Left Ventricular End-systolic Pressure Research Articles

Effect of dl-3n-butylphthalide on sympathetic remodeling at infarct border zone in rats with myocardial infarction

Objective To investigate the effect of dl-3n-Butylphthalide (NBP) on cardiac function and sympathetic remodeling in rats with myocardial infarction (MI). Methods Totally 50 male SD rats were randomly divided into 3 groups: Sham-operated (sham) group (n=10), myocardial infraction (MI) group (n=20) and MI with NBP group (n=20). A rat myocardial infarction model was established by ligating anterior descending branch of coronary artery. Rats in MI with NBP group were received the gavage treatment with NBP. Cardiac function was evaluated by hemodynamic detection at 7 day post-MI. Cardiac tissues were stained with hematoxylin and eosin as well as Masson trichrome. The distribution and density of growth associated protein-43- (GAP-43) and tyrosine hydroxytase- (TH) positive nerve at infarction border zone were detected by immunohistochemistry. The activation of nuclear factor-κB (NF-κB) signaling pathway was detected by western blot analysis. Results 8 rats died in MI group, in which 2 rats died within 24h. 7 rats died in MI with NBP group, and in which 3 rats died within 24 h. The left ventricular end-diastolic pressure (LVEDP) and left ventricular end-systolic pressure (LVESP) were (7.81±2.46) mmHg (1 mmHg=0.133 kPa) and (103.32±10.59) mmHg, (18.93±3.17) mmHg and (136.44±13.62) mmHg, (16.56±4.82) mmHg and (112.83±16.97) mmHg in sham group, MI group and MI with NBP group respectively. There were no significant differences in + dP/dt and - dP/dt between MI group and MI with NBP group (both P>0.05). Compared with sham group, the collagen volume fraction at infarct border zone was increased in MI group (P<0.05), but was reduced in MI with NBP group as compared to the MI group (P<0.05). The densities of GAP-43- and TH- positive nerves at infarct border zone were increased in MI group as compared with sham group, and reduced in MI with NBP group as compared with MI group (both P<0.05). NBP could reduced p-IKBα protein expression and increase IKBα protein expression in rats with MI. Conclusions NBP may improve the sympathetic remodeling after MI via the inhibition of NF-κB signaling pathway. Key words: Myocardial infarction; Apigenin; Parasympathetic nervous system

Effect of pre-arrest and post-arrest mild hypothermia on myocardial function of ventricular fibrillation after restoration of spontaneous circulation in rabbits

To study the effect of pre-arrest and post-arrest mild hypothermia after restoration of spontaneous circulation (ROSC) on myocardial function, ultrastructure, apoptosis of myocardial cells in rabbits with ventricular fibrillation. Sixty-two male New Zealand rabbits were randomly allocated into five groups: namely normothermic control group (NTC group, n = 10), hypothermia control group (HTC group, n = 10), normothermic resuscitation group (NTR group, n = 14), hypothermia pre-arrest group (HPRA group, n = 14), and hypothermia post-arrest group (HPOA group, n = 14). The normal temperature was controlled at (39.0 ± 0.5) centigrade, and the hypothermia (33.5±0.5) centigrade. Ventricular fibrillation cardiac arrest (CA) was reproduced in rabbits by transcutaneous epicardium electrical stimulation. The parameters of hemodynamics were monitored dynamically for 4 hours in all the groups, including heart rate (HR), left ventricular end diastolic and systolic pressure (LVEDP/LVESP), maximal rate of increase/decrease in left ventricular pressure (±dp/dt max), and mean arterial pressure (MAP). The body temperature of rabbits in hypothermia groups was maintained by surface cooling for 4 hours followed by rewarming. The survived rabbits were sacrificed at 48 hours after resuscitation, and myocardial apical tissue was harvested for observation of ultrastructure with electronic microscope, and to observe apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. (1) Resuscitation investigation: there was no significant difference in rate of ROSC, time of CPR and energy of defibrillation among HPRA, HPOA, and NTR groups [rate of ROSC: 85.71%, 71.43%, 71.43%; time of CPR (seconds): 45.3 ± 30.2, 61.2 ± 41.3, 82.3 ± 63.8; energy of defibrillation (J): 14.3 ± 8.9, 22.0 ± 15.5, 25.0 ± 15.8, all P > 0.05]. (2) Hemodynamics: compared with normal temperature groups, animals in hypothermia groups exhibited lower levels of HR (all P < 0.05). Compared with NTR group, HPRA group exhibited higher levels of LVESP (mmHg, 1 mmHg = 0.133 kPa) at 0.5, 1, 2 and 3 hours post ROSC (0.5 hour: 103.8 ± 14.3 vs. 91.6 ± 13.3, 1 hour: 107.2 ± 14.1 vs. 82.7 ± 8.5, 2 hours: 109.0 ± 16.9 vs. 88.8 ± 12.9, 3 hours: 109.1 ± 14.6 vs. 89.3 ± 14.3, all P < 0.05). Compared with NTR group and HPOA group, HPRA group exhibited lower levels of LVEDP (mmHg) at 0.5 hour post ROSC (3.70 ± 0.85 vs. 7.61 ± 2.73, 7.02 ± 3.12, both P < 0.05). Compared with NTR group, HPRA group exhibited lower levels of LVEDP at 1 hour post ROSC (4.34 ± 1.44 vs. 6.99±1.96, P < 0.05). In HPRA group, the level of +dp/dt max (mmHg/s) was higher than that of NTR group and HPOA group at 1 hour and 2 hours post ROSC (1 hour: 2 759.5 ± 321.6 vs. 2 123.0 ± 304.5, 2 283.7 ± 234.2, 2 hours: 2 730.6±425.1 vs. 2 221.5 ± 392.9, 2 252.6 ± 476.0, all P < 0.05). There were no significant differences in -dp/dt max and MAP levels among three CPR groups. (3) The survival rate at 48 hours post ROSC of NTR, HPRA and HPOA groups was 60%, 75%, and 100%, respectively. Compared with NTR group, higher survival rate was found in HPOA group at 48 hour post ROSC (P < 0.05). (4) Compared with NTR group, less damage to myocardial ultrastructure was found in HPRA and HPOA groups. Apoptosis index (AI) was lower in HPRA and HPOA groups than that in NTR group [(28.05 ± 9.82) %, (26.39 ± 8.98) % vs. (42.02 ± 13.36) %, both P < 0.05]. Our study shows that mild hypothermia has no effect on ROSC rate. Pre-arrest hypothermia can ameliorate myocardial systolic function of rabbit in early stage after ROSC, and it has no negative influence on diastolic function. Post-arrest mild hypothermia produces no negative influence on myocardial function of rabbit, but it improves 48 hours survival rate in ROSC rabbits. Both pre-arrest and post-arrest mild hypothermia therapy can attenuate myocardial injury in CA model of rabbits by ameliorating mitochondrial injuries and suppressing apoptosis of myocardial cells.

Cardiovascular effects in rats after intratracheal instillation of metal welding particles

Studies have indicated that pulmonary exposure to welding fumes can induce a series of adverse effects in the respiratory system, including infection, bronchitis, siderosis and decreased pulmonary function. Recent clinical and epidemiological studies have found that pulmonary exposure to welding fumes is also associated with a higher incidence of cardiovascular events. However, there is insufficient evidence to confirm a direct effect of welding fumes on the cardiovascular system. The present study investigated the effects of pulmonary exposure to welding fumes on the heart and the vascular system in rats. Two chemically distinct welding fumes generated from manual metal arc-hard surfacing (MMA-HS) and gas metal arc-mild steel (GMA-MS) welding were tested. Three groups of rats were instilled intratracheally with MMA-HS (2 mg/rat), GMA-MS (2 mg/rat) or saline as control once a week for seven weeks. On days 1 and 7 after the last treatment, basal cardiovascular function and the cardiovascular response to increasing doses of adrenoreceptor agonists were assessed. MMA-HS treatment reduced the basal levels of left ventricle end-systolic pressure and dP/dtmax at 1 day post-treatment, and decreased dP/dtmin in response to isoproterenol (ISO) at 7 days post-treatment. Unlike MMA-HS, GMA-MS only affected left ventricular end-diastolic pressure in response to ISO at 7 days post-treatment. Treatment with MMA-HS or GMA-MS did not alter heart rate and blood pressure. Our findings suggest that exposure to different welding fumes can induce different adverse effects on the cardiovascular system, and that cardiac contractility may be a sensitive indicator of cardiovascular dysfunction.

Long-Term Administration of Neuropeptide Y in the Subcutaneous Infusion Results in Cardiac Dysfunction and Hypertrophy in Rats

Background/Aims: The purpose of the present study was to clarify whether chronically elevated plasma neuropeptide Y (NPY) might affect heart function and cardiac remodeling in rats. Methods: Male Wistar rats were administered NPY (85 μg for 30 days) by mini-osmotic pump subcutaneously implanted between the scapulae. Associated indices for heart function, cardiac remodeling and hypertrophy were evaluated. Results: Compared to the sham group, the baseline systolic blood pressure (SBP) in rats administered NPY was significantly increased; cardiac function was significantly decreased, as indicated by reduced ejection fraction (EF), left ventricular end-systolic pressure (LVESP), maximum change velocity of left ventricular pressure in the isovolumic contraction or relaxation period (±dp/dt_max) and increased left ventricular end-diastolic pressure (LVEDP); hematoxylin-eosin (H&E) staining detection displayed enlarged cell areas and a consistent increase in heart-to-body weight ratios (HW/BW) was observed; quantitative real time PCR (qRT-PCR) and Western blot analysis showed markedly increased expressions of β-myosin heavy chain (β-MHC), calcineurin (CaN) and phosphorylated p38 proteins, while no changes were found in the expressions of p38 total protein and the phosphorylations of JNK and ERK. Conclusion: This study reported for the first time that long-term elevated plasma concentration of NPY could induce cardiac dysfunction and cardiac hypertrophy and this phenomenon could, in part, be mediated by the Ca²⁺/CaM-dependent CaN pathway and p38 mitogen-activated protein kinase (MAPK) signal pathway in rats.

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&lt;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&lt;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&lt;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&lt;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&lt;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.

Acute impact of pacing at different cardiac sites on left ventricular rotation and twist in dogs.

ObjectivesWe evaluated the acute impact of different cardiac pacing sites on two-dimensional speckle-tracking echocardiography (STE) derived left ventricular (LV) rotation and twist in healthy dogs.MethodsTwelve dogs were used in this study. The steerable pacing electrodes were positioned into right heart through the superior or inferior vena cava, into LV through aorta across the aortic valve. The steerable pacing electrodes were positioned individually in the right atrium (RA), right ventricular apex (RVA), RV outflow tract (RVOT), His bundle (HB), LV apex (LVA) and LV high septum (LVS), individual pacing mode was applied at 10 minutes interval for at least 5 minutes from each position under fluoroscopy and ultrasound guidance and at stabilized hemodynamic conditions. LV short-axis images at the apical and basal levels were obtained during sinus rhythm and pacing. Offline STE analysis was performed. Rotation, twist, time to peak rotation (TPR), time to peak twist (TPT), and apical-basal rotation delay (rotational synchronization index, RSI) values were compared at various conditions. LV pressure was monitored simultaneously.ResultsAnesthetic death occurred in 1 dog, and another dog was excluded because of bad imaging quality. Data from 10 dogs were analyzed. RVA, RVOT, HB, LVA, LVS, RARV (RA+RVA) pacing resulted in significantly reduced apical and basal rotation and twist, significantly prolonged apical TPR, TPT and RSI compared to pre-pacing and RA pacing (all P<0.05). The apical and basal rotation and twist values were significantly higher during HB pacing than during pacing at ventricular sites (all P<0.05, except basal rotation at RVA pacing). The apical TPR during HB pacing was significantly shorter than during RVOT and RVA pacing (both P<0.05). The LV end systolic pressure (LVESP) was significantly lower during ventricular pacing than during pre-pacing and RA pacing.ConclusionsOur results show that RA and HB pacing results in less acute reduction on LV twist, rotation and LVESP compared to ventricular pacing.

Abstract 276: The Regulatory Effects Of Peroxiredoxin II On Phospholamban Phosphorylation And Cardiac Contractile Function In Vivo

Peroxiredoxin II (prxII), a cytosolic form of the anti-oxidant peroxiredoxin family, was recently found to be decreased in failing human hearts. Interestingly, in hyperdynamic hearts of two genetically modified mouse models with: a) phospholamban ablation; and b) overexpression of the active inhibitor-1 of protein phosphatase 1, the levels of this cellular peroxidase (prxII) were markedly increased. Acute overexpression of prxII by adenoviral-delivery in adult rat cardiomyocytes (Ad-prxII) was associated with decreases in the basal rates of contraction and relaxation, as well as calcium kinetics. Accordingly, Ad-prxII-AS infected cardiomyocytes exhibited enhanced contractile parameters and Ca-kinetics. The depressed or increased contractility by Ad-prxII or Ad-prxII-AS was associated with parallel decreases or increases in phosphorylation of phospholamban (Ser16 and Thr17). To determine the in vivo effects of prxII on cardiac contractility, three transgenic lines (TG) with 2-3 fold cardiac-specific overexpression of prxII were generated and their cardiac morphologic and functional phenotypes were characterized. The TG mice exhibited no alterations in cardiac pathology or morphology up to 4 months of age. However, langendorf perfusions revealed that cardiac contractility, including the rates of contraction and relaxation (±dp/dtmax) as well as the left ventricular end systolic pressure (LVESP), were significantly depressed in TG mice (to 75, 76 and 63%, respectively), compared to WTs (100%). The depressed function was not associated with any alterations in the expression levels of key SR calcium handling proteins: SERCA2, total phospholamban, calsequestrin and ryanodine receptor. However, the levels of the phosphorylated PLN at Ser16 were found to be reduced to 50% in the TG mice, compared to WTs. These findings indicate that prxII, an anti-oxidant protein, may regulate basal cardiac contractile performance in vivo through phospholamban phosphorylation.

Manganese ferrite-based nanoparticles induce ex vivo, but not in vivo, cardiovascular effects

Magnetic nanoparticles (MNPs) have been used for various biomedical applications. Importantly, manganese ferrite-based nanoparticles have useful magnetic resonance imaging characteristics and potential for hyperthermia treatment, but their effects in the cardiovascular system are poorly reported. Thus, the objectives of this study were to determine the cardiovascular effects of three different types of manganese ferrite-based magnetic nanoparticles: citrate-coated (CiMNPs); tripolyphosphate-coated (PhMNPs); and bare magnetic nanoparticles (BaMNPs). The samples were characterized by vibrating sample magnetometer, X-ray diffraction, dynamic light scattering, and transmission electron microscopy. The direct effects of the MNPs on cardiac contractility were evaluated in isolated perfused rat hearts. The CiMNPs, but not PhMNPs and BaMNPs, induced a transient decrease in the left ventricular end-systolic pressure. The PhMNPs and BaMNPs, but not CiMNPs, induced an increase in left ventricular end-diastolic pressure, which resulted in a decrease in a left ventricular end developed pressure. Indeed, PhMNPs and BaMNPs also caused a decrease in the maximal rate of left ventricular pressure rise (+dP/dt) and maximal rate of left ventricular pressure decline (−dP/dt). The three MNPs studied induced an increase in the perfusion pressure of isolated hearts. BaMNPs, but not PhMNPs or CiMNPs, induced a slight vasorelaxant effect in the isolated aortic rings. None of the MNPs were able to change heart rate or arterial blood pressure in conscious rats. In summary, although the MNPs were able to induce effects ex vivo, no significant changes were observed in vivo. Thus, given the proper dosages, these MNPs should be considered for possible therapeutic applications.

Establishment of a chronic left ventricular aneurysm model in rabbit.

ObjectivesTo establish a cost-effective and reproducible procedure for induction of chronic left ventricular aneurysm (LVA) in rabbits.MethodsAcute myocardial infarction (AMI) was induced in 35 rabbits via concomitant ligation of the left anterior descending (LAD) coronary artery and the circumflex (Cx) branch at the middle portion. Development of AMI was confirmed by ST segment elevation and akinesis of the occluded area. Echocardiography, pathological evaluation, and agar intra-chamber casting were utilized to validate the formation of LVA four weeks after the surgery. Left ventricular end systolic pressure (LVESP) and diastolic pressure (LVEDP) were measured before, immediately after and four weeks after ligation. Dimensions of the ventricular chamber, thickness of the interventricular septum (IVS) and the left ventricular posterior wall (LVPW) left ventricular end diastolic volume (LVEDV), systolic volume (LVESV), and ejection fraction (EF) were recorded by echocardiogram.ResultsThirty one (88.6%) rabbits survived myocardial infarction and 26 of them developed aneurysm (83.9%). The mean area of aneurysm was 33.4% ± 2.4% of the left ventricle. LVEF markedly decreased after LVA formation, whereas LVEDV, LVESV and the thickness of IVS as well as the dimension of ventricular chamber from apex to mitral valve annulus significantly increased. LVESP immediately dropped after ligation and recovered to a small extent after LVA formation. LVEDP progressively increased after ligation till LVA formation. Areas in the LV that underwent fibrosis included the apex, anterior wall and lateral wall but not IVS. Agar intra-chamber cast showed that the bulging of LV wall was prominent in the area of aneurysm.ConclusionsLigation of LAD and Cx at the middle portion could induce development of LVA at a mean area ratio of 33.4% ± 2.4% which involves the apex, anterior wall and lateral wall of the left ventricle.

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

Radiation-associated degenerative cardiovascular risks during normal aging and after adverse CV event 10 months post-initial exposure

Background: During the future exploration-type space missions, astronauts will be exposed to ionizing radiation (IR) for more than 1–2 years. The effect of cosmic IR during and after space flights on the cardiovascular (CV) system is unknown. Therefore, it is important to evaluate space IR effects on the CV system and determine potential post-mission degenerative excess relative risks (ERR) to the heart as a function of normal aging (IR + AGING model) as well as determine whether space IR may affect the processes of recovery after an adverse CV event (i.e. acute myocardial infarct, AMI) during normal aging (IR + AGING + AMI model).Methods: Nine-month-old C57BL6N male mice were IR once with proton (50 cGy, 1 GeV/n) or (56Fe 15 cGy, 1 GeV/n). IR-induced alterations in cardiac function were assessed by echocardiography (ECHO) and hemodynamic measurements (HEMO). AMI was induced by ligation of left anterior descending (LAD) coronary artery 10 months post-IR. Mice were monitored over 28 days post-AMI.Results: Compared with control, in the IR + AGING study group, left ventricular end-systolic pressure (LVESP) was significantly decreased in both 1H- and 56Fe-IR (P < 0.03, both), suggesting IR-associated decrease in contractile function 10 month post-IRs. However, compared with age-matched control mice (18 months), the LV end-diastolic pressure (LVEDP) was significantly increased (P < 0.05) and minimum LV pressure change (dP/dt min, mmHg/sec) was significantly decreased (P < 0.02) in 1H-IR but not 56Fe-IR mice, suggesting that a single 50 cGy full body 1H-IR decreases considerably the relaxation function of the heart 10 months post-AMI. Of note, an increase in LVEDP and a decrease in dP/dt min are indicators that heart is not pumping blood well and is an early independent prognostic CV risk factor for development of cardiac de-compensation.In all three IR + AGING + AMI study groups, in average, there was 10–15% mortality up to 3 days post-AMI surgery with ∼90% survival rate in all groups 28 days post-AMI. This is rather very good survival rate for 18- to 20-month-old mice after permanent LAD ligation. In the IR + AGING + AMI study group, the most harmful effects on myocardial recovery 10 months post-IR and 28 days post-AMI were observed in the 56Fe-IR group. LVESP was significantly decreased in 56Fe-IR vs control and 1H-IR mice (P < 0.04 and <0.02, respectively). LVEDP was 3-fold higher in 56Fe-IR vs 1H-IR mice (P < 0.004) but was only slightly higher (P = n.s.) compared with control mice. However, dP/dt max and dP/dt min were significantly decreased in 56Fe-IR vs control (P < 0.007 and <0.05, respectively) and 1H-IR mice (P < 0.0004 and <0.0015, respectively), suggesting that 56Fe-AMI hearts developed cardiac de-compensation.Summary: Our data in the IR + AGING study group strongly suggest that 10 months post-IR low-dose high-energy 1H-IR but not low-dose HZE (56Fe) particle IR affects considerably contractile and relaxation functions during normal aging. Conversely, our data in the IR + AGING + AMI study group at 10 months post-IR taken together with our previously reported data for AMI recovery 3 month after a single 50 cGy 1H-IR and 15 cGy 56Fe-IR indicate that 3 months and as long as 10 months after a single full-body IR, the 56Fe-IR is detrimental, whereas 1H-IR does not have negative effects on post-AMI recovery. In fact, single 1H-IR, at this dose, was considerably beneficial for post-AMI recovery at 3 months, as well as at 10 months post-IR.Major conclusions: Our longitudinal 1, 3 and 10 months studies in the IR + AGING and IR + AGING + AMI groups reveal that a single full-body low-dose 1H and HZE particle radiation (56Fe) have long-lasting negative effect on heart homeostasis during normal aging (predominantly 56Fe and at 10 months 1H-IR, as well), and present a significant CV risk for recovery after adverse CV event (exclusively 56Fe-IR, whereas 1H-IR at this dose could beneficial). Further, the divergent effects of low dose 1H-IR vs 56Fe-IR on heart function during normal aging vs after adverse CV event suggest significantly different biological responses responsible for this ion-dependent dichotomy over 10 months post-IR and necessitate further in-depth studies into underlying molecular mechanisms.

Transcatheter aortic valve implantation reduces grade of concomitant mitral and tricuspid valve regurgitation and pulmonary hypertension†

The presence of concomitant mitral (MR) or tricuspid regurgitation (TR) is a common issue in patients undergoing transcatheter aortic valve implantation (TAVI). The objective was (i) to analyse the outcomes of patients with concomitant moderate or more severe MR, (ii) to compare the outcomes with those of TAVI patients without concomitant MR and (iii) to evaluate the impact of TAVI on grade of concomitant MR. For creating a homogeneous study group, the study was restricted to transapical (TA)-TAVI patients. Since 2008, 615 patients have undergone TAVI at our institution, 386 of these using the TA approach with the Edwards SAPIEN™ bioprosthesis. Out of these, 116 (30.1%) presented with concomitant moderate or more severe MR. Mean logistic European System for Cardiac Operative Risk (EuroSCORE) was 18.1 ± 11.5%, EuroSCORE II 5.4 ± 0.7%. Intra- and post-hospital course, change in grade of MR, TR, right ventricular systolic pressure (RVSP) and tricuspid annular plane systolic excursion (TAPSE) were particularly analysed. Outcomes were compared with those of the remaining TA-TAVI patients (n = 270). Mean follow-up time was 471 ± 391 days, giving a total of 135 patient-years. Three patients (2.6%) died during primary hospital stay. Estimated 1-, 2-, 3- and 4-year survival rates were 76.7, 75.6, 68.3 and 50.6% for study and 78.1, 77.8, 61.1 and 55.0% for control groups, respectively. Postoperative morbidity and mortality did not differ significantly from those of the control group. Postoperatively, a significant reduction in MR (2.1 ± 0.2 to 1.5 ± 0.7; P < 0.01) and TR (1.9 ± 0.5 to 1.5 ± 0.7; P < 0.01) was observed. Likewise, RVSP decreased significantly from 46 ± 16 to 39 ± 15 mmHg (P < 0.01) and TAPSE non-significantly (21.9 ± 7.3 to 19.5 ± 5.5 mm; P = 0.07). After 3-6 months, 68.9% of the patients were at New York Heart Association (NYHA) Class I or II, 25% at Class III and 6.0% downgraded to Class IV. A reason for remaining in NYHA Class III or downgrading to NYHA Class IV could not be detected, and particularly, there was no impact of grade of MR/TR, left ventricular ejection fraction, TAPSE or right ventricular endsystolic pressure (RVESP) on outcomes or NYHA class. TA-TAVI in patients with concomitant moderate or more severe MR provides results comparable with those of TA-TAVI in general. Concomitant MR had no significant impact on the short- and mid-term outcomes. A significant reduction in MR, TR and pulmonary hypertension was observed after TA-TAVI during short-term follow-up. Nonetheless, a relevant number of patients did not experience an improvement in NYHA class.

Myocardial contractility indices based on strain imaging

Background The principal determinants of chronic left ventricular (LV) dysfunction are reduced myocardial contractility and afterload excess due to adverse LV remodeling. To determine the relative contribution of each to a given instance of LV dysfunction, reliable quantitative indices of both myocardial contractility and afterload are needed. At the LV chamber level, ventricular volume and LV pressure can be used in a ventricular elastance model. But at the myocardial level, afterload must be normalized per unit of myocardium, conventionally done using wall stress (WS) calculations, while myocardial function is best characterized as systolic myocardial deformation, or strain (ST). Prior experimental model studies have suggested that the ratio of strain to afterload may be an effective contractility index. However, this has not been evaluated in human disease. We have recently shown that a nongeometric LV end-systolic afterload index (NGI, = (end-systolic LV pressure(P) × volume (V))/LV mass(M), or PV/M), may be superior to conventional circumferential WS (CWS) as a quantitative measure of afterload at the myocardial level, and correlates more closely than CWS with circumferential ST(CST), Therefore, we evaluated the ratios CST/CWS and CST/PV/ M, as candidate contractility indices in normals(NL) and in patients with nonischemic dilated cardiomyopathy(CM).

Structural and functional alterations in the atrioventricular node and atrioventricular ring tissue in ischaemia-induced heart failure.

Heart failure (HF) causes dysfunction of the atrioventricular node (AVN) - first or second-degree heart block is a risk factor for sudden cardiac death in HF patients. The aim of the study was to determine if HF causes remodelling of the AVN and right atrioventricular ring (RAVR). HF was induced in rats (n=4) by ligation of the proximal left coronary artery, which resulted in a large infarct of the left ventricle. Sham-operated rats (n=4) were used as controls. Eight weeks after surgery, functional experiments were performed and the hearts were frozen. The body weight of HF rats was similar to control rats, but the mean heart weight of HF rats was significantly enlarged. In HF rats compared to controls, the left ventricle was dilated, left ventricular end-diastolic pressure elevated (21.0 ± 0.6 and 5.4 ± 0.2 mm Hg), left ventricular ejection fraction reduced (0.2 ± 0.02 and 0.5 ± 0.02) and left ventricular end-systolic pressure reduced (102 ± 4.2 and 127 ± 3.1 mm Hg). In HF rats, the in vivo and in vitro PR intervals were increased (41% and 20%), as was the Wenckebach cycle length, indicative of AVN dysfunction. The collagen content was significantly increased in the AVN and RAVR indicating fibrosis. Immunolabelling of caveolin3 (cell membrane marker) showed that there was hypertrophy in HF (cell diameter was increased by 63%, 39% in AVN, RAVR). The TUNEL assay showed that the myocytes of the AVN and RAVR in HF undergo apoptotic cell death. Immunolabelling showed that expression of HCN4 was significantly decreased in the AVN and RAVR (43% and 47%) in HF. We conclude that in HF there is remodelling of the AVN and RAVR and this remodelling may explain the AVN dysfunction.

Abstract 344: Periodic Acceleration (pGz) Improves Left Ventricular Function and Remodeling in Rats After Myocardial Infarction

BACKGROUND: Heart Failure (HF) post MI remains a important cause of mortality and morbidity Whole body periodic acceleration (pGz) is the repetitive motion of the supine body in a sinusoidal head to foot direction achieved with a motorized platform. pGz induces pulsatile shear stress on the vascular endothelium. Pulsatile shear stress activates endothelial nitric oxide synthase (eNOS) to produce increased release of nitric oxide (eNO). pGz pre-and postconditioning can induce cardioprotective affects in an in-vivo rat model of myocardial infarction (MI) reducing mortality, arrhythmias and infarct size. The effects of pGz on myocardial function and remodeling after MI are unknown. Left ventricular (LV) pressure-volume (PV) relationships are an invasive but comprehensive method to assess myocardial function. OBJECTIVE: We investigated the effects of pGz on LV function and remodeling induced by chronic MI in rats. Methods: After MI, rats (SD-300gms) were randomized to receive pGz (MI-pGz) (n=5) Control (MI-C) (n=5) for 4 weeks and a separate sham surgery group (n=5). In vivo LV pressure-volume relationships were analyzed using a conductance catheter (Millar Instruments, Texas). LV fibrosis was analyzed using trichrome staining and digital microscopy. RESULTS: pGz after MI reduced left ventricular fibrosis by 40% [MI-C 36( 4 )% vs MI-pGz 21(2)% (p &lt; 0.01) as a % of the LV]. There were no differences in heart rate between groups. pGz significantly improved ejection fraction (EF), left ventricular end systolic pressure (LVESP), dP/dtmax, and both end systolic (ESPVR) and diastolic (EDPVR) pressure volume relations (Table). Data: X(SD) * p&lt; 0.01 (Sham vs. MI-C) and † p&lt; 0.01 (MI-C vs MI-pGz) Conclusions: In a rat model HF induced by chronic MI, pGz markedly improved LV function. These findings have implications for cardiac rehabilitation post MI.

Abstract 18641: Relationship Between Effective Arterial Elastance and Specific Measures of Left Ventricular Afterload

Background: Effective arterial elastance (E A ), the ratio of left ventricular (LV) end-systolic pressure and stroke volume, was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. In conjunction with LV end-systolic elastance, it is used to assess combined “ventricular-arterial stiffening”. However, theoretical modeling studies indicate that E A is not prominently affected by arterial stiffness or pulsatile load. However, empirical data assessing the relationship between E A and specific measures of arterial load are not available. Methods: We used multiple linear regression to assess the relationship between E A and arterial load determined non-invasively from time-resolved central pressure-flow analyses performed at rest in a diverse clinical population of adults (n=133). We also investigated the sensitivity of E A to detect changes in pulsatile load induced by isometric handgrip exercise (n=72) and by the administration of 0.4 mg of sublingual nitroglycerin (n=30). Results: Measurements at rest demonstrated that Ea was essentially a function of SVR (standardized β=0.99; P &lt;0.0001), and heart rate (standardized β=0.18; P &lt;0.0001), without significant contributions from aortic characteristic impedance (standardized β=0.0001; P =0.98), total arterial compliance (standardized β=0.007; P =0.63) or reflection magnitude (β=0.02; P =0.20). Despite pronounced changes in indices of pulsatile load induced by isometric exercise and sublingual nitroglycerin, changes in E A were unrelated to changes in indices of pulsatile load in response to either intervention (all R 2 &lt;0.02). However, changes in Ea were essentially a linear function of the change in the SVR*heart rate product (isometric exercise R=0.98; nitroglycerin R=0.97; both P &lt;0.0001). Conclusions: Our empirical findings demonstrate, in agreement with modeling studies, that E A is essentially a function of resistive afterload and heart rate and is negligibly influenced by (and insensitive to) variations in pulsatile afterload. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.

Cardioprotective effects of adipokine apelin on myocardial infarction

Angiogenesis plays an important role in myocardial infarction. Apelin and its natural receptor (angiotensin II receptor-like 1, AGTRL-1 or APLNR) induce sprouting of endothelial cells in an autocrine or paracrine manner. The aim of this study is to investigate whether apelin can improve the cardiac function after myocardial infarction by increasing angiogenesis in infarcted myocardium. Left ventricular end-diastolic pressure (LVEDP), left ventricular end systolic pressure (LVESP), left ventricular developed pressure (LVDP), maximal left ventricular pressure development (±LVdp/dtmax), infarct size, and angiogenesis were evaluated to analyze the cardioprotective effects of apelin on ischemic myocardium. Assays of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, 5-bromo-2'-deoxyuridine incorporation, wound healing, transwells, and tube formation were used to detect the effects of apelin on proliferation, migration, and chemotaxis of cardiac microvascular endothelial cells. Fluorescein isothiocyanate-labeled bovine serum albumin penetrating through monolayered cardiac microvascular endothelial cells was measured to evaluate the effects of apelin on permeability of microvascular endothelial cells. In vivo results showed that apelin increased ±LV dp/dtmax and LVESP values, decreased LVEDP values (all p < 0.05), and promoted angiogenesis in rat heart after ligation of the left anterior descending coronary artery. In vitro results showed that apelin dose-dependently enhanced proliferation, migration, chemotaxis, and tube formation, but not permeability of cardiac microvascular endothelial cells. Apelin also increased the expression of vascular endothelial growth factor receptors-2 (VEGFR2) and the endothelium-specific receptor tyrosine kinase (Tie-2) in cardiac microvascular endothelial cells. These results indicated that apelin played a protective role in myocardial infarction through promoting angiogenesis and decreasing permeability of microvascular endothelial cells via upregulating the expression of VEGFR2 and Tie-2 in cardiac microvascular endothelial cells.

Myocardial protection by interferon-γ late preconditioning during cardiopulmonary bypass-associated myocardial ischemia-reperfusion in pigs

The impact of interferon-γ (IFN-γ) late preconditioning on myocardial ischemia-reperfusion injury during cardiopulmonary bypass (CPB) and the underlying mechanism were investigated. Using a porcine model of myocardial ischemia-reperfusion injury during CPB with a 60-min aorta cross-clamp, 20pigs (15±0.5kg) were treated randomly with either a 1-ml (20,000IU/kg) IFN-γ injection (IFN-γ group; n=10) or saline solution (control group; n=10) 24h prior to CPB. Heart rate, blood pressure, left ventricular end-systolic pressure (LVESP), left ventricular end-diastolic pressure (LVEDP), creatine kinase isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) were measured before CPB, before aortic clamping, and at post-reperfusion intervals of 10, 30, 60 and 120min. Heat shock protein 70 (HSP70), Mn-superoxide dismutase (Mn-SOD) and inducible nitric oxide synthase (iNOS) were measured by immunohistochemical staining in pre-CPB myocardial tissues. Myocardial cell apoptosis TUNEL measurement was assessed in samples obtained 60min following reperfusion. Both groups exhibited no statistical differences in age, weight, gender and preoperative cardiac function, and worsened left ventricular function, and hemodynamic index reductions, and significant cTnI and CK-MB leakage was observed 10 and 30min after reperfusion. At 10, 30 and 60min following reperfusion, ventricular function and leakage of the IFN-γ group were significantly improved, and expression of HSP70, iNOS and Mn-SOD increased and myocardial cell apoptosis decreased. IFN-γ late preconditioning exhibited preventative effects on myocardial tissues in pigs during CPB surgery, likely due to increased HSP70, Mn-SOD and iNOS expression.

Determinants of postoperative left ventricle dysfunction in patients with chronic asymptomatic severe mitral regurgitation due to myxomatous degeneration

Purpose: The evidence supporting early surgical intervention in patients with chronic asymptomatic mitral regurgitation (MR) is steadily accumulating. Although preoperative pulmonary hypertension and left ventricular (LV) enlargement are considered when deciding on surgery, the threshold above which they influence clinical outcomes remain poorly defined. Methods: One-hundred sixty eight asymptomatic patients of mean age 60.9±12.9 years underwent mitral valve repair of severe MR due to myxomatous degeneration between 2001 and 2012. Mean preoperative left atrial diameter, LV end-systolic diameter, and right ventricular systolic pressure were 48.2±7.6 mm, 34.7±7.4 mm, and 38.4±10.6 mm Hg, respectively. Preoperative LV ejection fraction was >60% in 137 (82%) and 24 (14%) had preoperative atrial fibrillation. Clinical and echocardiographic follow-up averaged 3.3 years, and extended to 9.1 years. Results: There were no perioperative deaths. Five-year survival and freedom from recurrent MR ≥2+ were 93.1±3.4% and 94.2±2.2%, respectively. A threshold preoperative right ventricular systolic pressure >45 mm Hg and (hazard ratio, HR, 3.55±1.65,p=0.007) and LV end-systolic pressure indexed to body surface area >19 mm/m2 (HR 3.63±1.99, p=0.02) were associated with postoperative LV dysfunction, defined as a LV ejection fraction <60%. Conclusion: Mitral valve repair can be performed with favorable early and late outcomes in patients with asymptomatic severe MR. The presence of preoperative pulmonary hypertension and minimal LV enlargement were associated with postoperative LV dysfunction in this otherwise healthy population. Mitral valve repair should be considered in asymptomatic patients with a preoperative right ventricular systolic pressure >45 mm Hg or an indexed LV end-systolic diameter >19mm/m2.

Abstract 059: N-acylhydrazone Derivative Improves Cardiac Hypertrophy and Dysfunction in Spontaneously Hypertensive Rats Submitted to Myocardial Infarction

Aims: Ventricular dysfunction is observed in arterial hypertension and myocardial infarction (MI). The N -acylhydrazone derivative, 3,4-methylenedioxybenzoyl-2-thienylhydrazone (LASSBio-294), which has been described as a potent cardiac inotropic agent with vasodilator properties, was orally administrated in spontaneously hypertensive rats (SHR) submitted to experimental MI. Methods and Results: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. Male SHR (12 - 14 week-old) were randomly divided in sham-operated (SHAM) and infarcted groups (MI) and were treated or not with LASSBio-294 (20 mg/kg p.o.) during 8 weeks. Under sevoflurane anesthesia, the animals were submitted to a ligature of the anterior descending coronary artery to produce the MI. After 8 weeks, rats were submitted to treadmill test and also, the following hemodynamic parameters were analyzed: left ventricular end diastolic pressure (LVEDP), left ventricular end-systolic pressure (LVESP) and LV contractility (dp/dt max ). Hypertrophy was measured using the relation between heart weight to body weight (heart/BW). The volume fraction of collagen (%) was determined by measuring the area of stained tissue within a given field by picrosirius red staining. The results are presented in the following table. Conclusions: Treatment of infarcted SHR with LASSBio-294 reduced intolerance to exercise, ventricular dysfunction, cardiac hypertrophy and fibrosis.