Left Ventricular End-systolic Pressure Volume Research Articles

Acute vasopressin neutralization improves cardiac function in rats with chronic heart failure

Vasopressin is one of the leading pathophysiological drivers of chronic heart failure (CHF) acting via V1a-, V1b- and V2 receptors. Selective V2 and dual V1a-V2 receptor antagonists increases plasma sodium levels, but failed to reduce mortality in clinical studies. Vasopressin neutralization is an original alternative to receptor blockers but its effect in CHF is unknown. For this purpose, we investigated the short-term cardiac and vascular effects of the vasopressin neutralizing aptamer NOX-F37. Left ventricular (LV) function (hemodynamic by LV catheterization) and LV tissue perfusion (MRI) as well as mesenteric artery endothelial function (flow-mediated dilation by arteriography) were determined 2 hours after NOX-F37 administration (80 nM/kg; IP) to rats with CHF induced by left coronary artery ligation. Two hours after administration, NOX-F37 improved LV systolic function, illustrated by the increase in LV end-systolic pressure volume relationship (CHF: 20.2 ± 0.0.7; CHF + NOX: 23.3 ± 1.0 mmHg/RVU; P < 0.05) and diastolic function, illustrated by the decrease in LV end-diastolic pressure volume relationship (CHF: 4.03 ± 0.48; CHF + NOX: 2.06 ± 0.21 mmHg/RVU; P < 0.01), together with an increase in LV tissue perfusion (CHF: 6.12 ± 0.24; CHF + NOX: 10.10 ± 0.26 ml/min/g LV tissue; P < 0.001). However, mesenteric artery flow-induced dilatation was not improved (% dilatation at 150 μL/min; CHF: 10 ± 7; CHF + NOX: 9 ± 8). These results illustrate the immediate beneficial effects of vasopressin neutralization on cardiac function in CHF, confirming the existence of a deleterious vasopressinergic tone in this pathophysiological context. Investigations still needed to evaluate the persistence of effects of vasopressin neutralization over time during chronic and could contribute to the resolution of acute heart failure.

The Utility of Intraventricular Pressure Gradient for Early Detection of Chemotherapy-Induced Subclinical Cardiac Dysfunction in Dogs.

Simple SummaryCardiotoxicity is a serious side effect of doxorubicin in cancer patients due to the risk of development of heart failure. Early detection of doxorubicin-induced cardiomyopa-thy (DXR-ICM) has become a major objective to reduce heart failure in cancer patients. Echocar-diography is the gold standard method to diagnose cardiac diseases when cardiac dysfunction is prominent; however, it still cannot predict or early diagnose heart failure before functional de-cline. The intraventricular blood flow is characterized by intraventricular pressure gradients (IVPG) that created due to the suction of blood by the ventricles. Currently, advanced imaging techniques allow non-invasive assessment of IVPG from color M-mode echocardiography (CMME) after image processing for the clinical setting. Studies revealed that IVPG indices are promising for the early diagnosis of cardiac dysfunction. In this study, we aimed to investigate the usefulness of IVPG to detect cardiac function changes after DXR administration in dogs. Early detection of doxorubicin (DXR)-induced cardiomyopathy (DXR-ICM) is crucial to improve cancer patient outcomes and survival. In recent years, the intraventricular pressure gradient (IVPG) has been a breakthrough as a sensitive index to assess cardiac function. This study aimed to evaluate the usefulness of IVPG for the early detection of chemotherapy-related cardiac dysfunction. For this purpose, six dogs underwent conventional, speckle tracking, and color M-mode echocardiography concomitantly with pressure-and-volume analysis by conductance catheter. The cardiac function measurements were assessed before DXR administration (baseline, Pre), at the end of treatment protocol (Post), and at 1.5 years follow-up (Post2). The result showed a significant reduction in the left ventricular end-systolic pressure-volume (Emax: 4.4 ± 0.7, 6.1 ± 1.6 vs. 8.4 ± 0.8 mmHg/mL), total-IVPG (0.59 ± 0.12, 0.62 ± 0.15 vs. 0.86 ± 0.12 mmHg), and mid-IVPG (0.28 ± 0.12, 0.31 ± 0.11 vs. 0.48 ± 0.08 mmHg), respectively in Post2 and Post compared with the baseline (p < 0.05). Mid-to-apical IVPG was also reduced in Post2 compared with the baseline (0.29 ± 0.13 vs. 0.51 ± 0.11). Meanwhile, the fraction shortening, ejection fraction, and longitudinal strain revealed no change between groups. Total and mid-IVPG were significantly correlated with Emax (R = 0.49; p < 0.05, both) but only mid-IVPG was a predictor for Emax (R2 = 0.238, p = 0.040). In conclusion, this study revealed that impairment of contractility was the initial changes observed with DXR-ICM in dogs and only IVPG could noninvasively detect subclinical alterations in cardiac function. Color M-mode echocardiography-derived IVPG could be a potential marker for the early detection of doxorubicin cardiomyopathy.

Left ventricular mechanoenergetics in excised, cross-circulated rat hearts under hypo-, normo-, and hyperthermic conditions

We investigated the effects of altering cardiac temperature on left ventricular (LV) myocardial mechanical work and energetics using the excised, cross-circulated rat heart model. We analyzed the LV end-systolic pressure–volume relationship (ESPVR) and linear relationship between myocardial oxygen consumption per beat (VO2) and systolic pressure–volume area (PVA; total mechanical energy per beat) in isovolumically contracting rat hearts during hypo- (32 °C), normo- (37 °C), and hyperthermia (42 °C) under a 300-beats per minute pacing. LV ESPVR shifted downward with increasing cardiac temperature. The VO2–PVA relationship was superimposable in these different thermal conditions; however, each data point of VO2–PVA shifted left-downward during increasing cardiac temperature on the superimposable VO2–PVA relationship line. VO2 for Ca2+ handling in excitation–contraction coupling decreased, which was associated with increasing cardiac temperature, during which sarcoplasmic reticulum Ca2+-ATPase (SERCA) activity was suppressed, due to phospholamban phosphorylation inhibition, and instead, O2 consumption for basal metabolism was increased. The O2 cost of LV contractility for Ca2+ also increased with increasing cardiac temperature. Logistic time constants evaluating LV relaxation time were significantly shortened with increasing cardiac temperature related to the acceleration of the detachment in cross-bridge (CB) cycling, indicating increased myosin ATPase activity. The results suggested that increasing cardiac temperature induced a negative inotropic action related to SERCA activity suppression in Ca2+ handling and increased myosin ATPase activity in CB cycling. We concluded that thermal intervention could modulate cardiac inotropism by changing CB cycling, Ca2+ handling, and basal metabolism in rat hearts.

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

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.

Pharmacologically Induced Hypothermia with WIN55,212-2 and Extracorporeal Life Support after Cardiac Arrest as a Preservation Strategy for Heart Transplantation

Purpose To investigate the hypothesis that induction of therapeutic hypothermia with cannabinoid receptor agonist WIN55,212-2 and extracorporeal life support (ECLS) after cardiac arrest is an effective heart preservation strategy. Methods and Materials Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted and rats were randomized to three groups of ten: normothermia, therapeutic hypothermia (32°C) and pharmacological hypothermia by WIN55,212 intravenous infusion (1 mg/kg/h). After 120 minutes heterotopic heart transplantation was performed in syngeneic donors using a working heart model. After 24 hours left ventricular (LV) systolic and diastolic functions were evaluated at different preloads using a conductance catheter. Results WIN55,212-2 led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p Conclusions Pharmacologically induced hypohermia with WIN55,212-2 during ECLS improve myocardial protection through activation of the pro-survival kinase Akt and ERK and could be an organ preservation strategy after cardiac arrest.

Left ventricular mechanical and energetic changes in long-term isoproterenol-induced hypertrophied hearts of SERCA2a transgenic rats

Overexpression of cardiac sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) has been suggested as a strategic intervention for cardiac failure. However, its benefit in wild-type (WT) rats with normal SERCA2a levels seems to be small. To investigate whether it would be beneficial in a cardiac failure model with down-regulated SERCA2a levels, we made a cardiac hypertrophy model using isoproterenol infusion (1.2mgkg−1day−1 for 1 or 4weeks; TG-ISO1w and TG-ISO4w, respectively) in SERCA2a transgenic (TG) rats and compared these rats with littermate WT rats that underwent the same treatments (WT-ISO1w and WT-ISO4w). We analyzed the left ventricular (LV) mechanoenergetics in the excised heart using our original cross-circulation system. The downward shift of curvilinear LV end-systolic pressure–volume relations (ESPVRs) observed in WT-ISO4w rats was abolished in TG-ISO4w rats. The slope and VO2 intercept of the VO2 (myocardial oxygen consumption per beat)–PVA (systolic pressure–volume area: total mechanical energy per beat) linear relation did not differ in any of the groups. The most important finding was a significantly smaller O2 cost of LV contractility in the TG-ISO4w group, which means that less O2 is needed to exert the same LV contractility, compared with the other groups. The increased ratio of SERCA2a/phospholamban returned to the level of the WT-control group only in the TG-ISO4w group. Longer-term up-regulation of mitochondrial transcription factor A for genes of mitochondrial enzymes producing ATP was observed in TG rats. In conclusion, longer-term overexpression of SERCA2a will be beneficial in the present cardiac failure model with down-regulated SERCA2a levels.

Role of calcium desensitization in the treatment of myocardial dysfunction after deep hypothermic circulatory arrest

IntroductionRewarming from deep hypothermic circulatory arrest (DHCA) produces calcium desensitization by troponin I (cTnI) phosphorylation which results in myocardial dysfunction. This study investigated the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan, a calcium sensitizer, on myocardial function after rewarming from DHCA.MethodsForty male Wistar rats (400 to 500 g) underwent cardiopulmonary bypass (CPB) through central cannulation and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After DHCA (20 minutes) and CPB-assisted rewarming (60 minutes) rats were randomly assigned to 60 minute intravenous infusion with levosimendan (0.2 μg/kg/min; n = 15), epinephrine (0.1 μg/kg/min; n = 15) or saline (control; n = 10). Systolic and diastolic functions were evaluated at different preloads with a conductance catheter.ResultsThe slope of left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) recovered significantly better with levosimendan compared to epinephrine (Ees: 85 ± 9% vs 51 ± 11%, P<0.003 and PRSW: 78 ± 5% vs 48 ± 8%, P<0.005; baseline: 100%). Levosimendan but not epinephrine reduced left ventricular stiffness shown by the end-diastolic pressure-volume relationship and improved ventricular relaxation (Tau). Levosimendan preserved ATP myocardial content as well as energy charge and reduced plasma lactate concentrations. In normothermia experiments epinephrine in contrast to Levosimendan increased cTnI phosphorylation 3.5-fold. After rewarming from DHCA, cTnI phosphorylation increased 4.5-fold in the saline and epinephrine group compared to normothermia but remained unchanged with levosimendan.ConclusionsLevosimendan due to prevention of calcium desensitization by cTnI phosphorylation is more effective than epinephrine for treatment of myocardial dysfunction after rewarming from DHCA.

Abstract 19637: Superiority of Calcium Sensitizer Over Beta-Adrenoceptor Agonist for Treatment of Myocardial Dysfunction after Deep Hypothermic Circulatory Arrest. Role of Calcium Desensitization

BACKGROUND: Rewarming from deep hypothermic circutatory arrest (DHCA) produced a calcium desensitization by cTnI phosphorylation that results in myocardial dysfunction. This study was aimed to investigate the acute overall hemodynamic and metabolic effects of epinephrine and levosimendan on myocardial function after rewarming from deep hypothermia. METHODS AND RESULTS Forty male Wistar rats (400-500 g) underwent cardiopulmonary bypass and were cooled to a core temperature of 13°C to 15°C within 30 minutes. After 15 minutes of DHCA, they were randomly assigned to treatment with levosimendan (0.1 μg/kg/min) (n=15) or epinephrine (0.1 μg/kg/min) (n =15) or saline as control (n =10). The rewarming lasted 60 minutes. Systolic and diastolic function was evaluated at different preloads with a conductance catheter. Levosimendan produced a significantly better recovery of the slope of the left ventricular end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than ephinephrine (as percentage of baseline respectively 85+9 vs 51+11, p=0.003 and 78+5 vs 48+8, p=0.005). Levosimendan and not ephinephrine compared to control reduced left ventricular stiffness expressed by end-diastolic pressure volume relationship (EDPVR) and improved ventricular relaxation described by Tau. Levosimendan preserved high-energy phosphates content and energy charge and reduced lactate plasma concentration. Ephinephrine (E) determined a significant cTnI phosphorylation during normothermia (N) and enhanced cTnI phosphorylation after DHCA (H/R). On the contrary levosimendan (L) prevent cTnI phosphorylation that was not different from normothermic control (Fig. 1). CONCLUSIONS: Levosimendan is more effective than epinephrine for treatment of myocardial dysfunction after DHCA. Ephinephrine has a detrimental effect on calcium desensitization that has a key role in myocardial dysfunction after rewarming from DHCA.

Abstract 18789: Pharmacologically Induced Hypothermia with Cannabinoid Receptor Agonist WIN55,212-2 vs Mild Therapeutic Hypothermia in a Rat Model of Cardiac Arrest with Extracorporeal Life Support

BACKGROUND: To compare the hemodynamic, cardioprotective and metabolic effects of cannabinoid receptor agonist WIN55,212-2 with mild therapeutic hypothermia and normothermic control on post-resuscitation myocardial function in a rat model of extracorporeal life support (ECLS). METHODS AND RESULTS: Ventricular fibrillation (VF) was induced in male Wistar rats. After 10 min of untreated VF, venoarterial ECLS was instituted for 60 min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32°C) and WIN55,212 intravenous infusion (1 mg/kg/h). Cooling to 32°C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. WIN55,212-2 administration produced pharmacologic hypothermia (32-34°C) and led to a significantly better recovery of the slope of the LV end-systolic pressure volume relationship (Ees) and Preload recruitable stroke work (PRSW) than hypothermia and normothermia: as percent of baseline 87+12 vs 54+9 vs 39+11 and 88+11 vs 59+10 vs 33+8 respectively (p&lt;.01). LV stiffness expressed by end-diastolic pressure volume relationship (EDPVR) was significantly lower after WIN55,212-2 administration (p&lt;.05). LV relaxation described by Tau was preserved after WIN55,212-2 treatment but not after hypothermia or normothermia (p&lt;.01). WIN55,212-2 and not hypothermia significantly increased phosphorylation of the kinase ERK1 and 2 (2.8+0.4 and 2.5+0.3 vs 0.5+0.2 and 0.4+0.1 -fold of baseline levels) (p&lt;.01). Both WIN55,212-2 and hypothermia but not normothermia increased phosphorylation of Akt. This resulted in a reduced cardiomyocyte apoptotic index (TUNEL, p&lt;.01). WIN55,212-2 but not hypothermia nor normothermia preserved high energy phosphates content and energy charge and reduced lactate plasma concentration. CONCLUSIONS: Pharmacologically induced hypothermia with WIN55,212-2 was more effective than mild therapeutic hypothermia in recovering myocardial function after ECLS and in improving myocardial protection through activation of the pro-survival kinases Akt and ERK1/2.

Cardioprotective effect of δ-opioid receptor agonist vs mild therapeutic hypothermia in a rat model of cardiac arrest with extracorporeal life support

BackgroundTo compare the effect of δ-opioid receptor agonist, d-Ala2-d-Leu5 enkephalin (DADLE) with normothermic control and therapeutic hypothermia on post resuscitation myocardial function in a model of extracorporeal life support (ECLS). MethodsVentricular fibrillation (VF) was induced in male Wistar rats. After 10min of untreated VF, venoarterial ECLS was instituted for 60min. At the beginning of ECLS animals were randomized to three groups of ten: normothermia, hypothermia (32°C) and DADLE intravenous infusion (1mg/kg/h). Cooling to 32°C or normothermia or drug infusion lasted for the entire ECLS. Plasma samples and myocardial biopsies were obtained and left-ventricular (LV) function was assessed by a conductance catheter at baseline and after weaning from ECLS. ResultsDADLE administration resulted in a significantly enhanced recovery of LV systolic function expressed by slope of the LV end-systolic pressure volume relationship (Ees) and preload recruitable stroke work (PRSW) than hypothermia and normothermia. LV stiffness indicated by end-diastolic pressure volume relationship (EDPVR) was significantly lower after DADLE administration (P<0.01). LV relaxation described by Tau was preserved after DADLE treatment but not after normothermia or mild hypothermia (P<0.01). Plasma lactate concentrations were lower in DADLE group (P<0.05). DADLE and not conventional hypothermia significantly increased phosphorylation of the kinases ERK1 and 2 (3.9±0.3 and 3.1±0.5 vs 0.4±0.1 and 0.3±0.1-fold of baseline levels) (P<0.001). Both DADLE and hypothermia but not normothermia increase phosphorylation of Akt. ConclusionsDADLE was more effective than mild therapeutic hypothermia in recovering myocardial function and activation of the pro-survival kinases Akt and ERK after ECLS.

Soluble epoxide hydrolase inhibition improves myocardial perfusion and function in experimental heart failure

The study addressed the hypothesis that soluble epoxide hydrolase (sEH) inhibition, which increases cardiovascular protective epoxyeicosatrienoic acids (EETs), exerts beneficial effects in an established chronic heart failure (CHF) model. In CHF rats, left ventricular (LV) function, perfusion and remodeling were assessed using MRI and invasive hemodynamics after 42-day (starting 8days after coronary ligation) and delayed 3-day (starting 47days after coronary ligation) treatments with the sEH inhibitor AUDA (twice 0.25mg/day). Delayed 3-day and 42-day AUDA increased plasma EETs demonstrating the effective inhibition of sEH. Delayed 3-day and 42-day AUDA enhanced cardiac output without change in arterial pressure, thus reducing total peripheral resistance. Both treatment periods increased the slope of the LV end-systolic pressure–volume relation, but only 42-day AUDA decreased LV end-diastolic pressure, relaxation constant Tau and the slope of the LV end-diastolic pressure–volume relation, associated with a reduced LV diastolic volume and collagen density. Delayed 3-day and, to a larger extent, 42-day AUDA increased LV perfusion associated with a decreased LV hypoxia-inducible factor-1alpha. Both treatment periods decreased reactive oxygen species level and increased reduced-oxidized glutathione ratio. Finally, MSPPOH, an inhibitor of the EET-synthesizing enzyme cytochrome epoxygenases, abolished the beneficial effects of 3-day AUDA on LV function and perfusion. Augmentation of EET availability by pharmacological inhibition of sEH increases LV diastolic and systolic functions in established CHF. This notably results from short-term processes, i.e. increased LV perfusion, reduced LV oxidative stress and peripheral vasodilatation, but also from long-term effects, i.e. reduced LV remodeling.

Tetrahydrobiopterin improves cardiac and pulmonary function after cardiopulmonary bypass☆

Tetrahydrobiopterin (BH4) is an important cofactor of endogenous nitric oxide synthesis. In the present preclinical study, we investigated the effects of BH4 on cardiac and pulmonary function during early reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation. Twelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 min of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or BH4 (n = 6). Left-ventricular end-systolic pressure volume relationship (E(es)) was measured by a combined pressure-volume conductance catheter at baseline and after 60 min of reperfusion. Left anterior descending (LAD) coronary (CBF) and pulmonary blood flow (PBF), endothelium-dependent vasodilatation to acetylcholine (ACh), endothelium-independent vasodilatation to sodium nitroprusside (SNP) and alveolo-arterial O₂ gradient were determined. The administration of BH4 led to a significantly better recovery of E(es) (given as percent of baseline: 85 ± 22 vs 46 ± 15%, p<0.05). CBF was also significantly higher in the BH4 group (38 ± 5 vs 22 ± 5 ml min⁻¹, p<0.05). While the vasodilatatory response to SNP was similar in both groups, injection of ACh resulted in a significantly higher increase in CBF (64 ± 12 vs 25 ± 12%, p < 0.05) and PBF (49 ± 15 vs 36 ± 14%, p<0.05) in the BH4-treated animals. Alveolo-arterial O₂ gradient was significantly lower after BH4 supplementation (80 ± 15 vs 49 ± 14 mm Hg, p < 0.05). Application of BH4 improves myocardial, endothelial and pulmonary function after cardiopulmonary bypass with hypothermic cardiac arrest. The observed protective effects indicate that BH4 could be a novel therapeutic option in the treatment of ischemia/reperfusion injury.

Effects of inosine on reperfusion injury after cardiopulmonary bypass

ObjectiveInosine, a break-down product of adenosine has been recently shown to exert inodilatory and anti-inflammatory properties. Furthermore inosine might be a key substrate of pharmacological post-conditioning. In the present pre-clinical study, we investigated the effects of inosine on cardiac function during reperfusion in an experimental model of cardioplegic arrest and extracorporal circulation.MethodsTwelve anesthetized dogs underwent hypothermic cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started after application of either saline vehicle (control, n = 6), or inosine (100 mg/kg, n = 6). Left ventricular end-systolic pressure volume relationship (ESPVR) was measured by a combined pressure-volume-conductance catheter at baseline and after 60 minutes of reperfusion. Left anterior descendent coronary blood flow (CBF), endothelium-dependent vasodilatation to acetylcholine (ACh) and endothelium-independent vasodilatation to sodium nitroprusside (SNP) were also determined.ResultsThe administration of inosine led to a significantly better recovery (given as percent of baseline) of ESPVR 90 ± 9% vs. 46 ± 6%, p < 0.05. CBF and was also significantly higher in the inosine group (56 ± 8 vs. 23 ± 4, ml/min, p < 0.05). While the vasodilatatory response to SNP was similar in both groups, ACh resulted in a significantly higher increase in CBF (58 ± 6% vs. 25 ± 5%, p < 0.05) in the inosine group.ConclusionsApplication of inosine improves myocardial and endothelial function after cardiopulmonary bypass with hypothermic cardiac arrest.

Vardenafil improves myocardial and endothelial function after cardiopulmonary bypass

Twelve anesthetized dogs, underwent hypothermic cardiopulmonary bypass. 6 digs received vardenafil (30 μg/kg) prior initiation of cardiopulmonary bypass. After 60 minutes of hypothermic cardiac arrest, reperfusion was started. Left ventricular end-systolic pressure volume relationship (Ees) was measured by a combined pressure-volume-conductance catheter at baseline and after 60 minutes of reperfusion. Left anterior descendent coronary blood flow (CBF) and endothelium-dependent vasodilatation to acetylcholine (ACH) were determined.

Adolescents’ Left Ventricular Response at Peak Wingate Anaerobic Test

Left ventricular function was evaluated in 14 adolescents (13.1 ± 1 years) at maximal oxygen uptake and at peak Wingate anaerobic test by means of echocardiography. Significant (p &lt; .05) differences between aerobic and Wingate test bouts were found for: cardiac output (15.5 ± 1.2 and 12.2 ± 1.1 L/min, respectively); left ventricular end-systolic pressure—volume ratio (5.2 ± 0.8 and 6.0 ± 0.7, respectively); ejection fraction (72.2 ± 5.2 and 65.2 ± 5.1%, respectively); and mean arterial blood pressure (102.9 ± 10.8 and 111.1 ± 11.3 mmHg, respectively). Data suggest that left ventricular function at peak Wingate anaerobic test was markedly lower from that observed at peak aerobic exercise as a result of a higher afterload response.

Left Ventricular Function at Peak All-Out Anaerobic Exercise in Older Men

Background: All-out anaerobic exercise may be dangerous for the older population, due to hypoxia and inappropriate blood pressure response. Objectives: This study compared and evaluated left ventricular function at peak all-out anaerobic effort in 12 well-trained older (58 ± 1 years) and 12 young men (22 ± 1 years). Methods: Subjects were studied by echocardiography at peak all-out anaerobic exercise, on a cycle ergometer. Results: Seven older subjects experienced ECG abnormalities. Significant (p < 0.05) differences between the older group and the young group, respectively, were noted for: cardiac output (9.8 ± 0.9 and 15.8 ± 0.9 l·min^–1), left ventricular end-systolic pressure-volume ratio (4.7 ± 0.8 and 4.4 ± 4.9), left ventricular end-diastolic volume (104.8 ± 6.9 and 125.7 ± 6.2 ml), ejection fraction (67.1 ± 6.0 and 59.8 ± 5.5%), left ventricular end-systolic pressure volume ratio (4.4 ± 0.4 and 4.8 ± 0.3 ratio), and total peripheral resistance (966.0 ± 84.0 and 660 ± 82.8 dyn·s^–1·cm^–5). Conclusions: Data suggest that during all-out anaerobic exercise, forces opposing ejection were not reduced enough to avoid left ventricular dysfunction and ECG abnormalities in the older subjects. This is attributed to functional changes with age in the myocardium and associated blood vessels, leading to impairment of left ventricular function and blunted inotropic and chronotropic responses to catecholamine. Therefore, an all-out anaerobic-type effort should not be given to an older subject due to the great hazardous potential.

A novel method of ?preparative? myocardial protection using green tea polyphenol in oral uptake

Reperfusion injury has been one of the serious problems in cardiac surgery and medicine. We report a novel method of myocardial protection. Eight Sprague-Dawley rats, group A, were administrated green tea polyphenol orally. Eight other rats, group B, received no medication. Isolated hearts were perfused with a Langendorff's apparatus, and reperfused after 90min arrest. The left ventricular (LV) function, size, weight and the oxidative stress spaciotemporal analysis were performed. The LV size in group B became enlarged by 1.8+/-0.12 (mean+/-SD), but in group A, the LV enlarged only 1.1+/-0.08 times. The heart weight ratio was lighter (1.35+/-0.05) in group A than in group B (1.49+/-0.03, P<0.05). The LV end-systolic pressure volume relationship remained higher in group A. Oxidative stress as shown by 8-hydroxy-2'-deoxyguanosine was lower in group A (81.5+/-11.6) than in group B (226.9+/-35.6, P<0.0001). Polyphenol labeled FITC was located in the cell membrane of cardiomyocite. Polyphenol can protect a heart from oxidative stress, and maintain good LV function after ischemic arrest and reperfusion. This pre-treatment by polyphenol may add further benefit to current treatments of myocardial protection.

Evaluation of left ventricular ejection fraction as a measure of pump performance in patients with chronic mitral regurgitation.

Left ventricular (LV) ejection fraction may not adequately detect a reduction in LV systolic performance resulting from chronic mitral regurgitation (MR), due to ventricular unloading into the low-impedance left atrium. To determine whether LV ejection fraction sufficiently gauges myocardial function in MR, nine patients were studied using micromanometer-measured LV pressures and biplane cineventriculography before and 1 year after mitral valve surgery. Six control patients were also studied. LV ejection fraction was normal in MR patients, despite an increase in LV end-systolic volume index. LV end-systolic pressure-volume and stress-volume ratios in MR patients were lower than in controls (P < 0.05 and P < 0.01), suggesting that LV systolic performance fell. One year after mitral valve surgery, LV ejection fraction decreased (P < 0.05) even though LV end-systolic volume index (P < 0.05), pressure-volume (P < 0.05), and stress-volume ratios (P < 0.01) all improved. Thus, LV ejection fraction inadequately reflected LV systolic function in MR patients before and after mitral valve surgery.

Force–length relationship in dogs as a measure of protective effect of imidapril on regional myocardial ischemia and reperfusion injury

Our laboratory previously reported that the end-systolic force–length relationship of the left ventricle provides a better method of evaluating myocardial contractile properties than the left ventricular end-systolic pressure–volume relationship, because it avoids deficiencies of the latter parameter such as dependence of its slope ( E max) on the volume intercept ( V 0). The slope ( E c) of the left ventricular end-systolic force–length relationship represents the contractility of functioning myocardium, while its length intercept ( L 0) reflects the length of non-functioning myocardium. However, the effect of regional myocardial ischemia on these parameters, as evaluated by the force–length relationship, remains unknown. To clarify the effects of regional ischemia and angiotensin-converting enzyme inhibition on the myocardium during ischemia–reperfusion, the changes in E c and L 0 were determined in anesthetized open-chest dogs. (1) Control group ( n=26): Before and after 15 min of complete coronary artery occlusion, as well as after 15 min of reperfusion, left ventricular pressure and volume were simultaneously recorded during inferior vena cava occlusion. The left ventricular force–length relationship was obtained from the pressure and volume of three cylindrical segments of the ventricle, and E c and L 0 were calculated. (2) Imidapril group ( n=14): Imidaprilat (1 μg/kg/min) was continuously infused from 30 min before ischemia to the end of the experiment, and the same procedures were followed as in the control group. Fourteen out of the 26 dogs (54%) in the control group died of reperfusion-induced ventricular arrhythmias, while only two of the 14 dogs (14%) in the imidapril group did so ( P<0.05). In the control group, E c was increased during ischemia and remained at the same level after reperfusion. However, E c was not altered in the imidapril group. Although L 0 was increased during ischemia and decreased after reperfusion in both groups, the percent increase of L 0 in the imidapril group was significantly smaller than in the control group (8% vs. 32%, P<0.05). With the improvement of these indices, the bradykinin concentration of coronary venous blood increased in the imidapril group ( P<0.01). These findings suggest that regional myocardial ischemia increased the average contractility of overall functioning myocardium despite the increased non-functioning myocardium. Moreover, imidapril has a cardioprotective effect against ischemia–reperfusion injury by decreasing infarct size, and through the antiarrhythmic effect and the reversal of increased overall contractility.