Measure Of Cardiac Contractility Research Articles

Detection of contractility changes in the heart from arterial blood pressure data using symmetric Projection Attractor Reconstruction

The potential for unintended drug induced changes in cardiac contractility is a major concern in medicines development. Whilst direct left ventricular pressure (LVP) measurement is the gold standard for measuring cardiac contractility in vivo, it is resource intensive and poses a welfare burden on research animals. In contrast, arterial blood pressure (BP) measurement has fewer challenges. Symmetric Projection Attractor Reconstruction (SPAR) is a signal processing technique which transforms physiological time-series signals into a corresponding visual image (‘attractor’), amplifying morphology changes within physiological waveforms. It was hypothesized that SPAR analysis of BP signals would provide a surrogate measure of cardiac contractility by specifically amplifying the maximum slope of the systolic upstroke. BP (abdominal aorta) signals obtained from beagle dogs, treated with positive and negative inotropes, were retrospectively analysed to identify signal features that correlated with the maximum upslope of the LVP signal from simultaneously acquired LVP recordings. SPAR transformation of BP signals quantified drug induced changes in the maximum slope of the systolic upstroke. We identified key SPAR metrics that provided >0.8 correlation with the LVP maximum upslope, outperforming the BP systolic upstroke alone. This was observed for all 4 different drugs, doses and time points evaluated across studies. Thus, we conclude that the SPAR measures derived from the BP signal could be used as a first pass in vivo screen to flag any risk of drug induced changes in cardiac contractility during the conduct of non-clinical medicines development, potentially reducing or replacing the need to perform direct left ventricular measurements.

BIO30: A Method to Monitor Ventricular Recovery Using VAD Signals Based on Parseval’s Power Theorem

Study: Recent studies highlight the growing interest in achieving ventricular recovery for VAD patients, thereby eliminating the need for cardiac transplantation. Hemodynamic measurements may be performed during periodic echocardiography for patients with probable recovery. However, there are no standard methods to evaluate ventricular recovery on a continuous outpatient basis. Such a method can help assess changes in cardiac function throughout daily activities, potentially optimized by a responsive VAD control algorithm. The objective of this study was to evaluate a surrogate measure of cardiac contractility based on VAD inherent signals using an in-silico simulation model of assisted circulation. Methods: Without loss of generality, hemodynamic power can be visualized as an electrical power signal in an implanted VAD. The power of a continuous periodic signal (the VAD Flow Rate signal), given by Parseval’s Power Theorem, is equivalently the average value integral over one period of the square of the magnitude of the signal (inclusive of all harmonic components). In this in-silico simulation study, we compute the ratio of this power with the norm (over multiple cardiac cycles) of the signal under steady-state conditions. We call this ratio the Power Factor of the VAD Flow Rate, represented by λVAD. Numerical simulations were conducted for different values of ventricular contractility (Emax Maximum Ventricular Elastance) from 0.5 to 2.0 mmHg/ml over a range of VAD speeds of 1000 to 8000 RPM (HeartMate 3® VAD Model) in steps of 100 RPM. Results: The figure below illustrates the relationship of the Power Factor to VAD speed for four levels of ventricular contractility. At 1000 RPM, the Power Factor for all Emax values was found to be equal. As the VAD speed increases above approximately 4000 RPM, the λVAD values diverge, demonstrating the direct relationship with Emax: having a peak of approximately 0.8 for the greatest ventricular contractility (Emax = 2.0). As speed increases further and approaches 8000 RPM, the values of λVAD once again converge. Another discriminating feature is the location (speed) of the local maximum (“hump”) in the curves within the range of 4000 and 6000 RPM, with the peak occurring at increasing speeds for increasing contractility. The cause of the hump is due to the cooperative relationship of the VAD and native ventricle, precisely the point of the aortic valve opening, allowing forward flow. At the lowest speeds, there is a slight negative flow through the VAD and, thus, a more subdued λVAD. Conclusion: This simulation study shows that the Power Factor of VAD flow rate has the potential as a noninvasive surrogate measure of ventricular recovery that can be monitored continuously. The metric is sensitive to the interaction between the native left ventricle and the VAD and thus helpful in developing feedback control that optimizes cardiac rehabilitation.Figure 1. Simulation results for the Power Factor of VAD Flow Rate as a function of different VAD Speeds (RPM).

Adrenergic control of the cardiovascular system in deer mice native to high altitude.

Studies of animals native to high altitude can provide valuable insight into physiological mechanisms and evolution of performance in challenging environments. We investigated how mechanisms controlling cardiovascular function may have evolved in deer mice (Peromyscus maniculatus) native to high altitude. High-altitude deer mice and low-altitude white-footed mice (P. leucopus) were bred in captivity at sea level, and first-generation lab progeny were raised to adulthood and acclimated to normoxia or hypoxia. We then used pharmacological agents to examine the capacity for adrenergic receptor stimulation to modulate heart rate (fH) and mean arterial pressure (Pmean) in anaesthetized mice, and used cardiac pressure-volume catheters to evaluate the contractility of the left ventricle. We found that highlanders had a consistently greater capacity to increase fH via pharmacological stimulation of β1-adrenergic receptors than lowlanders. Also, whereas hypoxia acclimation reduced the capacity for increasing Pmean in response to α-adrenergic stimulation in lowlanders, highlanders exhibited no plasticity in this capacity. These differences in highlanders may help augment cardiac output during locomotion or cold stress, and may preserve their capacity for α-mediated vasoconstriction to more effectively redistribute blood flow to active tissues. Highlanders did not exhibit any differences in some measures of cardiac contractility (maximum pressure derivative, dP/dtmax, or end-systolic elastance, Ees), but ejection fraction was highest in highlanders after hypoxia acclimation. Overall, our results suggest that evolved changes in sensitivity to adrenergic stimulation of cardiovascular function may help deer mice cope with the cold and hypoxic conditions at high altitude.

Acetate, a Short-Chain Fatty Acid, Acutely Lowers Heart Rate and Cardiac Contractility Along with Blood Pressure.

Short-chain fatty acids (SCFAs) are metabolites produced almost exclusively by the gut microbiota and are an essential mechanism by which gut microbes influence host physiology. Given that SCFAs induce vasodilation, we hypothesized that they might have additional cardiovascular effects. In this study, novel mechanisms of SCFA action were uncovered by examining the acute effects of SCFAs on cardiovascular physiology in vivo and ex vivo. Acute delivery of SCFAs in conscious radiotelemetry-implanted mice results in a simultaneous decrease in both mean arterial pressure and heart rate (HR). Inhibition of sympathetic tone by the selective β-1 adrenergic receptor antagonist atenolol blocks the acute drop in HR seen with acetate administration, yet the decrease in mean arterial pressure persists. Treatment with tyramine, an indirect sympathomimetic, also blocks the acetate-induced acute drop in HR. Langendorff preparations show that acetate lowers HR only after long-term exposure and at a smaller magnitude than seen in vivo. Pressure-volume loops after acetate injection show a decrease in load-independent measures of cardiac contractility. Isolated trabecular muscle preparations also show a reduction in force generation upon SCFA treatment, though only at supraphysiological concentrations. These experiments demonstrate a direct cardiac component of the SCFA cardiovascular response. These data show that acetate affects blood pressure and cardiac function through parallel mechanisms and establish a role for SCFAs in modulating sympathetic tone and cardiac contractility, further advancing our understanding of the role of SCFAs in blood pressure regulation. SIGNIFICANCE STATEMENT: Acetate, a short-chain fatty acid, acutely lowers heart rate (HR) as well as mean arterial pressure in vivo in radiotelemetry-implanted mice. Acetate is acting in a sympatholytic manner on HR and exerts negative inotropic effects in vivo. This work has implications for potential short-chain fatty acid therapeutics as well as gut dysbiosis-related disease states.

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction

Background and aimsSodium–glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions.MethodsPressure–volume (P–V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later.ResultsThe circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy.ConclusionEmpagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

Noninvasive Hemodynamic Monitoring of Cocaine-Induced Changes in Cardiac Output and Systemic Vascular Resistance in Subjects With Chronic Cocaine Use Disorder.

Cocaine use disorder (CUD) is a common problem in the United States and worldwide. The mechanisms by which cocaine induces acute cardiovascular toxicity are various. When systemically absorbed through inhaled or intravenous routes, cocaine induces an acute rise in the heart rate (HR) and blood pressure (BP) leading to a significant increase in the cardiac output (CO) and myocardial oxygen demand. Subjects with chronic CUD represent a special population that has experienced long-term cocaine exposure, often without showing signs of cardiovascular disease. We herein present prospectively collected data on the acute hemodynamic effects of intravenous cocaine in a cohort of nontreatment-seeking individuals with CUD without cardiovascular disease. Baseline physiologic data were collected while participants underwent infusion of escalating doses of cocaine (10, 20, and 40 mg administered over 2 minutes) at baseline and after receiving single-blind placebo treatment. Continuous noninvasive hemodynamic monitoring was performed throughout the infusion sessions using the ccNexfin finger cuffs (Edwards Lifesciences Corp, Irvine, CA). The recorded arterial BP tracings allowed for the measurement of beat-to-beat changes in HR, BP, stroke volume, CO, and systemic vascular resistance (SVR). None of the subjects experienced a treatment-related serious adverse event. Cocaine produced significant dose-dependent increases in median HR, BP, CO, and +dP/dt (a measure of cardiac contractility) and a significant dose-dependent reduction in median SVR. Intravenous cocaine in a cohort of otherwise healthy subjects with CUD produced dose-dependent increases in CO, largely explained by an increase in HR, accompanied by a dose-dependent decrease in SVR.

Characterizing the effects of in utero exposure to valproic acid on murine fetal heart development.

Recently, the use of the antiepileptic drug valproic acid (VPA) for the treatment of psychiatric conditions has been on the rise. However, studies have shown that in utero VPA exposure can affect embryonic development, including being associated with congenital heart defects. One proposed mechanism of VPA-initiated teratogenicity is the inhibition of histone deacetylase, which is involved in the regulation of transcription factors that regulate cardiogenesis. Myocyte enhancing factor 2C (Mef2c), a transcription factor involved in the development of cardiac structure and cardiomyocyte differentiation, has been shown to increase in response to in utero VPA exposure, associating with contractile dysfunction and myocardial disorganization. To characterize the effects of VPA on murine heart development, pregnant CD-1 mice were dosed with 400 mg/kg of VPA on gestational day (GD) 9. Using high-resolution ultrasound, we examined the effects of VPA on cardiac contractile function on GD 14-18, with fetal hearts being harvested on GD 19 for histological analysis. Lastly, we conducted quantitative real-time polymerase chain reaction to measure the relative Mef2c gene expression in GD 16 murine hearts. We observed structural anomalies at GD 19 in the hearts of VPA-treated mice. Additionally, our results showed alterations in measures of cardiac contractility, with a decrease or increase in cardiac contractile ability in VPA-treated mice depending on the GD and measurement taken. These results further characterize the effects of VPA on heart development and suggest that alterations in Mef2c gene expression, at least on GD 16, do not mediate VPA-induced cardiotoxicity in CD-1 mice.

Assessment of ventricular contractility in fetuses with an estimated fetal weight less than the tenth centile

To determine whether abnormal global, transverse, and longitudinal ventricular contractility of the heart in fetuses with an estimated fetal weight <10th centile is present, irrespective of Doppler studies of the umbilical artery and cerebroplacental ratio. This was a retrospective study of 50 fetuses with an estimated fetal weight <10th centile that were classified based on Doppler results from the pulsatility indices of the umbilical artery and middle cerebral artery, and the calculated cerebroplacental ratio (pulsatility indices of the umbilical artery/middle cerebral artery). Right and left ventricular measurements were categorized into 3 groups: (1) global ventricular contractility (fractional area change), (2) transverse ventricular contractility (24-segment transverse fractional shortening), and (3) basal-apical longitudinal contractility (longitudinal strain, longitudinal displacement fractional shortening, and basal lateral and septal wall annular plane systolic excursion). Z scores for the above measurements were computed for fetuses with an estimated fetal weight <10th centile using the mean and standard deviation derived from normal controls. Ventricular contractility measurements were considered abnormal if their Z score values were <5th centile (z score <-1.65) or >95th centile (Z score >1.65), depending on the specific ventricular measurement. The average gestational age at the time of the examination was 32 weeks 4 days (standard deviation 3 weeks 4 days). None of the 50 study fetuses demonstrated absent or reverse flow of the umbilical artery Doppler waveform. Eighty-eight percent (44/50) of fetuses had one or more abnormal measurements of cardiac contractility of 1 or both ventricles. Analysis of right ventricular contractility demonstrated 78% (39/50) to have 1 or more abnormal measurements, which were grouped as follows: global contractility 38% (19/50), transverse contractility 66% (33/50); and longitudinal contractility 48% (24/50). Analysis of left ventricular contractility demonstrated 1 or more abnormal measurements in 58% (29/50) that were grouped as follows: global contractility 38% (19/50); transverse contractility 40% (20/50); and longitudinal contractility 40% (20/50). Of the 50 study fetuses, 25 had normal pulsatility index of the umbilical artery and cerebroplacental ratios, 80% of whom had 1 or more abnormalities of right ventricular contractility and 56% of whom had 1 or more abnormalities of left ventricular contractility. Abnormal ventricular contractility for these fetuses was present in all 3 groups of measurements; global, transverse, and longitudinal. Those with an isolated abnormal pulsatility index of the umbilical artery (n=11) had abnormalities of transverse contractility of the right ventricular and global contractility in the left ventricle. When an isolated cerebroplacental ratio abnormality was present, the right ventricle demonstrated abnormal global, transverse, and longitudinal contractility, with the left ventricle only demonstrating abnormalities in transverse contractility. When both the pulsatility index of the umbilical artery and cerebroplacental ratio were abnormal (3/50), transverse and longitudinal contractility measurements were abnormal for both ventricles, as well as abnormal global contractility of the left ventricle. High rates of abnormal ventricular contractility were present in fetuses with an estimated fetal weight <10th centile, irrespective of the Doppler findings of the pulsatility index of the umbilical artery, and/or cerebroplacental ratio. Abnormalities of ventricular contractility were more prevalent in transverse measurements than global or longitudinal measurements. Abnormal transverse contractility was more common in the right than the left ventricle. Fetuses with estimated fetal weight less than the 10th centile may be considered to undergo assessment of ventricular contractility, even when Doppler measurements of the pulsatility index of the umbilical artery, and cerebroplacental ratio are normal.

Unobtrusive Estimation of Cardiac Contractility and Stroke Volume Changes Using Ballistocardiogram Measurements on a High Bandwidth Force Plate.

Unobtrusive and inexpensive technologies for monitoring the cardiovascular health of heart failure (HF) patients outside the clinic can potentially improve their continuity of care by enabling therapies to be adjusted dynamically based on the changing needs of the patients. Specifically, cardiac contractility and stroke volume (SV) are two key aspects of cardiovascular health that change significantly for HF patients as their condition worsens, yet these parameters are typically measured only in hospital/clinical settings, or with implantable sensors. In this work, we demonstrate accurate measurement of cardiac contractility (based on pre-ejection period, PEP, timings) and SV changes in subjects using ballistocardiogram (BCG) signals detected via a high bandwidth force plate. The measurement is unobtrusive, as it simply requires the subject to stand still on the force plate while holding electrodes in the hands for simultaneous electrocardiogram (ECG) detection. Specifically, we aimed to assess whether the high bandwidth force plate can provide accuracy beyond what is achieved using modified weighing scales we have developed in prior studies, based on timing intervals, as well as signal-to-noise ratio (SNR) estimates. Our results indicate that the force plate BCG measurement provides more accurate timing information and allows for better estimation of PEP than the scale BCG (r2 = 0.85 vs. r2 = 0.81) during resting conditions. This correlation is stronger during recovery after exercise due to more significant changes in PEP (r2 = 0.92). The improvement in accuracy can be attributed to the wider bandwidth of the force plate. ∆SV (i.e., changes in stroke volume) estimations from the force plate BCG resulted in an average error percentage of 5.3% with a standard deviation of ±4.2% across all subjects. Finally, SNR calculations showed slightly better SNR in the force plate measurements among all subjects but the small difference confirmed that SNR is limited by motion artifacts rather than instrumentation.

A Diet Rich in Medium-Chain Fatty Acids Improves Systolic Function and Alters the Lipidomic Profile in Patients With Type 2 Diabetes: A Pilot Study.

Excessive cardiac long-chain fatty acid (LCFA) metabolism/storage causes cardiomyopathy in animal models of type 2 diabetes. Medium-chain fatty acids (MCFAs) are absorbed and oxidized efficiently. Data in animal models of diabetes suggest MCFAs may benefit the heart. Our objective was to test the effects of an MCFA-rich diet vs an LCFA-rich diet on plasma lipids, cardiac steatosis, and function in patients with type 2 diabetes. This was a double-blind, randomized, 2-week matched-feeding study. The study included ambulatory patients in the general community. Sixteen patients, ages 37-65 years, with type 2 diabetes, an ejection fraction greater than 45%, and no other systemic disease were included. Fourteen days of a diet rich in MCFAs or LCFAs, containing 38% as fat in total, was undertaken. Cardiac steatosis and function were the main outcome measures, with lipidomic changes considered a secondary outcome. The relatively load-independent measure of cardiac contractility, S', improved in the MCFA group (P < .05). Weight-adjusted stroke volume and cardiac output decreased in the LCFA group (both P < .05). The MCFA, but not the LCFA, diet decreased several plasma sphingolipids, ceramide, and acylcarnitines implicated in diabetic cardiomyopathy, and changes in several sphingolipids correlated with improved fasting insulins. Although a diet high in MCFAs does not change cardiac steatosis, our findings suggest that the MCFA-rich diet alters the plasma lipidome and may benefit or at least not harm cardiac function and fasting insulin levels in humans with type 2 diabetes. Larger, long-term studies are needed to further evaluate these effects in less-controlled settings.

Doxorubicin: Comparison between 3-h continuous and bolus intravenous administration paradigms on cardio-renal axis, mitochondrial sphingolipids and pathology

Doxorubicin (DOX) is a potent and effective broad-spectrum anthracycline antitumor agent, but its clinical usefulness is restricted by cardiotoxicity. This study compared pharmacokinetic, functional, structural and biochemical effects of single dose DOX bolus or 3-h continuous iv infusion (3-h iv) in the Han–Wistar rat to characterize possible treatment-related differences in drug safety over a 72h observation period.Both DOX dosing paradigms significantly altered blood pressure, core body temperature and QA interval (indirect measure of cardiac contractility); however, there was no recovery observed in the bolus iv treatment group. Following the 3-h iv treatment, blood pressures and QA interval normalized by 36h then rose above baseline levels over 72h. Both treatments induced biphasic changes in heart rate with initial increases followed by sustained decreases. Cardiac injury biomarkers in plasma were elevated only in the bolus iv treatment group. Tissue cardiac injury biomarkers, cardiac mitochondrial complexes I, III and V and cardiac mitochondrial sphingolipids were decreased only in the bolus iv treatment group. Results indicate that each DOX dosing paradigm deregulates sinus rhythm. However, slowing the rate of infusion allows for functional compensation of blood pressure and may decrease the likelihood of cardiac myocyte necrosis via a mechanism associated with reduced mitochondrial damage.

Abstract P1-03-01: Cardiac function in BRCA1/2 mutation carriers with a history of breast cancer (BC) treated with anthracyclines (anthra)

Abstract Introduction: Animal data suggest that cardiac-specific loss of BRCA1/2 genes leads to increased cardiac dysfunction in the setting of stressors such as ischemia or anthra chemotherapy (CT). Women with BRCA1/2 mutations who develop BC may receive anthra-based CT. It is not known whether BRCA1/2 mutation carriers treated for early stage BC with anthra-based CT are at higher risk for anthra-induced cardiac toxicity than similarly treated women with sporadic BC. This study investigates left ventricular ejection fraction (LVEF) and myocardial global longitudinal strain (GLS), a novel echocardiographic measure of cardiac contractility, in women with and without BRCA1/2 mutations who were treated with anthra-based CT. Methods: We identified 41 women with a history of BRCA1/2 mutation-associated BC and 52 women with a history of sporadic BC, all of whom received anthra-based adjuvant or neoadjuvant CT. We excluded women who received HER2 therapy or who had stage IV disease. BC CT was completed at least 6 months prior to study enrollment. All participants completed a cardiac questionnaire and underwent a comprehensive 2D and 3D echocardiographic exam with assessment of myocardial GLS using speckle-tracking software (QLAB10, Philips, Andover, MA). Abnormal LVEF was defined as less than 55% (50-54.9% borderline reduced and 40-49% mildly reduced) and abnormal GLS was defined as absolute value of less than 18.9%. Patients with history of hypertension (HTN) were excluded from this analysis to avoid confounding effects of HTN on GLS. Results: We present data on 57 normotensive participants, 34 BRCA1/2 mutation-carriers and 23 non-mutation carriers. Mean age was 49.5 +/- 8.7 years in the BRCA mutation-carrier group and 51.1 +/- 8.7 years in the non-mutation carrier group (p=0.496). Women with BRCA1/2 mutations were more likely to be Caucasian (p=0.026) and have undergone oophorectomy (p&amp;lt;0.001). The average time from anthra treatment to study enrollment was 5 +/- 4.4 years. Groups were well balanced with regards to age, diabetes, hyperlipidemia, history of coronary disease, smoking and cumulative dose of anthra. Four BRCA1/2 mutation-carriers (12%) and 4 non-mutation carriers (17%) had reduced GLS (p= 0.450). Mean LVEF was similar between the groups: LVEF was borderline reduced in one BRCA1/2 mutation-carrier (3%) and borderline or mildly reduced in 4 non-mutation carriers (18%)(p= 0.091). Conclusions: In this population, reduced LVEF and myocardial GLS were present in a small percentage of women treated with anthra-based CT for early stage BC. However, reduction in LVEF and myocardial GLS did not differ between the BRCA1/2 mutation carriers and the women with a history of sporadic BC. Larger studies are needed to definitively rule out a difference in cardiac toxicity by BRCA mutation status in BC survivors treated with anthra. This project is supported by Fisher Center for Familial Cancer Research Award at Lombardi Comprehensive Cancer Center. AB is supported by Georgetown-Howard Universities Center for Clinical &amp; Translational Science (GHUCCTS) post-doctoral KL2 Award (5KL2TR000102-04). Citation Format: Filipa Lynce, Ana Barac, Karen L Smith, Mihriye Mete, Lynette Wray, Madeline Nardacci, Pia Herbolsheimer, Raquel Nunes, Sandra M Swain, Robert Warren, Claudine Isaacs. Cardiac function in BRCA1/2 mutation carriers with a history of breast cancer (BC) treated with anthracyclines (anthra) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-01.

Bleeding, hypothermia, acidosis and the normal ROTEM®

shock (HS) and acute pancreatitis (AP) is associated with multiple organ dysfunction syndrome (MODS) and death. Most common in MODS are cardiac and pulmonary dysfunction.The ‘gut-lymphhypothesis’ states thatMODSisdue to the releaseof toxic factors fromthe intestine intomesenteric lymph (ML). Significant composition changes to ML are associated with acute pancreatitis and other CI’s. ML is delivered to the systemic circulation via the thoracic duct and en route bypasses the liver avoidingpotential detoxification, beforefirst encountering the heart and then lungs. The aim of this study was to determine the effect of HS and AP conditioned ML on cardiac function and the effect of external drainage of ML. Methods: Groups (n=8 / group) of normal rats and those with taurocholate induced severe AP, a model of critical illness, had either no lymphatic intervention or thoracic duct (TD) ligation with external ML drainage (to protect the hearts from exposure to ML). After 6 hours the heart was removed from both groups for ex vivo functional measurements, including cardiac output and ventricular contractility (+dP/dt), relaxation (-dP/dt). In a separate experiment ML was collected from normal rats and those with HS and AP and infused into ex vivo perfused working hearts from donor normal rats to assess the impact on cardiac function. Results: Significant cardiac dysfunction was found in the hearts removed from rats with established AP alone (no lymphatic intervention) compared to the control group (p<0.05). Strikingly this dysfunction did not occur in rats with established AP and TD ligation with ML drainage. In the second experiment infusion of HS and AP conditioned ML resulted in an immediate, similar and significant reduction of cardiac output (p< 0.05) with corresponding significant reductions in the measures of cardiac contractility and relaxation (p<0.05) compared with normal lymph. Discussion:HS and AP conditioned ML causes significant cardiac dysfunction which can be prevented by TD ligation and external ML drainage. This cardio-depressant effect is likely to be important in other CI’s. The nature of the mediators in ML is still speculative but likely to be gut and pancreas derived serine proteases. The findings from this study have future implications in how we treat cardiac dysfunction and failure in critically ill patients.

A translational assessment of preclinical versus clinical tools for the measurement of cardiac contractility: Comparison of LV dP/dtmax with echocardiography in telemetry implanted beagle dogs

IntroductionRegarding evaluation of drug-induced changes in left ventricular contractility in safety pharmacology there is still a gap in knowledge between preclinically and clinically used measurements. MethodsAs a step towards translation of preclinical to clinical outcomes, this study in telemetered dogs was initiated to compare indexes of contractility, such as LV dP/dtmax (contractility measured as the maximum raise of pressure in the left ventricle) and LV dP/dtmax/P (contractility measured as the maximum raise of pressure in the left ventricle, corrected for pressure) (telemetry; both commonly preclinically used) and EF (ejection fraction) and FS (fractional shortening) (echocardiography; both commonly clinically used). Different inotropic states were induced by minoxidil, milrinone, isoprenaline, clonidine, atenolol and verapamil. ResultsBoth techniques demonstrated reproducible changes in contractility which showed a clear linear association. A change in LV dP/dtmax of 1000mmHg/s (in the range of 2500 to 7500mmHg/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of approximately 6%. A change of 10/s LV dP/dtmax/P (in the range of 35 to 85/s; in healthy dogs) corresponded with a change in ejection fraction of approximately 7% and a fractional shortening of 7%. DiscussionThe correlation found in this study could potentially enable a better – translational – assessment of the clinical relevance of changes in contractility indices measured with telemetry devices in preclinical safety studies.

Traditional, forgotten and new left ventricular systolic function parameters on a 64-row multidetector cardiac computed tomography: A reproducibility study

Multidetector computed tomography angiography (MDCT) can provide data regarding cardiac function if a retrospective scanning is applied. We aimed at examination of the reproducibility of traditional and more sensitive parameters of the left ventricular (LV) contractility by means of a 64-row CT in order to establish errors of measurement and to determine limits that allow for a reliable detection of their changes. A random sample of 25 individuals, including 15 females (aged 64 ± 13 years) and 10 males (54 ± 13 years), who had MDCT examination were retrospectively included in this study. Data reconstructions were performed on a dedicated workstation. In each case, axial image series were created with a 10% step from 0% to 90% of the RR interval using a 2 mm slice thickness. LV volume was determined in each phase. Detailed LV volume changes within phases were analyzed to determine the largest difference between the neighbor phases (peak ejection volume, PEV, mL) during systole and to calculate the peak ejection rate (PER i.e. PEV/phase duration [1/10th of RR interval], mL/s). The derived parameters were calculated as the PER normalized for LVEDV (PER-V, 1/s), the PER normalized for LVM (PER-M, mL/g × s) and the PER normalized for LVEDV times the PER normalized for LVM product (PER-VM, ml/g × s2). Considering the errors percentages, the respective values for intra- and inter-observer errors were around 5% and 8% for standard LV systolic measures. The percentage intra-observer errors' ranged between -7.8% and -10.8%, and the inter-observer errors' ranged between -11.8% and -15.7% for both PEV and PER. For the same reader, the percentage errors ranged between -8.7% and +11.9% for PER-V, -10% and +12.7% for PER-M and -18.2% and +24% for PER-VM. For the independent reader the corresponding values were -15.2% and +15.5%, -12.3% and +16.3%, and -26.6% and +30.9%. The intra- -class coeffi cients for repeated measurements for both the same reader (intra-observer) or independent reader (inter-observer) did reach values above 0.9 and around 0.8, respectively. We concluded that traditional LV systolic parameters, as well as more sensitive measures of cardiac contractility could be determined reliably by means of a 64-row MDCT. The errors for global LV systolic function measures amount to about 5%, for PEV and PER about 15% and for the PER-derived parameters about 25%. The measurement errors established might help to assess the signifi cance of changes in repeated MDCT examinations.

Chronic recordings of cardiac contractility in conscious rats via telemetry

Measurements of cardiac contractility in conscious freely moving animals are uncommon yet could offer considerable opportunity for understanding cardiovascular disease progression and treatment. We have utilized a new high‐fidelity solid‐state pressure sensor telemetry device for chronically measuring left ventricular pressure (LVP) and dP/dt in rats. The pressure sensor catheter tip (2‐Fr) was inserted into the left ventricular chamber through the apex of the heart and the telemeter body implanted in the abdomen. Data was measured up to 85 days after implant. The average daytime dP/dt max was 9706 ±264 mmHg/s, ranging from 8186 to 11382 mmHg/s (n=24). A circadian variation in dP/dt max and heart rate (HR) was observed with an average increase during the night phase in dP/dt max of 2198 ±280 mmHg/s and in HR of 60 ±5 bpm. The alpha‐adrenergic blocker propranolol, alpha‐adrenergic‐agonist isoproterenol, alpha1‐adrenergic agonist dobutamine, Ca2+ channel blocker verapamil and the calcium sensitizer levosimendan were administered repeatedly throughout the implant period, inducing changes in dP/dt max of −6000 to +13,000 mmHg/s from control and dose‐dependent time course changes in contractility. We propose that the chronic measurement of LVP in conscious rats can provide a valuable tool in cardiovascular research.

Cardiac Function in Congenital Adrenal Hyperplasia: A Pattern of Reversible Cardiomyopathy

To evaluate cardiac function in infants with congenital adrenal hyperplasia (CAH) before and after corticosteroid replacement therapy. This prospective, case-control study included 9 infants with CAH. Cardiac function was assessed by echocardiography at presentation and after corticosteroid replacement therapy. Six term infants underwent 2 echocardiograms each and served as the control group. Data on fractional shortening (FS), rate-corrected velocity of circumferential fiber shortening (Vcf), wall stress, tissue Doppler indices, myocardial performance index, left ventricular mass, and Vcf/wall stress were obtained. The infants with CAH exhibited myocardial dysfunction at baseline and lower systolic blood pressure (SBP) compared with the control group. FS, a measure of systolic contractility, differed significantly from before to after corticosteroid treatment (mean, 32.3%±4.7% pretreatment, 39.9%±5.0% posttreatment). Vcf, a preload-independent measure of cardiac contractility, also differed significantly before and after treatment (mean, 1.23±0.16 circumferences/second pretreatment, 1.45±0.22 circumferences/second posttreatment). SBP was also lower (mean, 84±9.3 mmHg) and improved with treatment (mean, 95±4.8 mmHg). The control group demonstrated no statistically significant changes in FS, Vcf, or SBP. There was a change in left ventricular mass in the control group between the 2 studies. Newborns with CAH have evidence for cardiac dysfunction at baseline that reverses with corticosteroid replacement therapy. These data suggest that corticosteroids play a direct role in modulating cardiac function in the newborn.

Arterial Stiffness and Walk Time in Patients with End-Stage Renal Disease

Background: End-stage renal disease patients experience increased prevalence of cardiovascular disease. Heart-artery interaction may be shifted, impacting blood pressure lability, and exercise tolerance. The coupling ratio consists of the ratio of indexed arterial elastance (EaI, arterial load) to ElvI, a measure of cardiac contractility or stiffness. Our purpose was to explore the relationship between elastances and functional capacity. We hypothesized that arterial stiffness (central pulse wave velocity, PWV) and elastances would be correlated to shuttle walk time. Methods: We used applanation tonometry, ultrasonography, and a shuttle walk test to evaluate our hypothesis. Spearman's correlations were used to assess relationships between variables. Block regression was also performed. Results: Forty-two subjects on maintenance hemodialysis participated. Average age=44±5 years, body surface area=2.01 kg/m². Mean EaI=4.45 and mean ElvI=6.89; the coupling ratio=0.82. Mean aortic pulse pressure=51 mmHg and PWV=9.6 m/s. PWV(r=-0.385) and EaI (r=-0.424) were significantly and inversely related to walking time while stroke volume index (SVI) was positively correlated to shuttle walk time (r=0.337), p<0.05 for all. Conclusions: We conclude that, like other clinical populations, both arterial and heart function predict walking ability and represent potential targets for intervention; arterial stiffness and SVI are strongly related to shuttle walk time in patients with ESRD.

Impedance cardiography in uncomplicated pregnancy and pre-eclampsia: A reliability study

It has been reported that cardiac contractility is altered in pre-eclampsia compared with normal pregnancy. Because of the non-invasive nature of impedance cardiography (ICG), this method is gaining popularity in the obstetric field. We assessed the reliability of ICG measurements in uncomplicated 3rd trimester pregnancies (UP) and pre-eclamptic pregnancies (PE). ICG measurements were recorded before and after three position changes, and this examination was done twice (session 1 and 2) per subject. For each of the 22 haemodynamic parameters, inter- and intrasession Pearson's correlation coefficients (PCC) were calculated for mean values of 30 measurements per position per subject. PCC was consistently ≥ 0.80 for contractility parameters ‘acceleration-’, ‘velocity-’ and ‘heather-index’ in both UP and PE. These data illustrate that correlation between repeated ICG measurements of cardiac contractility is high under standardised conditions, and that ICG may be useful to study changes of cardiac contractility in pregnancy.

Validation of an in vitro contractility assay using canine ventricular myocytes

Measurement of cardiac contractility is a logical part of pre-clinical safety assessment in a drug discovery project, particularly if a risk has been identified or is suspected based on the primary- or non-target pharmacology. However, there are limited validated assays available that can be used to screen several compounds in order to identify and eliminate inotropic liability from a chemical series. We have therefore sought to develop an in vitro model with sufficient throughput for this purpose.Dog ventricular myocytes were isolated using a collagenase perfusion technique and placed in a perfused recording chamber on the stage of a microscope at ~36°C. Myocytes were stimulated to contract at a pacing frequency of 1Hz and a digital, cell geometry measurement system (IonOptix™) was used to measure sarcomere shortening in single myocytes. After perfusion with vehicle (0.1% DMSO), concentration–effect curves were constructed for each compound in 4–30 myocytes taken from 1 or 2 dog hearts.The validation test-set was 22 negative and 8 positive inotropes, and 21 inactive compounds, as defined by their effect in dog, cynolomolgous monkey or humans. By comparing the outcome of the assay to the known in vivo contractility effects, the assay sensitivity was 81%, specificity was 75%, and accuracy was 78%.With a throughput of 6–8compounds/week from 1 cell isolation, this assay may be of value to drug discovery projects to screen for direct contractility effects and, if a hazard is identified, help identify inactive compounds.