Left Ventricular End-diastolic Pressure Volume Research Articles

Abstract 4138716: A novel Urocortin-2 analog COR-1167 corrects cardiac and renal dysfunction on top of Empagliflozin in a rat model of acute decompensated heart failure

Introduction: Urocortin-2 (UCN-2) is a peptide belonging to the corticotropin-releasing factor family that has cardiovascular, renal, metabolic and anti-inflammatory actions and improves cardiac function in human heart failure (HF) and cardiorenal dysfunction in chronic HF models. However, UCN-2 has a short half-life and intravenous delivery limits its therapeutic use. COR-1167 was discovered as a stable UCN-2 analog with qd pharmacological effects when injected subcutaneously. Hypothesis: Whether COR-1167 exerts chronic cardiorenal protection in Acute Decompensated HF (ADHF) is unknown, and in particular on background of SGLT2 inhibition, therefore both treatments were tested in a rat model of ADHF. Methods: Rats had coronary artery ligation to induce MI and a reduced ejection fraction phenotype. Three months later, rats were treated with vehicle or Empagliflozin (Empa) at 10 mg/kg/day PO. One month after starting Empa, two acute decompensation events were induced by administrating NaCl solution (1.8 g/kg, PO) on Day 0 and Day 14. Empa treated ADHF rats received vehicle or COR-1167 (3 µg/kg/day) by SC injections starting at 12 hours after the first decompensation and all treatments continued for 14 days. The groups were ADHF, ADHF + Empa and ADHF + Empa + COR-1167 (n=7-10/group). Left ventricular (LV) hemodynamics (cardiac catheters), cardiac output (echocardiography) and LV tissue perfusion (magnetic resonance imaging), cardiac mitochondrial coupling and ATP production (Seahorse) were measured 1 day after the second decompensation, while urine volume (uVol) and urine Na + excretion (uNa + ) collected from metabolic cages were analyzed 7 days after the first decompensation. Results: Compared to ADHF control rats, Empa treatment had no effect on systolic blood pressure (SBP), cardiac output (CO), LV end systolic pressure volume relationship (LVESPVR), LV end diastolic pressure volume relationship (LVEDPR), mitochondrial coupling and ATP production, but it increased myocardial perfusion, uVol and uNa + excretion. Compared to ADHF + Empa rats, COR-1167 treatment increased SBP, CO, LVESPVR, myocardial perfusion, mitochondrial coupling and ATP production, uVol, uNa + , while decreasing LVEDPVR. Conclusion: In the setting of ADHF, significant cardiorenal benefits and decongestion occurred when COR-1167 was administered on top of an SGLT2 inhibitor.

Abstract 12140: SCN1B Expression Modulates Sodium Influx in Cardiomyocytes and Diastolic Function in the Adult Heart

Voltage-gated sodium channels (VGSCs) are macromolecular complexes composed of a number of proteins regulating channel biophysical properties. VGSCs generate Na + current (I Na ) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of I Na . Variants in the gene SCN1B , encoding the VGSC β1 and β1B subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of β1/β1B subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knock-out, cKO) were studied. Myocytes from cKO mice had decreased levels of Scn1b transcripts (-85%) and increased densities of fast- (+20%) and slow-inactivating (+140%) components of I Na , with respect to cells from corresponding control (Ctrl) animals. By echocardiography, left ventricular (LV) mass, chamber volume, and systolic function were preserved in both male and female cKO mice, with respect to sex- and age-matched Ctrl animals. However, by transmitral flow Doppler echocardiography, cKO mice presented reduced velocity of the passive filling wave (-~20%), attenuated ratio of the passive-to-active filling velocity waves (-~20%), and prolonged isovolumic relaxation time (+~16%). Moreover, by pressure-volume (PV) loop assessment, cKO mice had steeper slope of the LV end diastolic PV relation and prolonged LV relaxation tau, suggesting impairment of diastolic function. Importantly, inhibition of late I Na with GS967 (0.5 mg/kg body weight) normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice, but had no consequences in Ctrl animals. At the cellular level, cKO myocytes presented delayed kinetics of Ca 2+ transients decay and cell shortening with respect to Ctrl myocytes. These defects were partly corrected by inhibition of the late I Na . Collectively, these results document that VGSC β1/β1B subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na + influx in cardiomyocytes.

Intra-aortic Balloon Pump Use With Extra Corporeal Membrane Oxygenation-A Mock Circulation Loop Study.

Venoarterial extracorporeal membrane oxygenation (ECMO) is used in cardiogenic shock refractory to inotropic support and intra-aortic balloon pump (IABP) support. Peripheral ECMO can lead to ventricular distention, and IABP can be used to mitigate these effects. The aim of this study was to quantify the effects of IABP concomitant with ECMO, under different simulated hemodynamic conditions in a mock circulatory loop. Different simulated states of isolated left ventricular (LV) failure and biventricular failure with graded LV failure severities were supported with ECMO and ECMO with IABP. The impact on left ventricular end-diastolic pressure (LVEDP), volume (LVEDV), coronary flow rate, and cerebral flow rate were evaluated. Left ventricular volumes and pressures increased from the heart failure states with the addition of ECMO. The IABP provided between 3% and 7% reductions in LVEDP and between 1% and 10% reductions in LVEDV. The addition of IABP had minimal effect on cerebral blood flow (0% to 7%), but the variable impact on coronary blood flow with increased diastolic coronary flow of 23% to 50%, but the reduction in mean coronary flow by up to 30%. The efficacy of the IABP was strongly related to ventricular contractility. This study demonstrates the need for careful IABP selection concomitant with ECMO.

386-P: Chronic Treatment with the Direct AMPK Activator PXL770 Improves Cardiac, Vascular, and Renal Function in Rodents with Diabetes-Related Cardiorenal Disease

Introduction: PXL770 is a direct AMP kinase activator. In models of T2DM and NASH, PXL770 improves hyperglycemia and dyslipidemia and reduces: steatosis, inflammation, fibrogenesis. Whether these beneficial effects are associated with an improvement in diabetes-related cardiac, vascular and renal dysfunctions is unknown. Methods: Diabetic ZSF-1 rats were treated for 90 days with PXL770 (150 mg/kg BID), then cardiac function (left ventricular (LV) hemodynamics), in vitro flow-mediated dilation (FMD; arteriograph) of mesenteric artery, renal histology and function (transcutaneous GFR) were assessed. Results: Untreated ZSF-1 rats exhibited LV diastolic dysfunction, i.e., increases in LV End-Diastolic Pressure (LVEDP; 8.3±1.0 vs. 5.6±0.6 mm Hg in lean, p<.05) and LV End-Diastolic Pressure Volume Relation (LVEDPVR; 5.4±0.6 vs. 1.1±0.2 mm Hg/RVU in lean, p<.05). Myocardial tissue perfusion was reduced (4.0±0.2 vs. 7.4±0.9 ml/min/g in lean, p<.05). Untreated rats exhibited impaired mesenteric FMD (% of preconstriction; 37±11 vs. 70±7% in lean, p<.05) and renal function and structure as shown by a reduction in GFR (4.4±0.5 vs. 5.6±0.5 ml/min in lean, p<.05) and increase in glomerular score (2.3±0.2 vs. 0.6±0.1 AU in lean, p<.05). Compared to untreated ZSF-1 rats, 90-day PXL770 reduced glycaemia (-31 %, p<.05) and plasma triglycerides (-44 %, p<.05). PXL770 decreased LVEDP (-28 %) and LVEDPVR (2.7±0.2 mm Hg/RVU, p<.05) and increased LV tissue perfusion (+30 %, p<.05). PXL770 improved mesenteric FMD (64±3%, p<.05) and increased GFR (6.0±0.1 ml/min, p<.05) and reduced glomerular score (1.6±0.2, p<.05). Conclusion: In ZSF-1 rats, improvement of metabolic status induced by long-term treatment with the AMP kinase activator PXL770 is associated with an improved LV diastolic, vascular and renal function/structure. PXL770 could have therapeutic utility for the treatment of metabolic diseases and related co-morbid conditions. Disclosure Y. Stephan: None. M. Soulié: None. L. Nicol: None. P. Gluais-dagorn: Employee; Self; Poxel SA. S. Hallakou-bozec: None. P. Mulder: None. Funding Poxel SA

Gene deletion of protein tyrosine phosphatase 1B limits cardiovascular dysfunction and mortality during endotoxinic shock

Sepsis-associated cardiovascular dysfunction is one of the main causes of mortality in critically ill patients. PTP1B is negative regulator of insulin signaling and endothelial Nitric Oxide (NO) production, two mechanisms likely involved in the pathogenesis of sepsis. We recently showed that gene deletion or pharmacological inhibition of PTP1B improves endothelial dysfunction and reduces the severity of heart failure. The aim of the present study was to assess the effect of PTP1B gene deletion on lipopolysaccharide (LPS)-induced cardiovascular dysfunction and mortality in mice. PTP1B-/- or wild-type (WT) mice received LPS (15mg/kg) or vehicle followed by subcutaneous saline resuscitation (30ml/kg). LPS significantly enhanced cardiac and arterial PTP1B mRNA expression. Compared with WT, PTP1B-/- mice displayed markedly reduced mortality (Survival 4 days after LPS: WT: 0%; PTP1B-/- 70%, p<0.01), associated with a higher locomotor activity. Evaluation of vascular function 8h after LPS in isolated mesenteric resistance arteries (arteriograph system) showed that PTP1B-/- LPS mice had improved contractile response to phenylephrine, and restored flow mediated, NO dependent-dilatation (% dilatation to 200μl/min: WT 6,3±3; PTP1B-/- 16,5±2, p<0.05) associated with significant increases in phosphorylation of Akt and eNOS, and reduced mRNA expression of VCAM-1, ICAM-1, COX-2, IL-1β, iNOS and Gp91phox (PCR). Evaluation of left ventricular (LV) function by echocardiography, and pressure-volume curves 8h after LPS revealed reduced cardiac dysfunction in PTP1B-/- mice as shown by an increased LV fractional shortening (WT 17,3±1; PTP1B-/- 24±1, p<0.05) and LV end systolic pressure-volume relation (WT 16±2; PTP1B-/- 20±2, p<0.05) together with reduced LV end diastolic pressure-volume relation (WT 4,7±1,7; PTP1B-/- 2.4±0.9 mmHg/RVU, p<0.05). Improved cardiac contractility was also observed ex-vivo in hearts isolated and perfused 8h after LPS (LV Developed Pressure: WT 25±5; PTP1B-/- 50±5 mmHg, p<0.05). Improved cardiac function was associated with significant decreases in myocardial markers of inflammation and oxidative stress (VCAM-1, ICAM-1, CD45, IL-1β, TNF-α and Gp91phox), reduced P38 and ERK1/2 phosphorylation and limited decrease of phospholamban phosphorylation (WT -42%; PTP1B-/- -22.8, p<0.05). Thus, we demonstrate for the first time that PTP1B gene deletion protects against lipopolysaccharide-induced cardiovascular dysfunction and mortality. These results suggest that PTP1B is an attractive target for the treatment of sepsis.

Abstract 255: A Normokalemic Nondepolarizing Cardioplegia Minimizes Myocardial Injury and Improves Cardiac Function in a Large Animal Model of Donation After Cardiocirculatory Death

Background: Procurement of donor hearts is typically preceded by delivery of a cold hyperkalemic cardioplegia (CP) that achieves arrest by depolarization of the membrane potential. This method has no intrinsic cardioprotective properties and may exacerbate ischemia-reperfusion (IR) injury. A tepid adenosine-lidocaine (AL) non-depolarizing CP has been shown to limit IR injury and improve myocardial functional recovery in a small animal model of orthotopic heart transplantation. We sought to determine the impact of AL CP on myocardial injury and function, in a porcine model of donation after cardio-circulatory death (DCD). Methods: Female Yorkshire pigs (60 kg) were subjected to a hypoxic cardiac arrest. Following a 15-minute standoff period donor hearts were procured, resuscitated ex-vivo, and transplanted into a recipient animal. Hearts in group 1 (N=7) were protected with a cold blood-Plegisol CP, perfused with a blood-crystalloid solution during ex-vivo assessment, and arrested with a cold blood-Plegisol CP prior to transplantation. Hearts in group 2 (N=5) were protected with a tepid AL-STEEN CP and perfused with a blood-STEEN solution in a continuous fashion during ex-vivo assessment and transplantation. Results: Animals in group 2 had a significantly longer ex-vivo perfusion time compared to those in group 1 (174±29 vs. 135±45 min, p&lt;0.05), yet they demonstrated significantly less weight gain (14±4 vs. 25±8 grams/hour, p&lt;0.05). Further, animals in group 2 exhibited less troponin I release during ex-vivo perfusion and had significantly better diastolic function following wean from cardiopulmonary bypass (left ventricular end-diastolic pressure volume relationship 0.115±0.052 vs. 0.508±0.223, p&lt;0.05). However, there was no significant difference in level of calpain activity between groups (171.3±68.6 vs. 140.12±50.6, p=0.36). Conclusion: A tepid non-depolarizing AL CP results in less myocardial edema during ex-vivo perfusion, minimizes myocardial injury, and improves diastolic function following transplantation of DCD hearts, but fails to eliminate the activation of calcium-dependent proteases. Further studies should investigate if a calpain inhibitor delivered at reperfusion could further minimize IR injury in DCD hearts.

Diastolic function during hemorrhagic shock in rabbits

Hemorrhage (H) is associated with a left ventricular (LV) dysfunction. However, the diastolic function has not been studied in detail. The main goal was to assess the diastolic function both during and 120min after bleeding, in the absence and in the presence of L-NAME. Also, the changes in mRNA and protein expression of nitric oxide synthase (NOS) isoforms were determined. New Zealand rabbits were divided into three groups: Sham group, H group (hemorrhage 20% blood volume), and H L-NAME group (hemorrhage treated with L-NAME). We evaluated systolic and diastolic ventricular functions in vivo and in vitro (Langendorff technique). Hemodynamic parameters and LV function were measured before, during, and at 120min after bleeding. We analyzed the isovolumic relaxation using t ½ in vivo (closed chest). After that, hearts were excised and perfused in vitro to measure myocardial stiffness. Samples were frozen to measure NOS mRNA and protein expression. The t½ increased during bleeding and returned to basal values 120min after bleeding. L-NAME blunted this effect. Data from the H group revealed a shift to the left in the LV end diastolic pressure-volume curve at 120min after bleeding, which was blocked by L-NAME. iNOS and nNOS protein expression and mRNA levels increased at 120min after the hemorrhage. Acute hemorrhage induces early and transient isovolumic relaxation impairment and an increase in myocardial stiffness 120min after bleeding. L-NAME blunted the LV dysfunction, suggesting that NO modulates ventricular function through iNOS and nNOS isoforms.

Comparative effects of cilazapril, carvedilol and their combination in preventing from left ventricular remodelling after acute myocardial infarction in rats

To compare the effects of cilazapril, carvedilol and their combination in preventing left ventricular remodelling (LVRM) after acute myocardial infarction (AMI) in rats. Twenty-four hours after left coronary artery ligation, 100 surviving AMI female Sprague-Dawley rats were randomly assigned to: (1) AMI control (n=25); (2) cilazapril (Cila, 1 mg/kg/day) (n=25); (3) carvedilol (Car, 1 mg/kg/day) (n=25), and (4) cilazapril (1 mg/kg/day)+ carvedilol (1 mg/kg/day) (combination) (n=25) groups. A sham-operated group (n=17) was selected randomly as a non-infarction control. After four weeks of therapy with the drugs given by gastric gavage, haemodynamic studies were performed, following which the rat hearts were fixed and pathologically analysed. Rats with MI size <35% or >55% were excluded. Complete data were obtained in 64 rats, comprising AMI control (n=13), Cila (n=12), Car (n=12), Combination (n=14), and sham-operated (n=13) groups. There were no significant differences in MI size between the four AMI groups (45.2 46.7%, p>0.05). Compared with the sham-operated group, left ventricular (LV) end diastolic pressure (LVEDP), volume (LVV), weight (LVW), septal thickness (STh) and right ventricular weight (RVW) were all significantly increased (all p<0.001) in the AMI group, while the LV pressure maximal rate of rise and fall ( dp/dt) was significantly decreased (all p<0.001). In comparison with the AMI group, LVEDP, LVV, LVW, STh and RVW were all significantly decreased, while dp/dt was significantly increased in the Cila, Car, and combination groups, with LVEDP and STh decreasing more in the combination group than in the two monotherapy groups (p<0.05 0.01). There were no significant differences in other variables between the three therapy groups. Cilazapril, carvedilol and their combination are all effective in preventing LVRM after AMI in rats, and in improving haemodynamics and LV function, with the combination therapy being superior to monotherapy in all respects.

CARDIODYNAMIC RESPONSE TO ESCHERICHIA COLI ENDOTOXEMIA

We tested the influence of in vivo volume resuscitation on intrinsic contractile properties of left ventricular (LV) preparations of endotoxemic guinea pigs. Escherichia coli endotoxin (LPS)-injected animals were divided into nonresuscitated and resuscitated groups. Volume resuscitation improved cardiac output and stroke volume, increased arterial pH and body temperature, and decreased mortality. In isovolumetric LV preparations isolated 4 h after LPS injection, LV systolic pressures (in mmHg) preparations isolated 4 h after LPS injection, LV systolic pressures (in mmHg) of LPS with (42 +/- 3) and without (42 +/- 2) fluid resuscitation were consistently less than control values (70 +/- 3). LV end-diastolic pressure-volume (compliance) decreased in LPS-nonresuscitated hearts, while LV compliance of LPS-resuscitated hearts was similar to control. Thus, intravascular volume expansion selectively improved LV diastolic compliance of LPS hearts without affecting LV systolic function. These findings suggest that LV systolic and diastolic dysfunctions associated with endotoxemia and Gram-negative sepsis may involve separate pathogenic mechanisms.

Ejection pressure and the diastolic left ventricular pressure-volume relation.

The influence of ejection pressure (EP) on the left ventricular end-diastolic pressure-volume (P-V) relation was examined in 24 paced, isolated canine hearts. A pressure servo system was used to control EP and monitor ventricular volume. For any given contractile state EP was varied: a) by 10- to 20-mmHg increments and the steady-state P-V response observed at each EP level (method A); or b) by instantaneously attaining the isovolumic condition (PO) from a given EDV and examining the immediate P-V response (method B). With either method it was possible to alter the P-V relation; the maximum variation occurred when, for a given EDV or EDP, EP was raised from a value less than 50% of its corresponding peak isovolumic pressure to PO. For the EDP range 2-25 mmHg, the direction and total magnitude of change were: 1) an increase in EDV 1.3-9 ml was required to maintain EDP constant; and 2) for a constant EDV, EDP decreased an average 16.5%+/-1.2 SE (6-23.9%; P less than .02). The EDP decline observed with method B was immediate and reversible within several beats upon returning to the ejecting mode. Thus, under the conditions of this experiment the diastolic pressure-volume relation is a physiological variable dependent on ejection pressure.