Increase In Ventricular Weight Research Articles

Pharmacological treatment with a melanocortin analogue protects against pressure‐overload‐induced cardiac hypertrophy

Melanocortins regulate important physiological functions such as energy balance and blood pressure, but their long‐term effects on cardiac remodeling remain unexplored. Therefore, using gain‐of‐function models of melanocortin activity, we investigated whether melanocortins affect physiological or pathological cardiac growth. First, we studied the effects of transgenic melanocortin overexpression (MSH‐OE) on physiological age‐related cardiac growth. 6‐month‐old MSH‐OE mice had lower heart weight with maintained cardiac function compared to age‐matched wild‐type mice. Second, we examined the effects of a stable melanocortin analogue (MT‐II) on pressure‐overload‐induced cardiac hypertrophy. We subjected 8‐week‐old C57Bl/6N mice to transverse aortic constriction (TAC) and treated them with either saline or MT‐II (0.3 mg/kg/day for 6 weeks, i.p.). Saline‐treated TAC mice displayed significant increases in ventricular weight and LV posterior wall thickness, and impaired systolic function compared to sham‐operated control mice. This pathological cardiac remodeling was attenuated in MT‐II‐treated TAC mice. Importantly, MT‐II‐treatment did not compromise cardiac function, but tended to rather improve LV contractility in TAC mice. In conclusion, these results establish melanocortin signaling as an antihypertrophic regulator in physiological and pathological cardiac remodeling.

Cardiac hypertrophy is enhanced in PPAR -/- mice in response to chronic pressure overload

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPARalpha modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARalpha aggravates the cardiac hypertrophic response to pressure overload. Male PPARalpha-/- and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (LV) wall thickness in PPARalpha-/- than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPARalpha-/- mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, alpha-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-alpha, cyclo-oxygenase-2) marker genes were higher in PPARalpha-/- than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPARalpha-/- mice, but were not further compromised by TAC. The present findings show that the absence of PPARalpha results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPARalpha exerts salutary effects during cardiac hypertrophy.

Differential expression and localization of annexin V in cardiac myocytes during growth and hypertrophy.

Recently it was shown that annexin V is the most prominent member of the annexin family in the adult heart [1]. Amongst others, annexin V has been suggested to play a role in developmental processes. The aim of the present study was to explore whether in the heart annexin V content and localization change during maturational and hypertrophic growth, in order to obtain indications that annexin V is involved in cardiac growth processes. First, in the intact rat heart annexin V content and localization were studied during perinatal development. It was clearly demonstrated that annexin V content in total heart transiently increased in the first week after birth, from 0.79 +/- 0.06 microg/mg protein at 1 day before birth to a peak value of 1.24 +/- 0.08 microg/mg protein 6 days after birth, whereafter annexin V protein levels declined to a value of 0.70 +/- 0.06 microg/mg protein at 84 days after birth (p < 0.05). Differences in annexin V content were also observed between myocytes isolated from neonatal and adult hearts [0.81 +/- 0.09 and 0.17 +/- 0.08 microg/mg protein, respectively (p < 0.05)]. Moreover, during cardiac maturational growth the subcellular localization of annexin V might change from a cytoplasmic to a more prominent sarcolemmal localization. Second, in vivo hypertrophy induced by aortic coarctation resulted in a marked degree of hypertrophy (22% increase in ventricular weight), but was not associated with a change in annexin V localization or content. The quantitative results obtained with intact hypertrophic rat hearts are supported by findings in neonatal ventricular myocytes, in which hypertrophy was induced by phenylephrine (10(-5) M). In the latter model no changes in annexin V content could be observed either. In conclusion, the marked alterations in annexin V content during the maturational growth in the heart suggest a possible involvement of this protein in this process. In contrast, the absence of changes in annexin V content and localization in hypertrophied hearts compared to age matched control hearts suggests that annexin V does not play a crucial role in the maintenance of the hypertrophic phenotype of the cardiac muscle cell. This notion is supported by observations in phenylephrine-induced hypertrophied neonatal cardiomyocytes.

Endothelin-1 Is Involved in Norepinephrine-Induced Ventricular Hypertrophy In Vivo

Endothelin-1 (ET-1) has potent effects on cell growth and induces hypertrophy of cultured ventricular myocytes. Catecholamines increase expression of ET-1 mRNA by cultured myocytes. We investigated the role of endogenous ET-1 in catecholamine-induced hypertrophy in vivo by studying the effects of continuous norepinephrine infusion on physical and molecular markers of ventricular hypertrophy, ventricular and noncardiac expression of ET-1 mRNA, and the acute effects of bosentan, an orally active ETA and ETB receptor antagonist. Seventy male Sprague-Dawley rats (175 to 200 g) were divided into four groups: (1) sham-operated rats, (2) norepinephrine-infused rats (600 micrograms.kg-1.h-1 by subcutaneous osmotic pump, up to 7 days), (3) sham-operated rats given bosentan, and (4) norepinephrine-infused rats given bosentan. Bosentan (100 mg/kg once daily) was administered by gavage for 6 days starting 1 day before operation. Norepinephrine caused increases in absolute ventricular weight and ratios of ventricular weight to body weight and ventricular RNA to protein. Ventricular expression of mRNAs for atrial natriuretic factor, skeletal alpha-actin, and beta-myosin heavy chain, which in adult rat ventricle are indicators of hypertrophy, also increased. Ventricular expression of ET-1 mRNA was elevated in the norepinephrine group at 1, 2, and 3 days. By 5 days, this had fallen to control levels. In lung, kidney, and skeletal muscle, norepinephrine did not significantly increase expression of ET-1 mRNA. Bosentan attenuated norepinephrine-induced increases in ventricular weight, ratio of RNA to protein, and expression of skeletal alpha-actin mRNA and beta-myosin heavy chain mRNA at 5 days, but it did not attenuate increased ventricular expression of atrial natriuretic factor mRNA. These data suggest that endogenous ET-1 plays a direct role in mediating norepinephrine-induced ventricular hypertrophy in vivo.

Coordination of nuclear and mitochondrial gene expression during the development of cardiac hypertrophy in rats.

We studied the coordination of nuclear and mitochondrial gene expression during cardiac hypertrophy following aortic stenosis or thyroid hormone treatment in rats. We measured mRNA levels for representative subunits of cytochrome-c oxidase, two encoded by mitochondrial DNA and two encoded by the nucleus, as well as the levels of one mitochondrial rRNA. In both models of hypertrophy, an increase of total tissue RNA, reflecting mainly cytosolic ribosomes, accompanied the increase in ventricular weight. Relative levels of mitochondrial rRNA remained unchanged, indicating a net synthesis of mitochondrial ribosomes as well. In both models, cytochrome-c oxidase activity and nuclear-encoded mRNAs remained fairly constant, whereas levels of mitochondrial mRNAs were transiently decreased 24 h after the growth stimulus. We conclude that, in the initial phase of hypertrophy, the signal regulating the synthesis of mitochondrial rRNA is synchronized with nuclear gene expression, whereas the signal regulating mitochondrial mRNA synthesis is not. We postulate that differential regulation of mitochondrial transcription and premature termination of the polycistronic transcript (the latter giving rise to the mitochondrial rRNAs) account for the observed results.

Induction of myocardial insulin-like growth factor-I gene expression in left ventricular hypertrophy.

Left ventricular hypertrophy is a generalized adaptation to increased afterload, but the growth factors mediating this response have not been identified. To explore whether the hypertrophic response was associated with changes in local insulin-like growth factor-I (IGF-I) gene regulation, we examined the induction of the cardiac IGF-I gene in three models of systolic hypertension and resultant hypertrophy. The model systems were suprarenal aortic constriction, uninephrectomized spontaneously hypertensive rats (SHR), and uninephrectomized, deoxycorticosterone-treated, saline-fed rats (DOCA salt). Systolic blood pressure reached hypertensive levels at 3 to 4 weeks in all three systems. A differential increase in ventricular weight to body weight (hypertrophy) occurred at 3 weeks in the SHR and aortic constriction models and at 4 weeks in the DOCA salt model. Ventricular IGF-I mRNA was detected by solution hybridization/RNase protection assay. IGF-I mRNA levels increased in all three systems coincident with the onset of hypertension and the development of ventricular hypertrophy. Maximum induction was 10-fold over control at 5 weeks in the aortic constriction model, 8-fold at 3 weeks in the SHR, and 6-fold at 6 weeks in the DOCA salt model. IGF-I mRNA levels returned to control values by the end of the experimental period despite continued hypertension and hypertrophy in all three systems. In contrast, ventricular c-myc mRNA content increased twofold to threefold at 1 week and returned to control levels by 2 weeks. Ventricular IGF-I receptor mRNA levels were unchanged over the time course studied. The increased ventricular IGF-I mRNA content was reflected in an increased ventricular IGF-I protein content, as determined both by radioimmunoassay and immunofluorescence histochemistry. We conclude that (1) hypertension induces significant increases in cardiac IGF-I mRNA and protein that occur coordinately with its onset and early in the development of hypertrophy, (2) IGF-I mRNA levels normalize as the hypertrophic response is established, (3) in comparison to IGF-I, both c-myc and IGF-I receptor genes are differentially controlled in experimental hypertension. These findings suggest that IGF-I may participate in initiating ventricular hypertrophy in response to altered loading conditions. The consistency of these findings in models of high-, moderate-, and low-renin hypertension suggests that they occur independently of the systemic renin-angiotensin endocrine axis.

Coronary vascular and myocardial lesions due to experimental constriction of the abdominal aorta

The development and evolution of arterial and myocardial lesions were morphologically evaluated in Wistar rats submitted to constriction of the abdominal aorta. The control (sham-operated) and operated groups were evaluated 1, 2, 4 and 6 weeks after surgery. The aorta-constricted groups developed arterial hypertension followed by myocardial hypertrophy evidenced from the first week onwards by the increase in ventricular weight and in the diameters of left and right ventricular myofibers. The histopathologic study of the myocardium revealed in aorta-constricted groups, since the first week, widespread necrotizing changes of the intramural coronary branches surrounded by multifocal areas of myofiber degeneration and necrosis. The lesions were more extensive in the wall of the right ventricle and were gradually replaced by scar tissue. At the 6th week patchy focal fibrotic scars were found scattered in the myocardium of both ventricles. There were no systemic lesions in aorta-constricted or sham-operated groups. The close association between the arterial and myocardial lesions shows that muscle necrosis and scars are due to ischemia. They may influence the contractile performance of the myocardium in this model of pressure-induced hypertrophy of the heart.

Muscle Fiber Orientation in the Development and Regression of Right Ventricular Hypertrophy in Pigs

The development and regression of right ventricular hypertrophy was investigated in 12 pigs with special reference to changes in ventricular function and myocardial fiber orientation. Nine ventricles were pressure-loaded by banding the pulmonary artery for 28-81 days, and four of them were then released from the load by removing the band. Right ventricular systolic pressure (RVSP), end-diastolic pressure (RVEDP) and end-systolic volume index (ESVI) increased significantly during banding and decreased after debanding. End-diastolic volume index (EDVI) and stroke volume index (SVI) showed no significant change during banding and after debanding. The weight of the right ventricle relative to both ventricles (RV/TV) and the thickness of muscle fibers were increased significantly in the loaded ventricles, and reduced again to the control level in ventricles released from the load. The intramyocardial distribution of angles (theta) of inclination of muscle fibers from the transverse plane of the outflow tract was estimated histometrically. There was a significantly larger proporation of circularly oriented fibers (magnitue of theta less than or equal to 30 degrees) in the pressure-loaded ventricles than in the control, whereas these fibers decreased again to the control level after removal of the pressure load. The present findings indicates that 1) the right ventricular hypertrophy induced by pressure loading is characterized not only by an increase in ventricular weight and muscle fiber thickness, but also by a change in intramyocardial fiber orientation, and 2) the hypertrophic right ventricle can regress both functionally and morphologically to a normal state after removal of the pressure load.

Renal hypertension impairs inotropic isoproterenol effect without beta-receptor changes.

Experiments were performed in male Wistar rats with renovascular hypertension (167 +/- 4.2 mmHg) produced by clipping the renal artery for a 3-wk period (2-kidney, 1-clip Goldblatt). The results were compared with those obtained in age-matched normotensive controls. Hypertension of 3-wk duration elicited a significant increase in ventricular weight (1.01 +/- 0.02 g) with respect to the controls (0.82 +/- 0.01 g) but had no significant effect on body weight. The inotropic responsiveness to beta-adrenergic stimulation was diminished in papillary muscles from renal hypertensive rats: the maximum increase in the maximal rate of rise of tension produced by isoproterenol was 27.39 +/- 5.4 and 11.77 +/- 2.91 g X mm-2 X s-1 (P less than 0.05) in control and hypertensive animals, respectively. Similar results were obtained when the estimated maximal velocity of shortening of the contractile element (Vmax) was used to assess myocardial contractility. The inotropic response to CaCl2 was also significantly depressed in the 2-kidney, 1-clip rats. However, the relaxant and the chronotropic responses to isoproterenol were not significantly modified in the Goldblatt rats. Assays of beta-adrenergic receptors to l-[3H]dihydroalprenolol binding, showed no significant changes in the number (expressed per mg of membrane protein) or in the affinity of the beta-receptors. These results suggest that at an early stage of the renal hypertensive model the impaired inotropic response to isoproterenol is not mediated by an alteration of the beta-receptors and should be searched at a postreceptor adenyl cyclase level.

Developmental aspects of beta-adrenergic receptors and catecholamine-sensitive adenylate cyclase in rat myocardium.

Summary: The ontogeny of β-adrenergic receptors and the characteristics of catecholamine sensitive adenylate cyclase activity were demonstrated in rat ventricular myocardium. β-Adrenergic receptors were identified by the binding of (—)-[3H]dihydroalprenolol, [(—)-[3H]DHA|, and (±)-[125I]iodohydroxy-benzylpindolol, (±)-[125[I]HYP. Heart weight, protein, and the number of β-adrenergic receptors per cell increased with advancing age; however, binding capacity (Bmax) per nig protein was lower in membrane from the adult rat (220 g body weight) than in membrane from the fetal or neonatal rat, 36.8 ±4.1 and 58.3 ± 6.3 fmoles·mg−1 protein, respectively, mean ± SE, P < 0.01. The age-dependent increase in the numbers of receptors per heart correlated well with the increases in ventricular weight. In contrast, protein content, Na+, K+-ATPase, 5′-nucleotidase, and adenylate cyclase content increased more rapidly than ventricular weight, and the developmental increase in [3H]DHA binding sites (per heart) did not keep up with increases in ventricular protein. Although specific activity of (—)-[3H]DHA binding was lower in the adult ventricle, the characteristics of the β-receptor did not vary with age; the subtype was β1 determined by classical agonist competition in fetal and adult ventricular membranes and the β1- and β2-adrenergic receptor subtypes were present in the ratio of 75% β1 and 25% β2 in both fetal and adult samples. Guanine nucleotides decreased agonist affinity for the inhibition of (±)-[125I]HYP binding equally in adult and fetal samples and enhanced the activation of adenylate cyclase by catecholamine. Basal adenylate cyclase activity was significantly higher in weanling, 13.4 ± 1.42, and adult, 14.2 ± 5.8, than in 21-day fetal or newborn ventricular membrane, 8.18 ± 1.5 pmoles cyclic adenosine 3′:5′-monophosphate produced mg−1· min−1 (mean ± S.D.). The percent activation by catecholamine (with and without GTP) was also slightly higher in samples from the older rats, P < 0.01. In the adult and weanling heart, both guanine triphosphate (GTP) and guanyl-5′-yl-imidodiphosphate [Gpp(NH)p] were effective in enhancing catecholamine sensitive activity. Maximal catalytic activation of adenylate cyclase was observed in the presence of (—)-epinephrine and Gpp(NH)p and was significantly higher (fold stimulation) in fetal or neonatal ventricular samples as compared to adult or weanling ventricular samples, P < 0.01. Speculation: The decreased specific activity (per mg protein) of β-adrenergic receptors in adult as compared to fetal and neonatal myocardium may therefore be related to the decreasing proportion of sarcolemmal protein versus total and particulate cell protein which occurs during hypertrophic cardiac growth, supporting the hypothesis that sarcolemmal surface area is a major determinant of β-receptor number. In contrast, sarcolemmal activities which mediate cellular functions by regulating the concentration of various substances within the cell, such as Na+, K+-ATPase, and adenylate cyclase, increased to a greater extent than (—)-[3H]DHA binding, and were more directly proportional to cell protein. The function and affinity of these β-adrenergic receptors in the rat myocardium are mediated by guanine nucleotides early in development, and age-dependent differences in the activation of catecholamine sensitive adenylate cyclase by GTP and Gpp(NH)p may relate to developmental differences in the properties of guanine nucleotide-dependent factors which mediate receptor occupancy and cyclic adenosine 3′:5′-monophosphate formation.

Left ventricular hypertrophy: A cytometric study on 42 human hearts

A histocytometric study of 42 left ventricles was carried out. The cases consisted of normal hearts as well as a number of hypertrophic hearts which were progressively heavier in weight. The results of this study were analyzed by computer. We found an increase in myocardial cell size correlated with an increase in the ventricular free wall weight, up to a critical weight of 250 g. Beyond that critical weight, cellular hyperplasia was evident, followed by the further development of hypertrophy, in relation to the increase of ventricular weight. At the “critical weight” the progressive increase of cellular diameter, which is less than the theoretical value, abruptly ends and then decreases considerably. In contrast, this same phenomena is not seen for the cell length. The myocardial cell length shows a constant gradual increase always greater than the theoretical value regardless of ventricular weight. For this reason the cellular hyperplasia specifically presents an increase in cellular length beyond the increase in cellular diameter, which is reduced. A multiplication of myocardial nuclei beyond the critical weight was also observed. The results obtained are of physiopathological significance owing to modifications of the capillary network and the interstitial tissues. A histocytometric study of 42 left ventricles was carried out. The cases consisted of normal hearts as well as a number of hypertrophic hearts which were progressively heavier in weight. The results of this study were analyzed by computer. We found an increase in myocardial cell size correlated with an increase in the ventricular free wall weight, up to a critical weight of 250 g. Beyond that critical weight, cellular hyperplasia was evident, followed by the further development of hypertrophy, in relation to the increase of ventricular weight. At the “critical weight” the progressive increase of cellular diameter, which is less than the theoretical value, abruptly ends and then decreases considerably. In contrast, this same phenomena is not seen for the cell length. The myocardial cell length shows a constant gradual increase always greater than the theoretical value regardless of ventricular weight. For this reason the cellular hyperplasia specifically presents an increase in cellular length beyond the increase in cellular diameter, which is reduced. A multiplication of myocardial nuclei beyond the critical weight was also observed. The results obtained are of physiopathological significance owing to modifications of the capillary network and the interstitial tissues.

Ventricular elastic modulus as a function of age in the Syrian golden hamster.

Analysis of passive right and left ventricular pressure-volume curves for hearts of 72 Syrian golden hamsters studied in vitro showed increases in ventricular weight, volume, and compliance at mid-age. Both ventricles were filled by syringe pumps at a constant rate. Ventricular compliance (dV/dP) was determined by electronic differentiation of the intraventricular pressures and formation of the ratio (dV/dt)/(dP/dt) as a continuous function of intraventricular pressure between 0 and 30 mm Hg. By relating, with justification, the left ventricle to a thin-walled elastic sphere, ventricular elastic moduli, E, for different ages were compared at constant levels of myocardial wall stress, sigma. The elastic modulus E proved to be a linear function of sigma. The slope of the E-sigma plot yielded a stiffness constant, K, for each age group. Body weight, heart weight, end-diastolic volume, and dV/dP all varied by more than 200% up and then down as a function of age, but K was not a significant function of age. These results suggest that the aging heart does not normally undergo substantial alterations in passive properties that affect the muscle cells and fibers themselves, but rather that the observed changes in compliance are primarily attributable to alterations in ventricular size.

Relation of ventricular volume, compliance, and mass in the normal and pulmonary arterial banded canine heart.

Right (RV) and left (LV) ventricular volumes, compliances, weights, and wall thicknesses were determined in the fresh post mortem hearts of 10 normal and eight pulmonary arterial banded (PAB) dogs. After two to 40 weeks of PA banding, the mean RV weight, 68·6 ± 5·4 g (mean ± SEM), was greater than normal (P < 0·001), with the maximum increase in RV weight occurring by the eighteenth week. Increases also occurred in the LV weights, but to a lesser extent and at a slower rate than in the right ventricle. Increases in wall thickness were greater at the ventricular bases than apices. In the PAB hearts, at 0 mm Hg (P), the mean RV volume, 59·5 ± 3·8 ml./m2, and LV volume, 40·5 ± 2·5 ml./m2, were both greater than normal (P<0·001); P RV and LV volumes correlated negatively with duration of pulmonary arterial banding and correlated positively with increases in ventricular weight. In the PAB hearts, the mean RV compliance (ΔVav/ΔVLV) was decreased at P5 to P15 (P<0·05) and approached normal at P20. We postulate that an increase in RV wall tension resulting from PA banding causes an initial dilatation of the ventricular chamber and if sustained stimulates myocardial hypertrophy; subsequent increases in mass decrease the chamber volume and result in a decrease in wall tension, allowing the ventricle to reach a stable level of hyper-function.