Lower Left Ventricular Developed Pressure Research Articles

The effect of ovariectomy on hemodynamic functions and the level of nitric oxide metabolites in the heart of rats

Background. A higher prevalence of cardiovascular disorders has been observed in women after menopause. This study aimed to determine the long-term effects of ovariectomy on hemodynamic functions and the level of nitric oxide metabolites (NOx) in the heart tissue of ovariectomized rats. Methods. Fourteen female Wistar rats were divided into two groups (n=7 in each group) of control and ovariectomized (OVX). OVX rat model was induced using the two dorsolateral skin incision method. Cardiac hemodynamic function indices, including the left ventricular developed pressure (LVDP), peak rate of positive changes in the left ventricular pressure (+dp/dt), and peak rate of negative changes in the left ventricular pressure (-dp/dt) were measured at the time of systole in hearts after 11 months of the ovariectomy. Serum and left ventricular levels of NOx were measured at the end of the study. Results. At the end of the study, OVX rats had lower LVDP (19%, P=0.001), +dp/dt (30%, P<0.001) and -dp/dt (23%, P=0.004) than control group. In addition, the OVX group had lower serum NOx levels (30%, P=0.021) compared to the control group; heart tissue NOx was also lower by 31% in the OVX rats, but it was not statistically significant (P=0.056). Conclusion. Long-term ovariectomy disrupts cardiac hemodynamic function in ovariectomized rats, which is associated with decreased NOx levels in serum. Practical Implications. Our findings indicated impaired cardiac function following long-term estrogen deficiency in OVX rats. These results can be used to prevent and treat the cardiovascular disease in post-menopausal women. However, these results need to be confirmed in humans.

Hyperhomocysteinemia Exacerbates Myocardial Ischemia‐Reperfusion Injury: Role of ER Stress and Autophagy

Objectives The correlation between hyperhomocysteinemia and severity of coronary artery disease has been reported. In this study, we investigated the effect of hyperhomocysteinemia on myocardial ischemia/reperfusion (I/R) injury with elucidating the role of ER stress and autophagy to further the mechanistic understanding of the impact posed by hyperhomocysteinemia on cardiac function. Methods Hearts from male Wistar rats fed with regular or high-methionine diet (2%, wt/wt) for 8 weeks were mounted on a Langendorff apparatus and subjected to 30-min global ischemia followed by 60-min reperfusion. Endoplasmic reticulum (ER) stress inhibitor 4-phenybutyric acid (4-PBA) and tauroursodeoxycholic acid (TDUCA), or autophagy inhibitor 3-methyladenine (3-MA) and chloroquine (CQ) were perfused for 15 min prior to the onset of the ischemia. Left ventricular function was monitored throughout the experiment. The protein expression of ER stress molecules GRP78, PERK, and IRE1 as well as autophagy markers SQSTM1/p62 and LC3II/LC3I were determined by western blotting. Results I/R decreasedleft ventricular systolic pressure (LVSP) and increased end-diastolic pressure (LVEDP) in both control and hyperhomocysteinemic rats. Compared with the control animals, hyperhomocysteinemic rats showed lower LVSP, higher LVEDP, and lower left ventricular developed pressure (LVDP), as well as attenuated maximum velocity of contraction (+dp/dtmax) and relaxation (-dp/dtmax) of the left ventricle after I/R. Pretreatment with ER stress or autophagy inhibitors partially restored these hemodynamic parameters whereas the restoration was less significant in hyperhomocysteinemic rats as compared to the controls. Protein analysis showed a higher level of upregulation in GRP78 expression and PERK phosphorylation in hearts from hyperhomocysteinemic rats than control animals after I/R. The protein level of SQSTM1/p62 was significantly higher and the expression ratio of LC3B-II/LC3B-I was significantly lower in the heart of hyperhomocysteinemic rats as compared to the control hearts after subjected to I/R. Conclusions Hyperhomocysteinemia exacerbates myocardial I/R injury through worsening ER stress and regulating autophagy.

Paclitaxel enhances the protective effect of myocardial ischemia preconditioning on ischemia/reperfusion injury in aged rat

Objective: To investigate if paclitaxel can enhance the protective effect of myocardial ischemia preconditioning on ischemia/reperfusion injury in aged ratand explore related mechanism. Methods: Primary cardiomyocytes of Sprague-Dawley rats were isolated by trypsin and divided into 5 groups(n=6 each): control group, hypoxia injury group, hypoxia preconditioning group, paclitaxel group,and paclitaxel+hypoxia preconditioning group. The structure of microtubules and the expression of hypoxia-inducible factor-1α(HIF-1α) were analyzed by immunofluorescence staining. The Langendorff isolated heart perfusion model was applied in 4 groups: hypoxia reperfusion injury group, hypoxia preconditioning group, paclitaxel group, and paclitaxel+hypoxia preconditioning group. Each group was further divided into elderly subgroup and adult subgroup (n=6 each). Left ventricular developed pressure and maximum rate of rise in left ventricular pressure were analyzed. Results: (1) Primary cardiomyocyte experiments showed that the myocardial tubular microtubule structure in control group was intact and evenly stained; most of the microtubules in the hypoxia-injured group were absent and the tubular tissue was broken; the hypoxia-induced damage on microtubule structure was smaller in the hypoxic preconditioning group compared with the hypoxic injury group (microtubule staining was not uniform, and the lattice structure was broken, but not that obvious as in the hypoxia group); the tubular structure of the microtubules of the paclitaxel group was basically complete, and the staining was basically uniform.The integrity of tubular structure was maintained to some extent, similar to a normal microtubule structure in paclitaxel+hypoxia preconditioning group. The expression of HIF-1α in the cytoplasm and nucleus was very low in the control group, which was evidenced in both cytoplasm and nucleus in the hypoxic injury group.The expression was further increased in hypoxic preconditioning group, significant nuclear HIF-1 expression was found in the paclitaxel group, the expression was aggregated in the nucleus in the Paclitaxel+ hypoxia preconditioning group. (2)In Langendorff isolated heart perfusion model, left ventricular developed pressure was similar between the elderly subgroup and the adult subgroup at the end of the infusion,after precondition, 5 minutes of reperfusion, 30 minutes of reperfusion, and 60 minutes of reperfusion in the hypoxic injury group (all P> 0.05).In the hypoxic injury group, both the elderly subgroup and the adult subgroup had lower left ventricular developed pressure at 30 minutes of reperfusion when compared with the end of the infusion((15.63±4.88) mmHg (1 mmHg=0.133 kPa) vs. (95.63±22.14)mmHg and (17.31±2.75)mmHg vs. (91.00±9.58)mmHg, respectively,all P<0.05). In the hypoxic preconditioning group, the adult subgroup had higher left ventricular developed pressure at 5 and 30 minutes of reperfusion when compared with the elderly subgroup((7.13±1.02) mmHg vs. (3.75±1.06)mmHg and (43.94±3.21)mmHg vs.(16.31±1.54)mmHg, respectively,all P<0.01). In the paclitaxel group, the adult subgroup had higher left ventricular developed pressure at 30 and 60 minutes of reperfusion when compared with the elderly subgroup((44.31±7.59)mmHg vs. (5.44±1.21)mmHg, (51.56±6.03)mmHg vs. (22.19±5.14)mmHg, respectively, all P<0.01). In the paclitaxel+hypoxia preconditioning group, both the elderly subgroup and the adult subgroup had lower left ventricular developed pressure at 30 minutes of reperfusion when compared with the end of the infusion((18.63±4.30)mmHg vs. (99.94±8.23) mmHg, P<0.01; (49.69±5.34)mmHg vs. (95.31±5.26)mmHg, P<0.05). Meanwhile, the adult subgroup had higher left ventricular developed pressure at 30 minutes of reperfusion when compared with the elderly subgroup((49.69±5.34)mmHg vs. (18.63±4.33)mmHg, P<0.01).The adult subgroup had higher change rate of maximum rate of rise in left ventricular pressure at 60 minutes of reperfusion when compared with the elderly subgroup in hypoxia preconditioning group, paclitaxel group, and paclitaxel combined hypoxia preconditioning group((62.83±3.92)% vs. (33.33±3.20)%, (44.17±2.32)% vs. (36.67±2.88)%, (72.50±2.66)% vs. (53.17±2.56)%, respectively,all P<0.01). Conclusion: Paclitaxel can enhance the myocardial protective effect of myocardial ischemia preconditioning through stabilizing microtubules of cardiomyocytes and promoting HIF-1α localization in the nucleus.

Exercise Protects against Cancer-induced Cardiac Cachexia.

This study aimed to determine the effect of exercise on tumor morphology and cardiac function. Fisher 344 rats (n = 28) were assigned to one of four groups: 1) sedentary non-tumor bearing (SED), 2) sedentary tumor bearing (SED + T), 3) wheel run non-tumor bearing (WR), or 4) wheel run tumor bearing (WR + T). Rats remained sedentary or exercised for 6 wk. At week 4, rats in tumor groups were inoculated with MatBIII tumor cells. At week 6, cardiac function was measured. SED + T animals exhibited significantly lower left ventricular developed pressure when compared with SED, WR, and WR + T (P < 0.05). This coincided with a significant increase in cardiac autophagy (increased LC3-II) in SED + T animals when compared with SED, WR, and WR + T (P < 0.05). Furthermore, SED + T hearts showed a significant increase in β-myosin heavy chain expression versus nontumor groups (P < 0.05). Tumor mass was significantly larger (P < 0.001) in SED + T animals when compared with WR + T animals, which was accompanied by a significant increase in tumor LC3-II protein expression (P < 0.05). Nonexercised tumor-bearing rats showed severe cardiac dysfunction and excessive, maladaptive autophagy in the heart and tumors. Voluntary exercise preserved cardiac function and attenuated the autophagic response in heart and tumor tissues. This preservation may be related to the reduced tumor growth in aerobically exercised rats, to the improved regulation of autophagy by exercise, or both.

Changes in mitochondrial properties may contribute to enhanced resistance to ischemia-reperfusion injury in the diabetic rat heart.

Diabetes mellitus, besides having deleterious effects, induces cardiac adaptation that may reduce the heart's susceptibility to ischemia-reperfusion (IR) injury. This study aimed to investigate whether changes in mitochondrial properties are involved in the mechanisms of increased resistance of the diabetic heart to IR. Adult male Wistar rats were made diabetic by a single dose of streptozotocin (65 mg·kg-1, i.p.), and on the day 8, Langendorff-perfused hearts were subjected to 30 min global ischemia and 40 min reperfusion. Baseline preischemic parameters in the diabetic hearts did not differ markedly from those in the nondiabetic controls, except for lower left ventricular developed pressure, higher mitochondrial membrane fluidity, and protein levels of manganese superoxide dismutase. On the other hand, diabetic hearts showed significantly better post-IR functional restoration and reduced arrhythmogenesis associated with lower reactive oxygen species production as compared with healthy controls. IR decreased membrane fluidity in both experimental groups; however, it led to a complete recovery of mitochondrial Mg2+-ATPase activity in diabetics in contrast to its reduction in nondiabetics. These findings indicate that the heart may become adapted to diabetes-induced alterations that might increase its tolerance to an ischemic insult. Preserved mitochondrial function might play a role in the mechanisms of the heart's resistance to IR injury in diabetics.

Cardiac dysfunction in adipose triglyceride lipase deficiency: treatment with a PPARα agonist

BACKGROUND AND PURPOSEAdipose triglyceride lipase (ATGL) has been identified as a rate-limiting enzyme of mammalian triglyceride catabolism. Deletion of the ATGL gene in mice results in severe lipid accumulation in a variety of tissues including the heart. In the present study we investigated cardiac function in ATGL-deficient mice and the potential therapeutic effects of the PPARα and γ agonists Wy14,643 and rosiglitazone, respectively.EXPERIMENTAL APPROACHHearts isolated from wild-type (WT) mice and ATGL(-/-) mice treated with Wy14,643 (PPARα agonist), rosiglitazone (PPARγ agonist) or vehicle were perfused at a constant flow using the Langendorff technique. Left ventricular (LV) pressure–volume relationships were established, and the response to adrenergic stimulation was determined with noradrenaline (NA).KEY RESULTSHearts from ATGL(-/-) mice generated higher LV end-diastolic pressure and lower LV developed pressure as a function of intracardiac balloon volume compared to those from WT mice. Likewise, passive wall stress was increased and active wall stress decreased in ATGL(-/-) hearts. Contractile and microvascular responses to NA were substantially reduced in ATGL(-/-) hearts. Cardiac contractility was improved by treating ATGL(-/-) mice with the PPARα agonist Wy14,643 but not with the PPARγ agonist rosiglitazone.CONCLUSIONS AND IMPLICATIONSOur results indicate that lipid accumulation in mouse hearts caused by ATGL gene deletion severely affects systolic and diastolic function, as well as the response to adrenergic stimulation. The beneficial effects of Wy14,643 suggest that the cardiac phenotype of these mice is partially due to impaired PPARα signalling.

The Cytoprotective Effects of Tumor Necrosis Factor Are Conveyed Through Tumor Necrosis Factor Receptor–Associated Factor 2 in the Heart

Activation of both type 1 and type 2 tumor necrosis factor (TNF) receptors (TNFR1 and TNFR2) confers cytoprotection in cardiac myocytes. Noting that the scaffolding protein TNF receptor-associated factor 2 (TRAF2) is common to both TNF receptors, we hypothesized that the cytoprotective responses of TNF were mediated through TRAF2. Mice with cardiac-restricted overexpression of low levels of TNF (MHCsTNF(3)) and TRAF2 (MHC-TRAF2(LC)) and mice lacking TNFR1, TNFR2, and TNFR1/TNFR2 were subjected to ischemia (30 minutes) reperfusion (30 minutes) injury ex vivo using a Langendorff apparatus. MHCsTNF(3) mice were protected against ischemia-reperfusion injury as shown by a significant approximately 30% greater left ventricular developed pressure, approximately 80% lower creatine kinase release, and Evans blue dye uptake compared with littermates. The extent of ischemia-reperfusion induced injury was similar in wild-type, TNFR1, and TNFR2 deficient mice; however, mice lacking TNFR1/TNFR2 had a significant approximately 40% lower left ventricular developed pressure, a approximately 65% greater creatine kinase release, and approximately 40% greater Evans blue dye uptake compared with littermates. Interestingly, MHC-TRAF2(LC) mice had a significant approximately 50% lower left ventricular developed pressure, a approximately 70% lower creatine kinase release, and approximately 80% lower Evans blue dye uptake compared with littermate controls after ischemia-reperfusion injury. Biochemical analysis of the MHC-TRAF2(LC) hearts showed that there was activation of nuclear factor-kappaB but not c-Jun N-terminal kinase activation. Taken together, these results suggest that TNF confers cytoprotection in the heart through TRAF2-mediated activation of nuclear factor-kappaB.

Effects Of Exercise Preconditioning Against Doxorubicin Cardiotoxicity Are Affected By Exercise Modality And Doxorubicin Dose

Previous studies have shown long-term and short-term exercise preconditioning protects against doxorubicin (DOX) cardiotoxicity. However, it is unclear to what extent exercise modality and DOX dosage may influence exercise-induced cardioprotection. PURPOSE: To determine whether the positive effects of short-term exercise preconditioning against DOX-induced cardiotoxicity are affected by exercise modality and DOX dose. METHODS: Male Sprague-Dawley rats were randomly assigned to sedentary (SED), wheel-run (WR), or treadmill-run (TM) groups. Animals in WR and TM participated in 5 days of either treadmill training or voluntary wheel-running. SED animals remained in their cages duration the 5 day period. After 5 days, animals were randomly assigned to receive 10 mg/kg DOX (SED + DOX10, WR + DOX10, TM + DOX10), 15 mg/kg DOX (SED + DOX15, WR + DOX15, TM + DOX15) or saline (SED + SAL, WR + SAL, TM + SAL). Following the exercise/sedentary period all animals then remained sedentary for 5 days after DOX/SAL treatments. Ex vivo left ventricular function was measured using an isolated working heart model. RESULTS: SED + DOX10, SED + DOX15, and TM + DOX15 had significantly lower left ventricular developed pressure (LVDP) (34%, 39% and 19%, respectively, P < 0.05). However, LVDP of TM + DOX10, WR + DOX10 and WR + DOX15 were not significantly different than SED + SAL (P > 0.05). In addition, maximal rate of left ventricular pressure development (+dP/dt) in SED + DOX10, SED + DOX15 and TM + DOX15 were significantly lower than SED + SAL (P < 0.05). This reduction in + dP/dt, however, was not observed in the TM + DOX10, WR + DOX10 and WR + DOX15. CONCLUSION: Short-term treadmill or voluntary wheel running attenuated DOX-induced early onset cardiac dysfunction in animals treated with 10mg/kg DOX. In contrast, only short-term voluntary wheel running protected against DOX-induced early onset cardiac dysfunction in animals treated with 15 mg/kg DOX. These data suggest that while both treadmill and voluntary wheel running can protect against DOX cardiotoxicity, wheel running appears to afford enhanced protection against at higher doses.

EFFECT OF ENTERAL VERSUS PARENTERAL NUTRITION ON INFLAMMATION AND CARDIAC FUNCTION IN A RAT MODEL OF ENDOTOXIN-INDUCED SEPSIS

The present study examined whether total enteral nutrition (TEN) and total parenteral nutrition (TPN) differentially modulates ghrelin, inflammatory mediator production, and cardiac dysfunction induced by LPS. Rats received isocaloric parenteral or enteral nutrition through implanted vascular catheters or gastrostomy tubes for 7 days. Enteral nutrition was provided in conventional (TEN-C) and immunonutrition (TEN-I) formulations. Subsequently, rats were injected i.v. with LPS. Serum ghrelin, TNF-alpha, and high mobility group box 1 levels were determined by enzyme-linked immunosorbent assay. Myocardiac function was also assessed via the Langendorff isolated heart technique. The TEN-C increased plasma ghrelin and inhibited inflammatory mediators both before and after LPS administration when compared with TPN or TEN-I. Furthermore, animals receiving TPN and TEN-I had significantly lower left ventricular developed pressure but increased pressure development during isovolumetric contraction (dP/dt(max)) and relaxation (dP/dt(min)) when compared with animals receiving TEN-C after LPS-induced shock (P < 0.05). We conclude that TEN-C more effectively increased plasma ghrelin levels than TPN and TEN-I. The maintenance of higher ghrelin levels in TEN-C rats was associated with inhibiting various inflammatory mediators and maintaining cardiac function during LPS-induced septic shock.

Endurance Training Protects Against Prostate Cancer Treatment-Induced Cardiac Dysfunction

A common treatment for prostate cancer patients is the use of androgen deprivation therapy (ADT) in which testosterone is reduced to near-castrate levels using chemical gonadectomy agents. Surgical castration has been shown to impair cardiac function, however very little has been done investigating the effects of chemical castration on cardiac function. In addition, endurance training has been shown to be cardioprotective following surgical castration, but very little has been done investigating the effects of endurance training on cardiac function following chemical castration. PURPOSE: This study examined the effects of an 8-week ADT treatment using a leutenizing hormone releasing hormone (LHRH) agonist and endurance training regimen on cardiac function. To help explain possible mechanisms behind altered cardiac function, myosin heavy chain (MHC) composition was analyzed. METHODS: 10-week-old male Sprague-Dawley rats were randomly assigned to either sedentary (SED, n = 20) or exercise (EX, n = 20) groups. Animals were further randomly assigned to receive an 8-week LHRH agonist treatment (SED-ADT, n=10; EX-ADT, n=10) or placebo (SED-CON, n=10; EX-CON, n=10). Animals in the exercise groups trained on a motorized treadmill during the 8-week treatment period, and on day 57, ex vivo cardiac function and MHC isoform composition were analyzed. RESULTS: Hearts from SED-ADT had a significantly lower left ventricular developed pressure than hearts from SED-CON, EX-CON, and EX-ADT (62.5±1.7 mmHgvs. 77.8±0.8 mmHg, 80.1±2.0 mmHg, and 80.3±1.5 mmHg, respectively, p <0.05). There was a significantly slower rate of left ventricular relaxation in hearts from SED-ADT when compared to SED-CON, EX-CON, and EX-ADT (−1719±50 mmHg·s−1 vs. −2258±185 mmHg·s−1,-2059±53 mmHg·s−1, and −2231±82 mmHg·s−1, respectively, p <0.05). In addition, ventricles from SED-ADT expressed a significantly higher percentage of the β-MHC isoform than SED-CON, EX-CON, and EX-ADT (11.9±0.7% vs. 9.4±0.7%, 9.3±0.6%, and 8.7±0.7%, respectively, p <0.05). Androgen deprivation therapy using a LHRH agonist depressed cardiac function, and endurance training attenuated this depression. CONCLUSIONS: An 8-week treatment with a LHRH agonist promoted cardiac dysfunction which may be due to a ventricular α- to β-MHC isoform shift. Endurance training protected against this chemical castration-induced cardiac dysfunction. One possible mechanism behind the cardioprotection is an attenuation of the α- to β-MHC isoform shift associated with LHRH agonist treatment.

Cardiac responses to burn injury in young and adult guinea pigs.

The present study examined functional and biochemical differences in young compared to adult hearts, and determined if developmental differences altered the ability of the young heart to respond to burn injury. Compared to the adult heart, hearts from young sham burns had diminished responsiveness to isoproterenol, extracellular calcium, and increases in either ventricular filling or coronary flow rate. In contrast, there were no age-related differences in maximal calcium uptake (360+/-11 vs. 367+/-14 nmol/mg) or calcium uptake velocity (59+/-2 vs. 60+/-4 nmol/mg/min) in sarcoplasmic reticulum (SR) vesicles isolated from adult and compared to young control hearts. Burn injury (43% TBSA for adults, 35% TBSA for young) impaired myocardial function in all hearts, regardless of age. Age-related differences in adult and young hearts persisted after burn trauma with significantly lower left ventricular developed pressure (49+/-2 vs. 63 +/-3 mmHg, P < 0.01), +dP/dt max (860+/-89 vs. 1151+/-62 mmHg/sec, P < 0.01), and -dP/dt max (790+/-39 vs. 901+/-50 mmHg/sec, P < 0.02) in young vs. adult burn hearts. Burn injury reduced cardiac SR maximal calcium uptake in adults (sham, 360+/-11; burn, 298+/-12 nmol/mg, P < 0.05), but not in young hearts (sham, 367+/-14; burn, 380+/-12 nmol/mg); however, burn trauma increased the SR calcium velocity/capacity ratio in both young and adult burn groups. Our data confirm age-related differences in ventricular performance in young and adult guinea pigs; these differences persisted after burn trauma. The burn-mediated changes in SR Ca2+ transport suggest that disturbances in intracellular calcium handling may contribute, in part, to post-burn cardiac contractile deficits regardless of age.

The preventive effect of verapamil on ethanol-induced cardiac depression: phosphorus-31 nuclear magnetic resonance and high-pressure liquid chromatographic studies of hamsters.

Alcoholic depression of left ventricular function was produced in normal hamsters by the administration of increasing concentrations of alcohol in drinking water (up to 50%) for 6 months. The result was assessed by phosphorus-31 nuclear magnetic resonance of isolated perfused hearts and high-pressure liquid chromatography of freeze-clamped tissues. Hemodynamic data and myocardial oxygen consumption were also monitored. Alcoholic hamsters had significantly higher inorganic phosphate and lower ATP levels, while maintaining normal intracellular pH, phosphocreatine, and creatine. Although coronary flow and oxygen consumption were maintained at normal levels, hamsters ingesting 50% ethanol had significantly lower left ventricular developed pressure and dP/dt. Treatment with verapamil during long-term ethanol consumption prevented the development of these metabolic and functional abnormalities. It is hypothesized that alcohol produces membrane abnormalities leading to adverse ion flux, and that these are largely prevented by concurrent administration of verapamil.