Increase In Stroke Work Research Articles

Restoring Cardiac Health: Abstinence Leads to Recovery from Alcohol-Induced Cardiomyopathy

Chronic drinking can lead to alcohol-induced cardiomyopathy (ACM), a disease currently without a cure. Using a mouse model of ACM, we observed significant cardiac dysfunction after 30 days. Our study’s goal was to investigate the potential restoration of cardiac function following a period of abstinence. Our hypothesis is that abstinence can lead to an observable recovery in overall cardiac function. C57BL/6J mice were given the Lieber-DeCarli liquid diet with 5% ethanol for 30 days, with two ethanol binges on days 10 and 30 (5 g/kg). After the 30-day ethanol exposure, the mice were transitioned to an ethanol-free diet for an additional 30 days. Left ventricular catheterization and echocardiography were conducted at the 30- and 60-day timepoints. 30 days of ethanol consumption led to significant decreases in both systolic and diastolic function. However, following a period of alcohol abstinence, there was a marked improvement. Specifically, the 30-day ethanol mice exhibited increases in stroke work and dP/dt max after 30 days of abstinence; stroke work increased from 1119 ± 89 mmHg*μL to 2032 ± 139 mmHg*μL (p < 0.0001), and dP/dt max increased from 8054 ± 664 mmHg/s to 11967 ± 449 mmHg/s (p < 0.001). Diastolic function also improved; dP/dt min from -7711 ± 561 mmHg/s to -10202 ± 594 (p < 0.01). We also found a significant increase in load-independent cardiac contractility, i.e. the slope of end systolic pressure volume relation: 6.89 ± 0.6 mmHg/μL to 10.59 ± 1.57 mmHg/μL (p < 0.05). In conclusion, abstinence after chronic ethanol exposure can lead to a restoration of cardiac function in C57BL/6J mice. This model parallels limited clinical data on abstinence and will allow us to study the underlying mechanisms responsible for the restoration of function. R21AA029747 (JG, CB), F30AA030472 (JE). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The impact of phosphodiesterase-5 inhibition or angiotensin-converting enzyme inhibition on right and left ventricular remodeling in heart failure due to chronic volume overload.

While phosphodiesterase-5 inhibition (PED5i) may prevent hypertrophy and failure in pressure-overloaded heart in an experimental model, the impact of PDE5i on volume-overload (VO)-induced hypertrophy is unknown. It is also unclear whether the hypertrophied right ventricle (RV) and left ventricle (LV) differ in their responsiveness to long-term PDE5i and if this therapy affects renal function. The goal of this study was to elucidate the effect of PDE5i treatment in VO due to aorto-caval fistula (ACF) and to compare PDE5i treatment with standard heart failure (HF) therapy with angiotensin-converting enzyme inhibitor (ACEi). ACF/sham procedure was performed on male HanSD rats aged 8 weeks. ACF animals were randomized for PDE5i sildenafil, ACEi trandolapril, or placebo treatments. After 20 weeks, RV and LV function (echocardiography, pressure-volume analysis), myocardial gene expression, and renal function were studied. Separate rat cohorts served for survival analysis. ACF led to biventricular eccentric hypertrophy (LV: +68%, RV: +145%), increased stroke work (LV: 3.6-fold, RV: 6.7-fold), and reduced load-independent systolic function (PRSW, LV: -54%, RV: -51%). Both ACF ventricles exhibited upregulation of the genes of myocardial stress and glucose metabolism. ACEi but not PDE5i attenuated pulmonary congestion, LV remodeling, albuminuria, and improved survival (median survival in ACF/ACEi was 41 weeks vs. 35 weeks in ACF/placebo, p = .02). PDE5i increased cyclic guanosine monophosphate levels in the lungs, but not in the RV, LV, or kidney. PDE5i did not improve survival rate and cardiac and renal function in ACF rats, in contrast to ACEi. VO-induced HF is not responsive to PDE5i therapy.

MATERNAL LEFT VENTRICULAR ADAPTATION IN TWIN PREGNANCY

Objective: During pregnancy, a maternal left ventricular (LV) remodeling occurs to face significant hemodynamic changes. Although twin pregnancy can require greater modifications than in singleton, limited data are currently available. The aim of the study was to longitudinally investigate maternal changes of LV function and compliance in twin pregnancy. Design and method: 35 uncomplicated twin pregnancy women underwent transthoracic echocardiography at first (T1, 10-15 weeks) and third trimester (T3, 30-35 weeks) of gestation. Left atrial (LA) and LV dimensions, LV volumes, systolic and diastolic function were measured, LV mass was calculated. Speckle-tracking imaging was used to evaluate global longitudinal strain (GLS). Non-invasive pressure-volume curves (PV loops) were reconstructed using a dedicated software. Results: Maternal LA and LV dimensions, LV volumes and mass increased from T1 to T3. Ejection fraction and GLS showed no changes between visits. Assessment of diastolic function (at pulsed wave Doppler and tissue Doppler) showed no changes in E/A ratio, while E/e’ ratio was higher at T3. At PV loops analysis, ventricular-arterial coupling (VAC) was stable due to the reduction of both LV end-systolic elastance (Ees) and arterial elastance (Ea). An increase in stroke work was observed. The increase in LV end-diastolic volumes from T1 to T3 with no changes in LV end-diastolic filling pressure suggested enhanced LV cavity compliance (rightward shift of the end-diastolic pressure-volume relationship, EDPVR). Conclusions: Maternal heart in uncomplicated twin pregnancy adapts to the increased hemodynamic load with an increase in stroke work and enhancement of LV volumes without altering ventricular filling pressure.

Metabolic Syndrome and C-reactive Protein are Associated With a Reduced Myocardial Mechano-energetic Efficiency.

Metabolic syndrome and elevated high-sensitivity C-reactive protein (hsCRP) levels are associated with risk of cardiovascular diseases. A reduced myocardial mechano-energetic efficiency (MEE) has been found to be an independent predictor of cardiovascular disease. To evaluate the association between metabolic syndrome and hsCRP levels with impaired MEE. Myocardial MEE was assessed by a validated echocardiography-derived measure in 1975 nondiabetic and prediabetic individuals subdivided into 2 groups according to the presence of metabolic syndrome. Individuals with metabolic syndrome exhibited increased stroke work and myocardial oxygen consumption estimated by rate pressure product, and a reduced MEE per gram of left ventricular mass (MEEi) compared with subjects without metabolic syndrome, after adjusting for age and sex. Myocardial MEEi progressively decreased in parallel with the increase in the number of metabolic syndrome components. In a multivariable regression analysis, both metabolic syndrome and hsCRP contributed to reduced myocardial MEEi independently of sex, total cholesterol, high-density lipoprotein, triglycerides, fasting, and 2-hour postload glucose levels. When the study population was divided into 4 groups by the presence or absence of metabolic syndrome and by hsCRP levels above and below 3 mg/L, hsCRP levels ≥3 mg/L were associated with reduced myocardial MEEi both in subjects with metabolic syndrome and in those without the syndrome. Nondiabetic and prediabetic individuals with metabolic syndrome exhibit increased stroke work and myocardial oxygen consumption, and an impaired MEEi, an established predictor of adverse cardiovascular events, and elevated hsCRP levels in combination with metabolic syndrome aggravate the myocardial MEEi impairment.

Enhancement of left ventricular compliance in twin pregnancy

Abstract Funding Acknowledgements Type of funding sources: None. Background The knowledge of maternal left ventricular adaptation in twin pregnancies is incomplete. Purpose The objective of this study was to longitudinally investigate maternal changes of left ventricular (LV) function and compliance in twin pregnancies. Methods Thirty-five women (age 35.3±4.8 years) with uncomplicated twin pregnancy were enrolled to undergo transthoracic echocardiography at 10-15 (T1) and 30-38 (T3) week’s gestation. Left atrial (LA) and LV dimensions, LV volumes and mass, diastolic parameters (at pulsed wave Doppler and tissue Doppler), global longitudinal strain (GLS) at speckle-tracking imaging, and non-invasive pressure-volume curves (PV loops) were measured and calculated. Results Maternal LA and LV dimensions, LV volumes and mass had an increasing trend from T1 to T3 (p<0.001 for all). E/A remained stable, while E/e’ ratio slightly increased during gestation. GLS showed no changes between the two visits. At PV loops analysis (Figure 1), LV end-systolic elastance (Ees) and arterial elastance (Ea) both decreased, with no changes in ventricular-arterial coupling (VAC). LV end-diastolic volumes increased from T1 to T3 with no changes in LV end-diastolic filling pressure; the rightward shift of the end-diastolic pressure-volume relationship (EDPVR) suggested enhanced LV cavity compliance (Figure 2). An increase in stroke work was observed. Conclusions During twin pregnancy GLS and VAC were not modified showing functional adaptation to enhanced haemodynamic load. Importantly, stroke work increase was sustained by enhancement in LV end-diastolic volume with unaltered filling pressure.

Impact of Impella RP Versus Vasoactive Treatment on Right and Left Ventricular Strain in a Porcine Model of Acute Cardiogenic Shock Induced by Right Coronary Artery Embolization.

Background The response of the left ventricle to cardiogenic shock (CS) caused by right ventricular (RV) infarction and the effect of treatment with either vasoactive treatment or Impella RP are not well described. We sought to determine RV and left ventricular longitudinal strain (LS) by echocardiography after initiation of either Impella RP or vasoactive treatment for CS induced by right coronary artery embolization. Methods and Results CS was induced with microsphere embolization in the right coronary artery in 20 pigs. Shock was defined as a reduction in cardiac output of ≥50% and/or an SvO2 <30%. At the time of CS either Impella RP or vasoactive treatment (norepinephrine and milrinone) was initiated. Echocardiography and conductance measures were obtained at baseline, when CS was present, and 30, 90, and 180 minutes after induction of CS. Of 20 animals, 14 completed the protocol and were treated with either vasoactive treatment (n=7) or Impella RP (n=7); 6 animals died (3 in each group). In the RV there was a significantly higher LS with the vasoactive treatment compared with Impella RP (-7.6% [4.5] to -6.0% [5.2] vs -4.5% [6.6] to -14.2% [10.6]; P<0.006). Left ventricular LS improved with both treatments compared with shock, but with a larger effect (-9.4% [3.2] to -17.9% [3.6]) on LS with vasoactive treatment than Impella RP (-9.8% [3.1] to -12.3% [4.6]; P<0.001). We found a significant correlation between stroke work and RV LS (r=-0.60, P<0.001) and left ventricular LS (r=-0.62, P<0.001). Conclusions We found significantly higher hemodynamic effects with vasoactive treatment compared with Impella RP in both the RV and left ventricular but at a cost of increased stroke work.

Abstract 13087: Right Atrial Adaptation in Pulmonary Hypertension: Pressure-Volume and Histological Analysis

Introduction: Pulmonary arterial hypertension (PAH) is associated with increased right atrial (RA) pressure and volume. We hypothesized that these patients have RA hypertrophy, increased stroke work, fibrosis and stiffness and that RA adaptation falls short in severe right ventricular (RV) diastolic stiffness (end-diastolic elastance; E ed ). Methods: RA pressure-volume loops were created through a novel method in controls (N=9) and patients (N=27). RA volume was measured on a magnetic resonance transverse stack of slices and pressure with catheterization. In a larger cohort of controls (N=20) and PAH patients with low (N=39) or high E ed (N=41), RA volume was measured on a 4-chamber view and stroke work estimated through multiplying active emptying by A-wave pressure. Atriovenous stiffness was measured as the slope from minimal pressure and volume and V-wave. In PAH-patients (N=4) and controls (N=5) that died or underwent heart- and lung-transplantation, we collected RA tissue to study hypertrophy and capillarization (CD31 and wheat germ agglutinin staining) and fibrosis (Masson’s trichrome staining). Results: Averaged pressure-volume loops show RA dilatation in patients and elevated pressure, especially during atrial contraction. Atriovenous stiffness was similar in PAH and controls, but higher in high E ed when compared to low E ed patients. RA stroke work and pressure rise during atrial contraction were higher in PAH. However, when corrected for E ed , these parameters were decreased in high E ed patients, indicating RA-RV uncoupling. Histological analysis showed increased RA hypertrophy, number of capillaries per cardiomyocyte and perivascular/interstitial fibrosis in PAH patients. Conclusions: In PAH patients there is RA hypertrophy and increased stroke work. In severe RV diastolic stiffness, RA adaptation falls short and RA-RV uncoupling occurs. Although there is increased fibrosis, atriovenous stiffness is not different between PAH and controls.

Ventricular-Vascular Uncoupling in Heart Failure: Effects of Arterial Baroreflex-Induced Sympathoexcitation at Rest and During Exercise.

Autonomic alterations in blood pressure are primarily a result of arterial baroreflex modulation of systemic vascular resistance and cardiac output on a beat-by-beat basis. The combined central and peripheral control by the baroreflex likely acts to maintain efficient energy transfer from the heart to the systemic vasculature; termed ventricular-vascular coupling. This level of control is maintained whether at rest or during exercise in healthy subjects. During heart failure, the ventricular-vascular relationship is uncoupled and baroreflex dysfunction is apparent. We investigated if baroreflex dysfunction in heart failure exacerbated ventricular-vascular uncoupling at rest, and during exercise in response to baroreceptor unloading by performing bilateral carotid occlusions in chronically instrumented conscious canines. We observed in healthy subjects that baroreceptor unloading caused significant increases in effective arterial elastance (Ea) at rest (1.2 ± 0.3 mmHg/ml) and during exercise (1.3 ± 0.2 mmHg/ml) that coincided with significant increases in stroke work (SW) (1.5 ± 0.2 mmHg/ml) and (1.6 ± 0.2 mmHg/ml) suggesting maintained ventricular-vascular coupling. Heart Failure significantly increased the effect of baroreceptor unloading on Ea at rest (3.1 ± 0.7 mmHg/ml) and during exercise (2.3 ± 0.5 mmHg/ml) whereas no significant increases in stroke work occurred, thus signifying further ventricular-vascular uncoupling. We believe that the enhanced ventricular-vascular uncoupling observed during baroreceptor unloading only worsens the already challenged orthostatic and exercise tolerance and thereby contributes to poor exercise performance and quality of life for heart failure patients.

P1421 Patients with severe aortic regurgitation showed systolic dysfunction and increased stroke work despite preserved EF; clues for reconsidering optimal time point of surgery

Abstract Background Current guidelines recommend surgery in patients with severe aortic regurgitation (AR) with clinical symptoms or subnormal ejection fraction (EF). Furthermore, surgery should be considered in patients with severe AR, preserved EF and increased left ventricular diameters (LVEDD &amp;gt;70mm, LVESD &amp;gt;50mm). The aim of the study was to investigate LV systolic function as well as mechanical energetics using non-invasive pressure-volume- and strain analysis in patients with severe AR and preserved EF as well as moderately dilated ventricles (LVEDD &amp;lt;70mm). Methods and Results Echocardiographic strain and single beat pressure-volume analyses were performed in patients with severe AR and moderately increased ventricular size (LVEDD &amp;lt; 70mm, EF &amp;gt;50% n = 39) as well as healthy, age-matched controls (n = 20) using echo-derived volume and arm-cuff blood pressure measurements. Load independent parameters of systolic contractile function like end-systolic elastance (Ees) and end-systolic volume at 100mmHg (ESV100) were calculated as well as stroke work ((SW) and total pressure volume area (PVA = SW + potential energy). Patients with AR demonstrated significant depression of systolic function beyond ejection fraction: global longitudinal strain was reduced compared to controls (-16 ±2.5% vs. -21.5 ±2%; p &amp;lt; 0.001). Accordingly load independent parameters of LV contractility like Ees (1.5mmHg/ml ±0.7 vs. 2.25mmHg/ml ±0.7; p &amp;lt; 0.001), ESV100 (65.7ml ±19.4 vs. 42.4ml ±19.8; p &amp;lt; 0.05) were reduced despite comparable ejection fractions (EF: 0.56% ±0.05 vs. 0.60% ±0.07 p = 0,10). End-diastolic volume of AR patients was markedly elevated (236ml ±90 vs. 136ml ±30; p &amp;lt; 0.001), while PVA (20470mmHg x ml ±10400 vs. 11907mmHg x ml ±2877; p &amp;lt; 0.01) and stroke work (13200mmHg x ml ±5700 vs. 7606 mmHG x ml ±2048; p&amp;lt; 0.01) were markedly elevated indicating waste of energy. Conclusion Patients with severe AR and moderately enhanced LV showed depressed values of contractility and waste of energy using more advanced parameters of LV systolic function although EF was preserved. The data may demonstrate that surgery is performed too late in many of those patients and may give clues for reconsidering guidelines to meet the optimal time point of surgery. .

Left ventricular and proximal aorta coupling in magnetic resonance imaging: aging together?

The importance of aorta-ventricular coupling in cardiovascular disease is recognized but underestimated. The contribution of the age-related decline in ascending aortic function compared with characteristic impedance and total peripheral resistance on left ventricular function and remodeling is poorly studied. Our aim was to evaluate the relation of proximal aortic distensibility and impedance with left ventricular geometry and function in asymptomatic individuals. We prospectively studied 100 subjects (47 men, 53 women, age: 20-84 yr). Aortic strain, distensibility, arch pulse wave velocity, characteristic impedance (Zc), total peripheral resistance, left ventricular (LV) volumes and mass, wall stress, and peak global circumferential myocardial strain and strain rates were determined by MRI. Central pressures were measured from tonometry. Ea/Ev, an index of vascular-ventricular coupling, and LV wall stress were preserved across age- or aortic-stiffness-stratified groups. Static and pulsatile components of aortic load were differentially associated with age. Increased total vascular resistance was associated with decreased LV strain and increased concentric remodeling [ratio of LV mass to end-diastolic volume (M/V ratio)] in all individuals. In younger individuals (<45 yr), aortic distensibility was related to LV strain and concentric remodeling (M/V ratio), whereas Zc was related to LV strain and concentric remodeling (M/V ratio) in older individuals (>45 yr). Early age-related stiffening of the ascending aorta is a component of LV afterload subsequently associated with increased aortic impedance and alterations in LV geometry, namely concentric remodeling, decreased myocardial strain, and increased stroke work such that LV wall stress and arterial-ventricular coupling are preserved. NEW & NOTEWORTHY Local flow and deformation can both be assessed with high precision noninvasively in the ascending aorta using MRI. Combined with central pressure measurement, they provide distensibility and impedance and simultaneous reference assessment of left ventricular deformation and geometry, hence a comprehensive evaluation of arterial-ventricular coupling to study physiology and disease.

Abstract 039: Differential Expression of miR-146b-5p Modulates Sex-Specific Cardiac Phenotypes in a Rat Model of Chronic Kidney Disease

Type 4 cardiorenal syndrome is a complex disorder in which primary chronic kidney disease (CKD) contributes to secondary cardiovascular disease (CVD). Although the pathological link between the kidney and heart are well-characterized, the molecular switches which drive cardiac pathology are not well understood. miRNAs have the potential to be master regulators of cellular signaling networks through modulation of RNA and protein expression profiles and have been shown to be important in both cardiovascular health and disease. Previous work in our laboratory identified a significant increase of miR-146b-5p expression in both the heart and the kidney in a 5/6 nephrectomy (5/6Nx) model of CKD in the Sprague-Dawley rat. To evaluate how miR-146b-5p is involved with pathological changes in the heart following 5/6Nx, echocardiography, blood pressure and left ventricle (LV) pressure-volume analyses were performed on male and female wild-type (WT) and miR-146b-5p null mutant (146b -/- ) rats for seven weeks following 5/6Nx or sham surgery. Structural analysis of the heart revealed that male and female rats exhibited significant hypertrophy of the LV wall in both the WT (+21% [1.50 vs. 1.24g] and +24% [1.00 vs. 0.81g] vs. sham, respectively; p&lt;0.001) and 146b -/- (+17% [1.36 vs. 1.17g] and +26% [1.03 vs. 0.82g] vs. sham, respectively; p&lt;0.001) genotypes. Furthermore, dilation of the LV chamber was observed in WT male (+9% LVIDd [9.45 vs. 8.67mm] vs. sham; p=0.032) and female (+29% LVIDd [9.39 vs. 7.30mm] and +36% LVIDs [5.80 vs. 4.86mm] vs. sham; p&lt;0.005) rats 7 weeks post-5/6Nx. However, LV dilation was attenuated in 146b -/- females (-18% LVIDd [8.18 vs. 9.39mm] and -26% LVIDs [4.88 vs. 5.80mm] vs. WT; p=0.07) but not in 146b -/- males. Functionally, LV pressure-volume analysis revealed 146b -/- females exhibit an increase in stroke work (+59% vs. sham; p=0.063) and a significantly elevated mean arterial blood pressure (+23mmHg vs. sham; p=0.02). These alterations in cardiovascular function are not observed in miR-146b -/- males. Taken together, these data suggest 146b -/- female rats may be resistant to eccentric dilation despite increased afterload and highlight the sex-specific modulation of cardiorenal phenotypes by miR-146b-5p following 5/6Nx.

Heat shock protein 72 may improve hypotension by increasing cardiac mechanical efficiency and arterial elastance in heatstroke rats

ObjectiveWe attempted to test the hypothesis that preinduction of heat shock protein (HSP) 72 in the heart would improve left ventricular performance in rat heatstroke. MethodsCardiac expression of HSP 72 was quantitatively evaluated by western blot analysis in rats 0h, 12h, or 72h after mild heat preconditioning (MHP; 43°C for 30min). They were subjected to severe heat stress (SHS; 43°C for 70min) to induce heatstroke. A 1.2F catheter-tip pressure transducer was inserted into the left ventricle of these group rats under general anesthesia to record hemodynamic in the closed chest with a pressure–volume loop module data recording and analysis system. ResultsAt the time point of heatstroke onset, compared with normothermic controls, group rats with 12h post-MHP had significantly increased cardiac HSP 72, decreased hyperthermia, decreased hypotension, decreased bradycardia, increased end-systolic pressure, increased end-diastolic pressure, increased stroke volume, decreased end-systolic volume, decreased end-diastolic pressure, increased cardiac output, increased ejection fraction, increased stroke work, increased arterial elastance, and decreased time constant of fall in ventricular pressure by Glantz-methods. With the loss of cardiac HSP 72 expression observed at 72h in post-MHP group rats, an insignificant protection against left ventricular performance was observed. ConclusionPreinduction of cardiac HSP 72 may improve hypotension in heatstroke rats by increasing both cardiac mechanical efficiency and arterial elastance.

Abstract 15288: Conductive Polymer Hydrogel for Enhancement of Electrical Propagation in Border Zone Myocardium after Myocardial Infarction

Introduction: After myocardial infarction (MI), cardiomyocyte death results in a non-contractile fibrotic scar and altered electrical properties, including delayed impulse propagation across the scar region which may contribute to ventricular dysfunction. Hydrogels such as chitosan have been used clinically to stabilize the LV free wall and prevent dilation. We chemically modified chitosan with the charge-carrying conductive polymer polypyrrole (PPy), yielding a biomaterial with more than 100X the conductivity of chitosan alone. Chitosan-PPy is capable of carrying electrical impulses and may enhance synchronous contraction. Methods: Biomaterials were synthesized under sterile conditions and were thoroughly characterized in vitro . Myocardial infarction was created by coronary artery ligation in Sprague-Dawley rats (n = 36), and 1 week later chitosan, chitosan-PPy or saline were injected into the border zone regions. Animals were followed for 8 or 16 weeks (n = 6/treatment/time-point) and cardiac conduction and function were assessed with ECG, echocardiography, impedance catheter analysis and finally Langendorff-perfused epicardial optical mapping. Results: Eight weeks post-injection, QRS duration was increased in saline and chitosan treated hearts, but was maintained in chitosan-PPy hearts until 16 weeks ( p &lt; 0.01), suggesting less maladaptive ventricular remodeling associated with slowing of depolarizing conduction in the chitosan-PPy group. Echocardiography revealed that fractional shortening was enhanced in chitosan-PPy treated hearts at both 8 and 16 weeks ( p &lt; 0.01). At 16 weeks, chitosan-PPy hearts had increased stroke work capacity, and better maintained (lower) end systolic volume ( p &lt; 0.05). Optical mapping demonstrated that chitosan-PPy-treated hearts had faster transverse conduction velocities measured along the border zone epicardial surface ( p &lt; 0.01). Conclusions: We synthesized and characterized a novel conductive polymer hydrogel that may be used therapeutically to enhance favorable cardiac recovery at the LV border zone following an MI. Chitosan-PPy enhanced heart function by augmenting synchronized contraction.

Difference between hemoglobin‐based oxygen carrier and non‐oxygen carrying plasma expander on cardiac function during hemorrhagic shock resuscitation (545.1)

Study aimed to establish the role of acellular hemoglobin (Hb) based oxygen carrier on cardiac function during anemia. Anesthetized Golden Syrian hamsters under mechanical ventilation with air were hemorrhage 30% of the animal’s blood volume followed by equal volume resuscitation with polymerized albumin (pHSA), or polymerized Hb (pHb, Hemopure, OPK Biotech, Boston, MS). Blood oxygen saturation of &gt;90% was maintained throughout experiment. Cardiac function was assessed through the use of a miniaturized conductance catheter inserted into the left ventricle with continuous pressure‐volume readings. All groups had an increase in stroke work, cardiac output, and ejection fraction compared to baseline. The ratio between dP/dtmax and end diastolic volume, an index of contractility, recovered to 94±33% from baseline for the pHSA, and decreased to 55± 13% from baseline for pHb one hour after resuscitation. To further elucidate the difference in contractility, the intrinsic effects of oxygenation will be investigated by the histology of hypoxic tissue using pimonidazole staining. Hemorrhage and resuscitation resulted in an increased in cardiac function for both treatments.Grant Funding Source: NIH R01 HL52684, R01 HL064395 and R01 HL062318 and ARMY: W81XWH‐11‐2‐0012

Effect of Transverse Aortic Constriction on Cardiac Structure, Function and Gene Expression in Pregnant Rats

BackgroundThere is an increased risk of heart failure and pulmonary edema in pregnancies complicated by hypertensive disorders. However, in a previous study we found that pregnancy protects against fibrosis and preserves angiogenesis in a rat model of angiotensin II induced cardiac hypertrophy. In this study we test the hypothesis that pregnancy protects against negative effects of increased afterload.MethodsPregnant (gestational day 5.5–8.5) and non-pregnant Wistar rats were randomized to transverse aortic constriction (TAC) or sham surgery. After 14.2±0.14 days echocardiography was performed. Aortic blood pressure and left ventricular (LV) pressure-volume loops were obtained using a conductance catheter. LV collagen content and cardiomyocyte circumference were measured. Myocardial gene expression was assessed by real-time polymerase chain reaction.ResultsHeart weight was increased by TAC (p<0.001) but not by pregnancy. Cardiac myocyte circumference was larger in pregnant compared to non-pregnant rats independent of TAC (p = 0.01), however TAC per se did not affect this parameter. Collagen content in LV myocardium was not affected by pregnancy or TAC. TAC increased stroke work more in pregnant rats (34.1±2.4 vs 17.5±2.4 mmHg/mL, p<0.001) than in non-pregnant (28.2±1.7 vs 20.9±1.5 mmHg/mL, p = 0.06). However, it did not lead to overt heart failure in any group. In pregnant rats, α-MHC gene expression was reduced by TAC. Increased in the expression of β-MHC gene was higher in pregnant (5-fold) compared to non-pregnant rats (2-fold) after TAC (p = 0.001). Nine out of the 19 genes related to cardiac remodeling were affected by pregnancy independent of TAC.ConclusionsThis study did not support the hypothesis that pregnancy is cardioprotective against the negative effects of increased afterload. Some differences in cardiac structure, function and gene expression between pregnant and non-pregnant rats following TAC indicated that afterload increase is less tolerated in pregnancy.

Myocardial contractile response to dobutamine in hypoplastic left heart syndrome post-Fontan

Background The systemic right ventricl e( RV) is at increased risk of developing heart failure. Combined MRI-catheterization (XMR) techniques offer a unique opportunity to study this condition. We assess pressure-volume relations in children with hypoplastic left heart syndrome (HLHS) post Fontan with stepwise increments of dobutamine stress. Methods Prospective data from anesthetized patients with HLHS undergoing clinical XMR were analyzed. A fluid filled MR compatible catheter placed in the systemic RV recorded pressures at rest, with dobutamine infusion at 10 mcg/kg/ min and at 20 mcg/kg/min. Simultaneous cine short axis stacks of the ventricle were performed. Pressure-volume loops were constructed. End-systolic pressure-volume relationship was derived at each state from a validated maximal pressure (Pmax) estimation method. Ventriculoarterial coupling (Ees:Ea) was compared to myocardial power and overall global function. Results Five patients with HLHS and exercise intolerance, mean age 7.8 years (range 3.5-11.6 yrs), weight 26 Kg (range 1646 Kg), time since Fontan completion (mean 3.2 years). No significant tricuspid regurgitation in any patient. Statistical analysis was performed using one-way ANOVA with post-hoc comparisons to assess subgroup variation where p < 0.05. There were significant increases in EF, indexed cardiac output, power and ventricular contractility (Ees) with increases limited to between rest and dobutamine 10 (p < 0.01) with no further significant increase at 20. iEDV fell significantly between rest and dobutamine 20 (p < 0.01). EDP and arterial elastance (Ea) did not change throughout. Ees:Ea increased between rest and dobutamine 10 only. dP/dtmin a measure of rate of relaxation fell with dobutamine 10 only. Conclusions In the systemic RV, load independent indices of contraction in response to dobutamine are similar to those recorded in the healthy left ventricle (LV). The systemic RV at rest works neither at maximal mechanical efficiency (Ees:Ea = 2) nor maximal stroke work efficiency at a given EDV (Ees:Ea = 1). Increased coupling with dobutamine, mediated through increased myocardial contractility, indicates at higher heart rates the RV moves towards improved mechanical efficiency though at higher levels of overall energy expenditure. The relative increase in stroke work (37%) is comparable to data published on the healthy LV. The systemic RV has a limited cardiac reserve. Despite appropriate responses in contractility to low dose dobutamine, the heart is unable to further augment power and cardiac output with administration of dobutamine 20. Indeed, the plateauing of dP/dtmin - a measure of relaxation - indicates that in the presence of tachycardia there is failure to adequately fill the heart. Hence cardiac output and contractility may be limited by a ceiling of maximal flow through the Fontan circuit. This gives us valuable insights into the physiology of children with HLHS postFontan.

Computational modelling to optimize the hybrid configuration for hypoplastic left heart syndrome†

Hybrid palliation for hypoplastic left heart syndrome (HLHS) is associated with mortality and late ventricular dysfunction. Increased ventricular workload and coronary perfusion limitation may be the important factors. Using mathematical modelling, this study investigated the effects of differing hybrid configurations on the demands on this single ventricle circulation. A multicompartmental Windkessel model of hybrid HLH-aortic atresia circulation was adopted, with a time-varying elastance representing ventricular functionality. The effects of diameter increases in bilateral pulmonary artery bandings (PABs) (+0.5, 2.5-4 mm) and ductal stent (+1, 4-10 mm) on cardiovascular haemodynamics, systemic oxygenation and ventricular energetics were assessed. Simulations showed that an increase in PAB diameter of 2.5-4 mm resulted in an increased Q (0.61-2.66), and diastolic stent backflow (-0.2 to -0.78 l/min) with reduced systemic perfusion (0.82-0.77 l/min) and diastolic pressures (48.3-41.2 mmHg). Arterial and venous saturations increased, SaO2 (%) was 62-88 and SvO(2) 41-65. To maintain mean systemic pressures, substantial increases in cardiac output (1.3-2.8 l/min) and ventricular stroke work (576-1360 mmHg ml) were required. A decrease in the ductal stent diameter over the range 10-7 mm had a negligible haemodynamic effect: reduced systemic systolic pressure (77-72 mmHg) and increase in ventricular stroke work (781-790 mmHg ml). When the ductal diameter was restricted to <7 mm, it resulted in a significant reduced systemic flow and increased stroke work. Optimal hybrid configuration was defined at PAB 3 mm and ductal stent ≥7 mm. In this model, increasing the PAB diameter, or a stent diameter <7 mm, substantially increased single ventricle workload and reduced systemic perfusion and diastolic pressure. This may compromise myocardial oxygen demand-supply, particularly in the setting of retrograde-dependent coronary perfusion.

Impact of Acute Pulmonary Embolization on Arterial Stiffening and Right Ventricular Function in Dogs

Pulmonary hypertension (PH) can impact right ventricular (RV) function and alter pulmonary artery (PA) stiffness. The response of the RV to an acute increase in pulmonary pressure is unclear. In addition, the relation between total pulmonary arterial compliance and local PA stiffness has not been investigated. We used a combination of right heart catheterization (RHC) and magnetic resonance imaging (MRI) to assess PA stiffening and RV function in dogs before and after acute embolization. We hypothesized that in moderate, acute PH the RV is able to compensate for increased afterload, maintaining adequate coupling. Also, we hypothesized that in the absence of PA remodeling the relative area change in the proximal PA (RAC, a noninvasive index of local area strain) correlates with the total arterial compliance (stroke volume-to-pulse pressure ratio). Our results indicate that, after embolization, RV function is able to accommodate the demand for increased stroke work without uncoupling, albeit at the expense of a reduction of efficiency. In this acute model, RAC showed excellent correlation with total arterial compliance. We used this correlation to assess PA pulse pressure (PP) from noninvasive MRI measurements of stroke volume and RAC. We demonstrated that in acute pulmonary embolism MRI estimates of PP are remarkably close to measurements from RHC. These results, if confirmed in chronic PH and clinically, suggest that monitoring of PH progression by noninvasive methods may be possible.

MECHANISMS BY WHICH CARDIAC RESYNCHRONIZATION THERAPY IMPROVES CARDIAC PERFORMANCE IN HEART FAILURE

This thesis assesses the mechanisms by which biventricular and left ventricular pacing improves cardiac performance in patients with heart failure. We demonstrated for the first time that CRT results in an improvement in acute haemodynamic variables in heart failure patients with a narrow QRS duration that is comparable to the effects seen in heart failure patients with a broad QRS duration. In addition, we have shown that both biventricular (BIVP) and left ventricular pacing (LVP) significantly reduce external constraint to left ventricular filling, resulting in an increase in effective filling pressure. In heart failure patients with evidence of external constraint at rest, the acute haemodynamic benefits of both BIVP and LVP were principally due to the relief of external constraint and preload recruitment. However, in those patients with evidence of electrical dyssynchrony and a broad QRS duration, a significant haemodynamic benefit was derived from an enhancement in left ventricular contractility, presumably as a result of a reduction in left ventricular dyssynchrony. Patients with external constraint appear to derive a greater haemodynamic benefit from pacing due to the significant increase in stroke work that is associated with relief of external constraint and preload recruitment, in addition to the increase in stroke work derived from enhanced contractility due to a reduction in dyssynchrony. These findings will inform better patient selection for this therapy and also optimisation of pacing strategy in individual patients.

Abstract 2416: Progressive Improvement in Cardiac Performance produced by Continuous Aortic Flow Augmentation in Patients Hospitalized with Acute Decompensated Heart Failure: Results from the MOMENTUM Trial

Previous studies indicate that superimposing continuous aortic flow augmentation (CAFA) on pulsatile aortic flow yields vasodilation, unloading, and improved cardiac performance. Whether improvement in indices of cardiac performance are dependent or independent of changes in hemodynamic load has not been examined. Multi-center Trial of Orqis® Medical Cancion® System for Enhanced Treatment of heart failure (HF) Unresponsive to Medical Therapy (MOMENTUM) is a randomized trial comparing CAFA plus medical therapy (n = 109) vs. medical therapy alone (n = 59) in patients hospitalized with HF inadequately responsive to therapy. Entry required reduced LVEF and cardiac index, elevated pulmonary capillary wedge pressure (PCWP), and either impaired renal function or high diuretic requirement, despite IV inotrope or vasodilator treatment. CAFA was achieved for up to 96 hrs using an arterial-to-arterial circuit (flow up to 1.5 L/min). Changes in cardiac performance were assessed using the relationship between stroke work (stroke volume x [Mean blood pressure-PCWP] x 0.00133, kg*cm) and PCWP. Figure shows hemodynamic effects (mean ± SEM) at baseline (B) and at hours post-B time. CAFA progressively improves LV performance (↑ Stroke Work and ↓ PCWP, p &lt; 0.05 for both) resulting in an upward-leftward shift in the Starling function curve. In contrast, medical therapy alone resulted in no change in cardiac performance (↓ Stroke Work and ↓ PCWP, p &lt; 0.05 for both), no shift in Starling curve. CAFA treatment, independent of changes in both preload and afterload, increased stroke work and decreased PCWP by progressively improving cardiac performance.