in a rat model of heterotopic heart transplantation. Donor Lewis rats were treated orally with either riociguat or placebo for two days (n = 9) in each transplanted group and (n = 7) in donor groups. Following explantation, hearts were heterotopically transplanted. After one hour reperfusion, left ventricular pressure-volume relations and coronary blood flow were recorded. Molecular biological measurements and histological examination were also completed. Left ventricular contractility (systolic pressure: 117 ± 13 vs. 48 ± 5 mmHg, p < 0.001; dP/dtmax: 2963 ± 221 vs. 1653 ± 159 mmHg/s, p < 0.001), active relaxation (dP/dtmin: −2014 ± 305 vs. −1063 ± 177 mmHg/s, p = 0.02; all at 120 µl of left ventricular volume), and alteration of coronary blood flow standardized to heart weight (2.55 ± 0.32 vs. 1.67 ± 0.22 ml/min/g, p = 0.03) were markedly increased following preconditioning with riociguat. Myocardial apoptosis markers were also significantly reduced in the riociguat pretreated group as well as the antioxidant markers were elevated. Pharmacological preconditioning with riociguat decreases ischemia-reperfusion injury and improves donor organ function in our animal model of heart transplantation. Therefore, riociguat might be a potential cardioprotective agent.

Thoracic endografting increases cardiac afterload and leads to left ventricular hypertrophy in dogs.

Aortic endografting can cause aortic stiffening. We aimed to determine the chronic effect of thoracic endografting on cardiac afterload, function and remodelling. Eleven dogs were included, and all except 1 was successfully assessed [endograft, n = 5; sham operation (control), n = 5]. We deployed a stent graft in the descending aorta. The ascending aortic pressure and flow were measured, and aortic input impedance was obtained by frequency analysis to determine characteristic impedance and arterial compliance. Left ventricular pressure-volume relations were measured with an admittance catheter. Measurements were performed before, 10 min after and 3 months after endografting. Following euthanasia, we weighed the left ventricle of each dog and measured the cardiomyocyte cell size. Arterial compliance decreased from 0.47 ± 0.07 to 0.36 ± 0.06 and to 0.31 ± 0.05 ml/mmHg (both P < 0.01 versus baseline), and characteristic impedance increased from 0.11 ± 0.04 to 0.19 ± 0.05 and to 0.21 ± 0.04 mmHg/ml/s (both P < 0.01 versus baseline) 10 min and 3 months after endografting, respectively. Pressure-volume relation analysis showed that arterial elastance increased from 5.3 ± 1.0 to 6.7 ± 1.6 (at 10 min) and to 6.8 ± 1.0 mmHg/ml (at 3 months) (both P < 0.05 versus baseline), but end-systolic elastance and ventriculo-arterial coupling remained unchanged. Left ventricular weight to body weight ratio and left ventricular cardiomyocyte cell width in the endograft group were larger compared with the control's results (5.06 ± 0.27 g/kg vs 4.20 ± 0.49 g/kg, P = 0.009, 15.1 ± 1.7 µm vs 13.9 ± 1.5 µm, P = 0.02, respectively). The mid-term effect of the descending aortic endografting on left ventricular contractility and efficiency in canine normal hearts was minimal. However, endografting resulted in increased cardiac afterload and left ventricular hypertrophy.

PEGylated carboxyhemoglobin bovine (SANGUINATE) ameliorates myocardial infarction in a rat model.

Artificial oxygen (O2) carriers were reported to be protective in ischemia/reperfusion (I/R) in various organs including the heart. In the current study, 20 rats underwent ligation (MI) of the left anterior descending artery, were treated with 10 mL/kg of PEGylated carboxyhemoglobin bovine (SANGUINATE, S+, n = 10) or saline (S−, n = 10) 10 minutes after MI and daily thereafter for 3 days, and were followed by weekly echocardiography for 4 weeks, when they had left ventricular pressure volume relationship (PVR) analyses followed by necropsy. Echocardiography showed an increase in end‐systolic dimension rather than end‐diastolic dimension, preserved fractional shortening (36 vs. 26%, P < .01), and milder mitral regurgitation in S+ compared with S‐ rats. PVR revealed a milder increase in end‐systolic volume, larger stroke volume (101 vs. 74 μL, P < .005) and cardiac output (33.4 vs. 23.8 mL/min, P = .004) in S+ rats in actual determination and under a wide range of standardized loading conditions 4 weeks after MI. Excised heart showed significantly limited area of MI (8.9 vs. 13.3%, P = .028). The results suggest that SANGUINATE in short‐term repeated doses may accelerate weight recovery, preserving the myocardium, mitral competence, and cardiac function after MI. The mechanism of action and optimal treatment for MI remain to be studied.

Abstract 16876: Saturated Arterial Vasoconstriction in the Fontan Circulation

Background: Cardiac afterload in the Fontan circulation is enhanced due to sequentially connected pulmonary circulation to the systemic circulation. As the augmentation of afterload, which includes both of venous and arterial components, markedly compromise stroke volume in the Fontan patients, identification of primary culprit is vitally important to determine therapeutic targets in preserving circulation and end-organ function. We tested our hypothesis that the augmentation of cardiac afterload in the Fontan circulation is attributed by the compensative arterial constriction in addition to the venous congestion. Methods: Transient inferior vena-caval occlusion (IVCO) was applied to induced venous congestion in 23 Fontan and 87 postoperative biventricular circulation patients(BVC), and augmentation of arterial elastance (Ea) was measured with constructing ventricular pressure-volume relationship. Results: As compared with BVC patients, lower cardiac output in the Fontan patient was attributed by the augmented afterload with similar contractile function. While increase of CVP was augmented in the Fontan pts as compared to those with BVC (p=0.0016), increase of Ea was similar in both groups, suggesting suppressed response of increasing Ea in the Fontan pts. This was further supported by the negative relationship between CVP increase and Ea augmentation (p=0.048). Consistent with this, increase of Ea by induced venous congestion was negatively correlated with mean circulatory filling pressure (p=0.025) as well as systemic vascular resistance (p=0.047). Importantly, augmentation of Ea was independent of renin-angiotensin-aldosterone system (RAAS). Conclusions: Augmentation of afterload by induced venous congestion was rather saturated in the Fontan circulation, suggesting chronic activation of excessive compensatory vasoconstriction at baseline, which involves entire vascular system. As this response was independent of RAAS activity, in addition to RAAS blockade, structural and functional interventions to suppress cardiovascular remodeling should be implemented for the further reduction of cardiac afterload.

Abstract 17396: RV Remodeling in Two Animal Models of Pulmonary Arterial Hypertension

Introduction: Right-ventricular function is a good indicator of pulmonary arterial hypertension (PAH) prognosis. By relating ventricular hemodynamics to wall mechanics, we aimed to discriminate the contributions of ventricular geometric remodeling and intrinsic changes in myocardial mechanical properties in two commonly used PAH animal models at end-systole (ES) and end-diastole (ED) to the maintenance of cardiac output during the early compensated phase. Methods: PAH was induced in 13 male Sprague-Dawley rats. The MCT group (N=4) was injected with a single dose of 60mg/kg of monoctroaline and kept in normoxia for 4 weeks. The SuHx group (N=9) was injected with a single dose of 20mg/kg of sugen, a VEGF inhibitor, and was placed on a hypoxia chamber for 3 weeks followed by 3 weeks of normoxia. 7 animals were used as a control group. In-vivo measurements of RV pressure and volume with preload changes were acquired. To relate ventricular pressure-volume relations to sarcomere mechanics, a computational model of the RV was developed. Using ventricular morphology and volume measurements from PAH groups, sarcomere material mechanics were adjusted to evaluate ES and ED functions in the treated animals. Results: ED pressures rose significantly in the treated groups (31.7 vs. 70.5 and 71.1 mmHg). ED and ES volumes remained the same in SuHx and CTL group, but increased significantly in the MCT group. RV hypertrophy increased in both PAH animal models, but it was significantly higher in the SuHx group. Even though differences in pressure, volume and morphology exist between the PAH groups, SV and CO were preserved in all treated animals. Model material parameters of increased in PAH, significantly in MCT maximal isometric tension. Conclusions: The model analysis suggests compensation to ESP rises was only possible due to a significant increase in the contractility of RV myocardium in the MCT and SuHx animals. No changes in diastolic function were found in the MCT animals, but there was an increase stiffness in the SuHx animals.

Inotropic Effects of Nicorandil on Cardiac Contractility Assessed by Left Ventricular Pressure-Volume Relationship Analyses in Anesthetized Monkeys.

Nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (KATP) channel agonist; however, its effects on integrated cardiac function have not been fully understood. This study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. Nicorandil was given intravenously at therapeutic doses of 0.2 and 2 mg/kg over 10 minutes to cynomolgus monkeys (n = 5) with a pause of 10 minutes between the 2 doses. Nicorandil at 0.2 mg/kg caused decreases in systemic blood pressure and left ventricular end-diastolic pressure by its vasodilating action. Nicorandil at 2 mg/kg also exhibited positive inotropic action demonstrated by increased slopes of preload recruitable stroke work relationship, which is a load-independent inotropic parameter. In load-dependent inotropic parameters, positive inotropy of nicorandil was also indicated by the shortened QA interval and increased contractility index; however, significant changes were not observed in the maximal upstroke velocity of left ventricular pressure. Moreover, reflex tachycardia accompanied by shortening of QT/QTc intervals was observed. Overall, the isoflurane-anesthetized monkey model with pressure-volume loop analysis revealed cardiac variables of nicorandil, including a positive inotropy contributable to cardiac performance in addition to its vasodilatory effect. These findings provide useful information when considering the prescription of nicorandil in patients.