Biomedical subjects

Helen Kiriazis

Publications and source records attributed to Helen Kiriazis.

12 recordsLinked to original sources

PubMed2006

Transgenic alpha1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival.

OBJECTIVE: Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression of the alpha1A-adrenergic receptors (alpha1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). METHODS: We subjected alpha1A-TG and non-TG mice (NTG) to MI and determined changes in left ventricular (LV) function and diastolic dimension (LVDd) by echocardiography prior to and at 1, 3, 7, 12 and 15 weeks thereafter. RESULTS: Although infarct size was similar in the NTG and alpha1A-TG groups (32+/-2 vs. 29+/-2% of LV, P=NS), mortality due to heart failure was lower after MI in the alpha1A-TG (37%, n=39) than that in the NTG animals (63%, n=56, P=0.026). NTG and alpha1A-TG mice showed similar reductions in LV fractional shortening (FS) and increases in LVDd at week-1 after MI. However, whereas NTG mice showed continuous deterioration over a 15-week period after MI in FS (fell by 40%, from 30+/-2 to 18+/-1%, P<0.01) and LVDd (increased by 24%, from 4.2+/-0.1 to 5.2+/-0.1 mm, P<0.01), the changes in both FS (fell by 14%, from 42+/-2 to 36+/-2%) and LVDd (increased by 8%, from 3.8+/-0.1 to 4.1+/-0.1 mm, both changes P<0.01 vs. NTG) were significantly less severe in the alpha1A-TG mice and did not progress after 3 weeks. At 15 weeks after MI, LV catheterization revealed better preservation of dP/dtmax in the alpha1A-TG vs. NTG mice (7270+/-324, vs. 5938+/-372 mmHg/s, P<0.05). CONCLUSION: Enhanced inotropy resulting from transgenic overexpression of alpha1A-AR is well maintained chronically after MI and limits echocardiography-determined LV remodeling, preserves function, and reduces acute heart failure death.

Actins↗

PubMed2006

Sex dimorphism in cardiac pathophysiology: experimental findings, hormonal mechanisms, and molecular mechanisms.

The higher cardiovascular risk in men and post-menopausal women implies a protective action of estrogen. A large number of experimental studies have provided strong support to this concept. However, the recent clinical trials with negative outcomes regarding hormone replacement therapy call for "post hoc" reassessment of existing information, models, and research strategies as well as a summary of recent findings. Sex steroid hormones, in particular estrogen, regulate numerous processes that are related to the development and progression of cardiovascular disease through a variety of signaling pathways. Use of genetically modified models has resulted in interesting information on diverse actions mediated by steroid receptors. By focusing on experimental findings, we have reviewed hormonal, cellular, and signaling mechanisms responsible for sex dimorphism and actions of hormone replacement therapy and addressed current limitations and future directions of experimental research.

Animals↗

PubMed2006

Inhibition of mTOR reduces chronic pressure-overload cardiac hypertrophy and fibrosis.

BACKGROUND AND OBJECTIVE: Inhibition of established left ventricular hypertrophy (LVH) and fibrosis may bring clinical benefits by reducing cardiac morbidity and mortality. The mammalian target of rapamycin, mTOR, is known to play a critical role in determining cell and organ size. We investigated whether mTOR inhibition can inhibit the chronic pressure-overload-induced LVH and fibrosis. METHODS: Male FVB/N mice underwent transverse aortic constriction (TAC) for 5 weeks to allow for establishment of LVH, followed by treatment with the mTOR inhibitor, Rapamune (2 mg/kg per day, gavage), for 4 weeks. Echocardiography was used to monitor changes in LVH and function. Haemodynamic, morphometric, histological and molecular analyses were conducted. RESULTS: Inhibition of mTOR by Rapamune was confirmed by a suppression of activated phosphorylation of ribosomal S6 protein and eukaryotic translation initiation factor-4E due to pressure overload. Despite a comparable degree of pressure overload between the vehicle- or Rapamune-treated TAC groups, Rapamune treatment for 4 weeks attenuated TAC-induced LVH by 46%, estimated by LV weight or myocyte size, and LV fractional shortening was also preserved versus vehicle-treated control (39 +/- 1 versus 32 +/- 2%, P < 0.05). Inhibition of established LVH by Rapamune was associated with a 38% reduction in collagen content. Moreover, altered gene expression due to pressure overload was largely restored. CONCLUSION: Despite sustained pressure overload, inhibition of mTOR by a 4-week period of Rapamune treatment attenuates chronically established LVH and cardiac fibrosis with preserved contractile function.

Analysis of Variance↗

PubMed2005

Relaxin reverses cardiac and renal fibrosis in spontaneously hypertensive rats.

The antifibrotic effects of the peptide hormone relaxin on cardiac and renal fibrosis were studied in 9- to 10-month-old male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Rats (n=8 to 9 per group) were allocated into 3 groups: WKY controls, vehicle-treated SHR (SHR-V), and relaxin-treated SHR (SHR-R). Relaxin (0.5 mg/kg per day) was administered via subcutaneously implanted osmotic mini-pumps over 2 weeks before hearts and kidneys were harvested for analysis. Collagen content was analyzed by hydroxyproline assay, gel electrophoresis, and quantitative histology. Zymography was used to determine matrix metalloproteinase (MMP) expression and Western blotting to determine proliferating cell nuclear antigen (PCNA) expression and alpha-smooth muscle actin (alpha-SMA)/myofibroblast expression, whereas cardiac hypertrophy was assessed by myocyte size and real-time polymerase chain reaction of associated genes. The left ventricular (LV) myocardium of SHR-V contained increased collagen levels (by 25+/-1%, P<0.01 using biochemical analysis and 3-fold; P<0.01 using quantitative histology), enhanced expression of PCNA (by 70+/-8%; P<0.01), alpha-SMA (by 32+/-2%; P<0.05), and the collagen-degrading enzyme MMP-9 (by 70+/-6%; P<0.05) versus respective levels measured in WKY controls. The kidneys of SHR-V also contained increased collagen (25+/-2%, P<0.05 using biochemical analysis and 2.4-fold; P<0.01 using quantitative histology). Relaxin treatment significantly normalized collagen content in the LV (P<0.01) and kidney (P<0.05), completely inhibited cell proliferation (P<0.01) and fibroblast differentiation (P<0.05) in the LV, and increased MMP-2 expression (by 25+/-1%; P<0.05) without affecting MMP-9 in the LV compared with that measured in SHR-V. Thus, relaxin is a potent antifibrotic hormone with a rapid-occurring efficacy that may have therapeutic potential for hypertensive disease.

Animals↗

PubMed2005

Preserved left ventricular structure and function in mice with cardiac sympathetic hyperinnervation.

Cardiac-specific overexpression of nerve growth factor (NGF), a neurotrophin, leads to sympathetic hyperinnervation of heart. As a consequence, adverse functional changes that occur after chronically enhanced sympathoadrenergic stimulation of heart might develop in this model. However, NGF also facilitates synaptic transmission and norepinephrine uptake, effects that would be expected to restrain such deleterious outcomes. To test this, we examined 5- to 6-mo-old transgenic (TG) mice that overexpress NGF in heart and their wild-type (WT) littermates using echocardiography, invasive catheterization, histology, and catecholamine assays. In TG mice, hypertrophy of the right ventricle was evident (+67%), but the left ventricle was only mildly affected (+17%). Left ventricular (LV) fractional shortening and fractional area change values as indicated by echocardiography were similar between the two groups. Catheterization experiments revealed that LV +/-dP/dt values were comparable between TG and WT mice and responded similarly upon isoproterenol stimulation, which indicates lack of beta-adrenergic receptor dysfunction. Although norepinephrine levels in TG LV tissue were approximately twofold those of WT tissue, TG plasma levels of the neuronal norepinephrine metabolite dihydroxyphenylglycol were fivefold those of WT plasma. A greater neuronal uptake activity was also observed in TG LV tissue. In conclusion, overexpression of NGF in heart leads to sympathetic hyperinnervation that is not associated with detrimental effects on LV performance and is likely due to concomitantly enhanced norepinephrine neuronal uptake.

Adrenergic beta-Agonists↗

PubMed2005

Mouse model of post-infarct ventricular rupture: time course, strain- and gender-dependency, tensile strength, and histopathology.

OBJECTIVE: Recent studies on mice with surgically induced acute myocardial infarction (AMI) have documented the frequent occurrence of ventricular rupture, an event not previously reported in other laboratory species. We have examined the natural history, histopathology and myocardial mechanical strength in mice with AMI. METHODS: AMI was induced by coronary artery occlusion and animals were monitored for fatal events. Gross and histological examinations were undertaken. RESULTS: Rupture occurred in the left ventricular free wall at 2-6 days after AMI. Incidence of rupture in male mice varied among three strains studied (3% for FVB/N, 27% for C57B/6J, and 59% for 129sv, P<0.05) and was lower in female than male mice (23% vs. 59%, P<0.05). Histologically, ruptured hearts had rapid-occurring and severe infarct expansion, multifocal intramural hemorrhage and leucoyte infiltration at the border zone and infarcted zone. In vitro, infarcted left ventricles demonstrated a 50-60% reduction in muscle tensile strength. This reduction preceded the onset of rupture and was related to the time-window of rupture and to infarct size. CONCLUSION: LV wall rupture in the mouse occurs within a narrow time-window after AMI and is strain- and gender-dependent. Infarct expansion, regional hemorrhage with formation of hematoma and leuocyte accumulation are important pathological changes leading to reduced myocardial tensile strength.

Animals↗

PubMed2005

Regression of pressure overload-induced left ventricular hypertrophy in mice.

As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of alpha-myosin heavy chain and sarcoplasmic reticulum Ca(2+)-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct time course. The extent of LVH regression was dependent on the duration of pressure overload, evidenced by the fact that restoration of LV structure and function was complete in animals subjected to 4 wk of aortic banding but incomplete in animals subjected to 8 wk of aortic banding. In conclusion, LVH regression comprises a variety of morphological, functional, and genetic components that show distinct time courses. A longer period of pressure overload is associated with a slower rate of LVH regression.

Animals↗

PubMed2004

I(f) channel inhibitor ivabradine lowers heart rate in mice with enhanced sympathoadrenergic activities.

1. Ivabradine selectively reduces heart rate (HR) by inhibiting the cardiac pacemaker I(f) current, thus prolonging the duration of spontaneous depolarization in the sinus node. The activity of ivabradine under conditions of enhanced sympathoadrenergic activity has been addressed by investigating the effects of repeated oral administration in mice with sympathoadrenergic activation due to either stress, cardiac-restricted overexpression of beta(2)-adrenergic receptors (beta(2)AR), or beta-agonist administration. HR and left ventricular fractional shortening (FS) were determined by echocardiography. 2. Initial experiments showed that the conscious restrained state was associated with stress-mediated sympathetic activation, while sympathetic withdrawal occurred under anaesthetized conditions. In wild-type mice, ivabradine reduced HR under both conscious and anaesthetized states, with a similar degree in absolute reduction under both states. FS was unchanged by the treatment. 3. Ivabradine was similarly effective in reducing HR in the beta(2)AR transgenic mice. Further, ivabradine at 10 mg kg(-1) day(-1) reduced the maximal HR increase in response to the beta-agonist isoproterenol, without modifying the response of contractile parameters. 4. These data indicate that oral administration of ivabradine in mice reduces HR while ventricular performance is maintained. This specific HR-reducing action of ivabradine is well preserved under conditions that are associated with significant activation of the sympathoadrenergic system.

Animals↗

PubMed2004

Genetic enhancement of ventricular contractility protects against pressure-overload-induced cardiac dysfunction.

In response to pressure-overload, cardiac function deteriorates and may even progress to fulminant heart failure and death. Here we questioned if genetic enhancement of left ventricular (LV) contractility protects against pressure-overload. Transgenic (TG) mice with cardiac-restricted overexpression (66-fold) of the alpha(1A)-adrenergic receptor (alpha(1A)-AR) and their non-TG (NTG) littermates, were subjected to transverse aorta constriction (TAC)-induced pressure-overload for 12 weeks. TAC-induced hypertrophy was similar in the NTG and TG mice but the TG mice were less likely to die of heart failure compared to the non-TG animals (P <0.05). The hypercontractile phenotype of the TG mice was maintained over the 12-week period following TAC with LV fractional shortening being significantly greater than in the NTG mice (42+/-2 vs 29+/-1%, P <0.01). In the TG animals, 11-week beta-AR-blockade with atenolol neither induced hypertrophy nor suppressed the hypercontractile phenotype. The hypertrophic response to pressure-overload was not altered by cardiac alpha(1A)-AR overexpression. Moreover, the inotropic phenotype of alpha(1A)-AR overexpression was well maintained under conditions of pressure overload. Although the functional decline in contractility with pressure overload was similar in the TG and NTG animals, given that contractility was higher before TAC in the TG mice, their LV function was better preserved and heart failure deaths were fewer after induction of pressure overload.

Actins↗

PubMed2003

Assessment of cardiac function by echocardiography in conscious and anesthetized mice: importance of the autonomic nervous system and disease state.

In this study, the authors sought to evaluate the mechanisms responsible for echocardiographically determined differences in cardiac structure and function between conscious and anesthetized mice to determine whether such differences were more or less evident in diseased states. Cardiac parameters were determined by transthoracic echocardiography. Mice anesthetized with a mixture of ketamine and xylazine showed reductions in heart rate (HR, 252 +/- 16 beats/min versus 734 +/- 9 beats/min) and fractional shortening (FS, 35% +/- 2% versus 59% +/- 2%) compared with conscious mice. Conscious mice responded little to the beta-agonist isoproterenol or atropine, but showed profound reductions in HR and FS in response to the beta(1)-antagonist atenolol. In contrast, both isoproterenol and atropine led to increases in HR and FS in anesthetized mice. The stress in conscious animals was reduced by the sedative midazolam, leading to partial restoration of responses to isoproterenol. Mice with constitutive activation of the beta-adrenergic system, due to cardiac overexpression of beta(2)-adrenergic receptors or with heart disease (myocardial infarct and pressure-overload hypertrophy) showed few differences in functional parameters between conscious and anesthetized states, attributable to pre-existing activation of the sympathetic and beta-adrenergic systems, even during anesthesia. The results indicate that the autonomic nervous system plays a critical role in the observed differences in cardiac structure and function between anesthetized and conscious mice.

Anesthetics↗

PubMed2003

Compensated hypertrophy of cardiac ventricles in aged transgenic FVB/N mice overexpressing calsequestrin.

Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed contractile parameters and hypertrophy in transgenic mice. To determine the long-term consequences of calsequestrin overexpression, the cardiac phenotype of young (2-3-months old) and aged (17 months old) transgenic FVB/N mice was characterized. Ventricular/body weight ratios, which were increased in young transgenics compared with wild-types, were unaltered with age. Left atria of aged transgenics exhibited enlargement and mineralization, but their ventricles did not display fibrosis, mineralization and other injuries. Although echocardiography suggested a time-dependent change in ventricular geometry and loading conditions in vivo, as well as an age-dependent reduction of left ventricular fractional shortening in transgenic mice, Langendorff-perfused hearts of young and aged transgenics indicated that there were no age-related reductions of contractile parameters (+/-dP/dt). Furthermore, neither genotype nor age altered lung/body weight ratios. Thus, our findings suggest that left ventricular performance in calsequestrin overexpressing mice becomes apparently depressed with age, but this depression is not associated with progressive reduction of left ventricular contractility and heart failure.

Aging↗

PubMed2002

Hypertrophy and functional alterations in hyperdynamic phospholamban-knockout mouse hearts under chronic aortic stenosis.

OBJECTIVE: To determine whether the hyperdynamic phospholamban-knockout hearts are capable of withstanding a chronic aortic stenosis. METHODS: The transverse section of the aorta was banded in phospholamban-knockout and their isogenic wild-type mice, which were followed with echocardiography in parallel, along with sham-operated mice, before and at 2.5, 5 and 10 weeks after surgery. RESULTS: Cardiac decompensation was evidenced by the presence of lung congestion in some banded knockouts and wild-types, giving rise to a subset of non-failing and failing hearts within each group. The incidence of heart failure was not genotype-dependent but rather associated with higher heart rates before surgery. The development of left ventricular hypertrophy was similar between knockouts and wild-types and longitudinal assessment of end-diastolic dimension indicated progressive increases after banding, with a greater dilation in failing mice. Fractional shortening was reduced in failing knockouts and wild-types to a similar degree, with an earlier onset in the knockouts. In addition, fractional shortening was decreased in non-failing knockouts but not wild-types. Ejection times shortened after aortic banding particularly for failing hearts. Assessment of the SR Ca(2+)-ATPase protein levels indicated similar downregulation for failing knockouts and wild-types, while the phospholamban levels were not significantly altered in wild-types. CONCLUSION: The hyperdynamic phospholamban-knockout hearts are able to compensate against a sustained aortic stenosis similar to wild-types.

Animals↗