Slope Of End-systolic Pressure-volume Relationship Research Articles

Correlation of Noninvasive Cardiac MRI Measures of Left Ventricular Myocardial Function and Invasive Pressure-Volume Parameters in a Porcine Ischemia-Reperfusion Model.

Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.

Intrinsic mechanisms of right ventricular autoregulation

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

Exploring the mechanisms responsible for reduced systolic function in high-gradient aortic stenosis

ObjectiveTo characterise the mechanics responsible for the reduced ejection fraction (rEF) in high-gradient severe aortic stenosis (AS).Methods21 patients with high-gradient severe AS (aortic valve area (AVA) <1.0 cm2 and mean...

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

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

Longitudinal strain reflects the interaction of myocardial contractility to afterload in rat models of hemodynamic overload-induced heart failure

Abstract Background Two-dimensional (2D) speckle tracking echocardiography (STE)-derived myocardial strain parameters are sensitive markers of left ventricular (LV) systolic function. Novel findings suggest that the contractile state of the myocardium, afterload and preload are major determinants of STE measurements. However, the hypothesis that longitudinal strain expresses the interaction between contractility and loading conditions rather than contractility alone in hemodynamic overload-induced heart failure (HF) has not been tested. Purpose This study aimed to explore the connection between longitudinal strain and contractility, afterload and preload in rat models of pressure overload (PO)- and volume overload (VO)-induced heart failure (HF). Methods Pressure overload (PO)-induced HF was evoked by transverse aortic constriction ([TAC], n=14). Volume overload (VO)-induced HF was established by an aortocaval fistula ([ACF], n=12). Age-matched sham operated animals served as controls. Pressure-volume analysis was carried out to compute cardiac contractility (slope of end-systolic pressure-volume relationship [ESPVR]), afterload (arterial elastance [Ea]) and ventriculo-arterial coupling ([VAC] = Ea/ESPVR). Preload was evaluated by meridional end-diastolic wall stress (σend-diastolic). STE was performed to assess global longitudinal strain (GLS). Results GLS was impaired in both PO-induced HF (−5.9±0.6 vs. −12.9±0.5%, TAC vs Sham, P&amp;lt;0.001) and VO-evoked HF (−11.7±0.7 vs. −13.5±0.4%, ACF vs Sham, P=0.048). Hemodynamic measurements indicated that the TAC group presented with maintained ESPVR, increased Ea and enhanced σend-diastolic. In contrast, the ACF group was characterized by reduced ESPVR, decreased Ea and enhanced σend-diastolic. Ordinary least squares non-linear regression revealed that GLS was predominantly determined by afterload (Ea) in the TAC model and by contractility (ESPVR) in the ACF model. In accordance, GLS showed a strong correlation with Ea in case of PO-induced HF (R= 0.848, P&amp;lt;0.001) and with ESPVR in case of VO-evoked HF (R=−0.526; P=0.008), respectively. Furthermore, GLS also demonstrated strong correlation with VAC in both the TAC and the ACF models. Of particular interest, a robust correlation between VAC and GLS could also be detected in the entire study population (R= 0.654, P&amp;lt;0.001). Conclusion Both afterload and contractility define GLS. Hence, under conditions when both factors become altered, GLS reflects VAC. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Cardiac functional consequences of stroke induced by transient middle cerebral artery occlusion in a rodent model

Abstract Background The cardiac functional consequences of ischaemic stroke are still need to be elucidated, while according to ethical issues only non-inasive measurents were carried out in patients underwent transient cerebral ischaemia. Purpose We aimed at investigating left ventricular function using non-invasive and invasive modalities in a rat model of transient focal ischaemia. Methods Age-matched, young adult rats were used for this study. Serial left ventricular echocardiographic measurements and speckle-tracking analysis were performed in rats (n=9) underwent transient middle cerebral artery occlusion (MCAO) before, during and immediately after the induction of stroke, with a follow-up at 24, 48, 72 hours; 7, 11 and 14 days. In another experimental setting, 48 hours after stroke induction (MCAO group, n=9) we characterized left ventricular function by pressure-volume analysis, that was compared to sham-operated controls (Co group, n=9). Results Serial echocardiographic measurements showed impaired systolic function, that was most severe 48 hours after MCAO (global circumferential strain, GCS: −14.8±2.6% 48 hours after MCAO vs. −19.3±2.4% baseline, p&amp;lt;0.05). A complete recovery of systolic functional deterioration was observed after 14 days (GCS: −19.2±2.5% 14 days after MCAO vs. −19.3±2.4% baseline, n.s.). Heart weight (normalized to tibial weight) did not differ between MCAO and Co animals. Pressure-volume analysis revealed unaltered diastolic function and showed unchanged load-independent contractility index values (slope of end-systolic pressure-volume relationship, ESPVR: 2.56±0.29mmHg/μl MCAO vs. 2.55±0.59 mmHg/μl Co, n.s.) after MCAO. There was a tendency towards increased systolic pressure and deteriorated ventriculo-arterial coupling in animals underwent stroke. Conclusions Our data suggests that MCAO is associated with reversible impairment of systolic function during echocardiographic measurements, however without alteration of intrinsic myocardial contractility. The tendency towards increased afterload might explain the observed alterations in rats underwent stroke. Funding Acknowledgement Type of funding source: None

Sex-related differences in cardiac and myofilament function in rats with pressure-overload induced left ventricular hypertrophy

Abstract Introduction Recent findings indicate that sex is a major determinant of left ventricular (LV) structure in pressure overload (PO)-induced LV myocardial hypertrophy (LVH). However, data are scare regarding sex-related differences in LV function in case of PO-evoked LVH. Aim Hence, in the present study we aimed at comprehensively investigating sex-related functional differences on the global cardiac level and also on the myofilament level in PO-induced LVH. Method Abdominal aortic banding (AB) was carried out to induce chronic PO for 6 or 12 weeks in male and female rats. Age- and sex-matched sham-operated animals served as controls. The development of LVH was followed by serial echocardiography. The extent of cardiomyocyte hypertrophy and myocardial fibrosis were evaluated by histology. Cardiac function was assessed by pressure-volume analysis. Force measurement was carried out in permeabilized cardiomyocytes to compute myofilament function. Results At week 6, robust myocardial hypertrophy, concentric LV geometry and moderate interstitial fibrosis were detected in both male and female AB rats. This early stage of PO-induced LVH was associated with increased LV contractility (slope of end-systolic pressure-volume relationship [ESPVR, mmHg/μl]: 3.09±0.18 Male-AB-wk6 vs. 1.79±0.22 Male-Sham-wk6 P&amp;lt;0.05; 3.68±0.77 Female-AB-wk6 vs. 1.87±0.21 Female-Sham-wk6 P&amp;lt;0.05) and enhanced myofilament Ca2+ sensitivity in both sexes (pCa50: 5.86±0.01 Male-AB-wk6 vs. 5.73±0.02 Male-Sham-wk6 P&amp;lt;0.05; 5.94±0.03 Female-AB-wk6 vs. 5.73±0.01 Female-Sham-wk6 P&amp;lt;0.05). At week 6, the augmented LV contractility effectively counterbalanced the increased afterload in both male and female AB groups. Hence, ventricular-arterial coupling (VAC) was maintained and LV systolic function was preserved in the AB groups in both sexes. In contrast, at week 12, marked sex differences could be observed. At this later stage, LVH was characterized by eccentric remodeling and intensified collagen accumulation in male AB rats. The initial LV contractility augmentation (slope of ESPVR, mmHg/μl: 1.74±0.13 Male-AB-wk12 vs. 1.31±0.17 Male-Sham-wk12 n.s.) as well as the enhanced myofilament Ca2+ sensitivity (pCa50: 5.78±0.02 Male-AB-wk12 vs. 5.75±0.01 Male-Sham-wk12 n.s.) diminished, leading to impaired VAC and reduced LV systolic function. On the contrary, in female AB rats, cardiac contractility (ESPVR, mmHg/ μl: 3.97±0.50 Female-AB-wk12 vs. 2.08±0.17 Female-Sham-wk12 P&amp;lt;0.05) and myofilament Ca2+ sensitivity (pCa50:5.85±0.02 Female-AB-wk12 vs. 5.78±0.01 Female-Sham-wk12 P&amp;lt;0.05) remained increased, resulting in adequate VAC and preserved LV systolic function at late-stage of PO-induced LVH as well. Conclusion The initially augmented LV contractility and enhanced myofilament Ca2+ sensitivity declines in male but not in female AB rats at later time points. Hence, characteristically different alterations occur in LV systolic function between the two sexes in late-stage of PO-evoked LVH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017.

Novel in vivo and in vitro mechanisms of positive inotropic effect of atractylodin.

This study was to investigate the inotropic effect of atractylodin and its underlying mechanism. The cardiac pressure-volume loop (P-V loop), Langendroff-perfused isolated rat heart, patch-clamp, Ca2+ transient and western blot techniques were used. The results demonstrated that atractylodin (3mg/kg, ip) remarkably increased the left ventricular stroke work, cardiac output, stroke volume, heart rate, ejection fraction, end-systolic pressure, peak rates of rise and fall of left ventricular pressures (+dP/dtmax , -dP/dtmax ), the slopes of end-systolic pressure-volume relationship (also named as end-systolic elastance, Ees) and reducing end-systolic volume and end-diastolic volume in the in vivo rat study. Also, atractylodin (3mg/kg, ip) significantly decreased diastolic blood pressure and the arterial elastance (Ea) without significant systolic blood pressure change. In addition, atractylodin (0.1, 1, 10µmol/L) also increased the isolated rat heart left ventricular developed pressure which is the difference between the systolic and diastolic pressure in non-pacing and pacing modes. Furthermore, JMV-2959 (1μmol/L), a ghrelin receptor unbiased antagonist, blocked the increased left ventricular developed pressure of atractylodin in isolated rat hearts. Finally, atractylodin (5µmol/L) increased the amplitude of Ca2+ transient by enhancing SERCA2a activity, the sarcoplasmic reticulum Ca2+ content and the phosphorylation of phospholamban at 16-serine. These results demonstrated that atractylodin had a positive inotropic effect by enhancing SERCA2a activity which might be mediated by acting ghrelin receptor in myocardium. In conclusion, atractylodin which had the positive inotropic effect and decreased diastolic blood pressure might serve as an agent for the treatment of heart failure in clinical settings.

Longitudinal Strain Reflects Ventriculoarterial Coupling Rather Than Mere Contractility in Rat Models of Hemodynamic Overload–Induced Heart Failure

Longitudinal strain (LS) is a sensitive marker of systolic function. Recent findings suggest that both myocardial contractility and loading conditions determine LS. The aim of this study was to investigate whether LS reflects the connection of cardiac contractility to afterload (termed ventriculoarterial coupling [VAC]) rather than mere contractility in rat models of hemodynamic overload-induced heart failure (HF). Pressure overload-induced HF was evoked by transverse aortic constriction (TAC; n=14). Volume overload-induced HF was established by an aortocaval fistula (ACF; n=12). Age-matched sham-operated animals served as controls for TAC (n=14) and ACF (n=12), respectively. Pressure-volume analysis was carried out to compute contractility (slope of end-systolic pressure-volume relationship [ESPVR]), afterload (arterial elastance [Ea]), and VAC (Ea/ESPVR). Preload was evaluated by meridional end-diastolic wall stress. Speckle-tracking echocardiography was performed to assess LS. The TAC group presented with maintained ESPVR, increased Ea, and enhanced meridional end-diastolic wall stress. In contrast, the ACF group was characterized by reduced ESPVR, decreased Ea, and enhanced meridional end-diastolic wall stress. VAC increased in both HF groups. Furthermore, LS was also impaired in both HF models (-5.9±0.6% vs -12.9±0.5%, TAC vs Shamt [P<.001], and -11.7±0.7% vs -13.5±0.4%, ACF vs Shama[P=.048]). Statistical analysis revealed that strain parameters were determined predominantly by afterload in the TAC group and by contractility in the ACF group, while preload had a minor effect. In the entire study population, LS showed a correlation with VAC (R=0.654, P<.001) but not with ESPVR (R=0.058, P=.668). Under pathophysiologic conditions when both contractility and afterload become altered, LS reflects VAC rather than mere contractility.

Rolipram, a PDE4 Inhibitor, Enhances the Inotropic Effect of Rat Heart by Activating SERCA2a.

This study was designed to investigate the hemodynamic effect of rolipram, a phosphodiesterase type 4 (PDE4) inhibitor, in normal rat hearts both in vivo and in vitro and its underlying mechanism. The pressure-volume loop, isolated heart, and Ca2+ transients triggered by field stimulation or caffeine were used to analyze the hemodynamic mechanism of rolipram. The results demonstrated that rolipram (3 mg/kg, ip) significantly increased the in vivo rat heart contractility by enhancing stroke work, cardiac output, stroke volume, end-systolic volume, end-diastolic volume, end-systolic pressure, heart rate, ejection fraction, peak rate of rise of left pressure (+dp/dtmax), the slopes of end-systolic pressure-volume relationship (slope of ESPVR) named as left ventricular end-systolic elastance, and reduced the slopes of end-diastolic pressure-volume relationship (slope of EDPVR). Meanwhile, the systolic blood pressure, diastolic blood pressure, and pulse pressure were significantly enhanced by rolipram. Also, rolipram deviated normal ventricular-arterial coupling without changing the arterial elastance. Furthermore, rolipram (0.1, 1, 10 μM) also exerted positive inotropic effect in isolated rat hearts by increasing the left ventricular development pressure, and +dp/dtmax in non-paced and paced modes. Rolipram (10 μM) increased the SERCA2a activity, Ca2+ content, and Ca2+ leak rate without changing diastolic Ca2+ level. Rolipram had significant positive inotropic effect with less effect on peripheral vascular elastance and its underlying mechanism was mediated by increasing SERCA2a activity. PDE4 inhibition by rolipram resulted in a positive inotropic effect and might serve as a target for developing agents for the treatment of heart failure in clinical settings.

Performance comparison of ventricular and arterial dP/dtmax for assessing left ventricular systolic function during different experimental loading and contractile conditions

BackgroundMaximal left ventricular (LV) pressure rise (LV dP/dtmax), a classical marker of LV systolic function, requires LV catheterization, thus surrogate arterial pressure waveform measures have been proposed. We compared LV and arterial (femoral and radial) dP/dtmax to the slope of the LV end-systolic pressure-volume relationship (Ees), a load-independent measure of LV contractility, to determine the interactions between dP/dtmax and Ees as loading and LV contractility varied.MethodsWe measured LV pressure-volume data using a conductance catheter and femoral and radial arterial pressures using a fluid-filled catheter in 10 anesthetized pigs. Ees was calculated as the slope of the end-systolic pressure-volume relationship during a transient inferior vena cava occlusion. Afterload was assessed by the effective arterial elastance. The experimental protocol consisted of sequentially changing afterload (phenylephrine/nitroprusside), preload (bleeding/fluid bolus), and contractility (esmolol/dobutamine). A linear-mixed analysis was used to assess the contribution of cardiac (Ees, end-diastolic volume, effective arterial elastance, heart rate, preload-dependency) and arterial factors (total vascular resistance and arterial compliance) to LV and arterial dP/dtmax.ResultsBoth LV and arterial dP/dtmax allowed the tracking of Ees changes, especially during afterload and contractility changes, although arterial dP/dtmax was lower compared to LV dP/dtmax (bias 732 ± 539 mmHg⋅s− 1 for femoral dP/dtmax, and 625 ± 501 mmHg⋅s− 1 for radial dP/dtmax). Changes in cardiac contractility (Ees) were the main determinant of LV and arterial dP/dtmax changes.ConclusionAlthough arterial dP/dtmax is a complex function of central and peripheral arterial factors, radial and particularly femoral dP/dtmax allowed reasonably good tracking of LV contractility changes as loading and inotropic conditions varied.

Ischemia/reperfusion injury study in isolated mouse hearts using a pressure-volume curve

Objective: To establish and assess the feasibility and sensitivity of left ventricular elasticity, compliance and stiffness for study of ischemia/reperfusion injury in an isolated mouse heart model utilizing the pressure-volume curve framework. Methods: An isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused Langendorff heart preparation was set up from 15 male C57/6BL mice aged 12-14 weeks. End-systolic pressure-volume relationship (ESPVR) and end-diastolic pressure-volume relationship (EDPVR) were obtained by measuring left ventricular (LV) systolic pressure (LVSP) and diastolic pressure under different balloon volumes. End-systolic elasticity (E(es)), end-diastolic stiffness (S(ed)) and compliance (C(ed)) were calculated from the slope of ESPVR and EDPVR. Measurements of LVSP, developed pressure (LVDP), end of diastolic pressure (EDP), the rate of pressure development dp/dt(max) and dp/dt(min) were monitored during 30 min stabilization, 20 min global ischemia and 40 min reperfusion. The reliability and coefficient of variation (CV) of these parameters were compared with E(es) and C(ed). Results: During stabilization, the heart rate was (395±40) bpm, LVDP was (126±25) mmHg, + dp/dt(max) was (5 590±625) mmHg/s, -dp/dt(min) was (-4 128±625) mmHg/s, E(es) was 5.7±0.3, C(ed) was 0.7±0.2, S(ed) was 1.4±0.1. Ischemia/reperfusion injury resulted in significant decrease in contractile function parameters. The recovery level of LVSP, LVDP, dp/dt(max) and dp/dt(min) were (57±19)%, (23±6)%, (23±7)% and (21±5)% (all P<0.001), respectively. The EDP increased to (5.4±2.0) times than the baseline after ischemia/reperfusion injury. The E(es) and C(ed) was deceased to (42±2)% and (33±2)%, compared with baseline. The stiffness was increased up to (3.1±0.2) times higher than the baseline. The CV of E(es,)S(ed) and C(ed) were lower than LVSP, LVDP, EDP, dp/dt(max,)dp/dt(min,)while the reliability of E(es), S(ed) and C(ed) were higher than the classic contractile function parameters. Conclusion: Pressure-volume curves are feasible during ischemia/reperfusion injury in the isolated mouse heart model with acceptable reliability and sensitivity.

Left Atrial Remodeling and Atrioventricular Coupling in a Canine Model of Early Heart Failure With Preserved Ejection Fraction

Left atrial (LA) compliance and contractility influence left ventricular stroke volume. We hypothesized that diminished LA compliance and contractile function occur early during the development of heart failure with preserved ejection fraction (HFpEF) and impair overall cardiac performance. Cardiac magnetic resonance imaging, echocardiography, left ventricular and LA pressure-volume studies, and tissue analyses were performed in a model of early HFpEF (elderly dogs, renal wrap-induced hypertension, exogenous aldosterone; n=9) and young control dogs (sham surgery; n=13). Early HFpEF was associated with LA enlargement, cardiomyocyte hypertrophy, and enhanced LA contractile function (median active emptying fraction 16% [95% confidence interval, 13-24]% versus 12 [10-14]%, P=0.008; end-systolic pressure-volume relationship slope 2.4 [1.9-3.2]mm Hg/mL HFpEF versus 1.5 [1.2-2.2]mm Hg/mL controls, P=0.01). However, atrioventricular coupling was impaired and the curvilinear LA end-reservoir pressure-volume relationship was shifted upward/leftward in HFpEF (LA stiffness constant [βLA] 0.16 [0.11-0.18]mm Hg/mL versus 0.06 [0.04-0.10]mm Hg/mL controls; P=0.002), indicating reduced LA compliance. Impaired atrioventricular coupling and lower LA compliance correlated with lower left ventricular stroke volume. Total fibrosis and titin isoform composition were similar between groups; however, titin was hyperphosphorylated in HFpEF and correlated with βLA. LA microvascular reactivity was diminished in HFpEF versus controls. LA microvascular density tended to be lower in HFpEF and inversely correlated with βLA. In early-stage hypertensive HFpEF, LA cardiomyocyte hypertrophy, titin hyperphosphorylation, and microvascular dysfunction occur in association with increased systolic and diastolic LA chamber stiffness, impaired atrioventricular coupling, and decreased left ventricular stroke volume. These data indicate that maladaptive LA remodeling occurs early during HFpEF development, supporting a concept of global myocardial remodeling.

Myocardial reverse remodeling after pressure unloading is associated with maintained cardiac mechanoenergetics in a rat model of left ventricular hypertrophy.

Pressure unloading represents the only effective therapy in increased afterload-induced left ventricular hypertrophy (LVH) as it leads to myocardial reverse remodeling (reduction of increased left ventricular mass, attenuated myocardial fibrosis) and preserved cardiac function. However, the effect of myocardial reverse remodeling on cardiac mechanoenergetics has not been elucidated. Therefore, we aimed to provide a detailed hemodynamic characterization in a rat model of LVH undergoing pressure unloading. Pressure overload was induced in Sprague-Dawley rats by abdominal aortic banding for 6 (AB 6th wk) or 12 wk (AB 12th wk). Sham-operated animals served as controls. Aortic debanding procedure was performed after the 6th experimental week (debanded 12th wk) to investigate the regression of LVH. Pressure unloading resulted in significant reduction of LVH (heart weight-to-tibial length ratio: 0.38 ± 0.01 vs. 0.58 ± 0.02 g/mm, cardiomyocyte diameter: 18.3 ± 0.1 vs. 24.1 ± 0.8 μm debanded 12th wk vs. AB 12th wk, P < 0.05), attenuated the extracellular matrix remodeling (Masson's score: 1.37 ± 0.13 vs. 1.73 ± 0.10, debanded 12th wk vs. AB 12th wk, P < 0.05), provided protection against the diastolic dysfunction, and reversed the maladaptive contractility augmentation (slope of end-systolic pressure-volume relationship: 1.39 ± 0.24 vs. 2.04 ± 0.09 mmHg/μl, P < 0.05 debanded 12th wk vs. AB 6th wk, P < 0.05). In addition, myocardial reverse remodeling was also associated with preserved ventriculoarterial coupling and increased mechanical efficiency (50.6 ± 2.8 vs. 38.9 ± 2.5%, debanded 12th wk vs. AB 12th wk, P < 0.05), indicating a complete functional and mechanoenergetic recovery. According to our best knowledge, this is the first study demonstrating that the regression of LVH is accompanied by maintained cardiac mechanoenergetics.

Chronic plus binge ethanol feeding induces myocardial oxidative stress, mitochondrial and cardiovascular dysfunction, and steatosis.

Alcoholic cardiomyopathy in humans develops in response to chronic excessive alcohol consumption; however, good models of alcohol-induced cardiomyopathy in mice are lacking. Herein we describe mouse models of alcoholic cardiomyopathies induced by chronic and binge ethanol (EtOH) feeding and characterize detailed hemodynamic alterations, mitochondrial function, and redox signaling in these models. Mice were fed a liquid diet containing 5% EtOH for 10, 20, and 40 days (d) combined with single or multiple EtOH binges (5 g/kg body wt). Isocalorically pair-fed mice served as controls. Left ventricular (LV) function and morphology were assessed by invasive pressure-volume conductance approach and by echocardiography. Mitochondrial complex (I, II, IV) activities, 3-nitrotyrosine (3-NT) levels, gene expression of markers of oxidative stress (gp91phox, p47phox), mitochondrial biogenesis (PGC1α, peroxisome proliferator-activated receptor α), and fibrosis were examined. Cardiac steatosis and fibrosis were investigated by histological/immunohistochemical methods. Chronic and binge EtOH feeding (already in 10 days EtOH plus single binge group) was characterized by contractile dysfunction (decreased slope of end-systolic pressure-volume relationship and preload recruitable stroke work), impaired relaxation (decreased time constant of LV pressure decay and maximal slope of systolic pressure decrement), and vascular dysfunction (impaired arterial elastance and lower total peripheral resistance). This was accompanied by enhanced myocardial oxidative/nitrative stress (3-NT; gp91phox; p47phox; angiotensin II receptor, type 1a) and deterioration of mitochondrial complex I, II, IV activities and mitochondrial biogenesis, excessive cardiac steatosis, and higher mortality. Collectively, chronic plus binge EtOH feeding in mice leads to alcohol-induced cardiomyopathies (National Institute on Alcohol Abuse and Alcoholism models) characterized by increased myocardial oxidative/nitrative stress, impaired mitochondrial function and biogenesis, and enhanced cardiac steatosis.

197 Left Atrial Remodelling and Atrioventricular Coupling in a Canine Model of Early Heart Failure with Preserved Ejection Fraction

Background Left atrial (LA) compliance and contractility are key determinants of left ventricular (LV) stroke volume. LA remodelling and dysfunction in heart failure with preserved ejection fraction (HFpEF) are considered to be late presenting features, secondary to hypertension-induced LV diastolic dysfunction and chronic LA pressure overload. However, a recent unifying hypothesis has stipulated that systemic and coronary microvascular inflammation drive HFpEF pathophysiology. Considering this paradigm, we hypothesised that diminished LA compliance and contractile function occur early during HFpEF development and further impair cardiac performance. Methods Cardiac magnetic resonance imaging, echocardiography, invasive LV and LA pressure volume (PV) analysis and tissue analysis were performed in an experimental model of early-stage HFpEF (elderly dogs with renal wrap induced hypertension and exogenous aldosterone; n = 9) and young control dogs (sham surgery; n = 13). Results Early HFpEF was associated with LA enlargement, LA myocyte hypertrophy, and enhanced LA contractile function (LA active emptying fraction 18 ± 6 vs 12 ± 2%, p = 0.03; LA end-systolic PV relationship slope: 2.7 ± 0.9 HFpEF vs 1.5 ± 0.6 mmHg/mL controls, p = 0.01). However left atrioventricular systolic coupling was impaired (ratio of LV to LA end-systolic PV relationship slope 1.3 ± 0.4 HFpEF vs 0.8 ± 0.4 Controls, p 2 , p = 0.07) and inversely correlated with LA s (r=-0.66, p = 0.006). Titin isoform composition (N2BA/N2B ratio) was similar between groups, but titin hyperphosphorylation was seen in HFpEF LA and LV tissue. LA titin hyperphosphorylation correlated with LA s (r = 0.54, p = 0.03). LA microvascular reactivity was also diminished in HFpEF versus controls. Conclusions Maladaptive LA remodelling is present in early-stage experimental HFpEF and compromises overall cardiac performance. Reduced LA compliance in HFpEF may relate to contributions from LA ischaemia and titin-based cardiomyocyte stiffening. Thus, pathophysiological mechanisms involved in the development of HFpEF directly affect both atrial and ventricular myocardium.

S-nitroso human serum albumin attenuates pulmonary hypertension, improves right ventricular–arterial coupling, and reduces oxidative stress in a chronic right ventricle volume overload model

This study examined the acute effect of intravenous S-nitroso human serum albumin (S-NO-HSA) infusion on overall hemodynamics and oxidative stress in a chronic left-to-right shunt-induced pulmonary arterial hypertension model with right ventricle (RV) failure. An aortocaval fistula (pulmonary-to-systemic blood flow ratio [Qp/Qs] > 2.0) was surgically created in 50 male Wistar rats. After 10 weeks, they were randomly treated with S-NO-HSA (n = 20) or human serum albumin (HSA; n = 25) infusion (0.5 µmol/kg/h) for 60 minutes. A sham group (n = 10) received S-NO-HSA. RV contractility, RV-vascular coupling, and ventricular interdependence were assessed in vivo at different pre-loads by biventricular conductance catheters. Heart and lung biopsy specimens were obtained for determination of high-energy phosphates, oxidative stress (oxidized glutathione/reduced glutathione), and endothelial nitric oxide synthase protein expression. S-NO-HSA, compared with HSA infusion, reduced RV afterload expressed by effective pulmonary arterial elastance (Ea; 0.49 ± 0.3 vs 1.2 ± 0.2 mm Hg/ml; p = 0.0005) and improved RV diastolic function (slope of end-diastolic pressure-volume relationship) as well as contractility indicated by slope of end-systolic pressure-volume relationship (Ees). Therefore an increase in efficiency of ventricular-vascular coupling (Ees/Ea) occurred after S-NO-HSA (0.35 ± 0.17 to 0.94 ± 0.21; p = 0.005), but not HSA infusion, leading to positive effect on ventricular interdependence with increased left ventricular stroke volume (56% ± 4% vs 19% ± 5%; p = 0.0013). S-NO-HSA, compared with HSA, treatment improved adenosine 5'-triphosphate (13.9 ± 1.1 vs 7.0 ± 1.8 µmol/g protein) and phosphocreatine (5.9 ± 3.3 vs 1.9 ± 0.6 µmol/g protein; p = 0.01) RV content and decreased the tissue oxidized glutathione/reduced glutathione ratio (p = 0.001). S-NO-HSA reduces pulmonary hypertension and improves RV systolic and diastolic function and RV-arterial coupling, with a positive effect on ventricular interdependence by increasing energetic reserve and reducing oxidative stress.

Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30%). Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10μg/kg/min) or vehicle (normal saline) for 6h in random order 1week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6h. LV pressure-volume relationship (PVR) was measured at baseline and 6h. Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2. Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.

Ventricular-Arterial Coupling, Remodeling, and Prognosis in Chronic Heart Failure

The objective of this study was to compare the physiological determinants of ejection fraction (EF)-ventricular size, contractile function, and ventricular-arterial (VA) interaction-and their associations with clinical outcomes in chronic heart failure (HF). EF is a potent predictor of HF outcomes, but represents a complex summary measure that integrates several components including left ventricular size, contractile function, and VA coupling. The relative importance of each of these parameters in determining prognosis is unknown. In 466 participants with chronic systolic HF, we derived quantitative echocardiographic measures of EF: cardiac size (end-diastolic volume [EDV]); contractile function (the end-systolic pressure volume relationship slope [Eessb] and intercept [V0]); and VA coupling (arterial elastance [Ea]/Eessb). We determined the association between these parameters and the following adverse outcomes: 1) the combined endpoint of death, cardiac transplantation, or ventricular assist device (VAD) placement; and 2) cardiac hospitalization. Over a median follow-up of 3.4 years, there were 76 deaths, 52 transplantations, 14 VAD placements, and 684 cardiac hospitalizations. EF was independently associated with death, transplantation, and VAD placement (adjusted hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.8 to 5.0 comparing third and first tertiles), as were EDV (HR: 2.6; 95% CI: 1.5 to 4.2); V0 (HR: 3.6; 95% CI: 2.1 to 6.1); and Ea/Eessb (HR: 2.1; 95% CI: 1.3 to 3.3). EDV, V0, and Ea/Eessb were also associated with risk of cardiac hospitalization. Eessb was not significantly associated with any adverse outcomes in adjusted analyses. Left ventricular size, V0, and VA coupling are associated with prognosis in systolic HF, but end-systolic elastance (Eessb) is not. Assessment of VA coupling via Ea/Eessb is an additional noninvasively derived metric that can be used to gauge prognosis in human HF.

Relevance of the volume-axis intercept,V0, compared with the slope of end-systolic pressure-volume relationship in response to large variations in inotropy and afterload in rats

The end-systolic pressure-volume relationship (ESPVR) is proposed and used as a reliable index of left ventricular (LV) contractility despite the fact that its afterload independence has been challenged. Furthermore, the physiological relevance of its volume-axis intercept, V(0), remains unclear. Systemic haemodynamics and pressure-volume loops obtained by inferior vena cava occlusion were recorded in 21 rats anaesthetized by isoflurane inhalation and instrumented with a conductance pressure-volume catheter in response to incremental I.V. doses of adrenaline, dobutamine, phenylephrine, metoprolol, papaverine and isoflurane inhalation. In conditions with large variations (± 100%) of both inotropy and afterload, infusion of negative inotropic drugs was associated with a dose-dependent rightward shift of ESPVR accompanied by a decrease in its slope (end-systolic elastance, E(es)), whereas positive inotropic agents produced an isolated decrease in V(0). With the predominant vasoactive drugs, there was a dose-dependent change in E(es) without major horizontal shifts, demonstrating that this slope mainly represents LV afterload rather than inotropy. When contractility was altered, V(0) was negatively correlated to the preload-adjusted contractility index, PAdP/dt(max), demonstrating that a reduced V(0) provides a good reflection of increased LV contractility. From these results, we computed a logarithmically adjusted E(es)/V(0) ratio, which resulted in reasonably strong concordance with PAdP/dt(max), including all the investigated drugs and dosages [n = 288; bias, 0.8 ± 16.2% (SD)]. Concordance with E(es) (bias, 7.2 ± 58.7%) or V(0) (bias, -0.6 ± 33.4%), used alone or with other commonly used contractility indices, was far less significant. In contrast to E(es), V(0) provides a relatively good LV contractility index because it is much less sensitive to afterload.