Jun Ikeda

Differential expression of α1, α3 and α5 integrin subunits in acute and chronic stages of myocardial infarction in rats

Objective: Anchoring cardiac myocytes to extracellular matrix, which is mediated mainly by integrins on their surfaces, is important for maintaining the architecture of myocardial tissues and transmitting mechanical force. We evaluated the expression of α integrin subunits on myocytes and the accumulation of interstitial collagen and fibronectin at acute and chronic stages after myocardial infarction. Methods: Myocardial infarction was induced by ligation of left coronary arteries in rats. The expression of α1, α3 and α5 integrin subunits, and accumulation of collagen and fibronectin were analyzed with immunohistochemistry or sirius-red staining. Results: In hearts without infarction, moderate expression of the α3 subunit and only slight expression of the α5 subunit were observed on myocytes. In the first week after infarction, the α1 subunit, collagen and fibronectin were increased only in the peri-infarcted area, while the α5 subunit was increased both in peri-infarcted and non-infarcted areas. At day 42, the expression of the α1 subunit and collagen were still increased, although the α5 subunit and fibronectin were decreased. The expression of the α3 subunit was not altered throughout the experimental period. Conclusion: These data suggest that integrin subunits play an important role in healing and remodeling processes after myocardial infarction.

Inhibition of matrix metalloproteinases prevents cardiac hypertrophy induced by β-adrenergic stimulation in rats

Insulin-like growth factor (IGF) -I is one of the candidates for cardiac hypertrophy induced by &bgr;-adrenergic stimulation. However, the mechanisms by which the biologic actions of IGF-I are regulated under this condition remain unclear. IGF-I becomes bioavailable for its receptors upon its dissociation from IGF-binding protein (IGFBP) through IGFBP degradation. Because matrix metalloproteinases (MMPs) have been implicated in the degradation of IGFBPs, the authors investigated the role of MMPs in the regulation of the IGF-I action through the degradation of IGFBPs in cardiac hypertrophy induced by &bgr;-adrenergic stimulation. They examined the expression of MMPs in cardiac tissues of rats infused with isoproterenol (3 mg/kg per day), the effect of a MMP inhibitor, SI-27 (5 mg/rat per day), on cardiac hypertrophy, and the expression of IGF-I and IGFBP-3. MMP-1 and -2 activities increased and IGFBP-3 was degraded in heart hypertrophied by isoproterenol. MMP inhibition caused a regression in the myocyte hypertrophy in association with the suppression of both IGF-I protein in myocytes and the degradation of IGFBP-3 protein. These results suggest that the induction of myocyte hypertrophy by isoproterenol is mediated, at least in part, by a modulation of the IGF-I axis.

Characteristics of the increase in plasma brain natriuretic peptide level in left ventricular systolic dysfunction, associated with muscular dystrophy in comparison with idiopathic dilated cardiomyopathy

To determine whether the plasma brain natriuretic peptide level increases differentially in muscular dystrophy and idiopathic dilated cardiomyopathy, we investigated the plasma brain natriuretic peptide level and echocardiographic parameters in patients with similarly low left ventricular ejection fraction. The plasma brain natriuretic peptide level was lower, and the left ventricular end-diastolic diameter was shorter in the patients with muscular dystrophy than in those with idiopathic dilated cardiomyopathy. The correlation between the plasma brain natriuretic peptide and left ventricular ejection fraction was shifted downward in the patients with muscular dystrophy compared with those with idiopathic dilated cardiomyopathy. Those between the brain natriuretic peptide and left ventricular end-diastolic diameter were superimposable, although the data from the muscular dystrophy patients were located at the shorter left ventricular end-diastolic diameter side. The plasma brain natriuretic peptide level may differentially increase in the two diseases with similar left ventricular systolic dysfunction. Differences in the left ventricular distension and in the physical activity might explain at least partially the different plasma brain natriuretic peptide levels.

Long-Term Right Ventricular Volume Overload Increases Myocardial Fluorodeoxyglucose Uptake in the Interventricular Septum in Patients With Atrial Septal Defect

BACKGROUND Several studies have shown that long-term right ventricular (RV) overload in animal models alters myocardial energy substrate metabolism. However, whether long-term RV volume overload alters this metabolism in the human is unclear. METHODS AND RESULTS We performed positron emission tomography with [(18)F]fluorodeoxyglucose (FDG) and single-photon emission tomography (SPECT) with [(201)Tl]TlCl (Tl) and [(123)I]15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) in 11 patients with atrial septal defect (ASD) and 11 control subjects. In the FDG study, we calculated myocardial metabolic rate of glucose (MMR) in interventricular septum (IVS) and left ventricular (LV) free wall. MMR was significantly increased in IVS compared with LV free wall in the ASD patients (420+/-35 versus 333+/-32 mol x kg(-1) x min(-1); P<0.05) but not in the control group (347+/-27 versus 357+/-25 mol x kg(-1) x min(-1)). In both ASD and control groups, SPECT count was not significantly different between IVS and LV free wall in Tl (ASD, 160+/-11 versus 177+/-12; control, 141+/-12 versus 157+/-14 counts per 15 minutes) and BMIPP studies (ASD, 203+/-14 versus 212+/-18; control, 162+/-16 versus 176+/-16 counts per 15 minutes). MMR in the IVS/LV free wall ratio in the ASD group significantly correlated with indices related to RV volume overload. CONCLUSIONS Given the assumption that long-term RV volume overload did not affect the lumped constant, the present study suggests that, unlike myocardial perfusion or fatty acid analogue uptake, myocardial glucose utilization in IVS relative to LV free wall is increased in relation to long-term RV volume overload in patients with ASD.

Overexpression of insulin-like growth factor-I in hearts of rats with isoproterenol-induced cardiac hypertrophy

Increased levels of plasma catecholamine lead to cardiac hypertrophy via the alpha-, beta-adrenergic receptors, and partially, type 1 angiotensin II (AT1) receptor. However, it remains unclear whether other factors are involved in catecholamine-induced cardiac hypertrophy. We investigated the expression of insulin-like growth factor (IGF)-I in hearts of male Wistar rats infused with a beta-adrenergic agent, isoproterenol (ISO) (3 mg/kg/day), with or without an AT1-receptor antagonist, TCV-116 (10 mg/kg/day). Cardiac myocytes became hypertrophied 1 day after the beginning of ISO administration. ISO induced a biphasic increase of cardiac myocytes positive for IGF-I protein in the early and late phases of the study period, whereas IGF-I gene expression was upregulated only in the late phase by ISO. TCV- 116 abolished the upregulation of IGF-I gene and protein expression in the late phase in association with the regression of cardiac hypertrophy. These results suggest that ISO-induced cardiac hypertrophy is mediated, at least in part, by IGF-I, the expression of which is upregulated through the activation of AT1 receptor.

Nitric oxide modulates sympathetic control of left ventricular contraction in vivo in the dog

Recently, evidence has been presented that nitric oxide (NO) modulates myocardial contraction induced by beta-adrenergic stimulation in vitro and in vivo. In this study, we investigated whether inhibition of the L-arginine NO system augments the positive inotropic response of the left ventricle to direct stimulation of the sympathetic nerves in vivo in the dog. Electrical stimulation was applied to the left stellate ganglion (LSG) for 1 min at submaximal (5 V, 2.5, 5 and 10 Hz) and supramaximal intensities (10 V, 10 Hz) in twelve anesthetized and vagotomized dogs. Next, in the same dogs, N(omega)-nitro L-arginine methylester (L-NAME) was infused into the left anterior descending (LAD) coronary artery, and LSG stimulation repeated using the same protocol. Finally, L-arginine was infused into the LAD artery, and LSG stimulation repeated. We used the maximum of the first derivative of left ventricular pressure (LV max d P/dt) as an index of the myocardial contractility. Plasma epinephrine and norepinephrine concentrations were measured in the coronary sinus at 5 V, 2.5 Hz before and after L-NAME treatment in five of twelve dogs. L-NAME treatment significantly augmented the inotropic response of the left ventricle (percent change in the LV max dP/dt) to LSG submaximal stimulation trains from 164 +/- 13 to.212 +/- 21 (P < 0.03), from 187 +/- 15 to 234 +/- 25 (P < 0.05) and from 220 +/- 19 to 280 +/- 33% (P < 0.05), respectively. This response was reversed by L-arginine treatment. However, the inotropic response to the supramaximal stimulation train did not change after L-NAME and L-arginine treatment. L-NAME significantly increased plasma norepinephrine concentration from 0.69 +/- 0.41 to 1.00 +/- 0.52 ng/ml without changing plasma epinephrine concentration in the coronary sinus. It is concluded that the inhibition of the L-arginine NO system augmented the positive inotropic effect on the left ventricle during sympathetic nerve stimulation in normal dogs in vivo.

The degree of increment in plasma catecholamines in patients with mitral stenosis by mild exercise

Although sympathetic excitation during mild exercise may readily occur in patients with mitral stenosis (MS), the degree of increment in plasma catecholamines has not been fully investigated. We imposed mild ergometric exercise (50 watts, 300 kg/min for 5 minutes) on five patients with mild MS (mitral valve area greater than or equal to 1.0 cm2) and eight with severe MS (mitral valve area less than 1.0 cm2) while they were undergoing cardiac catheterization. In patients with severe MS, total plasma catecholamine levels during exercise were remarkably higher (2821 +/- 783 [SEM] pg/ml) than in those with mild MS (957 +/- 113 pg/ml, p less than 0.05) and in seven control subjects (612 +/- 75 pg/ml, p less than 0.05). This marked increment could not be predicted by heart rate response, which did not differ between severe and mild MS (166 +/- 5 vs 153 +/- 10 bpm). In contrast with catecholamine change, the cardiac index in severe MS showed a very small increment. Results suggest that mild daily exercise can remarkably increase plasma catecholamine levels in severe MS, and this may accelerate various complications of this disorder.

Non-invasive estimation of human left ventricular end-diastolic pressure

Sato et al. (Electronic Letters 32, 949-950, 1996) reported that one can obtain a non-invasive estimate of left ventricular (LV) pressure at around end-diastole in an isolated canine preparation. In this study we examined whether this method can be applied to humans. Using the method proposed by Kanai et al. (IEEE. Trans. UFFC, 43, 791-810,1996), we detected small amplitude LV vibration from an ultrasonic pulse Doppler signal reflected from the interventricular septum in five patients (44-63 y.o., male;4, female;1). We measured the oscillation frequency of the LV wall through the wavelet transform of small amplitude LV vibration, and calculated LV pressure at around end-diastole from the values of oscillation frequency, internal radius and wall thickness using Mirskys equation. The estimated LV pressures at around end-diastole were similar to end-diastolic pressure measured directly by cardiac catheterization. These results show the possibility that this method allows for the non-invasive estimate of LV pressure at around end-diastole, and furthermore provides the basis for future clinical applicability of this technique.

Immunohistochemical Analysis of Platelet-derived Growth Factor-B Expression in Myocardial Tissues In Hypertrophic Cardiomyopathy

Intimal and/or medial hyperplasia of intramyocardial small vessels is thought to be one of the causes of myocardial ischemia in hypertrophic cardiomyopathy (HCM). However, the pathogenesis of such vascular lesions in HCM is not yet known. To evaluate the pathogenic role of platelet-derived growth factor (PDGF-B) and basic fibroblast growth factor (b-FGF), which have a potential to induce cellular and molecular changes observed in the vessels in HCM, we examined the expression of these molecules and PDGF receptors in cardiac tissues from six patients with HCM and seven controls using immunohistochemistry. The percentage of PDGF-B positive cells in the myocyte population in HCM was significantly higher than that in controls (52.6 +/- 16.2 (mean +/- SD) vs. 21.6 +/- 9.6, p < 0.01). PDGF-B was also observed in vascular regions in HCM (61.1 +/- 25.5% of arterioles) but not in controls. There were no significant differences in the expression of b-FGF and PDGF receptors in the myocyte and non-myocyte populations and the vascular regions between the HCM and control groups. Our study revealed that the expression of PDGF-B protein was up-regulated in HCM, suggesting the contribution of this molecule to the development of intramyocardial vasculopathy.

Influence of reduced presynaptic myocardial norepinephrine stores on left ventricular contractility

Many investigators have reported that myocardial norepinephrine content is decreased in congestive heart failure. However there have been no studies of how decrease in myocardial norepinephrine might influence myocardial contraction. To clarify whether decreased myocardial norepinephrine per se affects myocardial contraction, we observed the change in left ventricular contractility during 30 min of left stellate ganglion stimulation in control and acutely reserpinized dogs. We obtained left ventricular max dp/dt and left ventricular end-systolic pressure-segment length relationships as indicators of left ventricular contractility. Both parameters decreased after left stellate ganglion stimulation in reserpinized dogs (left ventricular max dp/dt: 2064 +/- 200 to 1608 +/- 168 mmHg/s, left ventricular end-systolic pressure-segment length slope 117 +/- 22 to 79 +/- 14 mmHg/mm, n = 8, P less than 0.05), while they did not change in controls. In reserpinized dogs, left ventricular norepinephrine content decreased to one-third that of controls before the stimulation, and further decreased after stimulation. These data indicate that lowered myocardial norepinephrine itself may be responsible for the negative effect on left ventricular contractility in congestive heart failure.