Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “pressure overload”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 109 records · Page 6Linked to original sources
PubMed1985

Increased right ventricular wall thickness in left ventricular pressure overload: echocardiographic determination of hypertrophic response of the "nonstressed" ventricle.

Left ventricular hypertrophy in left ventricular pressure overload occurs in response to excessive work load imposed on the left ventricle by increased impedance to ejection. Right ventricular hypertrophy may occur in patients with these findings, but has been considered to be secondary to pulmonary hypertension. To determine the frequency of right ventricular hypertrophy and its relation to increased left ventricular wall thickness in patients with left ventricular pressure overload, right ventricular wall thickness was measured using M-mode echocardiography with two-dimensional echocardiographic guidance in 65 patients with left ventricular pressure overload; 49 patients had essential hypertension and 16 had aortic valve stenosis. These measurements were compared with data from 13 patients with "thin-walled" dilated cardiomyopathy and 20 normal subjects. Average right ventricular wall thickness in hypertensive patients (7 +/- 2 mm) and patients with aortic stenosis (6 +/- 2 mm) was significantly greater than that in normal subjects (4 +/- 1 mm) and patients with dilated cardiomyopathy (4 +/- 1 mm) who had normal left ventricular wall thickness, even though left ventricular mass was increased in all patient groups. Increased right ventricular wall thickness was present in 40 (80%) of 49 patients with hypertension and 10 (63%) of 16 patients with aortic stenosis. The magnitude of increase in right ventricular wall thickness was linearly correlated (r = 0.76, p less than 0.005) with left ventricular wall thickness, but was not associated with pulmonary hypertension. It is concluded that increased right ventricular wall thickness is common in patients with left ventricular pressure overload, is directly related to increases in left ventricular wall thickness, and is independent of right ventricular hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed2000

Ventricular adrenomedullin concentration is a sensitive biochemical marker for volume and pressure overload in rats.

This study was designed to investigate the pathophysiological significance of adrenomedullin (AM) concentration in volume- and pressure-overloaded cardiac hypertrophy. We measured ventricular AM concentrations and compared them with changes of alpha-actin and myosin heavy chain (MHC) mRNA isoforms after the creation of an aortocaval (AC) shunt as a volume-overload model or the injection of monocrotaline (MCT) as a pressure-overload model, respectively. The left ventricular AM levels after the creation of AC shunt and the right ventricular AM levels after the injection of MCT were significantly increased and correlated with changes of the alpha-actin and MHC mRNA isoforms. However, the ventricular AM mRNA expressions were increased and correlated with ventricular AM concentrations only in the AC shunt model. These results suggest that the ventricular AM levels are upregulated in both the volume- and pressure-overloaded cardiac hypertrophy by differential transcriptional regulation and that the ventricular AM may be a biochemical marker for the volume and pressure overload to the ventricle.

Adrenomedullin↗
PubMed1997

Identification of a cis-acting regulatory element conferring inducibility of the atrial natriuretic factor gene in acute pressure overload.

To identify the cis-acting regulatory element(s) which control the induction of the atrial natriuretic factor (ANF) gene in acute pressure overload, DNA constructs consisting of promoter elements linked to a reporter gene were injected into the myocardium of dogs, which underwent aortic banding or were sham-operated. Expression of a reporter gene construct harboring the ANF promoter (-3400ANF) was induced 6-12-fold after 7 d of pressure overload. An internal deletion of 556 bp (nucleotide sequence -693 to -137) completely abrogated the inducibility of the ANF reporter gene construct. An activator protein-1 (AP1)-like site (-496 to -489) and a cAMP regulatory element (CRE) (-602 to -596) are located within the deleted sequence. Site-directed mutagenesis of the AP1-like site but not the CRE completely prevented the induction of this construct to acute pressure overload. Further, the AP1-like site was able to confer inducibility of a heterologous promoter (beta-myosin heavy chain) to higher values than controls. Gel mobility shift assay (GMSA) supershift analysis was performed using a radiolabeled probe of the ANF promoter (-506/-483) that included the AP1-like site (ATGAATCA) sequence, as well as a probe converted to contain an AP1 consensus sequence (ATGACTCA). GMSA analysis demonstrated that the ANF AP1-like element could bind both a constitutively expressed factor and the AP1 proteins, and conversion to a true AP1 site increased its affinity for AP1. However, 7 d after the onset of pressure overload, the AP1 proteins were present only at low levels, and the major complex formed by the ANF AP1-like probe was not supershifted by a jun antibody. Using a large animal model of pressure overload, we have demonstrated that a unique cis-acting element was primarily responsible for the overload induction of the ANF gene.

Animals↗
PubMed1993

Left ventricular pressure overload during postnatal development. Effects on coronary vasodilator reserve and tolerance to hypothermic global ischemia.

The effect of pressure overload during postnatal development on (1) coronary reserve and (2) tolerance to cardioplegic arrest and hypothermic ischemia was investigated. Left ventricular pressure overload was induced in 1-week-old rats by aortic constriction (group AC), with control rats (group C) undergoing sham operation. Relative to group C rats, left ventricular weight/body weight ratio in group AC increased by 50% to 80% at 3 weeks of age and by 100% to 120% at 6 weeks of age. At these ages, hearts were isolated from group C and AC rats and Langendorff-perfused with bicarbonate buffer at perfusion pressures of 75 and 110 mm Hg, respectively. In the first study, minimal coronary vascular resistance was assessed during perfusion with adenosine (10 mumol/L). There was no difference in total minimal coronary vascular resistance between groups C and AC at 3 weeks of age. Total minimal coronary vascular resistance decreased with increasing cardiac mass between 3 and 6 weeks of age in group C (from 6.9 +/- 0.4 to 4.5 +/- 0.2 mm Hg/ml/min, p < 0.05), but not in group AC. Between these ages, minimal coronary vascular resistance per unit heart weight increased to a greater extent in group AC (from 2.9 +/- 0.2 to 7.0 +/- 0.3 mm Hg/ml/min/gm, p < 0.05) than in group C (from 1.8 +/- 0.0 to 2.7 +/- 0.1 mm Hg/ml/min/gm, p < 0.05). In the second study, hearts were arrested with St. Thomas' Hospital cardioplegic solution (15 degrees C) and subjected to hypothermic (15 degrees C) global ischemia (210 minutes at 3 weeks and 180 minutes at 6 weeks) followed by 65 minutes of reperfusion. At 3 weeks of age, coronary resistance profiles, changes in left ventricular end-diastolic pressure, and recoveries of left ventricular developed pressure during reperfusion were similar in groups C and AC. At 6 weeks of age, however, group AC had greater coronary resistance during reperfusion, a greater increase in left ventricular end-diastolic pressure (28 +/- 5 versus 1 +/- 1 mm Hg, p < 0.05), and consequently a reduced recovery of left ventricular developed pressure (50.7% +/- 3.6% versus 75.9% +/- 4.0%, p < 0.05) relative to group C. Thus 2 weeks of left ventricular pressure overload during neonatal development in the rat has little effect on coronary reserve and ischemic tolerance. Prolonged (5 weeks) pressure overload, however, results in postischemic diastolic dysfunction, which may be due to perfusion abnormalities during reperfusion.

Animals↗
PubMed1993

Rapid expression of the Na(+)-Ca2+ exchanger in response to cardiac pressure overload.

This report identifies a rapid increase in the expression of cardiac Na(+)-Ca2+ exchanger mRNA in response to an acute pressure overload. This enhanced exchanger expression appeared within 1 h after the onset of right ventricular pressure overload in the cat and was sustained during cardiac overloading for at least 4 h. Maintenance of this right ventricular pressure overload for 48 h evoked an increase in the production of exchanger protein. Because of our previous finding that load imposition on the heart initiates cell growth and our hypothesis that this is in response to the enhanced entry of cellular cations, we then examined the effect of Na+ influx into cultured adult cardiac myocytes, or cardiocytes, in terms of early anabolic responses. Pressure overload of the heart and cardiocyte Na+ influx were found to produce a common, rapid result in terms of both enhanced Na(+)-Ca2+ exchanger expression and accelerated synthesis of general and contractile proteins, the hallmarks of cardiac hypertrophy.

Animals↗
PubMed1997

cAMP-mediated c-fos expression in pressure-overloaded acceleration of protein synthesis in adult rat heart.

OBJECTIVES: The aim was to determine whether proto-oncogene c-fos expression and acceleration of protein synthesis by acute pressure overload to the heart were coupled with a cAMP- and protein-kinase-A-dependent system in adult rat heart. METHODS: Isolated adult rat hearts were perfused as Langendorff preparations at a constant aortic pressure of 60 mmHg. In the pressure-overloaded group, aortic pressure was raised from 60 to 120 mmHg for the time indicated. Agents that increase cAMP were added to the perfusate at an aortic pressure of 60 mmHg. Furthermore, a selective protein kinase A inhibitor (H-89) or a selective protein kinase C inhibitor (calphostin C) was administered before the elevation of aortic pressure or the addition of the agents. cAMP content or rates of protein synthesis were measured by RIA or the incorporation of [14C]phenylalanine into total heart protein, respectively. c-fos mRNA expression was determined by Northern blot analysis. RESULTS: Elevation of aortic pressure in beating hearts and arrested hearts increased cAMP content at 2 min of perfusion by 36 and 41%, induced c-fos mRNA expression at 30-60 min of perfusion by 4.8- and 2.0-fold, and accelerated rates of protein synthesis during the 2nd hour of perfusion by 39 and 41% over control levels, respectively. Glucagon, forskolin or IBMX mimicked increases in these parameters by elevated aortic pressure. H-89 prevented these changes by elevated pressure overload or exposure to forskolin or IBMX in arrested hearts. On the other hand, calphostin C prevented the pressure-induced increases in c-fos expression and protein synthesis rates in arrested hearts. CONCLUSIONS: These results suggest that c-fos expression induced by acute pressure overload may be coupled with increased cAMP content and protein kinase A activity in addition to increased protein kinase C activity in adult rat heart.

1-Methyl-3-isobutylxanthine↗
PubMed1996

Cardiac sympathetic neuronal function in left ventricular volume and pressure overload.

OBJECTIVES: In heart failure cardiac sympathetic neuronal function and activity appear to be altered. Although these changes are widely accepted, controversy exists concerning the neurohormonal changes occurring in pressure and volume overloaded hearts. The present study in rabbits was performed to assess the effects of mechanical overload on cardiac sympathetic neuronal function and beta-adrenoceptor density, in relation to left ventricular function. METHODS: In nine rabbits the aortic valve was perforated to induce left ventricular volume overload. Pressure overload was induced by suprarenal banding of the aorta abdominalis (group 1). Five animals were sham operated (group 2). Subanalysis of group 1 was performed for non-failing (n = 5) and failing (n = 4) hearts. Heart failure was defined as any reduction in left ventricular fractional shortening 2 weeks after the second operation compared to baseline. RESULTS: In animals with cardiac overload, left ventricular weight was higher compared with the control animals, 7.99 +/- 1.13 vs. 6.16 +/- 0.86 g (P < 0.02). Left ventricular end diastolic diameter increased from 1.35 +/- 0.16 to 1.57 +/- 0.15 cm (P < 0.005) after surgically induced overload. Left ventricular end systolic diameter and fractional shortening did not change significantly. Myocardial noradrenaline (NA) concentration and beta-adrenoceptor density were significantly lower in group 1 than in group 2, 1005 +/- 393 vs. 1643 +/- 109 ng/g (P < 0.02) and 167 +/- 36 vs. 224 +/- 36 fmol/mg protein (P < 0.03), respectively. Myocardial [123I]-MIBG uptake did not significantly differ between group 1 and 2, 2.1 +/- 0.58 vs. 1.8 +/- 0.44 (%ID/g x kg). A significant positive correlation between myocardial NA concentration and beta-adrenoceptor density was found (r = 0.66, P < 0.02). Myocardial NA concentration was inversely related to left ventricular weight (r =-0.75, P < 0.003). CONCLUSION: The present data indicate that in a condition of cardiac volume and pressure overload, sympathetic activity is enhanced as shown by myocardial noradrenaline depletion and beta-adrenoceptor downregulation. In contrast, no cardiac neuronal dysfunction is observed, even in the stage of early heart failure.

3-Iodobenzylguanidine↗
PubMed1995

Endothelin-1 and its binding sites are upregulated in pressure overload cardiac hypertrophy.

The purpose of this study was to determine whether endothelin and endothelin receptors play an important role in the development of cardiac hypertrophy due to pressure overload in vivo. Cardiac hypertrophy was produced by placing a constricting clip around the suprarenal abdominal aorta of rats. Hemodynamic parameters and plasma and ventricular concentrations of endothelin-1 (ET-1) were measured in control unoperated rats, and 30 min, 2 and 6 h, and 1 and 8 days after operation in pressure overload rats and sham-operated rats. The density and dissociation constant of ET-1 binding sites were also measured in control rats and 1 and 8 days after pressure overload and sham operation. Additionally, in situ mRNA hybridization for preproendothelin-1 (preproET-1) mRNA was performed to determine which cells were responsible for increased ET-1 levels. Ventricular ET-1 levels increased markedly on day 8 of pressure overload, whereas plasma ET-1 levels increased transiently only 30 min after operation, quickly returning to control level. In addition, ventricular ET-1 levels on day 8 showed a significant positive correlation with the degree of cardiac hypertrophy. In situ mRNA hybridization revealed that cardiac myocytes expressed preproET-1 mRNA in hypertrophied hearts in vivo. In accord with the elevation of ventricular ET-1 levels, the density of ET-1 binding sites was increased significantly, without affecting their binding affinity, on day 8 of pressure overload. These data are compatible with the hypothesis that increases in locally produced ET-1 and the density of ET-1 binding sites have an important relationship with the development of cardiac hypertrophy in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

Involvement of the nicotinamide adenosine dinucleotide phosphate oxidase isoform Nox2 in cardiac contractile dysfunction occurring in response to pressure overload.

OBJECTIVES: This study sought to examine the role of Nox2 in the contractile dysfunction associated with pressure-overload left ventricular hypertrophy (LVH). BACKGROUND: Reactive oxygen species (ROS) production is implicated in the pathophysiology of LVH. The nicotinamide adenosine dinucleotide phosphate oxidase isoform, Nox2, is pivotally involved in angiotensin II-induced hypertrophy but is not essential for development of pressure-overload LVH. Its possible impact on contractile function is unknown. METHODS: The effects of aortic banding or sham surgery on cardiac contractile function and interstitial fibrosis were compared in adult Nox2-/- and matched wild-type (WT) mice. RESULTS: Banding induced similar increases in left ventricular (LV) mass in both groups. Banded Nox2-/- mice had better LV function than WT by echocardiography (e.g., fractional shortening 33.6 +/- 2.5% vs. 21.4 +/- 2.2%, p < 0.05). Comprehensive LV pressure-volume analyses also showed significant contractile dysfunction in banded WT compared with sham, whereas banded Nox2-/- mice had preserved function (e.g., maximum rate of rise of LV pressure: banded WT, 4,879 +/- 213; vs. banded Nox2-/-, 5,913 +/- 259 mm Hg/s; p < 0.05). Similar preservation of function was observed in isolated cardiomyocytes. The 24-h to 36-h treatment of banded WT mice with N-acetylcysteine resulted in recovery of contractile function. Cardiac interstitial fibrosis was significantly increased in banded WT but not Nox2-/- mice, together with greater increases in procollagen I and III mRNA expression. CONCLUSIONS: The Nox2 oxidase contributes to the development of cardiac contractile dysfunction and interstitial fibrosis during pressure overload, although it is not essential for development of morphologic hypertrophy per se. These data suggest divergent downstream effects of Nox2 on different components of the overall response to pressure overload.

Acetylcysteine↗
PubMed1993

Effect of hypertrophy induced by pressure overload or volume overload on reperfusion induced arrhythmias in anaesthetised rats.

OBJECTIVE: The aim was to determine the effect of myocardial hypertrophy on the incidence and severity of arrhythmias following reperfusion after experimental coronary artery occlusion, and to establish if the effect differed between pressure overload hypertrophy and volume overload hypertrophy. METHODS: The experiments were performed in rats. Pressure overload hypertrophy was induced by aortic banding, and volume overload hypertrophy by perforation of the aortic valve. Four weeks after surgery, coronary artery occlusion and reperfusion experiments were performed. RESULTS: Both pressure and volume overloaded hearts exhibited a similar degree of left ventricular hypertrophy of about 45% weight gain compared to control animals. The total number of ventricular premature beats during reperfusion was not significantly increased in either model of hypertrophy. In contrast to volume overload, the incidence of reperfusion induced ventricular fibrillation was significantly increased in pressure overloaded hearts. Furthermore, there was a significant correlation between number of ventricular premature beats and degree of left ventricular hypertrophy, as well as between duration of ventricular tachycardia and degree of hypertrophy in the pressure overloaded group. Such correlations were not observed in hypertrophy due to volume overload. Neither volume nor pressure overload hypertrophy significantly increased mortality from ventricular fibrillation. CONCLUSIONS: An increase in cardiac mass per se does not necessarily aggravate reperfusion arrhythmias. The susceptibility to arrhythmias in this model seems to be critically dependent on the nature of the stimulus triggering left ventricular hypertrophy.

Animals↗
PubMed1991

Effect of age on coronary circulation after imposition of pressure-overload in rats.

We examined the effects of pressure overload on coronary circulation in young adult (7 months old) and old rats (18 months old). Four weeks after the ascending aorta was banded, in vivo left ventricular pressure was measured to estimate the degree of pressure load. In the two age groups, similar increases in peak left ventricular pressure were observed (113 +/- 7 mm Hg in sham-operated rats versus 160 +/- 11 mm Hg in banded rats of the young adult group; 103 +/- 7 mm Hg in sham-operated rats versus 156 +/- 11 mm Hg in banded rats of the old group). After isolating the hearts, they were perfused with Tyrode's solution containing bovine red blood cells and albumin. Resting coronary perfusion pressure-flow relations and reactive hyperemic response after a 40-second ischemia were obtained under beating but nonworking conditions. In young adult banded rats, significant myocardial hypertrophy was observed at the organ level (124% of controls in left ventricular dry weight/body weight ratio; 119% in left ventricular dry weight/tibial length ratio) and at the cell level. Minimal coronary vascular resistance obtained by the perfusion pressure-peak flow relation during reactive hyperemia increased to 150% of controls, and coronary flow reserve decreased significantly. In contrast, myocardial hypertrophy was not observed at the organ or cell level in old banded rats. However, minimal coronary vascular resistance increased, and flow reserve decreased significantly. Thus, pressure overload with coronary arterial hypertension caused abnormalities of the coronary circulation in old subjects even in the absence of myocardial hypertrophy.

Aging↗
PubMedDate not supplied

The activation pattern of the antioxidant enzymes in the right ventricle of rat in response to pressure overload is of heart failure type.

In the left ventricle subjected to pressure overload activity, the antioxidant enzymes increased at the hyperfunctional stage. During the transition to heart failure, these enzymes are down-regulated, oxidative stress increases, and apoptosis progresses. Maladaptative activation of the antioxidant enzymes at an early stage may contribute to the intrinsic vulnerability of right ventricle to pressure overload. The authors studied changes in expression and activity of the enzymes manganese and copper-zinc superoxide dismutases, glutathione peroxidase, and catalase in the right ventricle of rat following induction of pulmonary hypertension by injection of monocrotaline. Increase in the manganese superoxide dismutase was delayed to the late failing stage, activity of glutathione peroxidase was depressed throughout, and only catalase was activated at the early stage before returning to control levels. This inability to activate antioxidant enzymes may contribute to the deleterious consequences of pressure overload on right ventricle systolic function.

Animals↗
PubMed2006

Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle in hamsters with chronic pressure overload induced by ascending aortic stenosis.

Cardiac remodeling and angiotensin II-forming enzyme activity of the left ventricle on chronic pressure overload were studied in male Syrian hamsters, whose chymase activity is similar to that of dogs. Pressure overload was achieved by banding at the ascending aorta (aortic stenosis). Echocardiography, histological analysis, and analysis of cardiac angiotensin-converting enzyme and chymase-like activities were performed. At 10 weeks after banding, concentric hypertrophy of the left ventricle was evident. At 20 weeks after banding, the ventricular weight-to-body ratio, cardiac fibrosis, and cardiac chymase-like activity were significantly increased, while cardiac angiotensin-converting enzyme activity was significantly decreased. This suggests that cardiac chymase, compared with cardiac angiotensin-converting enzyme, was activated against the chronic pressure overload and was responsible for the cardiac remodeling through the formation of angiotensin II. Considering the utility of the rodents, the interspecies similarity of the Ang II-forming pathway, and the effect of chymase in the hamsters, the present model is considered useful for studies evaluating the effect of Ang II and chymase in the canine heart with chronic pressure overload.

Angiotensin II↗
PubMed2000

Effects of indapamide in rats with pressure overload left ventricular hypertrophy.

We studied the in vivo effects of the antihypertensive diuretic agent indapamide on left ventricular (LV) morphology in chronically pressure-overloaded rat hearts. LV pressure and subsequently LV mass were increased by banding the ascending aorta over a period of 6 weeks. Thereafter, animals were treated with low-dose (1 mg/kg/day, n = 9) or high-dose (10 mg/kg/day, n = 9) indapamide for another 6 weeks. Low-dose indapamide treatment reduced LV weights as compared with vehicle-treated controls (n = 9; -12%; p = 0.008). Furthermore, low-dose indapamide treatment resulted in a decrease of myocyte volume (59.0 +/- 10.6 vs. 79.0 +/- 9.8 m3 x 10(-27); p < 0.05) and an improvement of molecular markers of hypertrophy: a reduction of LV atrial natriuretic factor mRNA expression (-37%; p < 0.05), and an increase of the V1/V3 myosin ratio (+121%; p < 0.05). Low-dose indapamide also reduced significantly plasma (-65%) and LV angiotensin-converting enzyme (ACE) activities (-74%) as well as LV mRNA levels (-24%). These changes were observed despite continued pressure overload of the LV and despite a lack of significant changes in sodium excretion with the prolonged administration of low-dose indapamide. High-dose indapamide treatment showed no significant effects on LV mass, structure, and gene expression. Furthermore, high-dose indapamide increased plasma renin activity substantially, whereas low-dose treatment was without effect on circulating renin. In conclusion, in rats with continuous LV pressure-overload low-dose treatment with indapamide leads to mild regression of cardiac hypertrophy, accompanied by a downregulation of components of the cardiac renin-angiotensin system. These effects may be mediated by mechanisms apart from the known diuretic and antihypertensive actions of indapamide, because sodium excretion and blood pressure were stable with long-term treatment and are unlikely to be related to LVH regression in this model.

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↗
PubMed1997

Cytoskeletal mechanics in pressure-overload cardiac hypertrophy.

We have shown that the cellular contractile dysfunction characteristic of pressure-overload cardiac hypertrophy results not from an abnormality intrinsic to the myofilament portion of the cardiocyte cytoskeleton but rather from an increased density of the microtubule component of the extramyofilament portion of the cardiocyte cytoskeleton. To determine how, in physical terms, this increased microtubule density mechanically overloads the contractile apparatus at the cellular level, we measured cytoskeletal stiffness and apparent viscosity in isolated cardiocytes via magnetic twisting cytometry, a technique by which magnetically induced force is applied directly to the cytoskeleton through integrin-coupled ferromagnetic beads coated with Arg-Gly-Asp (RGD) peptide. Measurements were made in two groups of cardiocytes from cats with right ventricular (RV) hypertrophy induced by pulmonary artery banding: (1) those from the pressure-overloaded RV and (2) those from the normally loaded same-animal control left ventricle (LV). Cytoskeletal stiffness increased almost twofold, from 8.53 +/- 0.77 dyne/cm2 in the normally loaded LV cardiocytes to 16.46 +/- 1.32 dyne/cm2 in the hypertrophied RV cardiocytes. Cytoskeletal apparent viscosity increased almost fourfold, from 20.97 +/- 1.92 poise in the normally loaded LV cardiocytes to 87.85 +/- 6.95 poise in the hypertrophied RV cardiocytes. In addition to these baseline data showing differing stiffness and, especially, apparent viscosity in the two groups of cardiocytes, microtubule depolymerization by colchicine was found to return both the stiffness and the apparent viscosity of the pressure overload-hypertrophied RV cells fully to normal. Conversely, microtubule hyperpolymerization by taxol increased the stiffness and apparent viscosity values of normally loaded LV cardiocytes to the abnormal values given above for pressure-hypertrophied RV cardiocytes. Thus, increased microtubule density constitutes primarily a viscous load on the cardiocyte contractile apparatus in pressure-overload cardiac hypertrophy.

Animals↗
PubMed2006

A cell-permeable NFAT inhibitor peptide prevents pressure-overload cardiac hypertrophy.

The activation of the calcineurin-nuclear factor of activated T cells cascade during the development of pressure-overload cardiac hypertrophy has been previously reported in a number of studies. In addition, numerous pharmacological studies involving calcineurin inhibitors such as FK506 and cyclosporine A have now demonstrated that these agents can prevent such hypertrophic responses in the heart. However, little is known regarding the roles of the calcineurin downstream effector--nuclear factor of activated T cells. Our present study has further examined the roles of nuclear factor of activated T cells in pressure-overload cardiac hypertrophy by employing a recently developed cell-permeable nuclear factor of activated T cells inhibitor peptide. Rat hearts were subjected to pressure overload attributable by 4 weeks of aortic banding, and then treated with this cell-permeable nuclear factor of activated T cells inhibitor peptide and a control peptide. Treatment with the inhibitor was found to significantly decrease the heart weight/body weight ratio, the size of cardiac myocytes, and the serum brain natriuretic peptide and atrial natriuretic peptide levels. These results suggest that nuclear factor of activated T cells functions in a key role in the development of cardiac hypertrophy during pressure overload. Inhibition of nuclear factor of activated T cells by a specific inhibitor peptide is a suitable method for characterization of the molecular mechanisms underlying cardiac hypertrophy as well as in the search for new promising therapies for disease.

Animals↗
PubMed2000

Microtubule depolymerization normalizes in vivo myocardial contractile function in dogs with pressure-overload left ventricular hypertrophy.

BACKGROUND: Because initially compensatory myocardial hypertrophy in response to pressure overloading may eventually decompensate to myocardial failure, mechanisms responsible for this transition have long been sought. One such mechanism established in vitro is densification of the cellular microtubule network, which imposes a viscous load that inhibits cardiocyte contraction. METHODS AND RESULTS: In the present study, we extended this in vitro finding to the in vivo level and tested the hypothesis that this cytoskeletal abnormality is important in the in vivo contractile dysfunction that occurs in experimental aortic stenosis in the adult dog. In 8 dogs in which gradual stenosis of the ascending aorta had caused severe left ventricular (LV) pressure overloading (gradient, 152+/-16 mm Hg) with contractile dysfunction, LV function was measured at baseline and 1 hour after the intravenous administration of colchicine. Cardiocytes obtained by biopsy before and after in vivo colchicine administration were examined in tandem. Microtubule depolymerization restored LV contractile function both in vivo and in vitro. CONCLUSIONS: These and additional corroborative data show that increased cardiocyte microtubule network density is an important mechanism for the ventricular contractile dysfunction that develops in large mammals with adult-onset pressure-overload-induced cardiac hypertrophy.

Animals↗