End-systolic Pressure-volume Relationship Research Articles

Abstract 12583: C-Type Natriuretic Peptide Improves Left Ventricular Systolic and Diastolic Functional Performance at Rest and During Exercise After Heart Failure

Background: In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise (Ex). C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family produced by the vascular endothelium and heart is elevated in HF. However, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and lusitropic actions may prevent this abnormal Ex response after HF. Methods: We assessed the effects of CNP on LV functional performance at rest and during submaximum Ex (3.5-5.5 mph for 6-8 min) in 10 instrumented dogs with pacing-induced HF. Since CNP mediated its biological actions via cGMP, we also measured plasma cGMP levels in response to CNP infusion at rest before and after HF. Results: CNP (2 μg/kg plus 0.4 μg/kg/min, iv, 20 min) caused a similar increase in cGMP levels before (7.2±3.8 to 24.7±4.9 pmol/ml) and after HF (20.2±4.4 to 71.6±5.0 pmol/ml). After HF, at rest, CNP reduced LV end-systolic pressure (P ES , CNP: 93 vs Baseline: 104 mmHg), arterial elastance (E A , 8.3 vs 11.7 mmHg/ml) and end-diastolic pressure (P ED , 37.2 vs 42.4 mmHg) (p<0.05). The peak mitral flow (dV/dt max , 201±51 vs 160±34ml/sec) was also increased due to decreased minimum LVP (LVP min , 17.1 vs 23.8 mmHg) and the time constant of LV relaxation (t, 40±4 vs 48±6 msec) (p<0.05). In addition, the slope of LV end-systolic pressure-volume relations (E ES ) was increased (5.6±0.7 vs 4.2±0.9 mmHg/ml). The LV-arterial coupling, quantified as E ES /E A , was improved (0.69±0.22 vs 0.48±0.16) (p<0.05). The beneficial effects persisted during Ex. At matched levels of Ex, treatment with CNP, Ex-induced significantly less increases in P ES (ΔP= 3.4±0.5 vs 7.4±0.8 mmHg), mean LAP (ΔP= -3.1±2.2 vs 3.6±2.9 mmHg), and LVP min (ΔP= -3.6±1.4 vs 1.4±1.2 mmHg) (p<0.05). With CNP, t was much shortened (Δ= -0.8±4.0 vs 2.8±3.2 ms), and the peak mitral flow was further augmented (ΔdV/dt max , 75±20 vs 43±12 ml/sec) (p<0.05). Conclusion: After HF, the generation of cGMP in response to CNP is not blunted. CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling and LV arterial coupling, thus improving LV performance, both at rest and during Ex after HF.

Abstract 20421: Polarizing State Induced by Adenosine, Lidocaine and Magnesium Administration After Prolonged Circulatory Arrest Improves Cardioprotection and Neuroprotection in a Rat Model of Cardiac Arrest With Extracorporeal Life Support

BACKGROUND: Polarized arrest, a new concept of myocardial protection, has been recently demonstrated to improve cardiac function after cardioplegic arrest during cardiac surgery. The present study investigated whether polarizing state after prolonged cardiac arrest would provide cardioprotective and neuroprotective effects after extracorporeal life support (ECLS). METHODS AND RESULTS: Ventricular fibrillation (VF) was induced in male Wistar rats. After 8 min of untreated VF, veno-arterial ECLS was instituted for 60 min inducing mild therapeutic hypothermia (32°C). At the beginning of ECLS animals were randomized to receive a single iv bolus of 4.5 mL/kg of polarizing solution with adenosine (47 μM), lidocaine (92 μM) and MgSO4 (1 mM) or same volume of saline as control. Restoration of spontaneous circulation was higher in rats that received polarizing solution (p = 0.03). After 24 h survival and neurologic deficit scores were improved and histological damage scores and brain TNF-α were attenuated compared to control (all p<0.05). Polarizing solution administration led to better recovery of left ventricle end-systolic pressure-volume relationship (Ees), preload recruitable stroke work (PRSW), end-diastolic pressure-volume relationship (EDPVR) and Tau (p<0.01). Polarized state enhanced phosphorilation of myocardial ERK1 and 2 and Akt, resulting in a lower apoptotic index (TUNEL, p<0.01). CONCLUSIONS: Polarized state induced by adenosine, lidocaine and magnesium increased survival, neurologic outcome and cardiac function after prolonged cardiac arrest treated with ECLS. Moreover it improved cardioprotection through activation of the pro-survival kinases Akt and ERK1/2.

Increased myocardial stiffness due to cardiac titin isoform switching in a mouse model of volume overload limits eccentric remodeling

We investigated the cellular and molecular mechanisms of diastolic dysfunction in pure volume overload induced by aortocaval fistula (ACF) surgery in the mouse. Four weeks of volume overload resulted in significant biventricular hypertrophy; protein expression analysis in left ventricular (LV) tissue showed a marked decrease in titin's N2BA/N2B ratio with no change in phosphorylation of titin's spring region. Titin-based passive tensions were significantly increased; a result of the decreased N2BA/N2B ratio. Conscious echocardiography in ACF mice revealed eccentric remodeling and pressure volume analysis revealed systolic dysfunction: reductions in ejection fraction (EF), +dP/dt, and the slope of the end-systolic pressure volume relationships (ESPVR). ACF mice also had diastolic dysfunction: increased LV end-diastolic pressure and reduced relaxation rates. Additionally, a decrease in the slope of the end diastolic pressure volume relationship (EDPVR) was found. However, correcting for altered geometry of the LV normalized the change in EDPVR and revealed, in line with our skinned muscle data, increased myocardial stiffness in vivo. ACF mice also had increased expression of the signaling proteins FHL-1, FHL-2, and CARP that bind to titin's spring region suggesting that titin stiffening is important to the volume overload phenotype. To test this we investigated the effect of volume overload in the RBM20 heterozygous (HET) mouse model, which exhibits reduced titin stiffness. It was found that LV hypertrophy was attenuated and that LV eccentricity was exacerbated. We propose that pure volume overload induces an increase in titin stiffness that is beneficial and limits eccentric remodeling.

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.

GPR55 deletion in mice leads to age-related ventricular dysfunction and impaired adrenoceptor-mediated inotropic responses.

G protein coupled receptor 55 (GPR55) is expressed throughout the body, and although its exact physiological function is unknown, studies have suggested a role in the cardiovascular system. In particular, GPR55 has been proposed as mediating the haemodynamic effects of a number of atypical cannabinoid ligands; however this data is conflicting. Thus, given the incongruous nature of our understanding of the GPR55 receptor and the relative paucity of literature regarding its role in cardiovascular physiology, this study was carried out to examine the influence of GPR55 on cardiac function. Cardiac function was assessed via pressure volume loop analysis, and cardiac morphology/composition assessed via histological staining, in both wild-type (WT) and GPR55 knockout (GPR55−/−) mice. Pressure volume loop analysis revealed that basal cardiac function was similar in young WT and GPR55−/− mice. In contrast, mature GPR55−/− mice were characterised by both significant ventricular remodelling (reduced left ventricular wall thickness and increased collagen deposition) and systolic dysfunction when compared to age-matched WT mice. In particular, the load-dependent parameter, ejection fraction, and the load-independent indices, end-systolic pressure-volume relationship (ESPVR) and E max, were all significantly (P<0.05) attenuated in mature GPR55−/− mice. Furthermore, GPR55−/− mice at all ages were characterised by a reduced contractile reserve. Our findings demonstrate that mice deficient in GPR55 exhibit maladaptive adrenergic signalling, as evidenced by the reduced contractile reserve. Furthermore, with age these mice are characterised by both significant adverse ventricular remodelling and systolic dysfunction. Taken together, this may suggest a role for GPR55 in the control of adrenergic signalling in the heart and potentially a role for this receptor in the pathogenesis of heart failure.

Nonlinear multiscale circulation model reproducable linear end-systolic pressure-volume relationship.

As a well-known property of the heart, many studies has reported that the left ventricular end-systolic pressure-volume relationship (ESPVR) is linear. However, the reason of the linearity is poorly understood. This article presents a multiscale circulation model to be a tool for theoretical analyses on the mechanism of the linearity of ESPVR. The model is composed of three sub-models; a detailed closed-loop lumped-parameter model for cardiovascular system, geometric left ventricle model, a comprehensive ventricular myocyte model. Although the present model integrates nonlinear sub-models, the model can successfully reproduce highly linear ESPVR without any arbitrary modifications.

Glucagon-like peptide-1 (7-36) but not (9-36) augments cardiac output during myocardial ischemia via a Frank-Starling mechanism.

This study examined the cardiovascular effects of GLP-1 (7-36) or (9-36) on myocardial oxygen consumption, function and systemic hemodynamics in vivo during normal perfusion and during acute, regional myocardial ischemia. Lean Ossabaw swine received systemic infusions of saline vehicle or GLP-1 (7-36 or 9-36) at 1.5, 3.0, and 10.0 pmol/kg/min in sequence for 30 min at each dose, followed by ligation of the left circumflex artery during continued infusion at 10.0 pmol/kg/min. Systemic GLP-1 (9-36) had no effect on coronary flow, blood pressure, heart rate or indices of cardiac function before or during regional myocardial ischemia. Systemic GLP-1 (7-36) exerted no cardiometabolic or hemodynamic effects prior to ischemia. During ischemia, GLP-1 (7-36) increased cardiac output by approximately 2 L/min relative to vehicle-controls (p = 0.003). This response was not diminished by treatment with the non-depolarizing ganglionic blocker hexamethonium. Left ventricular pressure-volume loops measured during steady-state conditions with graded occlusion of the inferior vena cava to assess load-independent contractility revealed that GLP-1 (7-36) produced marked increases in end-diastolic volume (74 ± 1 to 92 ± 5 ml; p = 0.03) and volume axis intercept (8 ± 2 to 26 ± 8; p = 0.05), without any change in the slope of the end-systolic pressure-volume relationship vs. vehicle during regional ischemia. GLP-1 (9-36) produced no changes in any of these parameters compared to vehicle. These findings indicate that short-term systemic treatment with GLP-1 (7-36) but not GLP-1 (9-36) significantly augments cardiac output during regional myocardial ischemia, via increases in ventricular preload without changes in cardiac inotropy.

Functional evaluation of human donation after cardiac death donor hearts using a continuous isolated myocardial perfusion technique: Potential for expansion of the cardiac donor population

To investigate the resuscitation potential and contractile function in adult human donation after cardiac death (DCD) hearts by ex vivo perfusion. With institutional review board approval and under the DCD protocol at the University of Wisconsin (UW) Organ Procurement Organization, 5 brain dead (BD) and 5 DCD donor hearts were evaluated. All BD hearts were declined for clinical transplantation because of coronary artery disease, advanced age, or social history. All hearts were preserved by flushing and cold storage with UW solution. By using our ex vivo perfusion system, the left ventricular end systolic pressure-volume relationship (LV-ESPVR) was assessed for 2 hours of oxygenated blood reperfusion. All BD (n = 5) and 4 DCD hearts were successfully resuscitated. One DCD heart was unable to be resuscitated due to prolonged warm ischemic time (WIT; 174 minutes). Mean WIT for resuscitated DCD hearts (from extubation to flushing with cold UW solution) was 34 ± 3 minutes (range, 26 to 40 minutes); mean cold ischemic time for BD donors was 211 ± 31 minutes compared with 177 ± 64 minutes for DCD donors. The calculated LV-ESPVRs for BD hearts after 1 and 2 hours of reperfusion were 6.9 ± 0.7 and 5.7 ± 1.0 mm Hg/mL, respectively; LV-ESPVRs for DCD hearts after 1 and 2 hours of reperfusion were 5.6 ± 1.5 (P = .45) and 3.0 ± 0.7 mm Hg/mL (P = .07), respectively. We successfully resuscitated and measured ex vivo cardiac function in human DCD and BD donor hearts. Resuscitation potential in DCD hearts was achieved when the WIT was less than 40 minutes. Contractile performance in DCD hearts tended to be lower compared with BD hearts. Further investigation with longer reperfusion periods seems warranted.

Load dependency in force–length relations in isolated single cardiomyocytes

The previously reported pressure–volume (PV) relationship in frog hearts shows that end-systolic PV relation (ESPVR) is load dependent, whereas ESPVR in canine hearts is load independent. To study intrinsic cardiac mechanics in detail, it is desirable to study mechanics in a single isolated cardiomyocyte that is free from interstitial connective tissue. Previous single cell mechanics studies used a pair of carbon fibers (CF) attached to the upper surface of opposite cell ends to stretch cells. These studies showed that end-systolic force–length (FL) relation (ESFLR) is load independent. However, the range of applicable mechanical load using the conventional technique is limited because of weak cell-CF attachment. Therefore, the behavior of ESFLR in single cells under physiologically possible conditions of greater load is not yet well known. To cover wider loading range, we contrived a new method to hold cell-ends more firmly using two pairs of CF attached to both upper and bottom surfaces of cells. The new method allowed stretching cells to 2.2 μm or more in end-diastolic sarcomere length. ESFLR virtually behaves in a load independent manner only with end-diastolic sarcomere length less than 1.95 μm. It exhibited clear load dependency with higher preload, especially with low afterload conditions. Instantaneous cellular elastance curves showed that decreasing afterload enhanced relaxation and slowed time to peak elastance, as previously reported. A simulation study of a mathematical model with detailed description of thin filament activation suggested that velocity dependent thin filament inactivation is crucial for the observed load dependent behaviors and previously reported afterload dependent change in Ca2+ transient shape.

Acute alcohol modulates cardiac function as PI3K/Akt regulates oxidative stress.

Clinical manifestations of alcohol abuse on the cardiac muscle include defective contractility with the development of heart failure. Interestingly, low alcohol consumption has been associated with reduced risk of cardiovascular disease. Although several hypotheses have been postulated for alcoholic cardiomyopathy and for the low-dose beneficial cardiovascular effects, the precise mechanisms and mediators remain largely undefined. We hypothesize that modulation of oxidative stress by PI3K/Akt plays a key role in the cardiac functional outcome to acute alcohol exposure. Thus, acutely exposed rat cardiac tissue and cardiocytes to low (LA: 5 mM), moderate (MA: 25 mM), and high (HA: 100 mM) alcohol were assessed for markers of oxidative stress in the presence and absence of PI3K/Akt activators (IGF-1 0.1 μM or constitutively active PI3K: Ad.BD110 transfection) or inhibitor (LY294002 1 μM or Akt-negative construct Ad.Akt(K179M) transfection). Acute LA reduced Akt, superoxide dismutase (SOD-3) and NFκB, ERK1, and p38 MAPK gene expression. Acute HA only increased that of SOD-3 and NFκB. These effects were generally inhibited by Ad.Akt(K179M) and enhanced with Ad.BD110 transfection. In parallel, LA reduced but HA enhanced Akt activity, which was reversed by IGF-1 and inhibited by Ad.Akt(K179M), respectively. Also, LA reduced caspase 3/7 activity and oxidative stress, while HA increased both. The former was blocked, while the latter effect was enhanced by Ad.Akt(K179M). The reverse was true with PI3K/Akt activation. This translated into reduced viability with HA, with no effect with LA. On the functional level, acute LA improved cardiac output and ejection fraction, mainly through increased stroke volume. This was accompanied with enhanced end-systolic pressure-volume relationship and preload recruitable stroke work. Opposite effect was recorded for HA. LA and HA in vivo functional effects were alleviated by LY and enhanced by IGF-1 treatment. Acute LA and HA seem to oppositely affect cardiac function through modulation of oxidative stress where PI3K/Akt plays a pivotal role.

Dexamethasone and recombinant human activated protein C improve myocardial function and efficiency during experimental septic shock.

Corticosteroids have been shown to reduce short-term mortality during septic shock and therefore recommended in the most severe patients as adjuvant therapy. Until recently, recombinant human activated protein C (APC) was also considered in the management of more severe cases. As myocardial depression has long been recognized as a manifestation of organ dysfunction during septic shock, we examined whether corticosteroids (dexamethasone, 150 µg/kg per hour) and/or APC (33 µg/kg per hour) treatments improve sepsis-induced cardiac dysfunction during cecal ligature and puncture-induced septic shock in Wistar rats. All rats received intravenous saline resuscitation (10 mL/kg per hour) and antibiotics. Eighteen hours after surgery, anesthesia was performed (isoflurane), and myocardial function was assessed using a conductance catheter introduced into the left ventricle. Rats were then killed; blood and heart were harvested for biological analysis, including radical oxygen species determination. Cecal ligature and puncture induced hypotension, depression of myocardial systolic performance (demonstrated by significant decreases in dP/dtmax [first derivative of maximal developed pressure during isovolumetric contraction], end-systolic pressure-volume relationship, and preload recruitable stroke work) and alteration of diastolic function (dP/dtmin [first derivative of minimal developed pressure during isovolumetric relaxation]), whereas dexamethasone, APC, and their combination thereof allowed correction of hemodynamic disorders and improved myocardial mechanical efficiency. Cecal ligature and puncture was associated with higher levels of nitric oxide and superoxide anion (O2) in heart (electron paramagnetic resonance studies) and consequently peroxynitrite. Dexamethasone and APC also improved cardiac dysfunction by downregulating the inducible nitric oxide synthase pathway and reducing myocardial oxidative stress.

Chronic overcirculation-induced pulmonary arterial hypertension in aorto-caval shunt

Pulmonary arterial hypertension is a common complication of congenital heart defects with left-to-right shunts. Current preclinical models do not reproduce clinical characteristics of shunt-related pulmonary hypertension. Aorto-caval shunt was firstly described as a model of right ventricle volume overload. The pathophysiology and the possible determination of pulmonary arterial hypertension of different periods of shunt exposure are still undefined.A method to create standardized, reproducible aorto-caval shunt was developed in growing rats (260±40g). Three groups of animals were considered: shunt exposure for 10weeks, shunt exposure for 20weeks and control (sham laparotomy).Echocardiography and magnetic resonance revealed increased right ventricular end diastolic area in shunt at 10weeks compared to control. Hemodynamic analysis demonstrated increased right ventricular afterload and increased effective pulmonary arterial elastance (Ea) in shunt at 20weeks compared to control (1.29±0.20 vs. 0.14±0.06mmHg/μl, p=0.004). At the same time point, the maximal slope of end-systolic pressure–volume relationship (Ees) decreased (0.5±0.2mmHg/ml vs. 1.2±0.3, p<0.001). Consequently, right ventricular–arterial coupling was markedly deteriorated with a ≈50% decrease in the ratio of end-systolic to pulmonary artery elastance (Ees/Ea). Finally, left ventricular preload diminished (≈30% decrease in left ventricular end-diastolic volume). Histology demonstrated medial hypertrophy and small artery luminal narrowing.Chronic exposure to aorto-caval shunt is a reliable model to produce right ventricular volume overload and secondary pulmonary arterial hypertension. This model could be an alternative with low mortality and high reproducibility for investigators on the underlying mechanisms of shunt-related pulmonary hypertension.

Cardiac responses to GLP‐1 receptor activation are impaired in the setting of metabolic syndrome (1078.7)

This study investigated the cardiovascular effects of the glucagon‐like peptide‐1 (GLP‐1) receptor agonist Exendin‐4 in lean vs. obese hearts. Left ventricular pressure‐volume relations were obtained following 24 hr intravenous infusion of saline‐vehicle or Exendin‐4 (30 fmol/kg/min) in lean (69 ± 4 kg) and obese (105 ± 2 kg) Ossabaw swine with metabolic syndrome (MetS). Measurements were obtained at rest, following 30 min occlusion of the left circumflex coronary artery, and following 2 hours of reperfusion. Baseline coronary flow, heart rate, and stroke volume were not different between vehicle‐treated lean and MetS swine. Exendin‐4 had no effect on end diastolic volume or stroke volume in lean or MetS swine. However, cardiac output and blood pressure were significantly increased relative to end‐diastolic filling volumes by Exendin‐4 administration in lean swine (P&lt;0.05). Load independent assessment of cardiac inotropy revealed that Exendin‐4 increased the slope of the end systolic pressure volume relationship (ESPVR) from 2.9 ± 2.7 to 10.6 ± 2.4 mmHg/ml (p&lt;0.05) in lean swine during ischemia. In contrast, Exendin‐4 had no effect on the relationship between cardiac output, blood pressure and end‐diastolic volume or on the ESPVR in MetS swine. These findings indicate that the cardiac inotropic actions of GLP‐1 receptor activation following ischemia/reperfusion injury are abolished in the setting of the metabolic syndrome.Grant Funding Source: Supported by NIH HL117620; NIH HL117620‐S1

Effects of Systemic [Pyr] Apelin‐13 Administration on Coronary and Peripheral Hemodynamics (LB643)

This study was designed to assess effects of acute apelin administration on cardiac and coronary performance in anesthetized, open‐chest swine. Systemic intravenous administration of pyr‐apelin 13 (3nM to 1μM) did not significantly affect coronary blood flow (0.37 + 0.07 to 0.29 + 0.06 mL/min/g; p=0.93) or myocardial oxygen consumption (46.47 + 8.64 to 36.84 + 5.93 μL O2/min/g; p=0.91). However, pyr‐apelin 13 elicited a dose‐dependent peripheral dilator response as mean aortic pressure was decreased by 12 + 4 mmHg at 1μM pyr‐apelin 13 (p=0.001). Left ventricular pressure volume relationships were assessed to establish the potential inotropic effects of pyr‐apelin 13. No changes in cardiac output (2074 + 347 to 2052 + 185 mL/min; p= 0.96), stroke volume (35 + 2 to 33 + 1 mL; p=0.34) or end systolic pressure volume relationship (Ees 10.55 + 3.78 to 18.23 + 3.84; p = 0.20) were noted in response to pyr‐apelin 13 (3nm to 1μM). Mass spectroscopic analyses of plasma samples at each dose confirmed a ~700 fold increase in plasma apelin concentrations (0.39 + 0.14 to 287.55 + 43.58 ng/mL; p&lt;0.001) with treatment. Taken together, these data support that acute systemic administration of pyr‐apelin 13 dose‐dependently decreases arterial pressure via reductions in systemic vascular resistance, independent of alterations in cardiac inotropic function.

0213: Gevokizumab, an IL1-beta modulating antibody exerts promising cardioprotective effects against ischemia-reperfusion injury in diabetic rats

Enhanced myocardial interleukin-1 beta (IL1-β) production is involved in ischemia/reperfusion (I/R) induced left ventricular (LV) dysfunction. We tested neutralization of IL-1β as a potential therapeutic target for the treatment of I/R induced LV dysfunction. We assessed in diabetic (Goto Kakizaki, GK) rats the preventive effects of gevokizumab, a potent modulator of IL-1β, administered once a week, started 4 weeks prior to a 20 min of transient ischemia induced by left coronary artery occlusion and continued 90 days after I/R, on LV remodeling/function (echocardiography) 7 and 90 days after I/R. LV hemodynamics (LV catheterization), LV tissue perfusion (MRI) and LV collagen density (image analysis) were assessed 90 days after I/R. I/R induced early LV expansion followed by late LV dilatation, associated with LV dysfunction as well as after 90 days, reduced LV tissue perfusion and LV collagen accumulation. Gevokizumab limited both early LV expansion as well as late LV dilatation, associated with an improved LV function. Ninety days after I/R, gevokizumab improved both LV systolic and LV diastolic functions, illustrated by the increase in LV end-systolic pressure volume relation, and the reductions in LV end-diastolic pressure and LV end-diastolic pressure volume relation. Moreover, long-term gevokizumab moderately increased LV tissue perfusion and significantly reduced LV collagen density. Our results, obtained using a clinically relevant model of I/R, suggest a therapeutic benefit of the IL-1β modulating antibody, gevokizumab, in myocardial I/R injury. LVDD: left ventricular diastolic diameters; LVFS:LV fractional shortening; LVESPVR and LVEDPVR: LV end-diastolic and end-systolic pressure volume relations. *:p<0.05 vs GK; † p<0.05 vs GK I/R

Physiological hemodynamical reactions to road-traffic noise in an experimental setting

Left ventricular hypertrophy (LVH) is more frequently associated with LV dilatation and systolic chamber dysfunction in males than in females. The mechanisms of this effect are uncertain. As excessive adrenergic stimulation may be responsible for LV dilatation and systolic chamber dysfunction in hypertension, we aimed to assess whether gender determines the adverse effects on LV chamber remodeling following 6 months of daily b-adrenergic receptor (AR) stimulation (isoproterenol [ISO] at 0.04 mg/ kg.day) in spontaneously hypertensive rats (SHR). LV dilatation was assessed in vivo from LV end diastolic diameter (EDD) (echocardiography) and ex vivo from the volume intercept at 0 mm Hg pressure (V0) of the LV diastolic pressure-volume relationship (isolated, perfused heart technique). LV systolic function was determined in vivo from LV endocardial fractional shortening (FSend) and ex vivo from the slope (LV end systolic elastance [LV Ees]) of the LV end systolic pressure-volume relationship (isolated, perfused heart technique). As compared to saline-treated male SHR, male SHR receiving ISO for 6 months developed an increased LV EDD and LV V0, and a decreased LV Ees (Table). In contrast, ISO administration failed to modify LV EDD, LV V0 or LV Ees in female SHR (Table). In conclusion, as compared to female SHR, male SHR are more susceptible to the adverse effects of chronic b-AR activation on LV cavity dimensions and systolic chamber function. These results suggest that the higher prevalence of LV dilatation and systolic chamber dysfunction in males than in females with LVH may be attributed to an increased susceptibility to the adverse effects of adrenergic stimulation.

Simulation of Dilated Heart Failure with Continuous Flow Circulatory Support

Lumped parameter models have been employed for decades to simulate important hemodynamic couplings between a left ventricular assist device (LVAD) and the native circulation. However, these studies seldom consider the pathological descending limb of the Frank-Starling response of the overloaded ventricle. This study introduces a dilated heart failure model featuring a unimodal end systolic pressure-volume relationship (ESPVR) to address this critical shortcoming. The resulting hemodynamic response to mechanical circulatory support are illustrated through numerical simulations of a rotodynamic, continuous flow ventricular assist device (cfVAD) coupled to systemic and pulmonary circulations with baroreflex control. The model further incorporated septal interaction to capture the influence of left ventricular (LV) unloading on right ventricular function. Four heart failure conditions were simulated (LV and bi-ventricular failure with/without pulmonary hypertension) in addition to normal baseline. Several metrics of LV function, including cardiac output and stroke work, exhibited a unimodal response whereby initial unloading improved function, and further unloading depleted preload reserve thereby reducing ventricular output. The concept of extremal loading was introduced to reflect the loading condition in which the intrinsic LV stroke work is maximized. Simulation of bi-ventricular failure with pulmonary hypertension revealed inadequacy of LV support alone. These simulations motivate the implementation of an extremum tracking feedback controller to potentially optimize ventricular recovery.

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.

Preclinical Evaluation of the Engineered Stem Cell Chemokine Stromal Cell–Derived Factor 1α Analog in a Translational Ovine Myocardial Infarction Model

After myocardial infarction, there is an inadequate blood supply to the myocardium, and the surrounding borderzone becomes hypocontractile. To develop a clinically translatable therapy, we hypothesized that in a preclinical ovine model of myocardial infarction, the modified endothelial progenitor stem cell chemokine, engineered stromal cell-derived factor 1α analog (ESA), would induce endothelial progenitor stem cell chemotaxis, limit adverse ventricular remodeling, and preserve borderzone contractility. Thirty-six adult male Dorset sheep underwent permanent ligation of the left anterior descending coronary artery, inducing an anteroapical infarction, and were randomized to borderzone injection of saline (n=18) or ESA (n=18). Ventricular function, geometry, and regional strain were assessed using cardiac MRI and pressure-volume catheter transduction. Bone marrow was harvested for in vitro analysis, and myocardial biopsies were taken for mRNA, protein, and immunohistochemical analysis. ESA induced greater chemotaxis of endothelial progenitor stem cells compared with saline (P<0.01) and was equivalent to recombinant stromal cell-derived factor 1α (P=0.27). Analysis of mRNA expression and protein levels in ESA-treated animals revealed reduced matrix metalloproteinase 2 in the borderzone (P<0.05), with elevated levels of tissue inhibitor of matrix metalloproteinase 1 and elastin in the infarct (P<0.05), whereas immunohistochemical analysis of borderzone myocardium showed increased capillary and arteriolar density in the ESA group (P<0.01). Animals in the ESA treatment group also had significant reductions in infarct size (P<0.01), increased maximal principle strain in the borderzone (P<0.01), and a steeper slope of the end-systolic pressure-volume relationship (P=0.01). The novel, biomolecularly designed peptide ESA induces chemotaxis of endothelial progenitor stem cells, stimulates neovasculogenesis, limits infarct expansion, and preserves contractility in an ovine model of myocardial infarction.

Dimensional reductions of a cardiac model for effective validation and calibration

Complex 3D beating heart models are now available, but their complexity makes calibration and validation very difficult tasks. We thus propose a systematic approach of deriving simplified reduced-dimensional models, in "0D"-typically, to represent a cardiac cavity, or several coupled cavities-and in "1D"-to model elongated structures such as muscle samples or myocytes. We apply this approach with an earlier-proposed 3D cardiac model designed to capture length-dependence effects in contraction, which we here complement by an additional modeling component devised to represent length-dependent relaxation. We then present experimental data produced with rat papillary muscle samples when varying preload and afterload conditions, and we achieve some detailed validations of the 1D model with these data, including for the length-dependence effects that are accurately captured. Finally, when running simulations of the 0D model pre-calibrated with the 1D model parameters, we obtain pressure-volume indicators of the left ventricle in good agreement with some important features of cardiac physiology, including the so-called Frank-Starling mechanism, the End-Systolic Pressure-Volume Relationship, as well as varying elastance properties. This integrated multi-dimensional modeling approach thus sheds new light on the relations between the phenomena observed at different scales and at the local versus organ levels.