Changes In Heart Function Research Articles

P 10: Enhancement of antioxidant defence against oxidative stress by timolol-treatment prevents age-/diabetes-related cardiac dysfunction via recovery of intracellular Ca2+ handling

Objectives We investigated whether defective intracellular Ca2+ handling can be controlled by timolol in age- as well as in diabetes-related cardiac dysfunction. Background It has been shown that the defects observed in mechanical activity of heart from both aging and diabetic subjects include alteration of intracellular Ca2+ handling via changes in critical processes responsible for its regulation, in part due to increased oxidative stress. Furthermore, increasing evidence shows a marked beneficial effect with beta-blockers, additional to their blocker actions, in the heart dysfunction via scavenging free radicals and/or acting as an antioxidant. Methods To explore the antioxidant role of chronic timolol treatment (25 mg/kg, daily, 12 weeks) on either age- or diabetes-related changes in heart function, we used Langendorff-perfused rat hearts to determine hemodynamic parameters, patch-clamp technique to monitor L-type Ca2+-current (ICaL), and confocal microscopy to study intracellular both global Ca2+ transients evoked by electrical stimulation and local Ca2+ changes (sparks) in quiescent cardiomyocytes loaded with fluorescence Ca2+ dye fluo-3AM. Results Normal cardiac function was well preserved in timololtreated either diabetic or 12-month old rats compared to their age-matched controls. Moreover, our data strongly point out that this reverse remodeling is associated with normalization of the diastolic Ca2+, rynodine receptor Ca2+ release channel (RyR2) macromolecular complex, ICaL function, unbalanced oxidant/antioxidant-defence system as well as cellular redox state both in circulation and in heart. The antioxidant N-acetyl-L-cysteine showed an effect similar to that of timolol. Conclusion Timolol, at a low concentration that is sufficient to produce antioxidant effect, improves the intracellular Ca2+ handling and contractile dysfunction by preventing the protein-thiol oxidation in leaky-RyR2 from both aged and diabetic rat hearts.

Abstract 10: Antifibrotic Effect of CCN5 in a Murine Model of Heart Failure

CCN family members are matricellular proteins with diverse roles in cell function. Recently, we showed that the differential expression of CCN2 and CCN5 during cardiac remodeling suggests that these two members of the CCN family play opposing roles during the development of cardiac hypertrophy and fibrosis. Since it is reported that an underlying morphological correlate of diastolic dysfunction is cardiac fibrosis, which leads to increased stiffness of the heart, we aimed to evaluate the role of CCN5 on cardiac fibrosis and function by the gene delivery using the cardiotropic AAV9 vector. We generated pressure-overload heart failure models in mouse by TAC operation. After 8-10 weeks of TAC on mice, HF was confirmed by Echocardiography. In those HF mice, AAV9-GFP (control) and AAV9-CCN5 were addressed by IV. Two more months later, cardiac function was evaluated by echocardiography and invasive hemodynamics. Protein and RNA expression levels of CCN5, several types of collagen and conventional TGF-beta signaling related genes were evaluated by western blot and quantitative real time PCR analysis. First, we were able to achieve about 4-5 fold increase of CCN5 expression by AAV9-CCN5 injection without any change in heart function. Second, CCN5 expression level in blood was not significantly altered after AAV9-CCN5 gene transfer because it may be the result of the cardiac tropism of the vector used. The HF model by TAC surgery was confirmed with echocardiography (FS (%)). Overall average FS (%) in HF was 41.87+/− 5.27 (n=16) and in non-surgery control mice was 58.39 +/− 2.06(n=4). After AAV9 injection, cardiac function of CCN5 injected mice was sustained but AAV9-GFP injected mice showed severe cardiac dysfunction and dilation (AAV-GFP (24.29+/− 9.11) vs AAV-CCN5 (42.66 +/− 4.73)). Third, western blot analysis showed that the downstream effectors, namely TGF-beta signaling pathways were significantly down-regulated in CCN5 injected mice. In addition, fibrotic area of the heart was tremendously reduced. Finally, CCN5 expression is significantly decreased in human heart failure patients compared to those in nonfailing donors. Taken together our data would indicate that CCN5 may be a promising therapeutic target to reduce cardiac fibrosis.

Abstract 68: Role of Substance P Signaling in the Pathogenesis of Murine Viral Myocarditis

Viral myocarditis is an important cause of heart failure in adolescents and young adults for which no specific treatment is currently available. Substance P (SP) is a neuropeptide and pain transmitter that activates RhoA, a small G-protein, shown to induce hypertrophy of neonatal rat ventricular myocytes. The current studies were performed to determine if SP signaling contributes to the pathogenesis of encephalomyocarditis virus (EMCV) infection, a well-established murine model of viral myocarditis. Aprepitant (1.2 mg/kg), a SP receptor antagonist, or fasudil (10mg/kg), a Rho A inhibitor, or saline control, was administered daily to mice orally by gavage 3 times for 3 days prior to intraperitoneal infection with 50 PFU of EMCV, and the mice monitored for 14 days. Pretreatment with aprepitant reduced mortality by 40% (25±7% vs. 65±7%), reduced heart-to-body weight ratio by 26% (0.0088±0.0001 vs. 0.0119±0.0001), reduced end systolic diameter (ESD) by 21% (3.0±0.2mm vs. 3.8±0.4mm), improved ejection fraction by 72% (57.2±4.7% vs. 33.2 ±9.3%), reduced chamber volume by 46% (34±5.0 μl vs. 62.7±30.8 μl), increased peak aortic flow velocity by 41% (87.0±24.7 vs. 61.7±20.1), and reduced cardiomyocyte diameter size by13% (11.0±0.1 μM vs. 12.7± 0.2 μM); p<.05 for all, Student’s t-test). Pretreatment with fasudil reduced heart-to-body weight ratio by 18% (0.0097±0.0001 vs. 0.0119±0.0001) and reduced cardiomyocyte diameter size by 12% (11.14±0.51 μM vs. 12.7± 0.2 μM; p<.05 for both), but did not significantly impact heart functional changes or mortality. These findings indicate that SP contributes to cardiac remodeling and dysfunction following ECMV infection and raises the possibility that inhibition of SP signaling may be of benefit in the treatment of patients with viral myocarditis.

Antihypertensive Role of Tissue Kallikrein in Hyperaldosteronism in the Mouse

Tissue kallikrein (TK) is synthesized in arteries and distal renal tubule, the main target of aldosterone. Urinary kallikrein excretion increases in hyperaldosteronism. We tested the hypothesis that TK is involved in the cardiovascular and renal effects of high aldosterone. Kallikrein-deficient mice (TK-/-), and wild-type (WT) littermates, studied on two different genetic backgrounds, were treated with aldosterone and high-NaCl diet for 1 month. Control mice received vehicle and standard NaCl diet. Treatment induced 5- to 7-fold increase in plasma aldosterone, suppressed renin secretion, and increased urinary TK activity. In 129SvJ-C57BL/6J mice, blood pressure monitored by radiotelemetry was not different between control TK-/- and WT mice. In TK-/- mice, aldosterone induced larger increases in blood pressure than in WT mice (+47 vs. +27 mm Hg; genotype-treatment interaction, P < 0.05). Night-day difference was also exacerbated in treated TK-/- mice (P < 0.01). Moderate cardiac septal hypertrophy was observed in hypertensive animals without major change in heart function. Aldosterone-salt increased kidney weight similarly in both genotypes but induced a 2-fold increase in renal mRNA abundance of epithelial sodium channel subunits only in TK-/- mice. The hypertensive effect of TK deficiency was also documented in treated C57BL/6J mice. In this strain, aldosterone-induced hypertension was only observed in TK-/- mice (+16 mm Hg, P < 0.01). These findings show that TK deficiency exacerbates aldosterone-salt-induced hypertension. This effect may be due at least in part to enhanced sodium reabsorption in the distal nephron aggravating sodium retention. The study suggests that kallikrein plays an antihypertensive role in hyperaldosteronism.

Hypothyroidism: age-related influence on cardiovascular nitric oxide system in rats

This study investigates whether changes in nitric oxide (NO) production participate in the cardiovascular manifestations of hypothyroidism and whether these changes are age-related. Sprague–Dawley rats aged 2 and 18 months old were treated with 0.02% methimazole (wt/vol) during 28 days. Left ventricular function was evaluated by echocardiography. Measurements of arterial blood pressure, heart rate, nitric oxide synthase (NOS) activity and NOS/caveolin-1 and -3 protein levels were performed. Hypothyroidism enhanced the age-related changes in heart function. Hypothyroid state decreased atrial NOS activity in both young and adult rats, associated with a reduction in protein levels of the three NOS isoforms in young animals and increased caveolin (cav) 1 expression in adult rats. Ventricle and aorta NOS activity increased in young and adult hypothyroid animals. In ventricle, changes in NOS activity were accompanied by an increase in inducible NOS isoform in young rats and by an increase in caveolins expression in adult rats. Greater aorta NOS activity level in young and in adult Hypo rats would derive from the inducible and the endothelial NOS isoform, respectively. Thyroid hormones would be one of the factors involved in the modulation of cardiovascular NO production and caveolin-1 and -3 tissue-specific abundance, regardless of age. Hypothyroidism appears to contribute in a differential way to aging-induced changes in the myocardium and aorta tissues. Low thyroid hormones levels would enhance the aging effect on the heart. Age-related changes in NO production participate in the cardiovascular manifestations of hypothyroidism.

Optical coherence tomography captures rapid hemodynamic responses to acute hypoxia in the cardiovascular system of early embryos

The trajectory to heart defects may start in tubular and looping heart stages when detailed analysis of form and function is difficult by currently available methods. We used a novel method, Doppler optical coherence tomography (OCT), to follow changes in cardiovascular function in quail embryos during acute hypoxic stress. Chronic fetal hypoxia is a known risk factor for congenital heart diseases (CHDs). Decreased fetal heart rates during maternal obstructive sleep apnea suggest that studying fetal heart responses under acute hypoxia is warranted. We captured responses to hypoxia at the critical looping heart stages. Doppler OCT revealed detailed vitelline arterial pulsed Doppler waveforms. Embryos tolerated 1 hr of hypoxia (5%, 10%, or 15% O(2) ), but exhibited changes including decreased systolic and increased diastolic duration in 5 min. After 5 min, slower heart rates, arrhythmic events and an increase in retrograde blood flow were observed. These changes suggested slower filling of the heart, which was confirmed by four-dimensional Doppler imaging of the heart itself. Doppler OCT is well suited for rapid noninvasive screening for functional changes in avian embryos under near physiological conditions. Analysis of the accessible vitelline artery sensitively reflected changes in heart function and can be used for rapid screening. Acute hypoxia caused rapid hemodynamic changes in looping hearts and may be a concern for increased CHD risk.

Ventricular myocyte contraction, intracellular calcium and expression of genes encoding cardiac muscle proteins in young and ageing Zucker diabetic fatty rat heart

Diabetes mellitus and its complications is a serious global health problem and the total number of people with this disease is projected to rise from 171 million in 2000 to 366 million in 2030. A recent study among Emirati citizens reported age-standardized rates for diabetes mellitus (diagnosed and undiagnosed) and pre-diabetes in those 30–64 years old as 29.0% and 24.2%, respectively. The association between type 2 diabetes mellitus and obesity is very strong and cardiovascular disease is the leading cause of morbidity and mortality among diabetic patients. The changes in ventricular myocyte contraction, intracellular calcium and the expression of genes encoding cardiac muscle proteins that take place in young (9–13 weeks) and ageing (30–34 weeks) Zucker diabetic fatty (ZDF) rat heart have been reviewed. Diabetes mellitus was associated with a fourfold elevation in non-fasting blood glucose in young and ageing ZDF rat compared with age-matched Zucker lean controls. Amplitude of shortening was unaltered in myocytes from young and ageing ZDF rats. Time to peak and time to half relaxation of shortening was prolonged in myocytes from young ZDF rats and was unaltered in myocytes from ageing ZDF rats compared with controls. Amplitude of the Ca2+ transient was unaltered in myocytes from young and ageing ZDF rats. Time to peak Ca2+ transient was prolonged in myocytes from young and ageing ZDF rats. L-type Ca2+ current was significantly reduced in myocytes from young and ageing ZDF rats. Sarcoplasmic reticulum Ca2+ transport did not appear to be altered in myocytes from young or ageing ZDF rats. Expression of genes encoding L-type Ca2+ channel proteins, plasma membrane transporters, sarcoplasmic reticulum Ca2+ and regulatory proteins and cardiac muscle proteins were variously up-regulated, down-regulated or unaltered in ventricles from young and ageing ZDF rats. Up-regulated genes in young ZDF rat heart included CACNA1C, CACNA1G, CACNA1H, ATP1A1 and MYH7, whereas down-regulated genes in young ZDF rat heart included ATP1B1, SLC9A1, ATP2A2, CALM1, MYH6, MYL2, ACTC1, TNNI3, TNNT2 and TNNC1. Up-regulated genes in ageing ZDF rat heart included CACNA1G, CACNA1H, ATP2A1 and MYL2, whereas down-regulated genes in ageing ZDF rat heart included CACNA2D3, SLC9A1, ATP2A2, MYH6 and TNNT2. Subtle changes in expression of genes encoding various cardiac muscle proteins may underlie functional changes in hearts of young and ageing ZDF rats compared with age-matched controls.

Is There any Time Dependant Echocardiographical Finding in Chronic Hemodialysis Patients?

BackgroundCardiac disease is the main cause of death in hemodialysis patients. In hemodialysis patients cardiovascular complications are great clinical challenge, and function, shape and left ventricle abnormalities are present in 70 - 80 percent of dialysis patients. Changes in heart function occur in hemodialysis period and are effective in patient’s prognosis. In this study we aim to evaluate time dependant clinical and echocardiographical findings in chronic hemodialysis patients.MethodsIn a cross-sectional study, 100 adult hemodialysis patients (51% male and 49% female with mean age 52.13 ± 12.69 years) visiting dialysis unit in Imam Reza and Madani hospitals between years 2010 and 2011 were studied in group 1 (hemodialysis ≤ 6 months), group 2 (hemodialysis for 6 months to 3 years) and group 3 (hemodialysis ≥ 3 years). Demographic, laboratory and echocardiographic findings were compared between groups.ResultsAmong demographic findings, group 3 had significantly higher diastolic blood pressure and weight gain and was older than other two groups (P < 0.05). By increase in hemodialysis period, patients had higher blood urea nitrogen and lower serum albumin levels (P < 0.05). Potassium level in group 2 was significantly higher than group 3 and that was higher than group 1. There was no difference between groups in left ventricular hypertrophy (LVH), left atrium dilatation, ejection fraction and mitral insufficiency. Diastolic dysfunction increased in line with increase in hemodialysis period (P = 0.007). Hemodialysis period was higher in patients with LVH than those without (34.80 ± 9.2 months versus 18.51 ± 2.22 months, P = 0.01).ConclusionIn hemodialysis patients, diastolic dysfunction increases by the hemodialysis time (years). LVH and LA dilation also increase during time, but not significantly.

Reversal of Cardiac Remodeling and Subcellular Defects by Prazosin in Heart Failure Due to Myocardial Infarction

Background: This study was undertaken to test if α-Adrenoceptor (AR) blockade with prazosin reverses cardiac remodeling and ameliorates subcellular defects in heart failure due to Myocardial Infarction (MI). Methods: Heart failure in rats was induced by MI for 12 wks and then treated with or without prazosin (10 mg/kg/ day) for 8 wks. Both control and experimental animals were assessed hemodynamically and echocardiographically for evaluating changes in heart function and cardiac remodeling, respectively. Left Ventricle (LV) was used for determining biomedical and molecular activities. Results: Cardiac dysfunction, as evident from depressed LV systolic pressure, rates of changes in pressure development and decay, cardiac output, ejection fraction and fractional shortening as well as increased LV end diastolic pressure, in 20 wks infarcted animals, was corrected partially by prazosin treatment. Different parameters of cardiac remodeling including increased LV posterior wall thickness and LV systolic diameter in failing hearts were fully or partially reversed whereas increased LV diastolic diameter was unaltered by prazosin therapy. Reversal of lung congestion and cardiac hypertrophy in MI animals by prazosin was associated with depression in the elevated levels of plasma norepinephrine, unlike epinephrine or dopamine. Depressions in Sarcoplasmic Reticular (SR) Ca2+-uptake activity as well as protein content for Ca2+-pump ATPase and phospholamban in failing hearts were reversed partially whereas depressed SR Ca2+-release activity and myofibrillar Ca2+-stimulated ATPase activity were not affected by prazosin. Alterations in mRNA levels for SR Ca2+-pump ATPase, SR Ca2+-release channels, and α-myosin heavy chain and β-myosin heavy chain in MI-induced heart failure were not influenced by prazosin treatment. Conclusions: It is suggested that the activation of α-AR system may be associated with cardiac remodeling and heart failure and the reverse cardiac remodeling by α-AR blockade may improve cardiac performance by attenuating defects in SR Ca2+-pump.

Frequency dependent effect of selective biphasic left vagus nerve stimulation on heart rate and arterial pressure

Activation of the parasympathetic pathway leads to negative chronotropic, dromotropic, and inotropic changes of heart function. The ability to selectively stimulate certain superficial compartments of peripheral nerves has been demonstrated previously. The aim of the present study was to find a clinically acceptable selective biphasic vagus nerve stimulation technique, which could allow gradual regulation of heart rate and systemic arterial pressure. In two patients, the left vagus nerve was stimulated with a combination of quasi-trapezoidal cathodic and rectangular anodic current pulses with different stimulation frequencies (10Hz, 20Hz, 30Hz) and increasing current. The heart rate and systemic arterial pressure decreased with increasing current at all different stimulation frequencies (p<0.05). The heart rate and arterial pressure response was more gradual with 10Hz compared to 20Hz/30Hz vagus nerve stimulation (p<0.05). In conclusion, selective vagus nerve stimulation, with a combination of quasi-trapezoidal cathodic and rectangular anodic current pulses at 10Hz, offers gradual heart rate and systolic arterial pressure control.

Cardioprotective effect of propranolol on diabetes-induced altered intracellular Ca2+ signaling in rat

We have previously shown that chronic treatment with propranolol had beneficial effects on heart function in rats during increasing-age in a gender-dependent manner. Herein, we hypothesize that propranolol would improve cardiac function in diabetic cardiomyopathy and investigated the benefits of chronic oral administration of propranolol on the parameters of Ca(2+) signaling in the heart of streptozotocin-diabetic rats. Male diabetic rats received propranolol (25 mg/kg, daily) for 12 weeks, 1 week after diabetes induction. Treatment of the diabetic rats with propranolol did not produce a hypoglycaemic effect whereas it attenuated the increased cell size. Basal and β-agonist response levels of left ventricular developed pressure were significantly higher in propranolol-treated diabetic rats relative to untreated diabetics while left ventricular end diastolic pressure of the treated diabetics was comparable to the controls. Propranolol treatment normalized also the prolongation of the action potential in papillary muscles from the diabetic rat hearts. This treatment attenuated the parameters of Ca(2+) transients, depressed Ca(2+) loading of the sarcoplasmic reticulum, and of the basal intracellular Ca(2+) level of diabetic cardiomyocytes. Furthermore, Western blot data indicated that the diabetes-induced alterations in the cardiac ryanodine receptor Ca(2+) release channel's hyperphosphorylation decreased the FKBP12.6 protein level. Also, the high phosphorylated levels of PKA and CaMKII were prevented with propranolol treatment. Chronic treatment with propranolol seems to prevent diabetes-related changes in heart function by controlling intracellular Ca(2+) signaling and preventing the development of left ventricular remodeling in diabetic cardiomyopathy.

Effects of fistular onion bulb extract on ischemia/reperfusion injury in cardiomyocytes of streptozotocin-induced diabetes mullitus rats

ObjectiveTo investigate effects of fistular onion bulb extract (FOB) preventing ischemia/reperfusion (I/R) injury in cardiomyocytes of streptozotocin-induced diabetes mellitus rats.MethodsDiabetes rats by streptozotocin-induced were fed FOB (100 g/kg/day) from six...

Brain natriuretic peptide: a marker of cardiac dysfunction with ventricular or dual-chamber pacing

Background/Objectives The inability of trials to exhibit the superiority in survival of atrioventricular compared to ventricular pacing can be partially explained by the apical stimulation of the right ventricle, which adversely aff ects both short- and long-term ventricular performance. We evaluated the impact of pacing mode (DDDR vs VVIR) on the brain natriuretic peptide (BNP) level in patients with sick-sinus syndrome (SSS).Methods Sixty-seven patients were treated with DDDR pacemaker implantation due to SSS. They were randomized during the fi rst post-implant day either to DDDR or VVIR pacing mode and were reevaluated after 30 days. Group A comprised 35 patients on DDDR pacing mode and group B 32 patients on VVIR pacing mode. Peripheral blood samples were drawn for BNP measurement at the time of randomization and one month later.Results BNP levels increased signifi cantly in both groups at 30 days (group A: 85.6 ± 29.5 pg/ml to 107.2 ± 34.6 pg/ml, group B: 82.7 ± 27.6 pg/ml to 253.1 ± 60.2 pg/ml). On day 30, BNP levels in group B were signifi cantly higher than in group A (P < 0.0001).Conclusions Pacing from the apex of the right ventricle provokes an increase in the BNP levels regardless of the pacing mode. BNP is probably a very early marker predicting the structural and/or functional heart changes after long-term pacing from the apex of the right ventricle.

Changes in cardiac heparan sulfate proteoglycan expression and streptozotocin-induced diastolic dysfunction in rats

BackgroundChanges in the proteoglycans glypican and syndecan-4 have been reported in several pathological conditions, but little is known about their expression in the heart during diabetes. The aim of this study was to investigate in vivo heart function changes and alterations in mRNA expression and protein levels of glypican-1 and syndecan-4 in cardiac and skeletal muscles during streptozotocin (STZ)-induced diabetes.MethodsDiabetes was induced in male Wistar rats by STZ administration. The rats were assigned to one of the following groups: control (sham injection), after 24 hours, 10 days, or 30 days of STZ administration. Echocardiography was performed in the control and STZ 10-day groups. Western and Northern blots were used to quantify protein and mRNA levels in all groups. Immunohistochemistry was performed in the control and 30-day groups to correlate the observed mRNA changes to the protein expression.ResultsIn vivo cardiac functional analysis performed using echocardiography in the 10-day group showed diastolic dysfunction with alterations in the peak velocity of early (E) diastolic filling and isovolumic relaxation time (IVRT) indices. These functional alterations observed in the STZ 10-day group correlated with the concomitant increase in syndecan-4 and glypican-1 protein expression. Cardiac glypican-1 mRNA and skeletal syndecan-4 mRNA and protein levels increased in the STZ 30-day group. On the other hand, the amount of glypican in skeletal muscle was lower than that in the control group. The same results were obtained from immunohistochemistry analysis.ConclusionOur data suggest that membrane proteoglycans participate in the sequence of events triggered by diabetes and inflicted on cardiac and skeletal muscles.

Clinical study of left ventricular global systolic function in patients with hypertension by three-dimensional ultrasound speckle tracking imaging

Objective To assess left ventricular (LV) global systolic function in patients with essential hypertension with normal geometric LV by 3-dimensional ultrasound speckle tracking imaging(3D-STI). Methods Fifty patients with essential hypertension were enrolled in this study, 29 normal subjects matched with age and sex were selected as control groups. LV global longitudinal peak systolic strain (GLS), radial peak systolic strain (GRS), circumferential peak systolic strain (GCS), LV global 3-dimentional radial peak systolic strain (3DGRS) were measured in all subjects by 3D-STI from the apical full-volume image and compared between groups. LV ejection fraction (LVEF) was acquired from 3D-STI.Results Compared with controls, LV GLS, GRS, GCS and 3DGRS were significantly reduced in patients with hypertension ( P ＜ 0.05 for all). A Pearson correlate revealed that LV GCS, GLS and GRS corresponded with LVEF( r1 =0.930, P1 ＜0.001; r2 = 0.705, P2 ＜0.001; r3 =0.474, P3 =0.001,respectively) in patients with hypertension, and LV GCS, GLS correlated with LVEF( r1 = 0. 838, P1 ＜0. 001; r2 = 0. 697, P2 ＜ 0. 001, respectively) in normal subjects. Conclusions LV global 3D strain decreases in patients with hypertension in the early period,3D-STI could evaluate the early change of heart function in patients with hypertension. LV circumferential movement plays a major role in the LV 3D movement and impacts on LVEF. Key words: Echocardiography,three-dimensional; Hypertension; Ventricular function,left; Speckle tracking imaging

Age-Related Changes in Heart Function by Serial Echocardiography in Women Aged 40–80 Years

To determine if a defined set of echocardiographic parameters at entry and exit of a longitudinal study over 5 years showed changes with aging. The cohort consisted of 484 randomly recruited women aged 40-80. They were examined by two echocardiography cardiologists, independent of the medical information for these women. Across the age decades (40-49, 50-59, 60-69, 70-79 years), body weight and body surface area (BSA) did not vary, and diastolic blood pressure (DBP) was stable; systolic blood pressure (SBP) progressively increased. There was gradual decline in left ventricular (LV) diastolic function, increase in LV muscle mass, and decrease in LV end-diastolic volume (LVEDV). The serial decrease in rate of change over 5 years in ejection fraction (ET) was small but significant across the four age decades. As expected, there were age-related changes in cardiac structure and function over time in women who showed no apparent cardiovascular disease (CVD) at entry to the study. The direction of these serial changes was toward the development of LV stiffness and likelihood of subsequent heart failure. The clinical significance of the decrease in rate of change in EF remains unclear.

Role of Phosphoinositide 3-kinase Signaling in Cardiac Aging

Background: Age is a major risk factor for cardiovascular disease. One reason for this is likely to be that an advance age increases the chance of exposure to cardiovascular risk factors. However, age-associated intrinsic changes to the cardiovascular system may also compromise the cardiovascular reserve capacity and decrease the threshold for primary diseases to manifest. It is also possible that the age-associated changes serve as a basis of primary diseases. Although age-associated morphological and functional changes of heart have been well characterized, the mechanism of cardiac aging is still not clear. Methods and Results: We analyzed age-associated changes in murine heart, and how suppression of the p110α isoform of phosphoinositide 3-kinase (PI3K) activity modified cardiac aging. Cardiac function declined in old mice associated with the expression of senescence markers. Accumulation of ubiqutinated protein and lipofuscin, as well as a comprehensive gene expression profiling, indicated that dysregulation of protein quality control was a characteristic of cardiac aging. Inhibition of PI3K preserved cardiac function and attenuated expression of the senescence markers associated with enhanced autophagy. Suppression of target of rapamycin, a downstream effector of PI3K, also prevented lipofuscin accumulation in the heart. Conclusion: Suppression of PI3K prevented many of age-associated changes in heart and preserved cardiac function of aged mice.

Evaluation of myocardial systolic function of heart failure induced by myocardial infarction in rats with strain and strain rate imagine

To quantitatively detect variation in regional myocardial systolic function in heart failure rat model induced by myocardial infarction by strain and strain rate imaging. Seventy 2-month-old adult male SD rats were randomly assigned to 4 groups: a 4-week and a 8-week group after the operation (each n = 25) had thoracotomy, the pericardium opened and the anterior descending branch of left coronary artery ligated; a sham operation group (n = 10) had thoracotomy and the arcula cordis opened, but did not ligate the artery; a control group (n = 10) had no treatment. The changes of general state of health of the rats were observed and recorded every day. To assess the change of heart function, echocardiography was used at the end of the 4th week and 8th week after the surgery. To evaluate the change of heart function in heart failure rats, we quantitatively analyzed the regional myocardial systolic function in all rats by strain and strain rate imaging and myocardium to detect the level of MMP-9 at the end of the 4th week and 8th week. The repeatability and discrepancies of the results were all analyzed. Obviously objective signs of heart failure manifested themselves in the survived mice 10 to 14 days after the surgery. Compared with the control group and the sham operation group, the fraction shortening (FS) and ejection fraction (EF) of the 4-week group after the operation were lower (P < 0.05), the left ventricle index (LV index) of the 8-week group after the operation was higher, left ventricle posterior wall index (LVPW index), interventricular septum index (IVS index), FS, and EF of the 8-week group after the operation were lower (P < 0.05), EF and FS of the 8-week group after the operation were lower than those of the 4-week group. Except the mid-inferior wall and base-inferior wall, the systolic peak strain, systolic peak strain rate, the strain of end-systole in all segments of the operation group were lower than those of the other 2 groups (P < 0.05). The post-systolic strain index of the operation group was higher than that of the other 2 groups (P < 0.05). Strain and strain rate imaging of echocardiography can quantitatively evaluate the changing of regional myocardial systolic function in the heart failure rat model induced by myocardial infarction, with good repeatability.

Control of sympathetic activity--new insights; new therapeutic targets?

Recently, a large international group of 25 investigators identified a candidate gene for hypertension which codes for phosducin (Pdc) as a novel player in the sympathetic nervous system [1]. In their study, a wide spectrum of findings documented its so-far unrecognized and apparently important role in experimental and human stress-induced hypertension. This conclusion is based on data ranging from detailed analyses of the sympathetic system in genetically manipulated Pdc �/� (knock-out) mice to the demonstration of its relevance in humans: in two separate cohorts, French Canadian and Afro-American individuals, respectively, a correlation was documented between singlenucleotide polymorphisms (SNPs) in the Pdc gene and stress-dependent blood pressure reactions. The target gene identified by the investigators codes for the G-protein regulator phosducin. In mice, targeted Pdc deletion increased blood pressure, increased catecholamine turnover in the peripheral sympathetic system and prolonged action potential firing. This finding suggests that Pdc is a hypotensive principle, explaining why reduced function of Pdc amplifies the hypertensive reaction to stressors. In other words: Pdc puts a brake on sympathetic activity, and conversely Pdc malfunction will lead to hypertension. What is the site of action of Pdc? The Pdc gene and the Pdc protein are expressed in sympathetic ganglia, although to a much lower extent than in the retina and pineal gland, but not in heart, blood vessels and kidney, important players in blood pressure control. To identify the site of action, experimental manipulations sequentially excluded changes in heart function, vascular function or function of the central nervous system as candidates. Early in life, cardiac morphology was not altered in Pdc�/�mice,butleftventricularcontractilitywasincreased despite no change of sensitivity to adrenoceptor agonists (norepinephrine, dobutamine)—consistent with increased sympathetic nerve traffic. In older animals (>4 months), however, significant hypertrophy was seen with expression of fetal genes as evidence of target organ injury.

Ultrasound Evaluation of Cardiac Function Following Administration of Sedatives in Horses

We studied using ultrasound investigation the changes of heart function parameters as a result of acepromazine and xylazine administration in 9 adult horses, mixed breed. Comparing with control group (unsedated horses) acepromazine induced RVFWs statistically increase (p<0,05). Acepromazine also determined statistically decrease of LVIDd (p<0,05) resulting a decrease of Vd (p<0.01). Xylazine induced decrease of LVFWd (p<0.01) and increase of Vd (p<0.5). Acepromazine did not induce statistically significant changes on other parameters: RVFWd, RVIDs, RVIDd, IVSs, IVSd, LVIDs, LVFWs and LVFWd. Comparing with control group, xylazine determined same results, and did not influence RVFWs, LVIDd, Vs and Vd, so, acepromazine and xylazine did not induce any statistically changes of SF% and EF %.